JP5817317B2 - A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenylglucitol compound as an active ingredient - Google Patents

A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenylglucitol compound as an active ingredient Download PDF

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JP5817317B2
JP5817317B2 JP2011176509A JP2011176509A JP5817317B2 JP 5817317 B2 JP5817317 B2 JP 5817317B2 JP 2011176509 A JP2011176509 A JP 2011176509A JP 2011176509 A JP2011176509 A JP 2011176509A JP 5817317 B2 JP5817317 B2 JP 5817317B2
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柿沼 浩行
浩行 柿沼
陽平 小橋
陽平 小橋
具通 長南
具通 長南
隆宏 大井
隆宏 大井
史康 塩澤
史康 塩澤
由紀 岩田
由紀 岩田
憲一 川部
憲一 川部
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Taisho Pharmaceutical Co Ltd
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本発明は、特異的に小腸でのグルコ−ス及びガラクトースの吸収に関わるナトリウム依存性グルコ−ス共輸送体1(以下、適宜に「SGLT1」と略記する。)の阻害活性を有する4−イソプロピルフェニル グルシトール化合物に関する。   The present invention specifically describes 4-isopropyl having an inhibitory activity on sodium-dependent glucose cotransporter 1 (hereinafter abbreviated as “SGLT1” as appropriate) that is involved in the absorption of glucose and galactose in the small intestine. The present invention relates to a phenyl glucitol compound.

血糖値はメタボリックシンドロームのバイオマーカーの一つとなっており、空腹時血糖が126mg/dL以上を示すと糖尿病と診断される。また、空腹時血糖が正常であっても、食後2時間血糖値が140〜200mg/dLの場合には、耐糖能異常(又は食後高血糖)と診断される。近年の疫学的研究によれば、耐糖能異常が心血管障害のリスクを高めると報告されている(非特許文献1及び2参照)。さらに、運動療法や薬物治療を施すことで耐糖能異常から2型糖尿病への移行を抑制し、高血圧の発症も有意に抑制することが報告されている(非特許文献3参照)。   The blood glucose level is one of the biomarkers of metabolic syndrome, and diabetes is diagnosed when the fasting blood glucose level is 126 mg / dL or more. Even if fasting blood glucose is normal, a glucose tolerance abnormality (or postprandial hyperglycemia) is diagnosed when the blood glucose level for 2 hours after meal is 140 to 200 mg / dL. Recent epidemiological studies have reported that impaired glucose tolerance increases the risk of cardiovascular disorders (see Non-Patent Documents 1 and 2). Furthermore, it has been reported that exercise therapy and drug treatment suppress the transition from impaired glucose tolerance to type 2 diabetes and significantly suppress the onset of hypertension (see Non-Patent Document 3).

以上のことから、食後高血糖を抑制することが糖尿病やメタボリックシンドロームの発症抑制に重要であると考えられ、食後高血糖をコントロールする薬剤の需要が高まりつつある。   From the above, suppressing postprandial hyperglycemia is considered to be important for suppressing the onset of diabetes and metabolic syndrome, and the demand for drugs that control postprandial hyperglycemia is increasing.

従来、食後高血糖改善薬としては、糖類の加水分解酵素を阻害し、小腸からの糖の吸収を遅延させるα−グルコシダ−ゼ阻害剤が汎用されてきたが、新しい作用機序を有する食後高血糖改善薬の開発も行われている。   Conventionally, α-glucosidase inhibitors that inhibit saccharide hydrolase and delay sugar absorption from the small intestine have been widely used as postprandial hyperglycemia-improving drugs. Development of drugs to improve blood glucose is also underway.

哺乳動物の小腸上皮には高い頻度でナトリウム依存性グルコ−ス共輸送体1(SGLT1)が発現している。このSGLT1は小腸において、ナトリウムに依存し、グルコ−ス及びガラクト−スの能動輸送を司ることが知られている。そこで、食事由来のグルコ−ス吸収を抑制し、食後高血糖の予防又は治療を行うという、SGLT1活性を阻害するピラゾ−ル誘導体が報告されている(特許文献1〜6参照)。また、SGLT1に加え、腎臓に発現するSGLT2活性を同時に阻害するC−フェニル グルシトール誘導体についての報告もある(特許文献7参照)。   Sodium-dependent glucose cotransporter 1 (SGLT1) is frequently expressed in the small intestinal epithelium of mammals. SGLT1 is known to depend on sodium in the small intestine and to control the active transport of glucose and galactose. Thus, pyrazole derivatives that inhibit SGLT1 activity have been reported (see Patent Documents 1 to 6), which suppresses dietary glucose absorption and prevents or treats postprandial hyperglycemia. In addition to SGLT1, there is also a report on a C-phenyl glucitol derivative that simultaneously inhibits SGLT2 activity expressed in the kidney (see Patent Document 7).

国際公開第WO2002/098893号パンフレットInternational Publication No. WO2002 / 098893 Pamphlet 国際公開第WO2004/014932号パンフレットInternational Publication No. WO2004 / 014932 Pamphlet 国際公開第WO2004/018491号パンフレットInternational Publication No. WO2004 / 018491 Pamphlet 国際公開第WO2004/019958号パンフレットInternational Publication No. WO2004 / 019958 Pamphlet 国際公開第WO2005/121161号パンフレットInternational Publication No. WO2005 / 121161 Pamphlet 国際公開第WO2004/050122号パンフレットInternational Publication No. WO2004 / 050122 Pamphlet 国際公開第WO2007/136116号パンフレットInternational Publication No. WO2007 / 136116 Pamphlet

Pan XR, et al. Diabetes Care, 第20巻, 537頁, 1997年Pan XR, et al. Diabetes Care, 20, 537, 1997 M Tominaga, et al. Diabetes Care, 第22巻, 920頁, 1999年M Tominaga, et al. Diabetes Care, 22, 920, 1999 J.−L. Chiasson, et al. Lancent, 第359巻, 2072頁, 2002年J.-L. Chiasson, et al. Lancent, 359, 2072, 2002

本発明の目的は、SGLT1活性を阻害し、消化管からのグルコ−ス吸収抑制作用を有する新しいタイプの糖尿病治療薬として期待される4−イソプロピルフェニル グルシトール化合物を提供することである。   The object of the present invention is to provide a 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity and is expected as a new type of therapeutic agent for diabetes having an inhibitory action on glucose absorption from the digestive tract.

本発明者らはC−フェニル グルシトール化合物のベンゼン環上の置換基として、イソプロピル基やメチル基を導入した。さらに、ベンゼン環から伸びる置換基の末端にアミノ基を有する置換ブテニル基を導入した。これら置換基の導入によって、SGLT1活性を阻害し、腎臓等の主要臓器に残留しない4−イソプロピルフェニル グルシトール化合物を見出すに至った。   The present inventors introduced an isopropyl group or a methyl group as a substituent on the benzene ring of the C-phenyl glucitol compound. Furthermore, a substituted butenyl group having an amino group was introduced at the end of the substituent extending from the benzene ring. The introduction of these substituents led to the discovery of 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity and does not remain in major organs such as the kidney.

以下に、本発明の4−イソプロピルフェニル グルシトール化合物(以下、「本発明化合物」という)の態様を述べる。   Hereinafter, embodiments of the 4-isopropylphenyl glucitol compound of the present invention (hereinafter referred to as “the compound of the present invention”) will be described.

(1)下記式(I)で表される4−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含有することを特徴とする糖尿病の予防又は治療剤: (1) A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenyl glucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:

Figure 0005817317
式中、
は水素原子、又はC1−4アルキル基であり、
は水素原子、又はメチル基であり、
は“アミノ基若しくはジC1−4アルキルアミノ基で置換されたC1−4アルキル基”、又はピペリジル基であり、
は水素原子であり、
又はRとRは隣接する窒素原子と共にピペリジノ基若しくはピペラジニル基を形成し、それらはC1−4アルキル基若しくはジメチルアミノ基で置換されていてもよい。
Figure 0005817317
Where
R 1 is a hydrogen atom or a C 1-4 alkyl group,
R 2 is a hydrogen atom or a methyl group,
R 3 is “an amino group or a C 1-4 alkyl group substituted with a diC 1-4 alkylamino group”, or a piperidyl group;
R 4 is a hydrogen atom,
Alternatively, R 3 and R 4 together with the adjacent nitrogen atom form a piperidino group or piperazinyl group, which may be substituted with a C 1-4 alkyl group or a dimethylamino group.

(2)下記群から選択される4−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含有することを特徴とする糖尿病の予防又は治療剤。 (2) A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenyl glucitol compound selected from the following group or a pharmaceutically acceptable salt thereof as an active ingredient.

Figure 0005817317
Figure 0005817317

(3)下記群から選択される4−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含有することを特徴とする糖尿病の予防又は治療剤。 (3) A prophylactic or therapeutic agent for diabetes comprising a 4-isopropylphenyl glucitol compound selected from the following group or a pharmaceutically acceptable salt thereof as an active ingredient.

Figure 0005817317
Figure 0005817317

本発明により、SGLT1活性を阻害する4−イソプロピルフェニル グルシトール化合物を提供することが可能となった。   According to the present invention, it has become possible to provide a 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity.

エタノール溶媒和物の粉末X線回折パターンを示す。1 shows a powder X-ray diffraction pattern of an ethanol solvate. エタノール溶媒和物の赤外吸収スペクトル(KBr法)を示す。The infrared absorption spectrum (KBr method) of an ethanol solvate is shown. エタノール溶媒和物の示差熱分析/熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of an ethanol solvate is shown. A形結晶の粉末X線回折パターンを示す。The powder X-ray diffraction pattern of A-form crystal is shown. A形結晶の示差熱分析/熱質量測定カーブを示す。The differential thermal analysis / thermal mass measurement curve of A-form crystal is shown.

本発明において使用する用語を以下に定義する。   The terms used in the present invention are defined below.

「C1-4アルキル基」とは、炭素原子を1−4個有する直鎖状又は分枝状のアルキル基を意味する。例えば、メチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、イソブチル基、tert−ブチル等が挙げられる。 The “C 1-4 alkyl group” means a linear or branched alkyl group having 1-4 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl and the like can be mentioned.

「ジC1-4アルキルアミノ基」とは、同一の又は異なる2つのC1-4アルキル基で置換されたアミノ基を意味する。例えば、ジメチルアミノ基やジエチルアミノ基等が挙げられる。 The “di-C 1-4 alkylamino group” means an amino group substituted with two identical or different C 1-4 alkyl groups. For example, a dimethylamino group, a diethylamino group, etc. are mentioned.

また、「製薬学的に許容される塩」とは、アルカリ金属類、アルカリ土類金属類、アンモニウム、アルキルアンモニウムなどとの塩、鉱酸又は有機酸との塩であり、例えば、ナトリウム塩、カリウム塩、カルシウム塩、アンモニウム塩、アルミニウム塩、トリエチルアンモニウム塩、ぎ酸塩、酢酸塩、プロピオン酸塩、酪酸塩、ヘキサン酸塩、オクタン酸塩、トリフルオロ酢酸塩、マレイン酸塩、酒石酸塩、クエン酸塩、ステアリン酸塩、コハク酸塩、エチルコハク酸塩、ラクトビオン酸塩、グルコン酸塩、グルクロン酸、グルコヘプトン酸塩、グルタール酸塩、ピメリン酸塩、スベリン酸塩、アゼライン酸塩、セバシン酸塩、1,9−ノナンジカルボン酸塩、ドデカン二酸塩、トリデカン二酸塩、テトラデカン二酸塩、ペンタデカン二酸塩、ヘキサデカン二酸塩、ヘプタデカン二酸塩、安息香酸塩、2−ヒドロキシ安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、エタンジスルホン酸塩、2−ヒドロキシエタンスルホン酸塩、ベンゼンスルホン酸塩、p−トルエンスルホン酸塩、1,5−ナフタレンジスルホン酸塩、ラウリル硫酸塩、乳酸塩、馬尿酸塩、フマル酸塩、マロン酸塩、トランスケイ皮酸塩、リンゴ酸塩、アスパラギン酸塩、グルタミン酸塩、アジピン酸塩、システインとの塩、N−アセチルシステインとの塩、塩酸塩、臭化水素酸塩、リン酸塩、硫酸塩、よう化水素酸塩、ニコチン酸塩、シュウ酸塩、ピクリン酸塩、チオシアン酸塩、ウンデカン酸塩、アクリル酸ポリマーとの塩、カルボキシビニルポリマーとの塩を挙げることができる。   In addition, the “pharmaceutically acceptable salt” is a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt, Potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, formate, acetate, propionate, butyrate, hexanoate, octanoate, trifluoroacetate, maleate, tartrate, Citrate, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucuronic acid, glucoheptonate, glutarate, pimelate, suberate, azelate, sebacate 1,9-nonanedicarboxylate, dodecanedioate, tridecanedioate, tetradecanedioate, pentadecanedioate Hexadecanedioate, heptadecanedate, benzoate, 2-hydroxybenzoate, methanesulfonate, ethanesulfonate, ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p -Toluenesulfonate, 1,5-naphthalenedisulfonate, lauryl sulfate, lactate, hippurate, fumarate, malonate, transcinnamate, malate, aspartate, glutamate , Adipate, salt with cysteine, salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picric acid And salts with thiocyanate, undecanoate, acrylic acid polymer, and carboxyvinyl polymer.

「水和物」とは、本発明化合物又はその塩の製薬学的に許容される水和物である。本発明化合物又はその塩は、大気にさらされ、あるいは製造過程で、水分を吸収し、吸着水がつく場合や、水和物となる場合がある。本発明における水和物には、そのような水和物も含まれる。   “Hydrate” is a pharmaceutically acceptable hydrate of the compound of the present invention or a salt thereof. The compound of the present invention or a salt thereof may be exposed to the atmosphere, or may absorb moisture during the production process to form adsorbed water or become a hydrate. The hydrate in the present invention includes such a hydrate.

本発明化合物は、SGLT1を阻害し、小腸からの糖の吸収を抑制して、IGTを改善することができる。   The compound of the present invention can inhibit SGLT1 and suppress absorption of sugar from the small intestine to improve IGT.

よって、本発明化合物は、SGLT1阻害剤、あるいは、糖尿病、糖尿病関連疾患及び糖尿病合併症の予防又は治療剤の有効成分として用いることができる。   Therefore, the compound of the present invention can be used as an active ingredient of a SGLT1 inhibitor or a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

ここで、「糖尿病」には、1型糖尿病、2型糖尿病の他、特定の原因によるその他の型の糖尿病が含まれる。   Here, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by a specific cause.

ここで、「糖尿病関連疾患」とは、高インスリン血症、糖代謝異常、高脂質血症、高コレステロール血症、高トリグリセリド血症、脂質代謝異常、高血圧、うっ血性心不全、浮腫、高尿酸血症、痛風などが挙げられる。   Here, “diabetes-related disease” means hyperinsulinemia, glucose metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, hyperuricemia Symptoms and gout.

ここで、「糖尿病合併症」は、急性合併症及び慢性合併症に分類される。   Here, “diabetic complications” are classified into acute complications and chronic complications.

「急性合併症」には、高血糖(ケトアシドーシスなど)、感染症(皮膚、軟部組織、胆道系、呼吸系、尿路感染など)などが挙げられる。   “Acute complications” include hyperglycemia (such as ketoacidosis), infections (such as skin, soft tissue, biliary system, respiratory system, urinary tract infection) and the like.

「慢性合併症」には、細小血管症(腎症、網膜症)、動脈硬化症(アテローム性動脈硬化症、心筋梗塞、脳梗塞、下肢動脈閉塞など)、神経障害(感覚神経、運動神経、自律神経など)、足壊疽などが挙げられる。   “Chronic complications” include microangiopathy (nephropathy, retinopathy), arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb arterial occlusion, etc.), neuropathy (sensory, motor, Autonomic nerves) and foot gangrene.

主要な合併症は、糖尿病網膜症、糖尿病腎症、糖尿病神経障害である。   The main complications are diabetic retinopathy, diabetic nephropathy, diabetic neuropathy.

本発明化合物は、医薬として、全身的又は局所的に、経口投与又は非経口投与することができる。
非経口投与としては、静脈内投与、経鼻投与、経皮投与、皮下投与、筋肉内投与、舌下投与があげられる。
The compound of the present invention can be administered orally or parenterally as a pharmaceutical systemically or locally.
Parenteral administration includes intravenous administration, nasal administration, transdermal administration, subcutaneous administration, intramuscular administration, and sublingual administration.

本発明化合物を医薬として提供する場合、固形剤、液剤等の種々の態様の製剤形態を適宜に採択することができる。その際、製薬学的に許容される担体を配合することも可能である。そのような担体の例としては、一般的な賦形剤、増量剤、結合剤、崩壊剤、被覆剤、糖衣剤、pH調整剤、溶解剤又は水性若しくは非水性溶媒などが挙げられる。本発明の化合物とこれらの担体から、錠剤、丸剤、カプセル剤、顆粒剤、粉剤、散剤、液剤、乳剤、懸濁剤、注射剤等であり、いずれも慣用の製剤技術(例えば、第15改正日本薬局方に規定する方法等)によって製造することができる。これらの投与剤型は、患者の症状、年齢、体重、及び治療の目的に応じて適宜選択することができる。
これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤(例えば、結晶セルロース、デンプン、乳糖、マンニトール)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン)、滑沢剤(例えば、ステアリン酸マグネシウム、タルク)、崩壊剤(例えば、カルボキシメチルセルロースカルシウム)、その他薬理学的に許容される各種添加剤を配合し、製造することができる。
When the compound of the present invention is provided as a pharmaceutical, various forms of preparations such as solid preparations and liquid preparations can be appropriately adopted. In that case, it is also possible to mix | blend a pharmaceutically acceptable carrier. Examples of such carriers include common excipients, bulking agents, binders, disintegrants, coating agents, dragees, pH adjusters, solubilizers or aqueous or non-aqueous solvents. From the compound of the present invention and these carriers, tablets, pills, capsules, granules, powders, powders, liquids, emulsions, suspensions, injections, etc., all of which are conventional pharmaceutical techniques (for example, No. 15 It can be manufactured by the method prescribed in the revised Japanese Pharmacopoeia. These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.

本発明化合物の投与量は、疾患、症状、体重、年齢、性別、投与経路等により異なってくるが、例えば、成人の糖尿病患者に経口投与する場合、通常1回量として0.001mg〜1000mg、好ましくは0.01mg〜200mgであり、0.1〜10mg/kg体重がより好ましい。この量を1日1回から数回に分けて投与することができる。   The dose of the compound of the present invention varies depending on the disease, symptom, body weight, age, sex, route of administration and the like. For example, when orally administered to an adult diabetic patient, the dose is usually 0.001 mg to 1000 mg, Preferably it is 0.01 mg-200 mg, and 0.1-10 mg / kg body weight is more preferable. This amount can be administered once to several times a day.

以下に、類似構造化合物に対する本発明化合物の優位性を示す。   The superiority of the compound of the present invention over the similar structure compound is shown below.

後掲する表2に本願類似化合物の糖負荷後の血糖低下作用と腎臓内濃度を示した。化合物4、10、11及び33は1mg/kg経口投与後の糖負荷試験において、強い血糖低下作用を示した。一方で、1mg/kg経口投与した7日後、化合物は排泄されず腎臓に残留する傾向が見られた。標的臓器はSGLT1が多く分布する小腸である。従って、標的臓器以外に化合物が長く残留することで、予期せぬ副作用が発現する場合がある。例えば、分子内に3級アミンの様な親水性基と芳香環の様な疎水性基をもつ化合物は、陽イオン性薬物と呼ばれる。これらは、リン脂質と疎水結合し、ライソゾーム内に取り込まれ全身の器官に蓄積されることがある。薬物によって、蓄積が見られる器官は異なり、クロロキンでは網膜障害、パーヘキシリンでは肺や小脳に変化が見られる(日薬理誌 Folia Pharmacol. Jpn. 113, 19-30, 1999)。   Table 2 below shows the blood glucose lowering action and the renal concentration of the similar compounds of the present application after sugar loading. Compounds 4, 10, 11 and 33 showed a strong hypoglycemic effect in a glucose tolerance test after oral administration of 1 mg / kg. On the other hand, 7 days after oral administration of 1 mg / kg, the compound tended to remain in the kidney without being excreted. The target organ is the small intestine where SGLT1 is distributed a lot. Therefore, unexpected side effects may occur when the compound remains for a long time other than the target organ. For example, a compound having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is called a cationic drug. They are hydrophobically bound to phospholipids and can be taken up into lysosomes and accumulated in systemic organs. Depending on the drug, the organs that accumulate are different, with chloroquine showing retinal damage and perhexiline with changes in the lungs and cerebellum (Nippon Pharmacology Folia Pharmacol. Jpn. 113, 19-30, 1999).

このようなことから、化合物が薬効を示した後に体内から速やかに排泄されることが望ましい。   For this reason, it is desirable that the compound is rapidly excreted from the body after showing its medicinal properties.

次に、本発明化合物の糖負荷後の血糖低下作用と腎臓内濃度を後掲の表3に示した。実施例1−2、5−2、6−2、13−2、15−2は上記類似化合物と同様に強い血糖降下作用を有した。しかし、意外にも化合物を3mg/kgの用量で3日間連続投与したにも関わらず、2日後に腎臓に残留しないという特徴を示した。このことは表2に示した類似化合物に比べて、本願化合物が医薬品として実用性に関連する重要な性質であると考える。   Next, Table 3 below shows the blood glucose lowering action and the renal concentration after the sugar load of the compound of the present invention. Examples 1-2, 5-2, 6-2, 13-2, and 15-2 had a strong hypoglycemic effect similar to the above similar compounds. However, surprisingly, the compound was characterized by the fact that it did not remain in the kidney after 2 days, even though the compound was administered continuously at a dose of 3 mg / kg for 3 days. Compared with the similar compounds shown in Table 2, this is considered to be an important property related to the utility of the present compound as a pharmaceutical product.

また、下記の実施例化合物は連投による毒性懸念も低いことが期待できる。   In addition, the following Example compounds can be expected to have low toxicity concerns due to continuous casting.

したがって、本発明の好ましい態様は、以下に示す実施例化合物である。   Accordingly, preferred embodiments of the present invention are the following example compounds.

Figure 0005817317
Figure 0005817317

以下に、本発明化合物(I)の製造方法を例を挙げて詳細に説明するが、例示されたものに特に限定されない。   Although the manufacturing method of this invention compound (I) is demonstrated in detail below by giving an example, it is not specifically limited to what was illustrated.

製造法1
本発明化合物(I)は以下の方法で合成することができる。
Manufacturing method 1
The compound (I) of the present invention can be synthesized by the following method.

ただし、Xはアセチル基またはC1−4アルキル基を示し、RはRもしくはアミノ基がtert−ブチルカーボネート(Boc)で保護されたRを示し、その他の記号は前記と同義である。 However, X is shows an acetyl group or a C 1-4 alkyl group, R 5 represents a R 3 wherein R 3 or an amino group is protected with tert- butyl carbonate (Boc), and other symbols are as defined above .

Figure 0005817317
Figure 0005817317

(1)工程1(Heck反応)
化合物(II)とオレフィンカルボン酸(III)をパラジウム触媒とホスフィンリガンド、及び適当な塩基の存在下、Heck反応を行うことにより化合物(IV)を得ることができる。このとき用いるパラジウム触媒としては、酢酸パラジウム、テトラキス(トリフェニルホスフィン)パラジウム、ジベンジリデンアセトンパラジウム、ビス(トリフェニルホスフィン)パラジウムクロリド、ビス(トリシクロヘキシルホスフィン)パラジウムクロリド、パラジウム活性炭等が挙げられる。ホスフィンリガンドとしてはトリフェニルホスフィンやトリ−o−トリルホスフィン等が挙げられる。また、塩基にはトリエチルアミン、N−エチル−N,N−ジイソプロピルアミン、炭酸カリウム、炭酸カルシウム、炭酸セシウム、カリウム t−ブトキシド等が用いられる。反応に用いられる溶媒としては、アセトニトリル、トルエン、テトラヒドロフラン等が挙げられる。反応温度は0℃から還流温度であるが、マイクロウェ−ブを用いることもある。
(1) Step 1 (Heck reaction)
Compound (IV) can be obtained by subjecting compound (II) and olefin carboxylic acid (III) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and an appropriate base. Examples of the palladium catalyst used at this time include palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone palladium, bis (triphenylphosphine) palladium chloride, bis (tricyclohexylphosphine) palladium chloride, and palladium activated carbon. Examples of the phosphine ligand include triphenylphosphine and tri-o-tolylphosphine. As the base, triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran and the like. The reaction temperature is from 0 ° C. to reflux temperature, but a microwave may be used.

(2)工程2(アミド基への変換)
化合物(IV)をアミン(RNH)と脱水縮合し、化合物(V)を得ることができる。この反応に使用する溶媒としては、クロロホルム、ジクロロメタン、N,N−ジメチルホルムアミド等が挙げられ、脱水縮合剤としては、N,N´−ジシクロヘキシルカルボジイミド(DCC)、N−エチル−N´−3−ジメチルアミノプロピルカルボジイミド塩酸塩(EDC−HCl)、1、1´−カルボニルジイミダゾ−ル(CDI)、EDC−HCl/1−ヒドロキシベンゾトリアゾ−ル一水和物(HOBt・HO)等が挙げられる。ここでの反応温度は0℃〜60℃である。
(2) Step 2 (Conversion to amide group)
Compound (IV) can be dehydrated and condensed with amine (R 5 R 4 NH) to obtain compound (V). Examples of the solvent used in this reaction include chloroform, dichloromethane, N, N-dimethylformamide, and examples of the dehydrating condensing agent include N, N′-dicyclohexylcarbodiimide (DCC) and N-ethyl-N′-3-. Dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl), 1,1′-carbonyldiimidazole (CDI), EDC-HCl / 1-hydroxybenzotriazole monohydrate (HOBt · H 2 O), etc. Is mentioned. The reaction temperature here is 0 ° C to 60 ° C.

(3)工程3(脱保護)
化合物(V)中のBoc基を酸性条件下除去し、アセチル(Ac)基を塩基性条件下除去することで化合物(I)を得ることができる。Boc基には、ジクロロメタン、クロロホルム、ジオキサン等の溶媒中、または無溶媒で塩酸またはトリフルオロ酢酸を作用させる。アセチル基には、ナトリウムメトキシド、水酸化ナトリウム、水酸化リチウム、炭酸カリウム、炭酸セシウム、トリエチルアミン等の塩基を用いることができる。溶媒としては、メタノール、エタノール、含水メタノール等が挙げられる。ここでの反応温度は0℃〜60℃である。
(3) Step 3 (deprotection)
Compound (I) can be obtained by removing the Boc group in compound (V) under acidic conditions and removing the acetyl (Ac) group under basic conditions. Hydrochloric acid or trifluoroacetic acid is allowed to act on the Boc group in a solvent such as dichloromethane, chloroform, dioxane or the like or without a solvent. For the acetyl group, a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used. Examples of the solvent include methanol, ethanol, hydrous methanol and the like. The reaction temperature here is 0 ° C to 60 ° C.

製造法2
本発明化合物(I)は以下に示す別ルートによって合成することもできる。ただし、記号は前記と同義である。
Manufacturing method 2
The compound (I) of the present invention can also be synthesized by another route shown below. However, the symbols are as defined above.

Figure 0005817317
Figure 0005817317

(4)工程4(Heck反応)
化合物(II)とオレフィンカルボン酸(VI)を用いて製造法1の工程1に記載したHeck反応を行うことにより、化合物(VII)を得ることができる。
(4) Step 4 (Heck reaction)
Compound (VII) can be obtained by performing Heck reaction described in Step 1 of Production Method 1 using Compound (II) and olefin carboxylic acid (VI).

(5)工程5(アミド基への変換)
化合物(VII)とアミン(VIII)を用いて製造法1の工程2に記載した脱水縮合反応を行うことにより、化合物(V)を得ることができる。
(5) Step 5 (Conversion to amide group)
Compound (V) can be obtained by performing the dehydration condensation reaction described in Step 2 of Production Method 1 using Compound (VII) and amine (VIII).

(6)工程6(脱保護)
上記で得られた化合物(V)を製造法1の工程3に記載した脱保護反応によって化合物(I)へ導くことができる。
(6) Step 6 (deprotection)
The compound (V) obtained above can be led to the compound (I) by the deprotection reaction described in Step 3 of Production Method 1.

製造法3
中間体(II)の製造法
本発明化合物(I)の製造に必要な中間体(II)の製造法を以下に示す。
Production method 3
Production method of intermediate (II) The production method of intermediate (II) necessary for the production of the compound (I) of the present invention is shown below.

ただし、Xはベンジル基又はC1−4アルキル基を示し、Xはトリメチルシリル基又はC1−4アルキル基を示し、その他の記号は前記と同義である。 However, X 1 represents a benzyl group or a C 1-4 alkyl group, X 2 represents a trimethylsilyl group or a C 1-4 alkyl group, and other symbols are as defined above.

Figure 0005817317
Figure 0005817317

(7)工程7(カップリング)
化合物(IX)にn−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム等の有機金属試薬を用いてアリ−ルリチウム試薬を調製することができる。これに、グルコノラクトン(X)を加えることで化合物(XI)を得ることができる。このとき反応に用いられる溶媒としては、テトラヒドロフラン、ジエチルエ−テル、トルエン等が挙げられる。反応温度は−80℃から室温であり、好ましくは−78℃〜−25℃である。
(7) Step 7 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for compound (IX). Compound (XI) can be obtained by adding gluconolactone (X) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(8)工程8(酸加水分解及びメチルエーテル化)
化合物(XI)中のシリル基を酸性条件下メタノール中で除去すると共に、糖の1位をメチルエーテル化し化合物(XII)を得ることができる。このとき用いる酸としては、塩酸、硫酸、メタンスルホン酸、p−トルエンスルホン酸一水和物、ピリジニウム p−トルエンスルホン酸等を用いることができる。反応温度は用いる酸によって異なるが、0℃〜100℃、好ましくは25℃〜80℃である。
(8) Step 8 (acid hydrolysis and methyl etherification)
The silyl group in compound (XI) can be removed in methanol under acidic conditions, and the 1-position of sugar can be methyletherified to obtain compound (XII). Examples of the acid used at this time include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonic acid, and the like. The reaction temperature varies depending on the acid used, but is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C.

