JP2010018611A - Preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications containing 1-phenyl 1-thio-d-glucitol derivative as effective ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To find a new preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications for inhibiting SGLT1 (sodium-dependent glucose cotransporter 1) expressed in the small intestine epithelium, and SGLT2 (sodium-dependent glucose cotransporter 2) expressed in the kidney, and having both an inhibiting action on glucose absorption through intestinal tracts and an excretion action of glucose in urine. <P>SOLUTION: The preventive or therapeutic agent for diabetes, diabetes-related diseases or diabetic complications contain, as an effective ingredient, a 1-phenyl 1-thio-D-glucitol compound represented by formula (I), etc. a pharmaceutically acceptable salt or hydrate thereof. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a pharmaceutical having inhibitory activity on sodium-dependent glucose cotransporter 1 (SGLT1) and sodium-dependent glucose cotransporter 2 (SGLT2) involved in glucose reabsorption in the kidney, particularly diabetes The present invention relates to a preventive or therapeutic agent for diabetes-related diseases or diabetic complications.

  When suffering from diabetes, the fasting blood glucose level is 126 mg / dL or more. Moreover, even if the fasting blood glucose level is normal, if it shows a high blood glucose level of 140 to 200 mg / dL after meal, it is diagnosed as abnormal glucose tolerance (hereinafter referred to as IGT (impaired glucose tolerance)). The In recent years, delaying the transition from IGT to diabetes is considered to reduce the risk of cardiovascular disorders. For example, in Da Qing IGT and Diabetes Study conducted in China in 1997, it was reported that the transition from IGT to type 2 diabetes was significantly suppressed by performing diet and exercise (see Non-Patent Document 1). . As an effective example of drug treatment, the transition from IGT to type 2 diabetes occurs when an α-glucosidase inhibitor acarbose that inhibits sugar hydrolase and delays the absorption of sugar from the small intestine is administered. Has been reported to further suppress the onset of hypertension (see Non-Patent Document 2).

  From the above, in order to suppress the onset of diabetes, it is important to control IGT by diet therapy, exercise and drug therapy. However, at present, the number of diabetic patients is increasing year by year, and new therapeutic drugs corresponding to various causes and pathologies are being demanded.

  The basis of diabetes treatment is diet therapy and exercise therapy, but it is necessary to adopt pharmacotherapy if it is difficult to maintain regular lifestyle habits or if these are not effective enough is there.

  It is known that sodium-dependent glucose cotransporter 1 (SGLT1) is expressed at high frequency in the small intestinal epithelium. This SGLT1 depends on sodium in the small intestine and is responsible for active transport of glucose or galactose (see Non-Patent Document 3). Further, it has been confirmed that SGLT1 mRNA and protein expression levels are increased in diabetes model rats (see Non-Patent Document 4). In recent years, synthesis examples of pyrazole derivatives that inhibit SGLT1 activity, suppress dietary glucose absorption, and improve IGT have been reported (see Patent Documents 1 to 6).

  In addition, sodium-dependent glucose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose once filtered by glomeruli is reabsorbed via SGLT2 (Non-patent Document). 5). When an SGLT2 inhibitor is administered to diabetic rats, it promotes glucose excretion into urine and induces a hypoglycemic effect, and SGLT2-specific inhibitors are now considered as target molecules for new antidiabetic drugs ( Non-patent document 6). Against this background, SGLT2 inhibitors have been studied and various glucose derivatives have been provided (see Patent Documents 7 and 8).

  Therefore, if SGLT1 and SGLT2 activities can be simultaneously inhibited, it is considered that a new type of anti-diabetic drug having both postprandial hyperglycemic inhibitory action based on SGLT1 inhibition and occasional hypoglycemic action based on SGLT2 inhibition can be provided.

  So far, 1-thio-D-glucitol derivatives that inhibit SGLT2 relatively strongly have been reported (see Patent Document 9). However, there has been no report on 1-phenyl 1-thio-D-glucitol derivatives that strongly inhibit both SGLT1 and SGLT2.

International Publication No. WO2002 / 098893 Pamphlet International Publication No. WO2004 / 014932 Pamphlet International Publication No. WO2004 / 018491 Pamphlet International Publication No. WO2004 / 019958 Pamphlet International Publication No. WO2005 / 121161 Pamphlet International Publication No. WO2004 / 050122 Pamphlet European Patent Application No. 0850948 International Publication No. WO2001 / 068660 Pamphlet International Publication No. WO2006 / 073197 Pamphlet

Pan XR, et al. Diabets Care, 20, 534, 1997 J.-L. Chiasson, et al. Lancent, 359, 2072, 2002 W. S. Lee, et al.. J. Biol. Chem. 269, 12032, 1994 Y. Fujita, et al. Diabetologia 41, 1459, 1998 E. M. Wright, Am. J. Physiol. Renal. Physiol., 280, F10, 2001 G. Toggenburger, et al. Biochem. Biophys. Acta., 688, 557, 1982

  The problem to be solved by the present invention is to provide a new type of therapeutic agent for diabetes that inhibits the activities of both SGLT1 and SGLT2 and has both an action to suppress glucose absorption from the digestive tract and an action to excrete urine sugar. is there.

  In order to solve the above-mentioned problems, the present inventors have intensively studied the effect of the aglycone substituent of the 1-thio-D-glucitol derivative on the SGLT inhibitory activity, and as a result, introduced certain substituents in combination. Thus, compound (VII) was found from compound (I) that strongly inhibits the activities of both SGLT1 and SGLT2, and the present invention was completed.

That is, the present invention
(1) Formula (I)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications,

(2) Formula (II)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications,

(3) Formula (III)

で表される１−フェニル １−チオ−Ｄ−グルシト−ル化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とする糖尿病、糖尿病関連疾患又は糖尿病性合併症の予防又は治療剤、

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications,

(4) Formula (IV)

で表される１−フェニル １−チオ−Ｄ−グルシト−ル化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とする糖尿病、糖尿病関連疾患又は糖尿病性合併症の予防又は治療剤、

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications,

(5) Formula (V)

で表される１−フェニル １−チオ−Ｄ−グルシト−ル化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とする糖尿病、糖尿病関連疾患又は糖尿病性合併症の予防又は治療剤、

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications,

(6) Formula (VI)

で表される１−フェニル １−チオ−Ｄ−グルシト−ル化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とする糖尿病、糖尿病関連疾患又は糖尿病性合併症の予防又は治療剤、

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications,

(7) Formula (VII)

で表される１−フェニル １−チオ−Ｄ−グルシト−ル化合物若しくはその製薬学的に許容される塩又はそれらの水和物を有効成分として含有することを特徴とする糖尿病、糖尿病関連疾患又は糖尿病性合併症の予防又は治療剤である。

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, It is a preventive or therapeutic agent for diabetic complications.

  A compound introduced by combining certain substituents on the aglycone of the 1-thio-D-glucitol derivative inhibited the activities of both SGLT1 and SGLT2. Moreover, these compounds showed an excellent blood glucose lowering action.

Used in the present invention,
“Pharmaceutically acceptable salt” is a salt with an alkali metal, alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt or potassium salt. , Calcium salt, ammonium salt, aluminum salt, triethylammonium salt, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, succinic acid Salt, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfonate With, lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine , Salts with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, undecanoate And a salt with an acrylic acid polymer and a salt with a carboxyvinyl polymer.

  “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 air or recrystallized to absorb moisture and form adsorbed water, or may become a hydrate. The hydrate in the present invention includes such a hydrate.

  Below, the manufacturing method of this invention compound (I) to (VII) is demonstrated.

Manufacturing method 1

Wherein, R ^A represents a methyl group, an ethyl group, a methoxy group or a methylthio group, R ^B represents a methyl group or a chlorine atom, R ^C represents a benzyl group or an allyl group.

(1) Step 1
Compound (1A) can be produced according to the pamphlet of International Patent Publication No. WO2006 / 073197. Moreover, it can manufacture according to the reference example shown below. A lithium reagent (2A) can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for the compound (1A). Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is -78 ° C to room temperature, preferably -78 ° C to -25 ° C. Alternatively, the Grignard reagent (2A) can be prepared using magnesium powder. Examples of the solvent used in the reaction include tetrahydrofuran, diethyl ether, diglyme and the like. Further, iodine or 1,2-dibromoethane may be used as an activator for magnesium.

  Next, compound (4A) can be obtained by adding thiolactone (3A) to compound (2A). The temperature at which thiolactone (3A) is added is preferably −78 ° C. to −25 ° C. when (2A) is a lithium reagent, and preferably −15 ° C. to 25 ° C. when (2A) is a Grignard reagent.

(2) Step 2 (reduction)
Compound (5A) can be synthesized by reacting compound (4A) with Et ₃ SiH, i-Pr ₃ SiH, t-BuMe ₂ SiH or Ph ₂ SiHCl in the presence of an acid. Examples of the acid used in this reaction include BF ₃ .Et ₂ O, CF ₃ COOH, MeSO ₃ H, InCl _{3 and the} like, and examples of the solvent include chloroform, dichloromethane, acetonitrile or a mixed solvent thereof. Is a mixed solvent with acetonitrile such as acetonitrile-chloroform and acetonitrile-dichloromethane. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 25 ° C.

(3) Step 3 (deprotection)
In the compound (5A) obtained above, when R ^C is a benzyl group, dehydrogenation can be achieved by catalytic hydrogenation under a hydrogen atmosphere using a catalyst such as palladium activated carbon, palladium hydroxide, or platinum-palladium activated carbon. Inventive compounds can be obtained by benzylation. 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.

In the debenzylation, acids such as BCl ₃ , BCl ₃ .Me ₂ S, BBr ₃ , AlCl ₃ , CF ₃ COOH, and TfOH can be used. Examples of the solvent used in this reaction include chloroform, dichloromethane, acetonitrile, diethyl ether, tetrahydrofuran, dimethyl sulfide, anisole and the like. Among them, a method using CF ₃ COOH, TfOH, or ethanedithiol in dimethyl sulfide is preferable. The reaction temperature is preferably -78 ° C to 40 ° C.
In the compound (5A), when R ^C is an allyl group (—CH ₂ CH═CH ₂ ), tert-butoxypotassium is allowed to act in dimethyl sulfoxide to effect isomerization (—CH═CHCH ₃ ), followed by hydrochloric acid. Alternatively, it can be removed using HgCl ₂ / HgO. Alternatively, it can be removed using Pd (PPh ₃ ) ₄ , PdCl ₂ , palladium activated carbon, etc. in the presence of an organic acid such as acetic acid, p-toluenesulfonic acid hydrate, N, N′-dimethylbarbituric acid. it can. Examples of the solvent used in this reaction include acetonitrile, diethyl ether, tetrahydrofuran and the like, and the reaction temperature is preferably 25 ° C to 100 ° C.

Manufacturing method 2
Compound (5A) can also be produced by the method shown below. Here, the symbols in the formula are as defined above.

(4) Step 4
By the method described in Step 1, an aryllithium reagent can be prepared from the intermediate compound (6A) using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium. On the other hand, a compound (7A) can be obtained by adding thiolactone (3AB). Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is -78 ° C to room temperature, preferably -78 ° C to -25 ° C.

(5) Step 5 (acid hydrolysis)
Compound (8A) can be produced by hydrolyzing the acetal group in compound (7A) using hydrochloric acid, p-toluenesulfonic acid monohydrate, or the like. As the solvent used at this time, tetrahydrofuran, ethanol, methanol, water or a mixed solvent thereof is preferable. The reaction temperature is 4 ° C. to 60 ° C., preferably room temperature. Moreover, although reaction time changes with reaction temperature, it is 1 hour-24 hours.

(6) Step 6
The phenyllithium reagent compound (10A) can be produced using n-butyllithium, sec-butyllithium, tert-butyllithium or the like for 4-substituted toluene (9A). Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is -78 ° C to room temperature, preferably -78 ° C to -25 ° C. The reaction time is preferably 5 to 30 minutes. In addition, Grignard reagent (10A) can be produced using metallic magnesium. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, diglyme and the like. Next, a reagent (10A) and a compound (8A) are made to react and a compound (11A) can be manufactured.

(7) Step 7 (reduction)
Compound (5A) can be synthesized by reacting compound (11A) with Et ₃ SiH, i-Pr ₃ SiH, t-BuMe ₂ SiH or Ph ₂ SiHCl in the presence of an acid. Examples of the acid used in this reaction include BF ₃ .Et ₂ O, CF ₃ COOH, InCl _{3 and the} like, and examples of the solvent include chloroform, dichloromethane, acetonitrile or a mixed solvent thereof, and acetonitrile- It is a mixed solvent with acetonitrile such as chloroform and acetonitrile-dichloromethane. The reaction temperature here is −60 ° C. to 25 ° C., preferably −30 ° C. to 0 ° C.

As a particularly preferable method, reduction of a highly reactive hemiacetal moiety is performed at a reaction temperature of −15 ° C. to −5 ° C. using about 1 equivalent of acid in an acetonitrile solvent. Next, the reaction temperature is raised to 0 ° C. to 5 ° C., and about 1 equivalent of acid is added to reduce the hydroxyl group at the benzyl position.

Production of thiolactone (3A)

Compound (3A) can be synthesized with reference to Yuasa, H., et al. J. Chem. Soc. Perkin Trans. 1, 2763, 1990. Alternatively, they can be synthesized according to the above scheme.

(8) Step 8
The 1-position hydroxyl group of compound (3B) (which can be produced with reference to WO 04/106352 pamphlet) is protected with a protecting group that is resistant to basic conditions and deprotectable under neutral or acidic conditions. For example, using 3,4-dihydro-2H-pyran (3,4-DHP) and p-toluenesulfonic acid monohydrate, protecting with tetrahydropyranyl group (THP group) to synthesize compound (3C) Can do. The solvent at this time is preferably tetrahydrofuran, diethyl ether, chloroform or the like.

