JP2013224263A - 4-isopropylphenyl glucitol compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To inhibit abnormal glucose intolerance and postprandial hyperglycemia in diabetic patients by inhibiting the absorption of glucose and the like.SOLUTION: There are provided a 4-isopropylphenyl glucitol compound represented by formula (I) and a pharmaceutically acceptable salt of the compound. In the formula, Rrepresents a hydrogen atom or a substituted 1-4C alkyl group; Rand Rrepresent each a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group; Rand Rrepresent each a hydrogen atom, a methyl group or a hydroxymethyl group; n represents 0 or 1; Rrepresents a hydrogen atom, a substituted piperidyl group or a substituted 1-6C alkyl group; Rrepresents a hydrogen atom or a 1-4C alkyl group; W represents a single bond, a methylene group or a carbonyl group; and Y represents a 1-4C alkylene group or a carbonyl group.

Description

  The present invention is 4-isopropyl having an inhibitory activity specific to sodium-dependent glucose cotransporter 1 (hereinafter abbreviated as “SGLT1” where appropriate) involved in the absorption of glucose and galactose in the small intestine. The present invention relates to a phenyl glucitol compound.

  The blood glucose level is one of the biomarkers of metabolic syndrome, and diabetes is diagnosed when the fasting blood glucose level is 126 mg / dL or more. Even if fasting blood glucose is normal, a glucose tolerance abnormality (or postprandial hyperglycemia) is diagnosed when the blood glucose level for 2 hours after meal is 140 to 200 mg / dL. Recent epidemiological studies have reported that impaired glucose tolerance increases the risk of cardiovascular disorders (see Non-Patent Documents 1 and 2). Furthermore, it has been reported that exercise therapy and drug treatment suppress the transition from impaired glucose tolerance to type 2 diabetes and significantly suppress the onset of hypertension (see Non-Patent Document 3).

  From the above, suppressing postprandial hyperglycemia is considered to be important for suppressing the onset of diabetes and metabolic syndrome, and the demand for drugs that control postprandial hyperglycemia is increasing.

  Conventionally, α-glucosidase inhibitors that inhibit saccharide hydrolase and delay sugar absorption from the small intestine have been widely used as postprandial hyperglycemia-improving drugs. Development of drugs to improve blood glucose is also underway.

  Sodium-dependent glucose cotransporter 1 (SGLT1) is frequently expressed in the small intestinal epithelium of mammals. SGLT1 is known to depend on sodium in the small intestine and to control the active transport of glucose or galactose. Thus, pyrazole derivatives that have been reported to inhibit SGLT1 activity to suppress dietary glucose absorption and to be used for the prevention or treatment of postprandial hyperglycemia (see Patent Documents 1 to 6). ). On the other hand, sodium-dependent glucose cotransporter 2 (SGLT2) is frequently expressed in the kidney, and glucose once filtered by the glomerulus is reabsorbed via SGLT2 (non-patent document). Reference 4). And it has been reported that the inhibition of SGLT2 activity promotes the excretion of sugar into urine and exhibits a blood glucose lowering effect (see Non-Patent Document 5). As a feature of SGLT2 inhibitor, it has an excellent effect of lowering blood glucose as needed, but it has a low effect of correcting postprandial hyperglycemia like SGLT1 inhibitor. There is also a report on a C-phenyl glucitol derivative that simultaneously inhibits SGLT2 activity in addition to SGLT1 activity (see Patent Document 7).

  On the other hand, for drugs that require continuous administration, such as postprandial hyperglycemic drugs, it is important that there is a wide safety range between the effective amount and the amount of toxicity and side effects. In particular, in the case of a drug remaining in the body, it is difficult to control the dose required for treatment, and the drug remaining in the body is added to express the effect of an excessive amount of drug. Cause toxic and side effects. For example, a cationic drug having a hydrophilic group such as a tertiary amine and a hydrophobic group such as an aromatic ring in the molecule is hydrophobically bound to a phospholipid, and is taken into a lysosome and accumulated in organs throughout the body. It is known that As typical examples, chloroquine caused retinal damage, and perhexiline had changes in the lungs and cerebellum, causing neuropathy (see Non-Patent Document 6).

  Therefore, it is desirable that the drug is rapidly excreted from the body after exhibiting the drug effect. In particular, in the postprandial hyperglycemia improving drug for which continuous administration is essential, a drug having no problem of persistence in the body is desired.

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 International Publication No. WO2007 / 136116 Pamphlet

Pan XR, et al. Diabetes Care, 20, 537, 1997 M Tominaga, et al. Diabetes Care, 22, 920, 1999 J.-L. Chiasson, et al. Lancent, 359, 2072, 2002 E. M. Wright, Am. J. Physiol. Renal. Physiol., 280, F10, 2001 G. Toggenburger, et al. Biochem. Biophys. Acta., 688, 557, 1982 The Japanese Pharmacology Journal Folia Pharmacol. Jpn. 113, 19, 1999

  An object of the present invention is to provide a 4-isopropylphenyl glucitol compound or a salt thereof exhibiting an SGLT1 inhibitory action with a wide safety range between a medicinal amount, toxicity, and side effect, and a medicament containing them.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a 4-isopropylphenyl glucitol compound represented by the following general formula (I) obtained by introducing a specific side chain at the end of aglycone is excellent. The present invention has been found by having SGLT1 activity inhibitory activity.

Hereinafter, embodiments of the 4-isopropylphenyl glucitol compound of the present invention (hereinafter referred to as “the compound of the present invention”) will be described.
(1) 4-Isopropylphenyl glucitol compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:

式中、
Ｒ¹は、水素原子又は“水酸基若しくはハロゲン原子で置換されても良いＣ_1-4アルキル基”であり、
Ｒ²及びＲ³は、同一若しくは異なって、水素原子、メチル基、エチル基若しくはヒドロキシメチル基であり、
又は、Ｒ²及びＲ³は、隣接する炭素原子と共にＣ_3-6シクロアルキル基を形成し、
Ｒ⁴及びＲ⁵は、同一若しくは異なって、水素原子、メチル基若しくはヒドロキシメチル基であり、
又は、Ｒ⁴及びＲ⁵は、隣接する炭素原子と共にＣ_3-6シクロアルキル基若しくはＣ_4-6ヘテロシクリル基を形成し、
ｎは０又は１であり、
Ｒ⁶は水素原子、“ベンジル基で置換されても良いピペリジル基”若しくは“同一若しくは異なって、水酸基、アミノ基、カルバモイル基、ウレイド基、Ｃ_2-7アルコキシカルボニル基、Ｃ_1-6アルキルアミノカルボニル基（該Ｃ_1-6アルキルアミノカルボニル基は、アミノ基、Ｃ_2-7アルコキシカルボニル基、カルバモイル基、ジＣ_1-4アルキルアミノ基若しくは水酸基から選ばれる１から３個の基で置換されても良い）、Ｃ_2-7アルカノイルアミノ基（該Ｃ_2-7アルカノイルアミノ基はアミノ基で置換されても良い）、Ｃ_1-6アルキルスルホニルアミノ基、ジＣ_1-4アルキルアミノ基、フェニル基（該フェニル基は水酸基で置換されても良い）、ピリジル基若しくはピペリジル基から選ばれる１から３個の基で置換されたＣ_1-6アルキル基”であり、
Ｒ⁷は、水素原子若しくはＣ_1-4アルキル基であり、
又は、Ｒ⁶及びＲ⁷は、隣接する窒素原子と共に“Ｃ_1-6アルキル基（該Ｃ_1-6アルキル基はＣ_2-7アルコキシカルボニル基若しくは水酸基で置換されても良い）、カルバモイル基若しくはＣ_2-7アルカノイル基（該Ｃ_2-7アルカノイル基はアミノ基で置換されても良い）から選ばれる１個の基で置換されても良いピペラジニル基”若しくは“水酸基、カルバモイル基、ウレイド基、ジＣ_1-4アルキルアミノ基、モルホリノ基、Ｃ_2-7アルコキシカルボニル基、Ｃ_1-6アルキルスルホニルアミノ基、Ｃ_1-6アルキルアミノ基（該Ｃ_1-6アルキルアミノ基は、アミノ基、カルバモイル基、ジＣ_1-4アルキルアミノ基で置換されても良い）、Ｃ_2-7アルカノイルアミノ基（該Ｃ_2-7アルカノイルアミノ基はアミノ基で置換されても良い）若しくはＣ_1-6アルキルアミノカルボニルアミノ基（該Ｃ_1-6アルキルアミノカルボニルアミノ基は１〜３個の水酸基で置換されても良い）から選ばれる１個の基で置換されても良いピペリジノ基“を形成し、
Ｗは単結合、メチレン基（ＣＨ₂）又はカルボニル基（Ｃ＝Ｏ）を示し、
ＹはＣ_1-4アルキレン基又はカルボニル基（Ｃ＝Ｏ）を示す。

Where
R ¹ is a hydrogen atom or a “C _1-4 alkyl group _optionally substituted with a hydroxyl group or a halogen atom”;
R ² and R ³ are the same or different and are a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group,
Or R ² and R ³ together with the adjacent carbon atom form a C _3-6 cycloalkyl group,
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a methyl group or a hydroxymethyl group,
Or R ⁴ and R ⁵ together with the adjacent carbon atom form a C _3-6 cycloalkyl group or a C _4-6 heterocyclyl group;
n is 0 or 1;
R ⁶ is a hydrogen atom, “piperidyl group optionally substituted with a benzyl group” or “same or different, hydroxyl group, amino group, carbamoyl group, ureido group, C _2-7 alkoxycarbonyl group, C _1-6 alkylamino group A carbonyl group (the C _1-6 alkylaminocarbonyl group is substituted with 1 to 3 groups selected from an amino group, a C _2-7 alkoxycarbonyl group, a carbamoyl group, a diC _1-4 alkylamino group or a hydroxyl group; C _2-7 alkanoylamino group (the C _2-7 alkanoylamino group may be substituted with an amino group), C _1-6 alkylsulfonylamino group, diC _1-4 alkylamino group, A phenyl group (the phenyl group may be substituted with a hydroxyl group), a pyridyl group or a C _1-6 alkyl group substituted with 1 to 3 groups selected from a piperidyl group;
R ⁷ is a hydrogen atom or a C _1-4 alkyl group,
Or R ⁶ and R ⁷ together with an adjacent nitrogen atom are a “C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with a C _2-7 alkoxycarbonyl group or a hydroxyl group), a carbamoyl group or A piperazinyl group which may be substituted with one group selected from a C _2-7 alkanoyl group (the C _2-7 alkanoyl group may be substituted with an amino group) or a hydroxyl group, a carbamoyl group, a ureido group, Di-C _1-4 alkylamino group, morpholino group, C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkylamino group (the C _1-6 alkylamino group is an amino group, A carbamoyl group, which may be substituted with a di-C _1-4 alkylamino group), a C _2-7 alkanoylamino group (the C _2-7 alkanoylamino group may be substituted with an amino group) or C _1-6 Alkylamino Ruboniruamino group (wherein the C _1-6 alkylaminocarbonyl amino group may be substituted with 1 to 3 hydroxyl groups) to form one may piperidino group which may be substituted with a group "chosen from,
W represents a single bond, a methylene group (CH ₂ ) or a carbonyl group (C═O),
Y represents a C _1-4 alkylene group or a carbonyl group (C═O).

(2) The 4-isopropylphenyl glucitol compound or pharmaceutically acceptable salt thereof according to (1) (except when W and Y are carbonyl groups at the same time):
Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , n, W and Y are as defined in (1).

(3) W is a single bond or a methylene group (CH ₂ ), the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) or (2):
Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , n and Y are as defined in (1).

(4) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) or (2), wherein W represents a carbonyl group (C═O):
Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , n and Y are as defined in (1).

(5) 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1), (2) or (4), wherein Y represents a C _1-4 alkylene group:
Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined in (1).

(6) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1), (2) or (4), wherein Y represents a carbonyl group (C═O):
Where
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and n are as defined in (1).

(7) R ¹ represents a hydrogen atom, R ² and R ³ represent a methyl group, R ⁴ and R ⁵ represent a methyl group, n represents 0, R ⁶ represents a “hydroxyl group, a di-C _1-4 alkylamino group “C _3-5 alkyl group substituted with one selected group”, R ⁷ represents a hydrogen atom, W represents a carbonyl group (C═O), and Y represents a carbonyl group (C═O). 1-, 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (4) or (6).

(8) The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1), (4), (6) or (7) shown below:

(9) A sodium-dependent glucose cotransporter 1 (SGLT1) activity inhibitor comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) as an active ingredient.

(10) A postprandial hyperglycemia remedy comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) as an active ingredient.

(11) A prophylactic or therapeutic agent for diabetes comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) as an active ingredient.

(12) Use of the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to (1) to (8) in the manufacture of a drug for preventing or treating diabetes.

  According to the present invention, it has become possible to provide a 4-isopropylphenyl glucitol compound that inhibits SGLT1 activity.

  The terms used in the present invention are defined below.

In the present invention, “n” is normal, “i” is iso, “s” and “sec” are secondary, “t” and “tert” are tertiary, “c” is cyclo, “o” "" Indicates ortho, "m" indicates meta, and "p" indicates para.
The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“C _1-4 alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, and tert-butyl group can be mentioned.
The “C _1-6 alkyl group” means a linear or branched alkyl group having 1-6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, n-pentyl group, i-pentyl group, neopentyl group, n-hexyl group, i-hexyl Groups.
The “C _3-6 cycloalkyl group” means a cyclic alkyl group having 3-6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
The “C _4-6 heterocyclyl group” is a _4- to 6-membered ring composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom or the same or different and 1 to 5 carbon atoms. Means a monocyclic saturated heterocyclic group. Examples include oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, tetrahydrothiopyranyl group, pyrrolidinyl group, piperidinyl group.
The “C _2-7 alkanoyl group” means a carbonyl group having “a linear or branched alkyl group having 1 to 6 carbon atoms”. Examples include acetyl group, propionyl group, n-butyryl group, i-butyryl group, n-valeryl group, i-valeryl group, and pivaloyl group.
The “C _1-6 alkylamino group” means an amino group having one “C _1-6 alkyl group” as a substituent. Examples thereof include a methylamino group, an ethylamino group, an n-propylamino group, an i-propylamino group, and an n-butylamino group.
The “di-C _1-4 alkylamino group” means an amino group having the above-mentioned “C _1-4 alkyl group” as the same or different two substituents. Examples thereof include a dimethylamino group, a diethylamino group, a di (n-propyl) amino group, a di (i-propyl) amino group, an ethylmethylamino group, and a methyl (n-propyl) amino group.
“C _2-7 alkoxycarbonyl group” means a group in which a “linear or branched alkoxy group having 1 to 6 carbon atoms” and a carbonyl group are bonded. Examples thereof include a methoxycarbonyl group and an ethoxycarbonyl group.
The “C _1-6 alkylaminocarbonyl group” means a group in which the above “C _1-6 alkylamino group” is bonded to a carbonyl group. An example is a methylaminocarbonyl group.
The “C _2-7 alkanoylamino group” means a group in which the above “C _2-7 alkanoyl group” and an amino group are bonded. For example, an acetamide group can be mentioned.
The “C _1-6 alkylsulfonylamino group” means a group in which the sulfonyl group to which the above “C _1-6 alkyl group” is bonded is bonded to an amino group. An example is a methanesulfonamide group.
The “C _1-6 alkylaminocarbonylamino group” means a group in which a carbonyl group to which the above “C _1-6 alkylamino group” is bonded is bonded to an amino group. An example is a methylaminocarbonylamino group.
“C _1-4 alkylene group” means a divalent hydrocarbon group having 1 to 4 carbon atoms. For example, a methylene group, an ethylene group, and a propylene group are mentioned.

  “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, formate, acetate, propionate, butyrate, hexanoate, octanoate, trifluoroacetate, maleate, tartrate, citric acid Salt, stearate, succinate, ethyl succinate, lactobionate, gluconate, glucuronate, glucoheptonate, glutarate, pimelate, suberate, azelate, sebacate, 1,9-nonanedicarboxylate, dodecanedioate, tridecanedioate, tetradecanedioate, pentadecanedioate, hex Sadecanedioate, heptadecanedioate, benzoate, 2-hydroxybenzoate, methanesulfonate, ethanesulfonate, ethanedisulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, p -Toluenesulfonate, 1,5-naphthalenedisulfonate, lauryl sulfate, lactate, hippurate, fumarate, malonate, transcinnamate, malate, aspartate, glutamate , Adipate, salt with cysteine, salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picric acid And salts with thiocyanate, undecanoate, acrylic acid polymer, and carboxyvinyl polymer.

  "The compound of the present invention or a salt thereof" also includes pharmaceutically acceptable hydrates thereof. The compound of the present invention or a salt thereof may be exposed to the atmosphere, or may absorb moisture during the production process to form adsorbed water or become a hydrate. The hydrate in the present invention includes such a hydrate.

  “Postprandial hyperglycemia-improving drug” refers to a drug that suppresses postprandial hyperglycemia, thereby suppressing the onset of postprandial hyperglycemia, such as diabetes or metabolic syndrome, or treating these diseases . Here, “postprandial hyperglycemia” refers to a state in which the blood glucose level is abnormally high after the meal, specifically, a state in which the blood glucose level for 2 hours after the meal exceeds 140 mg / dL.

  The usefulness of the compound of the present invention will be described below (for details, see the following test examples).

  The compound of the present invention has strong SGLT1 inhibitory activity. Therefore, it is considered that the compound of the present invention has a property that is excellent in practicality as a pharmaceutical having an excellent blood glucose lowering action.

  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, liquids, emulsions, suspensions and the like can be prepared from the compound of the present invention and these carriers.

  For example, the compound of the present invention and general excipients used for the production of solid preparations and the like can be mixed and then tableted to provide tablets for oral administration.

  In addition, the compound of the present invention can be included in α, β, γ-cyclodextrin, methylated cyclodextrin or the like to improve its solubility.

  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. 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 can be synthesized by the method shown below, but the following production method is an example of a general production method and does not limit the production method.

Manufacturing method 1
The compound (I) of the present invention in which W is a carbonyl group and Y is a single bond or a C _1-4 alkylene group can be synthesized by the following method.
Wherein X represents an acetyl group, an acetyloxy group or a C _1-4 alkyl group which may be substituted with a halogen atom, and R ^2A and R ^3A are the same or different and represent a hydrogen atom, a methyl group or an ethyl group,
Alternatively, R ^2A and R ^3A together with the adjacent carbon atom form a C _3-6 cycloalkyl group, a 2,2-dimethyldioxanyl group. R ^6A represents a R ⁶ wherein R ⁶ or an amino group is protected with tert- butyl carbonate (Boc), m represents an integer of 1 to 4, and other symbols are as defined above.

(1) Step 1 (acetylation or alkylation)
The intermediate (1B) can be produced by protecting the hydroxyl group of the compound (1A) with an acetyl group or performing alkylation such as methylation. Compound (1A) can be reacted with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base to obtain intermediate (1B). Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. Preferable examples of the base include triethylamine, collidine, pyridine and the like. 4-dimethylaminopyridine or the like can also be used as a catalyst. Moreover, preferable reaction temperature is 0 degreeC-room temperature. On the other hand, the intermediate (1B) can be obtained by reacting the compound (1A) with methyl iodide, ethyl iodide or the like in a solvent in the presence of an appropriate base. Examples of the solvent used for the reaction include chloroform, dichloromethane, tetrahydrofuran, N, N-dimethylformamide, acetone and the like. Examples of the base include potassium carbonate and cesium carbonate.

(2) Step 2 (Heck reaction)
Compound (1C) can be obtained by subjecting compound (1B) and olefin carboxylic acid (4A) to Heck reaction in the presence of a palladium catalyst, a phosphine ligand, and an appropriate base. Examples of the palladium catalyst used at this time include palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone palladium, bis (triphenylphosphine) palladium chloride, bis (tricyclohexylphosphine) palladium chloride, and palladium activated carbon. Examples of the phosphine ligand include triphenylphosphine and tri-o-tolylphosphine. As the base, triethylamine, N-ethyl-N, N-diisopropylamine, potassium carbonate, calcium carbonate, cesium carbonate, potassium t-butoxide and the like are used. Examples of the solvent used for the reaction include acetonitrile, toluene, tetrahydrofuran and the like. The reaction temperature is 0 ° C. to reflux temperature. A microwave may be used.

(3) Step 3 (Conversion to amide group)
Compound (1C) can be condensed with amine (4B) to give compound (1D). Examples of the solvent used in this reaction include chloroform, dichloromethane, N, N-dimethylformamide and the like, and examples of the condensing agent include N, N′-dicyclohexylcarbodiimide (DCC), N-ethyl-N′-3-dimethyl. Aminopropylcarbodiimide hydrochloride (EDC-HCl), 1,1′-carbonyldiimidazole (CDI), EDC-HCl / 1-hydroxybenzotriazole monohydrate (HOBt · H ₂ O), etc. Can be mentioned. The reaction temperature here is 0 ° C to 60 ° C.

(4) Step 4 (oxidation)
The compound (1E) can be obtained by oxidizing the primary alcohol of the compound (1D). As the solvent used in this reaction, chloroform, dichloromethane, dimethyl sulfoxide and the like are preferable, and as the oxidizing agent, Dess-Martin periodinane, IBX and the like are preferable. The reaction temperature here is 0 ° C. to room temperature.