(9)工程9(アセチル化)
化合物(XII)中の水酸基をアセチル基で保護することにより、化合物(XIII)を得ることができる。化合物(XII)と、無水酢酸、またはアセチルクロリド等を溶媒中、適当な塩基存在下反応させ化合物(XIII)を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、ジオキサン、酢酸エチル、テトラヒドロフラン、N,N−ジメチルホルムアミド等である。塩基としてはトリエチルアミン、コリジン、ピリジン等を用いることができる。反応の触媒として4−ジメチルアミノピリジンを用いることもできる。また、ここでの反応温度は0℃〜室温である。
(9) Step 9 (acetylation)
Compound (XIII) can be obtained by protecting the hydroxyl group in compound (XII) with an acetyl group. Compound (XIII) can be obtained by reacting compound (XII) with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base. Solvents used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. As the base, triethylamine, collidine, pyridine and the like can be used. 4-Dimethylaminopyridine can also be used as a catalyst for the reaction. The reaction temperature here is 0 ° C. to room temperature.

(10)工程10(還元)
化合物(XIII)とEtSiH、i−PrSiH、t−BuMeSiH又はPhSiHClを、ルイス酸の存在下で反応させ、化合物(XIV)を得ることができる。この反応に使用するルイス酸としては、BF・OEt、CFCOOH、InCl、TiCl、TMSOTf、p−トルエンスルホン酸、メタンスルホン酸等が挙げられ、溶媒としては、クロロホルム、ジクロロメタン、トルエン、テトラヒドロフラン、アセトニトリル又はそれらの混合溶媒が挙げられ、好ましい溶媒はアセトニトリル/クロロホルム、アセトニトリル/ジクロロメタン、アセトニトリル/テトラヒドロフラン、アセトニトリル/テトラヒドロフラン/トルエン等のアセトニトリルと他の溶媒との混合溶媒である。ここでの反応温度は−60℃〜25℃、好ましくは−30℃〜25℃である。
(10) Step 10 (reduction)
Compound (XIII) and Et 3 SiH, i-Pr 3 SiH, a t-BuMe 2 SiH or Ph 2 SiHCl, are reacted in the presence of a Lewis acid, it is possible to obtain compound (XIV). Examples of the Lewis acid used in this reaction include BF 3 .OEt 2 , CF 3 COOH, InCl 3 , TiCl 4 , TMSOTf, p-toluenesulfonic acid, methanesulfonic acid, and the like. Solvents include chloroform, dichloromethane, Examples include toluene, tetrahydrofuran, acetonitrile, or a mixed solvent thereof, and a preferable solvent is a mixed solvent of acetonitrile and another solvent such as acetonitrile / chloroform, acetonitrile / dichloromethane, acetonitrile / tetrahydrofuran, acetonitrile / tetrahydrofuran / toluene, and the like. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 25 ° C.

(11)工程11(脱保護)
化合物(XIV)中のXがベンジル基の場合は、パラジウム活性炭、水酸化パラジウム、又は白金−パラジウム活性炭等の触媒を用いて水素雰囲気下にて接触水素添加することにより、脱ベンジル化を行うことができる。中でもパラジウム活性炭、水酸化パラジウムが触媒として好ましい。この反応に使用する溶媒としては、メタノ−ル、エタノ−ル、イソプロパノ−ル、酢酸エチル、酢酸、およびこれらの混合溶媒が挙げられる。反応温度は室温から還流温度であるが、室温が好ましい。
(11) Step 11 (deprotection)
When X 1 in compound (XIV) is a benzyl group, debenzylation is performed by catalytic hydrogenation under a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon. be able to. Of these, palladium activated carbon and palladium hydroxide are preferred as the catalyst. Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, ethyl acetate, acetic acid, and a mixed solvent thereof. The reaction temperature is from room temperature to reflux temperature, but room temperature is preferred.

(12)工程12(臭素化)
化合物(XIV)、または上記工程11で得られた化合物と、臭素、N−ブロモスクシンイミド、臭化水素等を溶液中反応させて、化合物(XV)を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、酢酸、メタノール、N,N−ジメチルホルムアミド等である。ここでの反応温度は0℃〜室温である。
(12) Step 12 (bromination)
Compound (XV) can be obtained by reacting Compound (XIV) or the compound obtained in Step 11 above with bromine, N-bromosuccinimide, hydrogen bromide or the like in a solution. Examples of the solvent used for the reaction include chloroform, dichloromethane, acetic acid, methanol, N, N-dimethylformamide and the like. The reaction temperature here is 0 ° C. to room temperature.

(13)工程13(脱保護)
化合物(XV)中のアセチル基を塩基性条件下除去することで化合物(XVI)を得ることができる。塩基としては、ナトリウムメトキシド、水酸化ナトリウム、水酸化リチウム、炭酸カリウム、炭酸セシウム、トリエチルアミン等の塩基を用いることができる。溶媒としては、メタノール、エタノール、含水メタノール等を用いることができる。ここでの反応温度は0℃〜60℃である。
(13) Step 13 (deprotection)
Compound (XVI) can be obtained by removing the acetyl group in compound (XV) under basic conditions. As the base, a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used. As the solvent, methanol, ethanol, hydrous methanol, or the like can be used. The reaction temperature here is 0 ° C to 60 ° C.

(14)工程14(シリル化)
化合物(XVI)中の水酸基をトリメチルシリル基等のシリル基で保護することにより、化合物(XVII)を得ることができる。化合物(XVI)と、トリメチルシリルクロリド、トリエチルシリルクロリド、tert−ブチルジメチルシリルクロリド等を溶媒中、適当な塩基存在下反応させ化合物(XVII)を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、ジオキサン、酢酸エチル、テトラヒドロフラン、N,N−ジメチルホルムアミド等が挙げられる。塩基としてはトリエチルアミン、コリジン、ピリジン等を用いることができる。また、ここでの反応温度は0℃〜室温である。
(14) Step 14 (silylation)
Compound (XVII) can be obtained by protecting the hydroxyl group in compound (XVI) with a silyl group such as a trimethylsilyl group. Compound (XVII) can be obtained by reacting compound (XVI) with trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride and the like in a solvent in the presence of an appropriate base. Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. As the base, triethylamine, collidine, pyridine and the like can be used. The reaction temperature here is 0 ° C. to room temperature.

(15)工程15(カップリング)
化合物(XVII)にn−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム等の有機金属試薬を用いてアリ−ルリチウム試薬を調製することができる。これに、アルデヒド(XVIII)を加えることで化合物(XIX)を得ることができる。このとき反応に用いられる溶媒としては、テトラヒドロフラン、ジエチルエ−テル、トルエン等が挙げられる。反応温度は−80℃から室温であり、好ましくは−78℃〜−25℃である。
(15) Step 15 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for compound (XVII). Compound (XIX) can be obtained by adding aldehyde (XVIII) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(16)工程16(酸加水分解)
上記で得られた化合物(XIX)を製造法3の工程8に記載した酸加水分解反応によって化合物(XX)へ導くことができる。
(16) Step 16 (acid hydrolysis)
Compound (XIX) obtained above can be converted to compound (XX) by the acid hydrolysis reaction described in Step 8 of Production Method 3.

(17)工程17(アセチル化)
上記で得られた化合物(XX)を製造法3の工程9に記載したアセチル化反応によって化合物(XXI)へ導くことができる。
(17) Step 17 (acetylation)
Compound (XX) obtained above can be led to compound (XXI) by the acetylation reaction described in Step 9 of Production Method 3.

(18)工程18(還元)
上記で得られた化合物(XXI)を製造法3の工程10に記載した還元反応によって中間体(II)へ導くことができる。
(18) Step 18 (reduction)
Compound (XXI) obtained above can be led to intermediate (II) by the reduction reaction described in Step 10 of Production Method 3.

製造法4
中間体(II)の製造法
中間体(II)は以下に示す別ルートによって合成することもできる。ここでは、工程19から21までワンポットで行い工程数を短縮することができる。
Manufacturing method 4
Production Method of Intermediate (II) Intermediate (II) can also be synthesized by another route shown below. Here, steps 19 to 21 can be performed in one pot to reduce the number of steps.

ただし、記号は前記と同義である。   However, the symbols are as defined above.

Figure 0005817317
Figure 0005817317

(19)工程19(カップリング)
化合物(XXII)にn−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム等の有機金属試薬を用いてアリ−ルリチウム試薬を調製することができる。これに、グルコノラクトン(X)を加えることで化合物(XXIII)を得ることができる。このとき反応に用いられる溶媒としては、テトラヒドロフラン、ジエチルエ−テル、トルエン等が挙げられる。反応温度は−80℃から室温であり、好ましくは−78℃〜−25℃である。
(19) Step 19 (coupling)
An aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for compound (XXII). Compound (XXIII) can be obtained by adding gluconolactone (X) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is from -80 ° C to room temperature, preferably -78 ° C to -25 ° C.

(20)工程20(シリル化)
上記工程19に引き続いて、化合物(XXIII)の1位水酸基をトリメチルシリル基等のシリル基で保護することができる。工程19の反応液に、トリメチルシリルクロリドを反応させ化合物(XXIV)を得ることができる。反応に用いる溶媒および反応温度は、工程19と同じである。
(20) Step 20 (silylation)
Subsequent to step 19, the 1-position hydroxyl group of compound (XXIII) can be protected with a silyl group such as a trimethylsilyl group. The reaction solution in Step 19 can be reacted with trimethylsilyl chloride to obtain compound (XXIV). The solvent and reaction temperature used for the reaction are the same as in Step 19.

(21)工程21(カップリング)
上記工程20に引き続いて、生成した化合物(XXIV)にn−ブチルリチウム、sec−ブチルリチウム、tert−ブチルリチウム等の有機金属試薬を用いてアリ−ルリチウム試薬を調製することができる。これに、アルデヒド(XVIII)を加えることで化合物(XXV)を得ることができる。このとき反応に用いられる溶媒および反応温度は、工程19と同じである。
(21) Step 21 (coupling)
Subsequent to the step 20, an aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium or the like for the produced compound (XXIV). Compound (XXV) can be obtained by adding aldehyde (XVIII) to this. At this time, the solvent used in the reaction and the reaction temperature are the same as in Step 19.

(22)工程22(酸加水分解)
上記で得られた化合物(XXV)を製造法3の工程8に記載した酸加水分解反応によって化合物(XXVI)へ導くことができる。
(22) Step 22 (acid hydrolysis)
Compound (XXV) obtained above can be led to compound (XXVI) by the acid hydrolysis reaction described in Step 8 of Production Method 3.

(23)工程23(アセチル化)
上記で得られた化合物(XXVI)を製造法3の工程9に記載したアセチル化反応によって化合物(XXVII)へ導くことができる。
(23) Step 23 (acetylation)
Compound (XXVI) obtained above can be led to compound (XXVII) by the acetylation reaction described in Step 9 of Production Method 3.

(24)工程24(還元)
上記で得られた化合物(XXVII)を製造法3の工程10に記載した還元反応によって化合物(XXVIII)へ導くことができる。
(24) Step 24 (reduction)
Compound (XXVII) obtained above can be converted to compound (XXVIII) by the reduction reaction described in Step 10 of Production Method 3.

(25)工程25(アセチル化またはアルキル化)
化合物(XXVIII)の水酸基を、アセチル基で保護するまたはメチル化等のアルキル化を行うことで、中間体(II)を製造することができる。化合物(XXVIII)と、無水酢酸、またはアセチルクロリド等を溶媒中、適当な塩基存在下反応させ中間体(II)を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、ジオキサン、酢酸エチル、テトラヒドロフラン、N,N−ジメチルホルムアミド等である。塩基としてはトリエチルアミン、コリジン、ピリジン等が挙げられる。触媒として4−ジメチルアミノピリジン等を用いることもできる。また、ここでの反応温度は0℃〜室温である。一方、化合物(XXVIII)と、ヨウ化メチル、ヨウ化エチル、ヨウ化イロプロピル等を溶媒中、適当な塩基存在下反応させ中間体(II)を得ることができる。反応に用いる溶媒としては、クロロホルム、ジクロロメタン、テトラヒドロフラン、N,N−ジメチルホルムアミド、アセトン等である。塩基としては炭酸カリウム、炭酸セシウム等を用いることができる。
(25) Step 25 (acetylation or alkylation)
Intermediate (II) can be produced by protecting the hydroxyl group of compound (XXVIII) with an acetyl group or alkylating such as methylation. Intermediate (II) can be obtained by reacting compound (XXVIII) with acetic anhydride or acetyl chloride in a solvent in the presence of a suitable base. Solvents used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. Examples of the base include triethylamine, collidine, pyridine and the like. 4-dimethylaminopyridine or the like can also be used as a catalyst. The reaction temperature here is 0 ° C. to room temperature. On the other hand, intermediate (II) can be obtained by reacting compound (XXVIII) with methyl iodide, ethyl iodide, isopropyl iodide, or the like in a solvent in the presence of an appropriate base. Examples of the solvent used for the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetone and the like. As the base, potassium carbonate, cesium carbonate, or the like can be used.

以下に、参考例、実施例及び試験例を挙げ、本発明をより詳細に説明する。   Hereinafter, the present invention will be described in more detail with reference examples, examples and test examples.

参考例1 中間体(A)の製造   Reference Example 1 Production of Intermediate (A)

Figure 0005817317
(1)参考例1−1 化合物(A1)
Figure 0005817317
(1) Reference Example 1-1 Compound (A1)

Figure 0005817317
Figure 0005817317

3−イソプロピルフェノール(25g,0.184mol)の酢酸(200mL)溶液にヨウ素酸カリウム(7.88g,0.0368mol)の水懸濁液(75mL)とヨウ素(18.7g,0.0736mol)を加え、この反応溶液を室温で20時間攪拌した。ジエチルエーテル(400mL)と水(300mL)を加えた後に、有機層を分離した。その有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5)にて精製し、無色油状の化合物(A1)(27.6g,57%)を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.16 - 1.25 (m, 6 H) 2.64 - 2.98 (m, 1 H) 5.21 (s, 1 H) 6.57 (dd, J=8.13, 2.20 Hz, 1 H) 6.88 (d, J=2.20 Hz, 1 H) 7.54 (d, J=8.13 Hz, 1 H).
(2)参考例1−2 化合物(A2)
An aqueous suspension (75 mL) of potassium iodate (7.88 g, 0.0368 mol) and iodine (18.7 g, 0.0736 mol) were added to a solution of 3-isopropylphenol (25 g, 0.184 mol) in acetic acid (200 mL). In addition, the reaction solution was stirred at room temperature for 20 hours. After adding diethyl ether (400 mL) and water (300 mL), the organic layer was separated. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to give a colorless oily compound (A1) (27.6 g, 57%).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.16-1.25 (m, 6 H) 2.64-2.98 (m, 1 H) 5.21 (s, 1 H) 6.57 (dd, J = 8.13, 2.20 Hz, 1 H) 6.88 (d, J = 2.20 Hz, 1 H) 7.54 (d, J = 8.13 Hz, 1 H).
(2) Reference Example 1-2 Compound (A2)

Figure 0005817317
Figure 0005817317

化合物(A1)(26.5g,0.101mol)と炭酸カリウム(20.9g,0.152mol)のアセトニトリル懸濁液に臭化ベンジル(14.4mL,0.121mol)を加え室温で2時間攪拌した。メタノール(1.0mL)を加え30分攪拌した。不溶物をろ過し、ろ液を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=95:5)にて精製し、無色油状の化合物(A2)(30.2g,85%)を得た。
1H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=7.03 Hz, 6 H) 2.84 (sept, J=7.03 Hz, 1 H) 5.14 (s, 2 H) 6.62 (dd, J=8.35, 2.20 Hz, 1 H) 6.74 (d, J=2.20 Hz, 1 H) 7.23 - 7.58 (m, 5 H) 7.68 (d, J=8.35 Hz, 1 H).
(3)参考例1−3 化合物(A3)
Benzyl bromide (14.4 mL, 0.121 mol) was added to an acetonitrile suspension of compound (A1) (26.5 g, 0.101 mol) and potassium carbonate (20.9 g, 0.152 mol), and the mixture was stirred at room temperature for 2 hours. did. Methanol (1.0 mL) was added and stirred for 30 minutes. Insoluble matters were filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 95: 5) to obtain a colorless oily compound (A2) (30.2 g, 85%).
1 H NMR (200 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 7.03 Hz, 6 H) 2.84 (sept, J = 7.03 Hz, 1 H) 5.14 (s, 2 H) 6.62 (dd, J = 8.35, 2.20 Hz, 1 H) 6.74 (d, J = 2.20 Hz, 1 H) 7.23-7.58 (m, 5 H) 7.68 (d, J = 8.35 Hz, 1 H).
(3) Reference Example 1-3 Compound (A3)

Figure 0005817317
Figure 0005817317

化合物(A2)(30.2g,85.7mmol)のTHF(450mL)溶液に窒素雰囲気下、−78℃にて2.6M n−ブチルリチウムへキサン溶液(33mL,85.7mmol)を滴下し、同温にて15分間攪拌した。次いで2,3,4,6−テトラ−O−トリメチルシリル−D−グルコノ−1,5−ラクトン(40g,85.7mmol)のTHF(230mL)溶液を15分かけて滴下し、同温にて20分間攪拌した。反応液に飽和塩化アンモニウム水溶液(150mL)と水(100mL)を加えた。この混合物を室温まで温めた後に、酢酸エチルで2回抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。   To a THF (450 mL) solution of compound (A2) (30.2 g, 85.7 mmol), 2.6 M n-butyllithium hexane solution (33 mL, 85.7 mmol) was added dropwise at −78 ° C. in a nitrogen atmosphere. Stir for 15 minutes at the same temperature. Next, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (40 g, 85.7 mmol) in THF (230 mL) was added dropwise over 15 minutes. Stir for minutes. A saturated aqueous ammonium chloride solution (150 mL) and water (100 mL) were added to the reaction solution. The mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.

得られた残渣をメタンスルホン酸(2.9g)を含むメタノール(840mL)溶液に溶解し、室温で14.5時間攪拌した。トリエチルアミン(2.5mL)で中和し、反応混合物を濃縮した。   The obtained residue was dissolved in a methanol (840 mL) solution containing methanesulfonic acid (2.9 g) and stirred at room temperature for 14.5 hours. Neutralized with triethylamine (2.5 mL) and the reaction mixture was concentrated.

得られた残渣(46.4g)をピリジン(125mL)に溶解し、4℃に冷却した。この溶液に無水酢酸(75mL)と4−ジメチルアミノピリジン(102mg,0.835mmol)を加え、室温で19時間攪拌した。氷水(500mL)を加え、混合物を酢酸エチル(500mL)で2回抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し粗化合物(53g)を得た。   The obtained residue (46.4 g) was dissolved in pyridine (125 mL) and cooled to 4 ° C. Acetic anhydride (75 mL) and 4-dimethylaminopyridine (102 mg, 0.835 mmol) were added to this solution, and the mixture was stirred at room temperature for 19 hours. Ice water (500 mL) was added and the mixture was extracted twice with ethyl acetate (500 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain a crude compound (53 g).

この粗化合物のクロロホルム(250mL)とアセトニトリル(250mL)溶液に、窒素雰囲気下4℃にてEt3SiH(13.7mL,85.7mmol)とBF3・Et2O(10.9mL,85.7mmol)を加え、同温で1.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=5:1→2:1)にて精製し、淡黄色のアモルファスとして化合物(A3)(19.1g,40%;4工程)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=6.99 Hz, 6 H) 1.78 (s, 3 H) 2.01 (s, 6 H) 2.05 (s, 3 H) 2.86 (sept, J=6.99 Hz, 1 H) 3.80 (ddd, J=9.95, 4.59, 2.25 Hz, 1 H) 4.06 - 4.13 (m, 1 H) 4.19 - 4.27 (m, 1 H) 4.96 (d, J=9.95 Hz, 1 H) 5.10 (s, 2 H) 5.16 - 5.25 (m, 1 H) 5.33 (t, J=9.17 Hz, 1 H) 5.40 - 5.49 (m, 1 H) 6.79 (d, J=1.40 Hz, 1 H) 6.85 (dd, J=7.93, 1.40 Hz, 1 H) 7.26 - 7.52 (m, 6 H).
MS ESI/APCI Dual posi : 579[M+Na]+.
(4)参考例1−4 化合物(A4)
A solution of this crude compound in chloroform (250 mL) and acetonitrile (250 mL) was added to Et 3 SiH (13.7 mL, 85.7 mmol) and BF 3 .Et 2 O (10.9 mL, 85.7 mmol) at 4 ° C. in a nitrogen atmosphere. ) And stirred at the same temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 → 2: 1) to give the compound ( A3) (19.1 g, 40%; 4 steps) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 6.99 Hz, 6 H) 1.78 (s, 3 H) 2.01 (s, 6 H) 2.05 (s, 3 H) 2.86 (sept, J = 6.99 Hz, 1 H) 3.80 (ddd, J = 9.95, 4.59, 2.25 Hz, 1 H) 4.06-4.13 (m, 1 H) 4.19-4.27 (m, 1 H) 4.96 (d, J = 9.95 Hz , 1 H) 5.10 (s, 2 H) 5.16-5.25 (m, 1 H) 5.33 (t, J = 9.17 Hz, 1 H) 5.40-5.49 (m, 1 H) 6.79 (d, J = 1.40 Hz, 1 H) 6.85 (dd, J = 7.93, 1.40 Hz, 1 H) 7.26-7.52 (m, 6 H).
MS ESI / APCI Dual posi: 579 [M + Na] + .
(4) Reference Example 1-4 Compound (A4)

Figure 0005817317
Figure 0005817317

化合物(A3)(19.1g,34.3mmol)のメタノール(200mL)溶液に10%パラジウム活性炭(1.8g)を加え、水素雰囲気下、室温にて2時間攪拌した。反応液をセライト濾過後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1→1:1)にて精製し、無色アモルファスとして化合物(A4)(12.3g,77%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J=6.89 Hz, 6 H) 1.83 (s, 3 H) 2.01 (s, 3 H) 2.06 (s, 3 H) 2.12 (s, 3 H) 2.82 (sept, J=6.89 Hz, 1 H) 3.87 (ddd, J=9.60, 3.85, 2.25 Hz, 1 H) 4.14 - 4.21 (m, 1 H) 4.27 - 4.36 (m, 1 H) 4.59 (d, J=9.33 Hz, 1 H) 5.23 - 5.39 (m, 3 H) 6.70 (dd, J=7.93, 1.71 Hz, 1 H) 6.77 (d, J=1.71 Hz, 1 H) 6.80 (s, 1 H) 6.91 (d, J=7.93 Hz, 1 H).
MS ESI/APCI Dual posi : 489[M+Na]+.
MS ESI/APCI Dual nega : 501[M+Cl].
(5)参考例1−5 化合物(A5)
To a solution of compound (A3) (19.1 g, 34.3 mmol) in methanol (200 mL) was added 10% palladium activated carbon (1.8 g), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give the compound (A4) as a colorless amorphous product. (12.3 g, 77%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J = 6.89 Hz, 6 H) 1.83 (s, 3 H) 2.01 (s, 3 H) 2.06 (s, 3 H) 2.12 (s, 3 H) 2.82 (sept, J = 6.89 Hz, 1 H) 3.87 (ddd, J = 9.60, 3.85, 2.25 Hz, 1 H) 4.14-4.21 (m, 1 H) 4.27-4.36 (m, 1 H) 4.59 (d, J = 9.33 Hz, 1 H) 5.23-5.39 (m, 3 H) 6.70 (dd, J = 7.93, 1.71 Hz, 1 H) 6.77 (d, J = 1.71 Hz, 1 H) 6.80 (s, 1 H) 6.91 (d, J = 7.93 Hz, 1 H).
MS ESI / APCI Dual posi: 489 [M + Na] + .
MS ESI / APCI Dual nega: 501 [M + Cl] .
(5) Reference Example 1-5 Compound (A5)

Figure 0005817317
Figure 0005817317

化合物(A4)(12.3g,26.3mol)の酢酸(120mL)溶液に、臭素(4.2g,26.3mmol)を室温にて滴下した。反応混合液を1.5時間攪拌し、氷水(150mL)を加えた。この混合物を酢酸エチルで2回抽出し、合わせた有機層を飽和炭酸水素ナトリウム水溶液、10%チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣を2−プロパノール(20mL)に溶解し、ヘキサン(50mL)を滴下した。混合物を4℃で1時間攪拌し、析出した沈殿をろ過して無色粉末の化合物(A5)(9.8g,68%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 - 1.26 (m, 6 H) 1.89 (s, 3 H) 2.01 (s, 3 H) 2.07 (s, 3 H) 2.13 (s, 3 H) 3.22 (sept, J=6.74 Hz, 1 H) 3.87 (ddd, J=9.48, 3.73, 2.18 Hz, 1 H) 4.14 - 4.22 (m, 1 H) 4.28 - 4.36 (m, 1 H) 4.53 (d, J=9.33 Hz, 1 H) 5.16 - 5.39 (m, 3 H) 6.82 (s, 1 H) 7.14 (s, 1 H).
MS ESI/APCI Dual posi : 567[M+Na]+, 569[M+2+Na]+.
MS ESI/APCI Dual nega : 579[M+Cl], 581[M+2+Cl].
(6)参考例1−6 化合物(A6)
Bromine (4.2 g, 26.3 mmol) was added dropwise at room temperature to a solution of compound (A4) (12.3 g, 26.3 mol) in acetic acid (120 mL). The reaction mixture was stirred for 1.5 hours and ice water (150 mL) was added. This mixture was extracted twice with ethyl acetate, and the combined organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 2-propanol (20 mL), and hexane (50 mL) was added dropwise. The mixture was stirred at 4 ° C. for 1 hour, and the deposited precipitate was filtered to obtain a colorless powder of compound (A5) (9.8 g, 68%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12-1.26 (m, 6 H) 1.89 (s, 3 H) 2.01 (s, 3 H) 2.07 (s, 3 H) 2.13 (s, 3 H) 3.22 (sept, J = 6.74 Hz, 1 H) 3.87 (ddd, J = 9.48, 3.73, 2.18 Hz, 1 H) 4.14-4.22 (m, 1 H) 4.28-4.36 (m, 1 H) 4.53 (d, J = 9.33 Hz, 1 H) 5.16-5.39 (m, 3 H) 6.82 (s, 1 H) 7.14 (s, 1 H).
MS ESI / APCI Dual posi: 567 [M + Na] + , 569 [M + 2 + Na] + .
MS ESI / APCI Dual nega: 579 [M + Cl] , 581 [M + 2 + Cl] .
(6) Reference Example 1-6 Compound (A6)

Figure 0005817317
Figure 0005817317

化合物(A5)(12.2g,22.3mol)のメタノール(120mL)溶液に、トリエチルアミン(24mL)と水(24mL)を加えた。反応混合物を室温で15時間、さらに50℃で10時間攪拌し、溶媒を減圧下留去した。得られた残渣をN,N−ジメチルホルムアミド(106mL)に溶解し、窒素雰囲気下4℃にてトリエチルアミン(18.6mL)とクロロトリメチルシラン(14.3mL)を加えた。反応混合物を4℃にて1時間攪拌し、氷水(150mL)を加えた。この混合物をトルエンで3回抽出し、合わせた有機層を水、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、油状の化合物(A6)(17.4g)を得た。これを精製せずに次の反応に用いた。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.28 (s, 9 H) 0.08 (s, 9 H) 0.19 (s, 9 H) 0.20 (s, 9 H) 0.29 (s, 9 H) 1.16 (d, J=6.84 Hz, 3 H) 1.21 (d, J=6.84 Hz, 3 H) 3.17 - 3.37 (m, 1 H) 3.41 - 3.56 (m, 3 H) 3.62 - 3.72 (m, 1 H) 3.76 - 3.86 (m, 1 H) 4.46 (d, J=8.24 Hz, 1 H) 6.64 (s, 1 H) 7.47 (s, 1 H).
(7)参考例1−7 化合物(A7)
Triethylamine (24 mL) and water (24 mL) were added to a solution of compound (A5) (12.2 g, 22.3 mol) in methanol (120 mL). The reaction mixture was stirred at room temperature for 15 hours and further at 50 ° C. for 10 hours, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (106 mL), and triethylamine (18.6 mL) and chlorotrimethylsilane (14.3 mL) were added at 4 ° C. under a nitrogen atmosphere. The reaction mixture was stirred at 4 ° C. for 1 hour and ice water (150 mL) was added. The mixture was extracted three times with toluene, and the combined organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to obtain an oily compound (A6) (17.4 g). This was used in the next reaction without purification.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.28 (s, 9 H) 0.08 (s, 9 H) 0.19 (s, 9 H) 0.20 (s, 9 H) 0.29 (s, 9 H) 1.16 (d, J = 6.84 Hz, 3 H) 1.21 (d, J = 6.84 Hz, 3 H) 3.17-3.37 (m, 1 H) 3.41-3.56 (m, 3 H) 3.62-3.72 (m, 1 H) 3.76-3.86 (m, 1 H) 4.46 (d, J = 8.24 Hz, 1 H) 6.64 (s, 1 H) 7.47 (s, 1 H).
(7) Reference Example 1-7 Compound (A7)

Figure 0005817317
Figure 0005817317

化合物(A6)(13.4g,15.9mmol)のTHF(140mL)溶液に窒素雰囲気下、−78℃にて2.6M n−ブチルリチウムへキサン溶液(7.7mL,20.0mmol)を10分かけて滴下し、同温にて5分間攪拌した。次いで4−ブロモ−2−メチルベンズアルデヒド(3.2g,15.9mmol)のTHF(24mL)溶液を15分かけて滴下し、同温にて45分間攪拌した。反応液に飽和塩化アンモニウム水溶液(100mL)と水(100mL)を加えた。この混合物を室温まで温めた後に、酢酸エチルで2回抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。   To a solution of compound (A6) (13.4 g, 15.9 mmol) in THF (140 mL) at −78 ° C. in a nitrogen atmosphere was added 2.6 M n-butyllithium hexane solution (7.7 mL, 20.0 mmol). The solution was added dropwise over a period of time and stirred at the same temperature for 5 minutes. Then, a solution of 4-bromo-2-methylbenzaldehyde (3.2 g, 15.9 mmol) in THF (24 mL) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 45 minutes. A saturated aqueous ammonium chloride solution (100 mL) and water (100 mL) were added to the reaction solution. The mixture was warmed to room temperature and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.