(9) Step 9
The deprotection of the acetoxy group can be performed using a base such as sodium methoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine, etc., and methanol, ethanol, hydrous methanol, etc. are used as the solvent. Can do. Next, benzyl bromide, benzyl chloride or allyl bromide can be reacted with an appropriate base to obtain compound (3D). Examples of the base include triethylamine, N-ethyl-N, N-diisopropylamine, pyridine, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, tert-butoxypotassium and the like. Preferably, potassium carbonate, calcium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and sodium hydride are used. Examples of the solvent used in this reaction include N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, dimethoxyethane and the like, and the reaction temperature is preferably -20 ° C to 25 ° C.

(10) Step 10
Next, the protecting group at the 1-position can be deprotected to obtain compound (3E). For example, the THP group can be removed by treating compound (3D) with p-toluenesulfonic acid or pyridinium p-toluenesulfonic acid in methanol or ethanol.

(11) Step 11
Finally, compound (3E) can be treated with a suitable oxidizing agent to produce thiolactone (3A). As an oxidizing agent used for this reaction, dimethyl sulfoxide-acetic anhydride, Dess-Martin periodinane, IBX, etc. are preferable, and reaction temperature is 0 degreeC-40 degreeC.

  The compound of the present invention inhibits the activities of both SGLT1 and SGLT2, improves IGT by inhibiting glucose absorption from the digestive tract and urinary glucose excretion, and can prevent or treat diabetes.

  Therefore, the compound of the present invention can be used as an active ingredient of a SGLT1 and SGLT2 inhibitor, or a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

  Here, “diabetes” includes type 1 diabetes, type 2 diabetes, and other types of diabetes caused by a specific cause.

  Here, “diabetes-related disease” means obesity, hyperinsulinemia, glucose metabolism abnormality, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, high Examples include uricemia and gout.

  Here, “diabetic complications” are classified into acute complications and chronic complications.

  “Acute complications” include hyperglycemia (such as ketoacidosis), infections (such as skin, soft tissue, biliary system, respiratory system, urinary tract infection) and the like.

  “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.

  The main complications are diabetic retinopathy, diabetic nephropathy, diabetic neuropathy.

  The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is 0.1 to 1000 mg / kg body weight per day for an adult, 0.1 to 200 mg. / Kg body weight is preferable, and 0.1 to 10 mg / kg body weight is more preferable. This can be administered once to several times a day.

  The compound of the present invention is a therapeutic agent for diabetes having a different mechanism other than SGLT1 and SGLT2 activity inhibitor, for the purpose of enhancing the action of the compound or reducing the dose of the compound, It can be used in combination with drugs such as antihyperlipidemic agents, antihypertensive agents, antiobesity agents, diuretics, antithrombotic agents (hereinafter abbreviated as concomitant drugs). In this case, the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.

  Examples of diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast; insulin zinc; protamine insulin zinc; Insulin fragment or derivative (eg, INS-1 etc.), oral insulin preparation), insulin resistance improving agent (eg, pioglitazone or a salt thereof (preferably hydrochloride), rosiglitazone or a salt thereof (preferably maleate) Riboglitazone (CS-011) (R-119702), Sipoglitazar (TAK-654), Metaglidasen (MBX-1 0 2), Naveglitazar LY-5 1 9 8 1 8), MX-6054, Balaglitazone (NN-2344), T-1 3 1 (AMG131), PPA Rγ agonist, PPA Rγ antagonist, PPA Rγ / α dual agonist, α -Glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, phenformin, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)), insulin secretion promotion Sulfonylureas (eg, tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybazole, etc.), repaglinide, senaglinide, nateglinide, mitiglinide or its calcium Salt hydrate), GPR40 agonist, GPR40 antagonist, GLP-1 receptor agonist (eg, GLP-1, GLP-1 MR agent, Liraglutide (NN-2211), Exenatide (AC-2993) (exendin-4 ), Exenatide LAR, BIM-51077, A ib (8, 35) hGLP-1 (7, 37) NH2, CJC-1 13 1, AVE0010, GSK-716155), amylin agonist (eg, pramlintide), phosphor Tyrosine phosphatase inhibitors (eg, sodium vanadate), dipeptidyl peptidase I V inhibitors (eg, compounds described in WO02 / 038541, NVP-DPP-278, PT-100, P32 / 98, vildagliptin ( AF-237), P93 / 01, sitagliptin (MK-431), saxagliptin (BMS-477118), SYR-322, MP-513, T-6666, GRC-8200, etc.), β3 agonist ( Examples, AJ-9679, AZ40140, etc.), gluconeogenesis inhibitors (eg, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists, fructose-1,6-bisphosphatase inhibitors), SGLT (sodium- glucose transporter) inhibitors (eg, compounds described in WO04 / 014931, WO04 / 089967, WO06 / 073197, T-1095, Serglflozin (GSK-869682), GSK-1 9075, KGT-1251, KGT-1681, KGA-2727, BMS-512148, AVE2268, SAR7226, etc.), 11β-hydroxysteroid dehydrogenase inhibitor (eg, compounds described in WO06051662, BVT-3498, INCB13739), GPR119 agonist (Eg, PSN-632408, APD-668), adiponectin or agonist thereof, IKK inhibitor (eg, AS-2868), AMPK activator, leptin resistance ameliorating agent, somatostatin receptor agonist, glucokinase activation Examples include drugs (eg, Ro-28-1675), pancreatic lipase inhibitors (eg, orlistat, ATL-962), and DGAT-1 inhibitors.

  Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophic factors and their increasing agents (eg, NGF). , NT-3, BDNF, neurotrophin production / secretion promoter), nerve regeneration promoter (eg, Y-128), PKC inhibitor (eg, ruboxistaurine mesylate (LY-333531)) AGE inhibitors (eg, ALT946, pimagedin, pyratoxatin, N-phenacylthiazolium bromide (ALT766), ALT-711, EXO-2 26, pyridoline, pyridoxamine), active oxygen scavengers (eg, Thioctic acid), brain Tube expansion agent (e.g., tiapride, mexiletine), somatostatin receptor agonists (e.g., B I M 2 3 1 9 0), apoptosis signal regulating kinase--1 (ASK-1) inhibitors.

  Antihyperlipidemic agents include, for example, statin compounds (eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin, rosuvastatin, pitavastatin or their salts (eg, sodium salt, calcium salt)), squalene synthesis Enzyme inhibitors (eg, TAK-475), fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, avasimibe, elucimibe), anion exchange resin (Eg, cholestyramine), probucol, nicotinic acid drugs (eg, nicomol, niceritol), ethyl icosapentate, plant sterols (eg, soto) Isterol, γ-oryzanol), CETP inhibitors (eg, Torcetrapib, JTT-705, JTT-302, FM-VP4, etc.), cholesterol absorption inhibitors (eg, ezetimibe, etc.) Is raised.

  Examples of the antihypertensive agent include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, azilsartan (TAK-536) ), Calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromacarim, L-2 7 1 5 2, A L0 6 7 1, NIP-12 1), clonidine Is mentioned.

  Examples of anti-obesity agents include central anti-obesity agents (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, amphetopramone, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist (Eg, compounds described in WO06 / 035967, SB-5 6 8 8 4 9; SNAP-7 9 4 1, T-226296); neuropeptide Y antagonists (eg, CP-4 2 2 9 3 5); Cannabinoid receptor antagonists (eg, rimonabant (SR-1 4 1 7 1 6), SR-147778); ghrelin antagonists; 1 1β-hydroxysteroid dehydrogenase inhibitors (eg, BVT-3 4 98, INCB13739)), pancreatic lipase inhibitor (eg, orlistat, ATL-962), DGAT-1 inhibitor, β3 agonist (eg, A -9 6 7 7, AZ4 0 1 4 0), peptidic appetite suppressant (eg, leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonist (eg, Lynchtripto, FPL-15849), feeding Inhibitors (eg, P-57) can be mentioned.

  Examples of diuretics include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopentiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide. , Methiclotiazide), anti-aldosterone preparations (eg, spironolactone, triamterene), carbonic anhydrase inhibitors (eg, acetazolamide), chlorobenzenesulfonamide preparations (eg, chlorthalidone, mefluside, indapamide), azosemide, isosorbide, ethacrynic acid, Piretanide, bumetanide, furosemide.

  Examples of the antithrombotic agent include heparin (eg, heparin sodium, heparin calcium, dalteparin sodium, AVE-5026), warfarin (eg, warfarin potassium, etc.), antithrombin drug (eg, argatroban) , Ximelagatran, Dabigatran, Odiparcil, Lepirudin, bivalirudin, Desirudin, ART-123, Idraparinux, SR-12571, TCG-9737, TCG-9737, TCG-9737, TCG-9737 -30870, MPC-0920, Pegmusirudin, Org-426951, etc.), thrombolytic drugs ( Urokinase, tisokinase, alteplase, natepase, monteplase, pamiteplase, etc., platelet aggregation inhibitor (e.g., ticlopidine hydrochloride) ), Ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride, etc.), anti-Xa inhibitors (eg, Fondaparinux, BAY-59-7939, DU-176b, YM-150, SR-1x, SRp 1257, SRp. , Razababan, LY-517717 MLN-102, Octaparine, Otamixaban, EMD-503982, TC-10, CS-3030, AVE-3247, GSK-838893, KFA-1982, etc., plasma carboxypeptidase B (or active thrombin-activable fibrinobinitis) Inhibitors (also known as TAFIa]) (eg, AZD-9684, EF-6265, MN-462) and the like.

  The compound of the present invention can be administered as a pharmaceutical systemically or locally, orally or parenterally.

  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. Tablets, pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections and the like can be prepared from the compound of the present invention and these carriers.

Hereinafter, the present invention will be described in more detail with reference examples, examples and test examples.
Reference example 1
Production of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (compound (3AB))

(1) Production of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose 2,3,4,6-tetra-O-acetyl- To a solution of 5-thio-D-glucopyranose (2.0 g, 5.49 mmol) in chloroform (40 mL), 3,4-dihydro-2H-pyran (1.5 mL, 16.5 mmol) and p-toluenesulfonic acid 1 water The Japanese product (104 mg, 0.549 mmol) was added and stirred at room 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 = 1: 1) to give a pale yellow amorphous title compound (2.56 g). Obtained.

(2) Preparation of tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose Next, tetrahydro-2H-pyran-2-yl 2, To a methanol (40 mL) solution of 3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.5 g), a methanol solution of 25 wt% sodium methoxide (0.11 mL, 0.55 mmol) was added. The mixture was further stirred for 3 hours. A small amount of dry ice was added to neutralize the reaction solution, and then the reaction solution was concentrated. The obtained residue was dissolved in N, N-dimethylformamide (20 mL). This solution was added dropwise to a suspension of sodium hydride (1.3 g, 32.9 mmol; 60% oil) and N, N-dimethylformamide (4 mL) under ice cooling. The reaction was stirred at room temperature for 20 minutes, then cooled to 4 ° C. and benzyl bromide (5.6 g, 32.9 mmol) was added. The reaction solution was stirred at room temperature for 12 hours, methanol (5 mL) was added, and the mixture was stirred for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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 = 6: 1) to give the title compound (3.36 g, 96%, 2 steps). )

(3) Production of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucopyranose Tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-benzyl- A mixture of 5-thio-D-glucopyranose (3.30 g, 5.15 mmol), pyridinium p-toluenesulfonic acid (518 mg, 2.06 mmol) and ethanol (58 mL) was stirred at 80 ° C. for 2 hours. The reaction was cooled to room temperature and the solvent was concentrated. The obtained residue was dissolved in ethyl acetate. This solution was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the title compound (2.89 g, quant.) As colorless crystals.
¹³ C NMR (125 MHz, CHLOROFORM-d) δ 41.3, 67.8, 71.6, 73.0, 73.2, 75.6, 76.2,
81.9, 82.9, 84.4, 127.5, 127.7, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5, 137.8, 138.3, 138.8.

(4) Production of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone 2,3,4,6-tetra-O-benzyl-5-thio- A mixture of D-glucopyranose (2.82 g, 5.07 mmol), dimethyl sulfoxide (47 mL) and acetic anhydride (39 mL) was stirred at room temperature for 12 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 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: ethyl acetate = 6: 1) to give the title compound (2.3 g, 82%) as a colorless oil. )
¹ H NMR (200 MHz, CHLOROFORM-d) δ ppm 3.70 (d, J = 4.8 Hz, 2 H) 3.86-4.02 (m, 2 H) 4.09-4.22 (m, 2 H) 4.40-4.68 (m, 7 H) 4.83 (d, J = 11.4 Hz, 1 H) 7.12-7.41 (m, 20 H).

Reference example 2
Production of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane (Compound (6A))

(1) Preparation of 1- [4- (benzyloxy) -2-methylphenyl] ethanone To a solution of 4′-hydroxy-2′-methylacetophenone (3.06 g, 20 mmol) in N, N-dimethylformamide (20 mL) Potassium carbonate (3.66 g, 26.4 mmol), benzyl bromide (2.7 mL, 22.4 mmol) and n-Bu ₄ NI (0.75 g, 2.03 mmol) were added, and the mixture was stirred at room temperature for 14 hours. Under ice cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and then water and ethyl acetate were added to separate the organic layer. The extract was washed with an aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1 → 6: 1) to give the title compound ( 5.05 g, quant.).
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.55 (s, 3 H) 2.57 (s, 3 H) 5.11 (s, 2 H) 6.78 − 6.86 (m, 2 H) 7.30 − 7.47 (m, 5 H) 7.75 (dd, J = 7.93, 1.09 Hz, 1 H).

