WO2009096503A1 - Dérivé de benzylphényl-glucopyranoside - Google Patents

Dérivé de benzylphényl-glucopyranoside Download PDF

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Publication number
WO2009096503A1
WO2009096503A1 PCT/JP2009/051532 JP2009051532W WO2009096503A1 WO 2009096503 A1 WO2009096503 A1 WO 2009096503A1 JP 2009051532 W JP2009051532 W JP 2009051532W WO 2009096503 A1 WO2009096503 A1 WO 2009096503A1
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Prior art keywords
mmol
deoxy
phenyl
fluoro
hydroxymethyl
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PCT/JP2009/051532
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English (en)
Japanese (ja)
Inventor
Shigeo Yamanoi
Kazuki Mori
Mitsuhiro Iwamoto
Atsuko Nakashima
Takeshi Honda
Masanori Izumi
Tsuneaki Ogata
Ryo Okuyama
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Daiichi Sankyo Company, Limited
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Publication of WO2009096503A1 publication Critical patent/WO2009096503A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a compound having a human SGLT1 and / or SGLT2 activity inhibitory action.
  • Diabetes is a group of metabolic diseases characterized mainly by chronic hyperglycemia due to insufficient insulin action.
  • pharmacotherapy is given along with diet therapy and exercise therapy.
  • Diabetes treatment drugs include biguanides and thiazolidinediones that improve insulin resistance, sulfonylureas and glinides that promote insulin secretion from pancreatic ⁇ cells.
  • Systemic drugs, ⁇ -glucosidase inhibitors that inhibit sugar absorption, and the like are used.
  • Non-Patent Document 1 In recent years, research and development of drugs with a new mechanism that increases glucose excretion in urine and lowers blood glucose levels by inhibiting glucose reabsorption in the kidney has been promoted (for example, Non-Patent Document 1) reference).
  • This drug inhibits the reabsorption of sugar from raw urine by inhibiting sodium-dependent glucose transporter 2 (hereinafter referred to as SGLT2) present in the proximal tubule of the kidney It has been shown that blood glucose levels are reduced by suppressing and increasing the excretion of sugar outside the body (see, for example, Non-Patent Document 2).
  • SGLT2 sodium-dependent glucose transporter 2
  • compounds that inhibit human SGLT2 are expected to normalize blood glucose levels by increasing urinary glucose excretion and are associated with various types of diabetes associated with type 1 and type 2 diabetes and hyperglycemia It becomes an effective drug for diseases.
  • anti-obesity effect is expected by reducing sugar accumulation in the body by increasing sugar excretion.
  • SGLT1 another subtype of SGLT (Sodium-dependent glucose cotransporter 1: hereinafter referred to as SGLT1), is expressed mainly in the small intestine and is a transporter that absorbs sugar (glucose, galactose) from food.
  • SGLT1 sodium-dependent glucose cotransporter 1
  • SGLT1 sodium-dependent glucose cotransporter 1
  • drugs that suppress human SGLT1 and / or SGLT2 activity are potent type 1 and type 2 diabetes mellitus drugs, anti-obesity drugs, high anti-obesity drugs that have both urinary glucose excretion-increasing activity and glucose absorption inhibition activity from the small intestine. It is expected to be an effective drug for various related diseases accompanying blood glucose.
  • O-aryl glucoside compounds have human SGLT2 inhibitory activity (see, for example, Patent Documents 1 to 5).
  • Patent Documents 1 to 4 describes a compound having a substituent in the sugar moiety, and further describes or suggests that such a compound has a human SGLT1 inhibitory action. Absent.
  • Patent Document 5 discloses a compound having a substituent in the sugar moiety and also describes that it has an SGLT1 inhibitory action. However, it is a patent document filed before the priority date of the present application and published after the priority date. is there.
  • the present invention provides a compound having a novel structure and excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects or a hydrate thereof, type 1 diabetes, type 2 diabetes containing them as active ingredients Gestational diabetes, hyperglycemia due to other factors, impaired glucose tolerance (IGT), diabetes related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver) Metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc. or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection)
  • ITT impaired glucose tolerance
  • diabetes related diseases eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver
  • Metabolic syndrome edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.
  • R 1 is a hydrogen atom or a hydroxyl group
  • R 2 is a fluorine atom or a chlorine atom
  • R 3 is a methyl group optionally substituted with a halogen atom, an ethyl group optionally substituted with a halogen atom, a cyclopropyl group, or a methoxy group optionally substituted with a halogen atom
  • R 4 is a hydrogen atom or a methyl group, n is 1 or 2, m is 0 or 1;
  • R 1 is a hydrogen atom
  • R 4 is a hydrogen atom, and when R 1 is a hydroxyl group, R 4 is a methyl group.
  • R 1 is a hydrogen atom or a hydroxyl group
  • R 2 is a fluorine atom or a chlorine atom
  • R 3 is a methyl group optionally substituted with a halogen atom, an ethyl group optionally substituted with a halogen atom, a cyclopropyl group, or a methoxy group optionally substituted with a halogen atom
  • R 4 is a hydrogen atom or a methyl group, n is 1 or 2, m is 0 or 1;
  • R 1 is a hydrogen atom
  • R 4 is a hydrogen atom
  • R 4 is a methyl group
  • R 4 is a methyl group
  • R 1 is a hydroxyl group
  • R 4 is a methyl group
  • R 3 is not a methyl group, an ethyl group, a cyclopropyl group or a methoxy group
  • R 3 is not a methyl group, an ethyl group,
  • a method for inhibiting human SGLT1 and / or human SGLT2 activity comprising administering to a mammal a therapeutically effective amount of the compound or hydrate thereof according to any one of (1) to (7) above
  • (17) A method for treating or preventing a disease comprising administering to a mammal a therapeutically effective amount of the compound or hydrate thereof according to any one of (1) to (7) above
  • Diabetes-related diseases are obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, high uric acid
  • the diabetic complication is retinopathy, nephropathy, neuropathy, cataract, foot gangren
  • a compound or hydrate thereof having excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects.
  • these compounds or hydrates thereof are used as active ingredients, and type 1 diabetes, type 2 diabetes, gestational diabetes, hyperglycemia due to other factors, glucose intolerance, diabetes related diseases (for example, Obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia, gout, etc.) or Pharmaceutical compositions for treating and / or preventing diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) can be provided.
  • diabetic complications eg, retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • Table 1 shows preferred combinations of R 1 , R 2 , R 3 , R 4 , n and m in the general formula (I) or (II).
  • hydrate refers to a pharmaceutically acceptable hydrate of the compound of the present invention.
  • the compound of the present invention When the compound of the present invention is left in the air or recrystallized, it may absorb moisture and attach adsorbed water or become a hydrate. Such hydrates are also included in the “hydrate” in the present specification.
  • the compound of the present invention has an asymmetric carbon atom in the molecule, these isomers in which optical isomers exist, and mixtures of these isomers are all represented by a single formula, that is, the general formula (I) or It is represented by (II). Accordingly, the present invention includes all optical isomers and mixtures of optical isomers in an arbitrary ratio.
  • the compound (I) or (II) of the present invention can be produced, for example, according to Method A described later.
  • the target compound of each reaction is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insolubles are present, after removing by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the organic layer containing the target compound is separated, After washing with water or the like and drying with anhydrous sodium sulfate or the like, the solvent is distilled off. If necessary, the obtained compound can be separated and purified by a conventional method such as silica gel column chromatography.
  • the compound serving as a reaction substrate has a group that inhibits a desired reaction such as an amino group, a hydroxy group, or a carboxyl group
  • a protecting group may be introduced into the group and the introduced protecting group may be removed.
  • the protecting group is not particularly limited as long as it is a commonly used protecting group.For example, T. H. Greene, P. G. Wuts, Protective Groups in Organic Synthesis. Third Edition, ion1999, John Wiley & Sons, The protecting group described in Inc. etc. is mentioned.
  • Such protecting group introduction reaction and removal reaction can be carried out according to a conventional method such as the method described in the above-mentioned literature.
  • R 1 , R 2 , R 3 , R 4 , n and m are as defined above, and R 11 , R 12 and R 13 are the same or different and are a hydrogen atom or a protecting group.
  • Step A1 is a step for producing compound (2), and is performed by reacting compound (1) with trichloroacetonitrile in the presence of a base in an inert solvent.
  • Examples of the inert solvent used in the above reaction include halogenated hydrocarbons and ethers, preferably halogenated hydrocarbons, more preferably methylene chloride.
  • Examples of the base used in the above reaction include organic amines, and preferably 1,8-diazabicyclo [5.4.0] -7-undecene.
  • the reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is usually -20 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature, etc., but is usually 15 minutes to 48 hours, preferably 30 minutes to 5 hours.
  • Step A2 is a step for producing compound (I). After reacting compound (2) with compound (3) in the presence of a Lewis acid in an inert solvent, R 11 , R 12 and and removing the protecting group represented by R 13.
  • Examples of the inert solvent used when the compound (2) is reacted with the compound (3) include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, and preferably halogens Hydrocarbon, more preferably methylene chloride.
  • Lewis acid used in the above reaction examples include boron trifluoride-diethyl ether complex and trimethylsilyl trifluoromethanesulfonate, and boron trifluoride-diethyl ether complex is preferable.
  • the reaction temperature varies depending on the raw material compound, Lewis acid, inert solvent and the like, but is usually -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, Lewis acid, inert solvent, reaction temperature, etc., but is usually 5 minutes to 24 hours, preferably 10 minutes to 12 hours.
  • Step A3 is a step for producing compound (4), and is performed by reacting compound (1) with hydrobromic acetic acid in an inert solvent.
  • Examples of the inert solvent used in the above reaction include halogenated hydrocarbons, and methylene chloride is preferable.
  • the reaction temperature varies depending on the raw material compound, the inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.
  • the reaction time varies depending on the raw material compound, inert solvent, reaction temperature, etc., but is usually 5 to 50 hours, preferably 15 to 35 hours.
  • Step A4 is a step of producing compound (I). After reacting compound (4) with compound (3) in the presence of silver carbonate in an inert solvent, R 11 , R 12 and and removing the protecting group represented by R 13.
  • the removal of the protecting group may be performed in the same manner as in step A2.
  • Examples of the inert solvent used in the above reaction include halogenated hydrocarbons, aromatic hydrocarbons, ethers, nitriles, etc., preferably halogenated hydrocarbons, more preferably methylene chloride. .
  • the reaction temperature varies depending on the raw material compound, the inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.
  • the reaction time varies depending on the raw material compound, inert solvent, reaction temperature and the like, but is usually 5 to 150 hours, preferably 10 to 50 hours.
  • Compound (1) which is a raw material compound of Method A can be produced by, for example, the following Method B, and Compound (3) can be produced by, for example, the following Method C or Method D.
  • R 1 , R 4 , R 11 , R 12 and R 13 are as defined above, and R 14 is a hydrogen atom or a protecting group.
  • Step B1 is a step for producing compound (1) and is performed by removing the protecting group represented by R 14 .
  • the removal of the protecting group may be performed in the same manner as in step A2.
  • the reaction is performed by reacting hydrazine acetate in an inert solvent.
  • Examples of the inert solvent used in the above reaction include amides, and preferably dimethylformamide.
  • the reaction temperature varies depending on the raw material compound, inert solvent and the like, but is usually 0 to 50 ° C., preferably room temperature.
  • the reaction time varies depending on the raw material compound, inert solvent, reaction temperature, etc., but is usually 30 minutes to 35 hours, preferably 1 to 24 hours.
  • Step B2 is a step for producing compound (6), and is performed by acetylating R 14 in compound (5) in the presence of an acid catalyst in an inert solvent.
  • Examples of the inert solvent used in the above reaction include carboxylic acids and the like, and preferably acetic acid.
  • the acid catalyst used in the above reaction is preferably an inorganic acid, more preferably sulfuric acid.
  • the reaction temperature varies depending on the raw material compound, acid catalyst, inert solvent and the like, but is usually 0 to 50 ° C., preferably room temperature.
  • the reaction time varies depending on the raw material compound, acid catalyst, inert solvent, reaction temperature and the like, but is usually 3 to 48 hours, preferably 6 to 24 hours.
  • Step B3 is a step of producing compound (1), and is performed by reacting compound (6) with hydrazine acetate in an inert solvent. This step can be performed in the same manner as step B1.
  • Compound (14) in the following scheme is a compound in which n is 1 in compound (3).
  • Step C1 is a step for producing compound (9).
  • compound (7) is reacted with compound (8) in the presence of a base, and a catalytic amount of trimethylsilylcyanide is added to react. Is done.
  • inert solvent used in the above reaction examples include halogenated hydrocarbons, hydrocarbons, aromatic hydrocarbons, ethers, nitriles, etc., preferably nitriles, more preferably acetonitrile. is there.
  • Examples of the base used in the above reaction include organic amines, and preferably triethylamine.
  • the reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature to 60 ° C.
  • the reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature, etc., but is usually 10 minutes to 12 hours, preferably 2 to 4 hours.
  • Step C2 is a step of producing compound (10), and is performed by reacting compound (9) with a halogenating agent in an inert solvent.
  • Examples of the inert solvent used in the halogenation reaction that is the first stage of the above reaction include halogenated carbons, and preferably methylene chloride.
  • R 2 is fluorine, for example, dimethylaminosulfur trifluoride, 2,2-difluoro-1,3-dimethylimidazolidine, hydrogen fluoride-pyridine, etc.
  • R 2 is chlorine, for example, oxalyl dichloride, thionyl chloride, phosphorus oxychloride and the like are preferable, and oxalyl dichloride is preferable.
  • the reaction temperature varies depending on the raw material compound, halogenating agent, inert solvent and the like, but is usually -30 to 100 ° C, preferably 0 ° C to room temperature.
  • reaction time varies depending on the raw material compound, halogenating agent, inert solvent, reaction temperature, etc., but when R 2 is fluorine, it is usually 30 minutes to 12 hours, preferably 3 hours, and R 2 is chlorine. In this case, it is usually 30 minutes to 24 hours, preferably 1 to 3 hours.
  • Step C3 is a step of producing compound (11), and is performed by reacting compound (10) with an oxidizing agent in a basic solvent.
  • Examples of the basic solvent used in the above reaction include organic amines, and preferably N-methylmorpholine.
  • oxidizing agent used in the above reaction examples include heavy metal salts such as permanganic acid and chromic acid, halogens such as bromine and iodine, and 2,3-dichloro-5,6-dicyano-p-benzoquinone. , Preferably halogen, more preferably iodine.
  • the reaction temperature varies depending on the raw material compound, basic solvent, type of oxidizing agent, etc., but is usually 0 to 100 ° C., preferably room temperature.
  • the reaction time varies depending on the raw material compound, basic solvent, oxidizing agent, reaction temperature, etc., but is usually 15 minutes to 12 hours, preferably 30 minutes to 2 hours.
  • Step C4 is a step for producing compound (12), and is performed by reacting compound (11) with a reducing agent in an inert solvent.
  • Examples of the inert solvent used in the above reaction include ethers and alcohols, preferably ethers, more preferably tetrahydrofuran.
  • Examples of the reducing agent used in the above reaction include alkali metal borohydrides such as sodium borohydride and lithium borohydride, aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum, hydrogen And a hydride reagent such as sodium telluride, preferably an aluminum hydride compound, more preferably lithium aluminum hydride.
  • the reaction temperature varies depending on the raw material compound, the reducing agent, the inert solvent and the like, but is usually -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, reducing agent, inert solvent, reaction temperature, etc., but is usually 10 minutes to 10 hours, preferably 30 minutes to 1 hour.
  • Step C5 is a step for producing compound (13), and is performed by reacting vinyl acetate with compound (12) in the presence of a bis (dibutyltin chloride) oxide catalyst in an inert solvent.
  • Examples of the inert solvent used in the above reaction include ethers, and tetrahydrofuran is preferable.
  • the reaction temperature varies depending on the raw material compound, the inert solvent and the like, but is usually 0 to 50 ° C., preferably room temperature to 35 ° C.
  • the reaction time varies depending on the raw material compound, inert solvent, reaction temperature and the like, but is usually 1 to 100 hours, preferably 24 to 48 hours.
  • Step C6 is a step for producing compound (14), and is performed by reacting compound (13) with a reducing agent in the presence of an acid or a Lewis acid in an inert solvent.
  • inert solvent used in the above reaction examples include halogenated hydrocarbons, hydrocarbons, aromatic hydrocarbons, ethers, nitriles, etc., preferably nitriles, more preferably acetonitrile. is there.
  • Examples of the acid or Lewis acid used in the above reaction include trifluoroacetic acid, boron trifluoride-diethyl ether complex, aluminum chloride, and the like, and preferably boron trifluoride-diethyl ether complex.
  • Examples of the reducing agent used in the above reaction include trialkylsilane, alkali metal borohydride, aluminum hydride compound, etc., preferably trialkylsilane, and more preferably triethylsilane.
  • the reaction temperature varies depending on the raw material compound, acid or Lewis acid, reducing agent, inert solvent, etc., but is usually ⁇ 20 to 50 ° C., preferably 0 ° C. to room temperature.
  • the reaction time varies depending on the raw material compound, acid or Lewis acid, reducing agent, inert solvent, reaction temperature, etc., but is usually 30 minutes to 10 hours, preferably 1 to 2 hours.
  • Compound (22) in the following scheme is a compound in which n is 2 in compound (3).
  • Step D1 is a step of producing compound (15), and is performed by reacting compound (14) with a benzylating reagent in the presence of a base in an inert solvent.
  • Examples of the inert solvent used in the above reaction include amides, and preferably dimethylformamide.
  • Examples of the base used in the above reaction include inorganic bases, and potassium carbonate is preferable.
  • benzylating reagent used in the above reaction examples include benzyl halide, benzyl arylsulfonate, benzyl alkylsulfonate, and the like, preferably benzyl halide, more preferably benzyl bromide.
  • the reaction temperature varies depending on the raw material compound, base, benzylating reagent, inert solvent, etc., but is usually 0 to 100 ° C., preferably room temperature.
  • the reaction time varies depending on the raw material compound, base, benzylating reagent, inert solvent, reaction temperature, etc., but is usually 30 minutes to 48 hours, preferably 2 to 4 hours.
  • Step D2 is a step of producing compound (16), and is performed by reacting compound (15) with a base in an inert solvent.
  • Examples of the inert solvent used in the above reaction include water and alcohols, preferably alcohols, more preferably methanol.
  • Examples of the base used in the above reaction include inorganic bases, and potassium carbonate is preferable.
  • the reaction temperature varies depending on the raw material compound, base, inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.
  • the reaction time varies depending on the raw material compound, base, inert solvent, reaction temperature and the like, but is usually 10 minutes to 24 hours, preferably 1 to 18 hours.