得られた残渣をメタンスルホン酸(0.9g)を含むメタノール(200mL)溶液に溶解し、室温で0.5時間攪拌した。トリエチルアミンで中和し、反応混合物を濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=10:1→8:1)で精製し、無色アモルファスの化合物(A7)(5.75g,73%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.01 and 1.04 (each d, J=6.88 Hz, 3 H) 1.18 and 1.19 (each d, J=6.88 Hz, 3 H) 2.24 and 2.26 (each s, 3 H) 2.95 - 3.07 (m, 1 H) 3.35 - 3.69 (m, 5 H) 3.78 - 3.87 (m, 1 H) 4.37 - 4.50 (m, 1 H) 5.59 (s, 1 H) 6.80 (s, 1 H) 6.98 - 7.10 (m, 2 H) 7.24 - 7.30 (m, 1 H) 7.33 (s, 1 H).
MS ESI/APCI Dual posi : 479[M-OH]+, 481[M+2-OH]+
(8)参考例1−8 中間体(A)
The obtained residue was dissolved in a methanol (200 mL) solution containing methanesulfonic acid (0.9 g) and stirred at room temperature for 0.5 hour. Neutralized with triethylamine and the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1 → 8: 1) to obtain a colorless amorphous compound (A7) (5.75 g, 73%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.01 and 1.04 (each d, J = 6.88 Hz, 3 H) 1.18 and 1.19 (each d, J = 6.88 Hz, 3 H) 2.24 and 2.26 (each s , 3 H) 2.95-3.07 (m, 1 H) 3.35-3.69 (m, 5 H) 3.78-3.87 (m, 1 H) 4.37-4.50 (m, 1 H) 5.59 (s, 1 H) 6.80 (s , 1 H) 6.98-7.10 (m, 2 H) 7.24-7.30 (m, 1 H) 7.33 (s, 1 H).
MS ESI / APCI Dual posi: 479 [M-OH] + , 481 [M + 2-OH] + .
(8) Reference Example 1-8 Intermediate (A)

Figure 0005817317
Figure 0005817317

化合物(A7)(5.7g,11.5mmol)をピリジン(34mL)に溶解した。この溶液に無水酢酸(17mL)と4−ジメチルアミノピリジン(10mg)を加え、室温で0.5時間攪拌した。氷水(500mL)を加え、混合物を酢酸エチル(500mL)で2回抽出した。合わせた有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し粗化合物(8.5g)を得た。   Compound (A7) (5.7 g, 11.5 mmol) was dissolved in pyridine (34 mL). Acetic anhydride (17 mL) and 4-dimethylaminopyridine (10 mg) were added to this solution, and the mixture was stirred at room temperature for 0.5 hr. Ice water (500 mL) was added and the mixture was extracted twice with ethyl acetate (500 mL). The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain a crude compound (8.5 g).

この粗化合物(8.5g)のクロロホルム(80mL)とアセトニトリル(80mL)溶液に、窒素雰囲気下4℃にてEt3SiH(2.7mL,17.0mmol)とBF3・Et2O(2.2mL,17.0mmol)を加えた。反応液を室温まで温めた後に、同温で0.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣をヘキサン:酢酸エチル=4:1混合液から結晶化し、析出した沈殿をろ過して無色粉末の中間体(A)(5.3g,68%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=6.68 Hz, 3 H) 1.14 (d, J=6.68 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.37 (s, 3 H) 2.93 (sept, J=6.68 Hz, 1 H) 3.76 (ddd, J=9.87, 4.51, 2.25 Hz, 1 H) 3.87 (s, 2 H) 4.06 (dd, J=12.51, 2.25 Hz, 1 H) 4.27 (dd, J=12.51, 4.51 Hz, 1 H) 4.49 (d, J=9.64 Hz, 1 H) 5.10 - 5.33 (m, 3 H) 6.59 (d, J=8.39 Hz, 1 H) 6.97 (s, 1 H) 7.00 (s, 1 H) 7.20 (dd, J=8.39, 2.49 Hz, 1 H) 7.34 (d, J=2.49 Hz, 1 H).
MS ESI/APCI Dual posi : 713[M+Na]+, 715[M+2+Na]+
また、中間体(A)は参考例1−9、10、11に記載の方法でも合成することができる。
(9)参考例1−9 化合物(A8)
To a solution of the crude compound (8.5 g) in chloroform (80 mL) and acetonitrile (80 mL), Et 3 SiH (2.7 mL, 17.0 mmol) and BF 3 .Et 2 O (2. 2 mL, 17.0 mmol) was added. The reaction solution was warmed to room temperature and then stirred at the same temperature for 0.5 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was crystallized from a mixture of hexane: ethyl acetate = 4: 1, and the deposited precipitate was filtered to obtain colorless powder intermediate (A) (5.3 g, 68%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.68 Hz, 3 H) 1.14 (d, J = 6.68 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.37 (s, 3 H) 2.93 (sept, J = 6.68 Hz, 1 H) 3.76 (ddd, J = 9.87, 4.51 , 2.25 Hz, 1 H) 3.87 (s, 2 H) 4.06 (dd, J = 12.51, 2.25 Hz, 1 H) 4.27 (dd, J = 12.51, 4.51 Hz, 1 H) 4.49 (d, J = 9.64 Hz , 1 H) 5.10-5.33 (m, 3 H) 6.59 (d, J = 8.39 Hz, 1 H) 6.97 (s, 1 H) 7.00 (s, 1 H) 7.20 (dd, J = 8.39, 2.49 Hz, 1 H) 7.34 (d, J = 2.49 Hz, 1 H).
MS ESI / APCI Dual posi: 713 [M + Na] + , 715 [M + 2 + Na] + .
Intermediate (A) can also be synthesized by the methods described in Reference Examples 1-9, 10, and 11.
(9) Reference Example 1-9 Compound (A8)

Figure 0005817317
Figure 0005817317

3−イソプロピルフェノール(160g,1.18mol)の酢酸(1.6L)溶液に、氷冷で内温19℃を超えないように臭素(469g,2.94mol)の酢酸(320mL)溶液を32分かけて滴下し、室温で1時間攪拌した。トルエン(1.6L)を加えた後に氷冷し、内温20℃を超えないように10%亜硫酸ナトリウム水溶液(1.0L)を滴下して有機層を分離した。その有機層を10%亜硫酸ナトリウム水溶液(1.0L)、10%塩化ナトリウム水溶液(1.0L)で2回洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、淡黄色油状化合物(A8)(342g,99%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=6.84 Hz, 6 H) 3.25 (sept, J=6.84 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H) 7.61 (s, 1 H).
(10)参考例1−10 化合物(A9)
To a solution of 3-isopropylphenol (160 g, 1.18 mol) in acetic acid (1.6 L) was added ice-cooled bromine (469 g, 2.94 mol) in acetic acid (320 mL) for 32 minutes so that the internal temperature did not exceed 19 ° C. The mixture was added dropwise and stirred at room temperature for 1 hour. Toluene (1.6 L) was added and then ice-cooled, and a 10% aqueous sodium sulfite solution (1.0 L) was added dropwise so that the internal temperature did not exceed 20 ° C., and the organic layer was separated. The organic layer was washed twice with a 10% aqueous sodium sulfite solution (1.0 L) and a 10% aqueous sodium chloride solution (1.0 L) and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain a pale yellow oily compound (A8) (342 g, 99%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 6.84 Hz, 6 H) 3.25 (sept, J = 6.84 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H ) 7.61 (s, 1 H).
(10) Reference Example 1-10 Compound (A9)

Figure 0005817317
Figure 0005817317

化合物(A8)(512g,1.74mol)のクロロホルム(1.74L)溶液に、N、N−ジイソプロピルエチルアミン(364mL,2.09mol)を加えて氷冷した。クロロメチルメチルエーテル(159mL,2.09mol)を60分かけて滴下し、室温で1時間攪拌した。反応液を氷冷し、1M水酸化ナトリウム水溶液(1.5L)を滴下して有機層を分離した。その有機層を1M水酸化ナトリウム水溶液(1.5L)、水(1.5L)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣を減圧蒸留(0.93〜1.5hpa,122℃〜137℃)にて精製し、淡黄色油状化合物(A9)(548g,96%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J=6.84 Hz, 6 H) 3.28 (sept, J=6.84 Hz, 1 H) 3.52 (s, 3 H) 5.23 (s, 2 H) 7.06 (s, 1 H) 7.69 (s, 1 H).
MS ESI/APCI Dual posi : 339[M+H]+, 341[M+2+H]+.
N, N-diisopropylethylamine (364 mL, 2.09 mol) was added to a solution of compound (A8) (512 g, 1.74 mol) in chloroform (1.74 L), and the mixture was ice-cooled. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 60 minutes, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and 1M aqueous sodium hydroxide solution (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with 1M aqueous sodium hydroxide solution (1.5 L) and water (1.5 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation under reduced pressure (0.93 to 1.5 hpa, 122 ° C. to 137 ° C.) to obtain a pale yellow oily compound (A9) (548 g, 96%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.84 Hz, 6 H) 3.28 (sept, J = 6.84 Hz, 1 H) 3.52 (s, 3 H) 5.23 (s, 2 H ) 7.06 (s, 1 H) 7.69 (s, 1 H).
MS ESI / APCI Dual posi: 339 [M + H] + , 341 [M + 2 + H] + .

(11)参考例1−11 中間体(A)
化合物(A9)(210g,0.621mol)のTHF(3.1L)溶液に、アルゴン雰囲気下−86〜−74℃にて2.76M n−ブチルリチウムへキサン溶液(236mL,0.652mol)を20分かけて滴下し、同温にて35分間攪拌した。次いで2,3,4,6−テトラ−O−トリメチルシリル−D−グルコノ−1,5−ラクトン(305g,0.652mol)のTHF(890mL)溶液を同温にて38分かけて滴下し、同温にて50分間攪拌した。さらにトリメチルクロロシラン(82.8mL,0.652mmol)を4分かけて滴下し、同温にて3時間撹拌した。次いで2.76M n−ブチルリチウムへキサン溶液(326mL,0.901mol)を23分かけて滴下し、同温にて40分間攪拌した。最後に4−ブロモ−2−メチルベンズアルデヒド(136g,0.683mmol)のTHF(890mL)溶液を43分かけて滴下し、同温にて35分間撹拌した。反応液に水(3.1L)を加えて室温まで温めた。トルエン(3.1L)を加えて有機層を分離し、溶媒を減圧下留去した。
(11) Reference Example 1-11 Intermediate (A)
To a THF (3.1 L) solution of the compound (A9) (210 g, 0.621 mol), a 2.76 M n-butyllithium hexane solution (236 mL, 0.652 mol) was added at −86 to −74 ° C. in an argon atmosphere. The solution was added dropwise over 20 minutes and stirred at the same temperature for 35 minutes. Then, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (305 g, 0.652 mol) in THF (890 mL) was added dropwise at the same temperature over 38 minutes. Stir at temperature for 50 minutes. Further, trimethylchlorosilane (82.8 mL, 0.652 mmol) was added dropwise over 4 minutes, and the mixture was stirred at the same temperature for 3 hours. Subsequently, 2.76M n-butyllithium hexane solution (326 mL, 0.901 mol) was added dropwise over 23 minutes, and the mixture was stirred at the same temperature for 40 minutes. Finally, a solution of 4-bromo-2-methylbenzaldehyde (136 g, 0.683 mmol) in THF (890 mL) was added dropwise over 43 minutes and stirred at the same temperature for 35 minutes. Water (3.1 L) was added to the reaction solution and warmed to room temperature. Toluene (3.1 L) was added to separate the organic layer, and the solvent was distilled off under reduced pressure.

得られた残渣(633g)をメタノール(3.1L)に溶解し、メタンスルホン酸(4.03mL,0.0621mol)を加えて1時間加熱還流を行った。反応液を室温まで冷却後、トリエチルアミン(17.3mL,0.124mol)で中和し、反応混合物を濃縮した。濃縮物(413g)をトルエン(1.1L)に溶解し、水(1.65L)で3回洗浄した。その有機層に1M水酸化ナトリウム水溶液(0.55L)とトルエン(0.55L)を加えて抽出操作を行い、水層を分離した。その水層をトルエン(1.65L)で洗浄した。水層に2M塩酸(0.43L)とトルエン(1.1L)を加えて抽出し、有機層を分離した。その有機層を10%塩化ナトリウム水溶液(1.1L)で洗浄し、溶媒を減圧下留去した。   The obtained residue (633 g) was dissolved in methanol (3.1 L), methanesulfonic acid (4.03 mL, 0.0621 mol) was added, and the mixture was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, neutralized with triethylamine (17.3 mL, 0.124 mol), and the reaction mixture was concentrated. The concentrate (413 g) was dissolved in toluene (1.1 L) and washed 3 times with water (1.65 L). A 1M aqueous sodium hydroxide solution (0.55 L) and toluene (0.55 L) were added to the organic layer to perform extraction, and the aqueous layer was separated. The aqueous layer was washed with toluene (1.65 L). The aqueous layer was extracted with 2M hydrochloric acid (0.43 L) and toluene (1.1 L), and the organic layer was separated. The organic layer was washed with a 10% aqueous sodium chloride solution (1.1 L), and the solvent was distilled off under reduced pressure.

得られた残渣(273g)をTHF(1.01L)に溶解し、N、N−ジイソプロピルエチルアミン(776mL,4.53mol)、無水酢酸(381mL,4.03mol)と4−ジメチルアミノピリジン(615mg,5.04mmol)を加え、室温で21時間攪拌した。反応液を氷冷して水(1.0L)とトルエン(1.0L)を加え、有機層を分離した。その有機層を飽和炭酸水素ナトリウム水溶液(1.0L)で洗浄し、溶媒を減圧下留去した。
得られた残渣(390g)をアセトニトリル(3.85L)に溶解し、水(9.07mL,0.504mol)、t−BuMeSiH(334mL,2.02mmol)を加え、氷冷後TMSOTf(392mL,2.17mmol)を30分かけて滴下した。同温で1時間撹拌後、無水酢酸(95.2mL,1.01mol)を10分かけて滴下し、さらに同温で15分間撹拌した。反応液にトルエン(3.85L)と3%炭酸水素ナトリウム水溶液(1.92L)を加え、有機層を分離した。その有機層を3%炭酸水素ナトリウム水溶液(1.92L)、10%塩化ナトリウム水溶液(1.92L)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し得られた残渣を2−プロパノール(1.42L)から結晶化し、析出した沈殿をろ過して無色粉末の中間体(A)(201g,47%;4工程)を得た。
The obtained residue (273 g) was dissolved in THF (1.01 L), and N, N-diisopropylethylamine (776 mL, 4.53 mol), acetic anhydride (381 mL, 4.03 mol) and 4-dimethylaminopyridine (615 mg, 5.04 mmol) was added, and the mixture was stirred at room temperature for 21 hours. The reaction solution was ice-cooled, water (1.0 L) and toluene (1.0 L) were added, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (1.0 L), and the solvent was distilled off under reduced pressure.
The obtained residue (390 g) was dissolved in acetonitrile (3.85 L), water (9.07 mL, 0.504 mol), t-BuMe 2 SiH (334 mL, 2.02 mmol) were added, and after ice cooling, TMSOTf (392 mL). , 2.17 mmol) was added dropwise over 30 minutes. After stirring at the same temperature for 1 hour, acetic anhydride (95.2 mL, 1.01 mol) was added dropwise over 10 minutes, and the mixture was further stirred at the same temperature for 15 minutes. Toluene (3.85 L) and 3% aqueous sodium hydrogen carbonate solution (1.92 L) were added to the reaction solution, and the organic layer was separated. The organic layer was washed with 3% aqueous sodium hydrogen carbonate solution (1.92 L), 10% aqueous sodium chloride solution (1.92 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from 2-propanol (1.42 L). The deposited precipitate was filtered to obtain colorless powder of intermediate (A) (201 g, 47 %; 4 steps).

参考例2 中間体(B)の製造   Reference Example 2 Production of Intermediate (B)

Figure 0005817317
(1)参考例2−1 化合物(B1)
Figure 0005817317
(1) Reference Example 2-1 Compound (B1)

Figure 0005817317
Figure 0005817317

化合物(A1)(27.4g,0.104mol)と炭酸カリウム(21.7g,0.156mol)のアセトニトリル懸濁液(200mL)にヨウ化メチル(9.8mL,0.156mol)を加え40℃で2.5時間攪拌した。ヨウ化メチル(3.5mL,0.052mol)を更に加え、同温で1時間攪拌した。不溶物をろ過し、ろ液を酢酸エチルで希釈した。有機層を水、10%チオ硫酸ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン→ヘキサン:酢酸エチル=95:5)にて精製し、淡黄色油状の化合物(B1)(24.5g,85%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (d, J=6.84 Hz, 6 H) 2.87 (sept, J=6.84 Hz, 1 H) 3.88 (s, 3 H) 6.58 - 6.65 (m, 1 H) 6.70 (d, J=1.87 Hz, 1 H) 7.65 (d, J=8.08 Hz, 1 H).
MS ESI/APCI Dual posi : 277[M+H]+.
(2)参考例2−2 化合物(B2)
Methyl iodide (9.8 mL, 0.156 mol) was added to an acetonitrile suspension (200 mL) of compound (A1) (27.4 g, 0.104 mol) and potassium carbonate (21.7 g, 0.156 mol) at 40 ° C. For 2.5 hours. Methyl iodide (3.5 mL, 0.052 mol) was further added, and the mixture was stirred at the same temperature for 1 hour. Insoluble matter was filtered off, and the filtrate was diluted with ethyl acetate. The organic layer was washed with water, 10% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 95: 5) to obtain a light yellow oily compound (B1) (24.5 g, 85%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (d, J = 6.84 Hz, 6 H) 2.87 (sept, J = 6.84 Hz, 1 H) 3.88 (s, 3 H) 6.58-6.65 (m, 1 H) 6.70 (d, J = 1.87 Hz, 1 H) 7.65 (d, J = 8.08 Hz, 1 H).
MS ESI / APCI Dual posi: 277 [M + H] + .
(2) Reference Example 2-2 Compound (B2)

Figure 0005817317
Figure 0005817317

化合物(B1)(24.5g,88.6mmol)のTHF(100mL)溶液に窒素雰囲気下、−78℃にて2.6M n−ブチルリチウムへキサン溶液(34mL,88.6mmol)を滴下し、同温にて5分間攪拌した。次いで2,3,4,6−テトラ−O−トリメチルシリル−D−グルコノ−1,5−ラクトン(37.6g,80.5mmol)のTHF(60mL)溶液を25分かけて滴下し、同温にて10分間攪拌した。反応液に氷と水を加え、混合物を室温まで温めた後に、酢酸エチルで抽出した。合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。   To a THF (100 mL) solution of the compound (B1) (24.5 g, 88.6 mmol), a 2.6 M n-butyllithium hexane solution (34 mL, 88.6 mmol) was added dropwise at −78 ° C. in a nitrogen atmosphere. Stir at the same temperature for 5 minutes. Next, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (37.6 g, 80.5 mmol) in THF (60 mL) was added dropwise over 25 minutes to the same temperature. And stirred for 10 minutes. Ice and water were added to the reaction mixture, and the mixture was warmed to room temperature and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure.

得られた残渣をメタンスルホン酸(1.55g,16.1mmol)を含むメタノール(380mL)溶液に溶解し、室温で2時間攪拌した。トリエチルアミン(11.2mL,80.5mmol)で中和し、反応混合物を濃縮した。   The obtained residue was dissolved in a methanol (380 mL) solution containing methanesulfonic acid (1.55 g, 16.1 mmol) and stirred at room temperature for 2 hours. Neutralized with triethylamine (11.2 mL, 80.5 mmol) and the reaction mixture was concentrated.

得られた残渣(30.2g)をピリジン(100mL)に溶解し、無水酢酸(100mL)を加え、室温で14時間攪拌した。氷水(400mL)を加え、混合物を酢酸エチル(200mL)で2回抽出した。合わせた有機層を1M塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン→ヘキサン:酢酸エチル=6:4)にて精製し、淡黄色油状の化合物(B2)(32.8g,80%;3工程)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J=6.92 Hz, 6 H) 1.84 (s, 3 H) 1.97 (s, 3 H) 2.06 (s, 3 H) 2.10 (s, 3 H) 2.87 (sept, J=6.92 Hz, 1 H) 3.32 (s, 3 H) 3.87 (s, 3 H) 4.04 (ddd, J=10.18, 4.74, 2.41 Hz, 1 H) 4.17 - 4.23 (m, 1 H) 4.28 - 4.36 (m, 1 H) 5.25 (dd, J=10.18, 9.40 Hz, 1 H) 5.36 (d, J=10.18 Hz, 1 H) 5.60 (dd, J=10.18, 9.40 Hz, 1 H) 6.74 (d, J=1.55 Hz, 1 H) 6.79 (dd, J=8.08, 1.55 Hz, 1 H) 7.26 - 7.33 (m, 1 H).
MS ESI/APCI Dual posi : 533[M+Na]+.
(3)参考例2−3 化合物(B3)
The obtained residue (30.2 g) was dissolved in pyridine (100 mL), acetic anhydride (100 mL) was added, and the mixture was stirred at room temperature for 14 hours. Ice water (400 mL) was added and the mixture was extracted twice with ethyl acetate (200 mL). The combined organic layers were washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 6: 4) to give a pale yellow oily compound (B2) (32 8 g, 80%; 3 steps).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.92 Hz, 6 H) 1.84 (s, 3 H) 1.97 (s, 3 H) 2.06 (s, 3 H) 2.10 (s, 3 H) 2.87 (sept, J = 6.92 Hz, 1 H) 3.32 (s, 3 H) 3.87 (s, 3 H) 4.04 (ddd, J = 10.18, 4.74, 2.41 Hz, 1 H) 4.17-4.23 (m , 1 H) 4.28-4.36 (m, 1 H) 5.25 (dd, J = 10.18, 9.40 Hz, 1 H) 5.36 (d, J = 10.18 Hz, 1 H) 5.60 (dd, J = 10.18, 9.40 Hz, 1 H) 6.74 (d, J = 1.55 Hz, 1 H) 6.79 (dd, J = 8.08, 1.55 Hz, 1 H) 7.26-7.33 (m, 1 H).
MS ESI / APCI Dual posi: 533 [M + Na] + .
(3) Reference Example 2-3 Compound (B3)

Figure 0005817317
Figure 0005817317

化合物(B2)(32.8g,64.0mmol)のクロロホルム(150mL)とアセトニトリル(150mL)溶液に、窒素雰囲気下4℃にてEt3SiH(21mL,128mmol)とBF3・Et2O(49mL,385mmol)を加え、同温で1時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=2:1)にて精製し、淡黄色ガム状の化合物(B3)(22.9g,74%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J=6.99 Hz, 6 H) 1.77 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.07 (s, 3 H) 2.87 (sept, J=6.96 Hz, 1 H) 3.80 - 3.87 (m, 1 H) 3.84 (s, 3 H) 4.09 - 4.16 (m, 1 H) 4.22 - 4.29 (m, 1 H) 4.88 - 4.95 (m, 1 H) 5.18 - 5.27 (m, 1 H) 5.32 - 5.38 (m, 2 H) 6.71 (d, J=1.55 Hz, 1 H) 6.83 (dd, J=7.93, 1.55 Hz, 1 H) 7.23 - 7.30 (m, 1 H).
MS ESI/APCI Dual posi : 503[M+H]+.
MS ESI/APCI Dual nega : 515[M+Cl].
(4)参考例2−4 化合物(B4)
A solution of compound (B2) (32.8 g, 64.0 mmol) in chloroform (150 mL) and acetonitrile (150 mL) was added Et 3 SiH (21 mL, 128 mmol) and BF 3 .Et 2 O (49 mL) at 4 ° C. under a nitrogen atmosphere. , 385 mmol), and stirred at the same temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give a pale yellow gum-like compound (B3) (22 0.9 g, 74%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.99 Hz, 6 H) 1.77 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.07 (s, 3 H) 2.87 (sept, J = 6.96 Hz, 1 H) 3.80-3.87 (m, 1 H) 3.84 (s, 3 H) 4.09-4.16 (m, 1 H) 4.22-4.29 (m, 1 H) 4.88 -4.95 (m, 1 H) 5.18-5.27 (m, 1 H) 5.32-5.38 (m, 2 H) 6.71 (d, J = 1.55 Hz, 1 H) 6.83 (dd, J = 7.93, 1.55 Hz, 1 H) 7.23-7.30 (m, 1 H).
MS ESI / APCI Dual posi: 503 [M + H] + .
MS ESI / APCI Dual nega: 515 [M + Cl] .
(4) Reference Example 2-4 Compound (B4)

Figure 0005817317
Figure 0005817317

化合物(A4)の代わりに化合物(B3)を用いて、参考例1−5と同様の方法で淡黄色アモルファスの化合物(B4)(25.5g,96%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J=6.84 Hz, 3 H) 1.23 (d, J=6.84 Hz, 3 H) 1.80 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.09 (s, 3 H) 3.31 (sept, J=6.84 Hz, 1 H) 3.77 - 3.82 (m, 1 H) 3.83 (s, 3 H) 4.10 - 4.17 (m, 1 H) 4.22 - 4.30 (m, 1 H) 4.83 (d, J=9.48 Hz, 1 H) 5.17 - 5.38 (m, 3 H) 6.75 (s, 1 H) 7.49 (s, 1 H).
MS ESI/APCI Dual posi : 581[M+Na]+, 583[M+2+Na]+.
(5)参考例2−5 化合物(B5)
A pale yellow amorphous compound (B4) (25.5 g, 96%) was obtained in the same manner as in Reference Example 1-5 using compound (B3) instead of compound (A4).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J = 6.84 Hz, 3 H) 1.23 (d, J = 6.84 Hz, 3 H) 1.80 (s, 3 H) 2.01 (s, 3 H ) 2.05 (s, 3 H) 2.09 (s, 3 H) 3.31 (sept, J = 6.84 Hz, 1 H) 3.77-3.82 (m, 1 H) 3.83 (s, 3 H) 4.10-4.17 (m, 1 H) 4.22-4.30 (m, 1 H) 4.83 (d, J = 9.48 Hz, 1 H) 5.17-5.38 (m, 3 H) 6.75 (s, 1 H) 7.49 (s, 1 H).
MS ESI / APCI Dual posi: 581 [M + Na] + , 583 [M + 2 + Na] + .
(5) Reference Example 2-5 Compound (B5)

Figure 0005817317
Figure 0005817317

化合物(A5)の代わりに化合物(B4)を用いて、参考例1−6と同様の方法で茶色油状の化合物(B5)(30.3g)を得た。これを精製せずに次の反応に用いた。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.32 (s, 9 H) 0.09 (s, 9 H) 0.18 (s, 9 H) 0.20 (s, 9 H) 1.19 (d, J=6.84 Hz, 3 H) 1.23 (d, J=6.84 Hz, 3 H) 3.26 - 3.44 (m, 3 H) 3.52 - 3.58 (m, 2 H) 3.65 - 3.75 (m, 3 H) 3.76 - 3.83 (m, 1 H) 3.80 (s, 3 H) 4.60 (d, J=8.55 Hz, 1 H) 6.72 (s, 1 H) 7.51 (s, 1 H).
MS ESI/APCI Dual posi : 701[M+Na]+, 703[M+2+Na]+.
(6)参考例2−6 化合物(B6)
Using a compound (B4) instead of the compound (A5), a brown oily compound (B5) (30.3 g) was obtained in the same manner as in Reference Example 1-6. This was used in the next reaction without purification.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm -0.32 (s, 9 H) 0.09 (s, 9 H) 0.18 (s, 9 H) 0.20 (s, 9 H) 1.19 (d, J = 6.84 Hz , 3 H) 1.23 (d, J = 6.84 Hz, 3 H) 3.26-3.44 (m, 3 H) 3.52-3.58 (m, 2 H) 3.65-3.75 (m, 3 H) 3.76-3.83 (m, 1 H) 3.80 (s, 3 H) 4.60 (d, J = 8.55 Hz, 1 H) 6.72 (s, 1 H) 7.51 (s, 1 H).
MS ESI / APCI Dual posi: 701 [M + Na] + , 703 [M + 2 + Na] + .
(6) Reference Example 2-6 Compound (B6)

Figure 0005817317
Figure 0005817317

化合物(A6)の代わりに化合物(B5)を用いて、参考例1−7と同様の方法で茶色アモルファスの化合物(B6)(14.7g,60%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 and 1.25 (each d, J=6.84 Hz, 6 H) 1.80 (s, 2 H) 2.27 and 2.29 (each s, 3 H) 2.30 - 2.58 (m, 2 H) 2.82 - 3.06 (m, 2 H) 3.34 and 3.35 (each s, 3 H) 3.38 - 3.86 (m, 6 H) 4.56 - 4.73 (m, 1 H) 5.53 (d, J=3.11 Hz, 1 H) 6.75 - 7.35 (m, 5 H).
MS ESI/APCI Dual posi : 493[M-OH]+, 495[M+2-OH]+
(7)参考例2−7 中間体(B)
Using the compound (B5) instead of the compound (A6), a brown amorphous compound (B6) (14.7 g, 60%) was obtained in the same manner as in Reference Example 1-7.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.23 and 1.25 (each d, J = 6.84 Hz, 6 H) 1.80 (s, 2 H) 2.27 and 2.29 (each s, 3 H) 2.30-2.58 (m , 2 H) 2.82-3.06 (m, 2 H) 3.34 and 3.35 (each s, 3 H) 3.38-3.86 (m, 6 H) 4.56-4.73 (m, 1 H) 5.53 (d, J = 3.11 Hz, 1 H) 6.75-7.35 (m, 5 H).
MS ESI / APCI Dual posi: 493 [M-OH] + , 495 [M + 2-OH] +
(7) Reference Example 2-7 Intermediate (B)