(2) Preparation of 4- (benzyloxy) -5-bromo-2-methylbenzoic acid 1- [4- (benzyloxy) -2-methylphenyl] ethanone (20.9 g, 87.1 mmol) in acetone ( 300 mL) solution was added NaBr (9.86 g, 95.9 mmol) in water (100 mL), water (200 mL) and Oxone (Oxone monopersulfate, Aldrich) (59.0 g, 95.9 mmol). And stirred at room temperature for 2.5 hours. Under ice cooling, an aqueous solution (50 mL) of sodium sulfite (20 g) was added to the reaction solution, and then water and ethyl acetate were added to separate the organic layer. The organic layer was 20 wt. The extract was washed with an aqueous sodium sulfite 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 give 1- [4- (benzyloxy) -5-bromo-2-methylphenyl] ethanone and 1- [4- (benzyloxy) -3-bromo. A mixture (27.2 g) of 2-methylphenyl] ethanone was obtained. To this was added 5% sodium hypochlorite solution (300 mL, 255 mmol) and an aqueous solution (10 mL) of potassium hydroxide (4.80 g, 85.3 mmol), stirred at 120 ° C. for 1 hour, and then cooled to room temperature. The precipitated insoluble material was filtered off. 2N Hydrochloric acid was added to the insoluble material, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid 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 washed with methanol to give the title compound (16.6 g, 59%, 2 steps) as a colorless powder.
1H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.45 − 2.57 (m, 3 H) 5.28 (s, 2 H) 7.18 (s, 1 H) 7.31 − 7.54 (m, 5 H) 8.03 (s, 1 H) 12.83 (brs, 1 H).
ESI m / z = 319 (M−H), 321 (M + 2−H).

(3) Production of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane 4- (Benzyloxy) -5-bromo-2-methylbenzoic acid (16. 6 g, 51.7 mmol) in chloroform (80 mL) was added oxalyl chloride (5 mL, 56.9 mmol) and N, N-dimethylformamide (6 drops), stirred at room temperature for 1 hour, and then the reaction solution Then, 4- (benzyloxy) -5-bromo-2-methylbenzoyl chloride was obtained. Next, to a suspension of N, O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) in chloroform (60 mL) under ice-cooling, 4- (benzyloxy) -5- A solution of bromo-2-methylbenzoyl chloride in chloroform (60 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Under ice-cooling, water and chloroform were added to separate the organic layer, and the organic layer was 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 4- (benzyloxy) -5-bromo-N-methoxy-N-methylbenzamide. To this tetrahydrofuran (150 mL) solution was added lithium aluminum hydride (1.96 g, 51.7 mmol) at −10 ° C., and the mixture was stirred at the same temperature for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, ethyl acetate was added to separate the organic layer, and the organic layer was washed with 1N 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 to obtain 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde. Ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol) were added to this toluene (120 mL) solution, and heated under reflux for 1.5 hours using a Dean-Stark apparatus. did. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with water, 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: ethyl acetate = 5: 1). The product was further purified by NH silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.34 (s, 3 H) 3.92 − 4.19 (m, 4 H) 5.15 (s, 2 H) 5.87 (s, 1 H) 6.74 (s, 1 H) 7.27 − 7.51 (m, 5 H) 7.72 (s, 1 H).
ESI m / z = 348.

Reference example 3
2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (1,3-dioxolan-2-yl) -4-methylphenyl] -5-thio- Production of D-glucopyranose (compound 7A))

A solution of 2- [4- (benzyloxy) -5-bromo-2-methylphenyl] -1,3-dioxolane (12.9 g, 36.9 mmol) in tetrahydrofuran (100 mL) at −78 ° C. under a nitrogen atmosphere. 2.67M n-butyllithium hexane solution (14.5 mL, 36.9 mmol) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (9.77 g, 17.6 mmol) in tetrahydrofuran (40 mL) was added dropwise and brought to the same temperature. And stirred for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 → 2: 1) to give the title compound as a colorless and transparent amorphous substance. (10.6 g, 73%) was obtained.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.39 (s, 3 H) 3.46-3.72 (m, 2 H) 3.86-4.22 (m, 8 H) 4.43-5.00 (m, 8 H) 5.10 (s, 2 H) 5.92 (s, 1 H) 6.66-6.90 (m, 3 H) 7.00-7.38 (m, 23 H) 7.57 (brs, 1 H).
ESI m / z = 847 (M + Na ⁺ ).

Reference example 4
2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -5-thio-D-glucopyranose (compound (8A)) Manufacturing of

2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (1,3-dioxolan-2-yl) -4-methylphenyl] -5-thio- To a solution of D-glucopyranose (11.1 g, 13.5 mmol) in tetrahydrofuran (100 mL) was added 6N hydrochloric acid (100 mL) under ice cooling, and the mixture was stirred at room temperature for 12 hours. Under ice-cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 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, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the title compound (10.1 g) as a pale yellow oil. , Quant.).
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.64 (s, 3 H) 3.51-3.70 (m, 2 H) 3.84-4.29 (m, 4 H) 4.46-4.97 (m, 8 H) 5.04-5.24 (m , 2 H) 6.62-6.82 (m, 3 H) 6.99-7.38 (m, 23 H) 7.60 (brs, 1 H) 10.05 (s, 1 H).
ESI m / z = 803 (M + Na ⁺ ).

Reference Example 5
1- (Benzyloxy) -2-bromo-5-methyl-4- (4-methoxybenzyl) Preparation of benzene

  (1) To a solution of 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde (3.0 g, 9.83 mmol) in tetrahydrofuran (20 mL) at −18 ° C., 0.5 M 4-methoxyphenylmagnesium bromide In tetrahydrofuran (29.5 mL, 14.7 mmol) was added dropwise and stirred at −15 ° C. for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride 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: ethyl acetate = 4: 1) to give [1- (benzyloxy) as a colorless oil. -2-Bromo-5-methylphenyl] (4-methoxyphenyl) methanol (4.48 g) was obtained.

(2) Next, to a mixed solution of [1- (benzyloxy) -2-bromo-5-methylphenyl] (4-methoxyphenyl) methanol (4.40 g) in acetonitrile (20 mL) and chloroform (20 mL), At 4 ° C., Et ₃ SiH (3.1 mL, 19.7 mmol) and BF ₃ .Et ₂ O (1.2 mL, 9.83 mmol) were sequentially added. After stirring at the same temperature for 30 minutes, 2M aqueous potassium hydroxide solution (20 mL) was added. The resulting mixture was extracted with chloroform, and the organic layer was washed with 1M hydrochloric acid 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: ethyl acetate = 10: 1) to give the title compound (3.46 g, 89) as a colorless oil. %).
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.17 (s, 3 H) 3.79 (s, 3 H) 3.82 (s, 2 H) 5.12 (s, 2 H) 6.77 (s, 1 H) 6.82 (d, J = 8.4 Hz, 2 H) 7.02 (d, J = 8.4 Hz, 2 H) 7.19-7.45 (m, 4 H) 7.44-7.58 (m, 2 H).
EI m / z = 396, 398.

Reference Example 6
1- (Benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) Preparation of benzene

In the same manner as in Reference Example 5, the title compound was synthesized using 4-methylphenylmagnesium bromide instead of 4-methoxyphenylmagnesium bromide.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.17 (s, 3 H) 2.31 (s, 3 H) 3.84 (s, 2 H) 5.12 (s, 2 H) 6.76 (s, 1 H) 6.95-7.03 ( m, 2 H) 7.04-7.14 (m, 2 H) 7.22-7.58 (m, 6H).
EI m / z = 380, 382.

Reference Example 7
Preparation of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene

（１）［４−（ベンジルオキシ）−５−ブロモ−２−メチルフェニル］（４−エチルフェニル）メタノールの製造
１−ブロモ−４−エチルベンゼン（５．００ｇ、１６．４ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液に−６０℃にて、２．６６Ｍ ｎ−ＢｕＬｉのヘキサン溶液（６．４７ｍＬ、１７．２ｍｍｏｌ）を５分かけて滴下した。同温にて１５分攪拌した後に、この溶液に、４−（ベンジルオキシ）−５−ブロモ−２−メチルベンズアルデヒド（３．０３ｇ，１６．４ｍｍｏｌ）のテトラヒドロフラン（１５ｍＬ）溶液を滴下し、同温で１５分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、室温まで昇温し、これを酢酸エチルで抽出し、有機相を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。乾燥剤を炉別後、溶媒を減圧下留去して表題化合物を得た。

（２）１−（ベンジルオキシ）−２−ブロモ−４−（４−エチルベンジル）−５−メチルベンゼンの製造
次に、［４−（ベンジルオキシ）−５−ブロモ−２−メチルフェニル］（４−エチルフェニル）メタノールのクロロホルム（８０ｍＬ）の溶液に、０℃にて、Ｅｔ_３ＳｉＨ（３．９３ｍＬ、２４．６ｍｍｏｌ）とＢＦ_３・Ｅｔ_２Ｏ（２．４９ｍＬ、１９．７ｍｍｏｌ）を順次加え、同温にて３０分攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機相を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。乾燥剤を炉別後、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−（ヘキサン：酢酸エチル＝９８：２）にて精製し、無色油状の表題化合物（５．３１ｇ、８２％、２工程）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.22 (t, J=7.62 Hz, 3 H) 2.17 (s, 3 H) 2.61 (q, J=7.62 Hz, 2 H) 3.85 (s, 2 H) 5.12 (s, 2 H) 6.76 (s, 1 H) 7.01 (d, 2 H) 7.10 (d, 2 H) 7.27 - 7.43 (m, 4 H) 7.48 (d, 2 H).
ESI m/z = 412, 414 (M+NH₄ ⁺).

(1) Preparation of [4- (benzyloxy) -5-bromo-2-methylphenyl] (4-ethylphenyl) methanol 1-Bromo-4-ethylbenzene (5.00 g, 16.4 mmol) in tetrahydrofuran (30 mL) A hexane solution of 2.66M n-BuLi (6.47 mL, 17.2 mmol) was added dropwise to the solution at −60 ° C. over 5 minutes. After stirring at the same temperature for 15 minutes, a solution of 4- (benzyloxy) -5-bromo-2-methylbenzaldehyde (3.03 g, 16.4 mmol) in tetrahydrofuran (15 mL) was added dropwise to this solution. For 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, the temperature was raised to room temperature, this was extracted with ethyl acetate, the organic phase was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After drying the desiccant, the solvent was distilled off under reduced pressure to obtain the title compound.

(2) Production of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene Next, [4- (benzyloxy) -5-bromo-2-methylphenyl] ( 4-Ethylphenyl) methanol in chloroform (80 mL) at 0 ° C., Et ₃ SiH (3.93 mL, 24.6 mmol) and BF ₃ .Et ₂ O (2.49 mL, 19.7 mmol) were sequentially added. In addition, the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase 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 = 98: 2) to give the title compound (5.31 g, 82%) as a colorless oil. 2 steps).
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.22 (t, J = 7.62 Hz, 3 H) 2.17 (s, 3 H) 2.61 (q, J = 7.62 Hz, 2 H) 3.85 (s, 2 H) 5.12 (s, 2 H) 6.76 (s, 1 H) 7.01 (d, 2 H) 7.10 (d, 2 H) 7.27-7.43 (m, 4 H) 7.48 (d, 2 H).
ESI m / z = 412, 414 (M + NH ₄ ⁺ ).

Reference Example 8
Preparation of 1- (benzyloxy) -2-bromo-5-methyl-4- [4- (methylsulfanyl) benzyl] benzene

参考例７と同様の方法で４−ブロモトルエンの代わりに４−ブロモチオアニソールを用いて［４−（ベンジルオキシ）−５−ブロモ−２−メチルフェニル］［４−（メチルスルファニル）フェニル］メタノール（６．９３ｇ、６６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.05 (d, J=3.6 Hz, 1 H) 2.16 (s, 3 H) 2.47 (s, 3 H) 5.13 (s, 2 H) 5.86 (d, J=3.6 Hz, 1 H) 6.73 (s, 1 H) 7.22 (s, 4 H) 7.28 - 7.51 (m, 5 H) 7.70 (s, 1 H).
ESI m/z = 463 (M-Cl^-).
続いて［４−（ベンジルオキシ）−５−ブロモ−２−メチルフェニル］（４−エチルフェニル）メタノールの代わりに［４−（ベンジルオキシ）−５−ブロモ−２−メチルフェニル］［４−（メチルスルファニル）フェニル］メタノールを用いて薄茶色油状の表題化合物（６．２８ｇ、９４％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H) 2.46 (s, 3 H) 3.84 (s, 2 H) 5.12 (s, 2 H) 6.77 (s, 1 H) 6.98 - 7.06 (m, 2 H) 7.14 - 7.21 (m, 2 H) 7.23 - 7.51 (m, 6 H).
ESI m/z =430 (M+NH₄ ⁺).

[4- (Benzyloxy) -5-bromo-2-methylphenyl] [4- (methylsulfanyl) phenyl] methanol using 4-bromothioanisole instead of 4-bromotoluene in the same manner as in Reference Example 7. (6.93 g, 66%) was obtained.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.05 (d, J = 3.6 Hz, 1 H) 2.16 (s, 3 H) 2.47 (s, 3 H) 5.13 (s, 2 H) 5.86 (d, J = 3.6 Hz, 1 H) 6.73 (s, 1 H) 7.22 (s, 4 H) 7.28-7.51 (m, 5 H) 7.70 (s, 1 H).
ESI m / z = 463 (M -Cl -).
Subsequently, instead of [4- (benzyloxy) -5-bromo-2-methylphenyl] (4-ethylphenyl) methanol, [4- (benzyloxy) -5-bromo-2-methylphenyl] [4- ( Methylsulfanyl) phenyl] methanol was used to give the title compound (6.28 g, 94%) as a light brown oil.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H) 2.46 (s, 3 H) 3.84 (s, 2 H) 5.12 (s, 2 H) 6.77 (s, 1 H) 6.98-7.06 (m, 2 H) 7.14-7.21 (m, 2 H) 7.23-7.51 (m, 6 H).
ESI m / z = 430 (M + NH ₄ ⁺ ).