  • Step D3 is a step of producing compound (17), and is performed by reacting compound (16) with an oxidizing agent in an inert solvent.
  • Examples of the inert solvent used in the above reaction include hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, etc., preferably halogenated hydrocarbons, more preferably Chloroform.
  • the reaction temperature varies depending on the raw material compound, oxidizing agent, inert solvent and the like, but is usually 0 to 200 ° C., preferably the reflux temperature.
  • the reaction time varies depending on the raw material compound, oxidizing agent, inert solvent, reaction temperature, etc., but is usually 30 minutes to 48 hours, preferably 2 to 4 hours.
  • Step D4 is a step of producing compound (18), and is performed by reacting a phosphonium salt with a base in an inert solvent and further reacting with compound (17).
  • Examples of the inert solvent used in the above reaction include ethers, and tetrahydrofuran is preferable.
  • Examples of the phosphonium salt used in the above reaction include halogenated (methoxymethyl) triphenylphosphonium, and preferably (methoxymethyl) triphenylphosphonium chloride.
  • Examples of the base used in the above reaction include alkali metal bis (trimethylsilyl) amides and alkali metal dialkylamides, preferably alkali metal bis (trimethylsilyl) amide, more preferably lithium bis (trimethylsilyl) amide. It is.
  • the reaction temperature varies depending on the raw material compound, phosphonium salt, base, inert solvent and the like, but is usually -78 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, (methoxymethyl) phosphonium salt, base, inert solvent, reaction temperature, etc., but is usually 30 minutes to 24 hours, preferably 1 to 2 hours.
  • Step D5 is a step of producing compound (19), and is performed by hydrolyzing compound (18) in the presence of an acid catalyst in an inert solvent.
  • Examples of the inert solvent used in the above reaction include ethers, and preferably 1,4-dioxane.
  • Examples of the acid catalyst used in the above reaction include inorganic acids, aryl sulfonic acids, etc., preferably inorganic acids, more preferably hydrochloric acid.
  • the reaction temperature varies depending on the raw material compound, acid catalyst, inert solvent and the like, but is usually 0 ° C. to reflux temperature, preferably room temperature.
  • the reaction time varies depending on the raw material compound, acid catalyst, inert solvent, reaction temperature, etc., but is usually 5 minutes to 10 hours, preferably 10 minutes to 1 hour.
  • Step D6 is a step of producing compound (20), and is performed by reacting compound (19) with a reducing agent in an inert solvent.
  • Examples of the inert solvent used in the above reaction include ethers and alcohols, preferably alcohols, more preferably methanol.
  • Examples of the reducing agent used in the above reaction include alkali metal borohydrides such as sodium borohydride and lithium borohydride, aluminum hydride compounds such as lithium aluminum hydride and lithium triethoxide aluminum, hydrogen And a hydride reagent such as sodium telluride, preferably an alkali metal borohydride, more preferably sodium borohydride.
  • the reaction temperature varies depending on the raw material compound, the reducing agent, the inert solvent and the like, but is usually -30 ° C to reflux temperature, preferably 0 ° C to room temperature.
  • the reaction time varies depending on the raw material compound, reducing agent, inert solvent, reaction temperature, etc., but is usually 10 minutes to 10 hours, preferably 30 minutes to 1 hour.
  • Step D7 is a step for producing compound (21).
  • R 2 is fluorine
  • it is carried out by catalytic reduction of compound (20) in the presence of hydrogen and a metal catalyst in an inert solvent.
  • R 2 is chlorine
  • the reaction is carried out by reacting compound (20) with a Lewis acid in an inert solvent.
  • R 2 is fluorine
  • examples thereof include ethers and alcohols, preferably alcohols, more preferably methanol, and R 2 is chlorine.
  • ethers and alcohols preferably alcohols, more preferably methanol
  • R 2 is chlorine.
  • nitriles and the like can be mentioned, and acetonitrile is preferable.
  • metal catalysts such as platinum, palladium, rhodium and nickel, preferably a palladium catalyst, and more preferably a palladium carbon catalyst.
  • Examples of the Lewis acid used in the above reaction when R 2 is chlorine include trialkylsilyl halide, and trimethylsilyl iodide is preferable.
  • reaction temperature varies depending on the raw material compound, metal catalyst, inert solvent, etc., but is usually 0 to 100 ° C., preferably room temperature, and when R 2 is chlorine, the raw material Although it varies depending on the compound, Lewis acid, inert solvent and the like, it is usually 0 to 100 ° C., preferably 40 ° C.
  • reaction time when R 2 is fluorine, the starting compound, a metal catalyst in an inert solvent, varying reaction temperature and the like, usually, 10 minutes to 24 hours, preferably 30 minutes to 2 hours
  • Step D8 is a step for producing compound (22), and is performed by reacting compound (21) with vinyl acetate in the presence of a bis (dibutyltin chloride) oxide catalyst in an inert solvent. The method is carried out in the same manner as in the method of protecting the primary hydroxyl group of compound (12) in step C5 with an acetyl group.
  • the compounds of the present invention can be produced by using the above-mentioned methods, and examples described later from known compounds or methods well known in the art (for example, Chem. Ber, 71, 1938, 1843-1849, Carbohydr. Res. 1995). , 273,249-254, Bull.Chem.Soc.Jpn., 1982,55,938-942, Bull.Chem.Soc.Jpn., 1976,49,788-790, Org.Lett., 2003,5,3419-3421, Org. Biomol.Chem, 2003, 1,767-771, J. Chem. Soc., 1956, 2124-2126, WO 02/064606 pamphlet, Liebigs Ann. Chem, GE, 1992, 7, 747-758, etc.) Can be manufactured easily.
  • the compound of the present invention or a hydrate thereof exhibits excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects, type 1 diabetes, type 2 diabetes, gestational diabetes, other factors, hyperglycemia, glucose intolerance, Diabetes-related diseases (eg, obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia , Gout, etc.) or diabetic complications (eg, retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) are useful as an active ingredient of a pharmaceutical composition.
  • Diabetes-related diseases eg, obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteriosclerosis, hyperuricemia , Gout, etc
  • Such pharmaceutical compositions can be administered to mammals (eg, humans, horses, cows, pigs, preferably humans).
  • mammals eg, humans, horses, cows, pigs, preferably humans.
  • the administration form may be any of oral administration such as tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories.
  • excipients eg, lactose, corn starch, crystalline cellulose, D-mannitol, anhydrous calcium hydrogen phosphate, sucrose, etc.
  • disintegrants eg, corn starch, carmellose calcium, low substituted hydroxypropyl
  • binders eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, popidone, corn starch, methylcellulose, etc.
  • lubricants eg, magnesium stearate, calcium stearate, talc) , Stearic acid, etc.
  • fluidizing agents eg, light anhydrous silicic acid, talc, hydrous silicon dioxide, etc.
  • coating agents eg, hydroxypropyl methylcellulose, hydride
  • coating agents eg, hydroxypropyl methylcellulose, hydride
  • the amount of the compound of the present invention or hydrate thereof used varies depending on symptoms, age, etc., but in the case of oral administration, 1 to 2000 mg, preferably 10 to 400 mg per day, and in the case of intravenous administration, It is desirable to administer 0.1 to 500 mg per day, preferably 1 to 300 mg per day, one to several times per day depending on the symptoms.
  • Example 1a 4- (2-Fluoroethyl) benzoyl chloride 4- (2-fluoroethyl) benzoic acid (Bioorg. Med. Chem., 2005, 13, 77-78.) (1.8 g, 11 mmol) was salified The mixture was dissolved in methylene, added with oxalyl chloride (1.1 mL, 13 mmol) and N, N-dimethylformamide (0.1 mL, 1.3 mmol) under ice cooling, and stirred for 3 hours and a half while raising the temperature to room temperature. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude product (2.1 g) of the title compound as a colorless oil.
  • Example 1b Ethyl 4- [4- (2-fluoroethyl) benzoyl] -3-hydroxy-5-oxocyclohex-3-enecarboxylic acid 3-hydroxy-5-oxocyclohex-3-enecarboxylic acid
  • Ethyl (EP1571148A1) 2.0 g, 11 mmol
  • the crude product obtained in Example 1a 2.1 g, 11 mmol
  • triethylamine 4.6 mL, 33 mmol
  • Trimethylsilyl cyanide (0.21 mL, 1.6 mmol) was added to this suspension, and the mixture was stirred at 60 ° C. for 2 hours.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (20 mL) and saturated brine (20 mL, twice).
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (4.3 g) of the title compound.
  • Example 1c Ethyl 3-chloro-4- [4- (2-fluoroethyl) benzoyl] -5-oxocyclohex-3-enecarboxylate
  • 2-methyl-2-butene 2.8 mL, 26 mmol
  • oxalyl dichloride 0.83 mL, 9.8 mmol
  • N, N-dimethylformamide 0.13 mmol
  • reaction mixture was cooled to room temperature, diluted with methylene chloride (20 mL), and washed with saturated brine (20 mL, twice).
  • the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was concentrated under reduced pressure twice under azeotropy with toluene (10 mL) to obtain a crude product (2.2 g) of the title compound.
  • Example 1d Ethyl 3-chloro-4- [4- (2-fluoroethyl) benzoyl] -5-hydroxybenzoate
  • the crude product obtained in Example 1c (2.2 g, 6.5 mmol) was converted to N-methyl. It melt
  • the dark brown suspension was filtered through celite, diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (50 mL, 2 times), 30% aqueous sodium thiosulfate (20 mL), and saturated brine (20 mL). .
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude product (2.2 g) of the title compound.
  • Example 1e 3-Chloro-2- ⁇ 1- [4- (2-fluoroethyl) phenyl] -1-hydroxymethyl ⁇ -5- (hydroxymethyl) phenol
  • the crude product obtained in Example 1d ( 2.2 g, 6.5 mmol) was dissolved in tetrahydrofuran (65 mL), the gas phase was replaced with nitrogen, and lithium aluminum hydride (1.0 g, 26 mmol) was added in small portions under ice cooling. The mixture was stirred for 1 hour while warming to room temperature, and water (1 mL) was added dropwise under ice cooling to stop the reaction.
  • Example 1f Acetic acid 3-chloro-4- ⁇ 1- [4- (2-fluoroethyl) phenyl] -1-hydroxymethyl ⁇ -5-hydroxybenzyl
  • Compound obtained in Example 1e 1.0 g, 3.2 mmol
  • porcine pancreatic lipase 1.0 g was added.
  • the suspension was stirred at 37 ° C. for 8 hours, filtered through celite and washed with ethyl acetate (2 ⁇ 5 mL).
  • the obtained filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (1.1 g).
  • Example 1g Acetic acid 3-chloro-2- [4- (2-fluoroethyl) benzyl] -5-hydroxybenzyl
  • the crude product (0.90 g, 2.5 mmol) obtained in Example 1f was converted to acetonitrile (10 mL).
  • triethylsilane (1.2 mL, 7.6 mmol) and boron trifluoride-diethyl ether complex (0.47 mL, 3.8 mmol) were added under ice cooling, and the mixture was stirred at 0 ° C. for 1.5 hours.
  • the reaction mixture was diluted with ethyl acetate (20 mL), and washed successively with saturated aqueous sodium hydrogen carbonate solution (10 mL, twice) and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 5: 1, V / V) to give the title compound. (0.76 g, including about 20% of raw material).
  • Example 1h 5-Acetoxymethyl-3-chloro-2- [4- (2-fluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) (1.1 g, 1.8 mmol) was dissolved in methylene chloride (10 mL).
  • Example 1i 3-chloro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 1h
  • the obtained crude product (1.8 mmol) was dissolved in a solution consisting of tetrahydrofuran (6 mL) and methanol (6 mL), 2M aqueous sodium hydroxide solution (6 mL, 12 mmol) was added, and the mixture was stirred at room temperature for 30 min.
  • Example 2a (2-Chloro-4,6-dihydroxyphenyl) (4-ethylphenyl) methanone 1-Chloro-3,5-dimethoxybenzene (8.11 g, 47.0 mmol) was dissolved in toluene (40 mL), Aluminum chloride (6.26 g, 46.9 mmol) and 4-ethylbenzoyl chloride (6.89 mL, 47.0 mmol) were added, and the mixture was stirred at room temperature for 15 minutes, and then stirred at 85 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was added to 1N aqueous hydrochloric acid (300 mL) under ice cooling.
  • 1N aqueous hydrochloric acid 300 mL
  • Example 2b 5-chloro-2,2-dimethyl-4- (4-ethylphenyl) -4H-benzo [1,3] dioxin-7-ol
  • the crude product obtained in Example 2a (1.59 g , 5.75 mmol) was dissolved in methanol (15 mL), sodium borohydride (326 mg, 8.62 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 30 min. After cooling to 0 ° C., saturated aqueous ammonium chloride solution (1 mL) was added, and the solvent was removed under reduced pressure.
  • Example 2c Methyl 5-chloro-2,2-dimethyl-4- (4-ethylphenyl) -4H-benzo [1,3] dioxin-7-carboxylate
  • methylene chloride 10 mL
  • pyridine 0.235 mL, 2.91 mmol
  • trifluoromethanesulfonic anhydride 0.90 mL, 2.32 mmol
  • methylene chloride 20 mL
  • washed with water (20 mL, 3 times The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. Toluene azeotropy was performed to obtain a crude product of triflate (790 mg).
  • Example 2d 3-chloro-2- [1- (4-ethylphenyl) -1-methoxymethyl] -5- (hydroxymethyl) phenol Lithium aluminum hydride (103 mg, 2.71 mmol) in tetrahydrofuran (3 mL) After dissolution, under ice cooling, a tetrahydrofuran solution (4 mL) in which the compound obtained in Example 2c (651 mg, 1.80 mmol) was dissolved was added.
  • the reaction mixture was stirred at room temperature for 30 minutes, cooled to 0 ° C, water (0.1 mL), 5 mol / L aqueous sodium hydroxide solution (0.1 mL) and water (0.3 mL) were sequentially added, and the mixture was stirred at room temperature for 1 hour. And left at room temperature for 14 hours. After filtration through celite, the solvent was removed under reduced pressure to obtain an oily crude alcohol product (470 mg).
  • Example 2e Acetic acid 3-chloro-4- [1- (4-ethylphenyl) -1-methoxymethyl] -5-hydroxybenzyl Compound (401 mg, 1.31 mmol) obtained in Example 2d was added to tetrahydrofuran (4 mL). ), Vinyl acetate (4 mL) and bis (dibutyltin chloride) oxide (144 mg, 0.26 mmol) were added, and the mixture was stirred at room temperature for 72 hours. The solvent was removed under reduced pressure, and finally purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the title compound (380 mg) as an oil.
  • Example 2f Acetic acid 3-chloro-4- (4-ethylbenzyl) -5-hydroxybenzyl
  • the compound (380 mg, 1.09 mmol) obtained in Example 2e was dissolved in acetonitrile (8 mL) and cooled to 0 ° C. Thereafter, triethylsilane (0.520 mL, 3.26 mmol) and boron trifluoride-diethyl ether complex (0.210 mL, 1.67 mmol) were added, and the mixture was stirred at room temperature for 1 hour.
  • reaction mixture was diluted with ethyl acetate (40 mL) and washed successively with aqueous sodium hydrogen carbonate solution (40 mL) and saturated brine (40 mL).
  • aqueous sodium hydrogen carbonate solution 40 mL
  • saturated brine 40 mL
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure.
  • the residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 2: 1, V / V) to obtain the title compound (293 mg) as a white solid.
  • Example 2g 5-Acetoxymethyl-3-chloro-2- (4-ethylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco -Heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (722 mg, 1.18 mmol) was dissolved in methylene chloride (8 mL) and 0 After cooling to ° C., trichloroacetonitrile (0.597 mL, 5.91 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.018 mL, 0.12 mmol) were added, and the mixture was stirred for 1 hour under ice cooling.
  • reaction mixture was diluted with ethyl acetate (20 mL) and washed successively with saturated aqueous ammonium chloride (20 mL) and saturated brine (20 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Toluene (2 mL) was added and azeotroped under reduced pressure to give the corresponding imidate as a yellow amorphous.
  • Example 2f The compound (290 mg, 0.91 mmol) and imidate (890 mg, 1.18 mmol) obtained in Example 2f were dissolved in methylene chloride (8 mL), and molecular sieve 4A (manufactured by Nacalai Tesque, hereinafter referred to as MS4A) was added.
  • MS4A molecular sieve 4A
  • Boron trifluoride-diethyl ether complex (0.148 mL, 1.18 mmol) was added dropwise under ice cooling, and the mixture was stirred under ice cooling for 15 minutes and then at room temperature for 15 minutes.
  • Example 2h 3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside
  • methanol / methylene chloride 16 mL / 4 mL
  • potassium carbonate (1.63 g, 11.8 mmol) was added, and the mixture was stirred overnight at room temperature.
  • an appropriate amount of acetic acid was added for neutralization, and methanol was removed under reduced pressure.
  • Example 3a Ethyl 4- [4- (difluoromethoxy) benzoyl] -3-hydroxy-5-oxocyclohex-3-enecarboxylate ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate ( 2.0 g, 11 mmol) and 4- (difluoromethoxy) benzoyl chloride (J. Org. Chem. USSR, 1981, 1470-1475.) (2.3 g, 11 mmol) (2.3 g, 11 mmol) in the same manner as in Example 1b. Crude product (3.3 g) was obtained.
  • Example 3b Ethyl 4- [4- (difluoromethoxy) benzoyl] -3-fluoro-5-oxocyclohex-3-enecarboxylate
  • methylene chloride 10 mL
  • diethylaminosulfur trifluoride 1.7 mL, 13 mmol
  • the reaction mixture was diluted with ethyl acetate (30 mL), and washed successively with saturated brine (10 mL), saturated aqueous sodium hydrogen carbonate solution (20 mL, twice) and saturated brine (10 mL).
  • Example 3c Ethyl 4- [4- (difluoromethoxy) benzoyl] -3-fluoro-5-hydroxybenzoate
  • the compound obtained in Example 3b (1.2 g, 3.4 mmol) was converted to N-methylmorpholine (15 mL).
  • anhydrous sodium sulfate (1.2 g) and iodine (0.97 g, 3.8 mmol) were added at room temperature, followed by stirring at room temperature for 1 hour.
  • the dark brown suspension was filtered through celite, diluted with ethyl acetate (50 mL), and washed successively with 2M hydrochloric acid (50 mL, 2 times), 30% aqueous sodium thiosulfate (20 mL), and saturated brine (20 mL). .
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.2 g) of the title compound.
  • Example 3d Ethyl 4- ⁇ 1- [4- (difluoromethoxy) phenyl] -1-hydroxymethyl ⁇ -3-fluoro-5-hydroxybenzoate
  • the crude product obtained in Example 3c (1.5 g, 4.1 mmol) was dissolved in ethanol (20 mL), and sodium borohydride (0.31 g, 8.2 mmol) was added under ice cooling. The mixture was stirred for 2 hours while warming to room temperature, and saturated aqueous ammonium chloride (1 mL) was added dropwise under ice cooling to stop the reaction.