Figure 0005817317
Figure 0005817317

化合物(A7)の代わりに化合物(B6)を用いて、参考例1−8と同様の方法で無色アモルファスの中間体(B)(14.2g,88%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J=6.68 Hz, 3 H) 1.14 (d, J=6.68 Hz, 3 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.90 (sept, J=6.68 Hz, 1 H) 3.71 - 3.90 (m, 3 H) 3.86 (s, 3H) 3.85 - 3.87 (m, 1 H) 4.05 - 4.15 (m, 1 H) 4.19 - 4.28 (m, 1 H) 4.77 - 4.85 (m, 1 H) 5.11 - 5.23 (m, 1 H) 5.26 - 5.37 (m, 2 H) 6.54 (d, J=8.24 Hz, 1 H) 6.81 (s, 1 H) 6.96 (s, 1 H) 7.17 (dd, J=8.24, 2.64 Hz, 1 H) 7.32 (d, J=2.64 Hz, 1 H).
MS ESI/APCI Dual posi : 685[M+Na]+, 687[M+2+Na]+
参考例3 中間体(C)の製造
Using the compound (B6) instead of the compound (A7), a colorless amorphous intermediate (B) (14.2 g, 88%) was obtained in the same manner as in Reference Example 1-8.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.68 Hz, 3 H) 1.14 (d, J = 6.68 Hz, 3 H) 1.75 (s, 3 H) 1.99 (s, 3 H ) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.90 (sept, J = 6.68 Hz, 1 H) 3.71-3.90 (m, 3 H) 3.86 (s, 3H) 3.85 -3.87 (m, 1 H) 4.05-4.15 (m, 1 H) 4.19-4.28 (m, 1 H) 4.77-4.85 (m, 1 H) 5.11-5.23 (m, 1 H) 5.26-5.37 (m, 2 H) 6.54 (d, J = 8.24 Hz, 1 H) 6.81 (s, 1 H) 6.96 (s, 1 H) 7.17 (dd, J = 8.24, 2.64 Hz, 1 H) 7.32 (d, J = 2.64 Hz, 1 H).
MS ESI / APCI Dual posi: 685 [M + Na] + , 687 [M + 2 + Na] + .
Reference Example 3 Production of Intermediate (C)

Figure 0005817317
Figure 0005817317

4−ブロモ−2−メチルベンズアルデヒドの代わりに4−ブロモベンズアルデヒドを用いて、参考例1−7および参考例1−8と同様の方法で淡黄色アモルファスとして化合物(C)(2.26g)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J=6.84 Hz, 3 H) 1.09 (d, J=6.84 Hz, 3 H) 1.76 (s, 3 H) 2.01 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.91 - 3.06 (m, 1 H) 3.80 - 3.88 (m, 4 H) 3.91 (d, J=5.13 Hz, 2 H) 4.06 - 4.18 (m, 1 H) 4.20 - 4.31 (m, 1 H) 4.82 - 4.93 (m, 1 H) 5.15 - 5.43 (m, 3 H) 6.77 (s, 1 H) 6.92 (d, J=8.55 Hz, 2 H) 7.11 (s, 1 H) 7.36 (d, J=8.55 Hz, 2 H).
MS ESI/APCI Dual posi : 671[M+Na]+, 683[M+2+Na]+
参考例4 中間体(D)の製造
Using 4-bromobenzaldehyde instead of 4-bromo-2-methylbenzaldehyde, Compound (C) (2.26 g) was obtained as a pale yellow amorphous product in the same manner as in Reference Examples 1-7 and 1-8. It was.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 (d, J = 6.84 Hz, 3 H) 1.09 (d, J = 6.84 Hz, 3 H) 1.76 (s, 3 H) 2.01 (s, 3 H ) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.91-3.06 (m, 1 H) 3.80-3.88 (m, 4 H) 3.91 (d, J = 5.13 Hz, 2 H) 4.06-4.18 (m , 1 H) 4.20-4.31 (m, 1 H) 4.82-4.93 (m, 1 H) 5.15-5.43 (m, 3 H) 6.77 (s, 1 H) 6.92 (d, J = 8.55 Hz, 2 H) 7.11 (s, 1 H) 7.36 (d, J = 8.55 Hz, 2 H).
MS ESI / APCI Dual posi: 671 [M + Na] + , 683 [M + 2 + Na] +
Reference Example 4 Production of intermediate (D)

Figure 0005817317
(1)参考例4−1 化合物(D1)
Figure 0005817317
(1) Reference Example 4-1 Compound (D1)

Figure 0005817317
Figure 0005817317

2,2−ジメチル−3−ブテノイックアシッド(J. Org. Chem., 第65巻, 8402頁,2000年)(5.42g,47.5mmol)のクロロホルム(250mL)溶液に窒素雰囲気下、塩化オキサリル(4.43mL,49.9mmol)とN,N−ジメチルホルムアミド(3滴)を加え、室温で1.5時間攪拌した。その後反応液を氷冷し、トリエチルアミン(19.9mL,143mmol)とα−アミノイソブチリックアシッドメチルエステル塩酸塩(10.9g,71.2mmol)を加え、室温で1時間攪拌した。反応液に水を加え、クロロホルムで抽出後、有機層を3M塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン→ヘキサン:酢酸エチル=4:1)にて精製し、無色粉末の化合物(D1)(9.38g,93%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17 - 5.32 (m, 2 H) 6.02 (dd, J=17.56, 10.57 Hz, 1 H) 6.25 (br. s., 1 H).
MS ESI/APCI Dual posi : 214[M+H]+.
(2)参考例4−2 中間体(D)
A solution of 2,2-dimethyl-3-butenoic acid (J. Org. Chem., 65, 8402, 2000) (5.42 g, 47.5 mmol) in chloroform (250 mL) under a nitrogen atmosphere, Oxalyl chloride (4.43 mL, 49.9 mmol) and N, N-dimethylformamide (3 drops) were added, and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was ice-cooled, triethylamine (19.9 mL, 143 mmol) and α-aminoisobutyric acid methyl ester hydrochloride (10.9 g, 71.2 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 3M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4: 1) to give compound (D1) (9 .38 g, 93%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17-5.32 (m, 2 H) 6.02 (dd, J = 17.56 , 10.57 Hz, 1 H) 6.25 (br. S., 1 H).
MS ESI / APCI Dual posi: 214 [M + H] + .
(2) Reference Example 4-2 Intermediate (D)

Figure 0005817317
Figure 0005817317

化合物(D1)(9.38g,43.9mmol)のメタノール(20mL)溶液に4M水酸化ナトリウム水溶液(16.5mL,66.0mmol)を加え、室温で1時間攪拌した。その後、反応混合物を濃縮した。得られた残渣を水に溶解し、3M塩酸を加えて中和した。この混合物を酢酸エチルで抽出し、合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、無色粉末の中間体(D)(8.19g,94%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16 - 5.36 (m, 2 H) 6.01 (dd, J=17.49, 10.65 Hz, 1 H) 6.14 (s, 1 H).
MS ESI/APCI Dual posi : 200[M+H]+, 222[M+Na]+.
MS ESI/APCI Dual nega : 198[M-H].
参考例5 中間体(E)の製造
To a solution of compound (D1) (9.38 g, 43.9 mmol) in methanol (20 mL) was added 4M aqueous sodium hydroxide solution (16.5 mL, 66.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated. The obtained residue was dissolved in water and neutralized by adding 3M hydrochloric acid. This mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain colorless powder intermediate (D) (8.19 g, 94%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16-5.36 (m, 2 H) 6.01 (dd, J = 17.49, 10.65 Hz, 1 H) 6.14 (s, 1 H).
MS ESI / APCI Dual posi: 200 [M + H] + , 222 [M + Na] + .
MS ESI / APCI Dual nega: 198 [MH] .
Reference Example 5 Production of intermediate (E)

Figure 0005817317
Figure 0005817317

アルゴン雰囲気下、中間体(A)(5.0g,7.23mmol)、中間体(D)(2.59g,13.0mmol)、酢酸パラジウム(II)(328mg,1.45mmol)、トリ-o-トリルホスフィン(880mg,2.89mmol)、トリエチルアミン(3.0mL,9.00mmol)のアセトニトリル(24mL)懸濁液を、マイクロウェーブ照射下120℃で20分間攪拌した。反応液をセライトろ過し、酢酸エチルで洗浄した。ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1→酢酸エチル)にて精製し、淡黄色粉末の中間体(E)(4.59g,78%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J=6.84 Hz, 3 H) 1.40 (s, 6 H) 1.54 - 1.58 (m, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.98 - 3.10 (m, 1 H) 3.71 - 3.79 (m, 1 H) 3.94 (s, 2 H) 4.01 - 4.08 (m, 1 H) 4.24 (dd, J=12.43, 4.51 Hz, 1 H) 4.47 (d, J=9.17 Hz, 1 H) 5.07 - 5.32 (m, 3 H) 6.31 (d, J=16.32 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J=16.32 Hz, 1 H) 6.77 (d, J=7.62 Hz, 1 H) 6.92 (s, 1 H) 6.99 (s, 1 H) 7.12 - 7.18 (m, 1 H) 7.26 (s, 1 H) .
MS ESI/APCI Dual posi : 810[M+H]+, 832[M+Na]+ .
MS ESI/APCI Dual nega : 808[M−H].
参考例6 中間体(F)の製造
Under an argon atmosphere, intermediate (A) (5.0 g, 7.23 mmol), intermediate (D) (2.59 g, 13.0 mmol), palladium (II) acetate (328 mg, 1.45 mmol), tri-o -A suspension of tolylphosphine (880 mg, 2.89 mmol) and triethylamine (3.0 mL, 9.00 mmol) in acetonitrile (24 mL) was stirred at 120 ° C for 20 minutes under microwave irradiation. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain a pale yellow powder intermediate (E) (4.59 g, 78 %).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J = 6.84 Hz, 3 H) 1.40 (s, 6 H) 1.54-1.58 (m, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.98-3.10 (m, 1 H) 3.71-3.79 (m, 1 H) 3.94 (s, 2 H) 4.01-4.08 (m, 1 H) 4.24 (dd, J = 12.43, 4.51 Hz, 1 H) 4.47 (d, J = 9.17 Hz, 1 H) 5.07-5.32 (m , 3 H) 6.31 (d, J = 16.32 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J = 16.32 Hz, 1 H) 6.77 (d, J = 7.62 Hz, 1 H) 6.92 (s , 1 H) 6.99 (s, 1 H) 7.12-7.18 (m, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 810 [M + H] + , 832 [M + Na] + .
MS ESI / APCI Dual nega: 808 [M−H] .
Reference Example 6 Production of intermediate (F)

Figure 0005817317
Figure 0005817317

アルゴン雰囲気下、中間体(B)(2.0g,3.0mmol)、中間体(D)(1.08g,5.4mmol)、酢酸パラジウム(II)(136mg,0.6mmol)、トリ-o-トリルホスフィン(370mg,1.2mmol)、トリエチルアミン(1.26mL,9.0mmol)のアセトニトリル(10mL)懸濁液を、マイクロウェーブ照射下120℃で20分間攪拌した。反応液をセライトろ過し、酢酸エチルで洗浄した。ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=1:1→酢酸エチル)にて精製し、淡黄色粉末の中間体(F)(2.03g,87%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.17 (each d, J=6.99 Hz, 3 H) 1.38 (s, 6 H) 1.55 (s, 6 H) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.94 - 3.03 (m, 1 H) 3.76 - 3.83 (m, 1 H) 3.84 - 3.95 (m, 4 H) 4.06 - 4.15 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.81 (d, J=9.79 Hz, 1 H) 5.12 - 5.20 (m, 1 H) 5.23 - 5.35 (m, 2 H) 6.29 (s, 1H) 6.31 (d, J=16.32 Hz, 1 H) 6.52 (d, J=16.32 Hz, 1 H) 6.67 (d, J=8.08 Hz, 1 H) 6.81 (s, 1 H) 6.94 (s, 1 H) 7.06 - 7.14 (m, 1 H) 7.24 (s, 1 H).
MS ESI/APCI Dual posi : 782[M+H]+, 804[M+Na]+ .
MS ESI/APCI Dual nega : 780[M-H].
参考例7 中間体(G)の製造
Under an argon atmosphere, intermediate (B) (2.0 g, 3.0 mmol), intermediate (D) (1.08 g, 5.4 mmol), palladium (II) acetate (136 mg, 0.6 mmol), tri-o -A suspension of tolylphosphine (370 mg, 1.2 mmol) and triethylamine (1.26 mL, 9.0 mmol) in acetonitrile (10 mL) was stirred at 120 ° C for 20 minutes under microwave irradiation. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to obtain a pale yellow powder intermediate (F) (2.03 g, 87 %).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.17 (each d, J = 6.99 Hz, 3 H) 1.38 (s, 6 H) 1.55 (s, 6 H) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.94-3.03 (m, 1 H) 3.76-3.83 (m, 1 H) 3.84-3.95 (m, 4 H) 4.06-4.15 (m, 1 H) 4.16-4.25 (m, 1 H) 4.81 (d, J = 9.79 Hz, 1 H) 5.12-5.20 (m, 1 H) 5.23-5.35 (m, 2 H) 6.29 (s, 1H ) 6.31 (d, J = 16.32 Hz, 1 H) 6.52 (d, J = 16.32 Hz, 1 H) 6.67 (d, J = 8.08 Hz, 1 H) 6.81 (s, 1 H) 6.94 (s, 1 H ) 7.06-7.14 (m, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 782 [M + H] + , 804 [M + Na] + .
MS ESI / APCI Dual nega: 780 [MH] .
Reference Example 7 Production of intermediate (G)

Figure 0005817317
Figure 0005817317

中間体(A)の代わりに中間体(C)を用いて参考例5と同様の方法で淡黄色アモルファスの中間体(G)(854mg,60%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08 (d, J=6.84 Hz, 3 H) 1.12 (d, J=6.84 Hz, 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 6 H) 3.06 (sept, J=6.84 Hz, 1 H) 3.78 - 3.83 (m, 1 H) 3.84 (s, 3 H) 3.97 (s, 2 H) 4.07 - 4.18 (m, 1 H) 4.17 - 4.27 (m, 1 H) 4.87 (dd, J=6.76, 2.88 Hz, 1 H) 5.16 - 5.25 (m, 1 H) 5.27 - 5.40 (m, 2 H) 6.18 - 6.33 (m, 2 H) 6.54 (d, J=16.48 Hz, 1 H) 6.77 (s, 1 H) 7.03 (d, J=8.08 Hz, 2 H) 7.10 (s, 1 H) 7.29 (d, J=8.08 Hz, 2 H).
MS ESI/APCI Dual posi : 768[M+H]+, 790[M+Na]+.
MS ESI/APCI Dual nega : 766[M-H].
参考例8 中間体(H)の製造
A light yellow amorphous intermediate (G) (854 mg, 60%) was obtained in the same manner as in Reference Example 5 using the intermediate (C) instead of the intermediate (A).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08 (d, J = 6.84 Hz, 3 H) 1.12 (d, J = 6.84 Hz, 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H ) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 6 H) 3.06 (sept, J = 6.84 Hz, 1 H) 3.78-3.83 (m, 1 H) 3.84 (s, 3 H) 3.97 (s, 2 H) 4.07-4.18 (m, 1 H) 4.17-4.27 (m, 1 H) 4.87 (dd, J = 6.76, 2.88 Hz, 1 H) 5.16-5.25 (m, 1 H) 5.27- 5.40 (m, 2 H) 6.18-6.33 (m, 2 H) 6.54 (d, J = 16.48 Hz, 1 H) 6.77 (s, 1 H) 7.03 (d, J = 8.08 Hz, 2 H) 7.10 (s , 1 H) 7.29 (d, J = 8.08 Hz, 2 H).
MS ESI / APCI Dual posi: 768 [M + H] + , 790 [M + Na] + .
MS ESI / APCI Dual nega: 766 [MH] .
Reference Example 8 Production of intermediate (H)

Figure 0005817317
Figure 0005817317

アルゴン雰囲気下、中間体(A)(216g,0.312mol)、2,2−ジメチル−3−ブテノイックアシッド(53.4g,0.467mol)、酢酸パラジウム(II)(3.50g,15.6mmol)、トリ-o-トリルホスフィン(9.48g,31.2mmol)、トリエチルアミン(86.9mL,0.623mol)のアセトニトリル(623mL)懸濁液を、3時間加熱還流した。反応液を室温まで冷却した後にクロロホルム(300mL)とメタノール(100mL)を加えて希釈し、セライトろ過した。ろ液を減圧下濃縮し、得られた残渣を酢酸エチル(1.32L)に溶解させた。1M塩酸(0.96L)、10%塩化ナトリウム水溶液(1.2L)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、ろ液にさらに酢酸エチル(1.2L)を追加して、イソプロピルアミン(28.2mL,0.327mol)を加え、室温から0℃にかけて1時間撹拌した。析出した沈殿をろ過して中間体(H)のイソプロピルアミン塩を得た。この塩を酢酸エチル(1.2L)、1M塩酸(500mL)に溶解させて30分間撹拌し、有機層を分離した。その有機層を10%塩化ナトリウム水溶液(500mL)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して無色のアモルファスとして中間体(H)(207g,88%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.80 Hz, 3 H) 1.14 (d, J=6.80 Hz, 3 H) 1.43 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.37 (s, 3 H) 2.98 (sept, J=6.80 Hz, 1 H) 3.70 - 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J=12.43, 2.18 Hz, 1 H) 4.28 (dd, J=12.43, 4.35 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 5.11 - 5.20 (m, 1 H) 5.22 - 5.33 (m, 2 H) 6.33 - 6.49 (m, 2 H) 6.68 (d, J=7.93 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s, 1 H) 7.06 - 7.14 (m, 1 H) 7.23 (d, J=1.40 Hz, 1 H).
MS ESI/APCI Dual posi : 747[M+Na]+.
参考例9 中間体(I)の製造
Under an argon atmosphere, intermediate (A) (216 g, 0.312 mol), 2,2-dimethyl-3-butenoic acid (53.4 g, 0.467 mol), palladium (II) acetate (3.50 g, 15 .6 mmol), tri-o-tolylphosphine (9.48 g, 31.2 mmol) and triethylamine (86.9 mL, 0.623 mol) in acetonitrile (623 mL) were heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with chloroform (300 mL) and methanol (100 mL), and filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (1.32 L). It was washed with 1M hydrochloric acid (0.96 L), 10% aqueous sodium chloride solution (1.2 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, ethyl acetate (1.2 L) was further added to the filtrate, isopropylamine (28.2 mL, 0.327 mol) was added, and the mixture was stirred from room temperature to 0 ° C. for 1 hour. The deposited precipitate was filtered to obtain an isopropylamine salt of intermediate (H). This salt was dissolved in ethyl acetate (1.2 L) and 1 M hydrochloric acid (500 mL) and stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with 10% aqueous sodium chloride solution (500 mL) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain Intermediate (H) (207 g, 88%) as a colorless amorphous substance.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.80 Hz, 3 H) 1.14 (d, J = 6.80 Hz, 3 H) 1.43 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.37 (s, 3 H) 2.98 (sept, J = 6.80 Hz, 1 H) 3.70- 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J = 12.43, 2.18 Hz, 1 H) 4.28 (dd, J = 12.43, 4.35 Hz, 1 H) 4.43-4.50 (m, 1 H ) 5.11-5.20 (m, 1 H) 5.22-5.33 (m, 2 H) 6.33-6.49 (m, 2 H) 6.68 (d, J = 7.93 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s , 1 H) 7.06-7.14 (m, 1 H) 7.23 (d, J = 1.40 Hz, 1 H).
MS ESI / APCI Dual posi: 747 [M + Na] + .
Reference Example 9 Production of Intermediate (I)

Figure 0005817317
Figure 0005817317

2−アミノイソ酪酸(150g,1.45mol)を水(2.2L)に溶解し、炭酸ナトリウム(465g,4.39mol)を加えた。反応液を氷冷し、クロロギ酸ベンジル(227mL,1.60mol)の1,4−ジオキサン(0.63L)溶液を内温が10℃を超えないように45分かけて滴下した。室温で一晩撹拌後、反応液に水(3.5L)とトルエン(1.0L)を加え、水層を分離した。その水層にpH=1になるまで濃塩酸(700mL)を滴下した。酢酸エチル(1.0L)を加えて1時間撹拌し、有機層を分離した。その有機層を無水硫酸マグネシウムで乾燥して乾燥剤を濾別後、溶媒を減圧下留去した。   2-Aminoisobutyric acid (150 g, 1.45 mol) was dissolved in water (2.2 L) and sodium carbonate (465 g, 4.39 mol) was added. The reaction solution was ice-cooled, and a 1,4-dioxane (0.63 L) solution of benzyl chloroformate (227 mL, 1.60 mol) was added dropwise over 45 minutes so that the internal temperature did not exceed 10 ° C. After stirring overnight at room temperature, water (3.5 L) and toluene (1.0 L) were added to the reaction solution, and the aqueous layer was separated. Concentrated hydrochloric acid (700 mL) was added dropwise to the aqueous layer until pH = 1. Ethyl acetate (1.0 L) was added and stirred for 1 hour, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure.

得られた残渣(338g)をクロロホルム(1.7L)に溶解し、氷冷下N,N’−カルボニルジイミダゾール(253g,1.56mol)を内温が20℃を超えないように少量ずつ加えた。室温で30分間撹拌後、再度氷冷して1,2−ジアミノ−2−メチルプロパン(138g,1.56mol)を25分かけて滴下した。室温で1晩撹拌後、10%炭酸カリウム水溶液(1.7L)を加え、有機層を分離した。その有機層を無水硫酸マグネシウムで乾燥して乾燥剤を濾別後、溶媒を減圧下留去した。   The obtained residue (338 g) was dissolved in chloroform (1.7 L), and N, N′-carbonyldiimidazole (253 g, 1.56 mol) was added little by little so that the internal temperature did not exceed 20 ° C. under ice cooling. It was. After stirring at room temperature for 30 minutes, the mixture was ice-cooled again and 1,2-diamino-2-methylpropane (138 g, 1.56 mol) was added dropwise over 25 minutes. After stirring at room temperature overnight, 10% aqueous potassium carbonate solution (1.7 L) was added, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure.

得られた残渣(417g)をTHF(2.0L)に溶解し、BocO(355g,1.63mol)を加えて、室温で1.5時間撹拌した。その後反応液に飽和炭酸水素ナトリウム水溶液(1.0L)を加え、有機層を分離した。その有機層を無水硫酸マグネシウムで乾燥して乾燥剤を濾別後、溶媒を減圧下留去した。 The obtained residue (417 g) was dissolved in THF (2.0 L), Boc 2 O (355 g, 1.63 mol) was added, and the mixture was stirred at room temperature for 1.5 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (1.0 L) was added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was evaporated under reduced pressure.

得られた残渣(549g)をメタノール(2.75L)に溶解し、10%水酸化パラジウム(27.5g)を加え、水素雰囲気下室温にて4.5時間攪拌した。反応液をセライト濾過後、溶媒を減圧下留去し、得られた残渣をヘプタン:酢酸エチル=2/1混合液(1.75L)から結晶化し、析出した沈殿をろ過して無色粉末の中間体(I)(193g,53%;4工程)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.37 (s, 6 H) 1.43 (s, 9 H) 1.53 (br. s, 2 H) 3.39 (d, J=6.53 Hz, 2 H) 4.78 (br. s, 1 H) 8.04 (br. s, 1 H).
MS ESI/APCI Dual posi : 274[M+H]+, 296[M+Na]+.
MS ESI/APCI Dual nega : 308[M+Cl].
実施例1−1
The obtained residue (549 g) was dissolved in methanol (2.75 L), 10% palladium hydroxide (27.5 g) was added, and the mixture was stirred at room temperature in a hydrogen atmosphere for 4.5 hours. After the reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from a heptane: ethyl acetate = 2/1 mixture (1.75 L), and the deposited precipitate was filtered to obtain an intermediate of colorless powder. Body (I) (193 g, 53%; 4 steps) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.37 (s, 6 H) 1.43 (s, 9 H) 1.53 (br. S, 2 H) 3.39 (d, J = 6.53 Hz, 2 H) 4.78 (br.s, 1 H) 8.04 (br.s, 1 H).
MS ESI / APCI Dual posi: 274 [M + H] + , 296 [M + Na] + .
MS ESI / APCI Dual nega: 308 [M + Cl] .
Example 1-1

Figure 0005817317
Figure 0005817317

中間体(E)(200mg,0.25mmol)、1−ヒドロキシベンゾトリアゾ−ル1水和物(HOBt・HO)(57mg,0.37mmol)、N,N−ジメチルエチレンジアミン(65mg,0.74mmol)のN,N−ジメチルホルムアミド(3.0mL)溶液にN−エチル−N’−3−ジメチルアミノプロピルカルボジイミド塩酸塩(EDC−HCl)(71mg,0.37mmol)を加え、室温で8時間攪拌した。反応液を水(50mL)にあけ、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール=9:1)で精製し、無色アモルファスの化合物(1−1)(132mg,61%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13, 1.15 (each d, J=6.92Hz, each 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.23 (s, 6 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.41 (t, J=5.67 Hz, 2 H) 2.90 - 3.03 (m, 1 H) 3.25 - 3.34 (m, 2 H) 3.71 - 3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J=12.59, 2.18 Hz, 1 H) 4.23 - 4.32 (m, 1 H) 4.44 - 4.52 (m, 1 H) 5.11 - 5.20 (m, 1 H) 5.22 - 5.33 (m, 2 H) 6.33 (d, J=16.63 Hz, 1 H) 6.41 (br. s., 1 H) 6.51 (d, J=16.63 Hz, 1 H) 6.68 (d, J=7.77 Hz, 1 H) 6.77 (br. s., 1 H) 7.00 (s, 2 H) 7.12 (d, J=7.77 Hz, 1 H) 7.26 (s, 1 H).
MS ESI/APCI Dual posi : 880[M+H]+, 902[M+Na]+.
MS ESI/APCI Dual nega : 914[M+Cl].
実施例1−2
Intermediate (E) (200 mg, 0.25 mmol), 1-hydroxybenzotriazole monohydrate (HOBt.H 2 O) (57 mg, 0.37 mmol), N, N-dimethylethylenediamine (65 mg, 0 .74 mmol) in N, N-dimethylformamide (3.0 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride (EDC-HCl) (71 mg, 0.37 mmol). Stir for hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 9: 1) to obtain a colorless amorphous compound (1-1) (132 mg, 61%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13, 1.15 (each d, J = 6.92Hz, each 3 H) 1.38 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.23 (s, 6 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.41 (t, J = 5.67 Hz , 2 H) 2.90-3.03 (m, 1 H) 3.25-3.34 (m, 2 H) 3.71-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.59, 2.18 Hz, 1 H) 4.23-4.32 (m, 1 H) 4.44-4.52 (m, 1 H) 5.11-5.20 (m, 1 H) 5.22-5.33 (m, 2 H) 6.33 (d, J = 16.63 Hz, 1 H) 6.41 (br. S., 1 H) 6.51 (d, J = 16.63 Hz, 1 H) 6.68 (d, J = 7.77 Hz, 1 H) 6.77 (br. S., 1 H) 7.00 (s, 2 H ) 7.12 (d, J = 7.77 Hz, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 880 [M + H] + , 902 [M + Na] + .
MS ESI / APCI Dual nega: 914 [M + Cl] .
Example 1-2

Figure 0005817317
Figure 0005817317

化合物(1−1)(127mg,0.14mmol)のメタノール(2.0mL)溶液にナトリウムメトキシド(4.88M / MeOH,10μL)を加え、室温で1時間攪拌した。ドライアイスを少量加えて、反応液を中和し、溶媒を減圧下留去した。   Sodium methoxide (4.88 M / MeOH, 10 μL) was added to a methanol (2.0 mL) solution of the compound (1-1) (127 mg, 0.14 mmol), and the mixture was stirred at room temperature for 1 hour. A small amount of dry ice was added to neutralize the reaction solution, and the solvent was distilled off under reduced pressure.