(5) Step 5 (Reductive amination)
Compound (1F) can be obtained by reductive amination reaction using compound (1E) and an amine (R ^6A R ⁷ NH (4C)). Examples of the solvent used in this reaction include N, N-dimethylformamide, chloroform, dichloromethane, methanol and the like. Depending on the substrate, addition of acetic acid may improve the yield. Examples of the reducing agent include NaBH (OAc) ₃ , NaBH ₃ CN, and borane-2-picoline complex. The reaction temperature here is 0 ° C. to room temperature.
(6) Step 6 (deprotection)
Compound (I) can be obtained by removing the Boc group in compound (1F) under acidic conditions and removing the acetyl (Ac) group under basic conditions. Hydrochloric acid or trifluoroacetic acid is allowed to act on the Boc group in a solvent such as dichloromethane, chloroform, dioxane or the like or without a solvent. For the acetyl group, a base such as sodium methoxide, sodium ethoxide, sodium hydroxide, lithium hydroxide, potassium carbonate, cesium carbonate, triethylamine or the like can be used. Examples of the solvent include methanol, ethanol, hydrous methanol and the like. The reaction temperature here is 0 ° C to 60 ° C. When R ^2A and R ^3A form a 2,2-dimethyldioxanyl group with adjacent carbon atoms, the acetal group can be removed under acidic conditions and converted to a hydroxymethyl group. Examples of the solvent used in this reaction include tetrahydrofuran, dioxane, ethyl acetate, and examples of the acid include hydrochloric acid, trifluoroacetic acid, p-toluenesulfonic acid, and the like.

Manufacturing method 2
In addition, the compound (Ia) of the present invention in which W is a single bond or methylene group and Y is a carbonyl group can be synthesized by the following method.

(7) Step 7 (Heck reaction)
Compound (2C) can be obtained by performing Heck reaction described in Step 2 of Production Method 1 from Compound (1B) and acrylic acid or butenoic acid (4D).

(8) Step 8 (reduction)
Compound (2D) can be obtained by reducing the carboxy group of compound (2C). Examples of the solvent used in this reaction include tetrahydrofuran and diethyl ether. An example of the reducing agent is borane-tetrahydrofuran complex. The reaction temperature is 0 ° C to 60 ° C, preferably room temperature.

(9) Step 9 (bromination or mesylation)
The compound (2E) can be obtained by brominating or mesylating the primary alcohol of the compound (2D). As the solvent used in this reaction, chloroform, dichloromethane, tetrahydrofuran and the like are preferable. Examples of the bromination reagent include triphenylphosphine (PPh ₃ ) -DEAD-lithium bromide, PPh ₃ -carbon tetrabromide, N-bromosuccinimide (NBS), and the like. As a reagent for mesylation, methanesulfonyl chloride is used in the presence of triethylamine. The reaction temperature is 0 ° C. to room temperature. Moreover, since a methanesulfonyl derivative is unstable, it is preferable to use for a substitution reaction with the post-production process 10 and an amine (4E) promptly.

(10) Step 10 (amination)
Compound (2F) can be obtained by reacting compound (2E) with amine (4E). Examples of the solvent used in this reaction include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide and the like, and the reaction temperature is from room temperature to 150 ° C.

(11) Step 11 (deprotection)
Compound (2F) obtained above can be led to compound (Ia) by the deprotection reaction described in Step 6 of Production Method 1.

Production method 3
The compound (Ib) of the present invention in which W and Y are both carbonyl groups can be synthesized by the method shown below.

(12) Step 12 (Heck reaction)
Compound (3A) can be obtained by performing the Heck reaction described in Step 2 of Production Method 1 using Compound (1B) and Compound (4F).

(13) Step 13 (Conversion to amide group)
Compound (3B) can be obtained by performing the dehydration condensation reaction described in Step 3 of Production Method 1 using Compound (3A) and amine (4C).

(14) Step 14 (deprotection)
Compound (3B) obtained above can be led to compound (Ib) by the deprotection reaction described in Step 6 of Production Method 1.

Production method of intermediate (1A) Intermediate (1A) can be synthesized by the method shown below.
However, the symbols are as defined above.

(15) Step 15 (coupling)
An aryl lithium reagent can be prepared using an organometallic reagent such as n-butyllithium, sec-butyllithium, tert-butyllithium and the like for compound (5A). Compound (5C) can be obtained by adding gluconolactone (5B) to this. Examples of the solvent used for the reaction include tetrahydrofuran, diethyl ether, toluene and the like. The reaction temperature is −80 ° C. to room temperature, preferably −78 ° C. to −25 ° C.

(16) Step 16 (silylation)
Subsequent to the step 15, the 1-position hydroxyl group of the compound (5C) can be protected with a silyl group such as a trimethylsilyl group. The reaction liquid in Step 15 can be reacted with trimethylsilyl chloride to obtain compound (5D). The solvent and reaction temperature used for the reaction are the same as in Step 15.

(17) Step 17 (coupling)
Subsequent to the step 16, an aryl lithium reagent can be prepared by using an organometallic reagent such as n-butyllithium, sec-butyllithium, or tert-butyllithium for the compound (5D) produced. Compound (5F) can be obtained by adding aldehyde (5E) to this. At this time, the solvent used for the reaction and the preferred reaction temperature are the same as in Step 15.

(18) Step 18 (acid hydrolysis and methyl etherification)
The MOM group and silyl group in the compound (5F) can be simultaneously removed in methanol under acidic conditions, and the 1-position of the sugar can be methyletherified to obtain the compound (5G). Examples of the acid used at this time include hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid monohydrate, pyridinium p-toluenesulfonic acid, and the like. The reaction temperature varies depending on the acid used, but is 0 ° C to 100 ° C, preferably 25 ° C to 80 ° C.

(19) Step 19 (acetylation)
A compound (5H) can be obtained by protecting the hydroxyl group in the compound (5G) with an acetyl group. Compound (5H) can be obtained by reacting compound (5G) with acetic anhydride, acetyl chloride or the like in a solvent in the presence of a suitable base. Examples of the solvent used for the reaction include chloroform, dichloromethane, dioxane, ethyl acetate, tetrahydrofuran, N, N-dimethylformamide and the like. Examples of the base include triethylamine, collidine, pyridine and the like. 4-Dimethylaminopyridine can also be used as a catalyst for the reaction. The reaction temperature is 0 ° C. to room temperature.

(20) Step 20 (reduction)
Compound (1A) can be obtained by reacting compound (5H) 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 · OEt ₂ , CF ₃ COOH, InCl ₃ , TiCl ₄ , TMSOTf, p-toluenesulfonic acid monohydrate, methanesulfonic acid, and the like. , Dichloromethane, toluene, tetrahydrofuran, acetonitrile or a mixed solvent thereof, and a preferable solvent is a mixed solvent of acetonitrile and other solvents such as acetonitrile / chloroform, acetonitrile / dichloromethane, acetonitrile / tetrahydrofuran and acetonitrile / tetrahydrofuran / toluene. .

Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these descriptions.
Reference Example 1 Production of Intermediate (1A)

(1) Reference Example 1-1 Compound (5A)

３−イソプロピルフェノール（１６０ｇ,１．１８ｍｏｌ）の酢酸（１．６Ｌ）溶液に、氷冷で内温が１９℃を超えないように臭素（４６９ｇ,２．９４ｍｏｌ）の酢酸（３２０ｍＬ）溶液を３２分かけて滴下し、室温で１時間撹拌した。トルエン（１．６Ｌ）を加えた後に氷冷し、内温２０℃を超えないように１０％亜硫酸ナトリウム水溶液（１．０Ｌ）を滴下して有機層を分離した。その有機層を１０％亜硫酸ナトリウム水溶液（１．０Ｌ）、１０％食塩水（１．０Ｌ）で２回洗浄した後、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、淡黄色油状の２,４−ジブロモ−５−イソプロピルフェノール（３４２ｇ,９９％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=6.8 Hz, 6 H) 3.25 (sept, J=6.8 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H) 7.61 (s, 1 H).

To a solution of 3-isopropylphenol (160 g, 1.18 mol) in acetic acid (1.6 L), a solution of bromine (469 g, 2.94 mol) in acetic acid (320 mL) was added with ice-cooling so that the internal temperature did not exceed 19 ° C. The solution was added dropwise over a minute and stirred at room temperature for 1 hour. Toluene (1.6 L) was added and then ice-cooled, and a 10% aqueous sodium sulfite solution (1.0 L) was added dropwise so that the internal temperature did not exceed 20 ° C., and the organic layer was separated. The organic layer was washed twice with 10% aqueous sodium sulfite (1.0 L) and 10% brine (1.0 L), and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain 2,4-dibromo-5-isopropylphenol (342 g, 99%) as a pale yellow oil.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J = 6.8 Hz, 6 H) 3.25 (sept, J = 6.8 Hz, 1 H) 5.40 (s, 1 H) 6.96 (s, 1 H ) 7.61 (s, 1 H).

N, N-diisopropylethylamine (364 mL, 2.09 mol) was added to a chloroform (1.74 L) solution of 2,4-dibromo-5-isopropylphenol (512 g, 1.74 mol), and the mixture was ice-cooled. Chloromethyl methyl ether (159 mL, 2.09 mol) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, and 1M aqueous sodium hydroxide solution (1.5 L) was added dropwise to separate the organic layer. The organic layer was washed with 1M aqueous sodium hydroxide solution (1.5 L) and water (1.5 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by distillation under reduced pressure (0.93 to 1.5 hPa, 122 ° C. to 137 ° C.) to obtain a pale yellow oily compound (5A) (548 g, 96%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J = 6.8 Hz, 6 H) 3.28 (sept, J = 6.8 Hz, 1 H) 3.52 (s, 3 H) 5.23 (s, 2 H ) 7.06 (s, 1 H) 7.69 (s, 1 H).
MS ESI / APCI Dual posi: 339 [M + H] ⁺ , 341 [M + 2 + H] ⁺ .

(2) Reference Example 1-2 Intermediate (1A)
To a tetrahydrofuran (2.84 L) solution of the compound (5A) (200 g, 0.592 mol), a 2.69 M n-butyllithium hexane solution (231 mL, 0.621 mol) was added at −80 to −76 ° C. in an argon atmosphere. The solution was added dropwise over 20 minutes and stirred at the same temperature for 35 minutes. Next, a solution of 2,3,4,6-tetra-O-trimethylsilyl-D-glucono-1,5-lactone (290 g, 0.621 mol) in tetrahydrofuran (800 mL) was added dropwise over 55 minutes, and 50 ° C. at the same temperature. Stir for minutes. Further, trimethylchlorosilane (75.7 mL, 0.621 mol) was added dropwise over 15 minutes, and the mixture was stirred at the same temperature for 2 hours. Subsequently, 2.69M n-butyllithium hexane solution (319 mL, 0.858 mol) was added dropwise over 29 minutes, and the mixture was stirred at the same temperature for 40 minutes. Finally, a tetrahydrofuran (800 mL) solution of 4-bromo-2-methylbenzaldehyde (130 g, 0.651 mol) was added dropwise over 54 minutes, and the mixture was stirred at the same temperature for 30 minutes. Water (2.85 L) was added to the reaction solution and warmed to room temperature. Toluene (2.0 L) was added to separate the organic layer, and the solvent was distilled off under reduced pressure.

The obtained residue (546 g) was dissolved in methanol (3.0 L), methanesulfonic acid (3.84 mL, 0.0592 mol) was added, and the mixture was heated to reflux for 1.5 hours. The reaction mixture was cooled to room temperature, neutralized with triethylamine (25 mL, 0.179 mol), and the reaction mixture was concentrated. The concentrate was dissolved in toluene (1.0 L) and washed with water (0.5 L, 1.0 L). A 1 M aqueous sodium hydroxide solution (0.6 L) and toluene (1.0 L) were added to the organic layer to perform a liquid separation operation, and the aqueous layer was separated. The aqueous layer was washed with toluene (1.0 L, 0.5 L). To the aqueous layer, 10% hydrochloric acid (0.7 L) was added and extracted with toluene (1.0 L), and the organic layer was separated. The organic layer was washed with 10% brine (1.0 L) and water (0.5 L), and the solvent was evaporated under reduced pressure.
The obtained residue (314 g) was dissolved in pyridine (1.0 L), acetic anhydride (0.8 L, 8.51 mol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was ice-cooled, ice (1.5 L) and toluene (1.0 L) were added, and the mixture was stirred for 3 hr. The aqueous layer was separated, extracted with toluene (1.0 L), and the combined organic layer was washed twice with 2 M hydrochloric acid (1.5 L), 5% aqueous sodium hydrogen carbonate solution (1.0 L), 10% brine (1.0 L). ) And the solvent was distilled off under reduced pressure.

The obtained residue (350 g) was dissolved in acetonitrile (3.4 L), water (9.1 mL, 0.506 mol), Et ₃ SiH (328 mL, 2.05 mol) were added, and TMSOTf (403 mL, 2) was added under ice cooling. .23 mol) was added dropwise over 85 minutes. After stirring at the same temperature for 2 hours, 3% aqueous sodium hydrogen carbonate solution (1.92 L) was added dropwise over 40 minutes, the reaction solution was diluted with toluene (1.0 L) and stirred for 15 minutes, and then the organic layer was separated. . The aqueous layer was extracted with toluene (1.5 L), the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (1.5 L), and the solvent was distilled off under reduced pressure to obtain a colorless liquid intermediate (1A) (392 g). Got.
1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09-1.19 (m, 6 H) 1.69 (s, 3 H) 1.99 (s, 3 H) 2.05 (s, 3 H) 2.12 (s, 3 H) 2.25 (s, 3 H) 2.80-2.97 (m, 1 H) 3.66-3.96 (m, 3 H) 4.08-4.35 (m, 2 H) 4.42-4.57 (m, 1 H) 5.19-5.37 (m, 3 H ) 6.52 (s, 1 H) 6.57 (d, J = 8.1 Hz, 1 H) 6.87 (s, 1 H) 7.12-7.20 (m, 1 H) 7.30-7.33 (m, 1 H).
Reference Example 2 Production of intermediate (1B-1)

中間体（１Ａ）（６００ｇ,０．５９２ｍｏｌ）のピリジン(７７０ｍＬ)溶液に無水酢酸（３８５ｍＬ）を氷冷下１０分かけて滴下した。反応溶液を室温まで上げ、同温で１８時間撹拌し再び氷冷した後、氷（１．０Ｌ）で反応を停止した。反応溶液をトルエン（１．０Ｌ）で希釈した後、１．５時間撹拌した。有機層を分離し、２Ｍ塩酸（１．２５Ｌ）で２回、５％炭酸水素ナトリウム水溶液（１．０Ｌ）、１０％食塩水（１．０Ｌ）、水（０．５Ｌ）で洗浄し、減圧下濃縮した。残渣にイソプロピルアルコール（１．５Ｌ）を加え、８０℃に加熱して溶解した。室温で１．５時間撹拌した後、沈殿物を濾別乾燥した。得られた白色粉末をイソプロピルアルコール（８００ｍＬ）に８０℃に過熱下溶解し、１．５時間室温で撹拌、沈殿物を濾別、乾燥して（１Ｂ−１）（１８６ｇ,４５％）を白色粉末として得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H)1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.86 - 3.01 (m, 1 H) 3.72 - 3.80 (m, 1 H) 3.87 (s, 2 H) 4.01 - 4.09 (m, 1 H) 4.23 - 4.32 (m, 1 H) 4.46 - 4.53 (m, 1 H) 5.11 - 5.20 (m, 1 H) 5.22 - 5.29 (m, 2 H) 6.56 - 6.61 (m, 1 H) 6.98 - 7.01 (m, 2 H) 7.18 - 7.23 (m, 1 H) 7.32 - 7.35 (m, 1 H).
参考例３ 中間体（１Ｂ−２）の製造

Acetic anhydride (385 mL) was added dropwise to a solution of intermediate (1A) (600 g, 0.592 mol) in pyridine (770 mL) over 10 minutes under ice cooling. The reaction solution was raised to room temperature, stirred at the same temperature for 18 hours, and ice-cooled again, and then the reaction was stopped with ice (1.0 L). The reaction solution was diluted with toluene (1.0 L) and then stirred for 1.5 hours. The organic layer was separated, washed twice with 2M hydrochloric acid (1.25L), washed with 5% aqueous sodium hydrogen carbonate solution (1.0L), 10% brine (1.0L), water (0.5L) and reduced pressure. The bottom was concentrated. Isopropyl alcohol (1.5 L) was added to the residue and dissolved by heating to 80 ° C. After stirring at room temperature for 1.5 hours, the precipitate was filtered off and dried. The obtained white powder was dissolved in isopropyl alcohol (800 mL) at 80 ° C. under heating, stirred at room temperature for 1.5 hours, the precipitate was filtered off and dried to give (1B-1) (186 g, 45%) as white Obtained as a powder.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.86-3.01 (m, 1 H) 3.72-3.80 (m, 1 H) 3.87 (s , 2 H) 4.01-4.09 (m, 1 H) 4.23-4.32 (m, 1 H) 4.46-4.53 (m, 1 H) 5.11-5.20 (m, 1 H) 5.22-5.29 (m, 2 H) 6.56 -6.61 (m, 1 H) 6.98-7.01 (m, 2 H) 7.18-7.23 (m, 1 H) 7.32-7.35 (m, 1 H).
Reference Example 3 Production of intermediate (1B-2)

中間体（１Ａ）（３９２ｇ,０．５０６ｍｏｌ）と炭酸カリウム（７３．４ｇ,０．５３１ｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（０．９５Ｌ）懸濁液にヨウ化メチル（３３ｍＬ,０．５３０ｍｏｌ）のＮ,Ｎ−ジメチルホルムアミド（５０ｍＬ）溶液を滴下した。反応溶液を１時間撹拌した後、炭酸カリウム（７０．０ｇ,０．５０６ｍｏｌ）、ヨウ化メチル（３１．５ｍＬ,０．５０６ｍｏｌ）を加え１時間撹拌した。再び炭酸カリウム（７０．０ｇ,０．５０６ｍｏｌ）、ヨウ化メチル（３１．５ｍＬ,０．５０６ｍｏｌ）を加え１時間撹拌した。ヨウ化メチル（１５．８ｍＬ,０．２５４ｍｏｌ）を加え、室温で一晩撹拌した。５０℃で２時間撹拌した後、トルエン（１．２５Ｌ）で希釈、水（１．０Ｌ）を加えた。２層を分離し、有機層を水（１．０Ｌ）で２回、１０％食塩水（１．０Ｌ）で洗浄し、減圧下濃縮した。残渣にイソプロピルアルコール（３５０ｍＬ）を加え４０℃に加熱して溶解し、室温で撹拌した。得られた沈殿物を濾別、乾燥し（１Ｂ−２）（１５５ｇ,４６％）を白色粉末として得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=6.8 Hz, 3 H) 1.13 (d, J=6.8 Hz, 3 H) 1.55 (s, 3 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.83 - 2.96 (m, 1 H) 3.86 (s, 3 H) 4.08 - 4.17 (m, 1 H) 4.18 - 4.28 (m, 1 H) 4.78 - 4.89 (m, 1 H) 5.13 - 5.23 (m, 1 H) 5.27 - 5.35 (m, 2 H) 6.51 - 6.57 (m, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.12 - 7.20 (m, 1 H) 7.30 (s, 1 H).
参考例４ 中間体（１Ｂ−３）の製造

To a suspension of intermediate (1A) (392 g, 0.506 mol) and potassium carbonate (73.4 g, 0.531 mol) in N, N-dimethylformamide (0.95 L), methyl iodide (33 mL, 0.530 mol) Of N, N-dimethylformamide (50 mL) was added dropwise. After the reaction solution was stirred for 1 hour, potassium carbonate (70.0 g, 0.506 mol) and methyl iodide (31.5 mL, 0.506 mol) were added and stirred for 1 hour. Potassium carbonate (70.0 g, 0.506 mol) and methyl iodide (31.5 mL, 0.506 mol) were added again and stirred for 1 hour. Methyl iodide (15.8 mL, 0.254 mol) was added, and the mixture was stirred overnight at room temperature. The mixture was stirred at 50 ° C. for 2 hours, diluted with toluene (1.25 L), and water (1.0 L) was added. The two layers were separated, and the organic layer was washed twice with water (1.0 L), 10% brine (1.0 L), and concentrated under reduced pressure. Isopropyl alcohol (350 mL) was added to the residue and dissolved by heating to 40 ° C., followed by stirring at room temperature. The resulting precipitate was filtered off and dried to give (1B-2) (155 g, 46%) as a white powder.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.8 Hz, 3 H) 1.13 (d, J = 6.8 Hz, 3 H) 1.55 (s, 3 H) 1.75 (s, 3 H ) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.83-2.96 (m, 1 H) 3.86 (s, 3 H) 4.08-4.17 (m , 1 H) 4.18-4.28 (m, 1 H) 4.78-4.89 (m, 1 H) 5.13-5.23 (m, 1 H) 5.27-5.35 (m, 2 H) 6.51-6.57 (m, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.12-7.20 (m, 1 H) 7.30 (s, 1 H).
Reference Example 4 Production of intermediate (1B-3)

Process 1
A suspension of intermediate (1B-1) (100 g, 0.145 mol) in triethylamine-water-methanol (1: 1: 5, 1.12 L) was stirred at room temperature for 3 days. The reaction solution was concentrated, dissolved in 2M hydrochloric acid, acidified, and extracted twice with chloroform. The organic layers were combined, 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 an intermediate (1B-1a) (80.4 g) as a light brown amorphous.

Process 2
To a suspension of intermediate (1B-1a) (1.00 g, 2.08 mmol) and potassium carbonate (862 mg, 6.24 mmol) in N, N-dimethylformamide (6.0 mL), ethyl iodide (500 μL, 6. 24 mmol) was added and the mixture was stirred at 50 ° C. for 8 hours. Water was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 0: 100 → 10: 90) to obtain intermediate (1B-3a) (950 mg, 90%) as a colorless liquid.

