WO2022114138A1 - Method for producing amino acid derivative - Google Patents

Method for producing amino acid derivative Download PDF

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WO2022114138A1
WO2022114138A1 PCT/JP2021/043424 JP2021043424W WO2022114138A1 WO 2022114138 A1 WO2022114138 A1 WO 2022114138A1 JP 2021043424 W JP2021043424 W JP 2021043424W WO 2022114138 A1 WO2022114138 A1 WO 2022114138A1
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formula
compound
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solvent
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哲也 籔内
大輔 松田
英哲 田伏
淳 黒坂
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大正製薬株式会社
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
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    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
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    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/82—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
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    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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    • C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals

Definitions

  • the present invention is a compound that acts as an antagonist of mGlu2 and mGlu3 receptors belonging to subgroup II of metabotropic glutamate (mGlu) receptors (1R, 2R, 3R, 5R, 6R) -2-amino-6-.
  • the present invention relates to a method for producing a fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid.
  • the present invention also relates to a novel intermediate compound produced in this production process.
  • Excitatory amino acids such as glutamate regulate various physiological processes in the central nervous system (CNS) of mammals such as long-term potentiation (learning and memory), synaptic plasticity development, motor control, respiration, cardiovascular regulation and perception. ..
  • glutamate receptors are "ionotropic type in which the receptor has an ionotropic structure”: ionotropic glutamate receptor (iGluR) and "metabotropic type in which the receptor is coupled to G-protein”: metabolism. It is broadly classified into two classes of active glutamate receptors (mGluR) (Non-Patent Document 1). Both classes of receptors appear to mediate normal synaptic transmission according to excitatory pathways.
  • Non-Patent Document 2 Metabotropic glutamate receptors are classified into three groups according to their amino acid sequence homology, signal transduction mechanism, and pharmacological properties. Among them, the group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind to adenylcyclase and are cyclic adenosine monophosphate (cAMP) holscoline-stimulating. Suppresses accumulation (Non-Patent Document 3).
  • mGlu2 and mGlu3 receptors are G protein-coupled receptors that bind to adenylcyclase and are cyclic adenosine monophosphate (cAMP) holscoline-stimulating. Suppresses accumulation (Non-Patent Document 3).
  • Group II metabotropic glutamate receptors are mainly present in the presynapses of the glutamate nervous system and function as autoreceptors, thus suppressing excessive release of glutamate (Non-Patent Documents 4 and 5). ).
  • Compounds that antagonize Group II metabotropic glutamate receptors appear to be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders.
  • (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid is a group.
  • a compound that has a strong antagonism against metabolic glutamate receptors is used for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety and related diseases, bipolar disorders, and epilepsy, as well as drug dependence, It is useful for the treatment and prevention of neurological diseases such as cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, motor disorders associated with muscle rigidity, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders (Patent Documents). 1).
  • An object of the present invention is a compound (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4) represented by the formula (1) having a group II metabotropic glutamate receptor antagonism. -To provide a production method suitable for mass production of [fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid.
  • the present inventors synthesize the compound represented by the formula (1) without going through the synthetic intermediate compound represented by the formula (2).
  • the present invention is as follows. (I) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane represented by the formula (1) A method for producing -2,6-dicarboxylic acid.
  • R 1 indicates a C 1-6 alkyl group which may have a substituent or an aryl group which may have a substituent.
  • R 2 represents a C 1-6 alkyl group which may have a substituent.
  • R 3 indicates a C 1-6 alkyl group which may have a substituent or an aryl group which may have a substituent.
  • the compound (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro represented by the formula (1) does not go through the synthetic intermediate compound represented by the formula (2).
  • -Three-selective and efficient mass production of 3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid has become possible.
  • n is normal, “i” is iso, “s” and “sec” are secondary, and “t” and “tert” are tertiary. ), “C” indicates cyclo, “o” indicates ortho, “m” indicates meta, and “p” indicates para.
  • the "C 1-6 alkyl group” is an alkyl group having 1 to 6 carbon atoms, and indicates a linear or branched alkyl group.
  • neopentyl group 1,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3, 3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group , 1-ethylbutyl group, 1-ethyl-1-methylpropyl group and the like.
  • the "aryl group” indicates a monocyclic or condensed polycyclic aromatic hydrocarbon group, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthranyl group, a phenanthryl group and the like.
  • a functional group may have a substituent
  • the type of substituents present in the functional group, the number of substituents, and the positions of substitutions are not particularly limited, and when two or more substituents are present, they may be the same or different.
  • Examples of the substituent present in the functional group include a halogen atom, an oxo group, a nitro group, a cyano group, a hydroxy group, a sulfanyl group, a carboxy group, a carbamoyl group, a sulfo group, a sulfamoyl group, a sulfino group and a C 1-6 alkyl.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. These substituents may be further substituted with one or more other substituents. Examples of such examples include a C 1-6 halogenated alkyl group, a C 1-6 halogenated alkoxy group, a carboxy substituted C 1-6 alkyl group, a C 1-6 alkyl substituted amino group and the like. , Not limited to these. In the present invention, preferred embodiments are given below.
  • R 1 is a C 1-3 alkyl group
  • R 2 is a C 1-3 alkyl group
  • R 3 is an aryl group which may have a substituent. Particularly preferred embodiments are listed below.
  • R 1 is a methyl group, an ethyl group or an isopropyl group
  • R2 is a methyl or ethyl group
  • R 3 is a phenyl group substituted with a halogen atom
  • the present invention relates to a method for producing a compound represented by the formula (1). Further, in the present invention, the formulas (4), formulas (6), formulas (7), formulas (8), formulas (9), formulas (10), formulas (11) and formulas (11), which are intermediates for manufacturing them, are used. It relates to the compounds represented by 12), formula (13), formula (14), formula (15), formula (16) and formula (17).
  • the present invention can be carried out by the methods shown below. An embodiment of the present invention is shown in Scheme 1 below. Scheme 1
  • Step 1 After preparing the compound of formula (4) by reacting the compound of formula (3) with a sulfonyl chloride substituted with R1 in a solvent in the presence of a base, a polar solvent and a base are further added.
  • the formula (6) can be obtained by reacting with the compound of the formula (5).
  • a hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, petroleum ether, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, benzo Halogen solvents such as trifluoride, ether solvents such as tetrahydrofuran, 2-methyltetrahexyl, tetrahydropyran, ester solvents such as ethyl acetate and isopropyl acetate, ketone solvents such as acetone, 2-butanone and methylisobutylketone or these.
  • a hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, petroleum ether, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, benzo Halogen solvent
  • a mixed solvent of the above can be used.
  • an ether solvent such as tetrahydrofuran and 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a mixed solvent thereof and the like can be used.
  • the base for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate at the time of synthesizing the compounds of the formulas (4) and (6).
  • Inorganic bases such as potassium hydrogen carbonate, or organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, 2,4,6-tetramethylpyridine, or normal butyl lithium, sodium hydride, potassium hydride, sodium bis ( Trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and the like can be used.
  • the reaction temperature is usually possible from ⁇ 20 ° C. to the boiling point of the solvent at the time of synthesizing the compounds of the formulas (4) and (6), but is preferably in the range of ⁇ 20 ° C. to 40 ° C.
  • the amount of the base used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (3) at the time of synthesizing the compound of the formula (4), preferably 1 to 1.5 mol. It is in the range of equivalents.
  • synthesizing the compound of the formula (6) it can be used in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (4), preferably in the range of 1 to 1.5 molar equivalents.
  • the amount of the compound of the formula (5) to be used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (4), preferably in the range of 1 to 1.5 molar equivalents.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as the raw material, both during the synthesis of the compounds of the formulas (4) and (6).
  • the compound of the formula (6) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • Step 2 The compound of the formula (7) can be obtained by reacting the compound of the formula (6) in an alcohol solvent in the presence of a base.
  • the alcohol solvent for example, methanol, ethanol or the like can be used.
  • the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc., or triethylamine, diisopropylamine, etc.
  • Organic bases such as diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine, N, N-dimethyl-4-aminopyridine, or normal butyl lithium, sodium hydride, potassium hydride, sodium bis (trimethylsilyl) amide, potassium Bis (trimethylsilyl) amide, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonen (DBN), 1,1, 3,3-Tetramethylguanidine (TMG) and the like can be used.
  • the reaction temperature can usually range from ⁇ 20 ° C.
  • the amount of the base used can be in the range of 0.1 to 5 molar equivalents with respect to the compound of the raw material formula (6), preferably in the range of 0.1 to 2 molar equivalents.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (6).
  • the compound of the formula (7) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • Step 3 The compound of the formula (8) of the present invention can be obtained by reacting the compound of the formula (7) with an oxidizing agent in a solvent.
  • the solvent include hydrocarbon solvents such as toluene and benzene, halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride, tetrahydrofuran, 2-methyltetrachloride and diethyl ether.
  • Telt-butylmethyl ether 1,2-dimethoxyethane, diethoxymethane, 1,4-dioxane and other ether solvents
  • methanol ethanol
  • 2-propanol tert-butyl alcohol and other alcohol solvents
  • acetone 2 -Ketone-based solvents such as butanone and methylisobutylketone
  • ester-based solvents such as ethyl acetate and isopropyl acetate
  • acetonitrile N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, water or a mixed solvent thereof, etc.
  • oxidizing agent examples include 3-chloroperbenzoic acid, perbenzoic acid, monoperoxyphthalic acid, monoperoxyphthalic acid magnesium salt, peracid such as peracetic acid, methyltrioxorenium or tris (cetylpyridinium) peroxotangustrin.
  • Hydrogen peroxide in the presence of a catalyst such as acid salt (PCWP), urea-hydrogen peroxide adduct, hydrogen peroxide in the presence of a nitrile compound, hydrogen peroxide in the presence of a ketone compound such as acetone, acetone, etc.
  • PCWP acid salt
  • urea-hydrogen peroxide adduct hydrogen peroxide in the presence of a nitrile compound
  • hydrogen peroxide in the presence of a ketone compound such as acetone, acetone, etc.
  • Oxone (2KHSO 5 , KHSO 4 , K2 SO 4 ), dimethyldioxylan, tert - butylhydroperoxide, osmium tetraoxide and N-methylmorpholin-N-oxide, lead tetraacetate, iodosylbenzene in the presence of ketone compounds.
  • hydrogen peroxide diethyl ether complex, chromyl chloride, ozone and the like can be used.
  • the reaction temperature can usually be from ⁇ 80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 50 ° C.
  • the amount of the oxidizing agent used can be in the range of 0.5 to 5 molar equivalents with respect to the compound of the raw material formula (7), preferably in the range of 1 to 2 molar equivalents.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (7).
  • the compound of the formula (8) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • Step 4 The compound of the formula (10) is obtained by reacting the compound of the formula (8) with the compound of the formula (9) in a solvent in the presence or absence of a base.
  • the compound of formula (9) can be obtained by reacting 4 -fluorobenzyl alcohol with a sulfonyl chloride substituted with R3 in the presence of a base.
  • the solvent for both during the synthesis of the compounds of the formulas (9) and (10), for example, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, petroleum ether, dichloromethane, chloroform, 1,2-dichloroethane, and the like.
  • Halogen-based solvents such as carbon tetrachloride, chlorobenzene and benzotrifluoride, ether-based solvents such as tetrahydrofuran, 2-methyltetrahydrocarbon and tetrahydropyran, ester-based solvents such as ethyl acetate and isopropyl acetate, acetone, 2-butanone and methylisobutylketone.
  • a ketone solvent such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixed solvent thereof can be used.
  • the base for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate at the time of synthesizing the compounds of the formulas (9) and (10).
  • Inorganic bases such as potassium hydrogen carbonate, or organic bases such as triethylamine, diisopropylamine, N, N-diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine, or normal butyl lithium, sodium hydride, potassium hydride, Sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and the like can be used.
  • the reaction temperature can usually be from ⁇ 20 ° C.
  • the amount of the base used can be in the range of 1 to 5 molar equivalents with respect to the raw material compound in both the synthesis of the compounds of the formulas (9) and (10), preferably in the range of 1 to 2 molar equivalents. Is.
  • the amount of the compound of the formula (9) used at the time of synthesizing the compound of the formula (10) can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (8), and is preferably 1. It is in the range of ⁇ 2 molar equivalents.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as the raw material, both during the synthesis of the compounds of the formulas (9) and (10). Is.
  • the compound of the formula (9) can be obtained as a purified product or an unpurified product by a method such as recrystallization, reslurry or crystallization.
  • the compound of the formula (10) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • Step 5 The compound of the formula (10) is prepared by reacting the compound of the formula (10) with a base in a solvent, and then the compound of the formula (12) is added by adding a base in the presence of Lewis acid.
  • the compound of the formula (13) of the present invention can be obtained by preparing the above, quenching by adding alcohol or alcohol and acetic acid, and then further adding a base to react.
  • the formula (12) can also be synthesized by preparing the compound of the formula (11), adding a base to a silylating agent such as trimethylsilyl chloride and reacting, and then adding a Lewis acid.
  • an alcohol solvent such as methanol or ethanol
  • an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or tetrahydropyran
  • ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, toluene, normal hexane and the like can be used.
  • an alcohol solvent such as methanol and ethanol
  • an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran
  • water can be used as the solvent.
  • sodium methoxydo, sodium ethoxydo, or alcohol such as methanol or ethanol is mixed with sodium hydride, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide.
  • Sodium bis (trimethylsilyl) amide and the like are reacted in the reaction system to prepare sodium methoxydo and sodium ethoxydo.
  • Sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and the like can be used during the synthesis of the formula (12).
  • Ammonia / methanol solution, ammonia / ethanol solution, ammonia water and the like can be used in the synthesis of the formula (13).
  • Lewis acid examples include trialkylaluminum such as trimethylaluminum, triethylaluminum, tripropylaluminum, triisobutylaluminum and trinormaloctylaluminum, aluminum chloride, titanium chloride, trimethylsilyltrifluoromethanesulfonate, boron trifluoride / diethyl ether complex and the like. Can be used.
  • the alcohol used for quenching methanol, ethanol and the like can be used.
  • the amount of alcohol used can be in the range of 1 to 20 molar equivalents with respect to the compound of the raw material formula (12), preferably in the range of 1 to 10 molar equivalents.
  • the reaction temperature can usually be from ⁇ 20 ° C.
  • the amount of the base used can be in the range of 0.1 to 1 molar equivalent with respect to the compound of the raw material formula (10), preferably 0.2 to 0.2. It is in the range of 0.3 molar equivalents.
  • the compound of the formula (12) When synthesizing the compound of the formula (12), it can be used in the range of 1 to 2 molar equivalents with respect to the compound of the raw material formula (11), preferably in the range of 1 to 1.5 molar equivalents. When synthesizing the compound of the formula (13), it can be used in the range of 1 to 50 molar equivalents with respect to the compound of the raw material formula (12), preferably in the range of 5 to 20 molar equivalents.
  • the compounds of formulas (11) and (12) can be obtained as purified or unpurified products by chromatography.
  • the compound of formula (13) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • the amount of the solvent used can be in the range of 1 to 20 times by mass, preferably 3 to 10 times by mass, that of the raw material compound at the time of synthesizing the compounds of the formulas (11) and (12). .. At the time of synthesizing the compound of the formula (13), it can be used in the range of 10 to 40 times by mass, preferably 10 to 20 times by mass with respect to the raw material compound.
  • Step 6 The compound of the formula (14) of the present invention can be obtained by reacting the compound of the formula (13) with an oxidizing agent in a solvent in the presence or absence of an additive.
  • the solvent include hydrocarbon solvents such as toluene and benzene, halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride, tetrahydrofuran, 2-methyltetrachloride and diethyl ether.
  • Telt-butylmethyl ether 1,2-dimethoxyethane, diethoxymethane, 1,4-dioxane and other ether solvents
  • methanol ethanol
  • 2-propanol tert-butyl alcohol and other alcohol solvents
  • acetone 2 -Ketone-based solvents such as butanone and methylisobutylketone
  • ester-based solvents such as ethyl acetate and isopropyl acetate
  • acetonitrile N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, water or a mixed solvent thereof, etc.
  • the oxidizing agent one that oxidizes a secondary alcohol to a ketone can be generally used.
  • additives such as 2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO) in the presence of trichloroisocyanuric acid can be used (Reference: J. Org. Chem., 68). , 4999 (2003)).
  • TEMPO 2,2,6,6-tetramethylpiperidin-1-oxyl radical
  • the reaction temperature can usually be from ⁇ 20 ° C. to the boiling point of the solvent used, but is preferably in the range of ⁇ 20 ° C. to 30 ° C.