Reference Example 9
Preparation of 5-bromo-2-chloro-4-methoxybenzaldehyde

（１）１−ブロモ−４−クロロ−２−メトキシ−５−メチルベンゼンの製造
（ｉ）４−クロロ−２−メトキシ−５−メチルアニリン（２０．２ｇ、１１７ｍｍｏｌ）のアセトン（１００ｍＬ）溶液に４８％臭化水素水（５０ｍＬ、２．９３ｍｏＬ）を加え、亜硝酸ナトリウム（１０．１ｇ、１４６ｍｍｏｌ）の水溶液（７０ｍＬ）を氷冷下滴下し、室温まで昇温して１時間半攪拌した。
（ｉｉ）硫酸銅５水和物（８７．９ｇ、３５２ｍｍｏｌ）および臭化ナトリウム（３６．２ｇ、３５２ｍｍｏｌ）の水溶液（１６０ｍＬ）に、亜硫酸ナトリウム（２２．４ｇ、１７６ｍｍｏｌ）の水溶液（７０ｍＬ）を２０分間かけて滴下し、室温で３０分間攪拌後、氷冷下静置した。上澄み液をデカンテーションにより除去し、得られた沈殿物をさらに水（１Ｌ）で洗浄、上澄み液のデカンテーションを４回繰り返し、臭化銅を無色粉末として得た。そこへ４８％臭化水素水（５０ｍＬ、２．９３ｍｏＬ）を加えて攪拌し、（ｉ）で調製したジアゾニウム塩水溶液を４０分間かけて氷冷下滴下し、室温で１５時間攪拌した。反応溶液中のアセトンを減圧留去して得られた沈殿物を酢酸エチルで抽出し、有機層を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。乾燥剤を炉別後、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−（ヘキサン）にて精製し、無色結晶の表題化合物（２３．５ｇ）を得た。

(1) Production of 1-bromo-4-chloro-2-methoxy-5-methylbenzene (i) To a solution of 4-chloro-2-methoxy-5-methylaniline (20.2 g, 117 mmol) in acetone (100 mL) 48% aqueous hydrogen bromide (50 mL, 2.93 mol) was added, and an aqueous solution (70 mL) of sodium nitrite (10.1 g, 146 mmol) was added dropwise under ice cooling, and the mixture was warmed to room temperature and stirred for 1.5 hr.
(Ii) To an aqueous solution (160 mL) of copper sulfate pentahydrate (87.9 g, 352 mmol) and sodium bromide (36.2 g, 352 mmol), add an aqueous solution (70 mL) of sodium sulfite (22.4 g, 176 mmol). The mixture was added dropwise over a period of 30 minutes, stirred at room temperature for 30 minutes, and allowed to stand under ice cooling. The supernatant was removed by decantation, and the resulting precipitate was further washed with water (1 L), and the decantation of the supernatant was repeated 4 times to obtain copper bromide as a colorless powder. Thereto was added 48% aqueous hydrogen bromide (50 mL, 2.93 mol) and stirred, and the diazonium salt aqueous solution prepared in (i) was added dropwise over 40 minutes under ice-cooling, followed by stirring at room temperature for 15 hours. Acetone in the reaction solution was distilled off under reduced pressure, and the resulting precipitate was extracted with ethyl acetate. The organic layer was washed with 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) to obtain the title compound (23.5 g) as colorless crystals.

(2) Preparation of 1-bromo- (5-bromomethyl) -4-chloro-2-methoxybenzene Next, tetrachloride of 1-bromo-4-chloro-2-methoxy-5-methylbenzene (23.2 g) N-bromosuccinimide (19.2 g) and 2,2′-azobis (2-methylpropionitrile) (1.61 g) were added to a carbon (400 mL) solution, and the mixture was heated to reflux for 1 hour. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. 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 to obtain the title compound (33.5 g) as a colorless oil.

(3) Production of (5-bromo-2-chloro-4-methoxyphenyl) methanol 1-bromo- (5-bromomethyl) -4-chloro-2-methoxybenzene (33.4 g) in 1,4-dioxane ( 350 mL) solution was added an aqueous solution (350 mL) of sodium carbonate (52.0 g), and the mixture was heated to reflux for 1 hour. After allowing to cool, water (350 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain the title compound (25.8 g) as a colorless powder.

(4) Production of 5-bromo-2-chloro-4-methoxybenzaldehyde To a solution of (5-bromo-2-chloro-4-methoxyphenyl) methanol (25.8 g) in chloroform (300 mL), manganese dioxide (129 g, 1.48 mol) was added and stirred at room temperature for 18 hours. The insoluble material was filtered off with Celite, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1 → 30: 1) to give the title compound ( 20.0 g, 82%, 4 steps).
1H NMR (300 MHz, CHLOROFORM-d) δppm 3.99 (s, 3 H) 6.92 (s, 1 H) 8.12 (s, 1 H) 10.27 (s, 1 H).

Reference Example 10
Preparation of 5-bromo-2-chloro-4-hydroxybenzaldehyde

５−ブロモ−２−クロロ−４−メトキシベンズアルデヒド（１８．６ｇ、７４．４ｍｍｏｌ）のジメチルスルホキシド（３００ｍＬ）溶液にピリジン塩酸塩（４３．０ｇ、３７２ｍｍｏｌ）を加え１４５℃で３時間攪拌した。反応液を氷冷し、１０％塩酸水を加えて酸性とし，酢酸エチルで抽出し、有機層を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。乾燥剤を炉別後、溶媒を減圧下留去し、無色結晶（２０．１ｇ）を得た。これをクロロホルムで再結晶し、無色結晶として表題化合物（１１．７ｇ、６７％）を得た。
1H NMR (300 MHz, DMSO-d₆) δppm 7.07 (s, 1 H) 7.96 (s, 1 H) 10.08 (s, 1 H) 12.05 (brs, 1 H).

Pyridine hydrochloride (43.0 g, 372 mmol) was added to a solution of 5-bromo-2-chloro-4-methoxybenzaldehyde (18.6 g, 74.4 mmol) in dimethyl sulfoxide (300 mL), and the mixture was stirred at 145 ° C. for 3 hours. The reaction solution was ice-cooled, acidified with 10% aqueous hydrochloric acid, extracted with ethyl acetate, 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 to obtain colorless crystals (20.1 g). This was recrystallized from chloroform to obtain the title compound (11.7 g, 67%) as colorless crystals.
1H NMR (300 MHz, DMSO-d ₆ ) δppm 7.07 (s, 1 H) 7.96 (s, 1 H) 10.08 (s, 1 H) 12.05 (brs, 1 H).

Reference Example 11
Preparation of 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) benzaldehyde

５−ブロモ−２−クロロ−４−ヒドロキシベンズアルデヒド（１２．０ｇ、５１．０ｍｍｏｌ）、テトラブチルアンモニウムヨージド（９４１ｍｇ、２．５５ｍｍｏｌ）、炭酸カリウム（１１．３ｇ、８１．５ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（２５０ｍＬ）溶液にアリルブロミド（５．６１ｍＬ、６６．３ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応液を氷冷後、１０％塩酸水（５０ｍＬ）を加え、さらに水（２００ｍＬ）を加えたものを酢酸エチルで抽出後、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、得られた残渣をエタノールで再結晶し、無色粉末として表題化合物（１１．５g、８２％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 4.70 (dt, J=5.0, 1.6 Hz, 2 H) 5.40 (dq, J=10.6, 1.4 Hz, 1 H) 5.52 (dd, J=17.3, 1.1 Hz, 1 H) 6.04 (dd, J=17.0, 10.3 Hz, 1 H) 6.90 (s, 1 H) 8.13 (s, 1 H) 10.27 (s, 1 H).

N, N of 5-bromo-2-chloro-4-hydroxybenzaldehyde (12.0 g, 51.0 mmol), tetrabutylammonium iodide (941 mg, 2.55 mmol), potassium carbonate (11.3 g, 81.5 mmol) -Allyl bromide (5.61 mL, 66.3 mmol) was added to a dimethylformamide (250 mL) solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was ice-cooled, 10% aqueous hydrochloric acid (50 mL) was added, water (200 mL) was further added, and the mixture was extracted with ethyl acetate. 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 recrystallized from ethanol to obtain the title compound (11.5 g, 82%) as a colorless powder.
1H NMR (300 MHz, CHLOROFORM-d) δppm 4.70 (dt, J = 5.0, 1.6 Hz, 2 H) 5.40 (dq, J = 10.6, 1.4 Hz, 1 H) 5.52 (dd, J = 17.3, 1.1 Hz, 1 H) 6.04 (dd, J = 17.0, 10.3 Hz, 1 H) 6.90 (s, 1 H) 8.13 (s, 1 H) 10.27 (s, 1 H).

Reference Example 12
Preparation of 1-bromo-4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) benzene

（１）［５−ブロモ−２−クロロ−４−（プロパ−２−エン−１−イルオキシ）フェニル］（４−メトキシフェニル）メタノールの製造
１−ブロモ−４−メトキシベンゼン（１．４３ｍＬ、１１．４３ｍｍｏｌ）のテトラヒドロフラン（１００ｍＬ）溶液に−８０℃にて、２．６４Ｍ ｎ−ＢｕＬｉのヘキサン溶液（４．５４ｍＬ、１１．９８ｍｍｏｌ）を５分かけて滴下した。同温にて１５分攪拌した後に、この溶液に、５−ブロモ−２−クロロ−４−（プロパ−２−エン−１−イルオキシ）ベンズアルデヒド（３．００ｇ、１０．８９ｍｍｏｌ）のテトラヒドロフラン（５０ｍＬ）溶液を滴下し、徐々に室温まで昇温し、同温にて３０分間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、減圧濃縮してテトラヒドロフランを留去した。これを酢酸エチルで抽出し、有機相を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。乾燥剤を炉別後、溶媒を減圧下留去し、淡黄色油状物の表題化合物（３．７９ｇ）を得た。

(1) Preparation of [5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl] (4-methoxyphenyl) methanol 1-bromo-4-methoxybenzene (1.43 mL, 11 .43 mmol) in tetrahydrofuran (100 mL) at −80 ° C. was added dropwise a hexane solution of 2.64 M n-BuLi (4.54 mL, 11.98 mmol) over 5 minutes. After stirring at the same temperature for 15 minutes, this solution was mixed with 5-bromo-2-chloro-4- (prop-2-en-1-yloxy) benzaldehyde (3.00 g, 10.89 mmol) in tetrahydrofuran (50 mL). The solution was added dropwise, gradually warmed to room temperature, and stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure to distill off tetrahydrofuran. This was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the solvent was evaporated under reduced pressure to give the title compound (3.79 g) as a pale yellow oil.

(2) Production of 1-bromo-4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) benzene Next, [5-bromo-2-chloro-4- To a solution of (prop-2-en-1-yloxy) phenyl] (4-methoxyphenyl) methanol (3.77 g, 9.83 mmol) in chloroform (50 mL) at 0 ° C., Et ₃ SiH (2.35 mL, 14.74 mmol) and BF ₃ .Et ₂ O (1.49 mL, 11.79 mmol) were sequentially added, and the mixture was stirred at the same temperature for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase 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 (chloroform: hexane = 1: 4) to give the title compound (1.56 g, 39% as a colorless oil). 2 steps).
1H NMR (300 MHz, CHLOROFORM-d) δppm 3.79 (s, 3 H) 3.93 (s, 2 H) 4.57 (dt, J = 5.0, 1.6 Hz, 2 H) 5.32 (dd, J = 10.6, 1.4 Hz, 1 H) 5.50 (d, J = 1.6 Hz, 1 H) 5.91-6.15 (m, 1 H) 6.84 (d, J = 8.7 Hz, 2 H) 6.90 (s, 1 H) 7.09 (d, J = 8.7 (Hz, 2 H) 7.30 (s, 1 H).
EI m / z = 366, 368.

Reference Example 13
Preparation of 1-bromo-4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-2-yloxy) benzene

（１）［５−ブロモ−２−クロロ−４−（プロパ−２−エン−１−イルオキシ）フェニル］（４−メチルフェニル）メタノールの製造
参考例１２（１）と同様な方法で、１−ブロモ−４−メトキシベンゼンの代わりに４−ブロモトルエンを用いて合成した。シリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝８７：１３）にて精製し、無色固体として表題化合物（１．０４ｇ、３８％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.21 (d, J=3.57 Hz, 1 H) 2.33 (s, 3 H) 4.55 - 4.61 (m, 2 H) 5.33 (dq, J=10.57, 1.45 Hz, 1 H) 5.47 (dq, J=17.31, 1.59 Hz, 1 H) 5.96 - 6.11 (m, 2 H) 6.84 (s, 1 H) 7.15 (d, 2 H) 7.25 (d, 2 H) 7.80 (s, 1 H).

(1) Production of [5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl] (4-methylphenyl) methanol In the same manner as in Reference Example 12 (1), 1- Synthesis was performed using 4-bromotoluene instead of bromo-4-methoxybenzene. Purification by silica gel column chromatography (hexane: ethyl acetate = 87: 13) gave the title compound (1.04 g, 38%) as a colorless solid.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.21 (d, J = 3.57 Hz, 1 H) 2.33 (s, 3 H) 4.55-4.61 (m, 2 H) 5.33 (dq, J = 10.57, 1.45 Hz, 1 H) 5.47 (dq, J = 17.31, 1.59 Hz, 1 H) 5.96-6.11 (m, 2 H) 6.84 (s, 1 H) 7.15 (d, 2 H) 7.25 (d, 2 H) 7.80 (s , 1 H).

(2) Production of 1-bromo-4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-2-yloxy) benzene In the same manner as in Reference Example 12 (2), [5 [Bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl] (4-methoxyphenyl) methanol instead of [5-bromo-2-chloro-4- (prop-2-ene- 1-yloxy) phenyl] (4-methylphenyl) methanol. Purification by silica gel column chromatography (hexane: ethyl acetate = 87: 13) gave the title compound (827 mg, 83%) as a colorless oil.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.32 (s, 3 H) 3.96 (s, 2 H) 4.57 (dt, J = 5.05, 1.59 Hz, 2 H) 5.32 (dq, J = 10.57, 1.45 Hz, 1 H) 5.48 (dq, 1 H) 5.96-6.11 (m, J = 17.23, 10.39, 5.15, 5.15 Hz, 1 H) 6.90 (s, 1 H) 7.05 (d, 2 H) 7.11 (d, 2 H ) 7.31 (s, 1 H).
EI m / z = 350, 352.