Process 3
A solution of intermediate (1B-3a) (867 mg, 1.70 mmol) and acetic anhydride (4.3 mL) in pyridine (5.2 mL) was stirred at room temperature for 3 days. The reaction solution was added to ice water and extracted with toluene. The organic layer was washed successively with 2M hydrochloric acid and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 → 65: 35) to give an intermediate (1B-3) as a colorless amorphous product (1.00 g, 87%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.15 (m, 6 H) 1.46 (t, J = 6.9 Hz, 3 H) 1.75 (s, 3 H) 2.00 (s, 3 H) 2.04 ( s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.83-2.94 (m, 1 H) 3.72-3.90 (m, 3 H) 4.02-4.15 (m, 3 H) 4.19-4.28 ( m, 1 H) 4.76-4.89 (m, 1 H) 5.15-5.22 (m, 1 H) 5.27-5.38 (m, 2 H) 6.54 (d, J = 8.2 Hz, 1 H) 6.79 (s, 1 H ) 6.94 (s, 1 H) 7.16 (dd, J = 8.2, 1.7 Hz, 1 H) 7.31 (d, J = 1.7 Hz, 1 H).
MS ESI / APCI Dual posi: 699 [M + Na] ⁺ .
Reference Example 5 Production of intermediate (1B-4)

中間体（１Ａ）(４００ｍｇ,０．６２ｍｍｏｌ)、炭酸セシウム（６０２ｍｇ,１．８５ｍｍｏｌ）の脱水Ｎ,Ｎ−ジメチルホルムアミド(４ｍＬ)懸濁液に、氷冷でブロモフルオロメタン（２００μＬ）を加え、マイクロウェーブ照射下１００℃で１０分間撹拌した。反応液に酢酸エチルを加え、水、飽和食塩水で順次洗浄した後、硫酸ナトリウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して、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＝８０：２０→６６：３４）で精製し、淡褐色アモルファスとして中間体（１Ｂ−４）（２００ｍｇ,４８％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09 - 1.17 (m, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.86 - 2.98 (m, 1 H) 3.75 - 3.94 (m, 3 H) 4.06 - 4.15 (m, 1 H) 4.17 - 4.27 (m, 1 H) 4.73 - 4.84 (m, 1 H) 5.11 - 5.37 (m, 3 H) 5.61 - 5.66 (m, 1 H) 5.79 - 5.85 (m, 1 H) 6.55 (d, J=8.2 Hz, 1 H) 7.01 (s, 1 H) 7.05 (s, 1 H) 7.19 (dd, J=8.2, 2.0 Hz, 1 H) 7.33 (d, J=2.0 Hz, 1 H).
MS ESI/APCI Dual nega : 715[M+Cl]^-.
参考例６ 中間体（１Ｂ−５）の製造

To a suspension of intermediate (1A) (400 mg, 0.62 mmol), cesium carbonate (602 mg, 1.85 mmol) in dehydrated N, N-dimethylformamide (4 mL) was added bromofluoromethane (200 μL) with ice cooling, The mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. Ethyl acetate was added to the reaction mixture, washed successively with water and saturated brine, and dried over sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by NH-type silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 66: 34) to give an intermediate (1B -4) (200 mg, 48%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.09-1.17 (m, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.86-2.98 (m, 1 H) 3.75-3.94 (m, 3 H) 4.06-4.15 (m, 1 H) 4.17-4.27 (m, 1 H) 4.73-4.84 (m, 1 H) 5.11-5.37 (m, 3 H) 5.61-5.66 (m, 1 H) 5.79-5.85 (m, 1 H) 6.55 (d, J = 8.2 Hz, 1 H) 7.01 (s, 1 H) 7.05 ( s, 1 H) 7.19 (dd, J = 8.2, 2.0 Hz, 1 H) 7.33 (d, J = 2.0 Hz, 1 H).
MS ESI / APCI Dual nega: 715 [M + Cl] ^- .
Reference Example 6 Production of intermediate (1B-5)

中間体（１Ａ）(１５．３ｇ,２３．５ｍｍｏｌ)のアセトニトリル−水混合溶液（１：１,２３５ｍＬ）に内温−８．９℃で水酸化カリウム（１９．８ｇ,３５．２ｍｍｏｌ）を少しずつ加え、７分間撹拌した。次いで、内温−１．３℃でジエチル（ブロモジフルオロメチル）ホスホネート（９．４０ｇ,３５．２ｍｍｏｌ）を滴下し、７分間撹拌した。内温０．４℃で酢酸を加えて酸性とし、トルエン(３００ｍＬ)を加えて２層を分離後、有機層を無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、減圧濃縮し、残渣をシリカゲルクロマトグラフィー（ヘキサン：酢酸エチル＝９５：５→２５：７５）で精製し、無色アモルファスとして中間体（１Ｂ−５）（１０．４ｇ,６３％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.5 Hz, 3 H) 1.14 (d, J=6.5 Hz, 3 H) 1.77 (s, 3 H) 2.00 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.95 (spt, J=6.5 Hz, 1 H) 3.75 - 3.94 (m, 3 H) 4.07 - 4.24 (m, 2 H) 4.64 - 4.74 (m, 1 H) 5.11 - 5.21 (m, 1 H) 5.26 - 5.37 (m, 2 H) 6.23 - 6.77 (m, 2 H) 6.99 (s, 1 H) 7.06 (s, 1 H) 7.16 - 7.23 (m, 1 H) 7.32 - 7.37 (m, 1 H).
MS ESI/APCI Dual posi : 721[M+Na]⁺.
MS ESI/APCI Dual nega : 733[M+Cl]^-.
参考例７ 中間体（１Ｂ−６）の製造

Potassium hydroxide (19.8 g, 35.2 mmol) was slightly added to an acetonitrile-water mixed solution (1: 1, 235 mL) of intermediate (1A) (15.3 g, 23.5 mmol) at an internal temperature of -8.9 ° C. Added in portions and stirred for 7 minutes. Next, diethyl (bromodifluoromethyl) phosphonate (9.40 g, 35.2 mmol) was added dropwise at an internal temperature of −1.3 ° C., and the mixture was stirred for 7 minutes. Acetic acid was added to make it acidic at an internal temperature of 0.4 ° C., toluene (300 mL) was added to separate the two layers, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 95: 5 → 25: 75) to give intermediate (1B-5) (10.4 g, 63 as a colorless amorphous product). %).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.5 Hz, 3 H) 1.14 (d, J = 6.5 Hz, 3 H) 1.77 (s, 3 H) 2.00 (s, 3 H ) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.27 (s, 3 H) 2.95 (spt, J = 6.5 Hz, 1 H) 3.75-3.94 (m, 3 H) 4.07-4.24 (m, 2 H) 4.64-4.74 (m, 1 H) 5.11-5.21 (m, 1 H) 5.26-5.37 (m, 2 H) 6.23-6.77 (m, 2 H) 6.99 (s, 1 H) 7.06 (s, 1 H) 7.16-7.23 (m, 1 H) 7.32-7.37 (m, 1 H).
MS ESI / APCI Dual posi: 721 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 733 [M + Cl] ^- .
Reference Example 7 Production of intermediate (1B-6)

Process 1
To a suspension of intermediate (1B-1a) (1.00 g, 2.08 mmol), potassium carbonate (861 mg, 6.23 mmol) in N, N-dimethylformamide (5 mL), 2-iodoethanol (485 μL, 6. 23 mmol), and the mixture was stirred at 80 ° C. for 2 hours, 120 ° C. for 3.5 hours, and further at 150 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with 10% brine and water, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate only → ethyl acetate: ethanol: water = 15: 2: 1) to give intermediate (1B-6a) (370 mg as a colorless amorphous). 34%).

Process 2
Acetic anhydride (900 μL) was added to a solution of intermediate (1B-6a) (360 mg, 0.685 mmol) in pyridine (1.08 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was ice-cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 2M hydrochloric acid twice and 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 Intermediate (1B-6) (480 mg, 95%) as a colorless amorphous substance.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.15 (m, 6 H) 1.74 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.06 (s, 3 H) 2.17 (s, 3 H) 2.28 (s, 3 H) 2.88-2.94 (m, 1 H) 3.72-3.92 (m, 3 H) 4.04-4.33 (m, 4 H) 4.36-4.49 (m, 1 H) 4.52-4.64 (m, 1 H) 4.75 (br. S., 1 H) 5.19 (t, J = 9.2 Hz, 1 H) 5.30 (t, J = 9.2 Hz, 1 H) 5.41 (br. S., 1 H) 6.53 (d, J = 8.2 Hz, 1 H) 6.79 (s, 1 H) 6.93 (s, 1 H) 7.18 (d, J = 8.2 Hz, 1 H) 7.32 (s, 1 H).
MS ESI / APCI Dual posi: 757 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 769 [M + Cl] ^- .
Reference Example 8 Production of intermediate (1C-1)

アルゴン雰囲気下、中間体（１Ｂ−１）（２１６ｇ,０．３１２ｍｏｌ）、２,２−ジメチル−３−ブテノイックアシッド（５３．４ｇ,０．４６７ｍｏｌ）、酢酸パラジウム（ＩＩ）（３．５０ｇ,１５．６ｍｍｏｌ）、トリ−ｏ−トリルホスフィン（９．４８ｇ,３１．２ｍｍｏｌ）、トリエチルアミン（８６．９ｍＬ,０．６２３ｍｏｌ）のアセトニトリル（６２３ｍＬ）懸濁液を、３時間加熱還流した。反応液を室温まで冷却した後にクロロホルム（３００ｍＬ）とメタノール（１００ｍＬ）を加えて希釈し、セライトろ過した。ろ液を減圧下濃縮し、得られた残渣を酢酸エチル（１．３２Ｌ）に溶解させた。１Ｍ塩酸（０．９６Ｌ）、１０％食塩水（１．２Ｌ）で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、ろ液にさらに酢酸エチル（１．２Ｌ）を追加して、イソプロピルアミン（２８．２ｍＬ,０．３２７ｍｏｌ）を加え、室温から０℃にかけて１時間撹拌した。析出した沈殿をろ過して中間体（１Ｃ−１）のイソプロピルアミン塩を得た。この塩を酢酸エチル（１．２Ｌ）、１Ｍ塩酸（５００ｍＬ）に溶解させて３０分間撹拌し、有機層を分離した。その有機層を１０％食塩水（５００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去して無色アモルファスとして中間体（１Ｃ−１）（２０７ｇ,８８％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.43 (s, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J=6.8 Hz, 1 H) 3.70 - 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J=12.4, 2.2 Hz, 1 H) 4.28 (dd, J=12.4, 4.4 Hz, 1 H) 4.43 - 4.50 (m, 1 H) 5.11 - 5.20 (m, 1 H) 5.22 - 5.33 (m, 2 H) 6.33 - 6.49 (m, 2 H) 6.68 (d, J=7.9 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s, 1 H) 7.06 - 7.14 (m, 1 H) 7.23 (d, J=1.4 Hz, 1 H).
MS ESI/APCI Dual posi : 747[M+Na]⁺.
参考例９ 中間体（１Ｃ−２）の製造

Under an argon atmosphere, intermediate (1B-1) (216 g, 0.312 mol), 2,2-dimethyl-3-butenoic acid (53.4 g, 0.467 mol), palladium acetate (II) (3.50 g) , 15.6 mmol), a suspension of tri-o-tolylphosphine (9.48 g, 31.2 mmol), triethylamine (86.9 mL, 0.623 mol) in acetonitrile (623 mL) was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with chloroform (300 mL) and methanol (100 mL), and filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (1.32 L). It was washed with 1M hydrochloric acid (0.96 L), 10% brine (1.2 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, ethyl acetate (1.2 L) was further added to the filtrate, isopropylamine (28.2 mL, 0.327 mol) was added, and the mixture was stirred from room temperature to 0 ° C. for 1 hour. The deposited precipitate was filtered to obtain an isopropylamine salt of intermediate (1C-1). This salt was dissolved in ethyl acetate (1.2 L) and 1 M hydrochloric acid (500 mL) and stirred for 30 minutes, and the organic layer was separated. The organic layer was washed with 10% brine (500 mL) and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure to obtain an intermediate (1C-1) (207 g, 88%) as a colorless amorphous substance.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.43 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J = 6.8 Hz, 1 H) 3.70- 3.80 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J = 12.4, 2.2 Hz, 1 H) 4.28 (dd, J = 12.4, 4.4 Hz, 1 H) 4.43-4.50 (m, 1 H ) 5.11-5.20 (m, 1 H) 5.22-5.33 (m, 2 H) 6.33-6.49 (m, 2 H) 6.68 (d, J = 7.9 Hz, 1 H) 6.96 (s, 1 H) 6.99 (s , 1 H) 7.06-7.14 (m, 1 H) 7.23 (d, J = 1.4 Hz, 1 H).
MS ESI / APCI Dual posi: 747 [M + Na] ⁺ .
Reference Example 9 Production of intermediate (1C-2)

中間体（１Ｂ−１）（５０．０ｇ,７２．０ｍｍｏｌ）とビニル酢酸（１．６０ｇ,１７３ｍｍｏｌ）を出発原料として、参考例８に記載されている方法に準拠して、中間体（１Ｃ−２）（４４．０ｇ,８６％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J=6.8 Hz, 3 H) 1.14 (d, J=6.8 Hz, 3 H) 1.73 - 1.78 (m, 3 H) 1.98 - 2.00 (m, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.91 - 3.04 (m, 1 H) 3.28 (d, J=7.1 Hz, 2 H) 3.71 - 3.80 (m, 1 H) 3.91 (s, 2 H) 4.01 - 4.09 (m, 1 H) 4.27 (dd, J=12.4, 4.5 Hz, 1 H) 4.46 (d, J=9.6 Hz, 1 H) 5.09 - 5.32 (m, 3 H) 6.17 - 6.32 (m, 1 H) 6.47 (d, J=16.2 Hz, 1 H) 6.68 (d, J=7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.09 (dd, J=7.8, 1.8Hz, 1 H) 7.19 - 7.23 (m, 1 H).
参考例１０ 中間体（１Ｃ−３）の製造

In accordance with the method described in Reference Example 8, using intermediate (1B-1) (50.0 g, 72.0 mmol) and vinyl acetic acid (1.60 g, 173 mmol) as starting materials, intermediate (1C- 2) (44.0 g, 86%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.73-1.78 (m, 3 H) 1.98-2.00 ( m, 3 H) 2.03 (s, 3 H) 2.06 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.91-3.04 (m, 1 H) 3.28 (d, J = 7.1 Hz , 2 H) 3.71-3.80 (m, 1 H) 3.91 (s, 2 H) 4.01-4.09 (m, 1 H) 4.27 (dd, J = 12.4, 4.5 Hz, 1 H) 4.46 (d, J = 9.6 Hz, 1 H) 5.09-5.32 (m, 3 H) 6.17-6.32 (m, 1 H) 6.47 (d, J = 16.2 Hz, 1 H) 6.68 (d, J = 7.8 Hz, 1 H) 6.95 (s , 1 H) 6.99 (s, 1 H) 7.09 (dd, J = 7.8, 1.8Hz, 1 H) 7.19-7.23 (m, 1 H).
Reference Example 10 Production of intermediate (1C-3)

中間体（１Ｂ−２）（１０．０ｇ,０．０１５１ｍｏｌ）を出発原料として、参考例８に記載されている方法に準拠して、中間体（１Ｃ−３）（１０．４ｇ,９９％）を得た。
¹H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J=6.9 Hz, 3 H) 1.13 (d, J=6.9 Hz, 3 H) 1.43 (s, 6 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.01 - 2.06 (m, 6 H) 2.29 (s, 3 H) 2.90 - 2.98 (m, 1 H) 3.77 - 3.81 (m, 1 H) 3.81 - 3.91 (m, 5 H) 4.08 - 4.13 (m, 1 H) 4.21 (dd, J=12.2, 4.4 Hz, 1 H) 4.79 (br. d, J=8.3 Hz, 1 H) 5.17 (t, J=9.6 Hz, 1 H) 5.27 - 5.36 (m, 2 H) 6.35 (d, J=16.0 Hz, 1 H) 6.43 (d, J=16.0 Hz, 1 H) 6.64 (d, J=8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J=8.3 Hz, 1 H) 7.21 (s, 1 H).
MS ESI/APCI Dual posi : 719[M+Na]⁺.
参考例１１ 中間体（１Ｃ−４）の製造

Intermediate (1C-3) (10.4 g, 99%) according to the method described in Reference Example 8 using Intermediate (1B-2) (10.0 g, 0.0151 mol) as a starting material Got.
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.9 Hz, 3 H) 1.13 (d, J = 6.9 Hz, 3 H) 1.43 (s, 6 H) 1.75 (s, 3 H ) 1.99 (s, 3 H) 2.01-2.06 (m, 6 H) 2.29 (s, 3 H) 2.90-2.98 (m, 1 H) 3.77-3.81 (m, 1 H) 3.81-3.91 (m, 5 H ) 4.08-4.13 (m, 1 H) 4.21 (dd, J = 12.2, 4.4 Hz, 1 H) 4.79 (br.d, J = 8.3 Hz, 1 H) 5.17 (t, J = 9.6 Hz, 1 H) 5.27-5.36 (m, 2 H) 6.35 (d, J = 16.0 Hz, 1 H) 6.43 (d, J = 16.0 Hz, 1 H) 6.64 (d, J = 8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J = 8.3 Hz, 1 H) 7.21 (s, 1 H).
MS ESI / APCI Dual posi: 719 [M + Na] ⁺ .
Reference Example 11 Production of intermediate (1C-4)

中間体（１Ｂ−２）（６．００ｇ,９．０４ｍｍｏｌ）とビニル酢酸（２．３０ｍＬ,２７．１ｍｍｏｌ）を出発原料として、参考例８に記載されている方法に準拠して、中間体（１Ｃ−４）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07 - 1.16 (m, 6 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.28 (s, 3 H) 2.85 - 3.00 (m, 1 H) 3.15 - 3.21 (m, 2 H) 3.76 - 3.87 (m, 1 H) 3.86 (s, 3 H) 4.06 - 4.15 (m, 1 H) 4.18 - 4.28 (m, 1 H) 4.71 - 4.82 (m, 1 H) 5.12 - 5.43 (m, 3 H) 6.35 - 6.42 (m, 1 H) 6.58 (d, J=8.1 Hz, 1 H) 6.79 - 6.96 (m, 3 H) 7.05 (dd, J=8.1, 1.7 Hz, 1 H) 7.18 - 7.23 (m, 1 H).
MS ESI/APCI Dual posi : 691[M+Na]⁺.
参考例１２ 中間体（１Ｅ−１）の製造

Intermediate (1B-2) (6.00 g, 9.04 mmol) and vinyl acetic acid (2.30 mL, 27.1 mmol) were used as starting materials according to the method described in Reference Example 8, and the intermediate ( 1C-4) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.07-1.16 (m, 6 H) 1.75 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.28 (s, 3 H) 2.85-3.00 (m, 1 H) 3.15-3.21 (m, 2 H) 3.76-3.87 (m, 1 H) 3.86 (s, 3 H) 4.06-4.15 (m, 1 H) 4.18-4.28 (m, 1 H) 4.71-4.82 (m, 1 H) 5.12-5.43 (m, 3 H) 6.35-6.42 (m, 1 H) 6.58 (d, J = 8.1 Hz, 1 H) 6.79- 6.96 (m, 3 H) 7.05 (dd, J = 8.1, 1.7 Hz, 1 H) 7.18-7.23 (m, 1 H).
MS ESI / APCI Dual posi: 691 [M + Na] ⁺ .
Reference Example 12 Production of intermediate (1E-1)

Process 1
Intermediate (1C-1) (1.00 g, 1.38 mmol), 2-amino-2-methylpropan-1-ol (184 mg, 2.07 mmol), EDC-HCl (342 mg, 1.79 mmol), HOBt. A solution of H ₂ O (242 mg, 1.79 mmol) in N, N-dimethylformamide (30 mL) was stirred at room temperature overnight. After evaporating the solvent under reduced pressure, water was added 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 the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain crude intermediate (1D-1) (1.02 g).