  • the amount of TEMPO used can be in the range of 0.01 to 2 molar equivalents with respect to the compound of the raw material formula (13), preferably 0. It is in the range of 01 to 1 molar equivalent.
  • the amount of trichloroisocyanuric acid used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (13), preferably in the range of 1 to 2 molar equivalents.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (13). It is a range.
  • the compound of the formula (14) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • Step 7 After preparing the compound of formula (15) by reacting the compound of formula (14) with 2-methyl-2-propanesulfinamide in a solvent in the presence or absence of an additive, the solvent is further added.
  • the compound of the formula (16) can be obtained by reacting with a cyanating agent in the presence or absence of an additive and a base.
  • a cyanating agent in the presence or absence of an additive and a base.
  • the solvent for both during the synthesis of the compounds of the formulas (15) and (16), for example, hydrocarbon solvents such as toluene and benzene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride.
  • Halogen-based solvents such as tetrahydrofuran, 2-methyltetratetraester, diethyl ether, tert-butylmethyl ether, 1,2-dimethoxyethane, diethoxymethane, ether-based solvents such as 1,4-dioxane, methanol, ethanol, 2- Alcohol-based solvents such as propanol and tert-butyl alcohol, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixed solvent thereof and the like can be used.
  • titanium (IV) isopropoxide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) butoxide and the like may be used as additives.
  • ammonia, sodium bis (trimethylsilyl) amide and the like can be used as additives.
  • the amount of 2-methyl-2-propanesulfinamide used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (14), preferably in the range of 1 to 2 molar equivalents. (Reference: Chem. Rev., 110, 3660 (2010)).
  • 2-S- (-)-methyl-2-propanesulfinamide For the steric chemistry of 2-methyl-2-propanesulfinamide, either 2-S- (-)-methyl-2-propanesulfinamide or 2-N- (+)-methyl-2-propanesulfinamide is used.
  • the reaction between the cyanating agent and the compound of the formula (15) can proceed with high diastereoselectivity, and the compound of the formula (16) can be obtained in a high yield.
  • 2-S- (-)-methyl-2-propanesulfinamide it is better to use 2-S- (-)-methyl-2-propanesulfinamide than to use 2-N- (+)-methyl-2-propanesulfinamide.
  • 2-S- (-)-methyl-2-propanesulfinamide can be preferably used because it proceeds rapidly.
  • cyanating agent for example, trimethylsilyl cyanide (TMSCN), hydrogen cyanide, sodium cyanide, potassium cyanide, acetone cyanohydrin, diethylcyanophosphonate, diethylaluminum cyanide, tert-butyldimethylsilyl cyanide, tributyltin cyanide and the like are used. can do. (Reference: Chem. Rev., 111, 6947 (2011)).
  • the amount of the cyanating agent used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (15), preferably in the range of 1 to 2 molar equivalents.
  • the reaction temperature can usually be from ⁇ 20 ° C.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as a raw material, both during the synthesis of the compounds of the formulas (15) and (16). It is a range.
  • the reaction between the cyanating agent and the compound of the formula (15) proceeds with high diastereoselectivity, and the compound of the formula (16) can be obtained in a high yield.
  • the compound of the formulas (15) and (16) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, recrystallization or crystallization.
  • Step 8 The compound of the formula (16) is reacted in a solvent under acidic conditions to prepare the compound of the formula (17), and then further reacted in a solvent under acidic or basic conditions.
  • the compound of (1) can be obtained.
  • the solvent for both during the synthesis of the compounds of the formulas (17) and (1), for example, hydrocarbon solvents such as toluene and benzene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride.
  • Halogen-based solvents such as tetrahydrofuran, 2-methyltetrachloride, diethyl ether, tert-butylmethyl ether, 1,2-dimethoxyethane, diethoxymethane, ether-based solvents such as 1,4-dioxane, methanol, ethanol, 2- Alcohol-based solvents such as propanol and tert-butyl alcohol, ketone solvents such as acetone, 2-butanone and methylisobutylketone, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, water or these.
  • a mixed solvent or the like can be used.
  • Acidic conditions include, for example, hydrogen chloride, hydrogen bromide, phosphoric acid, polyphosphate, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride / diethyl ether.
  • Conditions such as mixing an acid such as a complex with a solvent can be mentioned.
  • Examples of the basic condition include conditions such as mixing a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide with a solvent.
  • oxidative conditions include conditions such as hydrogen peroxide, a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or an aqueous solution thereof, and a solvent such as dimethylsulfoxide.
  • the reaction temperature can usually be from ⁇ 20 ° C. to the boiling point of the solvent during the synthesis of the compound of formula (17).
  • synthesizing the compound of the formula (1) it is usually possible from ⁇ 20 ° C. to the boiling point of the solvent used, but it is preferably in the range of ⁇ 20 ° C. to 40 ° C.
  • the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as a raw material, both during the synthesis of the compounds of the formulas (17) and (1). It is a range.
  • the amount of hydrogen peroxide used under oxidative conditions can be in the range of 1 to 5 molar equivalents with respect to the compound of formula (17), preferably in the range of 1 to 2 molar equivalents.
  • the amount of the base used under the oxidative conditions can be used in the range of 0.1 to 5 molar equivalents with respect to the compound of the formula (17), preferably in the range of 0.1 to 2 molar equivalents.
  • the amount of the solvent such as dimethyl sulfoxide used under the oxidative conditions can be used in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (17).
  • the compound of formula (17) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
  • the compound of the formula (1) can be obtained as a purified product by a method such as chromatography, recrystallization, reslurry or crystallization, but an unpurified product can also be used as a raw material for a prodrug or the like.
  • MS mass spectrometry
  • ESI Electrospray ionization APCI: Atmospheric pressure chemical ionization wt%: Weight percent concentration
  • a suspension of acetonitrile (600 mL) of phthalic anhydride (248.9 g) and a urea-hydrogen adduct (244.5 g) was stirred at 35 ° C. for 1 hour to prepare a solution.
  • An acetonitrile solution (120 mL) of the compound (300 g) of the formula (21) was added to the obtained solution at an internal temperature of 40 ° C. or lower, and then the mixture was stirred at 40 ° C. or lower for 4 hours and at 25 ° C. for 15 hours.
  • a methanol solution of ammonia (658 mL, 7.0 M) was added dropwise to the reaction mixture, and the mixture was stirred at 25 ° C. for 2 days.
  • the reaction mixture was concentrated to 961 g, ethyl acetate (200 mL), tetrahydrofuran (100 mL) and aqueous citric acid solution (884 mL, 0.68 M) were added, and the mixture was stirred for 5 minutes at 25 ° C.
  • the organic layer was separated and washed with an aqueous citric acid solution (200 mL, 1.33 M) and a 10% Na 2 SO4 aqueous solution (200 mL).
  • reaction solution was cooled to 5 ° C. or lower under a nitrogen atmosphere, a methanol solution of ammonia (181 mL, 7.0 M) was added, and the mixture was stirred at 25 ° C. for 1 hour.
  • a methanol solution of ammonia (181 mL, 7.0 M) was added, and the mixture was stirred at 25 ° C. for 1 hour.
  • the reaction solution was cooled to 5 ° C. or lower, trimethylsilyl cyanide (14.6 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Then, the mixture was stirred at 25 ° C. for 20 hours. After cooling the reaction solution to 5 ° C.
  • the compound (100 g) of the formula (16') was dissolved in dimethyl sulfoxide (200 mL), concentrated hydrochloric acid (26.3 mL) was added to this solution at 25 ° C. or lower, and the mixture was stirred overnight at 25 ° C. A solution containing the compound of the formula (17) was obtained. This solution is added at 15 ° C. or lower to a mixed solution of 22% aqueous sodium hydroxide solution (578 g) and 30% hydrogen peroxide solution (64.4 mL) adjusted to 5 ° C. or lower in another reaction vessel. Then, the mixture was stirred at 45 ° C. for 75 minutes and at 90 ° C. for 2 hours. After cooling the reaction solution to 5 ° C.
  • the compound (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro represented by the formula (1) does not go through the synthetic intermediate compound represented by the formula (2).
  • -Three-selective and efficient mass production of 3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid has become possible.

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Abstract

Provided is a novel method for producing a (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicycle[3.1.0]hexane-2,6-dicarboxylic acid. This production method is characterized by relying on the conversion from a compound represented by formula (3).

Description

アミノ酸誘導体の製造方法Amino acid derivative manufacturing method
　本発明は、代謝活性型グルタミン酸（ｍＧｌｕ）受容体のサブグループＩＩに属するｍＧｌｕ２およびｍＧｌｕ３受容体のアンタゴニストとして作用する化合物である（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の製造方法に関する。また、本発明は、この製造工程で製造される新規な中間体化合物に関する。 The present invention is a compound that acts as an antagonist of mGlu2 and mGlu3 receptors belonging to subgroup II of metabotropic glutamate (mGlu) receptors (1R, 2R, 3R, 5R, 6R) -2-amino-6-. The present invention relates to a method for producing a fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid. The present invention also relates to a novel intermediate compound produced in this production process.
　グルタミン酸等の興奮性アミノ酸は、哺乳類の中枢神経系（ＣＮＳ）において、長期増強（学習及び記憶）、シナプス可塑性の発生、運動制御、呼吸、心血管調節及び知覚といった種々の生理的プロセスを調節する。現在、グルタミン酸受容体は、「受容体がイオンチャネル型構造を持つイオノトロピック型」：イオンチャネル型グルタミン酸受容体（ｉＧｌｕＲ）及び「受容体がＧ－タンパク質と共役しているメタボトロピック型」：代謝活性型グルタミン酸受容体（ｍＧｌｕＲ）の２つのクラスに大きく分類されている（非特許文献１）。いずれのクラスの受容体も、興奮性経路に従って正常なシナプス伝達に介在しているようである。これらは、また、発生段階から生涯を通じてシナプス結合の修飾に関与しているようである（非特許文献２）。代謝型グルタミン酸受容体は、アミノ酸配列の相同性、シグナル伝達機構及び薬理学的な特性から３つのグループに分類される。この中で、グループＩＩ代謝型グルタミン酸受容体（ｍＧｌｕ２およびｍＧｌｕ３受容体）は、Ｇタンパク質共役型受容体であり、アデニルサイクラーゼと結合し、サイクリックアデノシン１リン酸（ｃＡＭＰ）のホルスコリン刺激性の蓄積を抑制する（非特許文献３）。また、グループＩＩ代謝型グルタミン酸受容体は、主にグルタミン酸神経系のプレシナプスに存在し、自己受容体として機能するため、グルタミン酸の過剰遊離を抑制している（非特許文献４、非特許文献５）。グループＩＩ代謝型グルタミン酸受容体に拮抗する化合物は急性及び慢性の精神医学的疾患並びに神経学的疾患の治療または予防に有効であると考えられる。（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸は、グループＩＩ代謝型グルタミン酸受容体に対して強い拮抗作用を有する化合物であり、統合失調症、不安及びその関連疾患、二極性障害、てんかん等の精神医学的障害の治療及び予防、並びに、薬物依存症、認知障害、アルツハイマー病、ハンチントン舞踏病、パーキンソン病、筋硬直に伴う運動障害、脳虚血、脳不全、脊髄障害、頭部障害等の神経学的疾患の治療及び予防に有用である（特許文献１）。 Excitatory amino acids such as glutamate regulate various physiological processes in the central nervous system (CNS) of mammals such as long-term potentiation (learning and memory), synaptic plasticity development, motor control, respiration, cardiovascular regulation and perception. .. Currently, glutamate receptors are "ionotropic type in which the receptor has an ionotropic structure": ionotropic glutamate receptor (iGluR) and "metabotropic type in which the receptor is coupled to G-protein": metabolism. It is broadly classified into two classes of active glutamate receptors (mGluR) (Non-Patent Document 1). Both classes of receptors appear to mediate normal synaptic transmission according to excitatory pathways. These also appear to be involved in the modification of synaptic connections throughout life from the developmental stage (Non-Patent Document 2). Metabotropic glutamate receptors are classified into three groups according to their amino acid sequence homology, signal transduction mechanism, and pharmacological properties. Among them, the group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind to adenylcyclase and are cyclic adenosine monophosphate (cAMP) holscoline-stimulating. Suppresses accumulation (Non-Patent Document 3). In addition, Group II metabotropic glutamate receptors are mainly present in the presynapses of the glutamate nervous system and function as autoreceptors, thus suppressing excessive release of glutamate (Non-Patent Documents 4 and 5). ). Compounds that antagonize Group II metabotropic glutamate receptors appear to be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders. (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid is a group. II A compound that has a strong antagonism against metabolic glutamate receptors, and is used for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety and related diseases, bipolar disorders, and epilepsy, as well as drug dependence, It is useful for the treatment and prevention of neurological diseases such as cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, motor disorders associated with muscle rigidity, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders (Patent Documents). 1).
　グループＩＩ代謝型グルタミン酸受容体拮抗作用を有する式（１）に示される化合物、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸が開示されている（特許文献１）。 Group II Metabotropic glutamate receptor antagonizing compound represented by formula (1), (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy) ] Bicyclo [3.1.0] Hexane-2,6-dicarboxylic acid is disclosed (Patent Document 1).
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　上記式（１）に代表されるグループＩＩ代謝型グルタミン酸受容体に結合する化合物である（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－アルコキシ－ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸及びその合成中間体の合成法については、複数の報告がなされている（特許文献１、特許文献２、特許文献３、特許文献４、特許文献５、特許文献６、非特許文献５）。この（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－アルコキシ－ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の既存の合成法としては、式（２）に示される化合物を合成中間体としている。 (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxy-bicyclo [3. 1.0] Several reports have been made on the method for synthesizing hexane-2,6-dicarboxylic acid and its synthetic intermediate (Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, and Patent Document 5). , Patent Document 6, Non-Patent Document 5). As an existing method for synthesizing this (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-alkoxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid, the formula is used. The compound shown in (2) is used as a synthetic intermediate.
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　この合成経路では、工程数が多いことから総収率の低下を招くのみならず、製造費用の低減並びに製造期間の短縮化が困難であるという点で、なお一層の改良が必要とされていた。式（１）に示されるグループＩＩ代謝型グルタミン酸受容体に結合する化合物は、治療薬として有用であることから、これらの化合物の製造方法において、反応暴走等の安全性上の課題がなく、容易にスケールアップでき、費用対効果があって安全な試薬を用いることができ、工程数がより少なくて効率の良い、大量生産に適した製造方法の開発が必要とされている。 In this synthetic route, not only the total yield is lowered due to the large number of steps, but also it is difficult to reduce the manufacturing cost and the manufacturing period, so further improvement is required. .. Since the compound that binds to the group II metabotropic glutamate receptor represented by the formula (1) is useful as a therapeutic agent, there is no safety problem such as reaction runaway in the method for producing these compounds, and it is easy. There is a need to develop a manufacturing method suitable for mass production that can be scaled up, cost-effective and safe reagents can be used, and the number of steps is smaller and more efficient.
ＷＯ０３／０６１６９８WO03 / 061698 ＷＯ００／１２４６４WO00 / 12464 ＷＯ０２／００５９５WO02 / 00595 ＷＯ２００５／０４７２１５WO2005 / 047215 ＷＯ２０１１／０６１９３４WO2011 / 061934 ＷＯ２０１１／０６１９３５WO2011 / 061935
　本発明の目的は、グループＩＩ代謝型グルタミン酸受容体拮抗作用を有する式（１）に示される化合物（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の大量生産に適した製造方法を提供することである。 An object of the present invention is a compound (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4) represented by the formula (1) having a group II metabotropic glutamate receptor antagonism. -To provide a production method suitable for mass production of [fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid.
　本発明者らは、既存合成法の有する全ての課題を一挙に解決すべく、式（２）で示される合成中間体化合物を経ずに、式（１）に示される化合物を合成することのできる新規な合成経路及び新規な合成中間体化合物を見出し、本発明を完成した。 In order to solve all the problems of the existing synthetic method at once, the present inventors synthesize the compound represented by the formula (1) without going through the synthetic intermediate compound represented by the formula (2). We have found a novel synthetic pathway and a novel synthetic intermediate compound that can be used, and completed the present invention.
　すなわち本発明は、以下の通りである。
（Ｉ）式（１）に示される（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の製造方法であって、 That is, the present invention is as follows.
(I) (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane represented by the formula (1) A method for producing -2,6-dicarboxylic acid.