Reference Example 14
Preparation of 1-bromo-4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) benzene

（１）［５−ブロモ−２−クロロ−４−（プロパ−２−エン−１−イルオキシ）フェニル］（４−エチルフェニル）メタノールの製造
参考例１２（１）と同様な方法で、１−ブロモ−４−メトキシベンゼンの代わりに１−ブロモ−４−エチルベンゼンを用いて合成した。シリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝８７：１３）にて精製し、無色固体として表題化合物（１．９６ｇ、３５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.22 (t, J=7.54 Hz, 3 H) 2.20 (d, J=3.57 Hz, 1 H) 2.63 (q, J=7.67 Hz, 2 H) 4.58 (dd, J=5.05, 0.70 Hz, 2 H) 5.33 (dq, J=10.59, 1.44 Hz, 1 H) 5.48 (dq, J=17.25, 1.71, 1.55 Hz, 1 H) 5.95 - 6.15 (m, 2 H) 6.85 (s, 1 H) 7.17 (d, 2 H) 7.28 (d, 2 H) 7.82 (s, 1 H)．

(1) Production of [5-bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl] (4-ethylphenyl) methanol In the same manner as in Reference Example 12 (1), 1- The synthesis was performed using 1-bromo-4-ethylbenzene instead of bromo-4-methoxybenzene. Purification by silica gel column chromatography (hexane: ethyl acetate = 87: 13) gave the title compound (1.96 g, 35%) as a colorless solid.
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.22 (t, J = 7.54 Hz, 3 H) 2.20 (d, J = 3.57 Hz, 1 H) 2.63 (q, J = 7.67 Hz, 2 H) 4.58 (dd , J = 5.05, 0.70 Hz, 2 H) 5.33 (dq, J = 10.59, 1.44 Hz, 1 H) 5.48 (dq, J = 17.25, 1.71, 1.55 Hz, 1 H) 5.95-6.15 (m, 2 H) 6.85 (s, 1 H) 7.17 (d, 2 H) 7.28 (d, 2 H) 7.82 (s, 1 H).

(2) Production of 1-bromo-4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-2-yloxy) benzene In the same manner as in Reference Example 12 (2), [5 [Bromo-2-chloro-4- (prop-2-en-1-yloxy) phenyl] (4-methoxyphenyl) methanol instead of [5-bromo-2-chloro-4- (prop-2-ene- 1-yloxy) phenyl] (4-ethylphenyl) methanol. Purification by silica gel column chromatography (hexane: ethyl acetate = 87: 13) gave the title compound (1.55 g, 83%) as a colorless oil.
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.22 (t, J = 7.54 Hz, 3 H) 2.62 (q, J = 7.77 Hz, 2 H) 3.97 (s, 2 H) 4.58 (dt, J = 4.97, 1.55 Hz, 2 H) 5.32 (dq, J = 10.57, 1.45 Hz, 1 H) 5.48 (dq, J = 17.25, 1.66 Hz, 1 H) 6.04 (dddd, J = 17.25, 10.41, 5.13, 4.97 Hz, 1 H) 6.90 (s, 1 H) 7.08 (d, 2 H) 7.13 (d, 2 H) 7.33 (s, 1 H).
EI m / z = 364, 366.

Example 1
(1-A)
Of 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-methyl-5- (4-methylbenzyl) phenyl] -5-thio-D-glucopyranose Manufacturing

2.6M n of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene (3.01 g, 7.89 mmol) in tetrahydrofuran (15 mL) at −60 ° C. -A hexane solution of BuLi (3.3 mL, 8.68 mmol) was added dropwise over 4 minutes. After stirring for 30 minutes at the same temperature, 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (2.91 g, 5.26 mmol) was added to this solution. Of tetrahydrofuran (10 mL) was added dropwise and stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, the temperature was raised to room temperature, and this was extracted with ethyl acetate. The organic phase was washed with 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 = 5: 1) to give the title compound (2.44 g, 2.44 g, pale yellow gum). 54%).
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.20 (s, 3 H) 2.27 (s, 3 H) 3.46-3.59 (m, 1 H) 3.65 (dd, J = 9.6, 2.4 Hz, 1 H) 3.78- 4.16 (m, 5 H) 4.43-4.70 (m, 5 H) 4.75-4.97 (m, 4 H) 5.09 (s, 2 H) 6.70-7.42 (m, 31H).

(1-B)
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- (4-methylbenzyl) phenyl] -1 -Production of thio-D-glucitol

2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -4-methyl-5- (4-methylbenzyl) phenyl] -5-thio-D-glucopyranose ( 2.44 g, 2.85 mmol) in a mixed solution of chloroform (5.0 mL) and acetonitrile (12.0 mL) at −15 ° C., Et ₃ SiH (0.91 mL, 5.69 mmol) and BF ₃ .Et ₂ O (0.43 mL, 3.42 mmol) was sequentially added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase 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 = 8: 1) to give the title compound (2.1 g, 88% as a colorless powder). )

1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3 H) 2.25 (s, 3 H) 3.01-3.19 (m, 1 H) 3.49-3.60 (m, 1 H) 3.64-3.75 (m, 1 H) 3.77-3.97 (m, 5 H) 3.98-4.11 (m, 1 H) 4.48-4.66 (m, 5 H) 4.85 (s, 2 H) 4.90 (d, J = 10.7 Hz, 1 H) 4.97 -5.11 (m, 2 H) 6.66-7.52 (m, 31 H).
ESI m / z = 858 (M + NH ₄ ⁺ ).

Example 2
(2-A)
Of 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl] -5-thio-D-glucopyranose Manufacturing

2.6 M n of 1- (benzyloxy) -2-bromo-4- (4-methoxybenzyl) -5-methylbenzene (3.46 g, 8.71 mmol) in tetrahydrofuran (17 mL) at −50 ° C. -BuLi in hexane (3.7 mL, 9.58 mmol) was added dropwise over 5 minutes. After stirring at −60 ° C. for 30 minutes, 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (3.22 g, 5.81 mmol) was added to this solution. ) In tetrahydrofuran (10 mL) was added dropwise and stirred at the same temperature for 15 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, the temperature was raised to room temperature, this was extracted with ethyl acetate, the organic phase was washed with 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 = 5: 1) to give the title compound as a pale yellow gum (2.22 g). 44%).
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.20 (s, 3 H) 3.47-4.03 (m, 10 H) 4.02-4.21 (m, 2 H) 4.51 (s, 2 H) 4.63 (d, J = 10.7 (Hz, 1 H) 4.73-4.98 (m, 4 H) 5.10 (s, 2 H) 6.48-7.76 (m, 31 H).
ESI m / z = 895 (M + Na ⁺ ).

(2-B)
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl] -1 -Production of thio-D-glucitol

2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl] -5-thio-D-glucopyranose ( 2.20 g, 2.52 mmol) in a mixed solution of chloroform (6.0 mL) and acetonitrile (12.0 mL) at −15 ° C., Et ₃ SiH (0.80 mL, 5.04 mmol) and BF ₃ .Et ₂ O (0.38 mL, 3.02 mmol) was sequentially added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase 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) to give the title compound (2.15 g, 99%) as a colorless powder. )

1H NMR (300 MHz, CHLOROFORM-d) δppm 2.17 (s, 3 H) 3.00-3.23 (m, 1 H) 3.55 (t, J = 10.8 Hz, 1 H) 3.66-4.16 (m, 10 H) 4.45- 4.65 (m, 5 H) 4.85 (s, 2 H) 4.90 (d, J = 10.7 Hz, 1 H) 4.96-5.13 (m, 2 H) 6.51-7.46 (m, 31 H).
ESI m / z = 879 (M + Na).

Example 3
(3-A)
2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5-[(4-methoxyphenyl) (hydroxy) methyl] -4-methylphenyl] -5-thio -Production of D-glucopyranose

To a mixture of 1-bromo-4-methoxybenzene (520 mg, 2.78 mmol) and tetrahydrofuran (3 mL) was added 2.6 M n-BuLi in hexane (1.01 mL, 2.69 mmol) at -78 ° C. It was. Immediately thereafter, 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5-formyl-4-methylphenyl] -5-thio-D-glucopyranose (700 mg, 0.896 mmol) in tetrahydrofuran (3 mL) was added, and the mixture was further stirred for 30 minutes, and the temperature of the reaction mixture was raised to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase 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 the colorless amorphous title compound (570 mg, 72%). Obtained.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.03-2.24 (m, 3 H) 3.51-4.02 (m, 9 H) 4.49-5.16 (m, 10 H) 5.87 (brs, 1 H) 6.73-7.36 (m , 31 H).
ESI m / z = 911 (M + Na ⁺ ), 887 (M−H).

(3-B)
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl] -1 -Production of thio-D-glucitol

2,3,4,6-Tetra-O-benzyl-1-C- [2- (benzyloxy) -5-[(4-methoxyphenyl) (hydroxy) methyl] -4-methylphenyl] -5-thio To a solution of -D-glucopyranose (570 mg, 0.641 mmol) in acetonitrile (6.0 mL) at -10 ° C, Et ₃ SiH (0.308 mL, 1.93 mmol) and BF ₃ · Et ₂ O (0.9. 090 mL, 1.41 mmol) was sequentially added and stirred for 10 minutes. Chloroform (3.0 mL) was added to the reaction solution, followed by BF ₃ .Et ₂ O (0.090 mL, 1.41 mmol) at 0 ° C. The reaction mixture was stirred at 5 ° C. for 30 minutes, saturated aqueous sodium hydrogen carbonate solution was added, extracted with chloroform, the organic phase 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) to give the title compound (440 mg, 80%) as a colorless powder. Obtained. The spectral data was consistent with Example 2.

Example 4
Production of (1S) -1,5-anhydro-1- [4-methyl-5- (4-methylbenzyl) -2-hydroxyphenyl] -1-thio-D-glucitol (Compound (I))

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- (4-methylbenzyl) phenyl] -1 A mixture of thio-D-glucitol (2.1 g, 2.50 mmol), 20% palladium hydroxide activated carbon (2.06 g) and ethyl acetate (20 mL) -ethanol (20 mL) was stirred at room temperature for 50 hours under a hydrogen atmosphere. did. Insoluble matters in the reaction solution were filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (340 mg, 35%) as a colorless powder.
1H NMR (300 MHz, METHANOL-d ₄ ) δppm 2.07 (s, 3 H) 2.27 (s, 3 H) 2.92-3.04 (m, 1 H) 3.58 (dd, J = 10.3, 9.0 Hz, 1 H) 3.73 (dd, J = 11.5, 6.6 Hz, 1 H) 3.78-3.88 (m, 3 H) 3.94 (dd, J = 11.5, 3.8 Hz, 1 H) 4.29 (d, J = 10.6 Hz, 1 H) 6.60 ( s, 1 H) 6.94-6.98 (m, 2 H) 7.01-7.04 (m, 2 H) 7.05 (s, 1 H).
ESI m / z = 408 M + NH ₄ ⁺ ), 389 (MH).
Elemental Analysis Calcd for C ₂₁ H ₂₆ O ₅ S · H ₂ O: C, 61.72; H, 6.92. Found: C, 61.85; H, 6.78.

Example 5
Production of (1S) -1,5-anhydro-1- [5- (4-methoxybenzyl) -4-methyl-2-hydroxyphenyl] -1-thio-D-glucitol (compound (II))

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-methoxybenzyl) -4-methylphenyl] -1 A mixture of thio-D-glucitol (2.11 g, 2.46 mmol), 20% palladium hydroxide activated carbon (2.1 g) and ethyl acetate (20 mL) -ethanol (20 mL) was stirred at room temperature for 24 hours under a hydrogen atmosphere. did. Insoluble matters in the reaction solution were filtered through celite, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (690 mg, 69%) as a colorless powder.
1H NMR (300 MHz, METHANOL-d ₄ ) δppm 2.08 (s, 3 H) 2.91-3.06 (m, 1 H) 3.26 (t, 1 H) 3.59 (dd, J = 10.3, 8.9 Hz, 1 H) 3.68 -3.78 (m, 1 H) 3.74 (s, 3 H) 3.81 (s, 2 H) 3.82- 3.88 (m, 1 H) 3.94 (dd, J = 11.3, 3.7 Hz, 1 H) 4.29 (d, J = 10.6 Hz, 1 H) 6.60 (s, 1 H) 6.69-6.82 (m, 2 H) 6.96-7.03 (m, 2 H) 7.04 (s, 1 H).
ESI m / z = 429 (M + Na ⁺ )
Elemental Analysis Calcd for C ₂₁ H ₂₆ O ₆ S · H ₂ O: C, 59.27; H, 6.65. Found: C, 59.32; H, 6.40.