  • Example 3e Ethyl 4- [4- (difluoromethoxy) benzyl] -3-fluoro-5-hydroxybenzoate
  • the compound obtained in Example 3d (0.82 g, 2.3 mmol) was dissolved in ethanol (8 mL). The solution was stirred for 10 minutes while blowing nitrogen into the solution.
  • 2M hydrochloric acid (0.57 mL, 1.1 mmol) and 10% palladium carbon catalyst (containing water, 0.5 g) were added under a nitrogen stream, and the gas phase was replaced with hydrogen, followed by stirring at room temperature for 6 hours. The mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (0.76 g) as a colorless solid.
  • Example 3f 2- [4- (Difluoromethoxy) benzyl] -3-fluoro-5- (hydroxymethyl) phenol
  • the crude product obtained in Example 3e (0.76 g, 2.2 mmol) was added to tetrahydrofuran (10 mL). After the gas phase was replaced with nitrogen, lithium aluminum hydride (0.25 g, 6.6 mmol) was added in small portions under ice cooling. The mixture was stirred for 1 hour while warming to room temperature, and water (1 mL) was added dropwise under ice cooling to stop the reaction. The mixture was diluted with ethyl acetate (30 mL), and washed successively with 2M hydrochloric acid (10 mL, twice) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.65 g) of the title compound as a colorless solid.
  • Example 3g Acetic acid 4- [4- (difluoromethoxy) benzyl] -3-fluoro-5-hydroxybenzyl
  • the crude product obtained in Example 3f (0.65 g, 2.2 mmol) was added to vinyl acetate (5 mL) and Dissolved in a solution consisting of diisopropyl ether (5 mL), porcine pancreatic lipase (1.0 g) was added.
  • the suspension was stirred at 37 ° C. for 8 hours and the suspension was filtered through celite and washed with ethyl acetate (5 mL, 2 ⁇ ).
  • Example 3h 5-Acetoxymethyl-2- [4- (difluoromethoxy) benzyl] -3-fluorophenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ - D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.37 g, 0.60 mmol) in methylene chloride (4 mL) Dissolve and prepare an imidate in the same manner as Example 1h using trichloroacetonitrile (0.18 mL, 1.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2.7 ⁇ L, 0.018 mmol).
  • Example 3g Similar to Example 1h using the obtained imidate (0.45 g, 0.60 mmol), the compound obtained in Example 3g (0.20 g, 0.60 mmol) and boron trifluoride-diethyl ether complex (37 ⁇ L, 0.30 mmol). By this method, a mixture containing the title compound was obtained.
  • the mixture (0.60 mmol) was dissolved in a solution consisting of tetrahydrofuran (2 mL) and methanol (2 mL), 2M aqueous sodium hydroxide solution (2 mL, 4 mmol) was added, and the mixture was stirred at room temperature for 30 min.
  • Example 4a Ethyl 3-hydroxy-4- (4-methylbenzoyl) -5-oxocyclohex-3-enecarboxylate
  • Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (3.0 g, 16.3 mmol) was dissolved in acetonitrile (50 mL), triethylamine (6.8 mL, 48.8 mmol) and p-toluoyl chloride (2.26 mL, 17.1 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. Further, trimethylsilylcyanide (260 ⁇ L, 1.95 mmol) was added and stirred at 60 ° C. for 2 hours.
  • Example 4b Ethyl 3-chloro-4- (4-methylbenzoyl) -5-oxocyclohex-3-enecarboxylate
  • methylene chloride 10 mL
  • Oxalyl dichloride 300 ⁇ L, 3.5 mmol
  • 2-methyl-2-butene 1.25 mmol
  • N, N-dimethylformamide 100 ⁇ L, 1.29 mmol
  • Example 4c Ethyl 3-chloro-5-hydroxy-4- (4-methylbenzoyl) benzoate To the crude product (1.2 g) obtained in Example 4b, N-methylmorpholine (10 mL) and iodine ( 1.68 g, 6.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After filtration through celite, the mixture was diluted with toluene (10 mL), and washed successively with aqueous sodium sulfite solution (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-3: 1, V / V) to give the title compound (0.77 g) as a yellow solid.
  • Example 4d Ethyl 3-chloro-5-hydroxy-4- [1-hydroxy-1- (4-methylphenyl) methyl] benzoate
  • the compound obtained in Example 4c (0.77 g, 2.4 mmol) was dissolved in methanol. (6 mL) and tetrahydrofuran (1 mL) were dissolved in the solution. Under ice cooling, sodium borohydride (137 mg, 3.6 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Under ice cooling, a saturated aqueous ammonium chloride solution (5 mL) was added to the reaction solution, and the solvent was distilled off under reduced pressure.
  • Example 4e Ethyl 5-chloro-2,2-dimethyl-4- (4-methylphenyl) -4H-benzo [1,3] dioxin-7-carboxylate
  • acetone 6 mL
  • boron trifluoride-diethyl ether complex (220 ⁇ L, 1.8 mmol) was added at ⁇ 10 ° C., and the mixture was stirred for 3 hours while slowly warming to 0 ° C.
  • saturated aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, diluted with ethyl acetate (20 mL), and washed with saturated brine (10 mL).
  • Example 4f 5-chloro-2,2-dimethyl-4- (4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethanol
  • the compound obtained in Example 4e (0.65 g, 1.8 mmol) was dissolved in tetrahydrofuran (10 mL), and lithium aluminum hydride (101 mg, 2.7 mmol) was added under ice cooling, followed by stirring at room temperature for 2 hours.
  • Distilled water (5 mL) was added to the reaction mixture under ice cooling, diluted with ethyl acetate (10 mL), and washed successively with 2M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL), and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.55 g) of the title compound as a colorless solid.
  • Example 4g Acetic acid 5-chloro-2,2-dimethyl-4- (4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethyl
  • methylene chloride (7 mL) acetic anhydride (200 ⁇ L, 2.1 mmol)
  • pyridine 350 ⁇ L, 3.5 mmol
  • 4-dimethylaminopyridine 65 mg, 0.5 mmol
  • the reaction mixture was diluted with ethyl acetate (15 mL) and washed successively with 2M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL).
  • 2M hydrochloric acid 10 mL
  • saturated aqueous sodium hydrogen carbonate solution 10 mL
  • saturated brine 10 mL
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.65 g) of the title compound as a colorless oil.
  • Example 4h 3-chloro-5-hydroxy-4- (4-methylbenzyl) benzyl acetate
  • Acetic acid (0.65 g, 1.8 mmol) obtained in Example 4 g was dissolved in acetonitrile (7 mL) and iced. Under cooling, triethylsilane (850 ⁇ L, 5.3 mmol) and boron trifluoride-diethyl ether complex (340 ⁇ L, 2.7 mmol) were added, and the mixture was stirred at 0 ° C. for 1 hour.
  • Example 4i 5-Acetoxymethyl-3-chloro- (4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) (240 mg, 0.39 mmol) in methylene chloride (5 mL ), Trichloroacetonitrile (120 ⁇ L, 1.20 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 ⁇ L, 0.04 mmol) were added under ice cooling, and the mixture was stirred at 0 ° C.
  • the obtained imidate was dissolved in methylene chloride (5 mL), and the compound obtained in Example 4h (100 mg, 0.33 mmol) and boron trifluoride-diethyl ether complex (50 ⁇ L, 0.39 mmol) were added under ice cooling. And stirred at 0 ° C. for 2 hours. Triethylamine (100 ⁇ L, 0.72 mmol) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (10 mL) and washed with saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (350 mg) of the title compound.
  • Example 4j 3-Chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside
  • a solution consisting of tetrahydrofuran (1 mL) and methanol (4 mL) sodium carbonate (46 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 2 hours.
  • Example 5a Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate
  • Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (0.35 g, 1.9 mmol) was dissolved in acetonitrile (4 mL), triethylamine (0.79 mL, 5.7 mmol), 3-fluoro-4-methylbenzoyl chloride (J. Med. Chem., 1997, 40, 2064-2084.
  • Example 1b (0.33 g, 1.9 mmol) and trimethylsilylcyanide (0.030 mL, 0.23 mmol) were used in the same manner as in Example 1b to obtain a crude product.
  • the crude product was purified using silica gel flash column chromatography (methylene chloride: methanol, 10: 1, V / V) to obtain the title compound (0.61 g).
  • Example 5b Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-fluoro-5-oxocyclohex-3-enecarboxylate
  • the compound obtained in Example 5a (0.61 g, 1.9 mmol) was obtained.
  • the title compound (0.31 g) was obtained by dissolving in methylene chloride (8 mL) and using diethylaminosulfur trifluoride (0.75 mL, 5.7 mmol) in the same manner as Example 3b.
  • Example 5c Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-fluoro-5-hydroxybenzoate Dissolve the compound obtained in Example 5b (0.31 g, 0.96 mmol) in acetonitrile (3 mL). Then, ice cooling, triethylamine (0.40 mL, 2.9 mmol) and trimethylsilyl iodide (0.34 mL, 2.4 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was diluted with toluene (10 mL) under ice cooling, and washed twice with a phosphate buffer solution (pH 7, 5 mL).
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed successively with 1M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL), and saturated brine (5 mL).
  • 1M hydrochloric acid 10 mL
  • saturated aqueous sodium hydrogen carbonate solution 5 mL
  • saturated brine 5 mL
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 3: 1, V / V) to obtain the title compound (0.17 g).
  • Example 5d 3-Fluoro-2- [1- (3-fluoro-4-methylphenyl) -1-hydroxymethyl] -5- (hydroxymethyl) phenol
  • the compound obtained in Example 5c (0.17 g, 0.53 mmol) was dissolved in tetrahydrofuran (5 mL), and the title compound (0.13 g) was obtained as a crude product in the same manner as in Example 1e using lithium aluminum hydride (60 mg, 1.6 mmol).
  • Example 5e Acetic acid 3-fluoro-4- [1- (3-fluoro-4-methylphenyl) -1-hydroxymethyl] -5-hydroxybenzyl
  • Crude product obtained in Example 5d (0.13 g, 0.46 mmol) was dissolved in a solution consisting of vinyl acetate (3 mL) and diisopropyl ether (3 mL), porcine pancreatic lipase (0.13 g) was added, and the mixture was stirred at room temperature for 2 days. After completion of the reaction, the mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1, V / V) to obtain the title compound (0.12 g).
  • Example 5f Acetic acid 3-fluoro-4- (3-fluoro-4-methylbenzyl) -5-hydroxybenzyl
  • the compound (0.12 g, 0.37 mmol) obtained in Example 5e was dissolved in acetonitrile (3 mL).
  • Triethylsilane (0.18 mL, 1.1 mmol) and boron trifluoride-diethyl ether complex (70 ⁇ L, 0.56 mmol) were added at ⁇ 40 ° C., and the mixture was stirred for 1 hour while warming to room temperature.
  • Example 5g 5-acetoxymethyl-3-fluoro-2- (3-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.37 g, 0.60 mmol) in methylene chloride (4 mL) Prepared in the same manner as in Example 1h using trichloroacetonitrile (0.18 mL, 1.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2.7 ⁇ L, 0.018 mmol).
  • Example 5f Using this imidate (0.45 g, 0.60 mmol), the compound obtained in Example 5f (85 mg, 0.28 mmol) and boron trifluoride-diethyl ether complex (37 ⁇ L, 0.30 mmol), the same method as in Example 1h To give a mixture containing the title compound.
  • Example 5h 3-Fluoro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 5g
  • the resulting mixture (0.28 mmol) was dissolved in a solution consisting of tetrahydrofuran (2 mL) and methanol (1 mL), 2M aqueous sodium hydroxide solution (2 mL, 4 mmol) was added, and the title compound (84 mg) was prepared in the same manner as in Example 3i. Obtained as a colorless solid.
  • Example 6a 3-Fluoro-4-methylbenzoyl chloride 3-fluoro-4-methylbenzoic acid (880 mg, 5.71 mmol), oxalyl dichloride (0.50 mL, 5.71 mmol), catalytic amount of N, N-dimethylformamide
  • a crude product of the title compound (950 mg) was obtained as a colorless oil in the same manner as in Example 1a using tetrahydrofuran and tetrahydrofuran (10 mL).
  • Example 6b Ethyl 4- (3-fluoro-4-methylbenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate (950 mg, 5.16 mmol), using the crude product obtained in Example 6a (950 mg, 11 mmol), acetonitrile (10 mL), triethylamine (2.27 mL, 1.63 mmol) and trimethylsilylcyanide (0.087 mL, 0.65 mmol). In the same manner as in Example 1b, a crude product (1.65 g) of the title compound was obtained.
  • Example 6c Ethyl 3-chloro-4- (3-fluoro-4-methylbenzoyl) -5-oxocyclohex-3-enecarboxylate Crude product obtained in Example 6b (1.65 g, 5.15 mmol ), Methylene chloride (20 mL), 2-methyl-2-butene (2.19 mL, 20.6 mmol), oxalyl dichloride (0.46 mL, 5.36 mmol) and a catalytic amount of N, N-dimethylformamide as in Example 1c. By the method, a crude product (1.75 g) of the title compound was obtained.
  • Example 6d Ethyl 3-chloro-4- (3-fluoro-4-methylbenzoyl) -5-hydroxybenzoate
  • Crude product obtained in Example 6c (1.75 g, 5.15 mmol), N-methylmorpholine (20 mL), anhydrous sodium sulfate (14.6 g) and iodine (1.43 g, 5.63 mmol) were used in the same manner as in Example 1d to obtain a crude product of the title compound.
  • purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the amorphous title compound (1.28 g).
  • Example 6e Ethyl 5-chloro-2,2-dimethyl-4- (3-fluoro-4-methylphenyl) -4H-benzo [1,3] dioxin-7-benzoate Obtained in Example 6d
  • a crude diol product (1.28 g) was obtained in the same manner as in Example 2b using the compound (1.28 g, 3.80 mmol), methanol (12 mL) and sodium borohydride (290 mg, 7.67 mmol). Boron trifluoride-diethyl ether complex (0.475 mL, 3.78 mmol) cooled to ⁇ 10 ° C.
  • Example 6f 5-Chloro-2,2-dimethyl-4- (3-fluoro-4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethanol
  • Compound obtained in Example 6e (960 mg, 2.53 mmol), lithium aluminum hydride (96 mg, 2.53 mmol) and tetrahydrofuran (5 mL) were used in the same manner as in Example 2d to obtain a crude product (860 mg) of the title compound as an amorphous product.
  • Example 6g Acetic acid 5-chloro-2,2-dimethyl-4- (3-fluoro-4-methylphenyl) -4H-benzo [1,3] dioxin-7-ylmethyl Crude obtained in Example 6f The product (860 mg) was dissolved in pyridine (8.6 mL), acetic anhydride (2.2 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr.
  • Example 6h Acetic acid 3-chloro-4- (3-fluoro-4-methylbenzyl) -5-hydroxybenzyl
  • acetonitrile 15 mL
  • triethylsilane 1.14 mL, 7.09 mmol
  • boron fluoride-diethyl ether complex 0.450 mL, 3.58 mmol
  • Example 6i 5-Acetoxymethyl-3-chloro-2- (3-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (250 mg, 0.41 mmol), methylene chloride (4 mL), The imidate was prepared in the same manner as in Example 2g using trichloroacetonitrile (0.210 mL, 2.08 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 ⁇ L, 0.04 mmol).
  • Example 6h Using the obtained imidate (309 mg), the compound obtained in Example 6h (100 mg, 0.41 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.051 mL, 0.41 mmol) In the same manner as in Example 2g, a crude product (280 mg) of the title compound was obtained.
  • Example 6j 3-chloro-2- (3-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 6i Using the crude product (280 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (566 mg, 4.10 mmol), the title compound (76 mg) was obtained as a colorless solid in the same manner as in Example 2h. However, solidification was performed from hexane / ethyl acetate.
  • Example 7a 3,5-difluoro-4- [1- (3-fluoro-4-methoxyphenyl) -1-hydroxymethyl] benzonitrile Dissolve diisopropylamine (1.20 mL, 8.49 mmol) in tetrahydrofuran (7 mL) Then, n-butyllithium (2.60 mL, 7.19 mmol, 2.77 M n-hexane solution) was added dropwise under ice cooling.
  • the reaction mixture was diluted with ethyl acetate (60 mL), and washed successively with water (30 mL) and saturated aqueous sodium hydrogen carbonate solution (30 mL).
  • the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 3: 1 to 2: 1, V / V). To give the oily title compound (1.59 g).
  • Example 7b 3,5-difluoro-4- (3-fluoro-4-methoxybenzyl) benzonitrile
  • acetonitrile 16 mL
  • boron trifluoride-diethyl ether complex 1.0 mL, 7.9 mmol
  • the reaction mixture was diluted with ethyl acetate (60 mL), the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 2: 1, V / V) to obtain the title compound (1.05 g) as a colorless solid.
  • Example 7c 3-Benzyloxy-5-fluoro-4- (3-fluoro-4-methoxybenzyl) benzonitrile
  • the compound obtained in Example 7b (1.05 g, 3.79 mmol) and benzyl alcohol (0.53 g, 4.9 mmol) was dissolved in N, N-dimethylformamide (11 mL), and sodium hydride (63%, 0.22 g, 5.7 mmol) was added under ice cooling. After stirring at the same temperature for 2 hours, 2M hydrochloric acid was added dropwise to the reaction solution to stop the reaction.
  • reaction solution was diluted with ethyl acetate (100 mL), washed with water (50 mL, twice), and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 4: 1 to 2: 1, V / V) to give a mixture containing the title compound (1.05 g) was obtained.
  • Example 7d 3-Benzyloxy-5-fluoro-4- (3-fluoro-4-methoxybenzyl) benzoic acid
  • the mixture obtained in Example 7c (1.04 g, 2.85 mmol) was added to ethanol (14.5 mL).
  • the precipitated solid was collected by filtration, washed with water, and then dried under reduced pressure to obtain a mixture containing the title compound.
  • Example 7e 3-Fluoro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzoic acid
  • the mixture (2.85 mmol) obtained in Example 7d was taken from tetrahydrofuran (10 mL) and methanol (10 mL). The solution was dissolved in the solution, and nitrogen substitution was performed while stirring. A 10% palladium carbon catalyst (containing water, 0.20 g) was added to the reaction solution, and the gas phase was replaced with hydrogen, followed by stirring at room temperature for 40 minutes. The mixture was filtered through a membrane filter to remove the catalyst, and then the solvent was distilled off under reduced pressure to obtain a mixture (0.90 g) containing the title compound as a colorless solid.