Process 2
A chloroform suspension (20 mL) of intermediate (1D-1) (660 mg, 0.830 mmol) and Dess-Martin periodinane (422 mg, 1.25 mmol) was stirred at room temperature for 3 hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 4) to give intermediate (1E-1) (602 mg, 85% over 2 steps) as a yellow amorphous. )
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09-1.18 (m, 6 H) 1.33 (s, 6 H) 1.39 (s, 6 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.04 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.98 (spt, J = 6.9 Hz, 1 H) 3.73-3.80 (m, 1 H) 3.89 -3.98 (m, 2 H) 4.06 (dd, J = 12.4, 2.3 Hz, 1 H) 4.26 (dd, J = 12.4, 4.6 Hz, 1 H) 4.46-4.53 (m, 1 H) 5.11-5.18 (m , 1 H) 5.23-5.30 (m, 2 H) 6.13 (br.s, 1 H) 6.33 (d, J = 16.5 Hz, 1 H) 6.53 (d, J = 16.5 Hz, 1 H) 6.71 (d, J = 7.8 Hz, 1 H) 6.99-7.01 (m, 2 H) 7.13 (d, J = 7.8 Hz, 1 H) 7.26 (s, 1 H) 9.34 (s, 1 H).
Reference Example 13 Production of intermediate (1E-2)

Step 1 and Step 2
The method described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.0 g, 1.4 mmol) and 3-aminopropanol (0.14 mL, 1.8 mmol) as starting materials. In this way, intermediate (1E-2) (0.77 g, 72% for 2 steps) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.36 (s, 6 H) 1.77 (s, 3 H ) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.70 (t, J = 6.1 Hz, 2 H) 2.92- 3.04 (m, 1 H) 3.42-3.57 (m, 2 H) 3.71-3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.5, 2.0 Hz, 1 H) 4.26 (dd, J = 12.5, 4.6 Hz, 1 H) 4.45-4.51 (m, 1 H) 5.10-5.30 (m, 3 H) 6.27 (d, J = 16.0 Hz, 1 H) 6.47 (d, J = 16.0 Hz, 1 H) 6.70 (d, J = 7.9 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.08-7.14 (m, 1 H) 7.24 (s, 1 H) 9.77 (s, 1 H ).
Reference Example 14 Production of intermediate (1E-3)

Step 1 and Step 2
Intermediate (1C-1) (1.0 g, 1.4 mmol) and 3-amino-3-methylbutanol (0.19 g, 1.8 mmol, Journal of Labeled Compounds & Radiopharmaceuticals (2001), 44 (4), 265 -275.) As a starting material, intermediate (1E-3) (0.77 g, 2 steps 55%) was obtained according to the method described in steps 1 and 2 of Reference Example 12.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.34 (s, 6 H) 1.36 (s, 6 H ) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.90-3.04 (m, 1 H) 2.93 (d, J = 2.2 Hz, 2 H) 3.71-3.80 (m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.4, 1.9 Hz, 1 H) 4.27 (dd, J = 12.4, 4.5 Hz, 1 H) 4.45-4.53 (m, 1 H) 5.11-5.32 (m, 3 H) 5.74 (br.s, 1 H) 6.28 (d, J = 15.9 Hz, 1 H) 6.49 (d , J = 15.9 Hz, 1 H) 6.69 (d, J = 8.1 Hz, 1 H) 6.98-7.03 (m, 2 H) 7.09-7.15 (m, 1 H) 7.24-7.27 (m, 1 H) 9.73 ( t, J = 2.2 Hz, 1 H).
MS ESI / APCI Dual posi: 808 [M + H] ⁺ .
Reference Example 15 Production of intermediate (1E-4)

Process 1
To a chloroform solution (18 mL) of 4-amino-4-methyl-1-pentanol (1.06 g, 9.05 mmol) was added triethylamine (5.00 mL, 36.2 mmol) and tert-butyldimethylsilyl chloride (1.37 g, (9.05 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (chloroform: methanol = 9: 1 → 2: 8) to obtain an intermediate (4B-4a) as a brown oil (599 mg, 29%) was obtained.

Process 2
In accordance with the method described in Step 1 of Reference Example 12, using Intermediate (1C-1) (700 mg, 0.966 mmol) and Intermediate (4B-4a) (291 mg, 1.26 mmol) as starting materials Intermediate (1D-4a) (325 mg, 36%) was obtained as a colorless amorphous product.

Process 3
Intermediate (1D-4a) (317 mg, 0.338 mmol) was dissolved in a mixture (1 mL) of acetic acid: tetrahydrofuran: water = 3: 1: 1 and stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 1: 9) to obtain intermediate (1D-4) (244 mg, 88%) as a colorless amorphous substance. It was.

Process 4
Intermediate (1D-4) (240 mg, 0.291 mmol) as a starting material, Intermediate (1E-4) (195 mg, 82) as a yellow amorphous substance according to the method described in Step 2 of Reference Example 12 %).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.17 (m, 6 H) 1.27 (s, 6 H) 1.35 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.10 (m, 2 H) 2.31 (s, 3 H) 2.33-2.41 (m, 5 H) 2.91-3.03 (m, 1 H) 3.72-3.80 ( m, 1 H) 3.93 (s, 2 H) 4.05 (dd, J = 12.4, 2.3 Hz, 1 H) 4.27 (dd, J = 12.9, 4.4 Hz, 1 H) 4.46-4.52 (m, 1 H) 5.10 -5.19 (m, 1 H) 5.24-5.30 (m, 2 H) 5.48 (br.s, 1 H) 6.28 (d, J = 14.9 Hz, 1 H) 6.48 (d, J = 14.9 Hz, 1 H) 6.69 (d, J = 7.8 Hz, 1 H) 6.99-7.02 (m, 2 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.24 (s, 1 H) 9.72 (t, J = 1.8 Hz, 1 H).
MS ESI / APCI Dual posi: 822 [M + H] ⁺ .
Reference Example 16 Production of intermediate (1E-5)

Process 1
An aqueous solution (20 mL) of potassium hydrogen carbonate (1.55 g, 15.5 mmol) was added dropwise to an ethyl acetate (31 mL) solution of 1-aminocyclopropanecarboxylic acid ethyl ester (500 mg, 3.87 mmol) at ice temperature. Subsequently, benzyl chloroformate (0.829 ml, 5.80 mmol) was added dropwise under ice cooling. The reaction solution was stirred at room temperature overnight, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 0: 100 → 30: 70) to obtain intermediate (4B-5a) (700 mg, 69%).

Process 2
To a solution of intermediate (4B-5a) (700 mg, 2.67 mmol) in diethyl ether (15 mL) was added a suspension of lithium borohydride (126 mg, 5,79 mmol) in diethyl ether (10 mL) and stirred at room temperature overnight. did. Methanol and 1M hydrochloric acid were added and stirred at room temperature for 1 hour, and the aqueous layer was extracted with acetic acid. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: hexane = 0: 100 → 50: 50) to obtain intermediate (4B-5b) (465 mg, 79%).

Process 3
A suspension of intermediate (4B-5b) (465 mg, 2.20 mmol) and 5% palladium carbon (25 mg) in methanol (5.0 mL) was stirred under a hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain Intermediate (4B-5c) (171 mg, 89%).

Step 4 and Step 5
Using the intermediate (1C-1) (500 mg, 0.69 mmol) and the intermediate (4B-5c) (72 mg, 0.83 mmol) as starting materials, the methods described in steps 1 and 2 of Reference Example 12 were used. Based on the above, Intermediate (1E-5) (305 mg, 98% for 2 steps) was obtained as colorless amorphous.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.16 (m, 6 H) 1.42 (s, 6 H) 1.46-1.55 (m, 4 H) 1.78 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.91-3.06 (m, 1 H) 3.72-3.80 (m, 1 H) 3.91- 3.95 (m, 2 H) 4.01-4.08 (m, 1 H) 4.20-4.28 (m, 1 H) 4.46-4.52 (m, 1 H) 5.09-5.18 (m, 1 H) 5.22-5.29 (m, 2 H) 6.26-6.30 (m, 1 H) 6.35 (d, J = 16.2 Hz, 1 H) 6.55 (d, J = 16.2 Hz, 1 H) 6.68-6.74 (m, 1 H) 7.00 (s, 2 H ) 7.10-7.16 (m, 1 H) 7.26 (s, 1H) 9.06 (s, 1 H).
MS ESI / APCI Dual posi: 792 [M + H] ⁺ , 814 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 826 [M + Cl] ^- .
Reference Example 17 Production of intermediate (1E-6)

Step 1 and Step 2
Described in Step 1 and Step 2 of Reference Example 12 using intermediate (1C-1) (1.00 g, 1.38 mmol) and (1-aminocyclobutyl) methanol (210 mg, 2.07 mmol) as starting materials The intermediate (1E-6) (355 mg, 2 steps 32%) was obtained as a pale yellow amorphous based on the above method.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.19 (m, 6 H) 1.40 (s, 6 H) 1.78 (s, 3 H) 1.91-2.08 (m, 11 H) 2.22-2.40 (m , 8 H) 2.42-2.56 (m, 2 H) 2.91-3.05 (m, 1 H) 3.70-3.81 (m, 1 H) 3.94 (s, 2 H) 4.05 (dd, J = 12.4, 1.9 Hz, 1 H) 4.26 (dd, J = 12.4, 4.5 Hz, 1 H) 4.44-4.55 (m, 1 H) 5.10-5.20 (m, 1 H) 5.21-5.33 (m, 2 H) 6.28-6.41 (m, 2 H) 6.49-6.61 (m, 1 H) 6.71 (d, J = 7.9 Hz, 1 H) 7.00 (s, 2 H) 7.14 (d, J = 7.9 Hz, 1 H) 7.27 (s, 1 H) 9.55 (s, 1 H).
MS ESI / APCI Dual posi: 806 [M + H] ⁺ , 828 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 840 [M + Cl] ^- .
Reference Example 18 Production of intermediate (1E-7)

Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.00 g, 1.38 mmol) and 1-amino-1-cyclopentanemethanol (207 mg, 1.79 mmol) as starting materials. The intermediate (1E-7) (850 mg, 2 steps 71%) was obtained as a colorless amorphous product.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10-1.18 (m, 6 H) 1.39 (s, 6 H) 1.64-2.18 (m, 8 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.32 (s, 3 H) 2.37 (s, 3 H) 2.89-3.04 (m, 1 H) 3.71-3.81 (m, 1 H) 3.93 ( s, 2 H) 4.01-4.10 (m, 1 H) 4.25-4.30 (m, 1 H) 4.45-4.53 (m, 1 H) 5.10-5.20 (m, 1 H) 5.23-5.30 (m, 2 H) 6.18 (s, 1 H) 6.26-6.39 (m, 1 H) 6.47-6.60 (m, 1 H) 6.70 (d, J = 7.6 Hz, 1 H) 6.96-7.05 (m, 2 H) 7.10-7.16 ( m, 1 H) 7.23-7.26 (m, 1 H) 9.43 (s, 1 H).
MS ESI / APCI Dual posi: 820 [M + H] ⁺ , 842 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 854 [M + Cl] ^- .
Reference Example 19 Production of intermediate (1E-8)

Process 1
Chlorosulfonyl isocyanate (1.73 g, 12.2 mmol) was added to a solution of methylenecyclopentane (1.00 g, 12.2 mmol) in diethyl ether (12 mL) under ice cooling. The reaction solution was stirred at room temperature for 30 minutes, an aqueous sodium thiosulfate solution and a 10% aqueous potassium hydroxide solution were added under ice-cooling so that the pH was 10, and stirred at the same temperature for 2 hours. . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain Intermediate (4B-8a) (684 mg, 45%) as a colorless amorphous substance.

Process 2
A solution of intermediate (4B-8a) (680 mg, 5.43 mmol) and concentrated sulfuric acid (0.5 mL) in methanol (15 mL) was stirred at 75 ° C. for 40 minutes and at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. This solution was extracted with 1M hydrochloric acid and neutralized with potassium carbonate. This aqueous solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain Intermediate (4B-8b) (586 mg, 69%) as a colorless liquid. .

Process 3
A solution of intermediate (4B-8b) (580 mg, 3.69 mmol) and sodium carbonate (580 mg, 5.47 mmol) in water (12 mL) in 1,4-dioxane (0.58 mL, 4.06 mmol) of benzyl chloroformate (0.58 mL, 4.06 mmol) 3.0 mL) solution was added under ice cooling. The reaction solution was stirred at room temperature for 2 hours and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain Intermediate (4B-8c) (1.0 g, 93%) as a colorless liquid.

Process 4
Intermediate (4B-8c) (1.0 g, 3.43 mmol) as a starting material, intermediate (4B-8d) (440 mg, 49%) according to the method described in Step 2 of Reference Example 16 )

Process 5
According to the method described in Step 3 of Reference Example 16, using Intermediate (4B-8d) (440 mg, 1.67 mmol) as a starting material, Intermediate (4B-8e) (210 mg, 97%) Obtained.

Step 6, Step 7
Using the intermediate (1C-1) (500 mg, 0.690 mmol) and the intermediate (4B-8e) (107 mg, 0.830 mmol) as starting materials, the method described in steps 1 and 2 of Reference Example 12 was used. Based on the above, Intermediate (1E-8) (89 mg, 16% for 2 steps) was obtained as colorless amorphous.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8, Hz, 3 H) 1.33 (s, 6 H) 1.60-1.75 (m , 6 H) 1.77 (s, 3 H) 1.97-2.05 (m, 11 H) 2.31 (s, 3 H) 2.37 (s, 3 H) 2.91-3.05 (m, 3 H) 3.72-3.81 (m, 1 H) 3.93 (s, 2 H) 4.01-4.08 (m, 1 H) 4.20-4.26 (m, 1 H) 4.44-4.53 (m, 1 H) 5.16-5.20 (m, 1 H) 5.23-5.32 (m , 2 H) 5.76 (s, 1 H) 6.26 (d, J = 16.2 Hz, 1 H) 6.48 (d, J = 16.2 Hz, 1 H) 6.69 (d, J = 7.9 Hz, 1 H) 6.92-7.04 (m, 2 H) 7.08-7.15 (m, 1 H) 7.24 (s, 1 H) 9.70-9.76 (m, 1 H).
MS ESI / APCI Dual posi: 834 [M + H] ⁺ , 856 [M + Na] ⁺ .
Reference Example 20 Production of intermediate (1E-9)

Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-1) (1.00 g, 1.38 mmol) and (1-aminocyclohexyl) methanol (267 mg, 2.07 mmol) as starting materials. In accordance with the method, intermediate (1E-9) was obtained.
MS ESI / APCI Dual posi: 834 [M + H] ⁺ , 856 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 868 [M + Cl] ^- .
Reference Example 21 Production of intermediate (1E-10)

Process 1
20% hydroxylation to an ethanol solution (20 mL) of 3- (benzylamino) oxetane-3-carbonitrile (2.13 g, 11.3 mmol, Journal of American Chemical Society (2010), 132 (25), 8550-8551) An aqueous sodium solution was added at 0 ° C., and the mixture was heated to reflux for 2 hours. The mixture was cooled to 0 ° C. and adjusted to pH 7 by adding acetic acid. The produced white solid was collected by filtration, washed with cold water, and dried under reduced pressure. The obtained white solid methanol solution (5 mL) was cooled to 0 ° C., and 1 M trimethylsilyldiazomethane / diethyl ether solution was added thereto until the solution turned yellow. Subsequently acetic acid was added until the solution became colorless. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 3: 7) to give intermediate (4B-10a) (484 mg, 19%) as a colorless oil. Got.

Process 2
In a diethyl ether suspension (4 mL) of lithium aluminum hydride (99 mg, 2.61 mmol) cooled to 0 ° C. under an argon atmosphere, a solution of intermediate (4B-10a) (481 mg, 2.17 mmol) in diethyl ether (3 .2 mL) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 3 hours, then cooled to 0 ° C., and water (0.13 mL), 15% aqueous sodium hydroxide (0.13 mL), and water (0.39 mL) were slowly added. After the mixture was stirred at room temperature for 20 minutes, the precipitate was removed by celite filtration, and the precipitate was washed with diethyl ether (50 mL). The filtrate and washings were mixed, the solvent was distilled off under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 9: 1 → 0: 10) to give an intermediate (4B- 10b) (328 mg, 78%) was obtained.

Process 3
An ethanol suspension (5 mL) of intermediate (4B-10b) (326 mg, 1.69 mmol) and 20% palladium hydroxide on carbon (65 mg) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to give intermediate (4B-10c) (174 mg, 100%) as a pale yellow oil.

Step 4 and Step 5
Using the intermediate (1C-1) (815 mg, 1.12 mmol) and the intermediate (4B-10c) (174 mg, 1.69 mmol) as starting materials, the methods described in steps 1 and 2 of Reference Example 12 were used. Based on the above, Intermediate (1E-10) (483 mg, 69% for 2 steps) was obtained as colorless amorphous.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.10 (m, 6 H) 1.43 (s, 6 H) 1.79 (s, 3 H) 1.98 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.31 (s, 3 H) 2.36 (s, 3 H) 2.93-3.06 (m, 1 H) 3.71-3.80 (m, 1 H) 3.93 (s, 2 H) 4.04 (dd, J = 12.3, 2.2 Hz, 1 H) 4.23 (dd, J = 12.4, 4.6 Hz, 1 H) 4.48-4.52 (m, 1 H) 4.76 (d, J = 6.7 Hz, 2 H) 4.87 (d, J = 6.7 Hz, 2 H) 5.08-5.18 (m, 1 H) 5.18-5.33 (m, 2 H) 6.36 (d, J = 16.0 Hz, 1 H) 6.59 (d, J = 16.0 Hz, 1 H) 6.60 (br. s, 1 H) 6.73 (d, J = 7.9 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.15 (d, J = 7.9 Hz, 1 H) 7.27 (s, 1 H) 9.74 (s, 1 H).
MS ESI / APCI Dual posi: 808 [M + H] ⁺ .
Reference Example 22 Production of intermediate (1E-11)

Process 1
Tris (hydroxymethyl) aminomethane (5.0 g, 41 mmol), sodium hydrogen carbonate (5.2 g, 62 mmol) in ethyl acetate-water mixed suspension (1: 2, 60 mL) at room temperature with benzyl chloroformate (5. (0 mL, 35 mL) was added, and the mixture was stirred overnight at the same temperature. After filtering the reaction solution, the filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was washed with isopropyl ether and then dried under reduced pressure.
The obtained residue (8.1 g) was dissolved in N, N-dimethylformamide, 2,2-dimethoxypropane (4.3 mL, 35 mmol), p-toluenesulfonic acid monohydrate (6.3 g, 33 mmol). And stirred at room temperature overnight. Ethyl acetate was added thereto, washed with water, the aqueous layer was extracted with ethyl acetate, and the organic layers were combined. This was washed twice with 10% brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 95: 5) to obtain intermediate (4B-11a) (3.7 g, 39%). Obtained.

Process 2
A methanol suspension (36 mL) of intermediate (4B-11a) (3.6 g, 12 mmol), 10% palladium hydroxide carbon (0.72 g) was stirred overnight at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure to give intermediate (4B-11b) (1.5 g, 78%).

Step 3 and Step 4
The intermediate (1C-1) (7.0 g, 9.7 mmol) and intermediate (4B-11b) (1.5 g, 9.3 mmol) are used as starting materials, and are described in Step 1 and Step 2 of Reference Example 12. The intermediate (1E-11) (2.0 g, 2 steps 25%) was obtained according to the above method.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.42-1.46 (m, 12 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.90-3.02 (m, 1 H) 3.72-3.80 (m, 1 H) 3.89-3.97 (m, 4 H) 4.02-4.09 (m, 3 H) 4.27 (dd, J = 12.4, 4.7 Hz, 1 H) 4.45-4.52 (m, 1 H) 5.10-5.31 (m, 3 H) 6.37 (d, J = 16.0 Hz, 1 H) 6.58 (d, J = 16.0 Hz, 1 H) 6.66-6.73 (m, 2 H) 6.96-7.03 (m, 2 H) 7.09- 7.17 (m, 1 H) 7.24-7.29 (m, 1 H) 9.54 (s, 1 H).
Reference Example 23 Production of intermediate (1E-12)

Step 1 and Step 2
Intermediate (1C-12) (1.00 g, 1.44 mmol) as a starting material, intermediate (1E-12) as a yellow amorphous substance according to the method described in Step 1 and Step 2 of Reference Example 12 ) (815 mg, 73% over 2 steps).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.17 (m, 6 H) 1.39 (s, 6 H) 1.77 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.90-3.04 (m, 1 H) 3.11-3.21 (m, 2 H) 3.70-3.81 (m, 1 H) 3.92 ( s, 2 H) 4.00-4.10 (m, 1 H) 4.21-4.31 (m, 1 H) 4.41-4.55 (m, 1 H) 5.09-5.33 (m, 3 H) 6.03-6.13 (m, 1 H) 6.20-6.32 (m, 1 H) 6.46-6.56 (m, 1 H) 6.66-6.71 (m, 1 H) 6.95-7.03 (m, 2 H) 7.07-7.14 (m, 1 H) 7.21-7.25 (m , 1 H) 9.38 (s, 1 H).
MS ESI / APCI Dual posi: 766 [M + H] ⁺ , 788 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 800 [M + Cl] ^- .
Reference Example 24 Production of intermediate (1E-13)

Step 1 and Step 2
Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-2) (3.00 g, 4.31 mmol) and 3-amino-3-methylbutanol (567 mg, 5.60 mmol, Reference Example 14) as starting materials The intermediate (1E-13) (2.58 g, 2 steps 74%) was obtained as a pale yellow amorphous substance in accordance with the method described in 1).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.41 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.02 (s, 3 H) 2.05 (s, 3 H) 2.29 (s, 3 H) 2.37 (s, 3 H) 2.91-3.02 (m, 3 H) 3.08 (d, J = 6.2 Hz, 2 H) 3.72-3.80 (m, 1 H) 3.89-3.95 (m, 2 H) 4.05 (dd, J = 12.5, 1.9 Hz, 1 H) 4.45-4.53 (m, 1 H) 4.27 ( dd, J = 12.5, 4.6 Hz, 1 H) 5.09-5.19 (m, 1 H) 5.21-5.31 (m, 2 H) 5.61 (br. s, 1 H) 6.22 (dt, J = 16.0, 6.2 Hz, 1 H) 6.47 (d, J = 16.0 Hz, 1 H) 6.67 (d, J = 8.1 Hz, 1 H) 6.99 (s, 1 H) 7.00 (s, 1 H) 7.10 (d, J = 8.1 Hz, 1 H) 7.23 (s, 1 H) 9.75 (t, J = 2.2 Hz, 1 H).
MS ESI / APCI Dual posi: 780 [M + H] ⁺ , 802 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 814 [M + Cl] ^- .
Reference Example 25 Production of intermediate (1E-14)

Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-2) (3.00 g, 4.31 mmol) and 1-amino-1-cyclopentanemethanol (645 mg, 5.60 mmol) as starting materials. The intermediate (1E-14) (2.74 g, 81% for 2 steps) was obtained as a pale yellow amorphous product.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15-1.18 (m, 6 H) 1.68-1.89 (m, 9 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.08-2.17 (m, 2 H) 2.30 (s, 3 H) 2.37 (s, 3 H) 2.91-3.03 (m, 1 H) 3.18 (d, J = 7.1 Hz, 2 H) 3.72-3.81 ( m, 1 H) 3.89-3.95 (m, 2 H) 4.05 (dd, J = 12.4, 1.9 Hz, 1 H) 4.27 (dd, J = 12.4, 4.6 Hz, 1 H) 4.44-4.54 (m, 1 H ) 5.10-5.19 (m, 1 H) 5.21-5.32 (m, 2 H) 6.09 (br. S, 1 H) 6.26 (dt, J = 15.9, 7.1 Hz, 1 H) 6.51 (d, J = 15.9 Hz) , 1 H) 6.68 (d, J = 8.1 Hz, 1 H) 6.98 (s, 1 H) 7.00 (s, 1 H) 7.10 (d, J = 8.1 Hz, 1 H) 7.23 (s, 1 H) 9.47 (s, 1 H).
MS ESI / APCI Dual posi: 792 [M + H] ⁺ , 815 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 826 [MH] ^- .
Reference Example 26 Production of intermediate (1E-15)