Figure JPOXMLDOC01-appb-C000032
 （ａ）式（３）に示される化合物から式（４）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000032
 (A) A step of converting the compound represented by the formula (3) to the compound represented by the formula (4), and
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
 （式中、Ｒ1は、置換基を有してもよいＣ１－６アルキル基、又は置換基を有してもよいアリール基を示す。）
（ｂ）前記式（４）に示される化合物及び式（５）に示される化合物を反応させることにより式（６）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000034
 (In the formula, R 1 indicates a C 1-6 alkyl group which may have a substituent or an aryl group which may have a substituent.)
(B) A step of converting the compound represented by the formula (4) and the compound represented by the formula (5) into the compound represented by the formula (6) by reacting the compound.
Figure JPOXMLDOC01-appb-C000035
 （式中、Ｒ２は、置換基を有してもよいＣ１－６アルキル基を示す。）
Figure JPOXMLDOC01-appb-C000035
 (In the formula, R 2 represents a C 1-6 alkyl group which may have a substituent.)
Figure JPOXMLDOC01-appb-C000036
 （式中、Ｒ２は前記と同じ意味を示す。）
（ｃ）前記式（６）に示される化合物を式（７）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000036
 (In the formula, R 2 has the same meaning as described above.)
(C) A step of converting the compound represented by the formula (6) into the compound represented by the formula (7), and
Figure JPOXMLDOC01-appb-C000037
 （式中、Ｒ２は前記と同じ意味を示す。）
（ｄ）前記式（７）に示される化合物を式（８）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000037
 (In the formula, R 2 has the same meaning as described above.)
(D) A step of converting the compound represented by the formula (7) into the compound represented by the formula (8), and
Figure JPOXMLDOC01-appb-C000038
 （式中、Ｒ２は前記と同じ意味を示す。）
（ｅ）前記式（８）に示される化合物及び式（９）に示される化合物を反応させることにより式（１０）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000038
 (In the formula, R 2 has the same meaning as described above.)
(E) A step of converting the compound represented by the formula (8) and the compound represented by the formula (9) into the compound represented by the formula (10) by reacting the compound.
Figure JPOXMLDOC01-appb-C000039
 （式中、Ｒ３は、置換基を有してもよいＣ１－６アルキル基、又は置換基を有してもよいアリール基を示す。）
Figure JPOXMLDOC01-appb-C000039
 (In the formula, R 3 indicates a C 1-6 alkyl group which may have a substituent or an aryl group which may have a substituent.)
Figure JPOXMLDOC01-appb-C000040
 （式中、Ｒ２は前記と同じ意味を示す。）
（ｆ）前記式（１０）に示される化合物を式（１１）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000040
 (In the formula, R 2 has the same meaning as described above.)
(F) A step of converting the compound represented by the formula (10) into the compound represented by the formula (11), and
Figure JPOXMLDOC01-appb-C000041
 （式中、Ｒ２は前記と同じ意味を示す。）
（ｇ）前記式（１１）に示される化合物を式（１２）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000041
 (In the formula, R 2 has the same meaning as described above.)
(G) A step of converting the compound represented by the formula (11) into the compound represented by the formula (12), and
Figure JPOXMLDOC01-appb-C000042
 （式中、Ｒ２は前記と同じ意味を示す。）
（ｈ）前記式（１２）に示される化合物を式（１３）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000042
 (In the formula, R 2 has the same meaning as described above.)
(H) A step of converting the compound represented by the formula (12) into the compound represented by the formula (13), and
Figure JPOXMLDOC01-appb-C000043
 （ｉ）前記式（１３）に示される化合物を式（１４）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000043
 (I) A step of converting the compound represented by the formula (13) into the compound represented by the formula (14), and
Figure JPOXMLDOC01-appb-C000044
 （ｊ）前記式（１４）に示される化合物を式（１５）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000044
 (J) A step of converting the compound represented by the formula (14) into the compound represented by the formula (15), and
Figure JPOXMLDOC01-appb-C000045
 （ｋ）前記式（１５）に示される化合物を式（１６）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000045
 (K) A step of converting the compound represented by the formula (15) into the compound represented by the formula (16), and
Figure JPOXMLDOC01-appb-C000046
 （ｌ）前記式（１６）に示される化合物を式（１７）に示される化合物に変換する工程と、
Figure JPOXMLDOC01-appb-C000046
 (L) A step of converting the compound represented by the formula (16) into the compound represented by the formula (17), and
Figure JPOXMLDOC01-appb-C000047
 （ｍ）前記式（１７）に示される化合物を前記式（１）に示される化合物に変換する工程を含む製造方法。
（ＩＩ）　式（４）に示される化合物。
Figure JPOXMLDOC01-appb-C000047
 (M) A production method comprising a step of converting the compound represented by the formula (17) into the compound represented by the formula (1).
(II) The compound represented by the formula (4).
Figure JPOXMLDOC01-appb-C000048
 （式中、Ｒ１は前記と同じ意味を示す。）
（ＩＩＩ）　式（６）に示される化合物。
Figure JPOXMLDOC01-appb-C000048
 (In the formula, R 1 has the same meaning as described above.)
(III) The compound represented by the formula (6).
Figure JPOXMLDOC01-appb-C000049
 （式中、Ｒ２は前記と同じ意味を示す。）
（ＩＶ）　式（７）に示される化合物。
Figure JPOXMLDOC01-appb-C000049
 (In the formula, R 2 has the same meaning as described above.)
(IV) The compound represented by the formula (7).
Figure JPOXMLDOC01-appb-C000050
 （式中、Ｒ２は前記と同じ意味を示す。）
（Ｖ）　式（８）に示される化合物。
Figure JPOXMLDOC01-appb-C000050
 (In the formula, R 2 has the same meaning as described above.)
(V) The compound represented by the formula (8).
Figure JPOXMLDOC01-appb-C000051
 （式中、Ｒ２は前記と同じ意味を示す。）
（ＶＩ）　式（９）に示される化合物。
Figure JPOXMLDOC01-appb-C000051
 (In the formula, R 2 has the same meaning as described above.)
(VI) The compound represented by the formula (9).
Figure JPOXMLDOC01-appb-C000052
 （式中、Ｒ３は前記と同じ意味を示す。）
（ＶＩＩ）　式（１０）に示される化合物。
Figure JPOXMLDOC01-appb-C000052
 (In the formula, R 3 has the same meaning as described above.)
(VII) The compound represented by the formula (10).
Figure JPOXMLDOC01-appb-C000053
 （式中、Ｒ２は前記と同じ意味を示す。）
（ＶＩＩＩ）　式（１１）に示される化合物。
Figure JPOXMLDOC01-appb-C000053
 (In the formula, R 2 has the same meaning as described above.)
(VIII) The compound represented by the formula (11).
Figure JPOXMLDOC01-appb-C000054
 （式中、Ｒ２は前記と同じ意味を示す。）
（ＩＸ）　式（１２）に示される化合物。
Figure JPOXMLDOC01-appb-C000054
 (In the formula, R 2 has the same meaning as described above.)
(IX) The compound represented by the formula (12).
Figure JPOXMLDOC01-appb-C000055
 （式中、Ｒ２は前記と同じ意味を示す。）
（Ｘ）　式（１３）に示される化合物。
Figure JPOXMLDOC01-appb-C000055
 (In the formula, R 2 has the same meaning as described above.)
(X) The compound represented by the formula (13).
Figure JPOXMLDOC01-appb-C000056
 （ＸＩ）　式（１４）に示される化合物。
Figure JPOXMLDOC01-appb-C000056
 (XI) The compound represented by the formula (14).
Figure JPOXMLDOC01-appb-C000057
 （ＸＩＩ）　式（１５）に示される化合物。
Figure JPOXMLDOC01-appb-C000057
 (XII) The compound represented by the formula (15).
Figure JPOXMLDOC01-appb-C000058
 （ＸＩＩＩ）　式（１６）に示される化合物。
Figure JPOXMLDOC01-appb-C000058
 (XIII) The compound represented by the formula (16).
Figure JPOXMLDOC01-appb-C000059
 （ＸＩＶ）　式（１７）に示される化合物。
Figure JPOXMLDOC01-appb-C000059
 (XIV) The compound represented by the formula (17).
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　本発明の製造方法により、式（２）で示される合成中間体化合物を経ずに、式（１）に示される化合物（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の立体選択的でかつ効率的な大量生産が可能になった。 According to the production method of the present invention, the compound (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro represented by the formula (1) does not go through the synthetic intermediate compound represented by the formula (2). -Three-selective and efficient mass production of 3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid has become possible.
式（１６’）の化合物のＸ線の分子構造図を示す。The X-ray molecular structure diagram of the compound of the formula (16') is shown.
　本明細書において用いる用語は、以下の意味である。
　本発明において、「ｎ」はノルマル（ｎｏｒｍａｌ）を、「ｉ」はイソ（ｉｓｏ）を、「ｓ」及び「ｓｅｃ」はセカンダリー（ｓｅｃｏｎｄａｒｙ）を、「ｔ」及び「ｔｅｒｔ」はターシャリー（ｔｅｒｔｉａｒｙ）を、「ｃ」はシクロ（ｃｙｃｌｏ）を、「ｏ」はオルト（ｏｒｔｈｏ）を、「ｍ」はメタ（ｍｅｔａ）を、「ｐ」はパラ（ｐａｒａ）を示す。
　「Ｃ１－６アルキル基」とは、炭素数１から６のアルキル基であり、直鎖状、分枝鎖状のアルキル基を示す。例えば、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、２－メチルブチル基、１－メチルブチル基、ネオペンチル基、１，２－ジメチルプロピル基、１－エチルプロピル基、ｎ－ヘキシル基、４－メチルペンチル基、３－メチルペンチル基、２－メチルペンチル基、１－メチルペンチル基、３，３－ジメチルブチル基、２，２－ジメチルブチル基、１，１－ジメチルブチル基、１，２－ジメチルブチル基、１，３－ジメチルブチル基、２，３－ジメチルブチル基、２－エチルブチル基、１－エチルブチル基、１－エチル－１－メチルプロピル基等を挙げることができる。
　「アリール基」とは、単環式又は縮合多環式の芳香族炭化水素基を示し、例えば、フェニル基、１－ナフチル基、２－ナフチル基、アントラニル基、又はフェナンスリル基等が挙げられる。
　本明細書において、ある官能基について「置換基を有していてもよい」という場合には、該官能基上の化学的に可能な位置に１個又は２個以上の置換基が存在する場合があることを意味する。官能基に存在する置換基の種類、置換基の個数、及び置換位置は特に限定されず、２個以上の置換基が存在する場合には、それらは同一であっても異なっていてもよい。官能基に存在する置換基としては、例えば、ハロゲン原子、オキソ基、ニトロ基、シアノ基、ヒドロキシ基、スルファニル基、カルボキシ基、カルバモイル基、スルホ基、スルファモイル基、スルフィノ基、Ｃ１－６アルキル基、Ｃ２－６アルケニル基、Ｃ２－６アルキニル基、アリール基、Ｃ７－１２アラルキル基、Ｃ１－６アルコキシ基、アリールオキシ基、Ｃ７－１２アラルキルオキシ基、Ｃ１－６アルキルスルファニル基、アリールスルファニル基、Ｃ７－１２アラルキルオキシスルファニル基、Ｃ１－６アルカノイル基、アリールカルボニル基、Ｃ１－６アルキルスルホニル基、アリールスルホニル基、Ｃ１－６アルコキシカルボニル基、アミノ基、ヘテロアリール基、又は飽和又は部分飽和のヘテロシクリル基等を挙げることができるが、これらに限定されることはない。
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子及びヨウ素原子を意味する。
　これらの置換基は、さらに１種又は２種以上の他の置換基により置換されていてもよい。そのような例として、例えば、Ｃ１－６ハロゲン化アルキル基、Ｃ１－６ハロゲン化アルコキシ基、カルボキシ置換Ｃ１－６アルキル基、Ｃ１－６アルキル置換アミノ基等を挙げることができるが、これらに限定されることはない。
本発明において、好ましい態様を以下にあげる。
Ｒ１は、Ｃ１－３アルキル基であり；
　Ｒ２は、Ｃ１－３アルキル基であり；
　Ｒ３は、置換基を有してもよいアリール基である。
特に好ましい態様を以下にあげる。
　Ｒ１は、メチル基、エチル基又はイソプロピル基であり；
　Ｒ２は、メチル基又はエチル基であり；
　Ｒ３は、ハロゲン原子で置換されたフェニル基である。 The terms used herein have the following meanings.
In the present invention, "n" is normal, "i" is iso, "s" and "sec" are secondary, and "t" and "tert" are tertiary. ), “C” indicates cyclo, “o” indicates ortho, “m” indicates meta, and “p” indicates para.
The "C 1-6 alkyl group" is an alkyl group having 1 to 6 carbon atoms, and indicates a linear or branched alkyl group. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl. Group, neopentyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3, 3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group , 1-ethylbutyl group, 1-ethyl-1-methylpropyl group and the like.
The "aryl group" indicates a monocyclic or condensed polycyclic aromatic hydrocarbon group, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthranyl group, a phenanthryl group and the like.
In the present specification, when it is said that a functional group "may have a substituent", the case where one or more substituents are present at chemically possible positions on the functional group. Means that there is. The type of substituents present in the functional group, the number of substituents, and the positions of substitutions are not particularly limited, and when two or more substituents are present, they may be the same or different. Examples of the substituent present in the functional group include a halogen atom, an oxo group, a nitro group, a cyano group, a hydroxy group, a sulfanyl group, a carboxy group, a carbamoyl group, a sulfo group, a sulfamoyl group, a sulfino group and a C 1-6 alkyl. Group, C 2-6 alkenyl group, C 2-6 alkynyl group, aryl group, C 7-12 aralkyl group, C 1-6 alkoxy group, aryloxy group, C 7-12 aralkyloxy group, C 1-6 alkyl Sulfanyl group, arylsulfanyl group, C 7-12 aralkyloxysulfanyl group, C 1-6 alkanoyl group, arylcarbonyl group, C 1-6 alkylsulfonyl group, arylsulfonyl group, C 1-6 alkoxycarbonyl group, amino group, Heteroaryl groups, saturated or partially saturated heterocyclyl groups and the like can be mentioned, but are not limited thereto.
"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
These substituents may be further substituted with one or more other substituents. Examples of such examples include a C 1-6 halogenated alkyl group, a C 1-6 halogenated alkoxy group, a carboxy substituted C 1-6 alkyl group, a C 1-6 alkyl substituted amino group and the like. , Not limited to these.
In the present invention, preferred embodiments are given below.
R 1 is a C 1-3 alkyl group;
R 2 is a C 1-3 alkyl group;
R 3 is an aryl group which may have a substituent.
Particularly preferred embodiments are listed below.
R 1 is a methyl group, an ethyl group or an isopropyl group;
R2 is a methyl or ethyl group;
R 3 is a phenyl group substituted with a halogen atom.
本発明は、式（１）に示した化合物の製造方法に関するものである。また、本発明は、それらの製造中間体である式（４）、式（６）、式（７）、式（８）、式（９）、式（１０）、式（１１）、式（１２）、式（１３）、式（１４）、式（１５）、式（１６）および式（１７）に示した化合物に関するものである。
　本発明は、以下に示す方法によって実施することができる。本発明の一実施形態を下記スキーム１に示す。
スキーム１ The present invention relates to a method for producing a compound represented by the formula (1). Further, in the present invention, the formulas (4), formulas (6), formulas (7), formulas (8), formulas (9), formulas (10), formulas (11) and formulas (11), which are intermediates for manufacturing them, are used. It relates to the compounds represented by 12), formula (13), formula (14), formula (15), formula (16) and formula (17).
The present invention can be carried out by the methods shown below. An embodiment of the present invention is shown in Scheme 1 below.
Scheme 1
Figure JPOXMLDOC01-appb-C000061
 （式中、Ｒ１、Ｒ２、Ｒ３は、前記と同じ意味を示す。）
Figure JPOXMLDOC01-appb-C000061
 (In the formula, R 1 , R 2 , and R 3 have the same meanings as described above.)