  • Example 7f 3-Fluoro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenol
  • Lithium aluminum hydride (0.27 g, 7.1 mmol) was suspended in tetrahydrofuran (2 mL) and iced. Under cooling, a tetrahydrofuran solution (28 mL) in which the mixture (0.90 g, 2.85 mmol) obtained in Example 7e was dissolved was added dropwise. After stirring at 50 ° C. for 2 hours, water and 2M hydrochloric acid were added dropwise to the reaction solution under ice cooling to stop the reaction.
  • the reaction mixture was diluted with ethyl acetate (60 mL), washed with saturated brine (20 mL, twice), and the organic layer was dried over anhydrous magnesium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified using silica gel flash chromatography (hexane: ethyl acetate, 1: 1, V / V) to obtain the title compound (0.61 g) as a colorless solid. .
  • Example 7g 3-fluoro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzyl acetate
  • the compound (0.60 g, 2.14 mmol) obtained in Example 7f was dissolved in tetrahydrofuran (3 mL).
  • Vinyl acetate (3 mL) and bis (dibutyltin chloride) oxide (0.35 g, 0.63 mmol) were added, and the mixture was stirred at room temperature for 3 days.
  • Example 7h 5-Acetoxymethyl-3-fluoro-2- (3-fluoro-4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.68 g, 1.1 mmol), methylene chloride (14 mL) , Trichloroacetonitrile (0.34 mL, 3.4 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (15 ⁇ L, 0.10 mmol) were used to prepare an imidate in the same manner as Example 1h.
  • Example 1h A crude product of the title compound was obtained in the same manner as above.
  • Example 7i 3-Fluoro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 7h
  • the crude product was dissolved in a solution consisting of tetrahydrofuran (2 mL) and methanol (6 mL), and a methanol solution (3 mL) in which sodium methoxide (28% methanol solution, 0.36 g, 1.9 mmol) was dissolved was added at room temperature. I left it all night.
  • Example 8a Ethyl 4- (3-fluoro-4-methoxybenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate
  • Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate 800 mg, 4.34 mmol
  • 3-fluoro-4-methoxybenzoyl chloride 819 mg, 4.34 mmol
  • acetonitrile 14 mL
  • triethylamine (1.82 mL, 13.1 mmol
  • trimethylsilylcyanide 0.070 mL, 0.52 mmol
  • Example 8b Ethyl 3-chloro-4- (3-fluoro-4-methoxybenzoyl) -5-oxocyclohex-3-enecarboxylate
  • Methylene chloride (18 mL
  • 2-methyl-2-butene (1.74 mL, 16.4 mmol)
  • oxalyl dichloride 0.348 mL, 4.06 mmol
  • a crude product (1.37 g) of the title compound was obtained.
  • Example 8c Ethyl 3-chloro-4- (3-fluoro-4-methoxybenzoyl) -5-hydroxybenzoate
  • Crude product obtained in Example 8b (1.37 g, 3.86 mmol), N-methylmorpholine (15.6 mL), anhydrous sodium sulfate (11.0 g) and iodine (1.18 g, 4.65 mmol) were used to give a crude product of the title compound in the same manner as in Example 1d.
  • purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to obtain the amorphous title compound (672 mg).
  • Example 8d Ethyl 3-chloro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzoate Compound (670 mg, 1.90 mmol) obtained in Example 8c, methanol (8 mL) and hydrogenation 3-chloro-4- [1- (3-fluoro-4-methoxyphenyl) -1-hydroxymethyl] -5-hydroxybenzoate was prepared in the same manner as in Example 2b using sodium boron (144 mg, 3.81 mmol). Ethyl acid (670 mg) was obtained as a crude product and used in the next reaction without purification.
  • Example 8e 3-chloro-4- (3-fluoro-4-methoxybenzyl) -5-hydroxybenzyl acetate
  • Acetic acid mixture (525 mg), lithium aluminum hydride (118 mg, 3.11 mmol) and Tetrahydrofuran (8 mL) was used to obtain a mixture (333 mg) as amorphous by the same method as in Example 2d.
  • this mixture (322 mg) was dissolved in acetonitrile (4 mL), triethylsilane (0.430 mL, 2.70 mmol) was added, and after cooling to 0 ° C., boron trifluoride-diethyl ether complex (0.170 mL, 1.35 mmol) was added. And stirred at room temperature for 3 hours. Ethyl acetate (40 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (20 mL).
  • Example 8f 5-Acetoxymethyl-3-chloro-2- (3-fluoro-4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (328 mg, 0.54 mmol), methylene chloride (5 mL), The imidate was prepared in the same manner as Example 2g using trichloroacetonitrile (0.272 mL, 2.69 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7 ⁇ L, 0.05 mmol).
  • Example 8e Using the resulting imidate (406 mg), the compound obtained in Example 8e (140 mg, 0.41 mmol), methylene chloride (5 mL), MS4A and boron trifluoride-diethyl ether complex (0.068 mL, 0.54 mmol) In the same manner as in Example 2g, a crude product (540 mg) of the title compound was obtained.
  • Example 8g 3-chloro-2- (3-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 8f
  • the title compound 73 mg was obtained as a colorless solid in the same manner as in Example 2h.
  • solidification was performed from hexane / ethyl acetate / methanol.
  • Example 9a 3,5-difluoro-4- [1- (2-fluoro-4-methoxyphenyl) -1-hydroxymethyl] benzonitrile diisopropylamine (1.20 mL, 8.49 mmol), n-butyllithium (2.60 mL, 7.19mmol, 2.77M n-hexane solution), 3,5-difluorobenzonitrile (1.00g, 7.19mmol), 2-fluoro-4-methoxybenzaldehyde (1.11g, 7.20mmol) and tetrahydrofuran (17mL)
  • the title compound (1.66 g) was obtained as a pale yellow solid in the same manner as in Example 7a.
  • the purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 4: 1 to 2: 1, V / V).
  • Example 9b 3,5-difluoro-4- (2-fluoro-4-methoxybenzyl) benzonitrile
  • the compound obtained in Example 9a (1.66 g, 5.66 mmol), triethylsilane (2.7 mL, 17 mmol),
  • the title compound (1.29 g) was obtained as a colorless solid in the same manner as in Example 7b using boron trifluoride-diethyl ether complex (1.1 mL, 8.7 mmol) and acetonitrile (17 mL).
  • the purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 9: 1, V / V).
  • Example 9c 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methoxybenzyl) benzonitrile
  • the compound obtained in Example 9b (1.28 g, 4.62 mmol), sodium hydride (63% 0.26 g, 6.8 mmol), benzyl alcohol (0.66 g, 6.1 mmol) and N, N-dimethylformamide (13 mL) were used to prepare a crude product of the title compound (0.95 g) in the same manner as in Example 7c. Obtained as a yellow solid.
  • Example 9d 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methoxybenzyl) benzoic acid
  • Crude product obtained in Example 9c (0.95 g, 2.6 mmol)
  • 5M sodium hydroxide A crude product (0.97 g) of the title compound was obtained as a pale yellow solid in the same manner as in Example 7d using an aqueous solution (2.6 mL, 13 mmol) and ethanol (13 mL).
  • Example 9e 3-Fluoro-4- (2-fluoro-4-methoxybenzyl) -5-hydroxybenzoic acid
  • Crude product obtained in Example 9d (0.97 g, 2.5 mmol), 10% palladium on carbon catalyst (Water content, 0.20 g), tetrahydrofuran (10 mL), methanol (10 mL) and hydrogen were used in the same manner as in Example 7e to obtain a crude product (0.75 g) of the title compound as a pale yellow solid.
  • Example 9f 3-Fluoro-2- (2-fluoro-4-methoxybenzyl) -5- (hydroxymethyl) phenol
  • Crude product obtained in Example 9e (465 mg, 1.58 mmol), lithium aluminum hydride (0.12 g, 3.2 mmol) and tetrahydrofuran (12 mL) were used, and the title compound (0.37 g) was obtained as a colorless solid in the same manner as in Example 7f.
  • the purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 1: 1 to 2: 3, V / V).
  • Example 9g Acetic acid 3-fluoro-4- (2-fluoro-4-methoxybenzyl) -5-hydroxybenzyl
  • bis (dibutyltin chloride) oxide (0.22 g, 0.40 mmol)
  • vinyl acetate (2 mL)
  • tetrahydrofuran (2 mL)
  • the purification was performed using silica gel flash chromatography (hexane: ethyl acetate, 2: 1 to 3: 2, V / V).
  • Example 9h 5-Acetoxymethyl-3-fluoro-2- (2-fluoro-4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.74 g, 1.2 mmol), methylene chloride (7.5 mL ), Trichloroacetonitrile (0.36 mL, 3.6 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (20 ⁇ L, 0.13 mmol) were prepared in the same manner as in Example 1h.
  • Example 1h A crude product of the title compound was obtained in the same manner as above.
  • Example 10a Ethyl 3-chloro-4- [4- (difluoromethoxy) benzoyl] -5-oxocyclohex-3-enecarboxylate
  • the compound obtained in Example 3b (1.7 g, 5.0 mmol) was salified. Dissolved in methylene (20 mL) and performed with 2-methyl-2-butene (2.2 mL, 20 mmol), oxalyl chloride (0.45 mL, 5.2 mmol) and N, N-dimethylformamide (0.1 mL, 0.13 mmol) A crude product of the title compound (1.8 g) was obtained in the same manner as in Example 1c.
  • Example 10b Ethyl 3-chloro-4- [4- (difluoromethoxy) benzoyl] -5-hydroxybenzoate
  • the crude product obtained in Example 10a (1.8 g, 6.5 mmol) was converted to N-methylmorpholine ( 20 mL), and a crude product (1.9 g) of the title compound was obtained in the same manner as in Example 1d using anhydrous sodium sulfate (1.8 g) and iodine (1.5 g, 6.0 mmol).
  • Example 10c 3-Chloro-2- ⁇ 1- [4- (difluoromethoxy) phenyl] -1-hydroxymethyl ⁇ -5- (hydroxymethyl) phenol
  • the crude product obtained in Example 10b (1.8 g 4.9 mmol) was dissolved in tetrahydrofuran (55 mL), and the title compound (1.3 g) was obtained as a yellow solid in the same manner as in Example 1e using lithium aluminum hydride (0.57 g, 15 mmol).
  • Example 10d Acetic acid 3-chloro-4- ⁇ 1- [4- (difluoromethoxy) phenyl] -1-hydroxymethyl ⁇ -5-hydroxybenzyl
  • Example 10c 1.3 g, 4.0 mmol
  • the crude product obtained by the same method as in Example 1f is purified by silica gel flash chromatography using porcine pancreatic lipase (0.6 g). Purification using hexane: ethyl acetate, 4: 1, V / V) gave the title compound (0.99 g).
  • Example 10e Acetic acid 3-chloro-4- [4- (difluoromethoxy) benzyl] -5-hydroxybenzyl
  • the compound (0.99 g, 2.56 mmol) obtained in Example 10d was dissolved in acetonitrile (10 mL).
  • acetonitrile 10 mL
  • boron trifluoride-diethyl ether complex 0.49 mL, 3.9 mmol
  • Example 10f 5-Acetoxymethyl-3-chloro-2- [4- (difluoromethoxy) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ - D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.61 g, 1.0 mmol) in methylene chloride (4 mL) Dissolve and prepare the imidate by the same method as Example 1h using trichloroacetonitrile (0.3 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4.3 ⁇ L, 0.03 mmol).
  • Example 10g 3-Chloro-2- [4- (difluoromethoxy) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 10f
  • the mixture (0.40 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and the title compound (2) was added in a manner similar to Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). 32 mg) was obtained as a colorless solid.
  • Example 11a Ethyl 3-fluoro-4- [4- (2-fluoroethyl) benzoyl] -5-oxocyclohex-3-enecarboxylate
  • the crude product obtained in Example 1b (2.0 g, 6.2 mmol) was dissolved in methylene chloride (18 mL), and the title compound (1.6 g) was obtained in the same manner as in Example 3b using diethylaminosulfur trifluoride (2.5 mL, 19 mmol).
  • Example 11b Ethyl 3-fluoro-4- [4- (2-fluoroethyl) benzoyl] -5-hydroxybenzoate
  • the compound obtained in Example 11a (1.6 g, 4.9 mmol) was converted to N-methylmorpholine ( 16 mL) and the crude product (1.6 g) of the title compound was obtained in the same manner as in Example 3c using anhydrous sodium sulfate (1.6 g) and iodine (1.4 g, 5.4 mmol).
  • Example 11c Ethyl 3-fluoro-4- ⁇ 1- [4- (2-fluoroethyl) phenyl] -1-hydroxymethyl ⁇ -5-hydroxybenzoate
  • the crude product obtained in Example 11b (1.6 g, 4.9 mmol) was dissolved in ethanol (20 mL), and the title compound (0.83 g) was obtained as a colorless solid in the same manner as in Example 3d using sodium borohydride (0.37 g, 9.8 mmol).
  • Example 11d Ethyl 3-fluoro-4- [4- (2-fluoroethyl) benzyl] -5-hydroxybenzoate
  • the compound (0.83 g, 2.5 mmol) obtained in Example 11c was added to ethanol (15 mL). Dissolved, and the crude product of the title compound was obtained in the same manner as in Example 3e using 10% hydrogen chloride methanol (0.5 mL, 2.5 mmol) and 10% palladium carbon catalyst (containing water, 0.5 g).
  • the resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 5: 1, V / V) to obtain the title compound (0.37 g) as a colorless solid.
  • Example 11e 3-Fluoro-2- [4- (2-fluoroethyl) benzyl] -5- (hydroxymethyl) phenol
  • the compound (0.37 g, 1.2 mmol) obtained in Example 11d was added to tetrahydrofuran (15 mL).
  • the title compound (0.33 g) was obtained as a crude product in the same manner as in Example 3f using lithium aluminum hydride (0.13 g, 3.5 mmol).
  • Example 11f Acetic acid 3-fluoro-4- [4- (2-fluoroethyl) benzyl] -5-hydroxybenzyl
  • the crude product obtained in Example 11e (0.33 g, 1.2 mmol) was converted into vinyl acetate (5 mL).
  • diisopropyl ether (5 mL)
  • the porcine pancreatic lipase 1.0 g
  • the title compound (0.35 g) was obtained as a pale brown solid in the same manner as in Example 3 g.
  • Example 11g 5-Acetoxymethyl-3-fluoro-2- [4- (2-fluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.61 g, 1.0 mmol) in methylene chloride (4 mL
  • the imidate was prepared in the same manner as in Example 1h using trichloroacetonitrile (0.30 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4 ⁇ L, 0.03 mmol).
  • Example 11f Using this imidate (0.75 g, 1.0 mmol), the compound obtained in Example 11f (0.25 g, 0.78 mmol) and boron trifluoride-diethyl ether complex (39 ⁇ L, 0.39 mmol), the same method as in Example 1h Gave a mixture containing the title compound.
  • Example 11h 3-Fluoro-2- [4- (2-fluoroethyl) benzyl] -5-hydroxymethyl-phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 11g
  • the title compound was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL) in the same manner as in Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). (0.21 g) was obtained as a colorless solid.
  • Example 12 3-Fluoro-5-hydroxymethyl-2- (4-trifluoromethoxybenzyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside (No. 3 in Table 1)
  • Example 12a Ethyl 3-hydroxy-5-oxo-4- [4- (trifluoromethoxy) benzoyl] cyclohex-3-enecarboxylate ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate ( 1.3 g, 7.3 mmol) and 4- (trifluoromethoxy) benzoyl chloride (J. Med. Chem., 45 (14), 2002, 3112-3129.) (1.6 g, 7.3 mmol) In the same manner, a crude product (2.4 g) of the title compound was obtained.
  • Example 12b 3-Fluoro-5-oxo-4- [4- (trifluoromethoxy) benzoyl] cyclohex-3-enecarboxylic acid ethyl ester
  • Crude product obtained in Example 12a (1.8 g, 5.4 mmol ) was dissolved in methylene chloride (15 mL), and the title compound (1.5 g) was obtained as a yellow oil by the same method as Example 3b using diethylaminosulfur trifluoride (2.1 mL, 16 mmol).
  • Example 12c Ethyl 3-fluoro-5-hydroxy-4- [4- (trifluoromethoxy) benzoyl] benzoate
  • the compound obtained in Example 12b (1.5 g, 4.5 mmol) was converted to N-methylmorpholine (18 mL).
  • Example 1d using anhydrous sodium sulfate (1.5 g) and iodine (1.3 g, 5.0 mmol), a crude product (1.5 g) of the title compound was obtained.
  • Example 12d 3-Fluoro-5-hydroxy-4- ⁇ 1-hydroxy-1- [4- (trifluoromethoxy) phenyl] methyl ⁇ ethyl benzoate
  • the crude product obtained in Example 12c (1.5 g 4.5 mmol) was dissolved in ethanol (15 mL), and the title compound (1.0 g) was obtained in the same manner as in Example 3d using sodium borohydride (0.34 g, 9.0 mmol).
  • Example 12e 3-Fluoro-5-hydroxymethyl-2- ⁇ 1-hydroxy-1- [4- (trifluoromethoxy) phenyl] methyl ⁇ phenol
  • the compound obtained in Example 12d (1.0 g, 3.0 mmol ) was dissolved in tetrahydrofuran (20 mL), and the title compound (1.0 g) was obtained in the same manner as in Example 1e (but without purification) using lithium aluminum hydride (0.46 g, 12 mmol). Obtained as a crude product.
  • Example 12f 3-fluoro-5-hydroxy-4- ⁇ 1-hydroxy-1- [4- (trifluoromethoxy) phenyl] methyl ⁇ benzyl acetate
  • Acetic acid 1.0 g, 3.0 mmol
  • vinyl acetate 5 mL
  • diisopropyl ether 5 mL
  • the crude product obtained in the same manner as in Example 1f was purified by silica gel flash using porcine pancreatic lipase (1.0 g). Purification using chromatography (hexane: ethyl acetate, 4: 1, V / V) gave the title compound (0.65 g).
  • Example 12g 3-fluoro-5-hydroxy-4- [4- (trifluoromethoxy) benzyl] benzyl acetate
  • the compound (0.65 g, 1.7 mmol) obtained in Example 12f was dissolved in acetonitrile (10 mL).
  • Triethylsilane (0.83 mL, 5.2 mmol) and boron trifluoride-diethyl ether complex (0.33 mL, 2.6 mmol) were used in the same manner as in Example 1g to obtain the title compound (0.18 g).
  • Example 12h 5-Acetoxymethyl-3-fluoro-2- [4- (trifluoromethoxy) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.61 g, 1.0 mmol) in methylene chloride (4 mL)
  • the imidate was prepared in the same manner as Example 1h using trichloroacetonitrile (0.3 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4.3 ⁇ L, 0.03 mmol).