Step 1, Step 2, Step 3
Starting from intermediate (1B-1) (1.00 g, 1.45 mmol) and 2,2-diethylbut-3-enoic acid (493 mg, 3.47 mmol, Journal of Heterocyclic Chemistry (2005), 42, 327) Based on the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12, Intermediate (1E-15) (709 mg, 3 steps 60%) was obtained as a colorless amorphous substance.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.84-0.93 (m, 6 H) 1.11-1.18 (m, 6 H) 1.34 (s, 6 H) 1.75-1.86 (m, 4 H) 1.78 (s , 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.33 (s, 3 H) 2.36 (s, 3 H) 2.91-3.04 (m, 1 H) 3.72- 3.81 (m, 1 H) 3.94 (s, 2 H) 4.01-4.09 (m, 1 H) 4.21-4.31 (m, 1 H) 4.44-4.55 (m, 1 H) 5.10-5.19 (m, 1 H) 5.22-5.32 (m, 2 H) 6.11 (s, 1 H) 6.23-6.32 (m, 1 H) 6.46-6.55 (m, 1 H) 6.67-6.73 (m, 1 H) 7.01 (s, 1 H) 7.02 (s, 1 H) 7.10-7.16 (m, 1 H) 7.25-7.27 (m, 1 H) 9.36 (s, 1 H).
MS ESI / APCI Dual posi: 823 [M + H] ⁺ , 845 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 857 [M + Cl] ^- .
Reference Example 27 Production of intermediate (1E-16)

Step 1, Step 2, Step 3
Intermediate Example (1B-1) (146 mg, 0.21 mmol) and 1-vinylcyclobutanecarboxylic acid (40 mg, 0.32 mmol, Journal of Heterocyclic Chemistry (2005), 42,327) were used as starting materials. Based on the method described in Step 1 and Step 2 of Example 12, intermediate (1E-16) (709 mg, 3 steps 60%) was obtained as a colorless amorphous substance.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.18 (m, 6 H) 1.34 (s, 6 H) 1.78 (s, 3 H) 1.88-2.67 (m, 6 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.32 (s, 3 H) 2.37 (s, 3 H) 2.92-3.04 (m, 1 H) 3.71-3.81 (m, 1 H) 3.94 ( s, 2 H) 4.01-4.10 (m, 1 H) 4.22-4.32 (m, 1 H) 4.45-4.54 (m, 1 H) 5.10-5.20 (m, 1 H) 5.22-5.32 (m, 2 H) 5.88-5.94 (m, 1 H) 6.33-6.42 (m, 1 H) 6.53-6.62 (m, 1 H) 6.70 (d, J = 7.8 Hz, 1 H) 7.00 (s, 1 H) 7.01 (s, 1 H) 7.11-7.17 (m, 1 H) 7.25-7.30 (m, 1 H) 9.37 (s, 1 H).
MS ESI / APCI Dual posi: 806 [M + H] ⁺ .
MS ESI / APCI Dual nega: 840 [M + Cl] ^- .
Reference Example 28 Production of intermediate (1E-17)

Step 1, Step 2, Step 3
Intermediate (1B-1) (683 mg, 0.990 mmol) and 2,2-dimethyl-5-vinyl-1,3-dioxane-5-carboxylic acid (276 mg, 1.48 mmol, Journal of Heterocyclic Chemistry (2005), 42,327) as a starting material, intermediate (1E-17) (709 mg, 3 steps 66% as a colorless amorphous) according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. )
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08-1.16 (m, 6 H) 1.41 (s, 6 H) 1.48 (s, 3 H) 1.53 (s, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.27 (s, 3 H) 2.36 (s, 3 H) 2.87-3.03 (m, 1 H) 3.69-3.81 (m, 1 H) 3.91 (s, 2 H) 4.01-4.32 (m, 6 H) 4.42-4.51 (m, 1 H) 5.10-5.19 (m, 1 H) 5.22-5.31 (m, 2 H) 6.22-6.29 ( m, 1 H) 6.38-6.46 (m, 1 H) 6.67 (d, J = 7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.04-7.10 (m, 1 H) 7.23 (s, 1 H) 7.46 (s, 1 H) 9.43 (s, 1 H).
MS ESI / APCI Dual posi: 866 [M + H] ⁺ , 888 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 864 [MH] ^- , 900 [M + Cl] ^- .
Reference Example 29 Production of intermediate (1E-18)

Step 1 and Step 2
Intermediate (1C-18) (9.00 g, 0.0129 mol) was used as a starting material, and the intermediate (1E-18) was converted into a yellow amorphous substance according to the method described in Step 1 and Step 2 of Reference Example 12. ) (7.60 g, 77% over 2 steps).
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.09-1.18 (m, 6 H) 1.32 (s, 6 H) 1.38 (s, 6 H) 1.77 (s, 3 H) 1.98 (s, 3 H) 2.00-2.07 (m, 6 H) 2.33 (s, 3 H) 2.95 (spt, J = 6.8 Hz, 1 H) 3.77-3.94 (m, 6 H) 4.08-4.15 (m, 1 H) 4.22 (dd, J = 11.9, 4.6 Hz, 1 H) 4.82 (br. S., 1 H) 5.14-5.20 (m, 1 H) 5.27-5.35 (m, 2 H) 6.11 (br. S, 1 H) 6.31 (d , J = 16.5 Hz, 1 H) 6.52 (d, J = 16.5 Hz, 1 H) 6.67 (d, J = 7.8 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.10 (d , J = 7.8 Hz, 1 H) 7.24 (s, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 766 [M + H] ⁺ , 788 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 800 [M + Cl] ^- .
Reference Example 30 Production of intermediate (1E-19)

Step 1 and Step 2
Intermediate (1C-19) (6.05 g, 9.04 mmol) was used as a starting material according to the method described in Step 1 and Step 2 of Reference Example 12, and the intermediate (1E-19 ) (3.44 g, 2 steps 52%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.38 (s, 6 H) 1.76 (s, 3 H ) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.31 (s, 3 H) 2.88-2.99 (m, 1 H) 3.16 (dd, J = 7.2, 1.2 Hz, 2 H) 3.76-3.84 (m, 1 H) 3.86-3.88 (m, 5 H) 4.07-4.14 (m, 1 H) 4.18-4.26 (m, 1 H) 4.78-4.84 (m, 1 H) 5.13-5.22 (m, 1 H) 5.29-5.34 (m, 2 H) 6.07 (br.s, 1 H) 6.23 (dt, J = 15.7, 7.2 Hz, 1 H) 6.50 (d, J = 15.7 Hz, 1 H) 6.64 (d, J = 7.8 Hz, 1 H) 6.81 (s, 1 H) 6.98 (s, 1 H) 7.08 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H) 9.37 (s, 1 H).
MS ESI / APCI Dual posi: 738 [M + H] ⁺ , 760 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 736 [MH] ^- , 772 [M + Cl] ^- .
Reference Example 31 Production of intermediate (1E-20)

Step 1 and Step 2
Described in Step 1 and Step 2 of Reference Example 12 using Intermediate (1C-3) (668 mg, 0.959 mmol) and 3-amino-3-methylbutanol (129 mg, 1.25 mmol, Reference Example 14) as starting materials The intermediate (1E-20) (329 mg, 2 steps 44%) was obtained as a yellow amorphous based on the described method.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 7.0 Hz, 3 H) 1.14 (d, J = 7.0 Hz, 3 H) 1.33 (s, 6 H) 1.36 (s, 6 H ) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.02-2.06 (m, 6 H) 2.33 (s, 3 H) 2.90-2.95 (m, 3 H) 3.76-3.84 (m, 1 H) 3.84 -3.90 (m, 5 H) 4.06-4.14 (m, 1 H) 4.18-4.26 (m, 1 H) 4.79-4.85 (m, 1 H) 5.13-5.23 (m, 1 H) 5.26-5.36 (m, 2 H) 5.74 (s, 1 H) 6.26 (d, J = 16.3 Hz, 1 H) 6.48 (d, J = 16.3 Hz, 1 H) 6.65 (d, J = 7.9 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.09 (d, J = 7.9 Hz, 1 H) 7.23 (s, 1 H) 9.72 (t, J = 2.2 Hz, 1 H).
MS ESI / APCI Dual posi: 781 [M + H] ⁺ .
Reference Example 32 Production of intermediate (1E-21)

Step 1, Step 2, Step 3
Intermediate (1B-3) (1.00 g, 1.48 mmol) was used as a starting material, and the intermediate was converted to colorless amorphous according to the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12. (1E-21) (175 mg, 3 steps 15%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.06-1.18 (m, 6 H) 1.32 (s, 6 H) 1.38 (s, 6 H) 1.47 (t, J = 6.9 Hz, 3 H) 1.77 ( s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.33 (s, 3 H) 2.85-3.03 (m, 1 H) 3.72-3.97 (m, 3 H ) 4.01-4.16 (m, 3 H) 4.17-4.28 (m, 1 H) 4.72-4.91 (m, 1 H) 5.11-5.21 (m, 1 H) 5.27-5.37 (m, 2 H) 6.11 (s, 1 H) 6.26-6.35 (m, 1 H) 6.48-6.57 (m, 1 H) 6.67 (d, J = 7.9 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.10 (d , J = 7.9 Hz, 1 H) 7.25 (s, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 780 [M + H] ⁺ , 802 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 778 [MH] ^- , 814 [M + Cl] ^- .
Reference Example 33 Production of intermediate (1E-22)

Step 1, Step 2, Step 3
Intermediate (1B-6) (480 mg, 0.653 mmol) was used as a starting material, and intermediate (1E) was obtained as colorless amorphous according to the methods described in Steps 1 and 2 of Reference Example 8 and Reference Example 12. -22) (250 mg, 46% for 3 steps).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.33 (s, 6 H) 1.39 (s, 6 H ) 1.76 (s, 3 H) 1.98 (s, 3 H) 2.04 (s, 3 H) 2.05 (s, 3 H) 2.18 (s, 3 H) 2.32 (s, 3 H) 2.88-3.01 (m, 1 H) 3.76-3.91 (m, 3 H) 4.05-4.13 (m, 1 H) 4.15-4.30 (m, 3 H) 4.37-4.48 (m, 1 H) 4.53-4.63 (m, 1 H) 4.73 (br s., 1 H) 5.18 (t, J = 9.2 Hz, 1 H) 5.30 (t, J = 9.2 Hz, 1 H) 5.41 (br. s., 1 H) 6.11 (s, 1 H) 6.34 ( d, J = 16.0 Hz, 1 H) 6.55 (d, J = 16.0 Hz, 1 H) 6.67 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 ( d, J = 7.8 Hz, 1 H) 7.25 (s, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 838 [M + H] ⁺ , 860 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 872 [M + Cl] ^- .
Reference Example 34 Production of intermediate (1E-23)

Step 1, Step 2, Step 3
Intermediate (1B-4) (200 mg, 0.29 mmol) as a starting material, intermediate (1E) as colorless amorphous, according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. -23) (185 mg, 57% over 3 steps).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.18 (m, 6 H) 1.30-1.35 (m, 6 H) 1.39 (s, 6 H) 1.79 (s, 3 H) 1.99 (s, 3 H) 2.04 (s, 3 H) 2.04 (s, 3 H) 2.32 (s, 3 H) 2.89-3.04 (m, 1 H) 3.74-4.01 (m, 3 H) 4.06-4.15 (m, 1 H) 4.16-4.25 (m, 1 H) 4.75-4.84 (m, 1 H) 5.12-5.36 (m, 3 H) 5.61-5.68 (m, 1 H) 5.79-5.86 (m, 1 H) 6.12 (s, 1 H) 6.27-6.36 (m, 1 H) 6.48-6.57 (m, 1 H) 6.67 (d, J = 8.0 Hz, 1 H) 7.04 (s, 1 H) 7.06 (s, 1 H) 7.12 (dd, J = 8.0, 1.5 Hz, 1 H) 7.24-7.26 (m, 1 H) 9.33 (s, 1 H).
MS ESI / APCI Dual posi: 784 [M + H] ⁺ , 806 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 818 [M + Cl] ^- .
Reference Example 35 Production of intermediate (1E-24)

Step 1, Step 2, Step 3
Intermediate (1B-5) (10.6 g, 15.2 mmol) was used as a starting material, and the intermediate was converted to colorless amorphous according to the methods described in steps 1 and 2 of Reference Example 8 and Reference Example 12. (1E-24) (6.62 g, 3 steps 56%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.11-1.19 (m, 6 H) 1.35 (s, 6 H) 1.39 (s, 6 H) 1.80 (s, 3 H) 1.99 (s, 3 H) 2.01-2.09 (m, 6 H) 2.31 (s, 3 H) 2.93-3.06 (m, 1 H) 3.75-4.02 (m, 3 H) 4.07-4.25 (m, 2 H) 4.64-4.74 (m, 1 H) 5.10-5.22 (m, 1 H) 5.26-5.39 (m, 2 H) 6.15 (s, 1 H) 6.25-6.78 (m, 4 H) 7.02 (s, 1 H) 7.08 (s, 1 H) 7.13 (d, J = 7.8 Hz, 1 H) 7.27 (s, 1 H) 9.34 (s, 1 H).
MS ESI / APCI Dual posi: 802 [M + H] ⁺ , 824 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 836 [M + Cl] ^- .
Reference Example 36 Production of intermediate (2C-1)

Process 1
Under a nitrogen atmosphere, intermediate (1B-1) (2.50 g, 3.61 mmol), acrylic acid (625 mg, 8.67 mmol), palladium (II) acetate (81.0 mg, 0.361 mmol), tri-o- A suspension of trilylphosphine (220 mg, 0.722 mmol) and triethylamine (2.50 mL, 18.1 mmol) in acetonitrile (10 mL) was stirred at 120 ° C. for 30 minutes under microwave irradiation. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to give an intermediate (2B-1) as a pale yellow oil. ) (1.28 g, 52%).

Process 2
A solution of intermediate (2B-1) (1.13 g, 1.65 mmol), 0.93 M borane-tetrahydrofuran complex-tetrahydrofuran solution (2.67 mL, 2.48 mmol) in tetrahydrofuran (20 mL) was stirred overnight at room temperature. . After adding methanol, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 1: 1) to obtain intermediate (2C-1) (650 mg, 59 %).
¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.7 Hz, 3 H) 1.14 (d, J = 6.7 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.04 (s, 6 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.94-3.04 (m, 1 H) 3.72-3.77 (m, 1 H) 3.88-3.94 (m, 3 H) 4.05 (dd, J = 12.4, 2.1 Hz, 1 H) 4.26 (dd, J = 12.4, 4.6 Hz, 1 H) 4.29-4.32 (m, 2 H) 4.44-4.49 (m, 1 H) 5.12-5.16 (m, 1 H) 5.23-5.28 (m, 2 H) 6.34 (dt, J = 15.6, 6.0 Hz, 1 H) 6.57 (d, J = 15.6 Hz, 1 H) 6.69 (d, J = 7.8 Hz, 1 H) 6.95 (s, 1 H) 6.99 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H).
Reference Example 37 Production of intermediate (2E-1)

Process 1
To a solution of intermediate (1C-2) (0.59 g, 0.87 mmol) in tetrahydrofuran (1.7 mL), 0.93 M borane-tetrahydrofuran complex-tetrahydrofuran solution (1.0 mL, 0.93 mmol) was added dropwise at -78 ° C. did. After raising the reaction temperature to 0 ° C., the mixture was stirred at the same temperature for 3 hours, and methanol was added. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol = 100: 0 → 96: 4) to obtain intermediate (2D-1) (0.33 g, 82%).

Process 2
Triphenylphosphine (0.18 g, 0.68 mmol) was added to a chloroform solution (1.6 mL) of intermediate (2D-1) (0.33 g, 0.48 mmol) and carbon tetrabromide (0.25 g, 0.73 mmol). ) And stirred at the same temperature for 3 hours. Chloroform was added to the reaction solution, washed with water, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 30: 70 → 53: 47) to obtain intermediate (2E-1) (0.30 g, 82%). Got.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (d, J = 6.8 Hz, 3 H) 1.14 (d, J = 6.8 Hz, 3 H) 1.76 (s, 3 H) 1.99 (s, 3 H ) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.71-2.82 (m, 2 H) 2.91-3.05 (m, 1 H) 3.47 (t , J = 7.1 Hz, 2 H) 3.71-3.78 (m, 1 H) 3.91 (s, 2 H) 4.05 (dd, J = 12.4, 2.1 Hz, 1 H) 4.27 (dd, J = 12.4, 4.4 Hz, 1 H) 4.43-4.50 (m, 1 H) 5.10-5.30 (m, 3 H) 6.09-6.21 (m, 1 H) 6.44 (d, J = 15.9 Hz, 1 H) 6.68 (d, J = 7.9 Hz , 1 H) 6.96 (s, 1 H) 6.99 (s, 1 H) 7.05-7.11 (m, 1 H) 7.18-7.22 (m, 1 H).
Reference Example 38 Production process 1 of intermediate (3A-1)

２,２−ジメチル−３−ブテノイックアシッド（５．４２ｇ,４７．５ｍｍｏｌ,Ｊｏｕｒｎａｌ ｏｆ Ｏｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ（２０００）,６５,８４０２）のクロロホルム（２５０ｍＬ）溶液に窒素雰囲気下、塩化オキサリル（４．４３ｍＬ,４９．９ｍｍｏｌ）とＮ,Ｎ−ジメチルホルムアミド（３滴）を加え、室温で１．５時間撹拌した。その後反応液を氷冷し、トリエチルアミン（１９．９ｍＬ,１４３ｍｍｏｌ）とα−アミノイソブチリックアシッドメチルエステル塩酸塩（１０．９ｇ,７１．２ｍｍｏｌ）を加え、室温で１時間撹拌した。反応液に水を加え、クロロホルムで抽出後、有機層を３Ｍ塩酸、飽和炭酸水素ナトリウム水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン→ヘキサン：酢酸エチル＝４：１）にて精製し、無色粉末として中間体（４Ｆ−１）（９．３８ｇ,９３％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17 - 5.32 (m, 2 H) 6.02 (dd, J=17.6, 10.6 Hz, 1 H) 6.25 (br. s., 1 H).
MS ESI/APCI Dual posi : 214[M+H]⁺.
工程２

A solution of 2,2-dimethyl-3-butenoic acid (5.42 g, 47.5 mmol, Journal of Organic Chemistry (2000), 65,8402) in chloroform (250 mL) under a nitrogen atmosphere and oxalyl chloride (4.43 mL). , 49.9 mmol) and N, N-dimethylformamide (3 drops) were added and stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was ice-cooled, triethylamine (19.9 mL, 143 mmol) and α-aminoisobutyric acid methyl ester hydrochloride (10.9 g, 71.2 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with 3M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane → hexane: ethyl acetate = 4: 1) to give an intermediate (4F-1) as a colorless powder. ) (9.38 g, 93%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.27 (s, 6 H) 1.51 (s, 6 H) 3.73 (s, 3 H) 5.17-5.32 (m, 2 H) 6.02 (dd, J = 17.6 , 10.6 Hz, 1 H) 6.25 (br. S., 1 H).
MS ESI / APCI Dual posi: 214 [M + H] ⁺ .
Process 2

中間体（４Ｆ−１）（９．３８ｇ,４３．９ｍｍｏｌ）のメタノール（２０ｍＬ）溶液に４Ｍ水酸化ナトリウム水溶液（１６．５ｍＬ,６６．０ｍｍｏｌ）を加え、室温で１時間撹拌した。その後、反応混合物を濃縮した。得られた残渣を水に溶解し、３Ｍ塩酸を加えて中和した。この混合物を酢酸エチルで抽出し、合わせた有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。乾燥剤を濾別後、溶媒を減圧下留去し、無色粉末として中間体（４Ｆ−２）（８．１９ｇ,９４％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16 - 5.36 (m, 2 H) 6.01 (dd, J=17.5, 10.7 Hz, 1 H) 6.14 (s, 1 H).
MS ESI/APCI Dual posi : 200[M+H]⁺, 222[M+Na]⁺.
MS ESI/APCI Dual nega : 198[M-H]^-.
工程３

To a solution of intermediate (4F-1) (9.38 g, 43.9 mmol) in methanol (20 mL) was added 4M aqueous sodium hydroxide solution (16.5 mL, 66.0 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated. The obtained residue was dissolved in water and neutralized by adding 3M hydrochloric acid. This mixture was extracted with ethyl acetate, and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain Intermediate (4F-2) (8.19 g, 94%) as a colorless powder.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.54 (s, 6 H) 5.16-5.36 (m, 2 H) 6.01 (dd, J = 17.5, 10.7 Hz, 1 H) 6.14 (s, 1 H).
MS ESI / APCI Dual posi: 200 [M + H] ⁺ , 222 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 198 [MH] ^- .
Process 3