　工程１：式（３）の化合物を溶媒中、塩基の存在下、Ｒ１で置換されたスルホニルクロリドと反応させることにより式（４）の化合物を調製後、更に、極性溶媒と塩基を加え、式（５）の化合物と反応させることにより、式（６）を得ることができる。
溶媒としては、式（４）の合成時には、例えば、トルエン、キシレン、ベンゼン、ヘプタン、ヘキサン、石油エーテル等の炭化水素系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素、クロロベンゼン、ベンゾトリフルオリド等のハロゲン系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、テトラヒドロピラン等のエーテル系溶媒、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、アセトン、２－ブタノン、メチルイソブチルケトン等のケトン系溶媒又はこれらの混合溶媒等を使用することができる。式（６）の合成時には、例えば、テトラヒドロフラン、２－メチルテトラヒドロフラン等のエーテル系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド又はこれらの混合溶媒等を使用することができる。
塩基としては、式（４）、（６）の化合物の合成時共に、例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、リン酸ナトリウム、リン酸カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基、又はトリエチルアミン、ジイソプロピルアミン、ジイソプロピルエチルアミン、ピリジン、２，４，６－テトラメチルピリジン等の有機塩基、又はノルマルブチルリチウム、水素化ナトリウム、水素化カリウム、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド等を使用することができる。
反応温度は、式（４）、（６）の化合物の合成時共に、通常、－２０℃から溶媒の沸点まで可能であるが、好ましくは－２０～４０℃の範囲である。
塩基の使用量は、式（４）の化合物の合成時は、原料の式（３）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～１．５モル当量の範囲である。式（６）の化合物の合成時は、原料の式（４）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～１．５モル当量の範囲である。
式（５）の化合物の使用量は、原料の式（４）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～１．５モル当量の範囲である。
溶媒の使用量は、式（４）、（６）の化合物の合成時共に、原料の化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
式（６）の化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。 Step 1: After preparing the compound of formula (4) by reacting the compound of formula (3) with a sulfonyl chloride substituted with R1 in a solvent in the presence of a base, a polar solvent and a base are further added. The formula (6) can be obtained by reacting with the compound of the formula (5).
As the solvent, at the time of synthesis of the formula (4), for example, a hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, petroleum ether, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene, benzo Halogen solvents such as trifluoride, ether solvents such as tetrahydrofuran, 2-methyltetrahexyl, tetrahydropyran, ester solvents such as ethyl acetate and isopropyl acetate, ketone solvents such as acetone, 2-butanone and methylisobutylketone or these. A mixed solvent of the above can be used. At the time of synthesis of the formula (6), for example, an ether solvent such as tetrahydrofuran and 2-methyltetrahydrofuran, acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or a mixed solvent thereof and the like can be used.
As the base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate at the time of synthesizing the compounds of the formulas (4) and (6). , Inorganic bases such as potassium hydrogen carbonate, or organic bases such as triethylamine, diisopropylamine, diisopropylethylamine, pyridine, 2,4,6-tetramethylpyridine, or normal butyl lithium, sodium hydride, potassium hydride, sodium bis ( Trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and the like can be used.
The reaction temperature is usually possible from −20 ° C. to the boiling point of the solvent at the time of synthesizing the compounds of the formulas (4) and (6), but is preferably in the range of −20 ° C. to 40 ° C.
The amount of the base used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (3) at the time of synthesizing the compound of the formula (4), preferably 1 to 1.5 mol. It is in the range of equivalents. When synthesizing the compound of the formula (6), it can be used in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (4), preferably in the range of 1 to 1.5 molar equivalents.
The amount of the compound of the formula (5) to be used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (4), preferably in the range of 1 to 1.5 molar equivalents.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as the raw material, both during the synthesis of the compounds of the formulas (4) and (6). Is.
The compound of the formula (6) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
　工程２：式（６）の化合物をアルコール系溶媒中、塩基存在下、反応させることにより式（７）の化合物を得ることができる。 Step 2: The compound of the formula (7) can be obtained by reacting the compound of the formula (6) in an alcohol solvent in the presence of a base.
　アルコール系溶媒としては、例えばメタノール、エタノール等を使用することができる。
塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、リン酸ナトリウム、リン酸カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基、又はトリエチルアミン、ジイソプロピルアミン、ジイソプロピルエチルアミン、ピリジン、２，４，６－トリメチルピリジン、Ｎ，Ｎ－ジメチル－４－アミノピリジン等の有機塩基、又はノルマルブチルリチウム、水素化ナトリウム、水素化カリウム、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン（ＤＢＵ）、１，５－ジアザビシクロ［４．３．０］－５－ノネン（ＤＢＮ）、１，１，３，３－テトラメチルグアニジン（ＴＭＧ）等を使用することができる。
反応温度は、通常、－２０℃から使用する溶媒の沸点まで可能であるが、好ましくは－２０～４０℃の範囲である。
塩基の使用量は、原料の式（６）の化合物に対して０．１～５モル当量の範囲で使用することができ、好ましくは０．１～２モル当量の範囲である。
溶媒の使用量は、式（６）の化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
 式（７）の化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。 As the alcohol solvent, for example, methanol, ethanol or the like can be used.
Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc., or triethylamine, diisopropylamine, etc. Organic bases such as diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine, N, N-dimethyl-4-aminopyridine, or normal butyl lithium, sodium hydride, potassium hydride, sodium bis (trimethylsilyl) amide, potassium Bis (trimethylsilyl) amide, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), 1,5-diazabicyclo [4.3.0] -5-nonen (DBN), 1,1, 3,3-Tetramethylguanidine (TMG) and the like can be used.
The reaction temperature can usually range from −20 ° C. to the boiling point of the solvent used, but is preferably in the range of −20 ° C. to 40 ° C.
The amount of the base used can be in the range of 0.1 to 5 molar equivalents with respect to the compound of the raw material formula (6), preferably in the range of 0.1 to 2 molar equivalents.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (6).
The compound of the formula (7) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
　工程３：式（７）の化合物を溶媒中、酸化剤と反応させることにより、本発明の式（８）の化合物を得ることができる。
溶媒としては、例えば、トルエン、ベンゼン等の炭化水素系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素、クロロベンゼン、ベンゾトリフルオリド等のハロゲン系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、１，２－ジメトキシエタン、ジエトキシメタン、１，４－ジオキサン等のエーテル系溶媒、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブチルアルコール等のアルコール系溶媒、アセトン、２－ブタノン、メチルイソブチルケトン等のケトン系溶媒、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、酢酸、水又はこれらの混合溶媒等を使用することができる。
酸化剤としては、例えば、３－クロロ過安息香酸、過安息香酸、モノペルオキシフタル酸、モノペルオキシフタル酸マグネシウム塩、過酢酸等の過酸、メチルトリオキソレニウム又はトリス（セチルピリジニウム）ペルオキソタングストリン酸塩（ＰＣＷＰ）等の触媒存在下での過酸化水素、尿素－過酸化水素付加体、ニトリル化合物存在下での過酸化水素、アセトン等のケトン化合物存在下での過酸化水素、アセトン等のケトン化合物存在下でのオキソン（２ＫＨＳＯ５・ＫＨＳＯ４・Ｋ２ＳＯ４）、ジメチルジオキシラン、ｔｅｒｔ－ブチルヒドロペルオキシド、四酸化オスミウムとＮ－メチルモルホリン－Ｎ－オキシド、四酢酸鉛、ヨードシルベンゼンと三フッ化ホウ素ジエチルエーテル錯体、塩化クロミル、オゾン等を使用することができる。
反応温度は、通常、－８０℃から使用する溶媒の沸点まで可能であるが、好ましくは０～５０℃の範囲である。
酸化剤の使用量は、原料の式（７）の化合物に対して０．５～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である。
溶媒の使用量は、式（７）の化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
 式（８）の化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。 Step 3: The compound of the formula (8) of the present invention can be obtained by reacting the compound of the formula (7) with an oxidizing agent in a solvent.
Examples of the solvent include hydrocarbon solvents such as toluene and benzene, halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride, tetrahydrofuran, 2-methyltetrachloride and diethyl ether. , Telt-butylmethyl ether, 1,2-dimethoxyethane, diethoxymethane, 1,4-dioxane and other ether solvents, methanol, ethanol, 2-propanol, tert-butyl alcohol and other alcohol solvents, acetone, 2 -Ketone-based solvents such as butanone and methylisobutylketone, ester-based solvents such as ethyl acetate and isopropyl acetate, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, water or a mixed solvent thereof, etc. Can be used.
Examples of the oxidizing agent include 3-chloroperbenzoic acid, perbenzoic acid, monoperoxyphthalic acid, monoperoxyphthalic acid magnesium salt, peracid such as peracetic acid, methyltrioxorenium or tris (cetylpyridinium) peroxotangustrin. Hydrogen peroxide in the presence of a catalyst such as acid salt (PCWP), urea-hydrogen peroxide adduct, hydrogen peroxide in the presence of a nitrile compound, hydrogen peroxide in the presence of a ketone compound such as acetone, acetone, etc. Oxone (2KHSO 5 , KHSO 4 , K2 SO 4 ), dimethyldioxylan, tert - butylhydroperoxide, osmium tetraoxide and N-methylmorpholin-N-oxide, lead tetraacetate, iodosylbenzene in the presence of ketone compounds. And hydrogen peroxide diethyl ether complex, chromyl chloride, ozone and the like can be used.
The reaction temperature can usually be from −80 ° C. to the boiling point of the solvent used, but is preferably in the range of 0 to 50 ° C.
The amount of the oxidizing agent used can be in the range of 0.5 to 5 molar equivalents with respect to the compound of the raw material formula (7), preferably in the range of 1 to 2 molar equivalents.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (7).
The compound of the formula (8) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
　工程４：式（８）の化合物を溶媒中、塩基の存在下もしくは非存在下、式（９）の化合物と反応させることにより、式（１０）の化合物が得られる。式（９）の化合物は、４－フルオロベンジルアルコールを溶媒中、塩基の存在下、Ｒ３で置換されたスルホニルクロリドと反応させることにより得ることができる。
溶媒としては、式（９）、（１０）の化合物の合成時共に、例えば、トルエン、キシレン、ベンゼン、ヘプタン、ヘキサン、石油エーテル等の炭化水素系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素、クロロベンゼン、ベンゾトリフルオリド等のハロゲン系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、テトラヒドロピラン等のエーテル系溶媒、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、アセトン、２－ブタノン、メチルイソブチルケトン等のケトン系溶媒、アセトニトリル、ジメチルホルムアミド、ジメチルアセトアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド又はこれらの混合溶媒等を使用することができる。
塩基としては、式（９）、（１０）の化合物の合成時共に、例えば、水酸化ナトリウム、水酸化カリウム、水酸化リチウム、リン酸ナトリウム、リン酸カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基、又はトリエチルアミン、ジイソプロピルアミン、Ｎ，Ｎ-ジイソプロピルエチルアミン、ピリジン、２，４，６－トリメチルピリジン等の有機塩基、又はノルマルブチルリチウム、水素化ナトリウム、水素化カリウム、ナトリウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド等を使用することができる。
反応温度は、式（９）の化合物の合成時には、通常、－２０℃から溶媒の沸点まで可能であるが、好ましくは－２０～４０℃の範囲である。式（１０）の化合物の合成時には、通常、－２０℃から溶媒の沸点まで可能であるが、好ましくは０℃以上沸点以下の範囲である。
塩基の使用量は、式（９）、（１０）の化合物の合成時共に、原料の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である。
式（１０）の化合物の合成時における、式（９）の化合物の使用量は、原料の式（８）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である。
溶媒の使用量は、式（９）、（１０）の化合物の合成時共に、原料の化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
式（９）の化合物は、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。式（１０）の化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。 Step 4: The compound of the formula (10) is obtained by reacting the compound of the formula (8) with the compound of the formula (9) in a solvent in the presence or absence of a base. The compound of formula (9) can be obtained by reacting 4 -fluorobenzyl alcohol with a sulfonyl chloride substituted with R3 in the presence of a base.
As the solvent, for both during the synthesis of the compounds of the formulas (9) and (10), for example, hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, petroleum ether, dichloromethane, chloroform, 1,2-dichloroethane, and the like. Halogen-based solvents such as carbon tetrachloride, chlorobenzene and benzotrifluoride, ether-based solvents such as tetrahydrofuran, 2-methyltetrahydrocarbon and tetrahydropyran, ester-based solvents such as ethyl acetate and isopropyl acetate, acetone, 2-butanone and methylisobutylketone. Etc., a ketone solvent such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixed solvent thereof can be used.
As the base, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate at the time of synthesizing the compounds of the formulas (9) and (10). , Inorganic bases such as potassium hydrogen carbonate, or organic bases such as triethylamine, diisopropylamine, N, N-diisopropylethylamine, pyridine, 2,4,6-trimethylpyridine, or normal butyl lithium, sodium hydride, potassium hydride, Sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide and the like can be used.
The reaction temperature can usually be from −20 ° C. to the boiling point of the solvent at the time of synthesizing the compound of the formula (9), but is preferably in the range of −20 ° C. to 40 ° C. When synthesizing the compound of the formula (10), it is usually possible from −20 ° C. to the boiling point of the solvent, but it is preferably in the range of 0 ° C. or higher and lower than the boiling point.
The amount of the base used can be in the range of 1 to 5 molar equivalents with respect to the raw material compound in both the synthesis of the compounds of the formulas (9) and (10), preferably in the range of 1 to 2 molar equivalents. Is.
The amount of the compound of the formula (9) used at the time of synthesizing the compound of the formula (10) can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (8), and is preferably 1. It is in the range of ~ 2 molar equivalents.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as the raw material, both during the synthesis of the compounds of the formulas (9) and (10). Is.
The compound of the formula (9) can be obtained as a purified product or an unpurified product by a method such as recrystallization, reslurry or crystallization. The compound of the formula (10) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
　工程５： 式（１０）の化合物を溶媒中、塩基と反応させることで式（１１）のジアステレオマー混合化合物を調製後、ルイス酸の存在下、塩基を加えることにより式（１２）の化合物を調製し、アルコールもしくはアルコールと酢酸等を添加することでクエンチした後、さらに塩基を加えて反応させることにより、本発明の式（１３）の化合物を得ることができる。また、式（１１）の化合物を調製後、トリメチルシリルクロリド等のシリル化剤と塩基を加えて反応させた後、ルイス酸を添加することで式（１２）を合成することもできる。
溶媒としては式（１１）の合成時には、例えば、メタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、テトラヒドロピラン等のエーテル系溶媒等を使用することができる。式（１２）の合成時にはテトラヒドロフラン、２－メチルテトラヒドロフラン、テトラヒドロピラン等のエーテル系溶媒、トルエン、ノルマルヘキサン等を使用することができる。式（１３）の合成時にはメタノール、エタノール等のアルコール系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、テトラヒドロピラン等のエーテル系溶媒、水を溶媒として使用することができる。
塩基としては式（１１）の合成時にはナトリウムメトキシド、ナトリウムエトキシド、またはメタノールやエタノール等のアルコールに水素化ナトリウム、ナトリウムビス（トリメチルシリル）アミド、リチウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド等を反応系内で反応させて調製したナトリウムメトキシド、ナトリウムエトキシドを使用することもできる。式（１２）の合成時にはナトリウムビス（トリメチルシリル）アミド、リチウムビス（トリメチルシリル）アミド、カリウムビス（トリメチルシリル）アミド、ナトリウムビス（トリメチルシリル）アミド等を使用することができる。式（１３）の合成時にはアンモニア/メタノール溶液、アンモニア/エタノール溶液、アンモニア水等を使用することができる。
ルイス酸としてはトリメチルアルミニウム、トリエチルアルミニウム、トリプロピルアルミニウム、トリイソブチルアルミニウム、トリノルマルオクチルアルミニウム等のトリアルキルアルミニウム、塩化アルミニウム、塩化チタン、トリメチルシリルトリフルオロメタンスルホナート、三フッ化ホウ素・ジエチルエーテル錯体等を使用することができる。
クエンチに使用するアルコールとしてはメタノール、エタノール等が使用できる。またアルコールの使用量としては原料の式（１２）の化合物に対して１～２０モル当量の範囲で使用することができ、好ましくは１～１０モル当量の範囲である。
反応温度は、式（１１）の化合物の合成時は、通常、－２０℃から室温まで可能であるが、好ましくは１０℃～室温の範囲である。式（１２）の化合物の合成時は、通常、－４０℃から室温まで可能であるが、好ましくは－２０℃から室温の範囲である。式（１３）の化合物の合成時は、通常、－２０℃から室温まで可能であるが、好ましくは０℃から室温の範囲である。
塩基の使用量は、式（１１）の化合物の合成時は、原料の式（１０）の化合物に対して０．１～１モル当量の範囲で使用することができ、好ましくは０．２～０．３モル当量の範囲である。式（１２）の化合物の合成時は、原料の式（１１）の化合物に対して１～２モル当量の範囲で使用することができ、好ましくは１～１．５モル当量の範囲である。式（１３）の化合物の合成時は、原料の式（１２）の化合物に対して１～５０モル当量の範囲で使用することができ、好ましくは５～２０モル当量の範囲である。
式（１１）と式（１２）の化合物はクロマトグラフィーによる精製物又は未精製物として得ることができる。式（１３）化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。
溶媒の使用量は式（１１）、（１２）の化合物の合成時には原料の化合物に対して１倍から２０質量倍の範囲で使用することができ、好ましくは３～１０質量倍の範囲である。式（１３）の化合物の合成時には原料の化合物に対して１０倍から４０質量倍の範囲で使用することができ、好ましくは１０～２０質量倍の範囲である。 Step 5: The compound of the formula (10) is prepared by reacting the compound of the formula (10) with a base in a solvent, and then the compound of the formula (12) is added by adding a base in the presence of Lewis acid. The compound of the formula (13) of the present invention can be obtained by preparing the above, quenching by adding alcohol or alcohol and acetic acid, and then further adding a base to react. Further, the formula (12) can also be synthesized by preparing the compound of the formula (11), adding a base to a silylating agent such as trimethylsilyl chloride and reacting, and then adding a Lewis acid.