  • Example 12i 3-Fluoro-5-hydroxymethyl-2- [4- (trifluoromethoxy) benzyl] phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside Mixture obtained in Example 12h (0.50 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and the title compound (0.12 g) was prepared in the same manner as in Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). ) was obtained as a colorless solid.
  • Example 13a 5-Acetoxymethyl-3-fluoro-2- (4-methylbenzyl) phenyl 4-deoxy-2,3,6-tri-O-benzoyl- ⁇ -D-glucopyranoside 4-deoxy-2, 3,6-tri-4-O-benzoyl-D-glucopyranoside (Liebig Ann.
  • Example 4i using 5-hydroxybenzyl (WO2008 / 016132 (PCT / JP2007 / 65231)) (100 mg, 0.35 mmol), boron trifluoride-diethyl ether complex (44 ⁇ L, 0.35 mmol) and methylene chloride (5 mL) In the same manner as above, a crude product (285 mg) of the title compound was obtained.
  • 5-hydroxybenzyl WO2008 / 016132 (PCT / JP2007 / 65231)
  • boron trifluoride-diethyl ether complex 44 ⁇ L, 0.35 mmol
  • methylene chloride 5 mL
  • Example 13b 3-Fluoro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy- ⁇ -D-glucopyranoside
  • Crude product obtained in Example 13a (285 mg, 0.35 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (48 mg, 0.35 mmol) were used in the same manner as in Example 4j to obtain the title compound (90 mg) as a colorless solid.
  • Example 4h The compound obtained in Example 4h (100 mg, 0.33 mmol), boron trifluoride-diethyl A crude product (291 mg) of the title compound was obtained in the same manner as in Example 4i using an ether complex (41 ⁇ L, 0.33 mmol) and methylene chloride (5 mL).
  • Example 14b 3-Chloro-5-hydroxymethyl-2- (4-methylbenzyl) phenyl 4-deoxy- ⁇ -D-glucopyranoside
  • Crude product obtained in Example 14a (291 mg, 0.33 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (46 mg, 0.33 mmol) were used in the same manner as in Example 4j to obtain the title compound (106 mg) as a colorless solid.
  • Example 15a 5-Acetoxymethyl-2- (4-ethylbenzyl) -3-fluorophenyl 4-deoxy-2,3,6-tri-O-benzoyl- ⁇ -D-glucopyranoside 4-deoxy-2, 3,6-tri-4-O-benzoyl-D-glucopyranoside (189 mg, 0.40 mmol), trichloroacetonitrile (120 ⁇ L, 1.20 mmol), 1,8-diazabicyclo [5.4.0] -7-undecene (6 ⁇ L, 0.04 mmol) ) And methylene chloride (5 mL), and an imidate was prepared in the same manner as in Example 4i.
  • Example 15b 2- (4-Ethylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy- ⁇ -D-glucopyranoside
  • Example 15a 3-(2-Ethylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy- ⁇ -D-glucopyranoside
  • Tetrahydrofuran (1 mL
  • methanol 4 mL
  • calcium carbonate 46 mg, 0.33 mmol
  • Example 2f Using the resulting imidate (248 mg), the compound obtained in Example 2f (100 mg, 0.31 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.050 mL, 0.40 mmol) In the same manner as in Example 2g, a crude product (270 mg) of the title compound was obtained.
  • Example 16b 3-chloro-2- (4-ethylbenzyl) -5- (hydroxymethyl) phenyl 4-deoxy- ⁇ -D-glucopyranoside
  • Crude product obtained in Example 16a 270 mg
  • the title compound (126 mg) was obtained as a colorless solid in the same manner as in Example 2h using methylene chloride (8 mL / 2 mL) and potassium carbonate (550 mg, 3.98 mmol). However, solidification was performed from hexane / ethyl acetate.
  • Example 17b 2- (4-Cyclopropylbenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 4-deoxy- ⁇ -D-glucopyranoside
  • the crude product obtained in Example 17a (301 mg, 0.32 mmol) ), Tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (44 mg, 0.32 mmol) were obtained in the same manner as in Example 4j to obtain the title compound (107 mg) as a colorless solid.
  • Example 18a 4- (2,2,2-trifluoroethyl) benzoyl chloride 4- (2,2,2-trifluoroethyl) benzoic acid (Liebigs Ann. Chem., 1983, 9, 1510-1523. ) (786 mg, 3.85 mmol), oxalyl dichloride (0.385 mL, 4.42 mmol), catalytic amounts of N, N-dimethylformamide and tetrahydrofuran (6 mL) in the same manner as in Example 1a to give a crude product of the title compound Product (857 mg) was obtained.
  • Example 18b Ethyl 3-hydroxy-5-oxo-4- [4- (2,2,2-trifluoroethyl) benzoyl] cyclohex-3-enecarboxylate 3-hydroxy-5-oxocyclohexa-3 -Ethylencarboxylate (709 mg, 3.85 mmol), crude product obtained in Example 18a (857 mg, 3.85 mmol), acetonitrile (10 mL), triethylamine (1.61 mL, 11.5 mmol) and trimethylsilylcyanide (0.062 mL, 0.46 mmol) was used in the same manner as in Example 1b to obtain a crude product of the title compound (1.42 g).
  • Example 18c Ethyl 3-fluoro-5-oxo-4- [4- (2,2,2-trifluoroethyl) benzoyl] cyclohex-3-enecarboxylate
  • the crude product obtained in Example 18b ( 1.42 g, 3.61 mmol), methylene chloride (15 mL) and diethylaminosulfur trifluoride (1.51 mL, 11.5 mmol) were used to give the title compound (953 mg) as a white solid in the same manner as in Example 3b.
  • Example 18c Using the compound obtained in Example 18c (953 mg, 2.56 mmol), N-methylmorpholine (12 mL), anhydrous sodium sulfate (7.27 g) and iodine (779 mg, 3.07 mmol), the title was prepared in the same manner as in Example 1d. A crude product of the compound was obtained. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to give the amorphous title compound (614 mg).
  • Example 18e 3-Fluoro-5-hydroxymethyl-2- [1-hydroxy-1- ⁇ 4- (2,2,2-trifluoroethyl) phenyl ⁇ methyl] phenol
  • Compound obtained in Example 18d (610 mg, 1.65 mmol) was dissolved in tetrahydrofuran (15 mL), cooled to 0 ° C., lithium aluminum hydride (187 mg, 4.93 mmol) was added, and the mixture was stirred at room temperature for 30 min.
  • Example 18f 3-Fluoro-5-hydroxymethyl-2- [1-methoxy-1- ⁇ 4- (2,2,2-trifluoroethyl) phenyl ⁇ methyl] phenol
  • the product (540 mg, 1.64 mmol) was dissolved in methanol (10 mL), paratoluenesulfonic acid monohydrate (157 mg, 0.83 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr.
  • the reaction mixture was cooled to room temperature, triethylamine was added, and the mixture was concentrated under reduced pressure.
  • the residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 1: 4, V / V) to give the title compound (508 mg) as an oil.
  • Example 18g Acetic acid 3-fluoro-5-hydroxy-4- ⁇ 1-methoxy-1- [4- (2,2,2-trifluoroethyl) phenyl] methyl ⁇ benzyl
  • Compound obtained in Example 18f (508 mg, 1.48 mmol), tetrahydrofuran (5 mL), vinyl acetate (5 mL) and bis (dibutyltin chloride) oxide (325 mg, 0.59 mmol) were used in the same manner as in Example 2e to give the oily title compound (525 mg). Obtained.
  • Example 18h 3-Fluoro-5-hydroxy-4- [4- (2,2,2-trifluoroethyl) benzyl] benzyl acetate
  • Acetic acid 525 mg, 1.36 mmol
  • acetonitrile 10 mL
  • triethylsilane 0.650 mL, 4.08 mmol
  • boron trifluoride-diethyl ether complex 0.256 mL, 2.04 mmol
  • Example 18i 5-Acetoxymethyl-3-fluoro-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl -D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (267 mg, 0.44 mmol), The imidate was prepared in the same manner as in Example 2g using methylene chloride (5 mL), trichloroacetonitrile (0.221 mL, 2.19 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7 ⁇ L, 0.05 mmol).
  • Example 18j 3-Fluoro-5-hydroxymethyl-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside
  • methanol / methylene chloride 8 mL / 2 mL
  • potassium carbonate 604 mg, 4.34 mmol
  • the title compound was obtained as a white solid. Obtained. However, solidification was performed from hexane / ethyl acetate / methanol.
  • Example 19a Methyl 4-acetyl-3-fluorobenzoate 4-acetyl-3-fluorophenyl sulfonate (Org. Lett., 2002, 4 (26), 4717-4718.) (8.69 g, 30.4 mmol) in N, N-dimethylformaldehyde (120 mL), methanol (24.6 mL, 606 mmol), palladium acetate (682 mg, 3.03 mmol), 1,3-bis (diphenylphosphino) propane (1.25 g, 3.03 mmol) ) And triethylamine (84.0 mL, 606 mol) were added, and the mixture was stirred at room temperature for 16 hours under a carbon monoxide atmosphere.
  • Example 19b Methyl 3-fluoro-4- (1-hydroxyethyl) benzoate
  • the compound obtained in Example 19a (3.67 g, 18.7 mmol) was dissolved in methanol (40 mL) and cooled to 0 ° C.
  • Sodium borohydride (850 mg, 22.5 mmol) was added and stirred at 0 ° C. for 1 hour.
  • a saturated aqueous ammonium chloride solution (2 mL) was added to the reaction solution, and the solvent was removed under reduced pressure.
  • Example 19c 4-Ethyl-3-fluorobenzoic acid
  • the compound obtained in Example 19b (3.67 g, 18.7 mmol) was dissolved in methanol (35 mL), 2 mol / L hydrochloric acid (1.09 mL) and 10% wet Palladium / carbon (600 mg) was added, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
  • the reaction solution was filtered through celite to remove palladium. Subsequently, a 5 mol / L aqueous sodium hydroxide solution (8 mL) and an appropriate amount of tetrahydrofuran were added to the reaction solution, and the mixture was stirred at 50 ° C. for 1 hour.
  • Example 19d 4-ethyl-3-fluorobenzoyl chloride The compound obtained in Example 19c (730 mg, 4.34 mmol), oxalyl dichloride (0.43 mL, 4.95 mmol), catalytic amounts of N, N-dimethylformamide and A crude product of the title compound (810 mg) was obtained as a colorless oil by a method similar to Example 1a using tetrahydrofuran (6 mL).
  • Example 19e Ethyl 4- (4-ethyl-3-fluorobenzoyl) -3-hydroxy-5-oxocyclohex-3-enecarboxylate
  • Ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate 800 mg, 4.34 mmol
  • acetonitrile 9 mL
  • triethylamine 1.82 mL, 13.1 mmol
  • trimethylsilylcyanide 0.070 mL, 0.52 mmol
  • Example 19f Ethyl 3-chloro-4- (4-ethyl-3-fluorobenzoyl) -5-oxocyclohex-3-enecarboxylate
  • Crude product obtained in Example 19e (1.45 g, 4.34 mmol ), Methylene chloride (18 mL), 2-methyl-2-butene (1.84 mL, 17.3 mmol), oxalyl dichloride (0.39 mL, 4.55 mmol) and a catalytic amount of N, N-dimethylformamide and
  • a crude product (1.52 g) of the title compound was obtained.
  • Example 19g Ethyl 3-chloro-4- (4-ethyl-3-fluorobenzoyl) -5-hydroxybenzoate
  • Crude product obtained in Example 19f (1.52 g, 4.34 mmol), N-methylmorpholine (18 mL), anhydrous sodium sulfate (12.3 g) and iodine (1.32 g, 5.20 mmol) were used to give a crude product of the title compound in the same manner as in Example 1d.
  • the resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to give the amorphous title compound (1.04 g).
  • Example 19h Ethyl 5-chloro-4- (4-ethyl-3-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-benzoate obtained in Example 19g
  • a crude diol product (1.04 g) was obtained in the same manner as in Example 2b, using the compound (1.04 g, 2.96 mmol), methanol (12 mL) and sodium borohydride (220 mg, 5.82 mmol).
  • Example 19i 5-chloro-4- (4-ethyl-3-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ylmethanol
  • Compound obtained in Example 19h (730 mg, 1.86 mmol), lithium aluminum hydride (71 mg, 1.87 mmol) and tetrahydrofuran (8 mL) were used in the same manner as in Example 2d to obtain a crude product of the title compound (664 mg) as an oil.
  • Example 19j Acetic acid 5-chloro-4- (4-ethyl-3-fluorophenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ylmethyl Crude obtained in Example 19i Using the product (664 mg), pyridine (6.6 mL) and acetic anhydride (1.7 mL), the title compound (720 mg) was obtained in the same manner as in Example 6g.
  • Example 19k Acetic acid 3-chloro-4- (4-ethyl-3-fluorobenzyl) -5-hydroxybenzyl Compound (720 mg, 1.83 mmol) obtained in Example 19j, acetonitrile (12 mL), triethylsilane ( 0.880 mL, 5.47 mmol) and boron trifluoride-diethyl ether complex (0.350 mL, 2.79 mmol) were used in the same manner as in Example 2f to obtain the title compound (491 mg) as a colorless solid.
  • Example 19l 5-acetoxymethyl-3-chloro-2- (4-ethyl-3-fluorobenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) 318 mg, 0.52 mmol), methylene chloride (5 mL), trichloroacetonitrile (0.263 mL, 2.60 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (7 ⁇ L, 0.05 mmol) as in Example 2g
  • the imidate was prepared by the method.
  • Example 19k Performed using the obtained imidate (393 mg), the compound obtained in Example 19k (135 mg, 0.40 mmol), methylene chloride (5 mL), MS4A and boron trifluoride-diethyl ether complex (0.065 mL, 0.52 mmol). In the same manner as in Example 2g, a crude product (380 mg) of the title compound was obtained.
  • Example 19m 3-Chloro-2- (4-ethyl-3-fluorobenzyl) -5-hydroxymethylphenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside Crude obtained in Example 19l
  • the title compound (67 mg) was obtained as a white solid in the same manner as in Example 2h using the product (380 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (720 mg, 5.21 mmol). However, solidification was performed from hexane / ethyl acetate / methanol.
  • the reaction mixture was diluted with ethyl acetate (50 mL), and washed successively with 10% brine (10 mL, 3 times) and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.2 g) of the title compound.
  • Example 20b 3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) benzaldehyde
  • the crude product obtained in Example 20a (1.2 g, 3.3 mmol) was dissolved in chloroform (12 mL).
  • Manganese (4.3 mL, 50 mmol) was added, and the mixture was stirred with heating under reflux for 2.5 hours.
  • the suspension was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain a crude product (1.2 g) of the title compound.
  • Example 20c 1-benzyloxy-3-fluoro-2- (4-methoxybenzyl) -5- (2-methoxyvinyl) benzene (methoxymethyl) triphenylphosphonium chloride (3.4 g, 10 mmol) was added to tetrahydrofuran (8 mL). And stirred under ice cooling. Lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 10 mL, 10 mmol) was added dropwise to this suspension, and the mixture was stirred for 30 minutes while warming to room temperature.
  • a tetrahydrofuran solution (8 mL) in which the crude product (1.2 g, 3.3 mmol) obtained in Example 20b was dissolved was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours.
  • a saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (20 mL, twice), and the organic layer was washed with saturated brine (10 mL, twice).
  • Example 20d 3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) phenylacetaldehyde
  • the compound obtained in Example 20c (0.92 g, 2.4 mmol) was dissolved in 1,4-dioxane (10 mL). Under ice-cooling, water (0.43 mL, 24 mmol) and 4M hydrogen chloride 1,4-dioxane solution (6.0 mL, 24 mmol) were added, and the mixture was stirred for 1 hour while warming to room temperature.
  • the solution was diluted with ethyl acetate (50 mL), and washed successively with 10% brine (10 mL, twice), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.87 g) of the title compound.
  • Example 20e 2- [3-Benzyloxy-5-fluoro-4- (4-methoxybenzyl) phenyl] ethanol
  • the crude product obtained in Example 20d (0.87 g, 2.4 mmol) was added to tetrahydrofuran (4 mL).
  • tetrahydrofuran (4 mL)
  • sodium borohydride (0.14 g, 3.6 mmol) was added under ice cooling.
  • the reaction solution was stirred for 40 minutes while warming to room temperature, and saturated aqueous ammonium chloride solution (1 mL) was added dropwise under ice cooling to stop the reaction.
  • Example 20f 3-Fluoro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenol
  • the compound obtained in Example 20e (0.57 g, 1.6 mmol) was mixed with tetrahydrofuran (3 mL) and methanol ( 3 mL), and stirred for 10 minutes while blowing nitrogen into the solution.
  • 10% palladium carbon catalyst (containing water, 0.12 g) was added under a nitrogen stream, and the gas phase was replaced with hydrogen, followed by stirring at room temperature for 1 hour.
  • the mixture was filtered through celite, and the solvent was removed under reduced pressure to obtain a crude product of the title compound (0.44 g).
  • Example 20g 2- [3-Fluoro-5-hydroxy-4- (4-methoxybenzyl) phenyl] ethyl acetate
  • the crude product obtained in Example 20f (0.44 g, 1.6 mmol) was dissolved in collidine (5.0 mL). ), Acetyl chloride (0.11 mL, 1.6 mmol) was added at ⁇ 20 ° C., and the mixture was stirred for 2 hours while raising the temperature to 0 ° C.
  • Water (1 mL) was added to the reaction mixture, diluted with ethyl acetate (30 mL), and washed successively with 30% aqueous citric acid solution (10 mL, twice) and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.51 g, including raw materials).
  • Example 20h 5- (2-acetoxyethyl) -3-fluoro-2- (4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (0.43 g, 0.71 mmol) in methylene chloride (4 mL)
  • the imidate was prepared in the same manner as in Example 1h using trichloroacetonitrile (0.20 mL, 2.1 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (3 ⁇ L, 0.02 mmol).
  • Example 11f Similar to Example 1h using this imidate (0.75 g, 1.0 mmol), the compound obtained in Example 11f (0.51 g, 1.6 mmol) and boron trifluoride-diethyl ether complex (0.05 mL, 0.4 mmol). By the method, a mixture containing the title compound was obtained.
  • Example 20i 3-Fluoro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside Mixture obtained in Example 20h (1.6 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and the title compound (64 mg) was prepared in the same manner as in Example 3i using 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol). Was obtained as a colorless solid.
  • Example 21a Acetic acid 3-benzyloxy-5-chloro-4- (4-methylbenzyl) benzyl Compound (500 mg, 3.3 mmol) obtained in Example 4h was dissolved in N, N-dimethylformamide (10 mL). Benzyl bromide (430 ⁇ L, 3.6 mmol) and potassium carbonate (680 mg, 4.9 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with distilled water (10 mL) and saturated brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (1.13 g) of the title compound as a yellow oily substance.