得られた残渣をNH型シリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=9:1→6:4)で精製し、無色アモルファスの化合物(1−2)(77mg,80%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.92 Hz, 6 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.23 (s, 6 H) 2.31 (s, 3 H) 2.40 (t, J=6.88 Hz, 2 H) 2.87 - 2.96 (m, 1 H) 3.28 (t, J=6.88 Hz, 2 H) 3.34 - 3.41 (m, 2 H) 3.43 - 3.50 (m, 1 H) 3.51 - 3.57 (m, 1 H) 3.67 (dd, J=12.15, 2.52 Hz, 1 H) 3.84 (d, J=11.46 Hz, 1 H) 3.89 (s, 2 H) 4.47 (d, J=9.63 Hz, 1 H) 6.39 (d, J=16.05 Hz, 1 H) 6.50 (d, J=16.05 Hz, 1 H) 6.75 (d, J=8.25 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.11 (d, J=8.25 Hz, 1 H) 7.25 (s, 1 H) .
MS ESI/APCI Dual posi : 670[M+H]+.
MS ESI/APCI Dual nega : 668[M-H], 704[M+Cl].
Anal. Calcd for C37H55N3O8・1.4H2O: C, 63.94; H,8.38; N,6.05. Found: C, 64.13; H, 8.39; N, 5.88.
実施例2−1
The obtained residue was purified by NH-type silica gel column chromatography (chloroform: methanol = 9: 1 → 6: 4) to obtain a colorless amorphous compound (1-2) (77 mg, 80%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.92 Hz, 6 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.23 (s, 6 H) 2.31 (s , 3 H) 2.40 (t, J = 6.88 Hz, 2 H) 2.87-2.96 (m, 1 H) 3.28 (t, J = 6.88 Hz, 2 H) 3.34-3.41 (m, 2 H) 3.43-3.50 ( m, 1 H) 3.51-3.57 (m, 1 H) 3.67 (dd, J = 12.15, 2.52 Hz, 1 H) 3.84 (d, J = 11.46 Hz, 1 H) 3.89 (s, 2 H) 4.47 (d , J = 9.63 Hz, 1 H) 6.39 (d, J = 16.05 Hz, 1 H) 6.50 (d, J = 16.05 Hz, 1 H) 6.75 (d, J = 8.25 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.11 (d, J = 8.25 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] + .
MS ESI / APCI Dual nega: 668 [MH] , 704 [M + Cl] .
Anal. Calcd for C 37 H 55 N 3 O 8 · 1.4H 2 O: C, 63.94; H, 8.38; N, 6.05. Found: C, 64.13; H, 8.39; N, 5.88.
Example 2-1

Figure 0005817317
Figure 0005817317

N,N−ジメチルエチレンジアミンの代わりにピペラジンを用いて実施例1−1と同様の方法で無色アモルファスの化合物(2−1)(103mg,47%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.16 (each d, J=6.99 Hz, each 3 H) 1.38 (s, 6 H) 1.61 (s, 6 H) 1.71 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.27 (s, 3 H) 2.79 - 2.87 (m, 4 H) 2.87 - 2.99 (m, 1 H) 3.56 - 3.66 (m, 4 H) 3.75 - 3.94 (m, 3 H) 4.12 - 4.20 (m, 1 H) 4.25 - 4.34 (m, 1 H) 4.44 - 4.52 (m, 1 H) 5.23 - 5.32 (m, 3 H) 6.30 (d, J=16.32 Hz, 1 H) 6.48 (d, J=16.32 Hz, 1 H) 6.53 (s, 1 H) 6.68 (d, J=7.77 Hz, 1 H) 6.88 (s, 1 H) 6.97 (s, 1 H) 7.05 - 7.12 (m, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 836[M+H]+, 858[M+Na]+.
MS ESI/APCI Dual nega : 834[M-H], 870[M+Cl].
実施例2−2
A colorless amorphous compound (2-1) (103 mg, 47%) was obtained in the same manner as in Example 1-1 using piperazine instead of N, N-dimethylethylenediamine.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.16 (each d, J = 6.99 Hz, each 3 H) 1.38 (s, 6 H) 1.61 (s, 6 H) 1.71 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.27 (s, 3 H) 2.79-2.87 (m, 4 H) 2.87-2.99 (m, 1 H) 3.56-3.66 ( m, 4 H) 3.75-3.94 (m, 3 H) 4.12-4.20 (m, 1 H) 4.25-4.34 (m, 1 H) 4.44-4.52 (m, 1 H) 5.23-5.32 (m, 3 H) 6.30 (d, J = 16.32 Hz, 1 H) 6.48 (d, J = 16.32 Hz, 1 H) 6.53 (s, 1 H) 6.68 (d, J = 7.77 Hz, 1 H) 6.88 (s, 1 H) 6.97 (s, 1 H) 7.05-7.12 (m, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 836 [M + H] + , 858 [M + Na] + .
MS ESI / APCI Dual nega: 834 [MH] , 870 [M + Cl] .
Example 2-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(2−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(2−2)(52mg,66%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.42 Hz, 6 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.31 (s, 3 H) 2.70 (br. s, 4 H) 2.90 - 2.95 (m, 1 H) 3.36 - 3.39 (m, 2 H) 3.43 - 3.61 (m, 7 H) 3.65 - 3.69 (m, 1 H) 3.84 (d, J=11.92 Hz, 1 H) 3.88 (s, 2 H) 4.46 (d, J=9.63 Hz, 1 H) 6.38 (d, J=16.05 Hz, 1 H) 6.47 (d, J=16.05 Hz, 1 H) 6.76 (d, J=7.79 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.10 (d, J=7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 668[M+H]+, 690[M+Na]+.
MS ESI/APCI Dual nega : 664[M-H], 702[M+Cl].
実施例3−1
A colorless amorphous compound (2-2) (52 mg, 66%) was obtained in the same manner as in Example 1-2 using the compound (2-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.42 Hz, 6 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.31 (s, 3 H) 2.70 (br s, 4 H) 2.90-2.95 (m, 1 H) 3.36-3.39 (m, 2 H) 3.43-3.61 (m, 7 H) 3.65-3.69 (m, 1 H) 3.84 (d, J = 11.92 Hz , 1 H) 3.88 (s, 2 H) 4.46 (d, J = 9.63 Hz, 1 H) 6.38 (d, J = 16.05 Hz, 1 H) 6.47 (d, J = 16.05 Hz, 1 H) 6.76 (d , J = 7.79 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.10 (d, J = 7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 668 [M + H] + , 690 [M + Na] + .
MS ESI / APCI Dual nega: 664 [MH] , 702 [M + Cl] .
Example 3-1

Figure 0005817317
Figure 0005817317

N,N−ジメチルエチレンジアミンの代わりに1−メチルピペラジンを用いて実施例1−1と同様の方法で無色アモルファスの化合物(3−1)(135mg,61%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13, 1.15 (each d, J=6.84 Hz, each 3 H) 1.37 (s, 6 H) 1.60 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 3 H) 2.30 (s, 3 H) 2.33 - 2.41 (m, 7 H) 2.88 - 3.04 (m, 1 H) 3.60 - 3.70 (m, 4 H) 3.72 - 3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J=12.59, 2.33 Hz, 1 H) 4.27 (dd, J=12.59, 4.51 Hz, 1 H) 4.43 - 4.54 (m, 1 H) 5.10 - 5.20 (m, 1 H) 5.22 - 5.32 (m, 2 H) 6.31 (d, J=16.48 Hz, 1 H) 6.49 (d, J=16.48 Hz, 1 H) 6.68 (d, J=8.08 Hz, 1 H) 6.86 (s, 1 H) 7.00 (s, 2 H) 7.08 - 7.14 (m, 1 H) 7.24 (s, 1 H).
MS ESI/APCI Dual posi : 892[M+H]+, 914[M+Na]+ .
MS ESI/APCI Dual nega : 926[M+Cl].
実施例3−2
A colorless amorphous compound (3-1) (135 mg, 61%) was obtained in the same manner as in Example 1-1 using 1-methylpiperazine instead of N, N-dimethylethylenediamine.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.37 (s, 6 H) 1.60 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 3 H) 2.30 (s, 3 H) 2.33-2.41 (m, 7 H) 2.88-3.04 (m, 1 H) 3.60-3.70 (m, 4 H) 3.72-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.59, 2.33 Hz, 1 H) 4.27 (dd, J = 12.59, 4.51 Hz, 1 H) 4.43-4.54 (m, 1 H) 5.10-5.20 (m, 1 H) 5.22-5.32 (m, 2 H) 6.31 (d, J = 16.48 Hz, 1 H) 6.49 (d, J = 16.48 Hz, 1 H) 6.68 (d, J = 8.08 Hz, 1 H) 6.86 (s, 1 H) 7.00 (s, 2 H) 7.08-7.14 (m, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 892 [M + H] + , 914 [M + Na] + .
MS ESI / APCI Dual nega: 926 [M + Cl] .
Example 3-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(3−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(3−2)(79mg,79%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.10 (d, J=6.88 Hz, 6 H) 1.37 (s, 6 H) 1.44 (s, 6 H) 2.16 (s, 3 H) 2.22 - 2.38 (m, 7 H) 2.87 - 2.96 (m, 1 H) 3.35 - 3.41 (m, 2 H) 3.42 - 3.51 (m, 2 H) 3.51 - 3.56 (m, 1 H) 3.56 - 3.71 (m, 5 H) 3.84 (d, J=12.38 Hz, 1 H) 3.88 (s, 2 H) 4.47 (d, J=9.63 Hz, 1 H) 6.38 (d, J=16.51 Hz, 1 H) 6.46 (d, J=16.51 Hz, 1 H) 6.75 (d, J=8.25 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.09 (d, J=8.25 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 682[M+H]+, 704[M+Na]+.
MS ESI/APCI Dual nega : 680[M-H], 716[M+Cl].
実施例4−1
A colorless amorphous compound (3-2) (79 mg, 79%) was obtained in the same manner as in Example 1-2 using the compound (3-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.10 (d, J = 6.88 Hz, 6 H) 1.37 (s, 6 H) 1.44 (s, 6 H) 2.16 (s, 3 H) 2.22-2.38 (m, 7 H) 2.87-2.96 (m, 1 H) 3.35-3.41 (m, 2 H) 3.42-3.51 (m, 2 H) 3.51-3.56 (m, 1 H) 3.56-3.71 (m, 5 H ) 3.84 (d, J = 12.38 Hz, 1 H) 3.88 (s, 2 H) 4.47 (d, J = 9.63 Hz, 1 H) 6.38 (d, J = 16.51 Hz, 1 H) 6.46 (d, J = 16.51 Hz, 1 H) 6.75 (d, J = 8.25 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.09 (d, J = 8.25 Hz, 1 H) 7.22 (s, 1 H ).
MS ESI / APCI Dual posi: 682 [M + H] + , 704 [M + Na] + .
MS ESI / APCI Dual nega: 680 [MH] , 716 [M + Cl] .
Example 4-1

Figure 0005817317
Figure 0005817317

N,N−ジメチルエチレンジアミンの代わりに1−エチルピペラジンを用いて実施例1−1と同様の方法で無色ガム状の化合物(4−1A)(87.9mg,38%)と無色ガム状の化合物(4−1B)(42.9mg,19%)を得た。   A colorless gum compound (4-1A) (87.9 mg, 38%) and a colorless gum compound in the same manner as in Example 1-1 using 1-ethylpiperazine instead of N, N-dimethylethylenediamine (4-1B) (42.9 mg, 19%) was obtained.

化合物(4−1A)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 (t, J=7.23 Hz, 3 H) 1.12 - 1.16 (m, 6 H) 1.37 (s, 6 H) 1.61 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.34 - 2.44 (m, 9 H) 2.90 - 3.05 (m, 1 H) 3.60 - 3.72 (m, 4 H) 3.72 - 3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J=12.36, 1.94 Hz, 1 H) 4.27 (dd, J=12.36, 4.43 Hz, 1 H) 4.48 (d, J=9.79 Hz, 1 H) 5.15 (t, J=9.79 Hz, 1 H) 5.22 - 5.31 (m, 2 H) 6.31 (d, J=16.2 Hz, 1 H) 6.49 (d, J=16.2 Hz, 1 H) 6.68 (d, J=8.08 Hz, 1 H) 6.86 - 6.93 (m, 1 H) 7.00 (s, 2 H) 7.11 (d, J=8.08 Hz, 1 H) 7.24 (s, 1 H).
MS ESI/APCI Dual posi : 907[M+H]+, 929[M+Na]+.
MS ESI/APCI Dual nega : 941[M+Cl].
Compound (4-1A)
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 (t, J = 7.23 Hz, 3 H) 1.12-1.16 (m, 6 H) 1.37 (s, 6 H) 1.61 (s, 6 H) 1.77 ( s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.34-2.44 (m, 9 H) 2.90-3.05 (m, 1 H ) 3.60-3.72 (m, 4 H) 3.72-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.36, 1.94 Hz, 1 H) 4.27 (dd, J = 12.36, 4.43 Hz , 1 H) 4.48 (d, J = 9.79 Hz, 1 H) 5.15 (t, J = 9.79 Hz, 1 H) 5.22-5.31 (m, 2 H) 6.31 (d, J = 16.2 Hz, 1 H) 6.49 (d, J = 16.2 Hz, 1 H) 6.68 (d, J = 8.08 Hz, 1 H) 6.86-6.93 (m, 1 H) 7.00 (s, 2 H) 7.11 (d, J = 8.08 Hz, 1 H ) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 907 [M + H] + , 929 [M + Na] + .
MS ESI / APCI Dual nega: 941 [M + Cl] .

化合物(4−1B)
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03 - 1.19 (m, 9 H) 1.37 (s, 6 H) 1.62 (s, 6 H) 1.71 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.27 (s, 3 H) 2.33 - 2.46 (m, 6 H) 2.93 (sept, J=6.76 Hz, 1 H) 3.58 - 3.71 (m, 4 H) 3.73 - 3.91 (m, 3 H) 4.12 - 4.21 (m, 1 H) 4.24 - 4.34 (m, 1 H) 4.48 (d, J=9.17 Hz, 1 H) 5.21 - 5.34 (m, 3 H) 6.30 (d, J=16.1 Hz, 1 H) 6.48 (d, J=16.1 Hz, 1 H) 6.53 (s, 1 H) 6.68 (d, J=7.93 Hz, 1 H) 6.88 (s, 1 H) 6.99 (s, 1 H) 7.08 (d, J=7.93 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 865[M+H]+, 887[M+Na]+.
MS ESI/APCI Dual nega : 899[M+Cl].
実施例4−2
Compound (4-1B)
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.03-1.19 (m, 9 H) 1.37 (s, 6 H) 1.62 (s, 6 H) 1.71 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.27 (s, 3 H) 2.33-2.46 (m, 6 H) 2.93 (sept, J = 6.76 Hz, 1 H) 3.58-3.71 (m, 4 H ) 3.73-3.91 (m, 3 H) 4.12-4.21 (m, 1 H) 4.24-4.34 (m, 1 H) 4.48 (d, J = 9.17 Hz, 1 H) 5.21-5.34 (m, 3 H) 6.30 (d, J = 16.1 Hz, 1 H) 6.48 (d, J = 16.1 Hz, 1 H) 6.53 (s, 1 H) 6.68 (d, J = 7.93 Hz, 1 H) 6.88 (s, 1 H) 6.99 (s, 1 H) 7.08 (d, J = 7.93 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 865 [M + H] + , 887 [M + Na] + .
MS ESI / APCI Dual nega: 899 [M + Cl] .
Example 4-2

Figure 0005817317
Figure 0005817317

化合物(4−1A)(87.9mg,0.0973mmol)と化合物(4−1B)(42.9mg,0.0486mmol)にトリエチルアミン/水/メタノール(1/1/5,5mL)を加えた。反応混合物を室温で1晩攪拌し、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール=8:2)で精製し、無色アモルファスの化合物(4−2)(79.2mg,78%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 0.98 (t, J=7.23 Hz, 3 H) 1.10 (d, J=6.88 Hz, 6 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23 - 2.42 (m, 9 H) 2.85 - 2.99 (m, 1 H) 3.35 - 3.41 (m, 2 H) 3.42 - 3.48 (m, 1 H) 3.50 - 3.56 (m, 1 H) 3.55 - 3.71 (m, 5 H) 3.81 - 3.90 (m, 3 H) 4.47 (d, J=9.63 Hz, 1 H) 6.39 (d, J=16.1 Hz, 1 H) 6.46 (d, J=16.1 Hz, 1 H) 6.71 - 6.77 (m, 1 H) 6.80 (s, 1 H) 6.98 (s, 1 H) 7.09 (d, J=7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 696[M+H]+, 718[M+Na]+.
MS ESI/APCI Dual nega : 694[M-H].
Anal. Calcd for C39H57N3O8・1.2H2O : C, 65.3; H, 8.34; N, 5.86. Found : C, 65.3; H, 8.36; N, 5.68.
実施例5−1
Triethylamine / water / methanol (1/1/5, 5 mL) was added to the compound (4-1A) (87.9 mg, 0.0973 mmol) and the compound (4-1B) (42.9 mg, 0.0486 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 8: 2) to obtain a colorless amorphous compound (4-2) (79.2 mg, 78%).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 0.98 (t, J = 7.23 Hz, 3 H) 1.10 (d, J = 6.88 Hz, 6 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23-2.42 (m, 9 H) 2.85-2.99 (m, 1 H) 3.35-3.41 (m, 2 H) 3.42-3.48 (m, 1 H) 3.50-3.56 (m, 1 H) 3.55-3.71 (m, 5 H) 3.81-3.90 (m, 3 H) 4.47 (d, J = 9.63 Hz, 1 H) 6.39 (d, J = 16.1 Hz, 1 H) 6.46 (d, J = 16.1 Hz, 1 H ) 6.71-6.77 (m, 1 H) 6.80 (s, 1 H) 6.98 (s, 1 H) 7.09 (d, J = 7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 696 [M + H] + , 718 [M + Na] + .
MS ESI / APCI Dual nega: 694 [MH] .
Anal. Calcd for C 39 H 57 N 3 O 8・ 1.2H 2 O: C, 65.3; H, 8.34; N, 5.86. Found: C, 65.3; H, 8.36; N, 5.68.
Example 5-1

Figure 0005817317
Figure 0005817317

中間体(E)(205mg,0.253mmol)、HOBt・HO(68mg,0.506mmol)、4−ジメチルアミノピペリジン(65mg,0.506mmol)のN,N−ジメチルホルムアミド(2.0mL)溶液にEDC−HCl(97mg,0.506mmol)を加え、70℃で2時間攪拌した。反応液を水(50mL)にあけ、酢酸エチル(50mL)で抽出した。有機層を飽和食塩水(20mL)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール=3:1)で精製し、無色アモルファスの化合物(5−1)(80mg,34%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.76 Hz, 3 H) 1.15 (d, J=6.76 Hz, 3 H) 1.30 - 1.49 (m, 2 H) 1.38 (s, 6 H) 1.61 (s, 6 H) 1.77 (s, 3 H) 1.84 (d, J=12.75 Hz, 2 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 6 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.81 (t, J=12.28 Hz, 2 H) 2.97 (sept, J=6.76 Hz, 1 H) 3.76 (ddd, J=10.03, 4.66, 2.25 Hz, 1 H) 3.92 (s, 2 H) 4.05 (dd, J=12.43, 2.25 Hz, 1 H) 4.28 (dd, J=12.43, 4.66 Hz, 1 H) 4.33 - 4.53 (m, 3 H) 5.10 - 5.34 (m, 3 H) 6.31 (d, J=15.00 Hz, 1 H) 6.50 (d, J=15.00 Hz, 1 H) 6.68 (d, J=8.08 Hz, 1 H) 6.97 - 7.04 (m, 2 H) 7.11 (d, J=8.08 Hz, 1 H) 7.25 (s, 1 H).
MS ESI/APCI Dual posi : 920[M+H]+
MS ESI/APCI Dual nega : 954[M+Cl]
実施例5−2
Intermediate (E) (205 mg, 0.253 mmol), HOBt · H 2 O (68 mg, 0.506 mmol), 4-dimethylaminopiperidine (65 mg, 0.506 mmol) in N, N-dimethylformamide (2.0 mL) To the solution, EDC-HCl (97 mg, 0.506 mmol) was added and stirred at 70 ° C. for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 3: 1) to obtain a colorless amorphous compound (5-1) (80 mg, 34%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.76 Hz, 3 H) 1.15 (d, J = 6.76 Hz, 3 H) 1.30-1.49 (m, 2 H) 1.38 (s, 6 H) 1.61 (s, 6 H) 1.77 (s, 3 H) 1.84 (d, J = 12.75 Hz, 2 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 6 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.81 (t, J = 12.28 Hz, 2 H) 2.97 (sept, J = 6.76 Hz, 1 H) 3.76 (ddd, J = 10.03, 4.66, 2.25 Hz, 1 H) 3.92 (s, 2 H) 4.05 (dd, J = 12.43, 2.25 Hz, 1 H) 4.28 (dd, J = 12.43, 4.66 Hz, 1 H) 4.33-4.53 ( m, 3 H) 5.10-5.34 (m, 3 H) 6.31 (d, J = 15.00 Hz, 1 H) 6.50 (d, J = 15.00 Hz, 1 H) 6.68 (d, J = 8.08 Hz, 1 H) 6.97-7.04 (m, 2 H) 7.11 (d, J = 8.08 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 920 [M + H] + .
MS ESI / APCI Dual nega: 954 [M + Cl] .
Example 5-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(5−1)を用いて、実施例1−2と同様の方法で、無色アモルファスの化合物(5−2)(33mg,53%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.08 (d, J=6.42 Hz, 6 H) 1.21 - 1.32 (m, 2 H) 1.35 (s, 6 H) 1.43 (s, 6 H) 1.73 (br. s., 2 H) 2.16 (s, 6 H) 2.28 (s, 3H) 2.28 - 2.37 (m, 1 H) 2.89 (sept, J=6.42 Hz, 1 H) 3.31 - 3.33 (m, 2 H) 3.44 (t, J=8.71 Hz, 1 H) 3.48 - 3.56 (m, 1 H) 3.66 (dd, J=11.92, 2.75 Hz, 1 H) 3.83 (d, J=11.92 Hz, 1 H) 3.86 (s, 2 H) 4.45 (d, J=9.63 Hz, 1 H) 6.35 - 6.41 (m, 1 H) 6.43 - 6.47 (m, 1 H) 6.72 (d, J=7.79 Hz, 1 H) 6.78 (s, 1 H) 6.96 (s, 1 H) 7.08 (d, J=7.79 Hz, 1 H) 7.21 (s, 1 H).
MS ESI/APCI Dual posi : 710[M+H]+
MS ESI/APCI Dual nega : 708[M-H]
Anal. Calcd for C40H59N3O8・1.5H2O : C, 65.19 ; H, 8.50; N, 5.70. Found : C, 64.81; H, 8.46; N, 5.61.
実施例6−1
A colorless amorphous compound (5-2) (33 mg, 53%) was obtained in the same manner as in Example 1-2 except that the compound (5-1) was used instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.08 (d, J = 6.42 Hz, 6 H) 1.21-1.32 (m, 2 H) 1.35 (s, 6 H) 1.43 (s, 6 H) 1.73 (br. s., 2 H) 2.16 (s, 6 H) 2.28 (s, 3H) 2.28-2.37 (m, 1 H) 2.89 (sept, J = 6.42 Hz, 1 H) 3.31-3.33 (m, 2 H) 3.44 (t, J = 8.71 Hz, 1 H) 3.48-3.56 (m, 1 H) 3.66 (dd, J = 11.92, 2.75 Hz, 1 H) 3.83 (d, J = 11.92 Hz, 1 H) 3.86 (s, 2 H) 4.45 (d, J = 9.63 Hz, 1 H) 6.35-6.41 (m, 1 H) 6.43-6.47 (m, 1 H) 6.72 (d, J = 7.79 Hz, 1 H) 6.78 ( s, 1 H) 6.96 (s, 1 H) 7.08 (d, J = 7.79 Hz, 1 H) 7.21 (s, 1 H).
MS ESI / APCI Dual posi: 710 [M + H] + .
MS ESI / APCI Dual nega: 708 [MH] .
Anal.Calcd for C 40 H 59 N 3 O 8・ 1.5H 2 O: C, 65.19; H, 8.50; N, 5.70. Found: C, 64.81; H, 8.46; N, 5.61.
Example 6-1

Figure 0005817317
Figure 0005817317

中間体(E)(680mg,0.746mmol)のクロロホルム(5.0mL)溶液にN,N’−カルボニルジイミダゾール(182mg,1.12mmol)を加え、室温で1時間攪拌した。次いで、1,2−ジアミノ−2−メチルプロパン(79mg,0.895mmol)を加え、室温で18時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで2回抽出した。合わせた有機層を、無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム→クロロホルム:メタノール=85:15)で精製し、無色アモルファスの化合物(6−1)(140mg,21%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 - 1.17 (m, 6 H) 1.11 (s, 6 H) 1.39 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.89 - 3.05 (m, 1 H) 3.14 (d, J=5.91 Hz, 2 H) 3.76 (ddd, J=9.71, 4.51, 2.10 Hz, 1 H) 3.93 (s, 2 H) 4.05 (dd, J=12.51, 2.10 Hz, 1 H) 4.27 (dd, J=12.51, 4.51 Hz, 1 H) 4.49 (d, J=7.46 Hz, 1 H) 5.11 - 5.20 (m, 1 H) 5.23 - 5.31 (m, 2 H) 6.26 (s, 1 H) 6.29 - 6.38 (m, 1 H) 6.48 - 6.57 (m, 1 H) 6.69 (d, J=7.93 Hz, 1 H) 6.97 - 7.03 (m, 3 H) 7.12 (d, J=7.93 Hz, 1 H) 7.25 (s, 1 H).
MS ESI/APCI Dual posi : 880[M+H]+.
実施例6−2
N, N′-carbonyldiimidazole (182 mg, 1.12 mmol) was added to a solution of intermediate (E) (680 mg, 0.746 mmol) in chloroform (5.0 mL), and the mixture was stirred at room temperature for 1 hour. Then, 1,2-diamino-2-methylpropane (79 mg, 0.895 mmol) was added and stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform: methanol = 85: 15) to obtain a colorless amorphous compound (6-1) (140 mg, 21%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.17 (m, 6 H) 1.11 (s, 6 H) 1.39 (s, 6 H) 1.53 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.89-3.05 (m, 1 H) 3.14 (d, J = 5.91 Hz, 2 H) 3.76 (ddd, J = 9.71, 4.51, 2.10 Hz, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.51, 2.10 Hz, 1 H) 4.27 (dd, J = 12.51 , 4.51 Hz, 1 H) 4.49 (d, J = 7.46 Hz, 1 H) 5.11-5.20 (m, 1 H) 5.23-5.31 (m, 2 H) 6.26 (s, 1 H) 6.29-6.38 (m, 1 H) 6.48-6.57 (m, 1 H) 6.69 (d, J = 7.93 Hz, 1 H) 6.97-7.03 (m, 3 H) 7.12 (d, J = 7.93 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 880 [M + H] + .
Example 6-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(6−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(6−2)(104mg,98%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.02 (s, 6 H) 1.05 - 1.10 (m, 6 H) 1.35 (s, 6 H) 1.44 (s, 6 H) 2.29 (s, 3 H) 2.85 - 2.93 (m, 1 H) 3.09 (s, 2 H) 3.34 - 3.39 (m, 2 H) 3.42 - 3.47 (m, 1 H) 3.52 (t, J=9.40 Hz, 1 H) 3.63 - 3.69 (m, 1 H) 3.80 - 3.85 (m, 1 H) 3.86 (s, 2 H) 4.46 (d, J=9.63 Hz, 1 H) 6.35 - 6.41 (m, 1 H) 6.44 - 6.51 (m, 1 H) 6.73 (d, J=7.79 Hz, 1 H) 6.78 (s, 1 H) 6.96 (s, 1 H) 7.06 - 7.10 (m, 1 H) 7.23 (s, 1 H).
MS ESI/APCI Dual posi : 670[M+H]+, 692[M+Na]+.
MS ESI/APCI Dual nega : 668[M-H]-, 704[M+Cl].
A colorless amorphous compound (6-2) (104 mg, 98%) was obtained in the same manner as in Example 1-2 using the compound (6-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.02 (s, 6 H) 1.05-1.10 (m, 6 H) 1.35 (s, 6 H) 1.44 (s, 6 H) 2.29 (s, 3 H ) 2.85-2.93 (m, 1 H) 3.09 (s, 2 H) 3.34-3.39 (m, 2 H) 3.42-3.47 (m, 1 H) 3.52 (t, J = 9.40 Hz, 1 H) 3.63-3.69 (m, 1 H) 3.80-3.85 (m, 1 H) 3.86 (s, 2 H) 4.46 (d, J = 9.63 Hz, 1 H) 6.35-6.41 (m, 1 H) 6.44-6.51 (m, 1 H) 6.73 (d, J = 7.79 Hz, 1 H) 6.78 (s, 1 H) 6.96 (s, 1 H) 7.06-7.10 (m, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] + , 692 [M + Na] + .
MS ESI / APCI Dual nega: 668 [MH] - , 704 [M + Cl] .

また、化合物(6−2)は、次の実施例6−3及び6−4に記載の方法でも合成することができる。
実施例6−3
Compound (6-2) can also be synthesized by the methods described in Examples 6-3 and 6-4 below.
Example 6-3

Figure 0005817317
Figure 0005817317

中間体(H)(205g,0.273mol)、中間体(I)(97.0g,0.355mol)、HOBt・HO(62.7g,0.410mol)、トリエチルアミン(114mL,0.819mol)のN,N−ジメチルホルムアミド(1.98L)溶液にEDC−HCl(78.5g,0.410mol)を加え、室温で11時間攪拌した。反応液にトルエン(1.0L)と10%塩化ナトリウム水溶液(2.0L)を加え、有機層を分離した。水層をトルエン(1.0L)から抽出し、合わせた有機層を5%塩化ナトリウム水溶液(1.0L)で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去した。得られた残渣を2−プロパノール(300mL)に50℃で溶解させ、ヘプタン(2.7L)を滴下した。混合溶液を氷冷で1時間攪拌し、析出した沈殿をろ過して無色粉末の化合物(6−3)(221g,83%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.88 Hz, 3 H) 1.14 (d, J=6.88 Hz, 3 H) 1.26 (s, 6 H) 1.39 (s, 6 H) 1.44 (s, 9 H) 1.55 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.97 (sept, J=6.88 Hz, 1 H) 3.41 (d, J=5.60 Hz, 2 H) 3.72 - 3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd, J=12.43, 2.02 Hz, 1 H) 4.28 (dd, J=12.43, 4.51 Hz, 1 H) 4.45 - 4.52 (m, 1 H) 4.65 (s, 1 H) 5.11 - 5.19 (m, 1 H) 5.22 - 5.33 (m, 2 H) 6.29 - 6.39 (m, 1 H) 6.46 - 6.57 (m, 2 H) 6.69 (d, J=8.00 Hz, 1 H) 6.96 - 7.03 (m, 2 H) 7.11 (dd, J=8.00, 1.63 Hz, 1 H) 7.24 - 7.26 (m, 1 H) 7.59 (br. s, 1 H).
実施例6−4
Intermediate (H) (205 g, 0.273 mol), Intermediate (I) (97.0 g, 0.355 mol), HOBt · H 2 O (62.7 g, 0.410 mol), triethylamine (114 mL, 0.819 mol) ) In N, N-dimethylformamide (1.98 L) was added EDC-HCl (78.5 g, 0.410 mol), and the mixture was stirred at room temperature for 11 hours. Toluene (1.0 L) and 10% aqueous sodium chloride solution (2.0 L) were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted from toluene (1.0 L), and the combined organic layers were washed with 5% aqueous sodium chloride solution (1.0 L) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 2-propanol (300 mL) at 50 ° C., and heptane (2.7 L) was added dropwise. The mixed solution was stirred with ice cooling for 1 hour, and the deposited precipitate was filtered to obtain a colorless powder of compound (6-3) (221 g, 83%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.88 Hz, 3 H) 1.14 (d, J = 6.88 Hz, 3 H) 1.26 (s, 6 H) 1.39 (s, 6 H ) 1.44 (s, 9 H) 1.55 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.97 (sept, J = 6.88 Hz, 1 H) 3.41 (d, J = 5.60 Hz, 2 H) 3.72-3.80 (m, 1 H) 3.92 (s, 2 H) 4.05 (dd , J = 12.43, 2.02 Hz, 1 H) 4.28 (dd, J = 12.43, 4.51 Hz, 1 H) 4.45-4.52 (m, 1 H) 4.65 (s, 1 H) 5.11-5.19 (m, 1 H) 5.22-5.33 (m, 2 H) 6.29-6.39 (m, 1 H) 6.46-6.57 (m, 2 H) 6.69 (d, J = 8.00 Hz, 1 H) 6.96-7.03 (m, 2 H) 7.11 ( dd, J = 8.00, 1.63 Hz, 1 H) 7.24-7.26 (m, 1 H) 7.59 (br. s, 1 H).
Example 6-4

化合物(6−3)(220g,0.225mol)のクロロホルム(3.0L)溶液に、室温でトリフルオロ酢酸(297mL,3.88mol)を10分かけて滴下し、同温にて20時間攪拌した。反応液をトルエン(3.0L)で希釈して濃縮した。濃縮物を酢酸エチル(3.0L)に溶解し、10%炭酸ナトリウム水溶液(1.2L)、飽和食塩水(1.0L)で洗浄し、溶媒を減圧下留去した。   To a chloroform (3.0 L) solution of the compound (6-3) (220 g, 0.225 mol) is added dropwise trifluoroacetic acid (297 mL, 3.88 mol) at room temperature over 10 minutes, followed by stirring at the same temperature for 20 hours. did. The reaction solution was diluted with toluene (3.0 L) and concentrated. The concentrate was dissolved in ethyl acetate (3.0 L), washed with 10% aqueous sodium carbonate solution (1.2 L) and saturated brine (1.0 L), and the solvent was evaporated under reduced pressure.