As the solvent, for example, an alcohol solvent such as methanol or ethanol, an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran or tetrahydropyran can be used at the time of synthesis of the formula (11). At the time of synthesizing the formula (12), ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, toluene, normal hexane and the like can be used. At the time of synthesis of the formula (13), an alcohol solvent such as methanol and ethanol, an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran and tetrahydropyran, and water can be used as the solvent.
As a base, at the time of synthesis of the formula (11), sodium methoxydo, sodium ethoxydo, or alcohol such as methanol or ethanol is mixed with sodium hydride, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide. , Sodium bis (trimethylsilyl) amide and the like are reacted in the reaction system to prepare sodium methoxydo and sodium ethoxydo. Sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide and the like can be used during the synthesis of the formula (12). Ammonia / methanol solution, ammonia / ethanol solution, ammonia water and the like can be used in the synthesis of the formula (13).
Examples of the Lewis acid include trialkylaluminum such as trimethylaluminum, triethylaluminum, tripropylaluminum, triisobutylaluminum and trinormaloctylaluminum, aluminum chloride, titanium chloride, trimethylsilyltrifluoromethanesulfonate, boron trifluoride / diethyl ether complex and the like. Can be used.
As the alcohol used for quenching, methanol, ethanol and the like can be used. The amount of alcohol used can be in the range of 1 to 20 molar equivalents with respect to the compound of the raw material formula (12), preferably in the range of 1 to 10 molar equivalents.
The reaction temperature can usually be from −20 ° C. to room temperature during the synthesis of the compound of the formula (11), but is preferably in the range of 10 ° C. to room temperature. When synthesizing the compound of the formula (12), it is usually possible from −40 ° C. to room temperature, but preferably in the range of −20 ° C. to room temperature. When synthesizing the compound of the formula (13), it is usually possible from −20 ° C. to room temperature, but preferably in the range of 0 ° C. to room temperature.
When synthesizing the compound of the formula (11), the amount of the base used can be in the range of 0.1 to 1 molar equivalent with respect to the compound of the raw material formula (10), preferably 0.2 to 0.2. It is in the range of 0.3 molar equivalents. When synthesizing the compound of the formula (12), it can be used in the range of 1 to 2 molar equivalents with respect to the compound of the raw material formula (11), preferably in the range of 1 to 1.5 molar equivalents. When synthesizing the compound of the formula (13), it can be used in the range of 1 to 50 molar equivalents with respect to the compound of the raw material formula (12), preferably in the range of 5 to 20 molar equivalents.
The compounds of formulas (11) and (12) can be obtained as purified or unpurified products by chromatography. The compound of formula (13) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
The amount of the solvent used can be in the range of 1 to 20 times by mass, preferably 3 to 10 times by mass, that of the raw material compound at the time of synthesizing the compounds of the formulas (11) and (12). .. At the time of synthesizing the compound of the formula (13), it can be used in the range of 10 to 40 times by mass, preferably 10 to 20 times by mass with respect to the raw material compound.
　工程６：式（１３）の化合物を溶媒中、添加剤の存在下もしくは非存在下、酸化剤と反応させることにより、本発明の式（１４）の化合物を得ることができる。
溶媒としては、例えば、トルエン、ベンゼン等の炭化水素系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素、クロロベンゼン、ベンゾトリフルオリド等のハロゲン系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、１，２－ジメトキシエタン、ジエトキシメタン、１，４－ジオキサン等のエーテル系溶媒、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブチルアルコール等のアルコール系溶媒、アセトン、２－ブタノン、メチルイソブチルケトン等のケトン系溶媒、酢酸エチル、酢酸イソプロピル等のエステル系溶媒、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、酢酸、水又はこれらの混合溶媒等を使用することができる。
酸化剤としては、一般的に第２級アルコールからケトンへ酸化するものが使用できる。例えば、トリクロロシアヌル酸存在下での２，２，６，６－テトラメチルピペリジン－１－オキシルラジカル（ＴＥＭＰＯ）等の添加剤を使用することができる（参考文献：Ｊ．Ｏｒｇ．Ｃｈｅｍ．，６８，　４９９９（２００３））。
上記のＴＥＭＰＯ及びトリクロロシアヌル酸を用いた酸化反応の場合、反応温度は、通常、－２０℃から使用する溶媒の沸点まで可能であるが、好ましくは－２０℃～３０℃の範囲である。
ＴＥＭＰＯ及びトリクロロシアヌル酸を用いた酸化反応の場合、ＴＥＭＰＯの使用量は、原料の式（１３）の化合物に対して０．０１～２モル当量の範囲で使用することができ、好ましくは０．０１～１モル当量の範囲である。トリクロロシアヌル酸の使用量は、原料の式（１３）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である。
ＴＥＭＰＯ及びトリクロロシアヌル酸を用いた酸化反応の場合、溶媒の使用量は、式（１３）の化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
 式（１４）の化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。 Step 6: The compound of the formula (14) of the present invention can be obtained by reacting the compound of the formula (13) with an oxidizing agent in a solvent in the presence or absence of an additive.
Examples of the solvent include hydrocarbon solvents such as toluene and benzene, halogen-based solvents such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride, tetrahydrofuran, 2-methyltetrachloride and diethyl ether. , Telt-butylmethyl ether, 1,2-dimethoxyethane, diethoxymethane, 1,4-dioxane and other ether solvents, methanol, ethanol, 2-propanol, tert-butyl alcohol and other alcohol solvents, acetone, 2 -Ketone-based solvents such as butanone and methylisobutylketone, ester-based solvents such as ethyl acetate and isopropyl acetate, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, water or a mixed solvent thereof, etc. Can be used.
As the oxidizing agent, one that oxidizes a secondary alcohol to a ketone can be generally used. For example, additives such as 2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO) in the presence of trichloroisocyanuric acid can be used (Reference: J. Org. Chem., 68). , 4999 (2003)).
In the case of the above-mentioned oxidation reaction using TEMPO and trichloroisocyanuric acid, the reaction temperature can usually be from −20 ° C. to the boiling point of the solvent used, but is preferably in the range of −20 ° C. to 30 ° C.
In the case of the oxidation reaction using TEMPO and trichlorocyanulic acid, the amount of TEMPO used can be in the range of 0.01 to 2 molar equivalents with respect to the compound of the raw material formula (13), preferably 0. It is in the range of 01 to 1 molar equivalent. The amount of trichloroisocyanuric acid used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (13), preferably in the range of 1 to 2 molar equivalents.
In the case of the oxidation reaction using TEMPO and trichloroisocyanuric acid, the amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (13). It is a range.
The compound of the formula (14) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
　工程７：式（１４）の化合物を溶媒中、添加剤の存在下もしくは非存在下、２－メチル－２－プロパンスルフィンアミドと反応させることにより式（１５）の化合物を調製後、更に、溶媒中、添加剤及び塩基の存在下もしくは非存在下、シアノ化剤と反応させることにより式（１６）の化合物を得ることができる。
　溶媒としては、式（１５）、（１６）の化合物の合成時共に、例えば、トルエン、ベンゼン等の炭化水素系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素、クロロベンゼン、ベンゾトリフルオリド等のハロゲン系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、１，２－ジメトキシエタン、ジエトキシメタン、１，４－ジオキサン等のエーテル系溶媒、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブチルアルコール等のアルコール系溶媒、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド又はこれらの混合溶媒等を使用することができる。
　式（１５）の化合物の合成時には、添加剤として、例えば、チタニウム（ＩＶ）イソプロポキシド、チタニウム（ＩＶ）メトキシド、チタニウム（ＩＶ）エトキシド、チタニウム（ＩＶ）プロポキシド、チタニウム（ＩＶ）ブトキシド等を使用することができる。式（１６）の化合物の合成時には、添加剤として、アンモニア、ナトリウムビス（トリメチルシリル）アミド等を使用することができる。
　２－メチル－２－プロパンスルフィンアミドの使用量は、原料の式（１４）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である（参考文献：Ｃｈｅｍ．　Ｒｅｖ．，１１０，３６６０　（２０１０））。
　２－メチル－２－プロパンスルフィンアミドの立体化学は、２－Ｓ－（－）－メチル－２－プロパンスルフィンアミド、２－Ｎ－（＋）－メチル－２－プロパンスルフィンアミドのいずれも使用することができ、シアノ化剤と式（１５）の化合物の反応は、高いジアステレオ選択性で進行して、式（１６）の化合物を高い収率で得ることができる。式（１５）化合物の合成時は、２－Ｎ－（＋）－メチル－２－プロパンスルフィンアミドに比べて、２－Ｓ－（－）－メチル－２－プロパンスルフィンアミドを用いた場合のほうが速やかに進行ことから、好ましくは２－Ｓ－（－）－メチル－２－プロパンスルフィンアミドを使用することができる。
　シアノ化剤としては、例えば、トリメチルシリルシアニド（ＴＭＳＣＮ）、シアン化水素、シアン化ナトリウム、シアン化カリウム、アセトンシアノヒドリン、ジエチルシアノホスホネート、ジエチルアルミニウムシアニド、ｔｅｒｔ－ブチルジメチルシリルシアニド、トリブチルチンシアニド等を使用することができる。（参考文献：Ｃｈｅｍ．Ｒｅｖ．，１１１，６９４７（２０１１））。
　シアノ化剤の使用量は、原料の式（１５）の化合物に対して１～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である。
反応温度は、式（１５）の化合物の合成時には、通常、－２０℃から溶媒の沸点まで可能である。式（１６）の化合物の合成時には、通常、－２０℃から使用する溶媒の沸点まで可能であるが、好ましくは－２０℃～４０℃の範囲である。
　溶媒の使用量は、式（１５）、（１６）の化合物の合成時共に、原料となる化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
　シアノ化剤と式（１５）の化合物の反応は、高いジアステレオ選択性で進行し、式（１６）の化合物を高い収率で得ることができる。
 式（１５）、（１６）の化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。 Step 7: After preparing the compound of formula (15) by reacting the compound of formula (14) with 2-methyl-2-propanesulfinamide in a solvent in the presence or absence of an additive, the solvent is further added. The compound of the formula (16) can be obtained by reacting with a cyanating agent in the presence or absence of an additive and a base.
As the solvent, for both during the synthesis of the compounds of the formulas (15) and (16), for example, hydrocarbon solvents such as toluene and benzene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride. Halogen-based solvents such as tetrahydrofuran, 2-methyltetratetraester, diethyl ether, tert-butylmethyl ether, 1,2-dimethoxyethane, diethoxymethane, ether-based solvents such as 1,4-dioxane, methanol, ethanol, 2- Alcohol-based solvents such as propanol and tert-butyl alcohol, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixed solvent thereof and the like can be used.
At the time of synthesizing the compound of the formula (15), for example, titanium (IV) isopropoxide, titanium (IV) methoxide, titanium (IV) ethoxide, titanium (IV) propoxide, titanium (IV) butoxide and the like may be used as additives. Can be used. At the time of synthesizing the compound of the formula (16), ammonia, sodium bis (trimethylsilyl) amide and the like can be used as additives.
The amount of 2-methyl-2-propanesulfinamide used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (14), preferably in the range of 1 to 2 molar equivalents. (Reference: Chem. Rev., 110, 3660 (2010)).
For the steric chemistry of 2-methyl-2-propanesulfinamide, either 2-S- (-)-methyl-2-propanesulfinamide or 2-N- (+)-methyl-2-propanesulfinamide is used. The reaction between the cyanating agent and the compound of the formula (15) can proceed with high diastereoselectivity, and the compound of the formula (16) can be obtained in a high yield. When synthesizing the compound of formula (15), it is better to use 2-S- (-)-methyl-2-propanesulfinamide than to use 2-N- (+)-methyl-2-propanesulfinamide. 2-S- (-)-methyl-2-propanesulfinamide can be preferably used because it proceeds rapidly.
As the cyanating agent, for example, trimethylsilyl cyanide (TMSCN), hydrogen cyanide, sodium cyanide, potassium cyanide, acetone cyanohydrin, diethylcyanophosphonate, diethylaluminum cyanide, tert-butyldimethylsilyl cyanide, tributyltin cyanide and the like are used. can do. (Reference: Chem. Rev., 111, 6947 (2011)).
The amount of the cyanating agent used can be in the range of 1 to 5 molar equivalents with respect to the compound of the raw material formula (15), preferably in the range of 1 to 2 molar equivalents.
The reaction temperature can usually be from −20 ° C. to the boiling point of the solvent during the synthesis of the compound of formula (15). When synthesizing the compound of the formula (16), it is usually possible from −20 ° C. to the boiling point of the solvent used, but it is preferably in the range of −20 ° C. to 40 ° C.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as a raw material, both during the synthesis of the compounds of the formulas (15) and (16). It is a range.
The reaction between the cyanating agent and the compound of the formula (15) proceeds with high diastereoselectivity, and the compound of the formula (16) can be obtained in a high yield.
The compound of the formulas (15) and (16) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, recrystallization or crystallization.
　工程８：式（１６）の化合物を溶媒中、酸性条件下反応させることにより、式（１７）の化合物を調製後、更に、溶媒中、酸性条件又は塩基性条件にて反応させることにより、式（１）の化合物を得ることができる。
溶媒としては、式（１７）、（１）の化合物の合成時共に、例えば、トルエン、ベンゼン等の炭化水素系溶媒、ジクロロメタン、クロロホルム、１，２－ジクロロエタン、四塩化炭素、クロロベンゼン、ベンゾトリフルオリド等のハロゲン系溶媒、テトラヒドロフラン、２－メチルテトラヒドロフラン、ジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、１，２－ジメトキシエタン、ジエトキシメタン、１，４－ジオキサン等のエーテル系溶媒、メタノール、エタノール、２－プロパノール、ｔｅｒｔ－ブチルアルコール等のアルコール系溶媒、アセトン、２－ブタノン、メチルイソブチルケトン等のケトン系溶媒、アセトニトリル、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、ジメチルスルホキシド、酢酸、水又はこれらの混合溶媒等を使用することができる。
酸性条件としては、例えば、塩化水素、臭化水素、リン酸、ポリリン酸、メタンスルホン酸、ｐ－トルエンスルホン酸、トリフルオロメタンスルホン酸、ギ酸、酢酸、トリフルオロ酢酸、三フッ化ホウ素・ジエチルエーテル錯体等の酸と、溶媒を混合して実施する等の条件が挙げられる。
塩基性条件としては、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化バリウム等の塩基と、溶媒を混合して実施する等の条件が挙げられる。
式（１）の化合物の合成時には、酸化的条件にて反応させることができる。
酸化的条件としては、例えば、過酸化水素と、水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の塩基又はその水溶液と、ジメチルスルホキシド等の溶媒を使用して実施する等の条件が挙げられる。（参考文献：Ｓｙｎｔｈｅｓｉｓ，　９４９－９５０　（１９８９））
反応温度は、式（１７）の化合物の合成時には、通常、－２０℃から溶媒の沸点まで可能である。式（１）の化合物の合成時には、通常、－２０℃から使用する溶媒の沸点まで可能であるが、好ましくは－２０℃～４０℃の範囲である。
溶媒の使用量は、式（１７）、（１）の化合物の合成時共に、原料となる化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
酸化的条件における過酸化水素の使用量は、式（１７）の化合物対して１～５モル当量の範囲で使用することができ、好ましくは１～２モル当量の範囲である。
酸化的条件における塩基の使用量は、式（１７）の化合物に対して０．１～５モル当量の範囲で使用することができ、好ましくは０．１～２モル当量の範囲である。
酸化的条件におけるジメチルスルホキシド等の溶媒の使用量は、式（１７）の化合物に対して１～１００質量倍の範囲で使用することができ、好ましくは１～２０質量倍の範囲である。
式（１７）化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物、又は未精製物として得ることができる。
式（１）化合物は、クロマトグラフィー、再結晶、リスラリー又は晶析等の方法による精製物として得ることができるが、未精製物をプロドラッグ体等の原料として用いることもできる。 Step 8: The compound of the formula (16) is reacted in a solvent under acidic conditions to prepare the compound of the formula (17), and then further reacted in a solvent under acidic or basic conditions. The compound of (1) can be obtained.