  • Example 21b 3-Benzyloxy-5-chloro-4- (4-methylbenzyl) benzyl alcohol
  • the crude product obtained in Example 21a (1.13 g, 2.9 mmol) was dissolved in methanol (12 mL).
  • 1M aqueous potassium hydroxide solution (3.3 mL, 3.3 mmol) was added, and the mixture was stirred at room temperature for 18 hours.
  • the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate (10 mL), and washed successively with distilled water (10 mL) and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (0.91 g) of the title compound as a yellow oily substance.
  • Example 21c 3-Benzyloxy-5-chloro-4- (4-methylbenzyl) benzaldehyde
  • the crude product (0.91 g, 2.6 mmol) obtained in Example 21b was dissolved in chloroform (10 mL) Manganese (2.85 g, 32.8 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. After filtration through celite, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.68 g) as a brown solid.
  • Example 21d 1-benzyloxy-3-chloro-5- (2-methoxyvinyl) -2- (4-methylbenzyl) benzene (methoxymethyl) triphenylphosphonium chloride (2.0 g, 5.4 mmol) in toluene ( 5 mL) was added, and the solvent was distilled off under reduced pressure. To the residue were added tetrahydrofuran (4 mL) and lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 5.9 mL, 5.9 mmol) under ice cooling, and the mixture was stirred at room temperature for 1 hour.
  • Example 21c a tetrahydrofuran solution (6 mL) in which the crude product obtained in Example 21c (0.68 g, 1.9 mmol) was dissolved was added dropwise to the reaction solution, followed by stirring at room temperature for 1 hour.
  • the reaction mixture was diluted with ethyl acetate (10 mL) and washed successively with distilled water (10 mL) and saturated brine (5 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • the residue was purified using silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 5: 1, V / V) to obtain the title compound (0.95 g, quant.) As a yellow solid.
  • Example 21e 3-Benzyloxy-5-chloro-4- (4-methylbenzyl) phenylacetaldehyde
  • the compound obtained in Example 21d (0.95 g, 1.9 mmol) was dissolved in 1,4-dioxane (5 mL).
  • Distilled water (350 ⁇ L) and 4N hydrochloric acid 1,4-dioxane solution (5 mL) were added, and the mixture was stirred at room temperature for 10 minutes.
  • the reaction mixture was diluted with ethyl acetate (10 mL) and washed successively with distilled water (5 mL) and saturated brine (10 mL).
  • the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Example 21f 2- [3-Benzyloxy-5-chloro-4- (4-methylbenzyl) phenyl] ethanol
  • methanol 5 mL
  • sodium borohydride 60 mg, 1.6 mmol
  • the reaction mixture was stirred at 0 ° C. for 30 min.
  • saturated aqueous ammonium chloride solution 5 mL
  • saturated brine 10 mL
  • Example 21g 3-Chloro-5- (2-hydroxyethyl) -2- (4-methylbenzyl) phenol
  • the crude product (0.41 g, 1.1 mmol) obtained in Example 21f was added to acetonitrile (5 mL).
  • trimethylsilyl iodide (320 ⁇ L, 2.2 mmol) was added, and the mixture was stirred at 40 ° C. for 2 hours.
  • the reaction mixture was diluted with ethyl acetate (15 mL) and washed successively with 2M hydrochloric acid (10 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL).
  • Example 21h 2- ⁇ [3-Chloro-5-hydroxy-4- (4-methylbenzyl)] phenyl ⁇ ethyl acetate
  • the compound (122 mg, 0.4 mmol) obtained in Example 21 g was added to tetrahydrofuran (2 mL). Dissolved, vinyl acetate (2 mL, 21.6 mmol) and bis (dibutyltin chloride) oxide (24 mg, 0.04 mmol) were added and stirred at room temperature for 24 hours.
  • Example 21i 5- (2-acetoxyethyl) -3-chloro-2- (4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (255 mg, 0.42 mmol), trichloroacetonitrile (125 ⁇ L, 1.25 mmol), 1 , 8-diazabicyclo [5.4.0] -7-undecene (6 ⁇ L, 0.04 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i, and the compound obtained in Example 21h (111 mg, 0.35 mmol), boron trifluoride-diethyl ether complex (44 ⁇ L, 0.35 mmol
  • Example 21j 3-Chloro-5- (2-hydroxyethyl) -2- (4-methylbenzyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside
  • Compound obtained in Example 21i (391 mg, 0.35 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (48 mg, 0.35 mmol) were used in the same manner as in Example 4j to obtain the title compound (104 mg) as a colorless solid.
  • Example 22a 3-Chloro-4- (4-methoxybenzyl) -5- (methoxymethoxy) benzyl alcohol Acetic acid 3-chloro-5-hydroxy-4- (4-methoxybenzyl) benzyl (WO2008 / 016132 (PCT / JP2007 / 65231)) (500 mg, 1.6 mmol) dissolved in N, N-dimethylformamide (5 mL), and ice-cooled, chloromethyl methyl ether (180 ⁇ L, 2.4 mmol) and calcium carbonate (1.08 g, 7.8 mmol) And stirred at room temperature for 4 hours. Methanol (5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour.
  • Example 22b 3-Chloro-4- (4-methoxybenzyl) -5- (methoxymethoxy) benzaldehyde
  • the crude product obtained in Example 22a (511 mg, 1.6 mmol), chloroform (10 mL) and manganese dioxide ( 1.36 g (15.6 mmol) was used in the same manner as in Example 21c to obtain a crude product of the title compound (480 mg) as a pale yellow oily substance.
  • Example 22c 1-chloro-2- (4-methoxybenzyl) -3-methoxymethoxy-5- (2-methoxyvinyl) benzene
  • Crude product obtained in Example 22b (480 mg, 1.5 mmol), chloride (Methylmethoxy) triphenylphosphonium (1.60 g, 4.8 mmol), lithium bis (trimethylsilyl) amide (1M tetrahydrofuran solution, 4.7 mL, 4.7 mmol) and tetrahydrofuran (8 mL) were used in the same manner as in Example 21d.
  • the compound (810 mg, quant.) was obtained as a yellow oil.
  • the purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 20: 1 to 15: 1 to 10: 1, V / V).
  • Example 22d 3-chloro-5-hydroxy-4- (4-methoxybenzyl) phenylacetaldehyde
  • the compound obtained in Example 22c (810 mg, 1.5 mmol), 1,4-dioxane solution (4 mL) in 4N hydrochloric acid,
  • the title compound (210 mg) was obtained as a yellow oil in the same manner as in Example 21e using distilled water (280 ⁇ L) and 1,4-dioxane (4 mL).
  • the purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 8: 1 to 6: 1 to 4: 1, V / V).
  • Example 22e 3-Chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenol
  • the compound obtained in Example 22d (210 mg, 0.72 mmol), sodium borohydride (33 mg, 0.87) mmol) and methanol (2.5 mL) were used to give the title compound (157 mg) as a colorless oil in the same manner as in Example 21f.
  • Example 22f 2- ⁇ [3-Chloro-5-hydroxy-4- (4-methoxybenzyl)] phenyl ⁇ ethyl acetate
  • the compound obtained in Example 22e (157 mg, 0.54 mmol), vinyl acetate (2 mL, 21.61 mmol), bis (dibutyltin chloride) oxide (38 mg, 0.07 mmol) and tetrahydrofuran (2 mL) were used in the same manner as in Example 21h to obtain the title compound (218 mg) as a colorless solid.
  • the purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 4: 1 to 3: 1, V / V).
  • Example 22g 5-Acetoxymethyl-3-chloro-2- (4-methoxybenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco -Heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (220 mg, 0.36 mmol), trichloroacetonitrile (110 ⁇ L, 1.10 mmol), 1,8-diazabicyclo [5.4.0] -7-Undecene (6 ⁇ L, 0.04 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i, and the compound (100 mg, 0.30) obtained in Example 22f was prepared.
  • Example 22h 3-Chloro-5- (2-hydroxyethyl) -2- (4-methoxybenzyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside Crude obtained in Example 22g Using the product (320 mg, 0.30 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and calcium carbonate (41 mg, 0.30 mmol), the title compound (81 mg) was obtained as a colorless solid in the same manner as in Example 4j. .
  • Example 23a Ethyl 3-chloro-5-oxo-4- [4- (2,2,2-trifluoroethyl) benzoyl] cyclohex-3-enecarboxylate
  • the crude product obtained in Example 18b ( 1.34 g, 3.61 mmol), methylene chloride (15 mL), 2-methyl-2-butene (1.54 mL, 14.5 mmol), oxalyl dichloride (0.32 mL, 3.73 mmol) and a catalytic amount of N, N-dimethylformamide
  • a crude product (1.40 g) of the title compound was obtained.
  • Example 23b Ethyl 3-chloro-5-hydroxy-4- [4- (2,2,2-trifluoroethyl) benzoyl] benzoate
  • Crude product obtained in Example 23a (1.40 g, 3.60 mmol ), N-methylmorpholine (16 mL), anhydrous sodium sulfate (10.3 g) and iodine (1.10 g, 4.33 mmol) were used to give a crude product of the title compound in the same manner as in Example 1d.
  • the resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 3: 1, V / V) to give the amorphous title compound (1.02 g).
  • Example 23c 3-Chloro-5-hydroxymethyl-2- [1-hydroxy-1- ⁇ 4- (2,2,2-trifluoroethyl) phenyl ⁇ methyl] phenol Compound obtained in Example 23b (1.02 g, 2.64 mmol), tetrahydrofuran (30 mL) and lithium aluminum hydride (300 mg, 7.91 mmol) were used in the same manner as in Example 18e to obtain a crude product (866 mg) of the title compound.
  • Example 23d 3-chloro-5-hydroxymethyl-2- [1-methoxy-1- ⁇ 4- (2,2,2-trifluoroethyl) phenyl ⁇ methyl] phenol Crude obtained in Example 23c Using the product (866 mg, 2.50 mmol), methanol (16 mL) and paratoluenesulfonic acid monohydrate (238 mg, 1.25 mmol), the title compound (654 mg) as an oil was obtained in the same manner as in Example 18f. .
  • Example 23e Acetic acid 3-chloro-4- [1-methoxy-1- ⁇ 4- (2,2,2-trifluoroethyl) phenyl ⁇ methyl] -5-hydroxybenzyl
  • Compound obtained in Example 23d (654 mg, 1.81 mmol), tetrahydrofuran (6 mL), vinyl acetate (6 mL) and bis (dibutyltin chloride) oxide (302 mg, 0.55 mmol) were used in the same manner as in Example 2e to give the oily title compound (703 mg). Obtained.
  • Example 23f Acetic acid 3-chloro-4- [4- (2,2,2-trifluoroethyl) benzyl] -5-hydroxybenzyl
  • acetonitrile 15 mL
  • triethylsilane 0.34 mL, 5.24 mmol
  • boron trifluoride-diethyl ether complex 0.329 mL, 2.62 mmol
  • Example 23g 5-Acetoxymethyl-3-chloro-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl -D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (213 mg, 0.35 mmol), The imidate was prepared in the same manner as in Example 2g using methylene chloride (4 mL), trichloroacetonitrile (0.176 mL, 1.74 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (5 ⁇ L, 0.03 mmol).
  • Example 23f the compound obtained in Example 23f (105 mg, 0.23 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.044 mL, 0.34 mmol)
  • a crude product 280 mg of the title compound was obtained.
  • Example 23h 3-Chloro-5-hydroxymethyl-2- [4- (2,2,2-trifluoroethyl) benzyl] phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside
  • the title compound (84 mg) was obtained as a white solid in the same manner as in Example 2h using 23 g of the crude product (280 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (480 mg, 3.47 mmol). Obtained. However, solidification was performed from hexane / ethyl acetate.
  • Example 24a 2-Fluoro-4-methylbenzoyl chloride 2-fluoro-4-methylbenzoic acid (500 mg, 3.24 mmol), oxalyl dichloride (0.31 mL, 3.57 mmol) and a catalytic amount of N, N-dimethylformamide , Tetrahydrofuran (10 mL) was used to give a crude product of the title compound (560 mg) as a colorless oil in the same manner as in Example 1a.
  • Example 24b (2-chloro-6-hydroxy-4-methoxyphenyl) (2-fluoro-4-methylphenyl) methanone 1-chloro-3,5-dimethoxybenzene (560 mg, 3.24 mmol), toluene (3 mL ), Aluminum chloride (480 mg, 3.60 mmol) and the crude product obtained in Example 24a (560 mg, 3.24 mmol) using the same method as in Example 2a to obtain the crude product of the title compound (630 mg). Obtained as a solid.
  • Example 24c (2-Chloro-4,6-dihydroxyphenyl) (2-fluoro-4-methylphenyl) methanone
  • the crude product obtained in Example 24b (510 mg, 1.73 mmol) was converted to 1,2-dichloroethane. (5 mL), aluminum chloride (460 mg, 3.45 mmol) was added, and the mixture was stirred at 80 ° C. for 1.5 hr.
  • the reaction mixture was cooled to 0 ° C., added with an appropriate amount of ice, stirred for 5 minutes, extracted with ethyl acetate (40 mL), and washed with 2 mol / L hydrochloric acid (10 mL) and saturated sodium hydrogen carbonate solution (20 mL).
  • Example 24d 5-chloro-4- (2-fluoro-4-methylphenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-ol
  • the product (366 mg, 1.30 mmol), methanol (5 mL) and sodium borohydride (123 mg, 3.25 mmol) were used in the same manner as in Example 2b to obtain a crude triol product (360 mg).
  • Example 24e Methyl 5-chloro-4- (2-fluoro-4-methylphenyl) -2,2-dimethyl-4H-benzo [1,3] dioxin-7-carboxylate obtained in Example 24d Using the compound (310 mg, 0.96 mmol), methylene chloride (6 mL), pyridine (0.120 mL, 1.49 mmol) and trifluoromethanesulfonic anhydride (0.190 mL, 1.13 mmol), the triflate form was prepared in the same manner as in Example 2c. Crude product (437 mg) was obtained.
  • Example 24g 3-Chloro-2- ⁇ [1- (2-fluoro-4-methylphenyl) -1-methoxy] methyl ⁇ -5- (hydroxymethyl) phenol
  • Crude product obtained in Example 24f (241 mg, 0.72 mmol) was dissolved in methanol (5 mL), paratoluenesulfonic acid monohydrate (68 mg, 0.36 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hr. Triethylamine was added to the reaction solution, and the solvent was removed under reduced pressure.
  • purification using silica gel flash chromatography (hexane: ethyl acetate, 9: 1 to 3: 2, V / V) gave the title compound (210 mg) as an oil.
  • Example 24h 3-Chloro-4- ⁇ [1- (2-fluoro-4-methylphenyl) -1-methoxy] methyl ⁇ -5-hydroxybenzyl acetate
  • bis (dibutyltin chloride) oxide (112 mg, 0.20 mmol) were used in the same manner as in Example 2e to obtain the amorphous title compound (238 mg). It was.
  • Example 24i Acetic acid 3-chloro-4- (2-fluoro-4-methylbenzyl) -5-hydroxybenzyl
  • acetonitrile 5 mL
  • triethylsilane 0.322 mL, 2.01 mmol
  • boron trifluoride-diethyl ether complex 0.127 mL, 1.01 mmol
  • Example 24j 5-Acetoxymethyl-3-chloro-2- (2-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (236 mg, 0.39 mmol), methylene chloride (4 mL), The imidate was prepared in the same manner as Example 2g using trichloroacetonitrile (0.195 mL, 1.93 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 ⁇ L, 0.04 mmol).
  • Example 24i Using the resulting imidate (292 mg), the compound obtained in Example 24i (96 mg, 0.30 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.049 mL, 0.39 mmol) In the same manner as in Example 2g, a crude product (435 mg) of the title compound was obtained.
  • Example 24k 3-Chloro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 24j Using the same crude product (435 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (534 mg, 3.89 mmol) as in Example 2h, the title compound (86 mg) was obtained as a white solid. However, solidification was performed from hexane / ethyl acetate / methanol.
  • Example 25a (2-chloro-6-hydroxy-4-methoxyphenyl) (4-ethyl-2-fluorophenyl) methanone 1-chloro-3,5-dimethoxybenzene (855 mg, 4.95 mmol), toluene (5 mL ), Aluminum chloride (727 mg, 5.45 mmol) and 4-ethyl-2-fluorobenzoyl chloride (US2006 / 20146A1) (918 mg, 4.92 mmol) in the same manner as in Example 2a, the crude product (1.02 g) was obtained as a solid.
  • Example 25b (2-Chloro-4,6-dihydroxyphenyl) (4-ethyl-2-fluorophenyl) methanone Crude product obtained in Example 25a (1.02 g, 3.30 mmol), 1,2- A crude product of the title compound (824 mg) was obtained as a solid in the same manner as in Example 24c using dichloroethane (10 mL) and aluminum chloride (880 mg, 6.60 mmol).
  • Example 25c 5-Chloro-2,2-dimethyl-4- (4-ethyl-2-fluorophenyl) -4H-benzo [1,3] dioxin-7-ol
  • Product 815 mg, 2.77 mmol
  • sodium borohydride 262 mg, 6.93 mmol
  • Example 25d 5-Chloro-2,2-dimethyl-4- (4-ethyl-2-fluorophenyl) -4H-benzo [1,3] dioxin-7-carboxylate methyl obtained in Example 25c Using the compound (515 mg, 1.53 mmol), methylene chloride (10 mL), pyridine (0.185 mL, 2.29 mmol) and trifluoromethanesulfonic anhydride (0.308 mL, 1.83 mmol) in the same manner as in Example 2c, Crude product (717 mg) was obtained.
  • Example 25d Using the compound obtained in Example 25d (465 mg, 1.23 mmol), lithium aluminum hydride (70 mg, 1.84 mmol) and tetrahydrofuran (7 mL) in the same manner as in Example 2d, the crude product of the title compound (432 mg) was obtained as amorphous.
  • Example 25f 3-Chloro-2- [1- (4-ethyl-2-fluorophenyl) -1-methoxymethyl] -5- (hydroxymethyl) phenol
  • the crude product obtained in Example 25e (430 mg 1.23 mmol), methanol (10 mL), and paratoluenesulfonic acid monohydrate (116 mg, 0.61 mmol) were used to give the title compound (377 mg) as an oil in the same manner as in Example 24g.
  • Example 25g Acetic acid 3-chloro-4- [1- (4-ethyl-2-fluorophenyl) -1-methoxymethyl] -5-hydroxybenzyl
  • Compound obtained in Example 25f (377 mg, 1.16 mmol)
  • Tetrahydrofuran (4 mL)
  • vinyl acetate (4 mL)
  • bis (dibutyltin chloride) oxide (192 mg, 0.35 mmol) were used in the same manner as in Example 2e to obtain the oily title compound (414 mg).