Example 6
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -5- (4-ethylbenzyl) -4-methylphenyl] -1 -Production of thio-D-glucitol

１−（ベンジルオキシ）−２−ブロモ−４−（４−エチルベンジル）−５−メチルベンゼン（５．３１ｇ、１３．４ｍｍｏｌ）のテトラヒドロフラン（５０ｍＬ）溶液に−６０℃にて、２．６６Ｍ ｎ−ＢｕＬｉのヘキサン溶液（５．０５ｍＬ、１３．４ｍｍｏｌ）を５分かけて滴下した。同温にて１５分攪拌した後に、この溶液に、２，３，４，６−テトラ−Ｏ−ベンジル−５−チオ−Ｄ−グルコノ−１，５−ラクトン（６．７６ｇ，１２．２ｍｍｏｌ）のテトラヒドロフラン（２５ｍＬ）溶液を滴下し、同温で２時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、室温まで昇温した。これを酢酸エチルで抽出し、有機相を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。乾燥剤を炉別後、溶媒を減圧下留去して２，３，４，６−テトラ−Ｏ−ベンジル−１−C−［２−（ベンジルオキシ）−５−（４−エチルベンジル）−４−メチルフェニル］−５−チオ−D−グルコピラノースを得た。これをクロロホルム（３０ｍＬ）とアセトニトリル（３０ｍＬ）の混合溶液に溶解し、０℃に冷却した。次に、Ｅｔ_３ＳｉＨ（２．９２ｍＬ、１８．３ｍｍｏｌ）とＢＦ_３・Ｅｔ_２Ｏ（１．８６ｍＬ、１４．６ｍｍｏｌ）を順次加え、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、酢酸エチルで抽出し、有機相を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。乾燥剤を炉別後、溶媒を減圧下留去し得られた残渣をＮＨ型シリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝４：１）とシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝８７：１３）にて精製し、淡黄色ガム状の表題化合物（３．４１ｇ、３３％、２工程）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.16 (t, J=8.16 Hz, 3 H) 2.18 (s, 3 H) 2.48 - 2.61 (m, 2 H) 3.06 - 3.17 (m, 1 H) 3.54 (t, J=8.70 Hz, 1 H) 3.70 (d, J=10.26 Hz, 1 H) 3.76 - 3.98 (m, 5 H) 4.05 (d, J=11.81 Hz, 1 H) 4.50 - 4.64 (m, 5 H) 4.82 - 4.93 (m, 3 H) 5.00 - 5.10 (m, 2 H) 6.73 (s, 1 H) 6.78 (d, J=6.06 Hz, 2 H) 6.94 (br. s., 3 H) 7.09 - 7.19 (m, 5 H) 7.22 - 7.34 (m, 18 H) 7.35 - 7.44 (m, 2 H).
ESI m/z = 872 (M+NH₄ ⁺) , 889 (M+Cl^-).

2.66 M n of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene (5.31 g, 13.4 mmol) in tetrahydrofuran (50 mL) at −60 ° C. -BuLi in hexane (5.05 mL, 13.4 mmol) was added dropwise over 5 minutes. After stirring at the same temperature for 15 minutes, 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone (6.76 g, 12.2 mmol) was added to this solution. Of tetrahydrofuran (25 mL) was added dropwise and stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the temperature was raised to room temperature. This was extracted with ethyl acetate, and the organic phase 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 to remove 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -5- (4-ethylbenzyl)- 4-Methylphenyl] -5-thio-D-glucopyranose was obtained. This was dissolved in a mixed solution of chloroform (30 mL) and acetonitrile (30 mL), and cooled to 0 ° C. Next, Et ₃ SiH (2.92 mL, 18.3 mmol) and BF ₃ .Et ₂ O (1.86 mL, 14.6 mmol) were sequentially added and stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase 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 resulting residue was subjected to NH-type silica gel column chromatography (hexane: ethyl acetate = 4: 1) and silica gel column chromatography (hexane: ethyl acetate = 87: 13). To give the title compound (3.41 g, 33%, 2 steps) as a pale yellow gum.
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.16 (t, J = 8.16 Hz, 3 H) 2.18 (s, 3 H) 2.48-2.61 (m, 2 H) 3.06-3.17 (m, 1 H) 3.54 ( t, J = 8.70 Hz, 1 H) 3.70 (d, J = 10.26 Hz, 1 H) 3.76-3.98 (m, 5 H) 4.05 (d, J = 11.81 Hz, 1 H) 4.50-4.64 (m, 5 H) 4.82-4.93 (m, 3 H) 5.00-5.10 (m, 2 H) 6.73 (s, 1 H) 6.78 (d, J = 6.06 Hz, 2 H) 6.94 (br. S., 3 H) 7.09 -7.19 (m, 5 H) 7.22-7.34 (m, 18 H) 7.35-7.44 (m, 2 H).
ESI m / z = 872 (M + NH 4 +), 889 (M + Cl -).

Example 7
Production of (1S) -1,5-anhydro-1- [5- (4-ethylbenzyl) -2-hydroxy-4-methylphenyl] -1-thio-D-glucitol (compound (III))

実施例４と同様な方法で、(１Ｓ)−１，５−アンヒドロ−２，３，４，６−テトラ−Ｏ−ベンジル−１−［２−（ベンジルオキシ）−４−メチル−５−（４−メチルベンジル）フェニル］−１−チオ−Ｄ−グルシトールの代わりに（１Ｓ）−１，５−アンヒドロ−２，３，４，６−テトラ−Ｏ−ベンジル−１−［２−（ベンジルオキシ）−５−（４−エチルベンジル）−４−メチルフェニル］−１−チオ−Ｄ−グルシトールを用いて合成し、シリカゲルカラムグラフィ−の後にエタノールから再結晶を行い、無色粉末の表題化合物（３９２ｍｇ、２４％）を得た。
1H NMR (300 MHz, METHANOL-d4) δppm 1.19 (t, J=7.62 Hz, 3 H) 2.08 (s, 3 H) 2.58 (q, J=7.56 Hz, 2 H) 2.99 (ddd, J=10.22, 6.41, 3.73 Hz, 1 H) 3.25 (t, 1 H) 3.59 (dd, J=9.71, 8.47 Hz, 1 H) 3.74 (dd, J=11.50, 6.37 Hz, 1 H) 3.85 (t, J=9.64 Hz, 3 H) 3.95 (dd, J=11.42, 3.81 Hz, 1 H) 4.30 (d, J=10.41 Hz, 1 H) 6.61 (s, 1 H) 6.96 - 7.09 (m, 5 H).
ESI m/z = 422 (M+NH₄ ⁺) , 403 (M-H) , 439 (M+Cl^-).

In the same manner as in Example 4, (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- ( (1S) -1,5-anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) instead of 4-methylbenzyl) phenyl] -1-thio-D-glucitol ) -5- (4-ethylbenzyl) -4-methylphenyl] -1-thio-D-glucitol and recrystallized from ethanol after silica gel column chromatography to give the title compound (392 mg) as a colorless powder. 24%).
1H NMR (300 MHz, METHANOL-d4) δppm 1.19 (t, J = 7.62 Hz, 3 H) 2.08 (s, 3 H) 2.58 (q, J = 7.56 Hz, 2 H) 2.99 (ddd, J = 10.22, 6.41, 3.73 Hz, 1 H) 3.25 (t, 1 H) 3.59 (dd, J = 9.71, 8.47 Hz, 1 H) 3.74 (dd, J = 11.50, 6.37 Hz, 1 H) 3.85 (t, J = 9.64 Hz, 3 H) 3.95 (dd, J = 11.42, 3.81 Hz, 1 H) 4.30 (d, J = 10.41 Hz, 1 H) 6.61 (s, 1 H) 6.96-7.09 (m, 5 H).
ESI m / z = 422 (M + NH 4 +), 403 (MH), 439 (M + Cl -).

Example 8
(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- [4- (methylsulfanyl) benzyl] phenyl Production of 1-thio-D-glucitol

実施例６と同様の方法で１−（ベンジルオキシ）−２−ブロモ−４−（４−エチルベンジル）−５−メチルベンゼンの代わりに１−（ベンジルオキシ）−２−ブロモ−５−メチル−４−[４−（メチルスルファニル）ベンジル]ベンゼンを用いて薄黄色ガム状の表題化合物（３．２７ｇ、２７％、２工程）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.16 (s, 3 H) 2.39 (s, 3 H) 3.07 - 3.16 (m, 1 H) 3.49 - 3.60 (m, 1 H) 3.63 - 3.75 (m, 1 H) 3.76 - 4.10 (m, 6 H) 4.42 - 4.66 (m, 5 H) 4.85 (s, 2 H) 4.90 (d, J=10.6 Hz, 1 H) 4.97 - 5.11 (m, 2 H) 6.69 - 7.48 (m, 31 H).

In the same manner as in Example 6, instead of 1- (benzyloxy) -2-bromo-4- (4-ethylbenzyl) -5-methylbenzene, 1- (benzyloxy) -2-bromo-5-methyl- 4- [4- (methylsulfanyl) benzyl] benzene was used to give the title compound as a pale yellow gum (3.27 g, 27%, 2 steps).
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.16 (s, 3 H) 2.39 (s, 3 H) 3.07-3.16 (m, 1 H) 3.49-3.60 (m, 1 H) 3.63-3.75 (m, 1 H) 3.76-4.10 (m, 6 H) 4.42-4.66 (m, 5 H) 4.85 (s, 2 H) 4.90 (d, J = 10.6 Hz, 1 H) 4.97-5.11 (m, 2 H) 6.69 -7.48 (m, 31 H).

Example 9
Production of (1S) -1,5-anhydro-1- [2-hydroxy-4-methyl-5- [4- (methylsulfanyl) benzyl] phenyl] -1-thio-D-glucitol (Compound IV))

（１Ｓ）−１，５−アンヒドロ−２，３，４，６−テトラ−Ｏ−ベンジル−１−［２−（ベンジルオキシ）−４−メチル−５−［４−（メチルスルファニル）ベンジル］フェニル］−１−チオ−Ｄ−グルシトール（１．０９ｇ、１．２５ｍｍｏｌ）、ジメチルスルフィド（４．５ｍＬ）、ｍ−クレゾール（１．２ｍＬ）、トリフルオロ酢酸（７．５ｍＬ）、１，２-エタンジチオール（０．３ｍＬ）の混合溶液に−２０℃にてトリフルオロメタンスルホン酸（１．５ｍＬ）を滴下した。同温にて４０分攪拌した後に、反応液を飽和炭酸ナトリウム水溶液と氷の混合物に注いだ。酢酸エチルで抽出し、有機相を飽和炭酸ナトリウム水溶液、飽和食塩水で順次洗浄した後、無水硫酸マグネシウムで乾燥した。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＝５０：１→１０：１）にて精製し、更にエタノールから再結晶を行い、無色粉末の表題化合物（１６６ｍｇ、３１％）を得た。
1H NMR (300 MHz, METHANOL-d₄) δppm 2.08 (s, 3 H) 2.43 (s, 3 H) 2.99 (ddd, J=10.2, 6.4, 3.7 Hz, 1 H) 3.22 - 3.31 (m, 1 H) 3.59 (dd, J=10.3, 9.0 Hz, 1 H) 3.74 (dd, J=11.5, 6.4 Hz, 1 H) 3.80-3.88 (m, 3 H) 3.95 (dd, J=11.5, 3.7 Hz, 1 H) 4.30 (d, J=10.4 Hz, 1 H) 6.61 (s, 1 H) 6.99 - 7.08 (m, 3 H) 7.11 - 7.18 (m, 2 H).
ESI m/z = 440 (M+NH₄ ⁺) , 445 (M+Na⁺) , 421 (M-H) , 457 (M+Cl^-).

(1S) -1,5-Anhydro-2,3,4,6-tetra-O-benzyl-1- [2- (benzyloxy) -4-methyl-5- [4- (methylsulfanyl) benzyl] phenyl ] -1-thio-D-glucitol (1.09 g, 1.25 mmol), dimethyl sulfide (4.5 mL), m-cresol (1.2 mL), trifluoroacetic acid (7.5 mL), 1,2-ethane Trifluoromethanesulfonic acid (1.5 mL) was added dropwise at −20 ° C. to a mixed solution of dithiol (0.3 mL). After stirring at the same temperature for 40 minutes, the reaction solution was poured into a mixture of a saturated aqueous sodium carbonate solution and ice. The mixture was extracted with ethyl acetate, and the organic phase was washed successively with saturated aqueous sodium carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 10: 1), recrystallized from ethanol, and the title compound (166 mg, 31%).
1H NMR (300 MHz, METHANOL-d ₄ ) δppm 2.08 (s, 3 H) 2.43 (s, 3 H) 2.99 (ddd, J = 10.2, 6.4, 3.7 Hz, 1 H) 3.22-3.31 (m, 1 H ) 3.59 (dd, J = 10.3, 9.0 Hz, 1 H) 3.74 (dd, J = 11.5, 6.4 Hz, 1 H) 3.80-3.88 (m, 3 H) 3.95 (dd, J = 11.5, 3.7 Hz, 1 H) 4.30 (d, J = 10.4 Hz, 1 H) 6.61 (s, 1 H) 6.99-7.08 (m, 3 H) 7.11-7.18 (m, 2 H).
ESI m / z = 440 (M + NH 4 +), 445 (M + Na +), 421 (MH), 457 (M + Cl -).

Example 10
(10-A)
1-C- [4-Chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6-tetra-O-prop-2- Production of en-1-yl-5-thio-D-glucopyranose

実施例１（１−Ａ）と同様な方法で、１−（ベンジルオキシ）−２−ブロモ−５−メチル−４−（４−メチルベンジル） ベンゼンの代わりに１−ブロモ−４−クロロ−５−（４−メチルベンジル）−２−（プロパ−２−エン−２−イルオキシ）ベンゼン、２，３，４，６−テトラ−Ｏ−ベンジル−５−チオ−Ｄ−グルコノ−１，５−ラクトンの代わりに２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−５−チオ−Ｄ−グルコノ−１，５−ラクトンを用いて、無色油状の表題化合物（４２６ｍｇ、２９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.29 (s, 3 H) 3.34 - 3.47 (m, 1 H) 3.47 - 4.31 (m, 14 H) 4.37 (dd, J=12.43, 5.75 Hz, 1 H) 4.60 (d, J=4.82 Hz, 2 H) 4.88 (s, 1 H) 4.94 (d, J=1.55 Hz, 1 H) 5.08 - 5.38 (m, 7 H) 5.42 - 5.59 (m, 2 H) 5.78 - 6.15 (m, 4 H) 6.93 (s, 1 H) 6.98 - 7.08 (m, 4 H) 7.24 (br. s., 1 H)．
ESI m/z = 644 (M+NH₄ ⁺) , 625 (M-H) , 661 (M+Cl^-).