As the solvent, for both during the synthesis of the compounds of the formulas (17) and (1), for example, hydrocarbon solvents such as toluene and benzene, dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, chlorobenzene and benzotrifluoride. Halogen-based solvents such as tetrahydrofuran, 2-methyltetrachloride, diethyl ether, tert-butylmethyl ether, 1,2-dimethoxyethane, diethoxymethane, ether-based solvents such as 1,4-dioxane, methanol, ethanol, 2- Alcohol-based solvents such as propanol and tert-butyl alcohol, ketone solvents such as acetone, 2-butanone and methylisobutylketone, acetonitrile, N, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetic acid, water or these. A mixed solvent or the like can be used.
Acidic conditions include, for example, hydrogen chloride, hydrogen bromide, phosphoric acid, polyphosphate, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, boron trifluoride / diethyl ether. Conditions such as mixing an acid such as a complex with a solvent can be mentioned.
Examples of the basic condition include conditions such as mixing a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and barium hydroxide with a solvent.
When synthesizing the compound of the formula (1), it can be reacted under oxidative conditions.
Examples of the oxidative conditions include conditions such as hydrogen peroxide, a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or an aqueous solution thereof, and a solvent such as dimethylsulfoxide. (Reference: Synthesis, 949-950 (1989))
The reaction temperature can usually be from −20 ° C. to the boiling point of the solvent during the synthesis of the compound of formula (17). When synthesizing the compound of the formula (1), it is usually possible from −20 ° C. to the boiling point of the solvent used, but it is preferably in the range of −20 ° C. to 40 ° C.
The amount of the solvent used can be in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass, that of the compound as a raw material, both during the synthesis of the compounds of the formulas (17) and (1). It is a range.
The amount of hydrogen peroxide used under oxidative conditions can be in the range of 1 to 5 molar equivalents with respect to the compound of formula (17), preferably in the range of 1 to 2 molar equivalents.
The amount of the base used under the oxidative conditions can be used in the range of 0.1 to 5 molar equivalents with respect to the compound of the formula (17), preferably in the range of 0.1 to 2 molar equivalents.
The amount of the solvent such as dimethyl sulfoxide used under the oxidative conditions can be used in the range of 1 to 100 times by mass, preferably 1 to 20 times by mass with respect to the compound of the formula (17).
The compound of formula (17) can be obtained as a purified product or an unpurified product by a method such as chromatography, recrystallization, resurrection or crystallization.
The compound of the formula (1) can be obtained as a purified product by a method such as chromatography, recrystallization, reslurry or crystallization, but an unpurified product can also be used as a raw material for a prodrug or the like.
　以下に実施例を示し、本発明をさらに詳しく具体的に説明するが、本発明はこれらの記載により限定的に解釈されるものではない。下記実施例における収率は、反応条件により影響を受けているものがあり、最適化された反応条件を選択することによってさらに高い収率にすることが可能である。 Examples are shown below to explain the present invention in more detail, but the present invention is not limitedly interpreted by these descriptions. The yields in the following examples are influenced by the reaction conditions, and higher yields can be obtained by selecting the optimized reaction conditions.
　本実施例に記載した機器分析データは、以下の測定機器にて測定した。
核磁気共鳴装置（NMＲ）：AVENCEIIIHD400（Bruker；400MHz）、JNM-ECA600（日本電子；600ＭＨｚ）
質量分析（MS）：LCMS-IT-TOF（島津製作所）；イオン化法 ESI/APCI、1290 Infinity LC/MS（Agilent Technologies）；イオン化法 ESIまたはESI/APCI
高速液体クロマトグラフ分析（HPLC）：Prominence（島津製作所） The instrumental analysis data described in this example was measured with the following measuring instruments.
Nuclear Magnetic Resonance Device (NMR): AVENCEIIIHD400 (Bruker; 400MHz), JNM-ECA600 (JEOL; 600MHz)
Mass Spectrometry (MS): LCMS-IT-TOF (Shimadzu Seisakusho); Ionization method ESI / APCI, 1290 Infinity LC / MS (Agilent Technologies); Ionization method ESI or ESI / APCI
High Performance Liquid Chromatography Analysis (HPLC): Prominence (Shimadzu Corporation)
　本明細書中で用いられている各略語を次に示す。
ＭＳ：質量分析（mass spectrometry）
ＥＳＩ：エレクトロスプレーイオン化法（electrospray ionization）
ＡＰＣＩ：大気圧化学イオン化法（atomospheric pressure chemical ionization）
wt% ：重量パーセント濃度 The abbreviations used herein are shown below.
MS: mass spectrometry
ESI: Electrospray ionization
APCI: Atmospheric pressure chemical ionization
wt%: Weight percent concentration
　化合物の命名には、ＡＣＤ／Ｎａｍｅ ２０１５　（Ａｄｖａｎｃｅｄ　Ｃｈｅｍｉｓｔｒｙ　Ｄｅｖｅｌｏｐｍｅｎｔ　Ｉｎｃ．）等のソフトを使用している場合がある。 Software such as ACD / Name 2015 (Advanced Chemistry Development Inc.) may be used for naming the compound.
以下、実施例および比較例により本発明をさらに詳細に説明するが、本発明はこれら実施例に限定されない。
実施例１　
ジメチル　フルオロ［（１Ｒ，４Ｒ）－４－ヒドロキシシクロペント－２－エン－１－イル］プロパンジオアト（２１）の合成 Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these Examples.
Example 1
Synthesis of dimethylfluoro [(1R, 4R) -4-hydroxycyclopent-2-en-1-yl] propanedioato (21)
Figure JPOXMLDOC01-appb-C000062
 ［（１Ｒ，４Ｓ）－４－ヒドロキシシクロペント－２－エン－１－イル］　アセタート（３）（１００．０　ｇ）のテトラヒロドフラン（５００　ｍＬ）溶液に、２５℃でトリエチルアミン（８５．４　ｇ）を加えた。反応溶液を食塩-氷浴にて－１５℃に冷却し、メタンスルホニルクロリド（８８．６　ｇ）を１時間かけて滴下した後、２５℃で４時間撹拌した。不溶物をろ別し、析出物をテトラヒロドフランで洗浄して、式（１８）の化合物をテトラヒドロフラン溶液として得た。式（１８）の化合物は、本工程とは別に単離して同定した。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　２．００（１Ｈ，　ｍ）、２．０７（３Ｈ，　ｓ）、２．９５（１Ｈ，　ｍ）、３．０５（３Ｈ，　ｓ）、５．５１－５．５８（２Ｈ，　ｍ）、６．１５（１Ｈ，　ｍ）、６．２１（１Ｈ，　ｍ）。
　フルオロマロン酸ジメチル（１９）（１１６．４　ｇ）のテトラヒドロフラン（２３２　ｍＬ）溶液を０℃に冷却した。そこに、ナトリウムビス（トリメチルシリル）アミドのテトラヒロドフラン溶液（６３９　ｍＬ、１．１　Ｍ）を０．５時間かけて０℃以下を維持しながら滴下し、そのまま１．５時間攪拌した。そこに０℃以下を維持しながら、先に調製した式（１８）の化合物のテトラヒドロフラン溶液を０．５時間かけて滴下した。０．５時間同温度で撹拌した後、室温で１８時間攪拌した。この反応溶液に５℃以下を維持しながら、酢酸（５０．７　ｇ）およびメタノール（２８５　ｍＬ）を順次加えた後、１５℃に昇温させながら０．５時間撹拌した。その後、反応液を減圧下濃縮した。そこに再度メタノール（３８６　ｍＬ）を加え、減圧下濃縮した。そこに再度メタノール（３８６　ｍＬ）を加え、減圧下濃縮することで残渣（５８５　ｇ）を得た。得られた残渣に、水（５７９　ｍＬ）およびｔｅｒｔ－ブチルメチルエーテル（３８６　ｍＬ）を順次加え、有機層を分離した。得られた水層をｔｅｒｔ－ブチルメチルエーテル（３８６　ｍＬ）にて抽出した。有機層を合わせ、１０％食塩水（５００　ｍＬ）にて２回洗浄し、得られた有機層を無水硫酸マグネシウムにて乾燥、乾燥剤をろ別して、式（２０）の化合物を溶液として得た。式（２０）の化合物は、本工程とは別に単離して同定した。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　２．０１（１Ｈ，　ｍ）、２．０３（３Ｈ，　ｓ）、２．２８（１Ｈ，　ｍ）、３．８５（３Ｈ，　ｓ）、３．８６（３Ｈ，　ｓ）、３．８７－３．９５（１Ｈ，　ｍ）、５．７０（１Ｈ，　ｍ）、５．９２（１Ｈ，　ｍ）、６．０２（１Ｈ，　ｍ）　　ＭＳ　ｍ／ｚ　：２９７［Ｍ＋Ｎａ］＋。
　式（２０）の化合物の溶液を減圧下濃縮し、そこにメタノール（２８９　ｍＬ）を加え減圧下濃縮した。再度、メタノール（２８９　ｍＬ）を加え減圧下濃縮し、残渣を得た。得られた残渣にメタノール（９５３　ｍＬ）を加え、式（２０）の化合物のメタノール溶液を調製した。そこに、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン（ＤＢＵ）（５３．７　ｇ）を２５℃で加え、同温度で１時間撹拌した。この反応溶液に５℃以下を維持しながら、酢酸（２５．５　ｇ）を１０分間かけて加えた。その後、１５℃に昇温させながら０．５時間撹拌した。減圧下溶媒を留去した後、酢酸エチル（３８６　ｍＬ）および１０％食塩水（４８４　ｍＬ）を加え有機層を分離した。得られた水層を酢酸エチル（２９０　ｍＬ）で３回抽出した。有機層を合わせ、濃縮乾固して式（２１）の化合物（１７５．３　ｇ）を得た。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　１．８９（１Ｈ、ｍ）、２．２３（１Ｈ、ｍ）、３．８５（３Ｈ、ｓ）、３．８６（３Ｈ、ｓ）、３．８７（１Ｈ、ｓ）、３．８７－３．９５（１Ｈ、ｍ）、４．９５（１Ｈ、ｍ）、５．８０（１Ｈ、ｍ）、６．０３（１Ｈ、ｍ）
ＭＳ　ｍ／ｚ　：２５５．１［Ｍ＋Ｎａ］＋
実施例２　
ジメチル　フルオロ［（１Ｓ，２Ｒ，４Ｒ，５Ｒ）－４－ヒドロキシ－６－オキサビシクロ［３．１．０］ヘキサン－２－イル］プロパンジオアト（２２）の合成
Figure JPOXMLDOC01-appb-C000062
 [(1R, 4S) -4-hydroxycyclopent-2-en-1-yl] Triethylamine (85.) In a solution of acetate (3) (100.0 g) in tetrahirodofuran (500 mL) at 25 ° C. 4 g) was added. The reaction solution was cooled to −15 ° C. in a salt-ice bath, methanesulfonyl chloride (88.6 g) was added dropwise over 1 hour, and the mixture was stirred at 25 ° C. for 4 hours. The insoluble material was filtered off and the precipitate was washed with tetrahirodofuran to give the compound of formula (18) as a solution in tetrahydrofuran. The compound of formula (18) was isolated and identified separately from this step.
1H NMR (400 MHz, CHLOROFORM-d) δppm 2.00 (1H, m), 2.07 (3H, s), 2.95 (1H, m), 3.05 (3H, s), 5.51 -5.58 (2H, m), 6.15 (1H, m), 6.21 (1H, m).
A solution of dimethyl (19) fluoromalonate (116.4 g) in tetrahydrofuran (232 mL) was cooled to 0 ° C. A tetrahirodofuran solution (639 mL, 1.1 M) of sodium bis (trimethylsilyl) amide was added dropwise thereto while maintaining 0 ° C. or lower over 0.5 hours, and the mixture was stirred as it was for 1.5 hours. A tetrahydrofuran solution of the compound of the formula (18) prepared above was added dropwise thereto while maintaining 0 ° C. or lower over 0.5 hours. After stirring at the same temperature for 0.5 hours, the mixture was stirred at room temperature for 18 hours. Acetic acid (50.7 g) and methanol (285 mL) were sequentially added to this reaction solution while maintaining 5 ° C. or lower, and then the mixture was stirred for 0.5 hours while raising the temperature to 15 ° C. Then, the reaction solution was concentrated under reduced pressure. Methanol (386 mL) was added thereto again, and the mixture was concentrated under reduced pressure. Methanol (386 mL) was added thereto again, and the mixture was concentrated under reduced pressure to obtain a residue (585 g). Water (579 mL) and tert-butyl methyl ether (386 mL) were sequentially added to the obtained residue, and the organic layer was separated. The obtained aqueous layer was extracted with tert-butylmethyl ether (386 mL). The organic layers were combined and washed twice with 10% brine (500 mL), the obtained organic layer was dried over anhydrous magnesium sulfate, and the desiccant was filtered off to obtain the compound of formula (20) as a solution. .. The compound of formula (20) was isolated and identified separately from this step.
1H NMR (400 MHz, CHLOROFORM-d) δppm 2.01 (1H, m), 2.03 (3H, s), 2.28 (1H, m), 3.85 (3H, s), 3.86 (3H, s) 3.87-3.95 (1H, m) 5.70 (1H, m) 5.92 (1H, m), 6.02 (1H, m) MS m / z: 297 [M + Na] +.
The solution of the compound of the formula (20) was concentrated under reduced pressure, methanol (289 mL) was added thereto, and the mixture was concentrated under reduced pressure. Methanol (289 mL) was added again and concentrated under reduced pressure to obtain a residue. Methanol (953 mL) was added to the obtained residue to prepare a methanol solution of the compound of the formula (20). To this, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) (53.7 g) was added at 25 ° C., and the mixture was stirred at the same temperature for 1 hour. Acetic acid (25.5 g) was added to the reaction solution over 10 minutes while maintaining a temperature of 5 ° C. or lower. Then, the mixture was stirred for 0.5 hours while raising the temperature to 15 ° C. After distilling off the solvent under reduced pressure, ethyl acetate (386 mL) and 10% saline (484 mL) were added to separate the organic layer. The resulting aqueous layer was extracted 3 times with ethyl acetate (290 mL). The organic layers were combined and concentrated to dryness to obtain a compound (175.3 g) of the formula (21).