アルゴン雰囲気下、中間体（１Ｂ−１）（５．００ｇ,７．２３ｍｍｏｌ）、中間体（４Ｆ−２）（２．５９ｇ,１３．０ｍｍｏｌ）、酢酸パラジウム（ＩＩ）（３２８ｍｇ,１．４５ｍｍｏｌ）、トリ−ｏ−トリルホスフィン（８８０ｍｇ,２．８９ｍｍｏｌ）、トリエチルアミン（３．０ｍＬ,９．００ｍｍｏｌ）のアセトニトリル（２４ｍＬ）懸濁液を、マイクロウェーブ照射下１２０℃で２０分間撹拌した。反応液をセライトろ過し、酢酸エチルで洗浄した。ろ液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィ−（ヘキサン：酢酸エチル＝１：１→酢酸エチル）にて精製し、淡黄色粉末として中間体（３Ａ−１）（４．５９ｇ,７８％）を得た。
¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J=6.8 Hz, 3 H) 1.40 (s, 6 H) 1.54 - 1.58 (m, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.98 - 3.10 (m, 1 H) 3.71 - 3.79 (m, 1 H) 3.94 (s, 2 H) 4.01 - 4.08 (m, 1 H) 4.24 (dd, J=12.4, 4.5 Hz, 1 H) 4.47 (d, J=9.2 Hz, 1 H) 5.07 - 5.32 (m, 3 H) 6.31 (d, J=16.3 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J=16.3 Hz, 1 H) 6.77 (d, J=7.6 Hz, 1 H) 6.92 (s, 1 H) 6.99 (s, 1 H) 7.12 - 7.18 (m, 1 H) 7.26 (s, 1 H).
MS ESI/APCI Dual posi : 810[M+H]⁺, 832[M+Na]⁺ .
MS ESI/APCI Dual nega : 808[M-H]^-.
参考例Ａ−１ アミン中間体（４Ｃ−１）の製造

Under an argon atmosphere, intermediate (1B-1) (5.00 g, 7.23 mmol), intermediate (4F-2) (2.59 g, 13.0 mmol), palladium (II) acetate (328 mg, 1.45 mmol) , A suspension of tri-o-tolylphosphine (880 mg, 2.89 mmol) and triethylamine (3.0 mL, 9.00 mmol) in acetonitrile (24 mL) was stirred at 120 ° C. for 20 minutes under microwave irradiation. The reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 → ethyl acetate) to give intermediate (3A-1) (4.59 g) as a pale yellow powder. 78%).
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16, 1.18 (each d J = 6.8 Hz, 3 H) 1.40 (s, 6 H) 1.54-1.58 (m, 6 H) 1.76 (s, 3 H) 1.99 (s, 3 H) 2.03 (s, 3 H) 2.05 (s, 3 H) 2.28 (s, 3 H) 2.36 (s, 3 H) 2.98-3.10 (m, 1 H) 3.71-3.79 (m, 1 H) 3.94 (s, 2 H) 4.01-4.08 (m, 1 H) 4.24 (dd, J = 12.4, 4.5 Hz, 1 H) 4.47 (d, J = 9.2 Hz, 1 H) 5.07-5.32 (m , 3 H) 6.31 (d, J = 16.3 Hz, 1 H) 6.35 (s, 1 H) 6.55 (d, J = 16.3 Hz, 1 H) 6.77 (d, J = 7.6 Hz, 1 H) 6.92 (s , 1 H) 6.99 (s, 1 H) 7.12-7.18 (m, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 810 [M + H] ⁺ , 832 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 808 [MH] ^- .
Reference Example A-1 Production of amine intermediate (4C-1)

Process 1
CDI (1.52 g, 9.36 mmol) was added to a solution of N- (tert-butoxycarbonyl) -1,2-diaminoethane (1.00 g, 6.24 mmol) in N, N-dimethylformamide (25 mL) at room temperature. For 3 hours. A 28% aqueous ammonia solution (25 mL) was added thereto, and the mixture was stirred for 3 hours under reflux with heating. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue and washed with water. The aqueous layer was extracted with a mixed solvent of ethyl acetate / hexane, and the obtained organic layer and the previous organic layer were combined and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 95: 5 → 85: 15) to obtain intermediate (4C-1a) ( 1.19 g, 94%).

Process 2
To a solution of intermediate (4C-1a) (1.19 g, 5.86 mmol) in ethyl acetate (30 mL) was added 4M hydrogen chloride / ethyl acetate (30 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate to obtain amine intermediate (4C-1) (1.19 g) as a pale yellow oil.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.72-2.88 (m, 2 H) 3.13-3.25 (m, 2 H).
MS ESI / APCI Dual posi: 104 [M + H] ⁺ , 126 [M + Na] ⁺ .
Reference Example A-2 Production of amine intermediate (4C-2)

Process 1
To a solution of N- (tert-butoxycarbonyl) -1,2-diaminoethane (500 mg, 3.12 mmol) and triethylamine (650 μL, 4.68 mmol) in tetrahydrofuran (16 mL) was added methanesulfonyl chloride (290 μL, 3.75 mmol) was added. After removing the ice bath, the mixture was stirred for 3 hours, water was added thereto, extraction was performed with ethyl acetate, and the obtained organic layer was dried over sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 90: 10) to obtain the intermediate (4C-2a) ( 606 mg, 82%).

Process 2
Amine intermediate (4C-2) (338 mg) was obtained as a light brown solid from intermediate (4C-2a) (599 mg, 2.51 mmol) by the same method as in step 2 of Reference Example A-1.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 2.84-2.96 (m, 2 H) 2.96 (s, 3 H) 3.15-3.28 (m, 2 H).
MS ESI / APCI Dual posi: 139 [M + H] ⁺ , 161 [M + Na] ⁺ .
Reference Example A-3 Production of amine intermediate (4C-3)

Process 1
(2-Amino-2-methyl-propyl) -carbamic acid-tertbutyl ester (4.39 g, 23.3 mmol), sodium bicarbonate (2.94 g, 35.0 mmol) in ethyl acetate-water mixed suspension (1: 2, 45 mL) was added benzyl chloroformate (5.18 g, 30.3 mmol) at room temperature, and the mixture was stirred overnight at the same temperature. After filtering the reaction solution, the filtrate was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 80: 20 → 50: 50) to obtain intermediate (4C-3a) (7.34 g, 98%) as a colorless solid.

Process 2
4M Hydrogen chloride / ethyl acetate (30 mL) was added to an ethyl acetate solution (30 mL) of intermediate (4C-3a) (7.34 g, 22.8 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain Intermediate (4C-3b) (6.17 g).

Process 3
Triethylamine (800 μL, 5.79 mmol) was added to a solution of intermediate (4C-3b) (1.0 g, 3.86 mmol) in chloroform (16 mL), and then methanesulfonyl chloride (360 μL, 4.64 mmol) was cooled with ice. ) Was added. After removing the ice bath, the mixture was stirred overnight. Water was added to the reaction solution, followed by extraction with chloroform, and the resulting organic layer was dried over sodium sulfate. After filtering off the desiccant, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 → 33: 67) to give the intermediate (4C-3c) as a colorless oil. ) (1.08 g, 93%).

Process 4
A suspension of intermediate (4C-3c) (1.08 g, 3.59 mmol), 20% palladium hydroxide on carbon (216 mg) in methanol (18 mL) was stirred overnight at room temperature under a hydrogen atmosphere. The reaction solution was filtered through celite, and the solvent was evaporated under reduced pressure to obtain an amine intermediate (4C-3) (596 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.01 (s, 6 H) 2.79 (s, 2 H) 2.91 (s, 3 H).
MS ESI / APCI Dual posi: 167 [M + H] ⁺ .
MS ESI / APCI Dual nega: 165 [MH] ^- .
Reference Example A-4 Production of amine intermediate (4C-4)

Process 1
N-carbobenzoxy-1,2-diaminoethane hydrochloride (1.0 g, 4.33 mmol), 2- (tert-butoxycarbonylamino) isobutyric acid (1.15 g, 5.64 mmol), EDC-HCl (762 mg) , 5.64 mmol), HOBt · H ₂ O (1.08 g, 5.64 mmol), triethylamine (1.8 mL, 13 mmol) in N, N-dimethylformamide (22 mL) was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, washed with water, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 → 20: 80) to obtain intermediate (4C-4a) ( 1.66 g) was obtained.

Process 2
The intermediate (4C-4a) (1.66 g, 4.38 mmol) was used as a starting material in accordance with the method described in Step 4 of Reference Example A-3, and the amine intermediate (4C- 4) (1.1 g) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.48 (s, 6 H) 2.54 (br. S., 2 H) 2.89-2.95 (m, 2 H) 3.33-3.45 ( m, 2 H) 4.99 (br. s., 1 H) 6.96 (br. s., 1 H).
MS ESI / APCI Dual posi: 246 [M + H] ⁺ .
MS ESI / APCI Dual nega: 280 [M + Cl] ^- .
Reference Example A-5 Production of amine intermediate (4C-5)

Step 1 and Step 2
The intermediate (4C-3b) (1.0 g, 3.86 mmol) was used as a starting material, and the amine intermediate (as colorless amorphous) was prepared according to the method described in Step 1 and Step 2 of Reference Example A-4. 4C-5) (490 mg) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.26 (s, 6 H) 1.43 (s, 9 H) 1.52 (s, 6 H) 3.34 (d, J = 5.8 Hz, 2 H).
MS ESI / APCI Dual posi: 274 [M + H] ⁺ , 296 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 308 [M + Cl] ^- .
Reference Example A-6 Production of amine intermediate (4C-6)

Step 1 and Step 2
Starting from 1-carbobenzoxypiperazine (1.00 g, 4.54 mmol) as a starting material, according to the method described in Step 1 and Step 2 of Reference Example A-4, the amine intermediate ( 4C-6) (1.05 g) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H) 1.50 (s, 6 H) 2.82-2.90 (m, 4 H) 3.63-3.75 (m, 4 H).
MS ESI / APCI Dual posi: 272 [M + H] ⁺ , 284 [M + Na] ⁺ .
Reference Example A-7 Production of amine intermediate (4C-7)

Process 1
To a solution of Cbz-glycine (100 mg, 0.358 mmol) in tetrahydrofuran (2 mL) was added CDI (1.4 g, 8.9 mmol) at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To this, 2-methylpropane-1,2-diamine (63.2 mg, 0.717 mmol) was added and further stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 97: 3 → 25: 75) to give intermediate (4C-7a) (100 mg, 59%) as a white solid. Obtained.

Process 2
A solution of intermediate (4C-7a) (100 mg, 0.358 mmol), Boc ₂ O (0.12 mL, 0.537 mmol), and triethylamine (0.075 mL, 0.537 mmol) in chloroform (1.5 mL) at room temperature. Stir overnight. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85: 15 → 20: 80) to obtain intermediate (4C-7b) (136 mg, 100%) as a colorless oil. Obtained.

Process 3
Starting from intermediate (4C-7b) (63 mg, 0.166 mmol) as a starting material, the amine intermediate (4C-7) was obtained as a colorless oil according to the method described in Step 4 of Reference Example A-3. (40 mg, 98%) was obtained.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.44 (s, 9 H) 3.39 (s, 2 H) 3.45 (d, J = 6.4 Hz, 2 H) 4.84 (br. s., 1 H) 7.72 (br. s., 1 H).
MS ESI / APCI Dual posi: 246 [M + H] ⁺ , 268 [M + Na] ⁺ .
Reference Example A-8 Production of amine intermediate (4C-8)

Process 1
CDI (1.4 g, 8.9 mmol) was added to a solution of Cbz-Aib-OH (2.0 g, 8.4 mmol) in tetrahydrofuran (84 mL) at room temperature, and the mixture was stirred at the same temperature for 1 hour. To this was added glycinamide hydrochloride (0.98 g, 8.9 mmol), and the mixture was further stirred at the same temperature for 3 days. The reaction mixture was concentrated under reduced pressure, 4% aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 2 hr. The resulting crystals were collected by filtration, washed well with water and dried under reduced pressure. The obtained crystals were purified by silica gel chromatography (chloroform: methanol = 20: 1 → 87: 13) to obtain an intermediate (4C-8a) (1.2 g, 47%).

Process 2
Based on the method described in Step 4 of Reference Example A-3, using Intermediate (4C-8a) as a starting material, amine intermediate (4C-8) (0.67 g) was obtained. This contained a compound other than the desired product, but was used in the next reaction without further purification.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 6 H) 3.63 (s, 2 H) 7.08 (br. S., 2 H) 8.17 (br. S, 1 H).
MS ESI / APCI Dual posi: 160 [M + H] ⁺ .
MS ESI / APCI Dual nega: 158 [MH] ^- , 194 [M + Cl] ^- .
Reference Example A-9 Production of amine intermediate (4C-9)

Step 1 and Step 2
It is described in Step 1 and Step 2 of Reference Example A-4 using Cbz-Aib-OH (1.0 g, 4.21 mmol) and 2-amino-2-methylpropanamide (516 mg, 5.05 mmol) as starting materials. According to the above method, amine intermediate (4C-9) (668 mg) was obtained as a colorless oil.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.22 (s, 6 H) 1.39 (s, 6 H).
MS ESI / APCI Dual posi: 188 [M + H] ⁺ .
MS ESI / APCI Dual nega: 186 [MH] ^- , 222 [M + Cl] ^- .
Reference Example A-10 Production of amine intermediate (4C-10)

Step 1 and Step 2
Process of Reference Example A-4 using Cbz-Aib-OH (500 mg, 2.11 mmol) and tert-butyl (1-amino-2-methylpropan-2-yl) carbamate (476 mg, 2.53 mmol) as starting materials According to the method described in 1 and Step 2, amine intermediate (4C-10) (477 mg) was obtained as colorless amorphous.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 6 H) 1.44 (s, 9 H) 1.57 (s, 6 H) 3.39 (d, J = 5.8 Hz, 2 H) 7.99-8.38 ( m, 1 H).
MS ESI / APCI Dual posi: 274 [M + H] ⁺ .
MS ESI / APCI Dual nega: 308 [M + Cl] ^- .
Reference Example A-11 Production of amine intermediate (4C-11)

Step 1 and Step 2
Described in Step 1 and Step 2 of Reference Example A-8 using Cbz-Aib-OH (3.00 g, 12.6 mmol) and tris (hydroxymethyl) aminomethane (1.60 g, 13.3 mmol) as starting materials. According to the method, amine intermediate (4C-11) (634 mg) was obtained as a colorless solid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.39 (s, 6 H) 3.69 (s, 6 H).
MS ESI / APCI Dual posi: 207 [M + H] ⁺ .
MS ESI / APCI Dual nega: 205 [MH] ^- , 241 [M + Cl] ^- .
Reference Example A-12 Production of amine intermediate (4C-12)

Step 1 and Step 2
The method described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and glycine methyl ester / hydrochloride (1.6 g, 13 mmol) as starting materials. To obtain an amine intermediate (4C-12) (1.3 g, 87% for 2 steps).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.21 (s, 6 H) 3.64 (s, 3 H) 3.81-3.89 (m, 2 H) 8.31 (br. S, 1 H).
MS ESI / APCI Dual posi: 175 [M + H] ⁺ .
Reference Example A-13 Production of amine intermediate (4C-13)

Step 1 and Step 2
Conforms to the methods described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 3-aminopropanol (0.96 mL, 13 mmol) as starting materials. Thus, an amine intermediate (4C-13) (0.31 g, 46% for 2 steps) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.38 (s, 6 H) 1.62-1.72 (m, 2 H) 3.35-3.44 (m, 2 H) 3.57 (t, J = 5.4 Hz, 2 H) .
MS ESI / APCI Dual posi: 161 [M + H] ⁺ .
MS ESI / APCI Dual nega: 159 [MH] ^- .
Reference Example A-14 Production of amine intermediate (4C-14)

Step 1 and Step 2
Conforms to the methods described in steps 1 and 2 of Reference Example A-8 using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 4-aminobutanol (1.2 mL, 13 mmol) as starting materials. Thus, an amine intermediate (4C-14) (0.52 g, 2 steps 71%) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.36 (s, 6 H) 1.56-1.64 (m, 4 H) 3.27 (q, J = 6.6 Hz, 2 H) 3.64-3.72 (m, 2 H) 7.72 (br. S., 1 H).
MS ESI / APCI Dual posi: 175 [M + H] ⁺ , 197 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 173 [MH] ^- .
Reference Example A-15 Production of amine intermediate (4C-15)

Step 1 and Step 2
Using Cbz-Aib-OH (1.0 g, 4.2 mmol) and 5-aminopentanol (1.4 mL, 13 mmol) as starting materials, the methods described in steps 1 and 2 of Reference Example A-8 were used. Based on the above, amine intermediate (4C-15) (0.52 g, 2 steps 82%) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35 (s, 6 H) 1.37-1.47 (m, 2 H) 1.49-1.70 (m, 4 H) 3.23 (q, J = 6.8 Hz, 2 H) 3.65 (t, J = 6.4 Hz, 2 H) 7.65 (br. S., 1 H).
MS ESI / APCI Dual posi: 189 [M + H] ⁺ , 211 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 187 [MH] ^- .
Reference Example A-16 Production of amine intermediate (4C-16)

Step 1 and Step 2
3- (Benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.80 g, 3.2 mmol, WO2004018491) and glycinamide hydrochloride (0.35 g, 3.2 mmol)) as starting materials, Based on the method described in Step 1 and Step 2 of Reference Example A-4, amine intermediate (4C-16) (0.49 g, 2 steps 89%) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.25 (s, 6 H) 2.88 (s, 2 H) 3.86 (s, 2 H).
MS ESI / APCI Dual posi: 174 [M + H] ⁺ , 196 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 172 [MH] ^- , 208 [M + Cl] ^- .
Reference Example A-17 Production of amine intermediate (4C-17)

Step 1 and Step 2
Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (1.0 g, 4.0 mmol, WO2004018491) and glycine methyl ester hydrochloride (0.79 g, 6.3 mmol) as starting materials, Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-17) (0.58 g, 2 steps 77%) was obtained.
¹ H NMR (300 MHz, DMSO-d ₆ ) δ ppm 1.03 (s, 6 H) 2.56 (s, 2 H) 3.62 (s, 3 H) 3.80 (d, J = 5.9 Hz, 2 H) 8.34-8.46 (m, 1 H).
MS ESI / APCI Dual posi: 189 [M + H] ⁺ .
MS ESI / APCI Dual nega: 187 [MH] ^- .
Reference Example A-18 Production of amine intermediate (4C-18)

Step 1 and Step 2
Reference example using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 3-aminopropanol (0.46 mL, 6.0 mmol) as starting materials Based on the method described in Step 1 and Step 2 of A-8, amine intermediate (4C-18) (0.30 g, 87% for 2 steps) was obtained as a colorless solid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.16 (s, 6 H) 1.61-1.71 (m, 2 H) 1.98 (br. S., 2 H) 2.79 (s, 2 H) 3.41 (s, 2 H) 3.55-3.61 (m, 2 H) 8.18 (br.s., 1 H).
MS ESI / APCI Dual posi: 175 [M + H] ⁺ , 197 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 209 [M + Cl] ^- .
Reference Example A-19 Production of amine intermediate (4C-19)

Step 1 and Step 2
Reference example using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 4-aminobutanol (0.56 mL, 6.0 mmol) as starting materials According to the method described in Steps 1 and 2 of A-8, an amine intermediate (4C-19) (0.23 g, 2 steps 61%) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.55-1.66 (m, 4 H) 2.78 (s, 2 H) 3.24-3.33 (m, 2 H) 3.64-3.72 (m , 2 H) 7.90 (br. S., 1 H).
MS ESI / APCI Dual posi: 189 [M + H] ⁺ , 211 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 187 [MH] ^- .
Reference Example A-20 Production of amine intermediate (4C-20)

Step 1 and Step 2
Reference was made using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and 5-aminopentanol (0.6 mg, 6.0 mmol) as starting materials. According to the method described in Step 1 and Step 2 of Example A-8, amine intermediate (4C-20) (0.36 g, 87% for 2 steps) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.34-1.47 (m, 2 H) 1.48-1.66 (m, 4 H) 2.77 (s, 2 H) 3.21-3.29 (m , 2 H) 3.64 (t, J = 6.4 Hz, 2 H) 7.80 (br.s., 1 H).
MS ESI / APCI Dual posi: 203 [M + H] ⁺ , 225 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 201 [MH] ^- .
Reference Example A-21 Production of amine intermediate (4C-21)

Step 1 and Step 2
Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and N, N-dimethylethylenediamine (0.66 mL, 6.0 mmol) as starting materials, Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-21) (0.34 g, 2 steps 91%) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.15 (s, 6 H) 2.24 (s, 6 H) 2.42 (t, J = 6.3 Hz, 2 H) 2.76 (s, 2 H) 3.29-3.37 ( m, 2 H) 7.45 (br.s., 1 H).
MS ESI / APCI Dual posi: 188 [M + H] ⁺ .
Reference Example A-22 Production of amine intermediate (4C-22)

Step 1 and Step 2
Using 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.50 g, 2.0 mmol, WO2004018491) and N, N-dimethylpropylenediamine (0.76 mL, 6.0 mmol) as starting materials Based on the method described in Step 1 and Step 2 of Reference Example A-8, an amine intermediate (4C-22) (0.23 g, 2 steps 59%) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 6 H) 1.60-1.72 (m, 2 H) 2.25 (s, 6 H) 2.40 (t, J = 6.5 Hz, 2 H) 2.76 ( s, 2 H) 3.32-3.37 (m, 2 H) 8.28 (br.s., 1 H).
MS ESI / APCI Dual posi: 202 [M + H] ⁺ .
Reference Example A-23 Production of amine intermediate (4C-23)

Step 1 and Step 2
3- (Benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.502 g, 2.00 mmol, WO2004018491) and 4- (dimethylamino) butylamine dihydrochloride (1.13 g, 6.00 mmol) Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-23) (0.375 g, 87% for 2 steps) was obtained as a colorless liquid. It was.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.13 (s, 6 H) 1.49-1.57 (m, 4 H) 2.00 (br. S., 2 H) 2.25 (s, 6 H) 2.30-2.38 ( m, 2 H) 2.76 (s, 2 H) 3.19-3.30 (m, 2 H) 7.98 (br. s., 1 H).
MS ESI / APCI Dual posi: 216 [M + H] ⁺ , 228 [M + Na] ⁺ .
Reference Example A-24 Production of amine intermediate (4C-24)

Step 1 and Step 2
Starting material: 3- (benzyloxycarbonylamino) -2,2-dimethylpropanoic acid (0.502 g, 2.00 mmol, WO2004018491) and 5- (dimethylamino) pentylamine (0.78 g, 6.00 mmol) Based on the method described in Step 1 and Step 2 of Reference Example A-8, amine intermediate (4C-24) (0.505 g, 2 steps 100%) was obtained as a colorless liquid.
¹ H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.14 (s, 6 H) 1.30-1.40 (m, 2 H) 1.45-1.59 (m, 4 H) 2.26 (s, 6 H) 2.27-2.35 (m , 2 H) 2.77 (s, 2 H) 3.19-3.26 (m, 2 H) 7.88 (br. S., 1 H).
MS ESI / APCI Dual posi: 230 [M + H] ⁺ .
MS ESI / APCI Dual nega: 228 [MH] ^- .
Reference Example A-25 Production of amine intermediate (4C-25)

Process 1
It is described in Step 1 of Reference Example A-7 using Boc-Aib-OH (3.00 g, 14.8 mmol) and 1-benzylpiperidin-4-amine (2.95 g, 15.5 mmol) as starting materials. According to the method, intermediate (4C-25a) (1.56 g, 28%) was obtained as colorless crystals.