In the same manner as in Example 1 (1-A), 1-bromo-4-chloro-5 instead of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene -(4-Methylbenzyl) -2- (prop-2-en-2-yloxy) benzene, 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone Instead of 2,3,4,6-tetra-O-prop-2-en-1-yl-5-thio-D-glucono-1,5-lactone, the title compound (426 mg, 426 mg, 29%).
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.29 (s, 3 H) 3.34-3.47 (m, 1 H) 3.47-4.31 (m, 14 H) 4.37 (dd, J = 12.43, 5.75 Hz, 1 H) 4.60 (d, J = 4.82 Hz, 2 H) 4.88 (s, 1 H) 4.94 (d, J = 1.55 Hz, 1 H) 5.08-5.38 (m, 7 H) 5.42-5.59 (m, 2 H) 5.78 -6.15 (m, 4 H) 6.93 (s, 1 H) 6.98-7.08 (m, 4 H) 7.24 (br. S., 1 H).
ESI m / z = 644 (M + NH 4 +), 625 (MH), 661 (M + Cl -).

(10-B)
(1S) -1,5-Anhydro-1- [4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6- Production of tetra-O-prop-2-en-1-yl-1-thio-D-glucitol

実施例１（１−Ｂ）と同様な方法で、２，３，４，６−テトラ−Ｏ−ベンジル−１−Ｃ−［２−（ベンジルオキシ）−４−メチル−５−（４−メチルベンジル）フェニル］−５−チオ−Ｄ−グルコピラノースの代わりに１−Ｃ−［４−クロロ−５−（４−メチルベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１-イル−５−チオ−Ｄ−グルコピラノースを用いて、無色固体の表題化合物（２７１ｍｇ、６５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.29 (s, 3 H) 2.94 - 3.04 (m, 1 H) 3.25 (t, J=9.09 Hz, 1 H) 3.38 - 4.20 (m, 11 H) 4.28 (d, J=5.60 Hz, 2 H) 4.36 (dd, J=12.05, 5.98 Hz, 2 H) 4.54 (dt, J=4.97, 1.63 Hz, 2 H) 4.81 - 4.92 (m, 2 H) 5.09 - 5.32 (m, 7 H) 5.33 - 5.51 (m, 2 H) 5.80 - 6.10 (m, 4 H) 6.86 (s, 1 H) 7.02 (td, 2 H) 7.03 (d, 2 H) 7.22 (s, 1 H)．
ESI m/z = 628 (M+NH₄ ⁺) , 633 (M+Na⁺) , 645 (M+Cl^-).

In the same manner as in Example 1 (1-B), 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-methyl-5- (4-methyl) [Benzyl] phenyl] -5-thio-D-glucopyranose instead of 1-C- [4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl]- The title compound (271 mg, 65%) as a colorless solid was obtained using 2,3,4,6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.29 (s, 3 H) 2.94-3.04 (m, 1 H) 3.25 (t, J = 9.09 Hz, 1 H) 3.38-4.20 (m, 11 H) 4.28 ( d, J = 5.60 Hz, 2 H) 4.36 (dd, J = 12.05, 5.98 Hz, 2 H) 4.54 (dt, J = 4.97, 1.63 Hz, 2 H) 4.81-4.92 (m, 2 H) 5.09-5.32 (m, 7 H) 5.33-5.51 (m, 2 H) 5.80-6.10 (m, 4 H) 6.86 (s, 1 H) 7.02 (td, 2 H) 7.03 (d, 2 H) 7.22 (s, 1 H).
ESI m / z = 628 (M + NH 4 +), 633 (M + Na +), 645 (M + Cl -).

Example 11
Production of (1S) -1,5-anhydro-1- [4-chloro-2-hydroxy-5- (4-methylbenzyl) phenyl] -1-thio-D-glucitol (Compound (V))

（１Ｓ）−１，５−アンヒドロ−１−［４−クロロ−５−（４−メチルベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−１−チオ−Ｄ−グルシトール（２４２ｍｇ、０．３９６ｍｍｏｌ）のテトラヒドロフラン（８ｍＬ）溶液にＮ，Ｎ−ジメチルバルビツル酸（６１８ｍｇ、３．９６ｍｍｏｌ）とテトラキストリフェニルホスフィンパラジウム（９１．５ｍｇ、０．０７９２ｍｍｏｌ）を加え、９０℃で３時間攪拌した。反応液を室温まで冷却して水を加え、酢酸エチルで抽出し、有機相を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。乾燥剤を炉別後、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−（クロロホルム：メタノール＝９：１）にて精製し、更にヘキサン：酢酸エチル：エタノールから再結晶を行い、淡赤色粉末の表題化合物（６４．２ｍｇ、３９％）を得た。
1H NMR (600 MHz, METHANOL-d₄) δppm 2.26 (s, 3 H) 2.95 (ddd, J=10.09, 6.42, 3.67 Hz, 1 H) 3.22 (t, J=8.71 Hz, 1 H) 3.53 (t, 1 H) 3.67 - 3.79 (m, 2 H) 3.84 - 3.96 (m, 3 H) 4.25 (d, J=10.55 Hz, 1 H) 6.80 (s, 1 H) 7.01 (d, 2 H) 7.03 (d, 2 H) 7.12 (s, 1 H).
ESI m/z = 428 (M+NH₄ ⁺) , 433 (M+Na⁺) , 409 (M-H) , 445 (M+Cl^-).

(1S) -1,5-Anhydro-1- [4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6- To a solution of tetra-O-prop-2-en-1-yl-1-thio-D-glucitol (242 mg, 0.396 mmol) in tetrahydrofuran (8 mL) was added N, N-dimethylbarbituric acid (618 mg, 3.96 mmol). And tetrakistriphenylphosphine palladium (91.5 mg, 0.0792 mmol) were added, and the mixture was stirred at 90 ° C. for 3 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phase 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 (chloroform: methanol = 9: 1), and further recrystallized from hexane: ethyl acetate: ethanol. The title compound (64.2 mg, 39%) was obtained as a pale red powder.
1H NMR (600 MHz, METHANOL-d ₄ ) δppm 2.26 (s, 3 H) 2.95 (ddd, J = 10.09, 6.42, 3.67 Hz, 1 H) 3.22 (t, J = 8.71 Hz, 1 H) 3.53 (t , 1 H) 3.67-3.79 (m, 2 H) 3.84-3.96 (m, 3 H) 4.25 (d, J = 10.55 Hz, 1 H) 6.80 (s, 1 H) 7.01 (d, 2 H) 7.03 ( d, 2 H) 7.12 (s, 1 H).
ESI m / z = 428 (M + NH 4 +), 433 (M + Na +), 409 (MH), 445 (M + Cl -).

Example 12
(12-A)
1-C- [4-Chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6-tetra-O-prop-2- Production of en-1-yl-5-thio-D-glucopyranose

実施例１（１−Ａ）と同様な方法で、１−（ベンジルオキシ）−２−ブロモ−５−メチル−４−（４−メチルベンジル） ベンゼンの代わりに１−ブロモ−４−クロロ−５−（４−エチルベンジル）−２−（プロパ−２−エン−２−イルオキシ）ベンゼン、２，３，４，６−テトラ−Ｏ−ベンジル−５−チオ−Ｄ−グルコノ−１，５−ラクトンの代わりに２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１-イル−５−チオ−Ｄ−グルコノ−１，５−ラクトンを用いて、無色油状の表題化合物（１．００ｇ、３９％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.20 (t, J=7.62 Hz, 3 H) 2.59 (q, J=7.51 Hz, 2 H) 3.37 - 3.46 (m, 1 H) 3.47 - 4.42 (m, 15 H) 4.60 (d, J=4.35 Hz, 2 H) 4.87 (s, 1 H) 4.92 (d, J=3.89 Hz, 1 H) 5.08 - 5.37 (m, 7 H) 5.41 - 5.58 (m, 2 H) 5.79 - 6.14 (m, 4 H) 6.93 (s, 1 H) 7.06 (d, 2 H) 7.07 (d, 2 H) 7.26 (br. s., 1 H)．
ESI m/z = 639 (M-H) , 675 (M+Cl^-).

In the same manner as in Example 1 (1-A), 1-bromo-4-chloro-5 instead of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene -(4-Ethylbenzyl) -2- (prop-2-en-2-yloxy) benzene, 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone Instead of 2,3,4,6-tetra-O-prop-2-en-1-yl-5-thio-D-glucono-1,5-lactone, the title compound (1. 00 g, 39%).
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.20 (t, J = 7.62 Hz, 3 H) 2.59 (q, J = 7.51 Hz, 2 H) 3.37-3.46 (m, 1 H) 3.47-4.42 (m, 15 H) 4.60 (d, J = 4.35 Hz, 2 H) 4.87 (s, 1 H) 4.92 (d, J = 3.89 Hz, 1 H) 5.08-5.37 (m, 7 H) 5.41-5.58 (m, 2 H) 5.79-6.14 (m, 4 H) 6.93 (s, 1 H) 7.06 (d, 2 H) 7.07 (d, 2 H) 7.26 (br. S., 1 H).
ESI m / z = 639 (MH ), 675 (M + Cl -).

(12-B)
(1S) -1,5-Anhydro-1- [4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6- Production of tetra-O-prop-2-en-1-yl-1-thio-D-glucitol

実施例１（１−Ｂ）と同様な方法で、２，３，４，６−テトラ−Ｏ−ベンジル−１−Ｃ−［２−（ベンジルオキシ）−４−メチル−５−（４−メチルベンジル）フェニル］−５−チオ−Ｄ−グルコピラノースの代わりに１−Ｃ−［４−クロロ−５−（４−エチルベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１-イル−５−チオ−Ｄ−グルコピラノースを用いて、無色固体の表題化合物（５６４ｍｇ、６５％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.20 (t, J=7.54 Hz, 3 H) 2.59 (q, J=7.82 Hz, 2 H) 2.95 - 3.04 (m, 1 H) 3.25 (t, J=8.55 Hz, 1 H) 3.36 - 3.94 (m, 7 H) 3.99 (d, J=5.60 Hz, 2 H) 4.03 - 4.19 (m, 2 H) 4.27 (d, J=5.75 Hz, 2 H) 4.36 (dd, J=12.43, 5.44 Hz, 2 H) 4.54 (dt, J=4.82, 1.63 Hz, 2 H) 4.85 (dd, J=15.85, 2.64 Hz, 2 H) 5.06 - 5.32 (m, 7 H) 5.32 - 5.48 (m, 2 H) 5.80 - 6.10 (m, 4 H) 6.86 (s, 1 H) 7.06 (d, J=3.26 Hz, 4 H) 7.22 (br. s., 1 H)．
ESI m/z = 642 (M+NH₄ ⁺) , 647 (M+Na⁺) , 659 (M+Cl^-).

In the same manner as in Example 1 (1-B), 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-methyl-5- (4-methyl) [Benzyl] phenyl] -5-thio-D-glucopyranose instead of 1-C- [4-chloro-5- (4-ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl]- The title compound (564 mg, 65%) as a colorless solid was obtained using 2,3,4,6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose.
1H NMR (300 MHz, CHLOROFORM-d) δppm 1.20 (t, J = 7.54 Hz, 3 H) 2.59 (q, J = 7.82 Hz, 2 H) 2.95-3.04 (m, 1 H) 3.25 (t, J = 8.55 Hz, 1 H) 3.36-3.94 (m, 7 H) 3.99 (d, J = 5.60 Hz, 2 H) 4.03-4.19 (m, 2 H) 4.27 (d, J = 5.75 Hz, 2 H) 4.36 ( dd, J = 12.43, 5.44 Hz, 2 H) 4.54 (dt, J = 4.82, 1.63 Hz, 2 H) 4.85 (dd, J = 15.85, 2.64 Hz, 2 H) 5.06-5.32 (m, 7 H) 5.32 -5.48 (m, 2 H) 5.80-6.10 (m, 4 H) 6.86 (s, 1 H) 7.06 (d, J = 3.26 Hz, 4 H) 7.22 (br. S., 1 H).
ESI m / z = 642 (M + NH 4 +), 647 (M + Na +), 659 (M + Cl -).

Example 13
Production of (1S) -1,5-anhydro-1- [4-chloro-2-hydroxy-5- (4-ethylbenzyl) phenyl] -1-thio-D-glucitol (compound (VI))

実施例１１と同様な方法で、（１Ｓ）−１，５−アンヒドロ−１−［４−クロロ−５−（４−メチルベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−１−チオ−Ｄ−グルシトールの代わりに（１Ｓ）−１，５−アンヒドロ−１−［４−クロロ−５−（４−エチルベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−１−チオ−Ｄ−グルシトールを用いて、淡赤色粉末の表題化合物（９７．８ｍｇ、２９％）を得た。
1H NMR (600 MHz, METHANOL-d₄) δppm 1.18 (t, J=7.57 Hz, 3 H) 2.57 (q, J=7.64 Hz, 2 H) 2.96 (ddd, J=10.20, 6.53, 3.44 Hz, 1 H) 3.22 (t, J=8.94 Hz, 1 H) 3.54 (dd, J=10.32, 8.94 Hz, 1 H) 3.71 (dd, J=11.69, 6.65 Hz, 1 H) 3.76 (dd, J=10.32, 8.94 Hz, 1 H) 3.86 - 3.96 (m, 3 H) 4.25 (d, J=10.55 Hz, 1 H) 6.80 (s, 1 H) 7.01 - 7.07 (m, 4 H) 7.14 (s, 1 H)．
ESI m/z = 442 (M+NH₄ ⁺) , 423 (M-H) , 459 (M+Cl^-).