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.89 (1H, m), 2.23 (1H, m), 3.85 (3H, s), 3.86 (3H, s), 3.87 (1H, s) 3.87-3.95 (1H, m) 4.95 (1H, m) 5.80 (1H, m), 6.03 (1H, m)
MS m / z: 255.1 [M + Na] +
Example 2
Synthesis of dimethylfluoro [(1S, 2R, 4R, 5R) -4-hydroxy-6-oxabicyclo [3.1.0] hexane-2-yl] propanioato (22)
Figure JPOXMLDOC01-appb-C000063
 無水フタル酸（２４８．９　ｇ）と尿素－過酸化水素付加体（２４４．５　ｇ）のアセトニトリル（６００　ｍＬ）懸濁液を３５℃で１時間撹拌して溶液とした。得られた溶液に式（２１）の化合物（３００　ｇ）のアセトニトリル溶液（１２０　ｍＬ）を内温４０℃以下で加えた後、４０℃以下で４時間、２５℃で１５時間撹拌した。反応液を－１２℃に冷却した後、反応液に酢酸エチル（７５０　ｍＬ）、１０％硫酸ナトリウム水溶液（３００　ｇ）、５℃に冷却した３２％チオ硫酸ナトリウム水溶液（６６５　ｇ）と、５℃に冷却した２０％炭酸水素カリウム水溶液（１５００　ｇ）を加えた。反応液を５℃以下で１．５時間撹拌した後、有機層を分離した。水層を酢酸エチル（１．５　Ｌ）で抽出した後、有機層を合わせ、１０％硫酸ナトリウム水溶液（３００　ｇ）と１８％炭酸水素カリウム水溶液（９８　ｇ）の混合液および、７．５％硫酸ナトリウム水溶液（４００　ｇ）で３回洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥した後、乾燥剤をろ別し、ろ液を濃縮して残渣を得た。得られた残渣を酢酸エチル（６００　ｍＬ）に溶解させた後、ヘプタン（１．２　Ｌ）を加え、５℃以下で撹拌した。析出した固体をろ取後、減圧乾燥を行い、式（２２）の化合物（２７８　ｇ）を得た。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　１．４２－１．６１（１Ｈ、ｍ）、１．９５（１Ｈ、ｂｒ　ｄｄ　Ｊ＝１４．２，　８．３　Ｈｚ）、３．２３－３．４０（１Ｈ、ｍ）、３．４５（１Ｈ、ｓ）、３．５７　（１Ｈ、ｓ）、３．８７（６Ｈ、ｄ　Ｊ＝９．６　Ｈｚ）、４．００－４．１０（１Ｈ、ｍ）、４．４１（１Ｈ、ｂｒ　ｔ　Ｊ＝８．２　Ｈｚ）。
ＭＳ　ｍ／ｚ　：２４９．１［Ｍ＋Ｈ］＋
実施例３　
ジメチル　フルオロ｛（１Ｓ，２Ｒ，４Ｒ，５Ｒ）－４－［（４－フルオロフェニル）メトキシ］－６－オキサビシクロ［３．１．０］ヘキサン－２－イル｝プロパンジオアト（２４）の合成
Figure JPOXMLDOC01-appb-C000063
 A suspension of acetonitrile (600 mL) of phthalic anhydride (248.9 g) and a urea-hydrogen adduct (244.5 g) was stirred at 35 ° C. for 1 hour to prepare a solution. An acetonitrile solution (120 mL) of the compound (300 g) of the formula (21) was added to the obtained solution at an internal temperature of 40 ° C. or lower, and then the mixture was stirred at 40 ° C. or lower for 4 hours and at 25 ° C. for 15 hours. After cooling the reaction solution to -12 ° C, ethyl acetate (750 mL), a 10% sodium sulfate aqueous solution (300 g), and a 32% sodium thiosulfate aqueous solution (665 g) cooled to 5 ° C were added to the reaction solution at 5 ° C. A cooled 20% aqueous potassium hydrogen carbonate solution (1500 g) was added to the mixture. The reaction solution was stirred at 5 ° C. or lower for 1.5 hours, and then the organic layer was separated. After extracting the aqueous layer with ethyl acetate (1.5 L), the organic layers are combined, and a mixed solution of 10% sodium sulfate aqueous solution (300 g) and 18% potassium hydrogen carbonate aqueous solution (98 g) and 7.5%. It was washed 3 times with an aqueous sodium sulfate solution (400 g). The obtained organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the filtrate was concentrated to obtain a residue. The obtained residue was dissolved in ethyl acetate (600 mL), heptane (1.2 L) was added, and the mixture was stirred at 5 ° C. or lower. The precipitated solid was collected by filtration and dried under reduced pressure to obtain a compound (278 g) of the formula (22).
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.42-1.61 (1H, m) 1.95 (1H, br dd J = 14.2, 8.3 Hz), 3.23-3. 40 (1H, m), 3.45 (1H, s), 3.57 (1H, s), 3.87 (6H, dJ = 9.6 Hz), 4.00-4.10 (1H, m) 4.41 (1H, br t J = 8.2 Hz).
MS m / z: 249.1 [M + H] +
Example 3
Synthesis of dimethylfluoro {(1S, 2R, 4R, 5R) -4-[(4-fluorophenyl) methoxy] -6-oxabicyclo [3.1.0] hexane-2-yl} propanioato (24)
Figure JPOXMLDOC01-appb-C000064
 　水酸化ナトリウム（５０．７　ｇ）の水溶液（４９６　ｍＬ）に、０～５℃で、（４－フルオロフェニル）メタノール（１００　ｇ）のテトラヒドロフラン（９９　ｍＬ）溶液を加え、１０分間撹拌した。同温にて４－クロロベンゼンスルホニルクロリド　（２１８　ｇ）のテトラヒドロフラン（１９８　ｍＬ）溶液を２時間かけて加え、１．５時間撹拌した。ｔｅｒｔ－ブチルメチルエーテル（９００　ｍＬ）を加え、有機層を分層し、得られた有機層を水（５００　ｍＬ）で２回洗浄した。有機層を減圧濃縮し、得られた残渣に酢酸エチルを加え、減圧濃縮した。得られた残渣（４００　ｇ）に酢酸エチル（４００　ｍＬ）を加え、再度、減圧濃縮した。得られた残渣（４００　ｇ）にヘプタン（１２００　ｍＬ）を加え、室温にて１時間撹拌した。析出した結晶をろ取し、ヘプタン洗浄、減圧乾燥することで、式（２３）の化合物（１８８　ｇ）を固体として得た。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δ　ｐｐｍ　５．０７　（２　Ｈ，　ｓ）、６．９６　－　７．０６　（２　Ｈ，　ｍ）、　７．２１　－　７．２９　（２　Ｈ，　ｍ）、　７．５０　（２　Ｈ，　ｄ，　Ｊ＝８．３　Ｈｚ）、　７．８２　（２　Ｈ，　ｄ，　Ｊ＝８．３　Ｈｚ）
　式（２２）の化合物（１１０　ｇ）と式（２３）の化合物（１６５　ｇ）のクロロベンゼン（２３４　ｍＬ）溶液に、ヘプタン（１６８　ｍＬ）、Ｎ，Ｎ－ジイソプロピルエチルアミン（７６　ｇ）を加え、３０分間かけて８８℃まで昇温し、同温にて３時間撹拌した。２５℃まで放冷したのち、反応液へ酢酸エチル（５５０　ｍＬ）と１５ｗｔ％塩化ナトリウム水溶液（７７０　ｇ）を加えた。有機層を分層し、得られた有機層を水（７７０　ｍＬ）で洗浄した。有機層を減圧濃縮し、得られた残渣（３４７　ｇ）に２－プロパノール（１８０　ｍＬ）を加えて撹拌した。この溶液へ種晶（１００　ｍｇ）とヘプタン（１６０　ｍＬ）を加え、５℃以下で３０分間撹拌した。ヘプタン（１２００　ｍＬ）を加え、同温にて１時間、２５℃にて１５時間、５℃以下で１時間撹拌した。析出した固体をろ取し、２℃の５％の２－プロパノール／ヘプタン溶液で洗浄後、減圧乾燥することで、式（２４）の化合物（１１１　ｇ）を固体として得た。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　１．６７－１．７７（１　Ｈ、ｍ）、１．８０－１．８８（１　Ｈ、ｍ）、３．２６－　３．３９（１　Ｈ、ｍ）、３．３９－３．４１（１　Ｈ、ｍ）、３．５２－３．５９（１　Ｈ、ｍ）、３．８６（３　Ｈ、ｓ）、３．８８（３　Ｈ、ｓ）、４．１２－４．２３（１　Ｈ、ｍ）、４．４９－４．６２（２　Ｈ、ｍ）、６．９７－７．０８（２　Ｈ、ｍ）、７．２９－７．３８（２　Ｈ、ｍ）。
ＭＳ　ｍ／ｚ　：　３５７［Ｍ＋Ｈ］＋，　３７９［Ｍ＋Ｎａ］＋
Figure JPOXMLDOC01-appb-C000064
 A solution of (4-fluorophenyl) methanol (100 g) in tetrahydrofuran (99 mL) was added to an aqueous solution (496 mL) of sodium hydroxide (50.7 g) at 0-5 ° C., and the mixture was stirred for 10 minutes. A solution of 4-chlorobenzenesulfonyl chloride (218 g) in tetrahydrofuran (198 mL) was added at the same temperature over 2 hours, and the mixture was stirred for 1.5 hours. tert-Butylmethyl ether (900 mL) was added to separate the organic layer and the resulting organic layer was washed twice with water (500 mL). The organic layer was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was concentrated under reduced pressure. Ethyl acetate (400 mL) was added to the obtained residue (400 g), and the mixture was concentrated again under reduced pressure. Heptane (1200 mL) was added to the obtained residue (400 g), and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with heptane, and dried under reduced pressure to give the compound of formula (23) (188 g) as a solid.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.07 (2 H, s), 6.96-7.06 (2 H, m), 7.21-7.29 (2 H, m), 7.50 (2 H, d, J = 8.3 Hz), 7.82 (2 H, d, J = 8.3 Hz)
Heptane (168 mL) and N, N-diisopropylethylamine (76 g) are added to a solution of compound (110 g) of formula (22) and compound (165 g) of formula (23) in chlorobenzene (234 mL), and 30 The temperature was raised to 88 ° C. over 1 minute, and the mixture was stirred at the same temperature for 3 hours. After allowing to cool to 25 ° C., ethyl acetate (550 mL) and a 15 wt% sodium chloride aqueous solution (770 g) were added to the reaction solution. The organic layer was separated and the obtained organic layer was washed with water (770 mL). The organic layer was concentrated under reduced pressure, 2-propanol (180 mL) was added to the obtained residue (347 g), and the mixture was stirred. Seed crystals (100 mg) and heptane (160 mL) were added to this solution, and the mixture was stirred at 5 ° C. or lower for 30 minutes. Heptane (1200 mL) was added, and the mixture was stirred at the same temperature for 1 hour, at 25 ° C. for 15 hours, and at 5 ° C. or lower for 1 hour. The precipitated solid was collected by filtration, washed with a 5% 2-propanol / heptane solution at 2 ° C., and dried under reduced pressure to give the compound (111 g) of the formula (24) as a solid.
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.67-1.77 (1 H, m) 1.80-1.88 (1 H, m) 3.26-3.39 (1 H,) m) 3.39-3.41 (1 H, m), 3.52-3.59 (1 H, m), 3.86 (3 H, s), 3.88 (3 H, s) 4.12-4.23 (1 H, m), 4.49-4.62 (2 H, m), 6.97-7.08 (2 H, m), 7.29-7.38 (2 H, m).
MS m / z: 357 [M + H] +, 379 [M + Na] +
Figure JPOXMLDOC01-appb-C000065
 テトラヒドロフラン（４１０　ｍＬ）とメタノール（８．４　ｍＬ）の混合液にナトリウムメトキシド（４．１０　ｇ）、式（２４）の化合物（１００．０　ｇ）を加え、２５℃で３０分撹拌して、式（２５）の化合物を含む反応液を得た。式（２５）の化合物は、本工程とは別に単離して同定した。　
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　１．５８　－　１．７９　（ｍ，　１　Ｈ）　１．７３　－　１．７９　（ｍ，　１　Ｈ）　２．８７　－　２．９６　（ｍ，　１　Ｈ）、３．３５－３．５５（ｍ　１　Ｈ）、３．５８　（ｍ，　１　Ｈ）、３．８０－　３．８５　（ｍ，　３　Ｈ）、４．１７　－　４．２１　（ｍ，　１　Ｈ）　４．５５　－　４．６２　（ｍ，　２　Ｈ）、４．８５－５．０５（ｍ，　１　Ｈ）　７．０２　－　７．０７　（ｍ，　２　Ｈ）　７．３２　－　７．３７　（ｍ，　２　Ｈ）、ＭＳ　ｍ／ｚ　：　２９９［Ｍ＋Ｈ］＋、３２１［Ｍ＋Ｎａ］＋
　化合物（２５）を含む反応液を－２０℃に冷やし、トリイソブチルアルミニウムのトルエン溶液（２８０　ｍＬ、１．０　Ｍ）を３０分かけて滴下後、－２０℃で２０分撹拌した。反応混合物に、ナトリウムビス（トリメチルシリル）アミドのテトラヒドロフラン溶液（２８０　ｍＬ、１．１　Ｍ）を３０分かけて滴下後、－２０℃で２時間撹拌して、式（２６）の化合物を含む反応混合物を得た。式（２６）の化合物は、本工程とは別に単離して同定した。　
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　２．１０－２．３３　（ｍ，　４Ｈ）、２．８８　（ｄ，　Ｊ＝２．８　Ｈｚ，　１Ｈ）、３．７９　（ｓ，　３Ｈ）、３．８９－３．９８　（ｍ，　１Ｈ）、　４．２４　（ｄｄ，　Ｊ＝５．０，　２．３　Ｈｚ，　１Ｈ）、　４．５３　（ｓ，　２Ｈ）、７．０１－７．０９　（ｍ，　２Ｈ）、７．２７－７．３４　（ｍ，　２Ｈ）　　ＭＳ　ｍ／ｚ　：　３２１［Ｍ＋Ｎａ］＋
　式（２６）の化合物を含む反応混合物にメタノール（９３　ｍＬ）続いて酢酸（２３．７　ｍＬ）を滴下し、－２０℃で３０分撹拌した。反応混合物にアンモニアのメタノール溶液（６５８　ｍＬ、７．０　Ｍ）を滴下し、２５℃で２日間撹拌した。反応混合物を９６１ｇまで濃縮し、酢酸エチル（２００　ｍＬ），テトラヒドロフラン（１００　ｍＬ）、　クエン酸水溶液（８８４　ｍＬ、０．６８　Ｍ）を加えて５分間２５℃で撹拌した。有機層を分液し、クエン酸水溶液　（２００　ｍＬ、１．３３　Ｍ）、１０％Ｎａ２ＳＯ４水溶液（２００　ｍＬ）で洗浄した。水層に無水Ｎａ２ＳＯ４（１４．７　ｇ）を加えて２５℃で５分間撹拌後、酢酸エチル（２６５　ｍＬ）で３回抽出した。有機層を合わせ、１０％Ｎａ２ＳＯ４水溶液（２００　ｍＬ）で洗浄後、無水Ｎａ２ＳＯ４（２９５　ｇ）を加えて１時間乾燥した。活性炭（４０　ｇ）を入れて５分間撹拌後、セライト（登録商標）を用いてろ過、酢酸エチル（１　Ｌ）で洗浄してろ液を得た。ろ液を２８４　ｇまで濃縮し、ｎ－ヘプタン（２６５　ｍＬ）を加えて３４７　ｇまで濃縮した。残渣にｔｅｒｔ－ブチルメチルエーテル（１８４　ｍＬ）、ｎ－ヘプタン（９２　ｍＬ）を加え氷冷した。析出した固体をろ別し、ｔｅｒｔ－ブチルメチルエーテル（１３３　ｍＬ）とｎ－ヘプタン（１３３　ｍＬ）の混合溶媒で洗浄することで式（１３）の化合物（５０．８３　ｇ）を固体として得た。
１Ｈ　ＮＭＲ　（６００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　２．１４－２．３０（４　Ｈ、ｍ）、２．８７（１　Ｈ、ｂｒ　ｄ　Ｊ＝２．９）、３．９１（１　Ｈ、ｄｄｄ　Ｊ＝１３．６、７．０、５．０　Ｈｚ）、４．２４（１　Ｈ、ｄｄ　Ｊ＝２．９、５．０　Ｈｚ）、４．５２（１　Ｈ、ｄ　Ｊ＝１１．２　Ｈｚ）、４．５５（１　Ｈ、ｄ　Ｊ＝１１．２　Ｈｚ）、５．７０（１　Ｈ、ｂｒ　ｓ）、６．２５（１　Ｈ、ｂｒ　ｓ）、７．０４－７．０７（２　Ｈ、ｍ）、７．３０－７．３２（２　Ｈ、ｍ）
ＭＳ　ｍ／ｚ　：　２８４．２［Ｍ＋Ｈ］＋、３０６．１［Ｍ＋Ｎａ］＋
実施例５　
（１Ｒ，３Ｒ，５Ｒ，６Ｒ）－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－オキソビシクロ［３．１．０］ヘキサン－６－カルボキサミド（１４）の合成
Figure JPOXMLDOC01-appb-C000065
 Sodium methoxide (4.10 g) and the compound of formula (24) (100.0 g) were added to a mixture of tetrahydrofuran (410 mL) and methanol (8.4 mL), and the mixture was stirred at 25 ° C. for 30 minutes. , A reaction solution containing the compound of the formula (25) was obtained. The compound of formula (25) was isolated and identified separately from this step.
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.58-1.79 (m, 1H) 1.73-1.79 (m, 1H) 2.87-2.96 (m, 1H) 3.35-3.55 (m 1 H), 3.58 (m, 1 H), 3.80-3.85 (m, 3 H), 4.17-14.21 (m, 1 H) ) 4.55-4.62 (m, 2H) 4.85-5.05 (m, 1H) 7.02-7.07 (m, 2H) 7.32-7.37 (m) , 2 H), MS m / z: 299 [M + H] +, 321 [M + Na] +
The reaction solution containing the compound (25) was cooled to −20 ° C., a toluene solution of triisobutylaluminum (280 mL, 1.0 M) was added dropwise over 30 minutes, and the mixture was stirred at −20 ° C. for 20 minutes. A solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (280 mL, 1.1 M) was added dropwise to the reaction mixture over 30 minutes, and the mixture was stirred at −20 ° C. for 2 hours to contain the compound of formula (26). Got The compound of formula (26) was isolated and identified separately from this step.