Process 2
A chloroform solution (1.5 mL) of intermediate (4C-25a) (429 mg, 1.14 mmol) was cooled to 0 ° C., trifluoroacetic acid (1.5 mL) was slowly added, and the mixture was stirred at room temperature for 2 hours. Stir. The solvent was distilled off under reduced pressure to obtain the ditrifluoroacetate salt (574 mg, 100%) of the amine intermediate (4C-25).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.54 (s, 6 H) 1.77-1.86 (m, 2 H) 2.09-2.16 (m, 2 H) 3.09-3.16 (m, 2 H) 3.51- 3.57 (m, 2 H) 3.93-4.00 (m, 1 H) 4.31 (s, 2 H) 7.50 (s, 5 H).
MS ESI / APCI Dual posi: 276 [M + H] ⁺ , 298 [M + Na] ⁺ .
Reference Example A-26 Production of amine intermediate (4C-26)

Process 1
Reference Example A using 3-((tert-butoxycarbonyl) amino) -2,2-dimethylpropanoic acid (220 mg, 1.01 mmol) and 1-benzylpiperidin-4-amine (289 mg, 1.52 mmol) as starting materials According to the method described in Step 1 of -4, intermediate (4C-26a) (210 mg, 53%) was obtained as colorless crystals.

Process 2
Starting from intermediate (4C-26a) (184 mg, 0.472 mmol) as a starting material, ditrifluoromethane of amine intermediate (4C-26) was prepared according to the method described in Step 2 of Reference Example A-25. Acetic acid salt (244 mg, 100%) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.28 (s, 6 H) 1.75-1.85 (m, 2 H) 2.06-2.13 (m, 2 H) 3.00 (s, 2 H) 3.07-3.15 ( m, 2 H) 3.49-3.56 (m, 2 H) 3.92-4.00 (m, 1 H) 4.31 (s, 2 H) 7.50 (s, 5 H).
MS ESI / APCI Dual posi: 290 [M + H] ⁺ .
Example 1-1

Process 1
A chloroform solution (5 mL) of intermediate (1E-1) (145 mg, 0.182 mmol), 3-aminopropanol (16.5 mg, 0.219 mmol), NaBH (OAc) ₃ (46.3 mg, 0.219 mmol). Stir at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to obtain crude intermediate (1-1a) (102 mg).

Process 2
A methanol solution (2 mL) of intermediate (1-1a) (101 mg, 0.119 mmol) and sodium methoxide (4.88 M methanol solution, 0.242 mL, 1.19 mmol) was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (chloroform → chloroform: methanol = 7: 3) to obtain a colorless amorphous compound (1-1) (25 mg, 21% for 2 steps). .
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.5 Hz, 6 H) 1.29 (s, 6 H) 1.33 (s, 6 H) 1.55 (quin, J = 6.5 Hz, 2 H) 2.32 (s, 3 H) 2.59-2.65 (m, 4 H) 2.87-2.96 (m, 1 H) 3.37-3.41 (m, 2 H) 3.43-3.50 (m, 3 H) 3.52-3.57 (m , 1 H) 3.68 (dd, J = 12.2, 4.8 Hz, 1 H) 3.84 (dd, J = 12.2, 1.6 Hz, 1 H) 3.89 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H ) 6.34 (d, J = 16.1 Hz, 1 H) 6.49 (d, J = 16.1 Hz, 1 H) 6.74 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H ) 7.10 (d, J = 7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 643 [M + H] ⁺ , 675 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 641 [MH] ^- , 677 [M + Cl] ^- .
Example 1-2

Process 1
To a solution of intermediate (1E-1) (300 mg, 0.51 mmol) and 6-aminohexanamide (87 mg, 0.67 mmol) in methanol (5 mL), NaBH ₃ CN (42 mg, 0.67 mmol) was added, Stir overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 85: 15) to obtain an intermediate (1-2a) as a light brown amorphous (243 mg, 52%) was obtained.

Process 2
Based on the method described in Step 2 of Example 1-1, using Intermediate (1-2a) (243 mg, 0.27 mmol) as a starting material, colorless amorphous compound (1-2) (100 mg, 53%).
¹ H NMR (600 MHz, MEHTANOL-d ₄ ) δ ppm 1.07-1.15 (m, 6 H) 1.19-1.25 (m, 2 H) 1.29 (s, 6 H) 1.31-1.36 (m, 8 H) 1.45- 1.53 (m, 2 H) 2.12 (t, J = 7.6 Hz, 2 H) 2.32 (s, 3 H) 2.49 (t, J = 7.3 Hz, 2 H) 2.62 (s, 2 H) 2.87-2.94 (m , 1 H) 3.37-3.41 (m, 2 H) 3.46 (t, J = 8.9 Hz, 1 H) 3.53-3.59 (m, 1 H) 3.68 (dd, J = 12.2, 4.8 Hz, 1 H) 3.83- 3.87 (m, 1 H) 3.89 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.34 (d, J = 16.0 Hz, 1 H) 6.49 (d, J = 16.0 Hz, 1 H) 6.74 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.99 (s, 1 H) 7.10 (d, J = 7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 698 [M + H] ⁺ , 720 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 696 [MH] ^- , 732 [M + Cl] ^- .
Example 1-3

Process 1
A solution of intermediate (1E-1) (86 mg, 0.11 mmol), glycylglycinamide (18 mg, 0.14 mmol) and borane-2-picoline complex (15 mg, 0.14 mmol) in methanol-acetic acid (10: 1, 1.1 mL) was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 80: 20) to obtain intermediate (1-3a) (90 mg, 91%) as a colorless amorphous substance.

Process 2
A mixed suspension of intermediate (1-3a) (90 mg, 0.099 mmol) in triethylamine-water-methanol (1: 1: 5, 2 mL) was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate: ethanol: water = 10: 2: 1) to obtain a colorless amorphous compound (1-3) (44 mg, 64%). .
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.11 (d, J = 6.9 Hz, 6 H) 1.32 (s, 6 H) 1.35 (s, 6 H) 2.30 (s, 3 H) 2.69 (s , 2 H) 2.90-2.96 (m, 1 H) 3.24 (s, 2 H) 3.37-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.55 (t, J = 8.7 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.71 (d, J = 2.8 Hz, 2 H) 3.83-3.85 (m, 1 H) 3.89 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.5 Hz, 1 H) 6.51 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 699 [M + H] ⁺ , 721 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 697 [MH] ^- , 733 [M + Cl] ^- .

  The following Examples 1-4 to 1-25 and 1-27 to 1-40 are also used in Examples 1-1, 1-2, or 1-3 using the intermediate (1E-1) and the corresponding amine. Synthesis was performed according to any method described in the process. The structures, NMR data, and MS data of these compounds are shown in Table 1-1 to Table 1-10.

実施例１−４１

Example 1-41

Process 1
Using the intermediate (1E-1) (200 mg, 0.25 mmol) and 1- (ethoxycarbonylmethyl) piperazine (56 mg, 0.33 mmol) as starting materials, the method described in Step 1 of Example 1-1 was used. In conformity, intermediate (1-41a) (80 mg, 33%) was obtained as colorless amorphous.

Process 2
Intermediate (1-41a) (80 mg, 0.084 mmol), sodium ethoxide (20% ethanol solution, 0.17 mL) in ethanol (1 mL) was stirred at room temperature for 30 minutes. Acetic acid (0.058 mL, 1.0 mmol) was added to the reaction solution, the solvent was evaporated under reduced pressure, and the residue was subjected to NH silica gel column chromatography (ethyl acetate: ethanol: water = 30: 2: 1 → 7: 2). : 1) to obtain colorless amorphous compound (1-41) (8 mg, 10%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.11-1.15 (m, 6 H) 1.27 (t, J = 6.9 Hz, 3 H) 1.31 (s, 6 H) 1.33 (s, 6 H) 2.03 -2.25 (m, 4 H) 2.33 (s, 2 H) 2.34 (s, 3 H) 2.47 (br. S., 4 H) 2.70-2.78 (m, 2 H) 2.93-3.00 (m, 1 H) 3.34-3.39 (m, 2 H) 3.43-3.48 (m, 1 H) 3.51-3.56 (m, 1 H) 3.64-3.68 (m, 1 H) 3.82-3.92 (m, 3 H) 4.16 (q, J = 6.9 Hz, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.5 Hz, 1 H) 6.54 (d, J = 16.5 Hz, 1 H) 6.78 (d, J = 7.8 Hz, 1 H) 6.81 (s, 1 H) 6.99 (s, 1 H) 7.17 (d, J = 7.8 Hz, 1 H) 7.28 (s, 1 H).
MS ESI / APCI Dual posi: 740 [M + H] ⁺ , 762 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 738 [MH] ^- .

  Examples 1-42 to 1-57 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using the intermediate (1E-1) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 1-11 to 1-14.

実施例２−１

Example 2-1

Step 1 and Step 2
Using Intermediate (1E-2) (0.384 g, 0.492 mmol) and glycinamide hydrochloride (81.6 mg, 0.739 mmol) as starting materials, Step 1 of Example 1-2 and Example 1-3 In accordance with the method described in Step 2, a colorless amorphous compound (2-1) (133 mg, 43% in 2 steps) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.06-1.13 (m, 6 H) 1.35 (s, 6 H) 1.63-1.70 (m, 2 H) 2.30 (s, 3 H) 2.56 (t, J = 6.9 Hz, 2 H) 2.89-2.96 (m, 1 H) 3.16 (s, 2 H) 3.25 (t, J = 6.9 Hz, 2 H) 3.36-3.41 (m, 2 H) 3.43-3.48 (m , 1 H) 3.54 (t, J = 9.6 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.81-3.90 (m, 3 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.33 (d, J = 16.5 Hz, 1 H) 6.45 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 8.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.09 (d, J = 8.3 Hz, 1 H) 7.22 (s, 1 H).
MS ESI / APCI Dual posi: 628 [M + H] ⁺ , 650 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 626 [MH] ^- , 662 [M + Cl] ^- .

  The following Examples 2-2 to 2-12 were also prepared according to Examples 1-1, 1-2, or 1-3 using amines corresponding to Intermediate (1E-2) to Intermediate (1E-10). Synthesis was performed according to any method described in the process. The structures, NMR data, and MS data of these compounds are shown in Tables 2-1 to 2-3.

実施例３−１

Example 3-1

Process 1
A suspension of intermediate (1E-11) (150 mg, 0.17 mmol), acetic acid (11 μL, 0.19 mmol) and glycinamide hydrochloride (25 mg, 0.23 mmol) in N, N-dimethylformamide (2 mL) Stir at 70 ° C. for 30 minutes. After allowing to cool to room temperature, NaBH (OAc) ₃ (48 mg, 0.225 mmol) was added and stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, washed successively with water and saturated brine, and dried over sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 98: 2 → 91: 9) to give intermediate (3-1a) ( 131 mg, 82%).

Process 2
To a tetrahydrofuran solution of intermediate (3-1a) (130 mg, 0.14 mmol) was added 6M hydrochloric acid (140 μL, 0.85 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain Intermediate (3-1b) (150 mg).
Process 3
Based on the method described in Step 2 of Example 1-1, using Intermediate (3-1b) (150 mg) as a starting material, colorless amorphous compound (3-1) (82 mg, 53%) was obtained. Obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.09-1.13 (m, 6 H) 1.38 (s, 6 H) 2.30 (s, 3 H) 2.78 (s, 2 H) 2.90-2.96 (m, 1 H) 3.19 (s, 2 H) 3.36-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.51-3.56 (m, 1 H) 3.63-3.70 (m, 5 H) 3.84 (dd, J = 11.9, 1.4 Hz, 1 H) 3.89 (s, 2 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.0 Hz, 1 H) 6.55 (d, J = 16.0 Hz, 1 H) 6.76 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 674 [M + H] ⁺ , 696 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 708 [M + Cl] ^- .

  Examples 3-2 to 3-12 below are also described in the steps of Examples 1-1, 1-2, 1-3, or 3-1, using the intermediate (1E-11) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 3-1 to 3-3.

実施例４−１

Example 4-1

Step 1 and Step 2
Using Intermediate (1E-12) (300 mg, 0.392 mmol) and N, N-dimethylethylenediamine (51.8 mg, 0.588 mmol) as starting materials, steps 1 and 1-3 of Example 1-2 were used. Based on the method described in Step 2, colorless amorphous compound (4-1) (26.8 mg, 2 steps 11%) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.9 Hz, 6 H) 1.32 (s, 6 H) 2.17 (s, 6 H) 2.30 (s, 3 H) 2.38 (t , J = 6.6 Hz, 2 H) 2.67 (t, J = 6.6 Hz, 2 H) 2.77 (s, 2 H) 2.88-2.94 (m, 1 H) 3.05 (d, J = 7.3 Hz, 2 H) 3.36 -3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.52-3.56 (m, 1 H) 3.65-3.70 (m, 1 H) 3.84 (d, J = 12.4 Hz, 1 H) 3.88 (s , 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.25 (dt, J = 16.0, 7.3 Hz, 1 H) 6.45 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 7.8 Hz , 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.06 (d, J = 7.8 Hz, 1 H) 7.19 (s, 1 H).
MS ESI / APCI Dual posi: 628 [M + H] ⁺ , 650 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 626 [MH] ^- .

  Examples 4-2 to 4-16 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-12) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 4-1 to 4-5.

実施例５−１

Example 5-1

Step 1 and Step 2
Step 1 of Example 1-2 and Step of Example 1-3 using intermediate (1E-13) (135 mg, 0.174 mmol) and glycinamide hydrochloride (29.0 mg, 0.261 mmol) as starting materials In accordance with the method described in 2, a colorless amorphous compound (5-1) (46.7 mg, 43% for 2 steps) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.4 Hz, 6 H) 1.32 (s, 6 H) 1.91 (t, J = 7.8 Hz, 2 H) 2.30 (s, 3 H) 2.59 (t, J = 7.8 Hz, 2 H) 2.89-2.95 (m, 1 H) 3.03 (d, J = 7.3 Hz, 2 H) 3.17 (s, 2 H) 3.36-3.39 (m, 2 H ) 3.43-3.47 (m, 1 H) 3.54 (t, J = 9.4 Hz, 1 H) 3.65-3.70 (m, 1 H) 3.82-3.86 (m, 1 H) 3.88 (s, 2 H) 4.46 (d , J = 10.1 Hz, 1 H) 6.24 (dt, J = 16.0, 7.3 Hz, 1 H) 6.44 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 8.3 Hz, 1 H) 6.80 (s , 1 H) 6.95 (s, 1 H) 7.06 (d, J = 8.3 Hz, 1 H) 7.18 (s, 1 H).
MS ESI / APCI Dual posi: 628 [M + H] ⁺ , 650 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 626 [MH] ^- , 662 [M + Cl] ^- .

  Examples 5-2 to 5-4 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-13) and the corresponding amine. It was synthesized in accordance with the method. The structure, NMR data, and MS data of these compounds are shown in Table 5-1.

実施例６−１

Example 6-1

Step 1 and Step 2
Step 1 of Example 1-2 and Step of Example 1-3 using intermediate (1E-14) (300 mg, 0.379 mmol) and glycinamide hydrochloride (62.8 mg, 0.568 mmol) as starting materials In accordance with the method described in 2, colorless amorphous compound (6-1) (81.4 mg, 34% for 2 steps) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.9 Hz, 6 H) 1.60-1.76 (m, 6 H) 2.01 (m, 2 H) 2.29 (s, 3 H) 2.87 (s, 2 H) 2.92 (spt, J = 6.9 Hz, 1 H) 3.08 (d, J = 6.9 Hz, 2 H) 3.22 (s, 2 H) 3.36-3.41 (m, 2 H) 3.43-3.49 ( m, 1 H) 3.51-3.57 (m, 1 H) 3.67 (dd, J = 12.2, 4.8 Hz, 1 H) 3.81-3.90 (m, 3 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.22 -6.30 (m, 1 H) 6.45 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 7.3 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.06 (d, J = 7.3 Hz, 1 H) 7.19 (s, 1 H).
MS ESI / APCI Dual posi: 640 [M + H] ⁺ .
MS ESI / APCI Dual nega: 638 [MH] ^- , 674 [M + Cl] ^- .

  Examples 6-2 to 6-4 below are also any of those described in the steps of Examples 1-1, 1-2, or 1-3 using the intermediate (1E-14) and the corresponding amine. It was synthesized in accordance with the method. The structure, NMR data, and MS data of these compounds are shown in Table 6-1.

実施例７−１

Example 7-1

Step 1 and Step 2
Using the intermediate (1E-15) (200 mg, 0.24 mmol) and glycinamide hydrochloride (35 mg, 0.32 mmol) as starting materials, the method described in Step 1 and Step 2 of Example 1-1 was used. Based on this, a colorless amorphous compound (7-1) (67 mg, 42% for 2 steps) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 0.88 (t, J = 7.6 Hz, 6 H) 1.09-1.13 (m, 6 H) 1.33 (s, 6 H) 1.75-1.83 (m, 4 H 2.31 (s, 3 H) 2.65 (s, 2 H) 2.90-2.97 (m, 1 H) 3.18 (s, 2 H) 3.36-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.52 -3.57 (m, 1 H) 3.65-3.70 (m, 1 H) 3.82-3.86 (m, 1 H) 3.89 (s, 2 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.31 (d, J = 16.5 Hz, 1 H) 6.48 (d, J = 16.5 Hz, 1 H) 6.77 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] ⁺ , 692 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 668 [MH] ^- , 704 [M + Cl] ^- .

  Example 7-2 below is one of the methods described in the steps of Examples 1-1, 1-2, 1-3 using intermediate (1E-16) and glycinamide hydrochloride. Example 7-3 described in the steps of Example 1-1, 1-2, 1-3 or 3-1 using intermediate (1E-17) and glycinamide hydrochloride. It was synthesized according to any of the methods described. Table 7-1 shows the structures, NMR data, and MS data of these compounds.

実施例８−１

Example 8-1

Step 1 and Step 2
Using Intermediate (1E-18) (150 mg, 0.196 mmol) and N, N-dimethylethylenediamine (26.0 mg, 0.294 mmol) as starting materials, steps 1 and 1-3 of Example 1-1 were used. Based on the method described in Step 2, colorless amorphous compound (8-1) (77.1 mg, 2 steps 61%) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.15 (d, J = 6.4 Hz, 6 H) 1.30 (s, 6 H) 1.33 (s, 6 H) 2.10 (s, 6 H) 2.20 (t , J = 6.4 Hz, 2 H) 2.34 (s, 3 H) 2.58-2.63 (m, 4 H) 2.94-3.02 (m, 1 H) 3.34-3.39 (m, 2 H) 3.43-3.49 (m, 1 H) 3.48-3.54 (m, 1 H) 3.59-3.66 (m, 1 H) 3.80-3.88 (m, 4 H) 3.92 (s, 2 H) 4.61 (d, J = 9.6 Hz, 1 H) 6.35 ( d, J = 16.0 Hz, 1 H) 6.50 (d, J = 16.0 Hz, 1 H) 6.73 (d, J = 7.8 Hz, 1 H) 6.93 (s, 1 H) 7.08 (s, 1 H) 7.11 ( d, J = 7.8 Hz, 1 H) 7.26 (s, 1 H).
MS ESI / APCI Dual posi: 671 [M + H] ⁺ , 693 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 669 [MH] ^- , 705 [M + Cl] ^- .

  Examples 8-2 to 8-31 below are also described in the steps of Example 1-1, 1-2, 1-3 or 1-41 using the intermediate (1E-18) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 8-1 to 8-9.