得られた残渣(240g)をメタノール(1.5L)に溶解し、氷冷後トリエチルアミン(0.3L)、水(0.3L)を加えた。室温で13時間撹拌後、更にメタノール(1.5L)、トリエチルアミン(0.3L)、水(0.3L)を加えて室温で20時間撹拌した。反応混合物を濃縮し、メタノールで共沸した。得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル:エタノール:水=15:2:1→10:2:1)で精製し、無色アモルファスの化合物(6−2)(129g,86%;2工程)を得た。
実施例7−1
The obtained residue (240 g) was dissolved in methanol (1.5 L), and after ice cooling, triethylamine (0.3 L) and water (0.3 L) were added. After stirring at room temperature for 13 hours, methanol (1.5 L), triethylamine (0.3 L) and water (0.3 L) were further added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and azeotroped with methanol. The obtained residue was purified by silica gel column chromatography (ethyl acetate: ethanol: water = 15: 2: 1 → 10: 2: 1), and colorless amorphous compound (6-2) (129 g, 86%; 2 steps) )
Example 7-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)を用いて実施例1−1と同様の方法で無色アモルファスの化合物(7−1)(112mg,74%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J=6.84 Hz, each 3 H) 1.37 (s, 6 H) 1.51 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.23 (s, 6 H) 2.32 (s, 3 H) 2.41 (t, J=6.22 Hz, 2 H) 2.86 - 2.99 (m, 1 H) 3.25 - 3.33 (m, 2 H) 3.76 - 3.90 (m, 6 H) 4.07 - 4.15 (m, 1 H) 4.18 - 4.26 (m, 1 H) 4.76 - 4.85 (m, 1 H) 5.13 - 5.22 (m, 1 H) 5.26 - 5.36 (m, 2 H) 6.31 (d, J=16.48 Hz, 1 H) 6.37 (s, 1 H) 6.50 (d, J=16.48 Hz, 1 H) 6.61 - 6.67 (m, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.06 - 7.12 (m, 1 H) 7.24 (s, 1 H).
MS ESI/APCI Dual posi : 852[M+H]+.
MS ESI/APCI Dual nega : 886[M+Cl].
実施例7−2
A colorless amorphous compound (7-1) (112 mg, 74%) was obtained in the same manner as in Example 1-1 using the intermediate (F) instead of the intermediate (E).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J = 6.84 Hz, each 3 H) 1.37 (s, 6 H) 1.51 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.23 (s, 6 H) 2.32 (s, 3 H) 2.41 (t, J = 6.22 Hz, 2 H) 2.86-2.99 (m, 1 H) 3.25-3.33 (m, 2 H) 3.76-3.90 (m, 6 H) 4.07-4.15 (m, 1 H) 4.18-4.26 (m, 1 H) 4.76-4.85 (m, 1 H ) 5.13-5.22 (m, 1 H) 5.26-5.36 (m, 2 H) 6.31 (d, J = 16.48 Hz, 1 H) 6.37 (s, 1 H) 6.50 (d, J = 16.48 Hz, 1 H) 6.61-6.67 (m, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.06-7.12 (m, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 852 [M + H] + .
MS ESI / APCI Dual nega: 886 [M + Cl] .
Example 7-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(7−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(7−2)(69mg,78%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.13, 1.15 (each d, J=6.84 Hz, each 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.21 (s, 6 H) 2.32 (s, 3 H) 2.39 (t, J=6.88 Hz, 2 H) 2.93 - 3.02 (m, 1 H) 3.24 - 3.39 (m, 4 H) 3.42 - 3.48 (m, 1 H) 3.49 - 3.54 (m, 1 H) 3.58 - 3.65 (m, 1 H) 3.80 - 3.87 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J=9.63 Hz, 1 H) 6.39 (d, J=16.51 Hz, 1 H) 6.50 (d, J=16.51 Hz, 1 H) 6.73 (d, J=7.80 Hz, 1 H) 6.92 (s, 1 H) 7.08 (s, 1 H) 7.10 (d, J=7.80 Hz, 1 H) 7.25 (s, 1 H).
MS ESI/APCI Dual posi : 684[M+H]+.
MS ESI/APCI Dual nega : 682[M-H], 718[M+Cl].
Anal. Calcd for C38H57N3O8・1.7H2O: C, 63.88 ; H, 8.52 , N, 5.88. Found: C, 63.84; H, 8.41; N, 5.75.
実施例8−1
A colorless amorphous compound (7-2) (69 mg, 78%) was obtained in the same manner as in Example 1-2 using the compound (7-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.21 (s, 6 H ) 2.32 (s, 3 H) 2.39 (t, J = 6.88 Hz, 2 H) 2.93-3.02 (m, 1 H) 3.24-3.39 (m, 4 H) 3.42-3.48 (m, 1 H) 3.49-3.54 (m, 1 H) 3.58-3.65 (m, 1 H) 3.80-3.87 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J = 9.63 Hz, 1 H) 6.39 (d, J = 16.51 Hz, 1 H) 6.50 (d, J = 16.51 Hz, 1 H) 6.73 (d, J = 7.80 Hz, 1 H) 6.92 (s, 1 H) 7.08 (s, 1 H) 7.10 (d, J = 7.80 (Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 684 [M + H] + .
MS ESI / APCI Dual nega: 682 [MH] , 718 [M + Cl] .
Anal. Calcd for C 38 H 57 N 3 O 8・ 1.7H 2 O: C, 63.88; H, 8.52, N, 5.88. Found: C, 63.84; H, 8.41; N, 5.75.
Example 8-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)、N,N−ジメチルエチレンジアミンの代わりにN−t−ブトキシカルボニルエチレンジアミンを用いて実施例1−1と同様の方法で無色アモルファスの化合物(8−1)(145mg,89%)を得た。
MS ESI/APCI Dual posi : 924[M+H]+,946[M+Na]+.
MS ESI/APCI Dual nega : 958[M+Cl].
実施例8−2
A colorless amorphous compound (8-) was prepared in the same manner as in Example 1-1 except that intermediate (F) was used instead of intermediate (E), and Nt-butoxycarbonylethylenediamine was used instead of N, N-dimethylethylenediamine. 1) (145 mg, 89%) was obtained.
MS ESI / APCI Dual posi: 924 [M + H] + , 946 [M + Na] + .
MS ESI / APCI Dual nega: 958 [M + Cl] .
Example 8-2

Figure 0005817317
Figure 0005817317

化合物(8−1)のクロロホルム(3.0ml)溶液に、トリフルオロ酢酸(600μL)を加えて室温で3時間攪拌した。反応液を減圧下濃縮後、シリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=95:5→60:40)で精製して、無色アモルファスの化合物(8−2)(68mg、55%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14,1.16 (each d, J=6.37 Hz, each 3 H) 1.32 (br. s., 6 H) 1.42 (s, 6 H) 1.77 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.90 - 3.02 (m, 1 H) 3.22 - 3.34 (m, 2 H) 3.48 - 3.57 (m, 2 H) 3.76 - 3.96 (m, 6 H) 4.07 - 4.14 (m, 1 H) 4.17 - 4.25 (m, 1 H) 4.79 - 4.87 (m, 1 H) 5.12 - 5.22 (m, 1 H) 5.24 - 5.36 (m, 2 H) 6.32 (s, 1 H) 6.40 (d, J=16.63 Hz, 1 H) 6.51 (d, J=16.63 Hz, 1 H) 6.65 (d, J=8.55 Hz, 1 H) 6.82 (s, 1 H) 6.96 (s, 1 H) 7.07 - 7.13 (m, 1 H) 7.28 - 7.31 (m, 1 H) 8.04 (br. s., 2 H).
MS ESI/APCI Dual posi : 824[M+H]+, 846[M+Na]+.
MS ESI/APCI Dual nega : 858[M+Cl].
実施例8−3
Trifluoroacetic acid (600 μL) was added to a chloroform (3.0 ml) solution of the compound (8-1), and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 60: 40) to obtain a colorless amorphous compound (8-2) (68 mg, 55%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14, 1.16 (each d, J = 6.37 Hz, each 3 H) 1.32 (br. S., 6 H) 1.42 (s, 6 H) 1.77 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.90-3.02 (m, 1 H) 3.22-3.34 (m, 2 H) 3.48 -3.57 (m, 2 H) 3.76-3.96 (m, 6 H) 4.07-4.14 (m, 1 H) 4.17-4.25 (m, 1 H) 4.79-4.87 (m, 1 H) 5.12-5.22 (m, 1 H) 5.24-5.36 (m, 2 H) 6.32 (s, 1 H) 6.40 (d, J = 16.63 Hz, 1 H) 6.51 (d, J = 16.63 Hz, 1 H) 6.65 (d, J = 8.55 Hz, 1 H) 6.82 (s, 1 H) 6.96 (s, 1 H) 7.07-7.13 (m, 1 H) 7.28-7.31 (m, 1 H) 8.04 (br. S., 2 H).
MS ESI / APCI Dual posi: 824 [M + H] + , 846 [M + Na] + .
MS ESI / APCI Dual nega: 858 [M + Cl] .
Example 8-3

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(8−2)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(8−3)(22mg,44%)を得た。
1H NMR (600 MHz, METHANOL-d) δ ppm 1.13, 1.15 (each d, J=6.84 Hz, each 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.32 (s, 3 H) 2.63 - 2.71 (m, 2 H) 2.94 - 3.03 (m, 1 H) 3.23 (t, J=5.96 Hz, 2 H) 3.28 - 3.39 (m, 4 H) 3.43 - 3.48 (m, 1 H) 3.48 - 3.54 (m, 1 H) 3.62 (dd, J=12.15, 5.73 Hz, 1 H) 3.79 - 3.88 (m, 2 H) 3.92 (s, 2 H) 4.61 (d, J=9.63 Hz, 1 H) 6.40 (d, J=16.51 Hz, 1 H) 6.50 (d, J=16.51 Hz, 1 H) 6.74 (d, J=7.79 Hz, 1 H) 6.92 (s, 1 H) 7.07 (s, 1 H) 7.11 (d, J=7.79 Hz, 1 H) 7.26 (s, 1 H).
MS ESI/APCI Dual posi : 656[M+H]+.
MS ESI/APCI Dual nega : 654[M-H], 690[M+Cl].
実施例9−1
A colorless amorphous compound (8-3) (22 mg, 44%) was obtained in the same manner as in Example 1-2 using the compound (8-2) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.32 (s, 3 H ) 2.63-2.71 (m, 2 H) 2.94-3.03 (m, 1 H) 3.23 (t, J = 5.96 Hz, 2 H) 3.28-3.39 (m, 4 H) 3.43-3.48 (m, 1 H) 3.48 -3.54 (m, 1 H) 3.62 (dd, J = 12.15, 5.73 Hz, 1 H) 3.79-3.88 (m, 2 H) 3.92 (s, 2 H) 4.61 (d, J = 9.63 Hz, 1 H) 6.40 (d, J = 16.51 Hz, 1 H) 6.50 (d, J = 16.51 Hz, 1 H) 6.74 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.07 (s, 1 H) 7.11 (d, J = 7.79 Hz, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 656 [M + H] + .
MS ESI / APCI Dual nega: 654 [MH] , 690 [M + Cl] .
Example 9-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)、N,N−ジメチルエチレンジアミンの代わりにピペラジンを用いて実施例1−1と同様の方法で無色アモルファスの化合物(9−1)(42mg,38%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J=6.99 Hz, each 3 H) 1.37 (s, 6 H) 1.58 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.79 - 2.86 (m, 4 H) 2.88 - 2.99 (m, 1 H) 3.57 - 3.64 (m, 4 H) 3.76 - 3.95 (m, 6 H) 4.07 - 4.14 (m, 1 H) 4.18 - 4.26 (m, 1 H) 4.77 - 4.84 (m, 1 H) 5.13 - 5.22 (m, 1 H) 5.26 - 5.37 (m, 2 H) 6.29 (d, J=16.16 Hz, 1 H) 6.49 (d, J=16.16 Hz, 1 H) 6.64 (d, J=7.93 Hz, 1 H) 6.77 - 6.83 (m, 2 H) 6.99 (s, 1 H) 7.05 - 7.11 (m, 1 H) 7.22 (br. s., 1 H).
MS ESI/APCI Dual posi : 850[M+H]+, 872[M+Na]+.
MS ESI/APCI Dual nega : 884[M+Cl].
実施例9−2
A colorless amorphous compound (9-1) (42 mg, 38) was prepared in the same manner as in Example 1-1 using Intermediate (F) instead of Intermediate (E) and Piperazine instead of N, N-dimethylethylenediamine. %).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J = 6.99 Hz, each 3 H) 1.37 (s, 6 H) 1.58 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.79-2.86 (m, 4 H) 2.88-2.99 (m, 1 H) 3.57-3.64 ( m, 4 H) 3.76-3.95 (m, 6 H) 4.07-4.14 (m, 1 H) 4.18-4.26 (m, 1 H) 4.77-4.84 (m, 1 H) 5.13-5.22 (m, 1 H) 5.26-5.37 (m, 2 H) 6.29 (d, J = 16.16 Hz, 1 H) 6.49 (d, J = 16.16 Hz, 1 H) 6.64 (d, J = 7.93 Hz, 1 H) 6.77-6.83 (m , 2 H) 6.99 (s, 1 H) 7.05-7.11 (m, 1 H) 7.22 (br. S., 1 H).
MS ESI / APCI Dual posi: 850 [M + H] + , 872 [M + Na] + .
MS ESI / APCI Dual nega: 884 [M + Cl] .
Example 9-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(9−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(9−2)(27mg,94%)を得た。
1H NMR (600 MHz, METHANOL-d) δ ppm 1.14, 1.16 (each d, J=6.42Hz, each 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.32 (s, 3 H) 2.69 (br. s., 4 H) 2.95 - 3.03 (m, 1 H) 3.28 - 3.38 (m, 2 H) 3.42 - 3.52 (m, 2 H) 3.53 - 3.65 (m, 5 H) 3.80 - 3.84 (m, 1 H) 3.84 (s, 3 H) 3.92 (s, 2 H) 4.61 (d, J=9.17 Hz, 1 H) 6.39 (d, J=16.05 Hz, 1 H) 6.47 (d, J=16.05 Hz, 1 H) 6.74 (d, J=7.79 Hz, 1 H) 6.92 (s, 1 H) 7.06 (s, 1 H) 7.10 (d, J=7.79 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 682[M+H]+.
MS ESI/APCI Dual nega : 680[M-H], 716[M+Cl].
実施例10−1
A colorless amorphous compound (9-2) (27 mg, 94%) was obtained in the same manner as in Example 1-2 using the compound (9-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.14, 1.16 (each d, J = 6.42Hz, each 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.32 (s, 3 H ) 2.69 (br. S., 4 H) 2.95-3.03 (m, 1 H) 3.28-3.38 (m, 2 H) 3.42-3.52 (m, 2 H) 3.53-3.65 (m, 5 H) 3.80-3.84 (m, 1 H) 3.84 (s, 3 H) 3.92 (s, 2 H) 4.61 (d, J = 9.17 Hz, 1 H) 6.39 (d, J = 16.05 Hz, 1 H) 6.47 (d, J = 16.05 Hz, 1 H) 6.74 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.06 (s, 1 H) 7.10 (d, J = 7.79 Hz, 1 H) 7.22 (s, 1 H ).
MS ESI / APCI Dual posi: 682 [M + H] + .
MS ESI / APCI Dual nega: 680 [MH] , 716 [M + Cl] .
Example 10-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)、N,N−ジメチルエチレンジアミンの代わりにN−メチルピペラジンを用いて実施例1−1と同様の方法で無色アモルファスの粗化合物(10−1)(100mg)を得た。この物をさらに精製することなく、次の反応に用いた。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=8.5 Hz, 3 H) 1.15 (d, J=8.5 Hz, 3 H) 1.36 (s, 6 H) 1.56 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.32 (s, 3 H) 2.38 - 2.50 (m, 4 H) 2.85 - 3.02 (m, 1 H) 3.61 - 3.74 (m, 4 H) 3.76 - 3.84 (m, 1 H) 3.81 - 3.96 (m, 1 H) 3.86 (s, 3 H) 4.07 - 4.15 (m, 1 H) 4.18 - 4.27 (m, 1 H) 4.75 - 4.88 (m, 1 H) 5.11 - 5.24 (m, 1 H) 5.26 - 5.37 (m, 2 H) 6.22 - 6.38 (m, 1 H) 6.43 - 6.54 (m, 1 H) 6.59 - 6.70 (m, 2 H) 6.81 (s, 1 H) 6.96 - 7.02 (m, 1 H) 7.04 - 7.12 (m, 1 H) 7.20 - 7.26 (m, 1 H).
実施例10−2
Colorless amorphous crude compound (10-1) in the same manner as in Example 1-1 using intermediate (F) instead of intermediate (E) and N-methylpiperazine instead of N, N-dimethylethylenediamine (100 mg) was obtained. This product was used in the next reaction without further purification.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 8.5 Hz, 3 H) 1.15 (d, J = 8.5 Hz, 3 H) 1.36 (s, 6 H) 1.56 (s, 6 H ) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.32 (s, 3 H) 2.38-2.50 (m, 4 H) 2.85-3.02 (m , 1 H) 3.61-3.74 (m, 4 H) 3.76-3.84 (m, 1 H) 3.81-3.96 (m, 1 H) 3.86 (s, 3 H) 4.07-4.15 (m, 1 H) 4.18-4.27 (m, 1 H) 4.75-4.88 (m, 1 H) 5.11-5.24 (m, 1 H) 5.26-5.37 (m, 2 H) 6.22-6.38 (m, 1 H) 6.43-6.54 (m, 1 H 6.59-6.70 (m, 2 H) 6.81 (s, 1 H) 6.96-7.02 (m, 1 H) 7.04-7.12 (m, 1 H) 7.20-7.26 (m, 1 H).
Example 10-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(10−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(10−2)(8.0mg,9%;2工程)を得た。
1H NMR (600 MHz, METHANOL-d) δ ppm 1.09 - 1.16 (m, 6 H) 1.35 (s, 6 H) 1.42 (s, 6 H) 2.12 - 2.16 (m, 3 H) 2.23 - 2.33 (br. s., 4 H) 2.30 (s, 3 H) 2.92 - 3.01 (m, 1 H) 3.28 (s, 2 H) 3.30 - 3.38 (m, 1 H) 3.41 - 3.51 (m, 2 H) 3.55 - 3.66 (m, 5 H) 3.78 - 3.86 (m, 4 H) 3.90 (s, 2 H) 4.59 (d, J=9.17 Hz, 1 H) 6.33 - 6.39 (m, 1 H) 6.42 - 6.47 (m, 1 H) 6.72 (d, J=7.79 Hz, 1 H) 6.90 (s, 1 H) 7.04 - 7.11 (m, 2 H) 7.19 - 7.24 (m, 1 H).
MS ESI/APCI Dual posi : 696[M+H]+, 718[M+Na]+.
MS ESI/APCI Dual nega : 694[M-H]-, 730[M+Cl].
実施例11−1
Using the compound (10-1) instead of the compound (1-1), a colorless amorphous compound (10-2) (8.0 mg, 9%; 2 steps) was obtained in the same manner as in Example 1-2. It was.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.09-1.16 (m, 6 H) 1.35 (s, 6 H) 1.42 (s, 6 H) 2.12-2.16 (m, 3 H) 2.23-2.33 ( br. s., 4 H) 2.30 (s, 3 H) 2.92-3.01 (m, 1 H) 3.28 (s, 2 H) 3.30-3.38 (m, 1 H) 3.41-3.51 (m, 2 H) 3.55 -3.66 (m, 5 H) 3.78-3.86 (m, 4 H) 3.90 (s, 2 H) 4.59 (d, J = 9.17 Hz, 1 H) 6.33-6.39 (m, 1 H) 6.42-6.47 (m , 1 H) 6.72 (d, J = 7.79 Hz, 1 H) 6.90 (s, 1 H) 7.04-7.11 (m, 2 H) 7.19-7.24 (m, 1 H).
MS ESI / APCI Dual posi: 696 [M + H] + , 718 [M + Na] + .
MS ESI / APCI Dual nega: 694 [MH] - , 730 [M + Cl] .
Example 11-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)、N,N−ジメチルエチレンジアミンの代わりに1−エチルピペラジンを用いて実施例1−1と同様の方法で淡黄色アモルファスの化合物(11−1)(200mg,89%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 (t, J=7.23 Hz, 3 H) 1.11 (d, J=6.84 Hz, 3 H) 1.14 (d, J=6.84 Hz, 3 H) 1.36 (s, 6 H) 1.59 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.36 - 2.44 (m, 6 H) 2.93 (sept, J=6.84 Hz, 1 H) 3.61 - 3.71 (m, 4 H) 3.77 - 3.84 (m, 1 H) 3.83 - 3.94 (m, 5 H) 4.05 - 4.16 (m, 1 H) 4.18 - 4.27 (m, 1 H) 4.76 - 4.86 (m, 1 H) 5.14 - 5.23 (m, 1 H) 5.25 - 5.37 (m, 2 H) 6.29 (d, J=16.1 Hz, 1 H) 6.48 (d, J=16.1 Hz, 1 H) 6.64 (d, J=7.62 Hz, 1 H) 6.77 - 6.86 (m, 2 H) 6.99 (s, 1 H) 7.08 (d, J=7.62 Hz, 1 H) 7.22 (s, 1 H).
MS ESI/APCI Dual posi : 879[M+H]+, 901[M+Na]+.
MS ESI/APCI Dual nega : 913[M+Cl].
実施例11−2
A pale yellow amorphous compound (11-1) in the same manner as in Example 1-1 using Intermediate (F) instead of Intermediate (E) and 1-ethylpiperazine instead of N, N-dimethylethylenediamine (200 mg, 89%) was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 (t, J = 7.23 Hz, 3 H) 1.11 (d, J = 6.84 Hz, 3 H) 1.14 (d, J = 6.84 Hz, 3 H) 1.36 (s, 6 H) 1.59 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.36- 2.44 (m, 6 H) 2.93 (sept, J = 6.84 Hz, 1 H) 3.61-3.71 (m, 4 H) 3.77-3.84 (m, 1 H) 3.83-3.94 (m, 5 H) 4.05-4.16 ( m, 1 H) 4.18-4.27 (m, 1 H) 4.76-4.86 (m, 1 H) 5.14-5.23 (m, 1 H) 5.25-5.37 (m, 2 H) 6.29 (d, J = 16.1 Hz, 1 H) 6.48 (d, J = 16.1 Hz, 1 H) 6.64 (d, J = 7.62 Hz, 1 H) 6.77-6.86 (m, 2 H) 6.99 (s, 1 H) 7.08 (d, J = 7.62 (Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 879 [M + H] + , 901 [M + Na] + .
MS ESI / APCI Dual nega: 913 [M + Cl] .
Example 11-2