  • Example 25h Acetic acid 3-chloro-4- (4-ethyl-2-fluorobenzyl) -5-hydroxybenzyl
  • Compound (414 mg, 1.13 mmol) obtained in Example 25 g, acetonitrile (8 mL), triethylsilane ( 0.539 mL, 3.38 mmol) and boron trifluoride-diethyl ether complex (0.213 mL, 1.70 mmol) were used in the same manner as in Example 2f to obtain the title compound (271 mg) as a white solid.
  • Example 25i 5-Acetoxymethyl-3-chloro-2- (4-ethyl-2-fluorobenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (236 mg, 0.39 mmol), methylene chloride (4 mL), The imidate was prepared in the same manner as Example 2g using trichloroacetonitrile (0.195 mL, 1.93 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (6 ⁇ L, 0.04 mmol).
  • Example 25h Using the resulting imidate (292 mg), the compound obtained in Example 25h (100 mg, 0.30 mmol), methylene chloride (4 mL), MS4A and boron trifluoride-diethyl ether complex (0.049 mL, 0.39 mmol) In the same manner as in Example 2g, a crude product (409 mg) of the title compound was obtained.
  • Example 25j 3-Chloro-2- (4-ethyl-2-fluorobenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 25i Using the same crude product (409 mg), methanol / methylene chloride (8 mL / 2 mL) and potassium carbonate (534 mg, 3.89 mmol), the title compound (52 mg) was obtained as a white solid in the same manner as in Example 2h. However, solidification was performed from hexane / ethyl acetate / methanol.
  • Example 26a Ethyl 3-hydroxy-5-oxo-4- [4- (trifluoromethyl) benzoyl] cyclohex-3-enecarboxylate ethyl 3-hydroxy-5-oxocyclohex-3-enecarboxylate ( 1.0 g, 5.4 mmol), 4-trifluoromethylbenzoic acid chloride (1.16 g, 5.6 mmol), triethylamine (2.3 mL, 16.5 mmol), trimethylsilylcyanide (90 ⁇ L, 0.67 mmol) and acetonitrile (15 mL) In the same manner as in Example 4a, a crude product of the title compound (2.25 g) was obtained as a pale yellow solid.
  • Example 26b Ethyl 3-fluoro-5-oxo-4- [4- (trifluoromethyl) benzoyl] cyclohex-3-enecarboxylate
  • Crude product obtained in Example 26a (2.25 g, 5.4 mmol) was dissolved in methylene chloride (20 mL), diethylaminosulfur trifluoride (2.2 mL, 16.7 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 2 hr. Distilled water (5 mL) was added dropwise to the reaction solution, diluted with methylene chloride (10 mL), and washed successively with distilled water (10 mL, twice) and saturated brine (10 mL).
  • Example 26c Ethyl 3-fluoro-5-hydroxy-4- [4- (trifluoromethyl) benzoyl] benzoate Compound obtained in Example 26b (1.31 g, 3.7 mmol), triethylamine (1.5 mL, 10.8 mmol), acetonitrile (13 mL) and trimethylsilane iodide (1.3 mL, 9.1 mmol) were used in the same manner as in Example 5c to obtain a silyl enol ether as an oily crude product.
  • Example 5c the obtained oily crude product was sequentially treated with toluene (13 mL), silica gel SK-85 (5.2 g), potassium carbonate (506 mg, 3.7 mmol) and ethanol (13 mL). Purification using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1, V / V) gave the title compound (0.82 g) as a pale yellow solid.
  • Example 26d 3-Fluoro-5-hydroxymethyl-2- ⁇ 1-hydroxy-1- [4- (trifluoromethyl) phenyl] methyl ⁇ phenol
  • the compound obtained in Example 26c (0.82 g, 2.3 mmol ) was dissolved in tetrahydrofuran (12 mL), lithium aluminum hydride (0.26 g, 6.5 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 15 minutes.
  • Example 26e 3-Fluoro-5-hydroxymethyl-2- ⁇ 1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl ⁇ phenol
  • the crude product obtained in Example 26d (0.66 g, 2.1 mmol) was dissolved in methanol (10 mL), paratoluenesulfonic acid monohydrate (0.2 g, 1.1 mmol) was added, and the mixture was stirred at 50 ° C. for 4 hr.
  • Triethylamine (290 ⁇ L, 2.1 mmol) was added to the reaction solution under ice cooling.
  • Example 26f Acetic acid 3-fluoro-5-hydroxy-4- ⁇ 1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl ⁇ benzyl
  • Crude product obtained in Example 26e (0.74 g, 2.1 mol) was dissolved in diisopropyl ether (4 mL), vinyl acetate (4 mL, 43.2 mmol) and porcine pancreatic lipase (0.37 g) were added, and the mixture was stirred at 35 ° C. for 24 hours. After filtration, the solvent was distilled off under reduced pressure.
  • Example 26h 3-Fluoro-5-hydroxy-4- [4- (trifluoromethyl) benzyl] benzyl acetate
  • the compound (0.43 g, 1.2 mmol) obtained in Example 26g was dissolved in acetonitrile (5 mL). Under ice cooling, triethylsilane (550 ⁇ L, 3.5 mmol) and boron trifluoride-diethyl ether complex (440 ⁇ L, 3.5 mmol) were added, and the mixture was stirred at 50 ° C. for 4 hours.
  • Example 26i 5-Acetoxymethyl-3-fluoro- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D -Gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (275 mg, 0.45 mmol), trichloroacetonitrile (135 ⁇ L, 1.35 mmol), 1,8 -Imidabicyclo [5.4.0] -7-undecene (7 ⁇ L, 0.05 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i.
  • Example 26h The compound (0.14 g) obtained in Example 26h 0.41 mmol), boron trifluoride-diethyl ether complex (51 ⁇ L, 0.41 mmol) and methylene chloride (5 mL) were obtained in the same manner as in Example 4i to obtain a crude product (339 mg) of the title compound.
  • Example 26j 3-Fluoro-5-hydroxymethyl-2- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside Crude obtained in Example 26i Using the product (339 mg, 0.36 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (56 mg, 0.41 mmol), the title compound (100 mg) was obtained as a colorless solid in the same manner as in Example 4j. .
  • Example 27a Ethyl 3-chloro-5-oxo-4- [4- (trifluoromethyl) benzoyl] cyclohex-3-enecarboxylate Crude product obtained in Example 26a (2.25 g, 5.4 mmol)
  • Example 4b oxalyl dichloride (500 ⁇ L, 3.8 mmol), 2-methyl-2-butene (2.3 mL, 21.7 mmol), N, N-dimethylformamide (100 ⁇ L, 1.29 mmol) and methylene chloride (20 mL).
  • a crude product (2.5 g) of the title compound was obtained as a brown oily substance.
  • Example 27b Ethyl 3-chloro-5-hydroxy-4- [4- (trifluoromethyl) benzoyl] benzoate
  • Crude product obtained in Example 27a (2.5 g), N-methylmorpholine (10 mL)
  • the title compound (1.66 g) was obtained as a brown solid in the same manner as in Example 4c, using iodine and iodine (1.65 g, 6.5 mmol).
  • purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 5: 1-4: 1-3: 1, V / V).
  • Example 27c 3-Chloro-5-hydroxymethyl-2- ⁇ 1-hydroxy-1- [4- (trifluoromethyl) phenyl] methyl ⁇ phenol
  • the compound obtained in Example 27b (1.66 g, 4.5 mmol)
  • Lithium aluminum hydride (0.51 g, 13.4 mmol)
  • tetrahydrofuran (17 mL) were obtained in the same manner as in Example 26d to obtain a crude product of the title compound (1.44 g) as a colorless solid.
  • Example 27d 3-chloro-5-hydroxymethyl-2- ⁇ 1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl ⁇ phenol
  • the crude product obtained in Example 27c (1.44 g, 4.3 mmol), paratoluenesulfonic acid monohydrate (0.41 g, 2.2 mmol) and methanol (15 mL) were used in the same manner as in Example 26e to obtain a crude product of the title compound.
  • the product was purified by silica gel flash column chromatography (hexane: ethyl acetate, 4: 1-3: 1-2: 1, V / V) to give the title compound (0.31 g) as a colorless oil.
  • Example 27e 3-chloro-5-hydroxy-4- ⁇ 1-methoxy-1- [4- (trifluoromethyl) phenyl] methyl ⁇ benzyl acetate
  • Acetic acid (0.31 g, 0.89 mmol) obtained in Example 27d
  • Vinyl acetate (3 mL, 32.4 mmol)
  • porcine pancreatic lipase (0.16 g)
  • diisopropyl ether 3 mL
  • the purification was performed using silica gel flash column chromatography (hexane: ethyl acetate, 6: 1-5: 1-4: 1, V / V).
  • Example 27f Acetic acid 3-chloro-5-hydroxy-2- [4- (trifluoromethyl) benzyl] benzyl Compound obtained in Example 27e (0.33 g, 0.85 mmol), triethylsilane (400 ⁇ L, 2.5 mmol) ), Boron trifluoride-diethyl ether complex (320 ⁇ L, 2.5 mmol) and acetonitrile (3 mL) by a method similar to that in Example 26h, 3-chloro-5-hydroxymethyl-2- [4- (tri Fluoromethyl) benzyl] phenol (100 mg) was obtained.
  • Example 27g 5-Acetoxymethyl-3-chloro-2- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero-D-gluco-heptopyranoside (194 mg, 0.32 mmol), trichloroacetonitrile (95 ⁇ L, 0.95 mmol), 1 , 8-diazabicyclo [5.4.0] -7-undecene (5 ⁇ L, 0.03 mmol) and methylene chloride (5 mL) were used to prepare an imidate in the same manner as in Example 4i, and the compound obtained in Example 27f ( 95 mg, 0.26 mmol), boron trifluoride-diethyl ether complex (33 ⁇ L, 0.26 m
  • Example 27h 3-Chloro-5-hydroxymethyl-2- [4- (trifluoromethyl) benzyl] phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside Crude obtained in Example 27g Using the product (313 mg, 0.26 mmol), tetrahydrofuran (1 mL), methanol (4 mL) and potassium carbonate (36 mg, 0.26 mmol), the title compound (84 mg) was obtained as a colorless solid in the same manner as in Example 4j. .
  • Example 28a Methyl 4- (2,2-difluoroacetyl) benzoate
  • Methyl 4-acetylbenzoate (1.0 g, 5.6 mmol) was dissolved in a solution consisting of benzene (28 mL) and hexane (56 mL), and morpholine ( Using a hexane solution (15 mL) in which 2.3 mL, 26 mmol) and titanium trichloride (0.42 mL, 3.9 mmol) are dissolved, the literature is known (J. Org. Chem., 2005, 70 (14), 5763.) The method yielded the corresponding crude enamine product as a yellow oil.
  • Example 28b Methyl 4- (2,2-difluoro-1-hydroxyethyl) benzoate
  • the crude product obtained in Example 28a (1.2 g, 5.6 mmol) was obtained from methanol (5 mL) and tetrahydrofuran (5 mL).
  • the resulting solution was dissolved in sodium borohydride (0.32 g, 8.4 mmol) under ice cooling.
  • the reaction mixture was stirred for 2 hours while warming to room temperature, and saturated aqueous ammonium chloride solution (1 mL) was added dropwise under ice cooling to stop the reaction.
  • Example 28c Methyl 4- (2,2-difluoroethyl) benzoate
  • the compound synthesized in Example 28b (0.69 g, 3.2 mmol) was dissolved in tetrahydrofuran (10 mL), and thiocarbonyldiimidazole (0.86 g) was dissolved at room temperature. 4.8 mmol), and the mixture was stirred for 1 hour while heating under reflux.
  • the mixture was cooled, diluted with ethyl acetate (50 mL), and washed successively with 1M hydrochloric acid (5 mL), saturated sodium bicarbonate (10 mL), and saturated brine (10 mL).
  • Example 28d 4- (2,2-difluoroethyl) benzoic acid
  • the compound obtained in Example 28c (0.53 g, 2.6 mmol) was dissolved in 1,4-dioxane (3.4 mL), and 2M water at room temperature.
  • An aqueous sodium oxide solution (3.4 mL, 6.8 mmol) was added, and the mixture was stirred at 35 ° C. for 1 hour.
  • the reaction mixture was poured into 1M hydrochloric acid (20 mL), extracted with ethyl acetate (50 mL), and the organic layer was washed with saturated brine (10 mL). After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound (0.48 g) as a colorless solid.
  • Example 28e 4- (2,2-difluoroethyl) benzoyl chloride
  • the crude product (0.48 g, 2.6 mmol) obtained in Example 28d was dissolved in methylene chloride, and oxalyl chloride (1.1 mL) was cooled with ice. 13 mmol) and N, N-dimethylformamide (0.1 mL, 1.3 mmol) were added, and the mixture was stirred for 3 and a half hours while warming to room temperature. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude product (0.53 g) of the title compound as a colorless oil.
  • Example 28f Ethyl 4- [4- (2,2-difluoroethyl) benzoyl] -3-hydroxy-5-oxocyclohex-3-enecarboxylate 3-hydroxy-5-oxocyclohex-3-ene Using the ethyl carboxylate (EP1571148A1) (0.48 g, 2.6 mmol) and the crude product obtained in Example 28e (0.53 g, 2.6 mmol) in the same manner as in Example 1b, the crude product of the title compound (0.92 g) was obtained.
  • Example 28g Ethyl 4- [4- (2,2-difluoroethyl) benzoyl] -3-fluoro-5-oxocyclohex-3-enecarboxylate
  • the crude product obtained in Example 28f (0.95 g 2.7 mmol) was dissolved in methylene chloride (10 mL), and the title compound (0.47 g) was obtained in the same manner as in Example 3b using diethylaminosulfur trifluoride (1.1 mL, 8.1 mmol).
  • Example 28h Ethyl 4- [4- (2,2-difluoroethyl) benzoyl] -3-fluoro-5-hydroxybenzoate
  • the compound obtained in Example 28g (0.47 g, 1.3 mmol) was converted to N-methyl. It was dissolved in morpholine (6 mL), and a crude product (0.46 g) of the title compound was obtained in the same manner as in Example 3c using anhydrous sodium sulfate (0.47 g) and iodine (0.40 g, 1.6 mmol).
  • Example 28i Ethyl 4- ⁇ 1- [4- (2,2-difluoroethyl) phenyl] -1-hydroxymethyl ⁇ -3-fluoro-5-hydroxybenzoate
  • Crude product obtained in Example 28h (0.46 g, 1.3 mmol) was dissolved in a solution of tetrahydrofuran (3 mL) and methanol (2 mL), and the title compound (0.33 g) was prepared in the same manner as in Example 3d using sodium borohydride (98 mg, 2.6 mmol). ) was obtained as a colorless solid.
  • Example 28j Ethyl 4- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5-hydroxybenzoate
  • the compound obtained in Example 28i (0.33 g, 0.93 mmol) was added to ethanol (10 mL).
  • ethanol 10 mL
  • the crude product of the title compound (0.31 g) Got.
  • the crude product obtained in Example 28j (0.31 g, 0.93 mmol)
  • the product was dissolved in tetrahydrofuran (10 mL), and the crude product (0.31 g) of the title compound was obtained as a colorless solid in the same manner as in Example 3f using lithium aluminum hydride (0.14 g, 3.7 mmol).
  • Example 28l Acetic acid 4- [4- (2,2-difluoroethyl) benzyl] -3-fluoro-5-hydroxybenzyl
  • the crude product obtained in Example 28k (0.31 g, 0.93 mmol) was converted into vinyl acetate. (3 mL) and diisopropyl ether (3 mL) were dissolved in the solution, and the title compound (0.30 g) was obtained as a pale brown solid by the same method as Example 3 g using porcine pancreatic lipase (1.0 g).
  • Example 28m 5-Acetoxymethyl-3-fluoro-2- [4- (2,2-difluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D- Glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231 )) (0.61 g, 1.0 mmol) dissolved in methylene chloride (4 mL) and trichloroacetonitrile (0.30 mL, 3.0 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (4 ⁇ L, 0.03 mmol)
  • the imidate was prepared in the same manner as in Example 1h.
  • Example 28l Using this imidate (0.75 g, 1.0 mmol), the compound obtained in Example 28l (0.30 g, 0.89 mmol) and boron trifluoride-diethyl ether complex (56 ⁇ L, 0.44 mmol), the same method as in Example 1h Gave a mixture containing the title compound.
  • Example 28n 3-Fluoro-2- [4- (2,2-difluoroethyl) benzyl] -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside
  • Example 28m The mixture obtained in step (0.89 mmol) was dissolved in a solution consisting of tetrahydrofuran (3 mL) and methanol (3 mL), and 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol) was used in the same manner as in Example 3i. The title compound (0.12 g) was obtained as a colorless solid.
  • Example 29a Ethyl 3-chloro-4- [4- (2,2-difluoroethyl) benzoyl] -5-oxocyclohex-3-enecarboxylate
  • the crude product obtained in Example 28f (0.92 g , 2.6 mmol) in methylene chloride (10 mL), 2-methyl-2-butene (1.1 mL, 10 mmol), oxalyl dichloride (0.23 mL, 2.7 mmol) and N, N-dimethylformamide (0.05 mL, 0.07).
  • the crude product (0.96 g) of the title compound was obtained in the same manner as in Example 1b.
  • Example 29b Ethyl 3-chloro-4- [4- (2,2-difluoroethyl) benzoyl] -5-hydroxybenzoate
  • the crude product obtained in Example 29a (0.96 g, 2.6 mmol) was converted to N -Dissolved in methylmorpholine (12 mL), and obtained the crude product (0.96 g) of the title compound in the same manner as in Example 3c using anhydrous sodium sulfate (0.96 g) and iodine (0.79 g, 3.1 mmol). .
  • Example 29c 3-Chloro-2- ⁇ 1- [4- (2,2-difluoroethyl) phenyl] -1-hydroxymethyl ⁇ -5- (hydroxymethyl) phenol
  • the product (0.96 g, 2.6 mmol) was dissolved in tetrahydrofuran (30 mL) and the title compound (0.85 g) was obtained as a crude product in the same manner as in Example 1e using lithium aluminum hydride (0.38 g, 10 mmol). Obtained.
  • Example 29d Acetic acid 3-chloro-4- ⁇ 1- [4- (2,2-difluoroethyl) phenyl] -1-hydroxymethyl ⁇ -5-hydroxybenzyl
  • Crude product obtained in Example 29c 0.85 g, 2.6 mmol
  • the title compound (0.51 g) was purified by the same method as Example 3 g using porcine pancreatic lipase (2.0 g). Obtained as a solid.