実施例９−１

Example 9-1

Step 1 and Step 2
Using Intermediate (1E-19) (100 mg, 0.136 mmol) and N, N-dimethylethylenediamine (0.044 mL, 0.407 mmol) as starting materials, Step 1 of Example 1-2 and Example 1-3 Based on the method described in Step 2, a colorless amorphous compound (9-1) (5.0 mg, 2 steps 7%) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.14 (d, J = 6.4 Hz, 6 H) 1.32 (s, 6 H) 2.18 (s, 6 H) 2.32 (s, 3 H) 2.39 (t , J = 6.6 Hz, 2 H) 2.68 (t, J = 6.6 Hz, 2 H) 2.78 (s, 2 H) 2.95-2.99 (m, 1 H) 3.06 (d, J = 6.9 Hz, 2 H) 3.32 -3.38 (m, 2 H) 3.43-3.48 (m, 1 H) 3.48-3.54 (m, 1 H) 3.59-3.64 (m, 1 H) 3.80-3.86 (m, 4 H) 3.91 (s, 2 H ) 4.61 (d, J = 9.6 Hz, 1 H) 6.26 (dt, J = 16.5, 6.9 Hz, 1 H) 6.45 (d, J = 16.0 Hz, 1 H) 6.71 (d, J = 7.8 Hz, 1 H) ) 6.92 (s, 1 H) 7.06 (d, J = 7.8 Hz, 1 H) 7.08 (s, 1 H) 7.20 (s, 1 H).
MS ESI / APCI Dual posi: 642 [M + H] ⁺ , 664 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 640 [MH] ^- , 676 [M + Cl] ^- .

  Examples 9-2 to 9-15 below are also described in the steps of Examples 1-1, 1-2, 1-3 or 1-41 using the intermediate (1E-19) and the corresponding amine. It was synthesized according to any method. The structures, NMR data, and MS data of these compounds are shown in Tables 9-1 to 9-5.

実施例１０−１

Example 10-1

Step 1 and Step 2
Using Intermediate (1E-20) (0.329 g, 0.422 mmol) and glycinamide hydrochloride (60.6 mg, 0.548 mmol) as starting materials, Step 1 and Example 1-3 of Example 1-1 In accordance with the method described in Step 2, a colorless amorphous compound (10-1) (21.6 mg, 12% for 2 steps) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10-1.17 (m, 3 H) 1.15 (d, J = 6.6 Hz, 3 H) 1.25-1.39 (m, 12 H) 1.80 (t, J = 7.3 Hz, 2 H) 2.32 (s, 3 H) 2.59 (t, J = 7.3 Hz, 2 H) 2.94-3.03 (m, 1 H) 3.08 (s, 2 H) 3.31-3.38 (m, 2 H) 3.43-3.48 (m, 1 H) 3.49-3.54 (m, 1 H) 3.62 (dd, J = 11.9, 5.5 Hz, 1 H) 3.80-3.86 (m, 4 H) 3.91 (s, 2 H) 4.61 ( d, J = 9.2 Hz, 1 H) 6.34 (d, J = 16.5 Hz, 1 H) 6.46 (d, J = 16.5 Hz, 1 H) 6.73 (d, J = 7.8 Hz, 1 H) 6.92 (s, 1 H) 7.04-7.12 (m, 2 H) 7.23 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] ⁺ , 692 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 704 [M + Cl] ^- .

  Examples 10-2 to 10-5 below are also described in the steps of Examples 1-1, 1-2, or 1-3 using the intermediate (1E-20) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 10-1 to 10-2.

実施例１１−１

Example 11-1

Step 1 and Step 2
Using the intermediate (1E-21) (175 mg, 0.22 mmol) and glycinamide hydrochloride (32 mg, 0.29 mmol) as starting materials, the method described in Step 1 and Step 2 of Example 1-1 was used. Based on the above, colorless amorphous compound (11-1) (80 mg, 56% in 2 steps) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10-1.16 (m, 6 H) 1.30 (s, 6 H) 1.35 (s, 6 H) 1.41 (t, J = 6.9 Hz, 3 H) 2.32 (s, 3 H) 2.66 (s, 2 H) 2.95-3.02 (m, 1 H) 3.18 (s, 2 H) 3.33-3.38 (m, 2 H) 3.45 (t, J = 8.7 Hz, 1 H) 3.55-3.64 (m, 2 H) 3.83 (dd, J = 11.9, 1.8 Hz, 1 H) 3.92 (s, 2 H) 4.05-4.13 (m, 2 H) 4.59 (d, J = 9.6 Hz, 1 H ) 6.37 (d, J = 16.5 Hz, 1 H) 6.50 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 7.8 Hz, 1 H) 6.91 (s, 1 H) 7.05 (s, 1 H ) 7.11 (d, J = 7.8 Hz, 1 H) 7.24 (s, 1 H).
MS ESI / APCI Dual posi: 670 [M + H] ⁺ , 692 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 668 [MH] ^- , 704 [M + Cl] ^- .

  The following Examples 11-2 and 11-3 were also prepared using Examples 1-1, 1-2, or 1-, using Intermediate (1E-22), Intermediate (1E-23), and glycinamide / hydrochloride. Synthesis was performed according to any method described in the step 3. The structure, NMR data, and MS data of these compounds are shown in Table 11-1.

実施例１２−１

Example 12-1

Step 1 and Step 2
Using Intermediate (1E-24) (150 mg, 0.187 mmol) and N, N-dimethylethylenediamine (22 mg, 0.243 mmol) as starting materials, Step 1 of Example 1-1 and Step 2 of Example 1-3 The colorless amorphous compound (12-1) (22 mg, 17% for 2 steps) was obtained according to the method described in 1).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.12-1.17 (m, 6 H) 1.30 (s, 6 H) 1.33 (s, 6 H) 2.11 (s, 6 H) 2.22 (t, J = 6.6 Hz, 2 H) 2.32 (s, 3 H) 2.58-2.64 (m, 4 H) 3.02 (spt, J = 6.7 Hz, 1 H) 3.33-3.39 (m, 1 H) 3.42-3.47 (m, 1 H) 3.55-3.64 (m, 3 H) 3.85 (dd, J = 11.9, 2.3 Hz, 1 H) 3.98 (s, 2 H) 4.42 (d, J = 9.6 Hz, 1 H) 6.36 (d, J = 16.0 Hz, 1 H) 6.50 (d, J = 16.0 Hz, 1 H) 6.58-6.85 (m, 2 H) 7.08-7.18 (m, 3 H) 7.27 (s, 1 H).
MS ESI / APCI Dual posi: 706 [M + H] ⁺ , 728 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 704 [MH] ^- , 740 [M + Cl] ^- .

  Examples 12-2 to 12-20 below are also any of those described in the steps of Examples 1-1, 1-2 or 1-3 using the intermediate (1E-24) and the corresponding amine. It was synthesized in accordance with the method. The structures, NMR data, and MS data of these compounds are shown in Tables 12-1 to 12-6.

実施例１３−１

Example 13-1

Process 1
To a solution of intermediate (2C-1) (0.150 g, 0.225 mmol) and triethylamine (42.0 μL, 0.338 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (16 μL, 0.247 mmol), and 40 After stirring at ° C for 2 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in N, N-dimethylformamide (5 mL), amine intermediate (4C-10) (104 mg, 0.601 mmol) was added, and the mixture was stirred at 100 ° C. overnight. After evaporating the solvent under reduced pressure, the residue was roughly purified by NH silica gel column chromatography (ethyl acetate) to obtain an intermediate (13-1a).

Process 2
To a chloroform (1.0 mL) solution of intermediate (13-1a) was added trifluoroacetic acid (42 mg, 0.367 mmol) at room temperature, and the mixture was stirred at 50 ° C. for 4 hours, and then the reaction mixture was concentrated under reduced pressure. This residue was dissolved in methanol (1 mL), sodium methoxide (4.88 M methanol solution, 72.5 μL, 0.354 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The reaction solution was purified by preparative HPLC (Waters Sunfire 19 × 150 mm 5 μm, rate: 20 ml / min, element: A = acetonitrile, B = 0.1% trifluoroacetic acid aqueous solution, gradient: 10-90%) Compound (13-1) (2.2 mg, 1.5%) was obtained.
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.06-1.12 (m, 6 H) 1.34 (s, 6 H) 1.67 (s, 6 H) 2.32-2.35 (m, 3 H) 2.85-2.95 ( m, 1 H) 3.36-3.40 (m, 2 H) 3.42 (s, 2 H) 3.46 (s, 1 H) 3.50-3.56 (m, 1 H) 3.64-3.70 (m, 1 H) 3.78 (d, J = 7.3 Hz, 1 H) 3.82-3.87 (m, 1 H) 3.91 (s, 2 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.18-6.26 (m, 1 H) 6.77-6.84 (m , 3 H) 6.97 (s, 1 H) 7.15 (dd, J = 7.8, 1.4 Hz, 1 H) 7.27 (s, 1 H).
MS ESI / APCI Dual posi: 614 [M + H] ⁺ , 636 [M + Na] ⁺

  The following Examples 13-2 to 13-4 were also synthesized in accordance with the method described in the step of Example 13-1, using the intermediate (2C-1) and the corresponding amine. The structures, NMR data and MS data of these compounds are shown in Table 13-1.

実施例１４−１

Example 14-1

Process 1
A solution of intermediate (2E-1) (0.206 g, 0.270 mmol) and amine intermediate (4C-10) (0.225 g, 0.840 mmol) in N, N-dimethylformamide (1 mL) at 90 ° C. Stir for 5 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, 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. The desiccant was filtered off and concentrated under reduced pressure. The residue was subjected to silica gel chromatography twice (first time: chloroform: methanol = 90: 10 → 82: 12, second time: ethyl acetate: hexane = 50: 50 → 100: 0) Purification gave intermediate (14-1a) (55 mg, 22%).

Process 2
To a solution of intermediate (14-1a) (55 mg, 0.059 mmol) in chloroform (0.7 mL) was added trifluoroacetic acid at room temperature, and the mixture was stirred overnight at the same temperature. The reaction mixture was concentrated under reduced pressure. This residue was dissolved in methanol (1 mL), sodium methoxide (4.88 M methanol solution, 72.5 μL, 0.354 mmol) was added at room temperature, and the mixture was stirred for 2 hours. Acetic acid (40.5 μL, 0.708 mmol) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was subjected to NH silica gel chromatography twice (first time: chloroform: methanol = 95: 5 → 75: 25, 2nd: ethyl acetate: ethanol: water = 30: 2: 1 → 9: 2: 1) Purification was carried out to obtain colorless amorphous compound (14-1) (26 mg, 70%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.01 (s, 6 H) 1.08-1.12 (m, 6 H) 1.30 (s, 6 H) 2.30 (s, 3 H) 2.33-2.40 (m, 2 H) 2.60 (t, J = 6.7 Hz, 2 H) 2.89-2.96 (m, 1 H) 3.09 (s, 2 H) 3.35-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.51 -3.56 (m, 1 H) 3.64-3.70 (m, 1 H) 3.81-3.90 (m, 3 H) 4.47 (d, J = 9.6 Hz, 1 H) 6.16-6.26 (m, 1 H) 6.40 (d , J = 15.6 Hz, 1 H) 6.72 (d, J = 8.3 Hz, 1 H) 6.80 (s, 1 H) 6.96 (s, 1 H) 7.05 (d, J = 8.3 Hz, 1 H) 7.18 (s , 1 H).
MS ESI / APCI Dual posi: 628 [M + H] ⁺ , 650 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 626 [MH] ^- , 662 [M + Cl] ^- .

  The following Examples 14-2 to 14-16 were also synthesized according to the method described in the step of Example 14-1 using the amine corresponding to the intermediate (2E-1). The structures, NMR data, and MS data of these compounds are shown in 14-1 to 14-5.

実施例１５−１

Example 15-1

Process 1
In accordance with the method described in Step 1 of Reference Example 12, starting from intermediate (3A-1) (250 mg, 0.309 mmol) and 3-aminopropanol (53 mg, 0.711 mmol), colorless amorphous Intermediate (15-1a) (182 mg, 68%) was obtained.

Process 2
According to the method described in Step 2 of Example 1-3, using Intermediate (15-1a) (182 mg, 0.210 mmol) as a starting material, colorless amorphous compound (15-1) (80 mg, 58%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (d, J = 6.9 Hz, 6 H) 1.36 (s, 6 H) 1.46 (s, 6 H) 1.63-1.70 (m, 2 H) 2.32 (s, 3 H) 2.90-2.94 (m, 1 H) 3.26 (t, J = 6.9 Hz, 2 H) 3.37-3.40 (m, 2 H) 3.43-3.48 (m, 1 H) 3.52-3.58 (m , 3 H) 3.68 (dd, J = 12.2, 5.3 Hz, 1 H) 3.82-3.86 (m, 1 H) 3.89 (s, 2 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.38 (d, J = 16.5 Hz, 1 H) 6.50 (d, J = 16.5 Hz, 1 H) 6.75 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.97 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.25 (s, 1 H).
MS ESI / APCI Dual posi: 657 [M + H] ⁺ , 679 [M + Na] ⁺ .
MS ESI / APCI Dual nega: 655 [MH] ^- , 691 [M + Cl] ^- .

  The following Examples 15-2 to 15-5 were also synthesized in accordance with the method described in the step of Example 15-1, using the amine corresponding to the intermediate (3A-1). The structures, NMR data, and MS data of these compounds are shown in Table 15-1.

実施例１６−１

Example 16-1

Process 1

  To a tetrahydrofuran solution (2.8 mL) of intermediate (1C-1) (1.00 g, 1.38 mmol), 0.91 M borane-tetrahydrofuran complex (1.7 mL, 1.52 mmol) was added dropwise at −40 ° C. After raising the reaction temperature to 0 ° C., the mixture was stirred at the same temperature for 1 hour, and methanol was added to the reaction solution. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane = 65: 35 → 35: 65) to obtain intermediate (16-1a) (0.228 g, 23%). .

Process 2
To a solution of intermediate (16-1a) (0.237 g, 0.334 mmol), 3-amino-2,2-dimethylpropanamide (58.2 mg, 0.501 mmol, WO200401849) in chloroform (1.6 mL) was added NaBH ( OAc) ₃ (212 mg, 1.00 mmol) was added at room temperature and stirred at the same temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was filtered off and concentrated under reduced pressure. This residue was dissolved in methanol (1 mL), sodium methoxide (4.88 M methanol solution, 0.41 mL, 2.0 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. Acetic acid (229 μL, 4.01 mmol) was added to the reaction solution, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel chromatography (ethyl acetate: ethanol: water = 30: 2: 1 → 10: 2: 1). To obtain a pale yellow amorphous compound (16-1) (86 mg, 43%).
¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10 (s, 6 H) 1.23 (s, 6 H) 1.24 (s, 6 H) 2.30 (s, 3 H) 2.89 (s, 2 H) 2.89 -2.95 (m, 1 H) 2.95 (s, 2 H) 3.35-3.42 (m, 2 H) 3.46 (t, J = 8.9 Hz, 1 H) 3.51-3.56 (m, 1 H) 3.64-3.70 (m , 1 H) 3.81-3.91 (m, 3 H) 4.46 (d, J = 9.6 Hz, 1 H) 6.19 (d, J = 16.5 Hz, 1 H) 6.45 (d, J = 16.5 Hz, 1 H) 6.74 (d, J = 7.8 Hz, 1 H) 6.80 (s, 1 H) 6.95 (s, 1 H) 7.11 (d, J = 7.8 Hz, 1 H) 7.22 (s, 1 H).
MS ESI posi: 599 [M + H] ⁺ .

Test example 1
(1) Production of CHO-K1 cells stably expressing human SGLT1 Plasmid vectors expressing human SGLT1 protein were transfected into CHO-K1 cells using Lipofectamine 2000 (Invitrogen). SGLT1-expressing cells were cultured in the presence of geneticin at a concentration of 500 μg / mL, resistant strains were selected, and sugar uptake ability was obtained as an index by the system shown below.

(2) Sodium-dependent glucose uptake inhibition test in stably expressing cells The stably expressed cells were used in a sodium-dependent glucose uptake activity inhibition test.
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) was added to the stably expressing cells and incubated for 20 minutes. The pretreatment buffer is removed and the uptake buffer containing the test compound ([ ¹⁴ C] methyl α-D-glucopyranoside containing methyl α-D-glucopyranoside (1 mM), 145 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 60 minutes (SGLT2). After the reaction, the cells were washed twice with a 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) and 0.25 M. Dissolved in NaOH solution. After adding a liquid scintillator (Perkin Elmer) and mixing well, the radioactivity was measured using a β ray measuring apparatus. 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.
In determining the IC ₅₀ value, the test compound concentration (IC ₅₀ value) at which the sugar uptake amount was inhibited by 50% relative to the sugar uptake amount (100%) of the control group was calculated using appropriate 6 concentrations of the test compound. . The test results are shown in Tables 17-1 to 17-3.

  The inhibitory activity of the compound of the present invention against human SGLT2 can be confirmed according to the method of Test Example 2 below.

Test example 2
(1) Preparation of CHO-K1 cells that stably express human SGLT2 and sodium-dependent sugar uptake inhibition test in stably expressing cells A plasmid vector that expresses human SGLT2 protein was CHO using Lipofectamine LTX (Invitrogen). -Transfect K1 cells. SGLT2-expressing cells can be obtained by culturing in the presence of geneticin at a concentration of 1000 μg / mL, selecting a resistant strain, and using the system shown in (2) of Test Example 1 as an index, the sugar uptake ability.

  In addition, the superiority of the compound of the present invention over the prior art compound (the compound described in WO2007 / 136116) is shown from the persistence of the drug in the body. In the C-phenyl glucitol derivative described in the above document, the drug tends to remain in the kidney. The drug concentration in the kidney can be confirmed according to the method of Test Example 3 below.

Test example 3
(1) Renal concentration after repeated oral administration of the compound of the present invention for 3 days A 7-week-old SD / IGS rat (Nippon Charles River Co., Ltd., male, non-fasted) was prepared in 0.5% CMC aqueous solution. The compound of the present invention (3 mg / kg) is orally administered once a day for 3 consecutive days. At 48 hours after drug administration on the final day, whole blood is collected from the posterior vena cava under isoflurane anesthesia, and the kidney is removed after confirmation of euthanasia. After washing the tissue surface with physiological saline, weigh it, add 4 times the amount of purified water, and homogenize under ice cooling. After deproteinization by adding an acetonitrile / methanol solution containing an internal standard substance to the homogenate, the supernatant is subjected to LC-MS / MS (Applied Biosystems API 3000). It is possible to detect drug-derived ions generated by electrospray ionization in positive ion mode by selective reaction monitoring, and calculate the drug concentration in the homogenate from the peak area of the extracted ion chromatogram obtained by the internal standard method. it can.

  According to the present invention, a postprandial hyperglycemia-improving drug having strong SGLT1 inhibitory activity can be provided, and by inhibiting SGLT1 activity, contributing to effective treatment / prevention for diseases derived from postprandial hyperglycemia, It contributes to the promotion of health and the development of a healthy pharmaceutical industry.

Claims (7)

4-Isopropylphenyl glucitol compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:

Where
R ¹ is a hydrogen atom or a “C _1-4 alkyl group _optionally substituted with a hydroxyl group or a halogen atom”;
R ² and R ³ are the same or different and are a hydrogen atom, a methyl group, an ethyl group or a hydroxymethyl group,
Or R ² and R ³ together with the adjacent carbon atom form a C _3-6 cycloalkyl group,
R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a methyl group or a hydroxymethyl group,
Or R ⁴ and R ⁵ together with the adjacent carbon atom form a C _3-6 cycloalkyl group or a C _4-6 heterocyclyl group;
n is 0 or 1;
R ⁶ is a hydrogen atom, “piperidyl group optionally substituted with a benzyl group” or “same or different, hydroxyl group, amino group, carbamoyl group, ureido group, C _2-7 alkoxycarbonyl group, C _1-6 alkylamino group A carbonyl group (the C _1-6 alkylaminocarbonyl group is substituted with 1 to 3 groups selected from an amino group, a C _2-7 alkoxycarbonyl group, a carbamoyl group, a diC _1-4 alkylamino group or a hydroxyl group; C _2-7 alkanoylamino group (the C _2-7 alkanoylamino group may be substituted with an amino group), C _1-6 alkylsulfonylamino group, diC _1-4 alkylamino group, A phenyl group (the phenyl group may be substituted with a hydroxyl group), a pyridyl group or a C _1-6 alkyl group substituted with 1 to 3 groups selected from a piperidyl group;
R ⁷ is a hydrogen atom or a C _1-4 alkyl group,
Or R ⁶ and R ⁷ together with an adjacent nitrogen atom are a “C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with a C _2-7 alkoxycarbonyl group or a hydroxyl group), a carbamoyl group or A piperazinyl group which may be substituted with one group selected from a C _2-7 alkanoyl group (the C _2-7 alkanoyl group may be substituted with an amino group) or a hydroxyl group, a carbamoyl group, a ureido group, Di-C _1-4 alkylamino group, morpholino group, C _2-7 alkoxycarbonyl group, C _1-6 alkylsulfonylamino group, C _1-6 alkylamino group (the C _1-6 alkylamino group is an amino group, A carbamoyl group, which may be substituted with a di-C _1-4 alkylamino group), a C _2-7 alkanoylamino group (the C _2-7 alkanoylamino group may be substituted with an amino group) or C _1-6 Alkylamino Ruboniruamino group (wherein the C _1-6 alkylaminocarbonyl amino group may be substituted with 1 to 3 hydroxyl groups) to form one may piperidino group which may be substituted with a group "chosen from,
W represents a single bond, a methylene group (CH ₂ ) or a carbonyl group (C═O),
Y represents a C _1-4 alkylene group or a carbonyl group (C═O). The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein W represents a single bond or a methylene group (CH ₂ ):
However, in the formula:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , n and Y are as defined in claim 1. The 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein W represents a carbonyl group (C = O):
However, in the formula:
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , n and Y are as defined in claim 1.   A sodium-dependent glucose cotransporter 1 (SGLT1) activity inhibitor comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.   The postprandial hyperglycemia improving drug which contains the 4-isopropylphenyl glucitol compound or its pharmaceutically acceptable salt of Claims 1-3 as an active ingredient.   A prophylactic or therapeutic agent for diabetes comprising the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.   Use of the 4-isopropylphenyl glucitol compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the manufacture of a medicament for preventing or treating diabetes.