Figure 0005817317
Figure 0005817317

化合物(4−1A)、化合物(4−1B)の代わりに化合物(11−1)を用いて実施例4−2と同様の方法で無色アモルファスの化合物(11−2)(118mg,73%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 0.97 (t, J=7.11 Hz, 3 H) 1.10 - 1.19 (m, 6 H) 1.37 (s, 6 H) 1.45 (s, 6 H) 2.26 - 2.42 (m, 9 H) 2.97 (sept, J=6.76 Hz, 1 H) 3.32 - 3.40 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.48 - 3.55 (m, 1 H) 3.55 - 3.72 (m, 5 H) 3.79 - 3.89 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J=9.17 Hz, 1 H) 6.39 (d, J=16.5 Hz, 1 H) 6.46 (d, J=16.5 Hz, 1 H) 6.73 (d, J=7.79 Hz, 1 H) 6.92 (s, 1 H) 7.04 - 7.14 (m, 2 H) 7.23 (s, 1 H).
MS ESI/APCI Dual posi : 710[M+H]+, 732[M+Na]+.
MS ESI/APCI Dual nega : 744[M+Cl].
Anal. Calcd for C40H59N3O8・1.5H2O : C, 65.2; H, 8.48; N, 5.70. Found : C, 65.1; H, 8.38; N, 5.64.
実施例12−1
The colorless amorphous compound (11-2) (118 mg, 73%) was obtained in the same manner as in Example 4-2 using the compound (4-1A) and the compound (11-1) instead of the compound (4-1A). Got.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 0.97 (t, J = 7.11 Hz, 3 H) 1.10-1.19 (m, 6 H) 1.37 (s, 6 H) 1.45 (s, 6 H) 2.26 -2.42 (m, 9 H) 2.97 (sept, J = 6.76 Hz, 1 H) 3.32-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.48-3.55 (m, 1 H) 3.55-3.72 (m, 5 H) 3.79-3.89 (m, 4 H) 3.91 (s, 2 H) 4.61 (d, J = 9.17 Hz, 1 H) 6.39 (d, J = 16.5 Hz, 1 H) 6.46 (d, J = 16.5 Hz, 1 H) 6.73 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.04-7.14 (m, 2 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 710 [M + H] + , 732 [M + Na] + .
MS ESI / APCI Dual nega: 744 [M + Cl] .
Anal.Calcd for C 40 H 59 N 3 O 8・ 1.5H 2 O: C, 65.2; H, 8.48; N, 5.70. Found: C, 65.1; H, 8.38; N, 5.64.
Example 12-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)を用いて実施例5−1と同様の方法で、無色アモルファスの化合物(12−1)(55mg、40%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J=6.92 Hz, each 3 H) 1.28 - 1.47 (m, 8 H) 1.60 (s, 6 H) 1.73 - 1.89 (m, 5 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.22 - 2.35 (m, 10 H) 2.73 - 2.99 (m, 3 H) 3.76 - 3.84 (m, 1 H) 3.84 - 3.90 (m, 5 H) 4.07 - 4.15 (m, 1 H) 4.18 - 4.26 (m, 1 H) 4.34 - 4.50 (m, 2 H) 4.75 - 4.86 (m, 1 H) 5.13 - 5.23 (m, 1 H) 5.26 - 5.39 (m, 2 H) 6.30 (d, J=16.48 Hz, 1 H) 6.48 (d, J=16.48 Hz, 1 H) 6.63 (d, J=8.39 Hz, 1 H) 6.81 (s, 1 H) 6.94 - 7.01 (m, 2 H) 7.04 - 7.11 (m, 1 H) 7.23 (s, 1 H).
MSESI/APCI Dual posi : 892[M+H]+, 914[M+Na]+.
実施例12−2
A colorless amorphous compound (12-1) (55 mg, 40%) was obtained in the same manner as in Example 5-1, except that the intermediate (F) was used instead of the intermediate (E).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12, 1.14 (each d, J = 6.92 Hz, each 3 H) 1.28-1.47 (m, 8 H) 1.60 (s, 6 H) 1.73-1.89 (m , 5 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.22-2.35 (m, 10 H) 2.73-2.99 (m, 3 H) 3.76-3.84 (m, 1 H) 3.84-3.90 (m, 5 H) 4.07-4.15 (m, 1 H) 4.18-4.26 (m, 1 H) 4.34-4.50 (m, 2 H) 4.75-4.86 (m, 1 H) 5.13-5.23 (m, 1 H) 5.26-5.39 (m, 2 H) 6.30 (d, J = 16.48 Hz, 1 H) 6.48 (d, J = 16.48 Hz, 1 H) 6.63 (d, J = 8.39 Hz, 1 H ) 6.81 (s, 1 H) 6.94-7.01 (m, 2 H) 7.04-7.11 (m, 1 H) 7.23 (s, 1 H).
MSESI / APCI Dual posi: 892 [M + H] + , 914 [M + Na] + .
Example 12-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(12−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(12−2)(55mg,82%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.13, 1.15 (each d, J=6.84 Hz, each 3 H) 1.24 - 1.33 (m, 2 H) 1.37 (s, 6 H) 1.44 (s, 6 H) 1.75 (br. s, 2 H) 2.17 (s, 6 H) 2.30 - 2.39 (m, 4 H) 2.93 - 3.01 (m, 1 H) 3.28 - 3.38 (m, 5 H) 3.43 - 3.47 (m, 1 H) 3.47 - 3.53 (m, 1 H) 3.62 (dd, J=12.15, 5.73 Hz, 1 H) 3.80 - 3.86 (m, 3 H) 3.91 (s, 2 H) 4.48 (br. s., 2 H) 4.61 (d, J=9.63 Hz, 1 H) 6.40 (d, J=16.05 Hz, 1 H) 6.47 (d, J=16.05 Hz, 1 H) 6.73 (d, J=7.79 Hz, 1 H) 6.92 (s, 1 H) 7.06 - 7.11 (m, 2 H) 7.23 (s, 1 H).
MSESI/APCI Dual posi : 724[M+H]+, 746[M+Na]+ .
MSESI/APCI Dual nega : 722[M-H], 758[M+Cl].
Anal. Calcd for C41H61N3O8・2.5H2O: C, 64.04 ; H,8.65;N,5.46. Found: C, 64.01; H, 8.38;N,5.49.
実施例13−1
A colorless amorphous compound (12-2) (55 mg, 82%) was obtained in the same manner as in Example 1-2 using the compound (12-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.13, 1.15 (each d, J = 6.84 Hz, each 3 H) 1.24-1.33 (m, 2 H) 1.37 (s, 6 H) 1.44 (s, 6 H) 1.75 (br. S, 2 H) 2.17 (s, 6 H) 2.30-2.39 (m, 4 H) 2.93-3.01 (m, 1 H) 3.28-3.38 (m, 5 H) 3.43-3.47 ( m, 1 H) 3.47-3.53 (m, 1 H) 3.62 (dd, J = 12.15, 5.73 Hz, 1 H) 3.80-3.86 (m, 3 H) 3.91 (s, 2 H) 4.48 (br. s. , 2 H) 4.61 (d, J = 9.63 Hz, 1 H) 6.40 (d, J = 16.05 Hz, 1 H) 6.47 (d, J = 16.05 Hz, 1 H) 6.73 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.06-7.11 (m, 2 H) 7.23 (s, 1 H).
MSESI / APCI Dual posi: 724 [M + H] + , 746 [M + Na] + .
MSESI / APCI Dual nega: 722 [MH] , 758 [M + Cl] .
. Anal Calcd for C 41 H 61 N 3 O 8 · 2.5H 2 O:. C, 64.04; H, 8.65; N, 5.46 Found: C, 64.01; H, 8.38; N, 5.49.
Example 13-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)を用いて実施例6−1と同様の方法で無色アモルファスの化合物(13−1)(1.98g,99%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 6 H) 1.12 (d, J=6.84 Hz, 3 H) 1.14 (d, J=6.84 Hz, 3 H) 1.36 (s, 6 H) 1.56 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.85 - 3.02 (m, 1 H) 3.13 (d, J=5.91 Hz, 2 H) 3.76 - 3.84 (m, 1 H) 3.81 - 3.96 (m, 1 H) 3.86 (s, 3 H) 4.07 - 4.15 (m, 1 H) 4.18 - 4.27 (m, 1 H) 4.75 - 4.88 (m, 1 H) 5.11 - 5.24 (m, 1 H) 5.26 - 5.37 (m, 2 H) 6.22 - 6.38 (m, 1 H) 6.43 - 6.54 (m, 1 H) 6.59 - 6.70 (m, 1 H) 6.81 (s, 1 H) 6.96 - 7.02 (m, 2 H) 7.04 - 7.12 (m, 1 H) 7.20 - 7.26 (m, 1 H).
実施例13−2
A colorless amorphous compound (13-1) (1.98 g, 99%) was obtained in the same manner as in Example 6-1 using the intermediate (F) instead of the intermediate (E).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 (s, 6 H) 1.12 (d, J = 6.84 Hz, 3 H) 1.14 (d, J = 6.84 Hz, 3 H) 1.36 (s, 6 H ) 1.56 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 6 H) 2.30 (s, 3 H) 2.85-3.02 (m, 1 H) 3.13 (d, J = 5.91 Hz, 2 H) 3.76-3.84 (m, 1 H) 3.81-3.96 (m, 1 H) 3.86 (s, 3 H) 4.07-4.15 (m, 1 H) 4.18-4.27 (m, 1 H) 4.75-4.88 (m, 1 H) 5.11-5.24 (m, 1 H) 5.26-5.37 (m, 2 H) 6.22-6.38 (m, 1 H) 6.43-6.54 (m, 1 H) 6.59-6.70 (m , 1 H) 6.81 (s, 1 H) 6.96-7.02 (m, 2 H) 7.04-7.12 (m, 1 H) 7.20-7.26 (m, 1 H).
Example 13-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(13−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(12−2)(1.0g,65%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.01 (s, 6 H) 1.09 - 1.15 (m, 6 H) 1.35 (s, 6 H) 1.43 (s, 6 H) 2.31 (s, 3 H) 2.91 - 3.00 (m, 1 H) 3.08 (s, 2 H) 3.27 - 3.36 (m, 5 H) 3.41 - 3.46 (m, 1 H) 3.47 - 3.52 (m, 1 H) 3.60 (dd, J=11.92, 5.96 Hz, 1 H) 3.80 - 3.84 (m, 4 H) 3.90 (s, 2 H) 4.59 (d, J=9.63 Hz, 1 H) 6.36 - 6.41 (m, 1 H) 6.45 - 6.50 (m, 1 H) 6.71 (d, J=7.79 Hz, 1 H) 6.90 (s, 1 H) 7.06 (s, 1 H) 7.07 - 7.10 (m, 1 H) 7.20 - 7.25 (m, 1 H).
MS ESI/APCI Dual posi : 684[M+H]+.
MS ESI/APCI Dual nega : 682[M-H]-, 718[M+Cl].
実施例14−1
A colorless amorphous compound (12-2) (1.0 g, 65%) was obtained in the same manner as in Example 1-2 using the compound (13-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.01 (s, 6 H) 1.09-1.15 (m, 6 H) 1.35 (s, 6 H) 1.43 (s, 6 H) 2.31 (s, 3 H ) 2.91-3.00 (m, 1 H) 3.08 (s, 2 H) 3.27-3.36 (m, 5 H) 3.41-3.46 (m, 1 H) 3.47-3.52 (m, 1 H) 3.60 (dd, J = 11.92, 5.96 Hz, 1 H) 3.80-3.84 (m, 4 H) 3.90 (s, 2 H) 4.59 (d, J = 9.63 Hz, 1 H) 6.36-6.41 (m, 1 H) 6.45-6.50 (m , 1 H) 6.71 (d, J = 7.79 Hz, 1 H) 6.90 (s, 1 H) 7.06 (s, 1 H) 7.07-7.10 (m, 1 H) 7.20-7.25 (m, 1 H).
MS ESI / APCI Dual posi: 684 [M + H] + .
MS ESI / APCI Dual nega: 682 [MH] - , 718 [M + Cl] .
Example 14-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(F)、N,N−ジメチルエチレンジアミンの代わりに4−アミノ−1−t−ブトキシカルボニルピペリジンを用いて実施例1−1と同様の方法で淡黄色の油状化合物(14−1)(200mg,quant.)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J=6.99 Hz, 3 H) 1.14 (d, J=6.99 Hz, 3 H) 1.25 - 1.33 (m, 2 H) 1.36 (s, 6 H) 1.45 (s, 9 H) 1.48 (s, 6 H) 1.77 (s, 3 H) 1.79 - 1.93 (m, 2 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.90 - 2.98 (m, 3 H) 3.75 - 4.00 (m, 9 H) 4.07 - 4.15 (m, 1 H) 4.18 - 4.27 (m, 1 H) 4.79 - 4.86 (m, 1 H) 5.19 (d, J=10.10 Hz, 1 H) 5.26 - 5.35 (m, 2 H) 6.09 (s, 1 H) 6.26 (d, J=16.48 Hz, 1 H) 6.50 (d, J=16.48 Hz, 1 H) 6.65 (d, J=8.32 Hz, 1 H) 6.74 - 6.83 (m, 2 H) 6.99 (s, 1 H) 7.08 (dd, J=8.32, 2.72 Hz, 1 H) 7.22 (d, J=2.72 Hz, 1 H).
MS ESI/APCI Dual posi : 965[M+H]+, 987[M+Na]+.
MS ESI/APCI Dual nega : 999[M+Cl].
実施例14−2
In the same manner as in Example 1-1, intermediate (F) was used instead of intermediate (E), and 4-amino-1-tert-butoxycarbonylpiperidine was used instead of N, N-dimethylethylenediamine. An oily compound (14-1) (200 mg, quant.) Was obtained.
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.99 Hz, 3 H) 1.14 (d, J = 6.99 Hz, 3 H) 1.25-1.33 (m, 2 H) 1.36 (s, 6 H) 1.45 (s, 9 H) 1.48 (s, 6 H) 1.77 (s, 3 H) 1.79-1.93 (m, 2 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s , 3 H) 2.32 (s, 3 H) 2.90-2.98 (m, 3 H) 3.75-4.00 (m, 9 H) 4.07-4.15 (m, 1 H) 4.18-4.27 (m, 1 H) 4.79-4.86 (m, 1 H) 5.19 (d, J = 10.10 Hz, 1 H) 5.26-5.35 (m, 2 H) 6.09 (s, 1 H) 6.26 (d, J = 16.48 Hz, 1 H) 6.50 (d, J = 16.48 Hz, 1 H) 6.65 (d, J = 8.32 Hz, 1 H) 6.74-6.83 (m, 2 H) 6.99 (s, 1 H) 7.08 (dd, J = 8.32, 2.72 Hz, 1 H) 7.22 (d, J = 2.72 Hz, 1 H).
MS ESI / APCI Dual posi: 965 [M + H] + , 987 [M + Na] + .
MS ESI / APCI Dual nega: 999 [M + Cl] .
Example 14-2

Figure 0005817317
Figure 0005817317

化合物(14−1)(185mg,0.192mmol)のクロロホルム(2mL)溶液に、トリフルオロ酢酸(450μL)を加えた。反応混合物を室温で2時間攪拌し、溶媒を減圧下留去した。得られた残渣にトリエチルアミン/水/メタノール(1/1/5,4mL)を加え、反応混合物を室温で一晩攪拌した。溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=10:0→8:2)で精製し、無色アモルファスの化合物(14−2)(103mg,77%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.14 (d, J=5.50 Hz, 3 H) 1.15 (d, J=5.50 Hz, 3 H) 1.27 - 1.35 (m, 2 H) 1.37 (s, 6 H) 1.45 (s, 6 H) 1.78 (d, J=11.46 Hz, 2 H) 2.33 (s, 3 H) 2.56 - 2.68 (m, 2 H) 2.95 - 3.03 (m, 3 H) 3.33 - 3.37 (m, 2 H) 3.43 - 3.48 (m, 1 H) 3.49 - 3.53 (m, 1 H) 3.57 - 3.66 (m, 1 H) 3.68 - 3.75 (m, 1 H) 3.81 - 3.84 (m, 1 H) 3.85 (s, 3 H) 3.92 (s, 2 H) 4.61 (d, J=9.17 Hz, 1 H) 6.34 - 6.43 (m, 1 H) 6.45 - 6.56 (m, 1 H) 6.74 (d, J=7.79 Hz, 1 H) 6.92 (s, 1 H) 7.04 - 7.16 (m, 2 H) 7.26 (s, 1 H).
MS ESI/APCI Dual posi : 696[M+H]+, 718[M+Na]+.
実施例15−1
Trifluoroacetic acid (450 μL) was added to a solution of compound (14-1) (185 mg, 0.192 mmol) in chloroform (2 mL). The reaction mixture was stirred at room temperature for 2 hours, and the solvent was distilled off under reduced pressure. Triethylamine / water / methanol (1/1/5, 4 mL) was added to the resulting residue, and the reaction mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 0 → 8: 2) to give colorless amorphous compound (14-2) (103 mg, 77%). Obtained.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.14 (d, J = 5.50 Hz, 3 H) 1.15 (d, J = 5.50 Hz, 3 H) 1.27-1.35 (m, 2 H) 1.37 (s , 6 H) 1.45 (s, 6 H) 1.78 (d, J = 11.46 Hz, 2 H) 2.33 (s, 3 H) 2.56-2.68 (m, 2 H) 2.95-3.03 (m, 3 H) 3.33- 3.37 (m, 2 H) 3.43-3.48 (m, 1 H) 3.49-3.53 (m, 1 H) 3.57-3.66 (m, 1 H) 3.68-3.75 (m, 1 H) 3.81-3.84 (m, 1 H) 3.85 (s, 3 H) 3.92 (s, 2 H) 4.61 (d, J = 9.17 Hz, 1 H) 6.34-6.43 (m, 1 H) 6.45-6.56 (m, 1 H) 6.74 (d, J = 7.79 Hz, 1 H) 6.92 (s, 1 H) 7.04-7.16 (m, 2 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 696 [M + H] + , 718 [M + Na] + .
Example 15-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(G)を用いて実施例1−1と同様の方法で無色アモルファスの化合物(15−1)(103mg,94%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J=6.84 Hz, 3 H) 1.10 (d, J=6.84 Hz, 3 H) 1.38 (s, 6 H) 1.49 (s, 6 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.46 (s, 6 H) 2.64 - 2.78 (m, 2 H) 3.04 (sept, J=6.84 Hz, 1 H) 3.38 - 3.49 (m, 2 H) 3.78 - 3.83 (m, 1 H) 3.85 (s, 3 H) 3.87 - 4.04 (m, 2 H) 4.08 - 4.18 (m, 1 H) 4.18 - 4.30 (m, 1 H) 4.87 (d, J=9.48 Hz, 1 H) 5.16 - 5.27 (m, 1 H) 5.28 - 5.44 (m, 2 H) 6.35 (s, 1 H) 6.40 - 6.57 (m, 2 H) 6.77 (s, 1 H) 7.01 (d, J=8.24 Hz, 2 H) 7.13 (s, 1 H) 7.32 (d, J=8.24 Hz, 2 H) 7.40 (s, 1 H).
MS ESI/APCI Dual posi : 839[M+H]+.
MS ESI/APCI Dual nega : 873[M+Cl].
実施例15−2
A colorless amorphous compound (15-1) (103 mg, 94%) was obtained in the same manner as in Example 1-1 using the intermediate (G) instead of the intermediate (E).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J = 6.84 Hz, 3 H) 1.10 (d, J = 6.84 Hz, 3 H) 1.38 (s, 6 H) 1.49 (s, 6 H ) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.46 (s, 6 H) 2.64-2.78 (m, 2 H) 3.04 (sept, J = 6.84 Hz, 1 H) 3.38-3.49 (m, 2 H) 3.78-3.83 (m, 1 H) 3.85 (s, 3 H) 3.87-4.04 (m, 2 H) 4.08-4.18 (m, 1 H) 4.18-4.30 (m, 1 H) 4.87 (d, J = 9.48 Hz, 1 H) 5.16-5.27 (m, 1 H) 5.28-5.44 (m, 2 H) 6.35 (s, 1 H) 6.40-6.57 ( m, 2 H) 6.77 (s, 1 H) 7.01 (d, J = 8.24 Hz, 2 H) 7.13 (s, 1 H) 7.32 (d, J = 8.24 Hz, 2 H) 7.40 (s, 1 H) .
MS ESI / APCI Dual posi: 839 [M + H] + .
MS ESI / APCI Dual nega: 873 [M + Cl] .
Example 15-2

Figure 0005817317
Figure 0005817317

化合物(4−1A)、化合物(4−1B)の代わりに化合物(15−1)を用いて実施例4−2と同様の方法で無色アモルファスの化合物(15−2)(62.1mg,75%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.07 (d, J=6.76 Hz, 3 H) 1.09 (d, J=6.76 Hz, 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23 (s, 6 H) 2.41 (t, J=6.88 Hz, 2 H) 3.10 (sept, J=6.76 Hz, 1 H) 3.26 - 3.30 (m, 2 H) 3.35 - 3.45 (m, 2 H) 3.45 - 3.52 (m, 1 H) 3.54 - 3.60 (m, 1 H) 3.62 - 3.69 (m, 1 H) 3.79 - 3.89 (m, 4 H) 3.99 (s, 2 H) 4.65 (d, J=9.63 Hz, 1 H) 6.39 (d, J=16.51 Hz, 1 H) 6.52 (d, J=16.51 Hz, 1 H) 6.88 (s, 1 H) 7.07 (d, J=8.25 Hz, 2 H) 7.23 (s, 1 H) 7.31 (d, J=8.25 Hz, 2 H).
MS ESI/APCI Dual posi : 670[M+H]+.
MS ESI/APCI Dual nega : 704[M+Cl].
Anal. Calcd for C37H55N3O8・1.0H2O : C, 64.6; H, 8.36; N, 6.11. Found : C, 64.5; H, 8.31; N, 6.02.
実施例15−3
A colorless amorphous compound (15-2) (62.1 mg, 75) was prepared in the same manner as in Example 4-2 using the compound (4-1A) and the compound (4-1B) instead of the compound (4-1A). %).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.07 (d, J = 6.76 Hz, 3 H) 1.09 (d, J = 6.76 Hz, 3 H) 1.36 (s, 6 H) 1.44 (s, 6 H) 2.23 (s, 6 H) 2.41 (t, J = 6.88 Hz, 2 H) 3.10 (sept, J = 6.76 Hz, 1 H) 3.26-3.30 (m, 2 H) 3.35-3.45 (m, 2 H ) 3.45-3.52 (m, 1 H) 3.54-3.60 (m, 1 H) 3.62-3.69 (m, 1 H) 3.79-3.89 (m, 4 H) 3.99 (s, 2 H) 4.65 (d, J = 9.63 Hz, 1 H) 6.39 (d, J = 16.51 Hz, 1 H) 6.52 (d, J = 16.51 Hz, 1 H) 6.88 (s, 1 H) 7.07 (d, J = 8.25 Hz, 2 H) 7.23 (s, 1 H) 7.31 (d, J = 8.25 Hz, 2 H).
MS ESI / APCI Dual posi: 670 [M + H] + .
MS ESI / APCI Dual nega: 704 [M + Cl] .
Anal.Calcd for C 37 H 55 N 3 O 8・ 1.0H 2 O: C, 64.6; H, 8.36; N, 6.11. Found: C, 64.5; H, 8.31; N, 6.02.
Example 15-3

無色アモルファスの化合物(15−2)(純度99.9%)25mgをエタノール0.08mLに室温にて溶解させた後、1日間室温で撹拌させ結晶を得た。本結晶を室温で減圧乾燥し、無色の結晶27mg(回収率100%)を得た。この結晶の粉末X線回折パターン、示差熱分析/熱質量測定(TG/DTA)及び赤外吸収スペクトルを測定したところ、化合物(15−2)のエタノール溶媒和物の結晶であった。 得られた結晶は、粉末X線回折(Cu−Kα)において、2θ=5.9度、17.1度、17.6度及び21.5度にピークを有した。また、赤外線吸収スペクトルにおいて、特性吸収帯が3538cm-1、3357cm-1、2964cm-1、1673cm-1、1634cm-1及び1505cm-1にあった。そして、融点が108℃〜114℃であった。 25 mg of colorless amorphous compound (15-2) (purity 99.9%) was dissolved in 0.08 mL of ethanol at room temperature and stirred at room temperature for 1 day to obtain crystals. The crystals were dried under reduced pressure at room temperature to obtain 27 mg of colorless crystals (recovery rate 100%). When the powder X-ray diffraction pattern, differential thermal analysis / thermal mass measurement (TG / DTA) and infrared absorption spectrum of this crystal were measured, it was a crystal of the ethanol solvate of compound (15-2). The obtained crystals had peaks at 2θ = 5.9 degrees, 17.1 degrees, 17.6 degrees, and 21.5 degrees in powder X-ray diffraction (Cu—Kα). In the infrared absorption spectrum, characteristic absorption bands were 3538 cm −1 , 3357 cm −1 , 2964 cm −1 , 1673 cm −1 , 1634 cm −1 and 1505 cm −1 . And melting | fusing point was 108 to 114 degreeC.

該結晶の、粉末X線回折パターンを図1に、赤外吸収スペクトル(KBr法)を図2に、示差熱分析/熱質量測定カーブを図3に示す。
実施例15−4
The powder X-ray diffraction pattern of the crystal is shown in FIG. 1, the infrared absorption spectrum (KBr method) is shown in FIG. 2, and the differential thermal analysis / thermal mass measurement curve is shown in FIG.
Example 15-4

また、上記結晶は以下の方法でも得ることができた。
無色アモルファスの化合物(15−2)(純度96.0%)56gをエタノール135mLに66℃で溶解した後、撹拌しながらヘプタン135mLを加えて冷却し、45℃付近で、実施例15−3で得られた化合物(15−2)のエタノール溶媒和物の結晶を入れた後、1℃まで温度を下げた。析出した結晶をろ取した後に、40℃で減圧乾燥し、無色の結晶46g(回収率82%,純度99.1%)を得た。この結晶の粉末X線回折パターン、示差熱分析/熱質量測定(TG/DTA)及び赤外吸収スペクトルを測定したところ、化合物(15−2)のエタノール溶媒和物の結晶であった。
1H NMR (600 MHz, METHANOL- d4) δ ppm 1.06 (d, J=5.04 Hz, 3 H) 1.07 (d, J=5.50 Hz, 3 H) 1.15 (t, J=6.88 Hz, 3 H) 1.34 (s, 6 H) 1.43 (s, 6 H) 2.20 (s, 6 H) 2.37 (t, J=6.88 Hz, 2 H) 3.08 (quin, J=6.88 Hz, 1 H) 3.26 (t, J=6.88 Hz, 2 H) 3.28-3.30 (m, 4 H) 3.34 - 3.38 (m, 2 H) 3.43 - 3.49 (m, 1 H) 3.55 (t, J=9.17 Hz, 1 H) 3.58 (q, J=6.88 Hz, 2 H) 3.62 - 3.66 (m, 1 H) 3.78 - 3.85 (m, 4 H) 3.96 (s, 2 H) 4.63 (d, J=9.62 Hz, 1 H) 6.37 (d, J=16.50 Hz, 1 H) 6.50 (d, J=16.50 Hz, 1 H) 6.86 (s, 1 H) 7.05 (d, J=7.80 Hz, 2 H) 7.22 (s, 1 H) 7.29 (d, J=7.79 Hz, 2 H).
MS ESI/APCI Dual posi : 670[M+H]+.
MS ESI/APCI Dual nega : 704[M+Cl]-.
Anal. Calcd for C39H61N3O9・0.6H2O : C, 64.94; H, 8.61; N, 5.83. Found: C, 64.75; H, 8.46; N, 5.82.
実施例15−5
Further, the above crystal could be obtained by the following method.
After dissolving 56 g of colorless amorphous compound (15-2) (purity 96.0%) in 135 mL of ethanol at 66 ° C., 135 mL of heptane was added with stirring and cooled, and at about 45 ° C., in Example 15-3 After putting the ethanol solvate crystal of the obtained compound (15-2), the temperature was lowered to 1 ° C. The precipitated crystals were collected by filtration and then dried under reduced pressure at 40 ° C. to obtain 46 g of colorless crystals (recovery rate 82%, purity 99.1%). When the powder X-ray diffraction pattern, differential thermal analysis / thermal mass measurement (TG / DTA) and infrared absorption spectrum of this crystal were measured, it was a crystal of the ethanol solvate of compound (15-2).
1 H NMR (600 MHz, METHANOL- d 4 ) δ ppm 1.06 (d, J = 5.04 Hz, 3 H) 1.07 (d, J = 5.50 Hz, 3 H) 1.15 (t, J = 6.88 Hz, 3 H) 1.34 (s, 6 H) 1.43 (s, 6 H) 2.20 (s, 6 H) 2.37 (t, J = 6.88 Hz, 2 H) 3.08 (quin, J = 6.88 Hz, 1 H) 3.26 (t, J = 6.88 Hz, 2 H) 3.28-3.30 (m, 4 H) 3.34-3.38 (m, 2 H) 3.43-3.49 (m, 1 H) 3.55 (t, J = 9.17 Hz, 1 H) 3.58 (q, J = 6.88 Hz, 2 H) 3.62-3.66 (m, 1 H) 3.78-3.85 (m, 4 H) 3.96 (s, 2 H) 4.63 (d, J = 9.62 Hz, 1 H) 6.37 (d, J = 16.50 Hz, 1 H) 6.50 (d, J = 16.50 Hz, 1 H) 6.86 (s, 1 H) 7.05 (d, J = 7.80 Hz, 2 H) 7.22 (s, 1 H) 7.29 (d, J = 7.79 Hz, 2 H).
MS ESI / APCI Dual posi: 670 [M + H] + .
MS ESI / APCI Dual nega: 704 [M + Cl] - .
Anal. Calcd for C 39 H 61 N 3 O 9 , 0.6H 2 O: C, 64.94; H, 8.61; N, 5.83. Found: C, 64.75; H, 8.46; N, 5.82.
Example 15-5

また、以下の操作を行うことで、上記結晶とは別の結晶(A型結晶)を得た。
無色アモルファスの化合物(15−2)のエタノール溶媒和物0.10gにリン酸塩緩衝液(pH6.8)600μLを加え、25℃で24時間懸濁した。遠心分離(3000rpm,25℃,10分)後、上清を取り除き、室温で乾燥した。この結晶の粉末X線回折パターン及び示差熱分析/熱質量測定(TG/DTA)を測定したところ、A形結晶であった。
得られた結晶は、粉末X線回折(Cu−Kα)において、2θ=6.1度、13.7度、18.0度及び18.7度にピークを有した。また、融点が107℃〜113℃であった。
Further, by performing the following operation, a crystal different from the above crystal (A-type crystal) was obtained.
To 0.10 g of ethanol solvate of colorless amorphous compound (15-2), 600 μL of phosphate buffer (pH 6.8) was added and suspended at 25 ° C. for 24 hours. After centrifugation (3000 rpm, 25 ° C., 10 minutes), the supernatant was removed and dried at room temperature. When the powder X-ray diffraction pattern and differential thermal analysis / thermal mass measurement (TG / DTA) of this crystal were measured, it was an A-form crystal.
The obtained crystals had peaks at 2θ = 6.1 degrees, 13.7 degrees, 18.0 degrees, and 18.7 degrees in powder X-ray diffraction (Cu—Kα). Moreover, melting | fusing point was 107 to 113 degreeC.