  • Example 29e 3-chloro-4- [4- (2,2-difluoroethyl) benzyl] -5-hydroxybenzyl acetate
  • Acetic acid (10 mL) was prepared from the compound (0.40 g, 1.1 mmol) obtained in Example 29d.
  • triethylsilane (0.53 mL, 3.3 mmol) and boron trifluoride-diethyl ether complex (0.28 mL, 2.2 mmol) were used in the same manner as in Example 5f (but no purification was performed). To give a mixture containing the title compound.
  • Example 29f 5-Acetoxymethyl-3-chloro-2- [4- (2,2-difluoroethyl) benzyl] phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D- Glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231 )) (0.37 g, 0.60 mmol) dissolved in methylene chloride (4 mL) and trichloroacetonitrile (0.18 mL, 1.8 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (2 ⁇ L, 0.02 mmol)
  • the imidate was prepared in the same manner as in Example 1h.
  • Example 29e Using this imidate (0.45 g, 0.60 mmol), the compound obtained in Example 29e (0.13 g, 0.36 mmol) and boron trifluoride-diethyl ether complex (46 ⁇ L, 0.37 mmol), the same method as in Example 1h Gave a mixture containing the title compound.
  • Example 29g 3-chloro-2- [4- (2,2-difluoroethyl) benzyl] -5-hydroxymethyl-phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D -Glycero- ⁇ -D-gluco-heptopyranoside
  • the mixture (0.37 mmol) obtained in Example 29f was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and 2M aqueous sodium hydroxide solution (3.0 mL, 6.0 mmol) was used.
  • the title compound (0.12 g) was obtained as a colorless solid.
  • Example 30a 3,5-difluoro-4- [1- (2-fluoro-4-methylphenyl) -1-hydroxymethyl] benzonitrile diisopropylamine (1.12 mL, 7.92 mmol), n-butyllithium (2.59 mL, 7.17 mmol, 2.77 M n-hexane solution), 3,5-difluorobenzonitrile (1.00 g, 7.19 mmol), 2-fluoro-4-methylbenzaldehyde (1.00 g, 7.24 mmol) and tetrahydrofuran (20 mL)
  • the title compound (1.44 g) was obtained as a pale yellow solid in the same manner as in Example 7a.
  • Example 30b 3,5-Difluoro-4- (2-fluoro-4-methylbenzyl) benzonitrile
  • Sodium borohydride (1.69 g, 44.7 mmol) was dissolved in trifluoroacetic acid (30 mL) and brought to 0 ° C.
  • a methylene chloride solution (7 mL) in which the compound obtained in Example 30a (1.24 g, 4.47 mmol) was dissolved was added. Thereafter, the reaction solution was stirred at room temperature for 30 hours. However, during that time, sodium borohydride (2.00 g, 52.9 mmol) and trifluoroacetic acid (20 mL) were added in several portions until the reaction was completed.
  • reaction solution was added to a 10% aqueous sodium hydroxide solution (300 mL) cooled to 0 ° C.
  • the mixture was extracted with diethyl ether (300 mL), and washed successively with water (100 mL), saturated aqueous ammonium chloride (100 mL), and saturated brine (100 mL).
  • the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 10: 1, V / V).
  • the title compound (756 mg) was obtained as a white solid.
  • Example 30c 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methylbenzyl) benzonitrile
  • the compound obtained in Example 30b (756 mg, 2.89 mmol), sodium hydride (63%, 165 mg, 4.33 mmol), benzyl alcohol (387 mg, 3.58 mmol) and N, N-dimethylformamide (10 mL) were used in the same manner as in Example 7c to obtain the title compound (768 mg) as a white solid.
  • the purification was performed using silica gel flash chromatography (hexane: ethyl acetate 19: 1 to 10: 1, V / V).
  • Example 30d 3-Benzyloxy-5-fluoro-4- (2-fluoro-4-methylbenzyl) benzoic acid
  • 5M aqueous sodium hydroxide solution 2.2 mL, 11.0 mmol
  • ethanol 10 mL
  • Example 30e 3-Fluoro-4- (2-fluoro-4-methylbenzyl) -5-hydroxybenzoic acid
  • Crude product obtained in Example 30d (740 mg, 2.01 mmol), 10% palladium on carbon catalyst (
  • a crude product (553 mg) of the title compound was obtained in the same manner as in Example 7e using water (150 mg), tetrahydrofuran (7 mL), methanol (7 mL) and hydrogen.
  • Example 30f 3-Fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenol
  • Crude product obtained in Example 30e (553 mg, 1.99 mmol), lithium aluminum hydride (188 mg, 4.95 mmol) and tetrahydrofuran (20 mL) were used to give a crude product of the title compound (498 mg) in the same manner as in Example 7f.
  • Example 30g 3-fluoro-4- (2-fluoro-4-methylbenzyl) -5-hydroxybenzyl acetate
  • Acetic product (498 mg, 1.88 mmol) obtained in Example 30f, bis (dibutyltin chloride)
  • the title compound (522 mg) was obtained in the same manner as in Example 7g using oxide (312 mg, 0.56 mmol), vinyl acetate (5 mL) and tetrahydrofuran (5 mL).
  • Example 30h 5-Acetoxymethyl-3-fluoro-2- (2-fluoro-4-methylbenzyl) phenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) 311 mg, 0.51 mmol), methylene chloride (6 mL), trichloroacetonitrile (0.257 mL, 2.56 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (8 ⁇ L, 0.05 mmol) as in Example 1h
  • the imidate was prepared by the method.
  • Example 30g Same as Example 1h, using the compound obtained in Example 30g (122 mg, 0.40 mmol), imidate (0.51 mmol), methylene chloride (6 mL) and boron trifluoride-diethyl ether complex (0.064 mL, 0.51 mmol). In this way, a crude product of the title compound was obtained.
  • Example 30i 3-Fluoro-2- (2-fluoro-4-methylbenzyl) -5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 30h Using the crude product, methanol / methylene chloride (10 mL / 2.5 mL) and potassium carbonate (700 mg, 5.06 mmol), a crude product of the title compound was obtained in the same manner as in Example 2h. The resulting crude product was purified using silica gel flash chromatography (hexane: ethyl acetate, 1: 1 to methylene chloride: methanol, 10: 1, V / V) to give the title compound (87 mg).
  • Example 31a (4-Ethyl-2-fluorophenyl) methanol 4-ethyl-2-fluorobenzoyl chloride (US2006 / 20146 A1) (200 mg, 1.19 mmol), lithium aluminum hydride (90 mg, 2.37 mmol) and tetrahydrofuran (20 mL) was used to give a crude product of the title compound (194 mg) in the same manner as in Example 2d.
  • Example 31b 4-Ethyl-2-fluorobenzaldehyde
  • the crude product obtained in Example 31a (194 mg) was dissolved in methylene chloride (10 mL), and cooled with ice, pyridinium chlorochromate (540 mg, 2.51 mmol). And stirred at room temperature for 2 hours.
  • the reaction mixture was filtered through celite, the solvent was evaporated under reduced pressure, and the obtained residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 9: 1, V / V) to give the oily title compound ( 158 mg) was obtained.
  • Example 31c 3,5-difluoro-4- [1- (4-ethyl-2-fluorophenyl) -1-hydroxymethyl] benzonitrile diisopropylamine (0.85 mL, 6.01 mmol), n-butyllithium (1.97 mL, 5.46 mmol, 2.77 M n-hexane solution), 3,5-difluorobenzonitrile (759 mg, 5.46 mmol), the compound obtained in Example 31b (830 mg, 5.45 mmol) and tetrahydrofuran (12 mL) In the same manner as in Example 7a, the oily title compound (1.49 g) was obtained.
  • Example 31d 3,5-Difluoro-4- (4-ethyl-2-fluorobenzyl) benzonitrile
  • Sodium borohydride (1.94 g, 51.2 mmol) was dissolved in trifluoroacetic acid (35 mL) and brought to 0 ° C. After cooling, a methylene chloride solution (7 mL) in which the compound obtained in Example 31c (1.49 g, 5.12 mmol) was dissolved was added. Then, it stirred at room temperature for 30 hours. However, during that time, sodium borohydride (1.94 g, 51.2 mmol) and trifluoroacetic acid (20 mL) were added in several portions until the reaction was completed.
  • reaction solution was added to a 10% aqueous sodium hydroxide solution (330 mL) cooled to 0 ° C.
  • the mixture was extracted with diethyl ether (300 mL), and washed successively with water (100 mL), saturated aqueous ammonium chloride (100 mL), and saturated brine (100 mL).
  • the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel flash chromatography (hexane: ethyl acetate, 19: 1 to 10: 1, V / V).
  • the title compound (947 mg) was obtained as a white solid.
  • Example 31e 3-Benzyloxy-4- (4-ethyl-2-fluorobenzyl) -5-fluorobenzonitrile
  • the compound obtained in Example 31d (940 mg, 3.41 mmol), sodium hydride (63%, 195 mg, 5.12 mmol), benzyl alcohol (0.46 mL, 4.47 mmol) and N, N-dimethylformamide (12 mL) were used in the same manner as in Example 7c to obtain the title compound (1.11 g) as a white solid.
  • the purification was performed using silica gel flash chromatography (hexane: ethyl acetate 19: 1 to 10: 1, V / V).
  • Example 31f 3-Benzyloxy-4- (4-ethyl-2-fluorobenzyl) -5-fluorobenzoic acid
  • the compound obtained in Example 31e (1.11 g, 3.05 mmol), 5M aqueous sodium hydroxide solution
  • the crude product (1.01 g) of the title compound was obtained in the same manner as in Example 7d using 3.37 mL, 16.8 mmol) and ethanol (10 mL).
  • Example 31g 4- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5-hydroxybenzoic acid Crude product obtained in Example 31f (1.01 g, 2.64 mmol), 10% palladium on carbon catalyst (Water content, 300 mg), tetrahydrofuran (10 mL), methanol (10 mL) and hydrogen were used in the same manner as in Example 7e to obtain a crude product of the title compound (806 mg).
  • Example 31h 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenol
  • Example 31g 4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenol
  • Li aluminum hydride 342 mg, 9.0 mmol
  • tetrahydrofuran 10 mL
  • Example 31i 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5-hydroxybenzyl acetate
  • the crude product obtained in Example 31h (827 mg, 2.97 mmol), bis (dibutyltin chloride)
  • the title compound (871 mg) was obtained in the same manner as in Example 7g using oxide (164 mg, 0.30 mmol), vinyl acetate (10 mL) and tetrahydrofuran (10 mL).
  • Example 31j 5-Acetoxymethyl-2- (4-ethyl-2-fluorobenzyl) -3-fluorophenyl 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ -D-gluco-heptopyranoside 7-deoxy-2,3,4,6-tetra-O-benzoyl-D-glycero- ⁇ , ⁇ -D-gluco-heptopyranoside (WO2008 / 016132 (PCT / JP2007 / 65231)) 2.5 g, 4.08 mmol), methylene chloride (20 mL), trichloroacetonitrile (1.2 mL, 12.2 mmol) and 1,8-diazabicyclo [5.4.0] -7-undecene (61 ⁇ L, 0.41 mmol) and Example 1h In the same manner, imidate was prepared.
  • Example 1h using the compound obtained in Example 31i (870 mg, 2.7 mmol), imidate (4.1 mmol), methylene chloride (30 mL) and boron trifluoride-diethyl ether complex (0.38 mL, 3.0 mmol). In this way, a crude product of the title compound was obtained.
  • Example 31k 2- (4-Ethyl-2-fluorobenzyl) -3-fluoro-5- (hydroxymethyl) phenyl 7-deoxy-D-glycero- ⁇ -D-gluco-heptopyranoside obtained in Example 31j Using the crude product, methanol / methylene chloride (16 mL / 4 mL) and sodium methoxide (162.1 mg, 3.0 mmol), a crude product of the title compound was obtained in the same manner as in Example 2h.
  • the target DNA fragment is recovered from a single band corresponding to 2013 bases, cleaved with restriction enzymes HindIII and XhoI, and then placed on the HindIII / XhoI site of the vector pCMV-Script (Stratagene).
  • the SGLT1 expression plasmid pCMV-SGLT1 was introduced.
  • a HindIII / XhoI fragment was excised from pCMV-SGLT1 and introduced into the BamHI / XhoI site of pENTR1A (Gateway, Invitrogen) to create pENTR-SGLT1.
  • SGLT1-expressing retroviral vector pLPCX-SGLT1 was prepared using the retroviral vector pLPCX (Clontech) into which Gateway Vector Conversion System Cassette A (Invitrogen) was introduced as the destination plasmid.
  • the retrovirus pLPCX-SGLT1 obtained in 1) was transfected into integrin ⁇ v ⁇ 3-expressing HEK-293 cells, followed by antibiotic G418 (trade name: Geneticin, manufactured by Invitrogen), puromycin ( The cells were treated with Clontech), and stable expression cells HEK-SGLT1 of the target vector having resistance were obtained. Culture and maintenance of stably expressing cells were performed using DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin, 3 mM KGT-1075, 10% FBS.
  • HEK-SGLT1 cells were suspended in DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin and 10% FBS at a density of 10 6 cells / ml, and a 96-well culture plate coated with type I collagen ( 100 ⁇ l was seeded in each well of Corning).
  • the target DNA fragment is recovered from a single band corresponding to 2037 bases, cleaved with restriction enzymes HindIII and XhoI, and then placed on the HindIII / XhoI site of the vector pCMV-Script (Stratagene). Introduced. This was designated as SGLT2 expression plasmid pCMV-SGLT2.
  • a HindIII / XhoI fragment was excised from pCMV-SGLT2 and introduced into the BamHI / XhoI site of pENTR1A (Gateway, Invitrogen) to create pENTR-SGLT2.
  • SGLT2-expressing retrovirus vector pLPCX-SGLT2 was prepared using the retrovirus vector pLPCX (Clontech) into which Gateway Vector Conversion System Cassette A (Invitrogen) was introduced as a destination plasmid.
  • the retrovirus pLPCX-SGLT2 obtained in 1) was transfected into integrin ⁇ v ⁇ 3-expressing HEK-293 cells, followed by antibiotic G418 (trade name: Geneticin, manufactured by Invitrogen), puromycin ( The cells were treated with Clontech), and stable expression cells HEK-SGLT2 of the target vector having resistance were obtained.
  • Culture and maintenance of stably expressing cells were performed using DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin, 3 mM KGT-1075, 10% FBS.
  • HEK-SGLT2 cells were suspended in DMEM medium containing 250 mg / ml G418, 1 mg / ml puromycin and 10% FBS at a density of 10 6 cells / ml, and a 96-well culture plate coated with type I collagen ( 100 ⁇ l was seeded in each well of Corning).
  • Test Example 3 In vivo test Each test compound is suspended or dissolved in a solvent (0.5% methylcellulose solution) to a dose of 10 mL / kg, and multiple doses (preferably in the range of 0.03 to 10 mg / kg). (Included) is orally administered to C57BL / 6NCrlCrlj mice (7-10 weeks old, male) fasted overnight. In the control group, the solvent is orally administered at 10 mL / kg. 10 minutes after administration, glucose is orally administered at 2 g / 10 mL / kg.
  • the blood glucose level was measured over time (before glucose administration, 20, 40, 60, 120 minutes after administration), the area under the curve of the blood glucose level was calculated, and the rate of decrease in the area under the blood glucose level curve for each group from the control group
  • the efficacy of each test compound in the living body is evaluated by obtaining a 50% effective dose ED50 by using as an index.
  • the compound of the present invention or a hydrate thereof exhibits excellent human SGLT1 and / or SGLT2 inhibitory activity with low side effects, type 1 diabetes, type 2 diabetes, gestational diabetes, other factors, hyperglycemia, glucose intolerance ( impaired glucose tolerance (IGT), diabetes related diseases (eg obesity, hyperlipidemia, hypercholesterolemia, dyslipidemia, hypertension, fatty liver, metabolic syndrome, edema, heart failure, angina, myocardial infarction, arteries Sclerosis, hyperuricemia, gout, etc.) or diabetic complications (eg retinopathy, nephropathy, neuropathy, cataract, foot gangrene, infection, ketosis, etc.) It is useful as a pharmaceutical composition for the prevention or treatment of mammals (eg, humans, horses, cows or pigs, preferably humans).
  • mammals eg, humans, horses, cows or pigs, preferably humans.
  • SEQ ID NO: 1 PCR sense primer for human SGLT1
  • SEQ ID NO: 2 PCR antisense primer for human SGLT1
  • SEQ ID NO: 3 PCR sense primer for human SGLT2
  • SEQ ID NO: 4 PCR antisense primer for human SGLT2

Abstract

La présente invention concerne un composé ayant une nouvelle structure, peu d'effets secondaires indésirables et une excellente activité inhibitrice sur les SGLT1 et/ou SGLT2 humains, ou un hydrate du composé. L'invention concerne également une composition pharmaceutique destinée au traitement et/ou à la prévention du diabète de type 1, du diabète de type 2, du diabète gestationnel, de l'hyperglycémie induite par un autre facteur, d'une intolérance au glucose (IGT), de maladies associées au diabète ou de complications diabétiques, qui renferme le composé ou l'hydrate en tant que principe actif. L'invention concerne spécifiquement un composé représenté par la formule illustrée ci-dessous ou l'un de ses hydrates. [Formule chimique 1]
PCT/JP2009/051532 2008-01-31 2009-01-30 Dérivé de benzylphényl-glucopyranoside WO2009096503A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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WO2002064606A1 (fr) * 2001-02-14 2002-08-22 Kissei Pharmaceutical Co., Ltd. Derives glucopyranosyloxybenzylbenzene et leur utilisation medicale
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WO2008016132A1 (fr) * 2006-08-04 2008-02-07 Daiichi Sankyo Company, Limited Dérivé du benzyl phényl glucopyranoside

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WO2001068660A1 (fr) * 2000-03-17 2001-09-20 Kissei Pharmaceutical Co., Ltd. Derives glucopyranosyloxybenzylbenzene, preparations medicinales les contenant et intermediaires pour la preparation desdits derives
JP2004500416A (ja) * 2000-03-30 2004-01-08 ブリストル−マイヤーズ　スクイブ　カンパニー Ｏ−アリールグルコシドｓｇｌｔ２抑制剤および方法
WO2002028872A1 (fr) * 2000-09-29 2002-04-11 Kissei Pharmaceutical Co., Ltd. Derives de glucopyranosiloxybenzylbenzene et compositions therapeutiques contenant ces composes
WO2002044192A1 (fr) * 2000-11-30 2002-06-06 Kissei Pharmaceutical Co., Ltd. Derives de glucopyranosyloxybenzylbenzene, compositions medicinales contenant ces derives et produits intermediaires obtenus lors de l'elaboration de ces compositions
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WO2008016132A1 (fr) * 2006-08-04 2008-02-07 Daiichi Sankyo Company, Limited Dérivé du benzyl phényl glucopyranoside

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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