In the same manner as in Example 11, (1S) -1,5-anhydro-1- [4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] Instead of 2,3,4,6-tetra-O-prop-2-en-1-yl-1-thio-D-glucitol, (1S) -1,5-anhydro-1- [4-chloro- 5- (4-Ethylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6-tetra-O-prop-2-en-1-yl-1-thio The title compound (97.8 mg, 29%) was obtained as a pale red powder using -D-glucitol.
1H NMR (600 MHz, METHANOL-d ₄ ) δppm 1.18 (t, J = 7.57 Hz, 3 H) 2.57 (q, J = 7.64 Hz, 2 H) 2.96 (ddd, J = 10.20, 6.53, 3.44 Hz, 1 H) 3.22 (t, J = 8.94 Hz, 1 H) 3.54 (dd, J = 10.32, 8.94 Hz, 1 H) 3.71 (dd, J = 11.69, 6.65 Hz, 1 H) 3.76 (dd, J = 10.32, 8.94 Hz, 1 H) 3.86-3.96 (m, 3 H) 4.25 (d, J = 10.55 Hz, 1 H) 6.80 (s, 1 H) 7.01-7.07 (m, 4 H) 7.14 (s, 1 H) .
ESI m / z = 442 (M + NH 4 +), 423 (MH), 459 (M + Cl -).

Example 14
(14-A)
1-C- [4-Chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6-tetra-O-prop-2- Production of en-1-yl-5-thio-D-glucopyranose

実施例１（１−Ａ）と同様な方法で、１−（ベンジルオキシ）−２−ブロモ−５−メチル−４−（４−メチルベンジル）ベンゼンの代わりに１−ブロモ−４−クロロ−５−（４−メトキシベンジル）−２−（プロパ−２−エン−１−イルオキシ）ベンゼン、２，３，４，６−テトラ−Ｏ−ベンジル−５−チオ−Ｄ−グルコノ−１，５−ラクトンの代わりに２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−５−チオ−Ｄ−グルコノ−１，５−ラクトンを用いて、無色油状の表題化合物（１．３５ｇ、５４％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 3.35 - 3.47 (m, 1 H) 3.49 - 3.63 (m, 2 H) 3.69 (t, 2 H) 3.77 (s, 3 H) 3.80 - 4.42 (m, 10 H) 4.60 (d, J=5.0 Hz, 2 H) 4.82 - 4.99 (m, 2 H) 5.05 - 5.38 (m, 8 H) 5.41 - 5.60 (m, 2 H) 5.76 - 6.17 (m, 4 H) 6.73 - 6.84 (m, 2 H) 6.92 (s, 1 H) 6.99 - 7.11 (m, 2 H) 7.34 (brs., 1 H).
ESＩ m/z = 660 (M+NH₄ ⁺), 641 (M-H).

In the same manner as in Example 1 (1-A), instead of 1- (benzyloxy) -2-bromo-5-methyl-4- (4-methylbenzyl) benzene, 1-bromo-4-chloro-5 -(4-Methoxybenzyl) -2- (prop-2-en-1-yloxy) benzene, 2,3,4,6-tetra-O-benzyl-5-thio-D-glucono-1,5-lactone Instead of 2,3,4,6-tetra-O-prop-2-en-1-yl-5-thio-D-glucono-1,5-lactone, the title compound (1. 35 g, 54%).
1H NMR (300 MHz, CHLOROFORM-d) δppm 3.35-3.47 (m, 1 H) 3.49-3.63 (m, 2 H) 3.69 (t, 2 H) 3.77 (s, 3 H) 3.80-4.42 (m, 10 H) 4.60 (d, J = 5.0 Hz, 2 H) 4.82-4.99 (m, 2 H) 5.05-5.38 (m, 8 H) 5.41-5.60 (m, 2 H) 5.76-6.17 (m, 4 H) 6.73-6.84 (m, 2 H) 6.92 (s, 1 H) 6.99-7.11 (m, 2 H) 7.34 (brs., 1 H).
ESI m / z = 660 (M + NH ₄ ⁺ ), 641 (MH).

(14-B)
(1S) -1,5-Anhydro-1- [4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6- Production of tetra-O-prop-2-en-1-yl-1-thio-D-glucitol

実施例１（１−Ｂ）と同様な方法で、２，３，４，６−テトラ−Ｏ−ベンジル−１−Ｃ−［２−（ベンジルオキシ）−４−メチル−５−（４−メチルベンジル）フェニル］−５−チオ−Ｄ−グルコピラノースの代わりに１−Ｃ−［４−クロロ−５−（４−メトキシベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−５−チオ−Ｄ−グルコピラノースを用いて、無色固体の表題化合物（７５０ｍｇ、５６％）を得た。
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.88 - 3.08 (m, 1 H) 3.25 (t, J=9.0 Hz, 1 H) 3.35 - 4.66 (m, 20 H) 4.73 - 4.99 (m, 2 H) 5.06 - 5.33 (m, 7 H) 5.33 - 5.55 (m, 2 H) 5.72 - 6.18 (m, 4 H) 6.74 - 6.83 (m, 2 H) 6.86 (s, 1 H) 7.04 (d, J=8.7 Hz, 2 H) 7.21 (s, 1 H).
ESＩ m/z = 649 (M+Na⁺), 644 (M+NH₄ ⁺), 625 (M-H).

In the same manner as in Example 1 (1-B), 2,3,4,6-tetra-O-benzyl-1-C- [2- (benzyloxy) -4-methyl-5- (4-methyl) [Benzyl] phenyl] -5-thio-D-glucopyranose instead of 1-C- [4-chloro-5- (4-methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl]- The title compound (750 mg, 56%) was obtained as a colorless solid using 2,3,4,6-tetra-O-prop-2-en-1-yl-5-thio-D-glucopyranose.
1H NMR (300 MHz, CHLOROFORM-d) δppm 2.88-3.08 (m, 1 H) 3.25 (t, J = 9.0 Hz, 1 H) 3.35-4.66 (m, 20 H) 4.73-4.99 (m, 2 H) 5.06-5.33 (m, 7 H) 5.33-5.55 (m, 2 H) 5.72-6.18 (m, 4 H) 6.74-6.83 (m, 2 H) 6.86 (s, 1 H) 7.04 (d, J = 8.7 (Hz, 2 H) 7.21 (s, 1 H).
ESI m / z = 649 (M + Na ⁺ ), 644 (M + NH ₄ ⁺ ), 625 (MH).

Example 15
Production of (1S) -1,5-anhydro-1- [4-chloro-2-hydroxy-5- (4-methoxybenzyl) phenyl] -1-thio-D-glucitol (compound (VII))

実施例１１と同様な方法で、（１Ｓ）−１，５−アンヒドロ−１−［４−クロロ−５−（４−メチルベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−１−チオ−Ｄ−グルシトールの代わりに（１Ｓ）−１，５−アンヒドロ−１−［４−クロロ−５−（４−メトキシベンジル）−２−（プロパ−２−エン−１−イルオキシ）フェニル］−２，３，４，６−テトラ−Ｏ−プロパ−２−エン−１−イル−１−チオ−Ｄ−グルシトールを用いて合成し、シリカゲルカラムグラフィ−の後に活性炭（粉末）による脱色、酢酸エチルから再結晶を行い、無色粉末の表題化合物（１８０ｍｇ、３８％）を得た。
1H NMR (300 MHz, METHANOL-d₄) δppm 2.91 - 3.05 (m, 1 H) 3.24 (t, J=8.9 Hz, 1 H) 3.29 - 3.35 (m, 2 H) 3.57 (t, J=9.6 Hz, 1 H) 3.66 - 3.87 (m, 4 H) 3.87 - 4.00 (m, 3 H) 4.27 (d, J=10.4 Hz, 1 H) 6.74 - 6.87 (m, 3 H) 7.01 - 7.11 (m, 2 H) 7.14 (s, 1 H).
ESＩ m/z = 449 (M+Na⁺), 444 (M+NH₄ ⁺), 425 (M-H).

In the same manner as in Example 11, (1S) -1,5-anhydro-1- [4-chloro-5- (4-methylbenzyl) -2- (prop-2-en-1-yloxy) phenyl] Instead of 2,3,4,6-tetra-O-prop-2-en-1-yl-1-thio-D-glucitol, (1S) -1,5-anhydro-1- [4-chloro- 5- (4-Methoxybenzyl) -2- (prop-2-en-1-yloxy) phenyl] -2,3,4,6-tetra-O-prop-2-en-1-yl-1-thio Synthesis was performed using -D-glucitol, followed by silica gel column chromatography, decolorization with activated carbon (powder), and recrystallization from ethyl acetate to obtain the title compound (180 mg, 38%) as a colorless powder.
1H NMR (300 MHz, METHANOL-d ₄ ) δppm 2.91-3.05 (m, 1 H) 3.24 (t, J = 8.9 Hz, 1 H) 3.29-3.35 (m, 2 H) 3.57 (t, J = 9.6 Hz , 1 H) 3.66-3.87 (m, 4 H) 3.87-4.00 (m, 3 H) 4.27 (d, J = 10.4 Hz, 1 H) 6.74-6.87 (m, 3 H) 7.01-7.11 (m, 2 H) 7.14 (s, 1 H).
ESI m / z = 449 (M + Na ⁺ ), 444 (M + NH ₄ ⁺ ), 425 (MH).

  Formulation examples

Manufacturing Method The drug is mixed with lactose monohydrate, crystalline cellulose, carboxymethyl cellulose calcium and hydroxypropyl cellulose, and this mixture is pulverized with a pulverizer. The pulverized mixture is mixed for 1 minute with a stirring granulator and then granulated with water for 4-8 minutes. The obtained granulated product is dried at 70 ° C. for 40 minutes. The granulated dry powder is sieved with a 500 μm sieve. The granulated dry powder after sieving and magnesium stearate are mixed for 3 minutes at 30 rpm using a V-type mixer. The granules for tableting obtained using a rotary tableting machine are compression-molded and tableted as shown in Table 2.

Test example 1
(1) Cloning of human SGLT1 or human SGLT2 and introduction into expression vector Human SGLT1 sequence (NM_000343) was amplified from human small intestine-derived mRNA after reverse transcription and introduced into pCMV-tag5A (Stratagene) . The human SGLT2 sequence (NM_003041) was prepared from human kidney-derived mRNA by the same method and introduced into pcDNA3.1 + hygro (Invitrogen). It was confirmed that the sequence of each clone matched the reported sequence.

(2) Preparation of CHO-k1 cells stably expressing human SGLT1 or human SGLT2 Human SGLT1 and human SGLT2 expression vectors were transfected into CHO-k1 cells using Lipofectamine 2000 (Invitrogen). SGLT-expressing cells were cultured in the presence of geneticin (SGLT1) or hygromycin B (SGLT2) at a concentration of 500 μg / mL, resistant strains were selected, and the sugar uptake specific activity was obtained using the system shown below as an index.

(3) Sodium-dependent sugar uptake inhibition test in cells Cells stably expressing human SGLT1 or human SGLT2 were used in sodium-dependent sugar uptake activity inhibition tests.
Cells were incubated for 20 minutes in 1 mL 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). The pretreatment buffer is removed and the uptake buffer containing the test compound ([ ¹⁴ C] methyl α-D-glucopyranoside containing methyl α-D-glucopyranoside (0.1 mM for SGLT1 inhibition, 1 mM for SGLT2 inhibition), 200 μL of 140 mM NaCl, 2 mM KCl, 1 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM HEPES / 5 mM Tris, pH 7.4) was added, and an uptake reaction was performed at 37 ° C. for 30 minutes (SGLT1) or 1 hour (SGLT2). After the reaction, the cells were washed twice with 1 mL of washing buffer (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). Dissolved in 400 μL of 2M NaOH solution. After adding Aquazol 2 (Perkin Elmer) and mixing well, the amount of sugar uptake was calculated by measuring the radioactivity with a liquid scintillation counter (Beckman Coulter). 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.

Glucose uptake was measured using appropriate 6 concentrations of the test compound, and the concentration of the test compound that inhibited the uptake by 50% when the sugar uptake in the control group was taken as 100% was calculated as the IC ₅₀ value. did.

(4) Results Table 3 shows the SGLT inhibitory activities of Compound (I) to Compound (VII) and Compound 98 (disclosed in Patent Document 9). Compounds (I) to (VII), in which the ethoxy group of compound 98 is converted to a methyl group, ethyl group, methoxy group or methylthio group, are surprisingly 3 to 6 times stronger than compound 98 while retaining SGLT2 inhibitory activity. It was found to exhibit SGLT1 inhibitory activity.

(5) Test example 2
db / db mice (Japan Claire, male, 7 weeks old) were used as test animals for confirming the hypoglycemic effect in db / db mice. The test substance was suspended in a 0.5% aqueous carboxymethyl cellulose (CMC) solution and prepared to a concentration of 1 mg / 10 mL. On the day of the test, according to the blood sampling method and blood glucose level measuring method described below, the group was divided so that the difference in the blood glucose level and dispersion of db / db mice was as small as possible, and the number of mice per group was 6 . After measuring the body weight of the mice, the prepared test substance suspension was forcibly orally administered at a volume of 10 mL / kg using a mouse oral administration sonde, and only 0.5% CMC aqueous solution was administered to the control group. Blood was collected at a total of 8 points before the test substance administration (0 time) and 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration. The test was conducted under free feeding and drinking water.
Blood collection was performed using an heparin-coated blood collection tube from the orbital sinus of the diseased animal under ether anesthesia, and the blood glucose level was measured using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.). The hypoglycemic action intensity (%) is calculated by calculating the area under the blood glucose level-time curve (AUC) using the trapezoidal method from the blood glucose level at any time from 0 to 8 hours of each test substance administration group, and the decrease relative to that of the control group Expressed as a percentage.
(6) Results

According to the present invention, SGLT1 (sodium-dependent glucose cotransporter 1) expressed in the small intestinal epithelium and SGLT2 (sodium-dependent glucose cotransporter 2) expressed in the kidney are inhibited, and glucose from the digestive tract is inhibited. Prevention or treatment of diabetes, diabetes-related diseases or diabetic complications comprising 1-phenyl 1-thio-D-glucitol compound having both absorption inhibition and urinary glucose excretion as an active ingredient It is expected to provide an agent.

Claims (7)

Formula (I)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications. Formula (II)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications. Formula (III)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications. Formula (IV)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications. Formula (V)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications. Formula (VI)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications. Formula (VII)

1-phenyl 1-thio-D-glucitol compound represented by the above or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient, Preventive or therapeutic agent for diabetic complications.