該結晶の、粉末X線回折パターンを図4に、示差熱分析/熱質量測定カーブを図5に示す。
実施例16−1
The powder X-ray diffraction pattern of the crystal is shown in FIG. 4, and the differential thermal analysis / thermal mass measurement curve is shown in FIG.
Example 16-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(G)、N,N−ジメチルエチレンジアミンの代わりにピペラジンを用いて実施例1−1と同様の方法で無色アモルファスの化合物(16−1)(90mg,55%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J=6.6 Hz, 3 H) 1.11 (d, J=6.6 Hz, 3 H) 1.35 (s, 6 H) 1.77 (s, 6 H) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.25 (br. s., 2 H) 2.78 - 2.88 (m, 4 H) 2.96 - 3.12 (m, 1 H) 3.55 - 3.65 (m, 4 H) 3.78 - 3.88 (m, 1 H) 3.85 (s, 3 H) 3.88 - 4.04 (m, 2 H) 4.09 - 4.18 (m, 1 H) 4.20 - 4.30 (m, 1 H) 4.88 (d, J=9.48 Hz, 1 H) 5.15 - 5.27 (m, 1 H) 5.28 - 5.44 (m, 2 H) 6.22 - 6.33 (m, 1 H) 6.41 - 6.55 (m, 1 H) 6.72 - 6.85 (m, 2 H) 6.96 - 7.06 (m, 2 H) 7.14 (s, 1 H) 7.23 - 7.32 (m, 2 H).
MS ESI/APCI Dual posi : 836[M+H]+.
実施例16−2
A colorless amorphous compound (16-1) (90 mg, 55) was prepared in the same manner as in Example 1-1 except that intermediate (G) was used instead of intermediate (E) and piperazine was used instead of N, N-dimethylethylenediamine. %).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06 (d, J = 6.6 Hz, 3 H) 1.11 (d, J = 6.6 Hz, 3 H) 1.35 (s, 6 H) 1.77 (s, 6 H ) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.25 (br. S., 2 H) 2.78-2.88 (m, 4 H) 2.96-3.12 (m, 1 H) 3.55-3.65 (m, 4 H) 3.78-3.88 (m, 1 H) 3.85 (s, 3 H) 3.88-4.04 (m, 2 H) 4.09-4.18 (m, 1 H) 4.20-4.30 (m, 1 H) 4.88 (d, J = 9.48 Hz, 1 H) 5.15-5.27 (m, 1 H) 5.28-5.44 (m, 2 H) 6.22-6.33 (m, 1 H) 6.41-6.55 (m, 1 H) 6.72-6.85 (m, 2 H) 6.96-7.06 (m, 2 H) 7.14 (s, 1 H) 7.23-7.32 (m, 2 H).
MS ESI / APCI Dual posi: 836 [M + H] + .
Example 16-2

Figure 0005817317
Figure 0005817317

化合物(1−1)の代わりに化合物(16−1)を用いて実施例1−2と同様の方法で無色アモルファスの化合物(16−2)(52mg,70%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.06 (d, J=6.80 Hz, 3 H) 1.07 (d, J=6.80 Hz, 3 H) 1.34 (s, 6 H) 1.42 (s, 6 H) 2.67 (br. s., 4 H) 3.04 - 3.12 (m, 1 H) 3.27 - 3.30 (m, 2 H) 3.33 - 3.38 (m, 2 H) 3.43 - 3.49 (m, 1 H) 3.50 - 3.61 (m, 3 H) 3.61 - 3.66 (m, 1 H) 3.80 (s, 3 H) 3.83 (d, J=11.92 Hz, 1 H) 3.92 - 4.00 (m, 2 H) 4.63 (d, J=9.63 Hz, 1 H) 6.33 - 6.39 (m, 1 H) 6.44 - 6.49 (m, 1 H) 6.86 (s, 1 H) 7.06 (d, J=8.25 Hz, 2 H) 7.21 (s, 1 H) 7.27 (d, J=8.25 Hz, 2 H).
MS ESI/APCI Dual posi : 668[M+H]+, 690[M+Na]+.
MS ESI/APCI Dual nega : 666[M-H], 702[M+Cl].
実施例17−1
A colorless amorphous compound (16-2) (52 mg, 70%) was obtained in the same manner as in Example 1-2 using the compound (16-1) instead of the compound (1-1).
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.06 (d, J = 6.80 Hz, 3 H) 1.07 (d, J = 6.80 Hz, 3 H) 1.34 (s, 6 H) 1.42 (s, 6 H) 2.67 (br. S., 4 H) 3.04-3.12 (m, 1 H) 3.27-3.30 (m, 2 H) 3.33-3.38 (m, 2 H) 3.43-3.49 (m, 1 H) 3.50- 3.61 (m, 3 H) 3.61-3.66 (m, 1 H) 3.80 (s, 3 H) 3.83 (d, J = 11.92 Hz, 1 H) 3.92-4.00 (m, 2 H) 4.63 (d, J = 9.63 Hz, 1 H) 6.33-6.39 (m, 1 H) 6.44-6.49 (m, 1 H) 6.86 (s, 1 H) 7.06 (d, J = 8.25 Hz, 2 H) 7.21 (s, 1 H) 7.27 (d, J = 8.25 Hz, 2 H).
MS ESI / APCI Dual posi: 668 [M + H] + , 690 [M + Na] + .
MS ESI / APCI Dual nega: 666 [MH] , 702 [M + Cl] .
Example 17-1

Figure 0005817317
Figure 0005817317

中間体(E)の代わりに中間体(G)、N,N−ジメチルエチレンジアミンの代わりに1−メチルピペラジンを用いて実施例1−1と同様の方法で無色アモルファスの化合物(17−1)(187mg,95%)を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J=6.84 Hz, 3 H) 1.10 (d, J=6.84 Hz, 3 H) 1.36 (s, 6 H) 1.59 (s, 6 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.26 (s, 3 H) 2.32 - 2.40 (m, 4 H) 2.96 - 3.12 (m, 1 H) 3.59 - 3.71 (m, 4 H) 3.79 - 3.84 (m, 1 H) 3.85 (s, 3 H) 3.90 - 4.05 (m, 2 H) 4.10 - 4.16 (m, 1 H) 4.21 - 4.28 (m, 1 H) 4.87 (d, J=9.64 Hz, 1 H) 5.16 - 5.27 (m, 1 H) 5.29 - 5.44 (m, 2 H) 6.28 (d, J=16.4 Hz, 1 H) 6.49 (d, J=16.4 Hz, 1 H) 6.77 (s, 1 H) 6.83 (s, 1 H) 7.01 (d, J=8.08 Hz, 2 H) 7.13 (s, 1 H) 7.25 - 7.32 (m, 2 H).
MS ESI/APCI Dual posi : 850[M+H]+.
MS ESI/APCI Dual nega : 884[M+Cl].
実施例17−2
A colorless amorphous compound (17-1) (17-1) in the same manner as in Example 1-1 using Intermediate (G) instead of Intermediate (E) and 1-methylpiperazine instead of N, N-dimethylethylenediamine 187 mg, 95%).
1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.05 (d, J = 6.84 Hz, 3 H) 1.10 (d, J = 6.84 Hz, 3 H) 1.36 (s, 6 H) 1.59 (s, 6 H ) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.05 (s, 3 H) 2.06 (s, 3 H) 2.26 (s, 3 H) 2.32-2.40 (m, 4 H) 2.96-3.12 (m , 1 H) 3.59-3.71 (m, 4 H) 3.79-3.84 (m, 1 H) 3.85 (s, 3 H) 3.90-4.05 (m, 2 H) 4.10-4.16 (m, 1 H) 4.21-4.28 (m, 1 H) 4.87 (d, J = 9.64 Hz, 1 H) 5.16-5.27 (m, 1 H) 5.29-5.44 (m, 2 H) 6.28 (d, J = 16.4 Hz, 1 H) 6.49 ( d, J = 16.4 Hz, 1 H) 6.77 (s, 1 H) 6.83 (s, 1 H) 7.01 (d, J = 8.08 Hz, 2 H) 7.13 (s, 1 H) 7.25-7.32 (m, 2 H).
MS ESI / APCI Dual posi: 850 [M + H] + .
MS ESI / APCI Dual nega: 884 [M + Cl] .
Example 17-2

Figure 0005817317
Figure 0005817317

化合物(4−1A)、化合物(4−1B)の代わりに化合物(17−1)を用いて実施例4−2と同様の方法で無色アモルファスの化合物(17−2)(127mg,84%)を得た。
1H NMR (600 MHz, METHANOL-d4) δ ppm 1.05 (d, J=6.65 Hz, 3 H) 1.07 (d, J=6.65 Hz, 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.14 (s, 3 H) 2.23 - 2.40 (m, 4 H) 3.06 - 3.16 (m, 1 H) 3.34 - 3.42 (m, 2 H) 3.46 - 3.52 (m, 1 H) 3.51 - 3.73 (m, 6 H) 3.79 - 3.91 (m, 4 H) 3.98 (s, 2 H) 4.65 (d, J=9.63 Hz, 1 H) 6.38 (d, J=16.1 Hz, 1 H) 6.48 (d, J=16.1 Hz, 1 H) 6.88 (s, 1 H) 7.08 (d, J=8.25 Hz, 2 H) 7.23 (s, 1 H) 7.29 (d, J=8.25 Hz, 2 H).
MS ESI/APCI Dual posi : 682[M+H]+, 704[M+Na]+.
MS ESI/APCI Dual nega : 716[M+Cl].
Anal. Calcd for C38H55N3O8・1.6H2O : C, 64.2; H, 8.25; N, 5.91. Found : C, 64.3; H, 8.08; N, 5.89.
A colorless amorphous compound (17-2) (127 mg, 84%) was obtained in the same manner as in Example 4-2 using the compound (4-1A) and the compound (4-1B) instead of the compound (4-1B). Got.
1 H NMR (600 MHz, METHANOL-d 4 ) δ ppm 1.05 (d, J = 6.65 Hz, 3 H) 1.07 (d, J = 6.65 Hz, 3 H) 1.36 (s, 6 H) 1.45 (s, 6 H) 2.14 (s, 3 H) 2.23-2.40 (m, 4 H) 3.06-3.16 (m, 1 H) 3.34-3.42 (m, 2 H) 3.46-3.52 (m, 1 H) 3.51-3.73 (m , 6 H) 3.79-3.91 (m, 4 H) 3.98 (s, 2 H) 4.65 (d, J = 9.63 Hz, 1 H) 6.38 (d, J = 16.1 Hz, 1 H) 6.48 (d, J = 16.1 Hz, 1 H) 6.88 (s, 1 H) 7.08 (d, J = 8.25 Hz, 2 H) 7.23 (s, 1 H) 7.29 (d, J = 8.25 Hz, 2 H).
MS ESI / APCI Dual posi: 682 [M + H] + , 704 [M + Na] + .
MS ESI / APCI Dual nega: 716 [M + Cl] .
Anal. Calcd for C 38 H 55 N 3 O 8・ 1.6H 2 O: C, 64.2; H, 8.25; N, 5.91. Found: C, 64.3; H, 8.08; N, 5.89.

試験例1
(1)ヒトSGLT1を安定に発現するCHO−K1細胞の作製
ヒトSGLT1蛋白質を発現するプラスミドベクターを、リポフェクトアミン2000(インビトロジェン社)を用いてCHO−K1細胞にトランスフェクションした。SGLT1発現細胞は、500μg/mLの濃度のジェネティシンの存在下で培養し耐性株を選択し、下記に示す系により糖取り込み能を指標に取得した。
Test example 1
(1) Production of CHO-K1 cells stably expressing human SGLT1 Plasmid vectors expressing human SGLT1 protein were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT1-expressing cells were cultured in the presence of geneticin at a concentration of 500 μg / mL, resistant strains were selected, and sugar uptake ability was obtained as an index by the system shown below.

(2)ヒトSGLT2を安定に発現するCHO−K1細胞の作製
方法A(WO2007/136116に記載の方法):ヒトSGLT2カルボキシ末端の最終残基にLeuGluSerArgGlyProValが付加された蛋白質を発現するプラスミドベクターを、リポフェクトアミン2000(インビトロジェン社)を用いてCHO−K1細胞にトランスフェクションした。SGLT2発現細胞は、500μg/mLの濃度のハイグロマイシンBの存在下で培養し耐性株を選択し、下記に示す系により糖取り込み能を指標に取得した。本安定発現細胞を用いて算出された結果を表1に方法Aとして示した。
(2) Production of CHO-K1 cells that stably express human SGLT2 Method A (method described in WO2007 / 136116): A plasmid vector that expresses a protein in which LeuGluSerArgGlyProVal is added to the final residue of the human SGLT2 carboxy terminus, CHO-K1 cells were transfected using Lipofectamine 2000 (Invitrogen). SGLT2-expressing cells were cultured in the presence of hygromycin B at a concentration of 500 μg / mL, resistant strains were selected, and sugar uptake ability was obtained as an index using the system shown below. The results calculated using the stably expressing cells are shown in Table 1 as Method A.

方法B:ヒトSGLT2蛋白質を発現するプラスミドベクターを、リポフェクトアミンLTX(インビトロジェン社)を用いてCHO−K1細胞にトランスフェクションした。SGLT2発現細胞は、1000μg/mLの濃度のジェネティシンの存在下で培養し耐性株を選択し、下記に示す系により糖取り込み能を指標に取得した。本安定発現細胞を用いて算出された結果を表1に方法Bとして示した。   Method B: A plasmid vector expressing human SGLT2 protein was transfected into CHO-K1 cells using Lipofectamine LTX (Invitrogen). SGLT2-expressing cells were cultured in the presence of geneticin at a concentration of 1000 μg / mL, resistant strains were selected, and sugar uptake capacity was obtained as an index by the system shown below. The results calculated using the stably expressing cells are shown in Table 1 as Method B.

(3)安定発現細胞におけるナトリウム依存的糖取り込み阻害試験
上記で調製した安定発現細胞を用いて下記試験を行った。
(3) Sodium-dependent sugar uptake inhibition test in stably expressing cells The following tests were conducted using the stably expressing cells prepared above.

前処理用緩衝液(140mM 塩化コリン、2mM KCl、1mM CaCl、1mM MgCl、10mM HEPES/5mM Tris、pH7.4)を200μLをSGLT1安定発現細胞に、または2mLを各SGLT2安定発現細胞に加え、20分間インキュベーションした。前処理用緩衝液を除去し、試験化合物を含む取り込み用緩衝液([14C]メチル α−D−グルコピラノシドを含むメチル α−D−グルコピラノシド(1mM)、140mM NaCl、2mM KCl、1mM CaCl、1mM MgCl、10mM HEPES/5mM Tris、pH7.4)75μL(SGLT1の場合)、または200μL(SGLT2の場合)を加え、37℃にて30分(SGLT1)または60分(SGLT2)取り込み反応を行った。反応後細胞を洗浄用緩衝液(10mM メチル α−D−グルコピラノシド、140mM 塩化コリン2mM KCl、1mM CaCl、1mM MgCl、10mM HEPES/5mM Tris、pH7.4)200μL(SGLT1の場合)、または2mL(SGLT2の場合)で2回洗浄し、0.25M NaOH溶液75μL(SGLT1の場合)、または400μL(SGLT2の場合)に溶かした。液体シンチレーター(パーキンエルマー社)を加えよく混和した後、β線測定装置を用いて放射活性を測定した。対照群として試験化合物を含まない取り込み用緩衝液を調製した。また基礎取り込み用としてNaClに代えて塩化コリンを含む取り込み用緩衝液を調製した。 Add 200 μL of pretreatment buffer (140 mM choline chloride, 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) to SGLT1 stably expressing cells, or 2 mL to each SGLT2 stably expressing cells Incubated for 20 minutes. The pretreatment buffer is removed and the uptake buffer containing the test compound ([ 14 C] methyl α-D-glucopyranoside containing methyl α-D-glucopyranoside (1 mM), 140 mM NaCl, 2 mM KCl, 1 mM CaCl 2 , Add 1 μM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) 75 μL (for SGLT1) or 200 μL (for SGLT2) and perform uptake reaction at 37 ° C. for 30 minutes (SGLT1) or 60 minutes (SGLT2) It was. After reaction, the cells are washed with a buffer for washing (10 mM methyl α-D-glucopyranoside, 140 mM choline chloride 2 mM KCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 10 mM HEPES / 5 mM Tris, pH 7.4) 200 μL (for SGLT1), or 2 mL It was washed twice with (in the case of SGLT2) and dissolved in 75 μL of 0.25 M NaOH solution (in the case of SGLT1) or 400 μL (in the case of SGLT2). After adding a liquid scintillator (Perkin Elmer) and mixing well, radioactivity was measured using a β-ray measuring device. As a control group, an uptake buffer containing no test compound was prepared. For basal uptake, an uptake buffer containing choline chloride instead of NaCl was prepared.

IC50値を求めるにあたり、適当な6濃度の試験化合物を用い、対照群の糖取り込み量(100%)に対し、糖取り込み量が50%阻害される試験化合物濃度(IC50値)を算出した。試験結果を表1に示す。 In determining the IC 50 value, the test compound concentration (IC 50 value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. . The test results are shown in Table 1.

Figure 0005817317
Figure 0005817317

表1より、本発明化合物は、強いSGLT1阻害活性を有し、また、SGLT2阻害活性も弱いがある程度の活性を有することが示された。
以下に、類似構造化合物に対する本発明化合物の優位性を示す。
From Table 1, it was shown that the compounds of the present invention have strong SGLT1 inhibitory activity and also have some activity although SGLT2 inhibitory activity is weak.
The superiority of the compound of the present invention over the similar structure compound is shown below.

表2に本願類似化合物の糖負荷後の血糖低下作用と腎臓内濃度を示した。化合物4、10、11及び33は1mg/kg経口投与後の糖負荷試験において、強い血糖低下作用を示した。一方で、1mg/kg経口投与した7日後、化合物は排泄されず腎臓に残留する傾向が見られた。標的臓器はSGLT1が多く分布する小腸である。従って、標的臓器以外に化合物が長く残留することで、予期せぬ副作用が発現する場合がある。例えば、分子内に3級アミンの様な親水性基と芳香環の様な疎水性基をもつ化合物は、陽イオン性薬物と呼ばれる。これらは、リン脂質と疎水結合し、ライソゾーム内に取り込まれ全身の器官に蓄積されることがある。薬物によって、蓄積が見られる器官は異なり、クロロキンでは網膜障害、パーヘキシリンでは肺や小脳に変化が見られる。(日薬理誌 Folia Pharmacol. Jpn. 113, 19-30, 1999)   Table 2 shows the blood glucose lowering effect and intrarenal concentration of the similar compounds of the present application after sugar loading. Compounds 4, 10, 11 and 33 showed a strong hypoglycemic effect in a glucose tolerance test after oral administration of 1 mg / kg. On the other hand, 7 days after oral administration of 1 mg / kg, the compound tended to remain in the kidney without being excreted. The target organ is the small intestine where SGLT1 is distributed a lot. Therefore, unexpected side effects may occur when the compound remains for a long time other than the target organ. For example, a compound having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is called a cationic drug. They are hydrophobically bound to phospholipids and can be taken up into lysosomes and accumulated in systemic organs. Depending on the drug, the organs that accumulate are different, with chloroquine showing retinal damage and perhexiline with changes in the lungs and cerebellum. (Nippon Pharmacology Journal Folia Pharmacol. Jpn. 113, 19-30, 1999)

このようなことから、化合物が薬効を示した後に体内から速やかに排泄されることが望ましい。   For this reason, it is desirable that the compound is rapidly excreted from the body after showing its medicinal properties.

試験例2 ストレプトゾトシン糖尿病モデルラットにおける血糖値上昇抑制作用確認試験
(1)糖尿病モデルラットの作製
7週齢のSD/IGSラット(日本チャールスリバー株式会社,雄性)について約16時間の絶食後、エーテル麻酔下でストレプトゾトシン(STZ)50mg/kgを尾静脈内投与し、糖尿病モデルラットを作製した。同様にエーテル麻酔下、1.25mmol/Lクエン酸生理食塩液1mL/kgを尾静脈内投与し、正常対照ラットを作製した。STZまたは1.25mmol/Lクエン酸生理食塩液投与1週後(8週齢)、経口グルコース負荷試験に供した。
Test Example 2 Test for confirming inhibitory effect on blood glucose level in streptozotocin diabetic model rats (1) Preparation of diabetic model rats 7-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male) were fasted for about 16 hours and then anesthetized with ether. Under the above, streptozotocin (STZ) 50 mg / kg was administered into the tail vein to prepare a diabetes model rat. Similarly, under ether anesthesia, 1.25 mmol / L citrate physiological saline 1 mL / kg was administered into the tail vein to prepare normal control rats. One week after administration of STZ or 1.25 mmol / L citrate physiological saline (8 weeks of age), it was subjected to an oral glucose tolerance test.

(2)経口グルコース負荷試験
ラットを約16時間の絶食後、薬物投与群には、0.5%カルボキシメチルセルロースナトリウム(CMC)水溶液に溶解した薬物(1mg/kg)を、対照群には0.5%CMC水溶液のみ経口投与した。薬物投与5分後に、グルコース溶液(2g/kg)を経口投与し、薬物投与前(0time)、及び、経口投与0.25、0.5、1、2時間後の計5点で採血した。
(2) Oral glucose tolerance test After fasting rats for about 16 hours, in the drug administration group, a drug (1 mg / kg) dissolved in a 0.5% sodium carboxymethylcellulose (CMC) aqueous solution was added to the control group, and in the control group, the dose was 0. Only 5% CMC aqueous solution was orally administered. Five minutes after drug administration, glucose solution (2 g / kg) was orally administered, and blood was collected at a total of 5 points before drug administration (0 time) and 0.25, 0.5, and 1, 2 hours after oral administration.

採血は、エーテル麻酔下でラット尾静脈よりヘパリンコート採血管を用いて行い、遠心分離後、血漿を分取した。血漿中グルコース濃度の定量は、グルコースCIIテストワコー(和光純薬株式会社)を用いて測定した。血糖値上昇抑制作用強度は、各薬物投与群の0から1時間までの血糖値より台形法を用いて血糖値-時間曲線下面積(AUC)を算出し、basalを差し引いた血糖増加面積(ΔAUC)として表記し、対照群のそれに対する降下の割合で表記した。   Blood collection was performed using heparin-coated blood collection tubes from the rat tail vein under ether anesthesia, and after centrifugation, plasma was collected. The plasma glucose concentration was measured using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.). The blood glucose level increase inhibitory action strength is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level from 0 to 1 hour of each drug administration group, and the area of increased blood glucose (ΔAUC) by subtracting basal ) And expressed as a percentage of the drop relative to that of the control group.

結果を表2及び表3に示す。   The results are shown in Tables 2 and 3.

試験例3
(1)国際特許公開WO2007/136116号パンフレット記載の化合物4、10、11、33経口投与後1週間までの腎臓中濃度推移
7週齢のSD/IGSラット(日本チャールスリバー株式会社、雄性、非絶食)に、0.5%CMC水溶液にて調製した化合物4、10、33(各1mg/kg)、および化合物11(0.3mg/kg)を経口投与した。薬物投与後24、72、168時間にエーテル麻酔下、後大静脈より全採血し、安楽死確認後に腎臓を摘出した。生理食塩液で組織表面を洗浄後、重量を測定し4倍量の精製水を加え氷冷下ホモジナイズした。ホモジネートに内標準物質を含むアセトニトリル/メタノール溶液を加えて除タンパクした後、上清をLC−MS/MS(アプライドバイオシステムズAPI3000)に供した。ポジティブイオンモードのエレクトロスプレーイオン化法にて生成した薬物由来のイオンを選択反応モニタリングにて検出した。得られた抽出イオンクロマトグラムのピーク面積から内標準法にてホモジネート中薬物濃度を算出した。
ここで、化合物10および33の内部標準物質には、(1S)−1,5−アンヒドロ−1−[5−(4−エトキシベンジル)−2−メトキシ−4−メチルフェニル]−1−チオ−D−グルシトール,エチル−Dを用い、化合物4および11の内部標準物質には、化合物11および化合物11重水素標識体(トリスヒドロキシメチル−D;−C(CDOH))をそれぞれ用いた。
Test example 3
(1) Changes in renal concentration up to 1 week after oral administration of compounds 4, 10, 11, 33 described in the pamphlet of International Patent Publication No. WO 2007/136116 7-week-old SD / IGS rats (Nippon Charles River Co., Ltd., male, non- In the fasting, compounds 4, 10, 33 (each 1 mg / kg) and compound 11 (0.3 mg / kg) prepared in 0.5% CMC aqueous solution were orally administered. At 24, 72 and 168 hours after drug administration, whole blood was collected from the posterior vena cava under ether anesthesia, and the kidney was removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, the weight was measured, 4 times the amount of purified water was added, and the mixture was homogenized under ice cooling. After deproteinization by adding an acetonitrile / methanol solution containing an internal standard substance to the homogenate, the supernatant was subjected to LC-MS / MS (Applied Biosystems API3000). Drug-derived ions generated by the electrospray ionization method in the positive ion mode were detected by selective reaction monitoring. The drug concentration in the homogenate was calculated from the peak area of the extracted ion chromatogram obtained by the internal standard method.
Here, the internal standard substances of the compounds 10 and 33 include (1S) -1,5-anhydro-1- [5- (4-ethoxybenzyl) -2-methoxy-4-methylphenyl] -1-thio- D-glucitol and ethyl-D 5 were used, and compound 11 and compound 11 deuterium labeled (trishydroxymethyl-D 6 ; -C (CD 2 OH) 3 ) were used as internal standard substances of compounds 4 and 11, respectively. Using.

実験結果を表2に示す。   The experimental results are shown in Table 2.

(2)化合物1−2、5−2、6−2、13−2、15−2の3日間反復経口投与後の腎臓中濃度
7週齢のSD/IGSラット(日本チャールスリバー株式会社、雄性、非絶食)に、0.5%CMC水溶液にて調製した化合物1−2、5−2、6−2、13−2、15−2(3mg/kg)を1日1回3日間連続経口投与した。最終日の薬物投与後48時間にイソフルラン麻酔下、後大静脈より全採血し、安楽死確認後に腎臓を摘出した。生理食塩液で組織表面を洗浄後、重量を測定し4倍量の精製水を加え氷冷下ホモジナイズした。ホモジネート中薬物濃度の測定は、上記に示した試験例3の(1)と同じ方法で、内部標準物質に上記の化合物11を用い、LC−MS/MSにより行った。
(2) Renal concentration after repeated oral administration of compounds 1-2, 5-2, 6-2, 13-2, and 15-2 for 3 days SD / IGS rats (Nippon Charles River Co., Ltd., male) , Non-fasted) Compound 1-2, 5-2, 6-2, 13-2, 15-2 (3 mg / kg) prepared in 0.5% CMC aqueous solution was orally administered once a day for 3 consecutive days. Administered. At 48 hours after drug administration on the final day, whole blood was collected from the posterior vena cava under anesthesia with isoflurane, and the kidney was removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, the weight was measured, 4 times the amount of purified water was added, and the mixture was homogenized under ice cooling. The measurement of the drug concentration in the homogenate was performed by LC-MS / MS using the above compound 11 as an internal standard substance in the same manner as in Test Example 3 (1) shown above.

実験結果を表3に示す。   The experimental results are shown in Table 3.

Figure 0005817317
Figure 0005817317

国際特許公開WO2007/136116号パンフレットに開示の化合物4、10、11および33の構造を、下記に示す。   The structures of compounds 4, 10, 11, and 33 disclosed in International Patent Publication WO2007 / 136116 are shown below.

Figure 0005817317
Figure 0005817317

Figure 0005817317
Figure 0005817317

国際特許公開WO2007/136116号パンフレットに開示の化合物は1mg/kg経口投与後の糖負荷試験において、強い血糖低下作用を示した。しかし、1mg/kg経口投与した後、腎臓中から化合物の消失速度が緩慢で、7日後でも化合物は排泄されず腎臓に残留する傾向が見られた(表2)。   The compound disclosed in the pamphlet of International Patent Publication No. WO2007 / 136116 showed a strong hypoglycemic action in a glucose tolerance test after oral administration of 1 mg / kg. However, after oral administration of 1 mg / kg, the disappearance rate of the compound from the kidney was slow, and even after 7 days, the compound was not excreted and remained in the kidney (Table 2).

一方、本発明化合物は上記先行技術化合物と同様に強い血糖降下作用を有した。また、3mg/kgの用量で3日間連続投与したにも関わらず、投与2日後に意外にも化合物は腎臓に残留しないという特徴を示した(表3)。   On the other hand, the compound of the present invention had a strong hypoglycemic action like the above prior art compounds. In addition, despite the continuous administration for 3 days at a dose of 3 mg / kg, it was shown that the compound unexpectedly did not remain in the kidney 2 days after administration (Table 3).

この相違の原因として、本発明化合物は、体内に吸収された場合に腎臓に残留されずにすみやかに排泄されたと考えられる。   As a cause of this difference, it is considered that the compound of the present invention was rapidly excreted without remaining in the kidney when absorbed into the body.

したがって、本発明化合物は、体内残留性の傾向がなく、連続投与による副作用及び毒性が少ない医薬品として実用性に優れた性質を有すると考えられる。   Therefore, the compound of the present invention does not tend to remain in the body, and is considered to have a property that is excellent in practicality as a pharmaceutical with few side effects and toxicity due to continuous administration.

本発明化合物の製剤例を以下に示す。
製剤例1
以下の成分を含有するカプセル剤を製造する。
成分 式(I)で表される化合物 10mg
マンニトール 113mg
L−HPC 15mg
HPC−L 9mg
147mg
式(I)で表される化合物を30メッシュのふるいに通す。他の添加剤を混合した後30メッシュのふるいに通す。これらに精製水を添加し造粒した後、乾燥する。得られた乾燥顆粒をふるい(30メッシュ)で篩過し147mgを2号カプセルに充填する。
Formulation examples of the compound of the present invention are shown below.
Formulation Example 1
A capsule containing the following ingredients is produced.
Component Compound represented by formula (I) 10mg
Mannitol 113mg
L-HPC 15mg
HPC-L 9mg
147mg
The compound of formula (I) is passed through a 30 mesh screen. The other additives are mixed and then passed through a 30 mesh screen. Purified water is added to these and granulated, followed by drying. The obtained dried granules are sieved with a sieve (30 mesh), and 147 mg is filled into a No. 2 capsule.

製剤例2
以下の成分を含有する錠剤を製造する。
成分 式(I)で表される化合物 10mg
マンニトール 86mg
結晶セルロース 21mg
L−HPC 14mg
HPC−L 8mg
ステアリン酸マグネシウム 1mg
140mg
式(I)で表される化合物を30メッシュのふるいに通す。他の添加剤を混合した後30メッシュのふるいに通す。これらに精製水を添加し造粒した後、乾燥する。得られた乾燥顆粒をふるい(30メッシュ)で篩過し混合する。混合品にステアリン酸マグネシウムを添加し、打錠用顆粒を得る。本打錠用顆粒を打錠し140mgの錠剤を得る。
Formulation Example 2
A tablet containing the following ingredients is produced.
Component Compound represented by formula (I) 10mg
Mannitol 86mg
Crystalline cellulose 21mg
L-HPC 14mg
HPC-L 8mg
Magnesium stearate 1mg
140mg
The compound of formula (I) is passed through a 30 mesh screen. The other additives are mixed and then passed through a 30 mesh screen. Purified water is added to these and granulated, followed by drying. The obtained dried granules are sieved through a sieve (30 mesh) and mixed. Add magnesium stearate to the mixture to obtain tableting granules. The granules for tableting are compressed to obtain 140 mg tablets.

本発明により、小腸上皮に発現するSGLT1(ナトリウム依存性グルコ−ス共輸送体1)活性を阻害し、消化管からのグルコ−ス吸収を抑制し、かつ体内貯留性の傾向がない、4−イソプロピルフェニル グルシトール化合物を有効成分として含有することを特徴とする糖尿病の予防又は治療剤を提供することが期待される。   According to the present invention, SGLT1 (sodium-dependent glucose cotransporter 1) activity expressed in the small intestinal epithelium is inhibited, glucose absorption from the gastrointestinal tract is suppressed, and there is no tendency to retain in the body. It is expected to provide a prophylactic or therapeutic agent for diabetes, which comprises an isopropylphenyl glucitol compound as an active ingredient.

Claims (2)

下記式(I’)で表される4−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩を有効成分として含有し、さらに結晶セルロース、デンプン、乳糖、マンニトール、ヒドロキシプロピルセルロース、ポリビニルピロリドン、ステアリン酸マグネシウム、タルク及びカルボキシメチルセルロースカルシウムからなる群から選ばれる1種以上を含有することを特徴とする糖尿病の予防又は治療用の経口用製剤
Figure 0005817317
It contains a 4-isopropylphenyl glucitol compound represented by the following formula ( I ′ ) or a pharmaceutically acceptable salt thereof as an active ingredient , and further includes crystalline cellulose, starch, lactose, mannitol, hydroxypropylcellulose, polyvinylpyrrolidone, An oral preparation for the prevention or treatment of diabetes comprising one or more selected from the group consisting of magnesium stearate, talc and carboxymethylcellulose calcium :
Figure 0005817317
上記式(I’)で表される4−イソプロピルフェニル グルシトール化合物又はその製薬学的に許容される塩の投与量が1日当たり0.001mg〜1000mgである、請求項1に記載の経口用製剤。The oral preparation according to claim 1, wherein the dose of the 4-isopropylphenyl glucitol compound represented by the formula (I ') or a pharmaceutically acceptable salt thereof is 0.001 mg to 1000 mg per day.
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