1H NMR (400 MHz, CHLOROFORM-d) δppm 2.10-2-33 (m, 4H), 2.88 (d, J = 2.8 Hz, 1H), 3.79 (s, 3H), 3 .89-3.98 (m, 1H), 4.24 (dd, J = 5.0, 2.3 Hz, 1H), 4.53 (s, 2H), 7.01-7.09 (m) , 2H), 7.27-7.34 (m, 2H) MS m / z: 321 [M + Na] +
Methanol (93 mL) followed by acetic acid (23.7 mL) was added dropwise to the reaction mixture containing the compound of formula (26), and the mixture was stirred at −20 ° C. for 30 minutes. A methanol solution of ammonia (658 mL, 7.0 M) was added dropwise to the reaction mixture, and the mixture was stirred at 25 ° C. for 2 days. The reaction mixture was concentrated to 961 g, ethyl acetate (200 mL), tetrahydrofuran (100 mL) and aqueous citric acid solution (884 mL, 0.68 M) were added, and the mixture was stirred for 5 minutes at 25 ° C. The organic layer was separated and washed with an aqueous citric acid solution (200 mL, 1.33 M) and a 10% Na 2 SO4 aqueous solution (200 mL). Anhydrous Na 2 SO 4 (14.7 g) was added to the aqueous layer, the mixture was stirred at 25 ° C. for 5 minutes, and then extracted 3 times with ethyl acetate (265 mL). The organic layers were combined, washed with a 10% Na 2 SO 4 aqueous solution (200 mL), anhydrous Na 2 SO 4 (295 g) was added, and the mixture was dried for 1 hour. Activated carbon (40 g) was added, and the mixture was stirred for 5 minutes, filtered through Cerite (registered trademark), and washed with ethyl acetate (1 L) to obtain a filtrate. The filtrate was concentrated to 284 g, n-heptane (265 mL) was added and concentrated to 347 g. To the residue was added tert-butyl methyl ether (184 mL) and n-heptane (92 mL), and the mixture was ice-cooled. The precipitated solid was separated by filtration and washed with a mixed solvent of tert-butylmethyl ether (133 mL) and n-heptane (133 mL) to give the compound of formula (13) (50.83 g) as a solid. ..
1H NMR (600 MHz, CHLOROFORM-d) δppm 2.14-2.30 (4 H, m) 2.87 (1 H, br d J = 2.9) 3.91 (1 H, ddd J) = 13.6, 7.0, 5.0 Hz), 4.24 (1 H, dd J = 2.9, 5.0 Hz), 4.52 (1 H, d J = 11.2 Hz) , 4.55 (1 H, d J = 11.2 Hz), 5.70 (1 H, br s), 6.25 (1 H, br s), 7.04-7.07 (2 H,) m), 7.30-7.32 (2 H, m)
MS m / z: 284.2 [M + H] +, 306.1 [M + Na] +
Example 5
Synthesis of (1R, 3R, 5R, 6R) -6-fluoro-3-[(4-fluorophenyl) methoxy] -2-oxobicyclo [3.1.0] hexane-6-carboxamide (14)
Figure JPOXMLDOC01-appb-C000066
 　式（１３）の化合物（１．００　ｇ）の酢酸エチル（４　ｍＬ）懸濁液を調製し、そこに２５℃で２，２，６，６－テトラメチルピペリジン－１－オキシルラジカル（ＴＥＭＰＯ）（２７．８　ｍｇ）と酢酸（６３６　ｍｇ）を加えた。この反応液に、５℃以下で、別途調製したトリクロロシアヌル酸　（８２０　ｍｇ）の酢酸エチル（５　ｍＬ）溶液を加えた。その後、２５℃に昇温させながら２時間撹拌した。反応液をＫＣフロック（登録商標）を用いてろ過し、固体を酢酸エチル（７　ｍＬ）で洗浄した。得られたろ液を５℃以下に冷却し、２－プロパノール（７００　ｍｇ）を加え、室温に昇温させながら撹拌した。そこに、テトラヒドロフラン（１２　ｍＬ）、５％　炭酸水素ナトリウム水溶液（３６　ｍＬ）を順次加え室温下撹拌した後、有機層を分層し、得られた有機層を１０％　チオ硫酸ナトリウム水溶液（７　ｍＬ）および５％　食塩水（７　ｍＬ）で順次洗浄した。得られた有機層を無水硫酸マグネシウムで乾燥にて乾燥し、ろ過した後、溶媒を減圧下留去して式（１４）の化合物（１．０６　ｇ）を固体として得た。得られた固体の一部をシリカゲルカラム（ＯＨ－カラム，　ＳＮＡＰ　Ｕｌｔｒａ（２５　ｇ），　ＣＨＣｌ３：酢酸エチル＝８５：１５～１５：８５）にて精製することで、式（１４）の化合物の分析用サンプルを得た。
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　２．４１（１　Ｈ、ｍ）、２．５８－２．６３（２　Ｈ、ｍ）、２．７５（１　Ｈ、ｍ）、３．８６（１　Ｈ、ｄｄ　Ｊ＝１２．８、７．５　Ｈｚ）、４．６０（１　Ｈ、ｄ　Ｊ＝１１．５　Ｈｚ）、４．９３（１　Ｈ、ｄ　Ｊ＝１１．５　Ｈｚ）、５．６６　１　Ｈ、ｂｒ）、６．３５（１　Ｈ、ｂｒ）、７．０３（２　Ｈ、ｔ　Ｊ＝８．７　Ｈｚ）、７．３４（２　Ｈ、ｄｄ　Ｊ＝８．３、５．６　Ｈｚ）
ＭＳ　ｍ／ｚ　：３０４．１［Ｍ＋Ｎａ］＋　
実施例６　
（１Ｒ，２Ｓ，３Ｒ，５Ｒ，６Ｒ）－２－シアノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］－２－｛［（Ｓ）－２－メチルプロパン－２－スルフィニル］アミノ｝ビシクロ［３．１．０］ヘキサン－６－カルボキサミド（１６’）の合成
Figure JPOXMLDOC01-appb-C000066
 A suspension of ethyl acetate (4 mL) of compound (1.00 g) of formula (13) was prepared therein at 25 ° C. with 2,2,6,6-tetramethylpiperidin-1-oxyl radical (TEMPO). (27.8 mg) and acetic acid (636 mg) were added. A solution of trichloroisocyanuric acid (820 mg) prepared separately in ethyl acetate (5 mL) was added to the reaction solution at 5 ° C. or lower. Then, the mixture was stirred for 2 hours while raising the temperature to 25 ° C. The reaction was filtered through KC Flock® and the solid was washed with ethyl acetate (7 mL). The obtained filtrate was cooled to 5 ° C. or lower, 2-propanol (700 mg) was added, and the mixture was stirred while raising the temperature to room temperature. Sodium tetrahydrofuran (12 mL) and 5% sodium hydrogen carbonate aqueous solution (36 mL) were sequentially added thereto, and the mixture was stirred at room temperature, then the organic layer was separated, and the obtained organic layer was separated into a 10% sodium thiosulfate aqueous solution (7 mL). ) And 5% saline (7 mL) were washed sequentially. The obtained organic layer was dried over anhydrous magnesium sulfate, filtered, and then the solvent was evaporated under reduced pressure to give the compound (1.06 g) of the formula (14) as a solid. A part of the obtained solid was purified by a silica gel column (OH-column, SNAP Chloroform (25 g), CHCl 3 : ethyl acetate = 85: 15 to 15:85) to obtain the compound of the formula (14). A sample for analysis was obtained.
1H NMR (400 MHz, CHLOROFORM-d) δppm 2.41 (1 H, m), 2.58-2.63 (2 H, m) 2.75 (1 H, m) 3.86 (1) H, dd J = 12.8, 7.5 Hz) 4.60 (1 H, d J = 11.5 Hz) 4.93 (1 H, d J = 11.5 Hz) 5.66 1 H, br), 6.35 (1 H, br), 7.03 (2 H, t J = 8.7 Hz), 7.34 (2 H, dd J = 8.3, 5.6 Hz) )
MS m / z: 304.1 [M + Na] +
Example 6
(1R, 2S, 3R, 5R, 6R) -2-Cyano-6-fluoro-3-[(4-fluorophenyl) methoxy] -2-{[(S) -2-methylpropane-2-sulfinyl] amino } Synthesis of bicyclo [3.1.0] hexane-6-carboxamide (16')
Figure JPOXMLDOC01-appb-C000067
 　式（１４）の化合物　（２７．４　ｇ）、２－Ｓ－（－）－メチル－２－プロパンスルフィンアミド　（１５．４　ｇ）のトルエン（１５０　ｍＬ）懸濁液へ、窒素雰囲気下、室温にてオルトチタン酸テトライソプロピル（４６．４　ｍＬ）を加えた後、１０分間２５℃にて攪拌した。反応容器を加熱し、９０℃で２時間攪拌して、式（１５’ ）の化合物を含む反応溶液を得た。その後、式（１５’ ）の化合物を含む反応溶液を５０～６０℃で減圧下濃縮した。反応混合物へトルエン（１５０　ｍＬ）を加えた後、９０℃でさらに２時間攪拌し、その後、２５℃にて１５時間攪拌した。窒素雰囲気下、反応溶液を５℃以下に冷却した後，アンモニアのメタノール溶液（１８１　ｍＬ、７．０　Ｍ）を加えた後、２５℃にて１時間攪拌した。反応溶液を５℃以下に冷却し、トリメチルシリルシアニド（１４．６　ｍＬ）を滴下した後、同温度で１時間攪拌した。その後、２５℃にて２０時間攪拌した。反応溶液を５℃以下に冷却した後、メタノール（８７　ｍＬ），クエン酸二ナトリウム１．５水和物（７９．３　ｇ）を溶解した水（５２５　ｍＬ）を加えた。２５℃にて２０分間攪拌した後、酢酸エチル（５３４　ｍＬ）を加えた。混合物を４０℃に加熱した後、同温度で０．５時間攪拌した。水層を酢酸エチル（５２５　ｍＬ）で抽出後、有機層を合わせ、無水ＭｇＳＯ４（３６０　ｇ）で乾燥し、乾燥剤をろ別し、ろ液を濃縮した。得られた残渣に、２５℃にて酢酸エチル（９０　ｍＬ）を加えて５分間懸濁攪拌し、ｎ－ヘプタン（９０　ｍＬ）を加え、１時間懸濁攪拌した。析出した固体をろ取し、ｎ－ヘプタン（２４　ｍＬ）と酢酸エチル（３６　ｍＬ）の混合溶媒で１回洗浄した後、２時間窒素送風乾燥することで、式（１６’）の化合物（３３．９７　ｇ）を固体で得た（得られた化合物の絶対立体配置はＸ線構造解析により決定した。図１にＸ線の分子構造図を示す。）
１Ｈ　ＮＭＲ　（４００　ＭＨｚ，　ＣＨＬＯＲＯＦＯＲＭ－ｄ）　δｐｐｍ　１．２５（９　Ｈ、ｓ）、２．３８－２．４７（３　Ｈ、ｍ）、２．７４－２．７７（１　Ｈ、ｍ）、３．４６（１　Ｈ、ｓ）、３．８６－３．９１（１　Ｈ、ｍ）、４．５７（１　Ｈ、ｄ　Ｊ＝１１．６　Ｈｚ）、４．７４（１　Ｈ、ｄ　Ｊ＝１１．６　Ｈｚ）、５．７５（１　Ｈ、ｂｒ　ｓ）、６．４５（１　Ｈ、ｂｒ　ｓ）、７．０４－７．０８（２　Ｈ、ｍ）、７．３３－７．３７（２　Ｈ、ｍ）
ＭＳ　ｍ／ｚ　：４１２．２　［Ｍ＋Ｈ］＋、４３４．２　［Ｍ＋Ｎａ］＋
実施例７　
（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸（１）の合成
Figure JPOXMLDOC01-appb-C000067
 Toluene (150 mL) suspension of compound (27.4 g) of formula (14), 2-S- (-)-methyl-2-propanesulfinamide (15.4 g), at room temperature in a nitrogen atmosphere. After adding tetraisopropyl orthotitanate (46.4 mL), the mixture was stirred at 25 ° C. for 10 minutes. The reaction vessel was heated and stirred at 90 ° C. for 2 hours to obtain a reaction solution containing the compound of formula (15'). Then, the reaction solution containing the compound of the formula (15') was concentrated under reduced pressure at 50 to 60 ° C. Toluene (150 mL) was added to the reaction mixture, and the mixture was further stirred at 90 ° C. for 2 hours, and then at 25 ° C. for 15 hours. The reaction solution was cooled to 5 ° C. or lower under a nitrogen atmosphere, a methanol solution of ammonia (181 mL, 7.0 M) was added, and the mixture was stirred at 25 ° C. for 1 hour. The reaction solution was cooled to 5 ° C. or lower, trimethylsilyl cyanide (14.6 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. Then, the mixture was stirred at 25 ° C. for 20 hours. After cooling the reaction solution to 5 ° C. or lower, water (525 mL) in which methanol (87 mL) and disodium disodium 1.5 hydrate (79.3 g) were dissolved was added. After stirring at 25 ° C. for 20 minutes, ethyl acetate (534 mL) was added. The mixture was heated to 40 ° C. and then stirred at the same temperature for 0.5 hours. The aqueous layer was extracted with ethyl acetate (525 mL), the organic layers were combined, dried over anhydrous ו 4 (360 g), the desiccant was filtered off, and the filtrate was concentrated. Ethyl acetate (90 mL) was added to the obtained residue at 25 ° C., suspension stirring was performed for 5 minutes, n-heptane (90 mL) was added, and suspension stirring was performed for 1 hour. The precipitated solid was collected by filtration, washed once with a mixed solvent of n-heptane (24 mL) and ethyl acetate (36 mL), and then dried by blowing nitrogen for 2 hours to obtain the compound (33') of the formula (16'). .97 g) was obtained as a solid (the absolute configuration of the obtained compound was determined by X-ray structure analysis. FIG. 1 shows the molecular structure diagram of X-rays).
1H NMR (400 MHz, CHLOROFORM-d) δppm 1.25 (9 H, s), 2.38-2.47 (3 H, m), 2.74-2.77 (1 H, m), 3 .46 (1 H, s), 3.86-3.91 (1 H, m), 4.57 (1 H, d J = 11.6 Hz), 4.74 (1 H, d J = 11) .6 Hz), 5.75 (1 H, br s), 6.45 (1 H, br s), 7.04-7.08 (2 H, m), 7.33-7.37 (2) H, m)
MS m / z: 412.2 [M + H] +, 434.2 [M + Na] +
Example 7
(1R, 2R, 3R, 5R, 6R) -2-Amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) Synthesis of
Figure JPOXMLDOC01-appb-C000068
 　式（１６’）の化合物（１００　ｇ）をジメチルスルホキシド（２００　ｍＬ）に溶解し、この溶液に、濃塩酸（２６．３　ｍＬ）を２５℃以下で加えた後、２５℃で一晩撹拌して、式（１７）の化合物を含む溶液を得た。この溶液を、別の反応容器で５℃以下に調整した２２％水酸化ナトリウム水溶液（５７８　ｇ）と３０％過酸化水素水（６４．４　ｍＬ）の混合溶液に対して１５℃以下で加え、その後４５℃で７５分間、９０℃で２時間撹拌した。反応液を５℃以下に冷却した後、４Ｍの塩酸を加え、同温度で１時間撹拌した。析出した固体をろ取した後、５℃のエタノール（２５０　ｍＬ）と水（２５０　ｍＬ）の混合溶液で洗浄、窒素送風乾燥して式（１）の化合物（７５．３ｇ）を固体として得た。
１Ｈ　ＮＭＲ　（６００　ＭＨｚ，　ＤＭＳＯ－ｄ６）　δｐｐｍ　２．５４－２．２０（４Ｈ、ｍ）、３．９１（１Ｈ、ｂｒ　ｓ）、４．３８（１Ｈ、ｄ　Ｊ＝１１．１　Ｈｚ）、４．５３（１Ｈ、ｄ　Ｊ＝１１．６　Ｈｚ）、７．１２－７．１７（２Ｈ、ｍ）、７．３３－７．３７（２Ｈ、ｍ）　　
ＭＳ　ｍ／ｚ　：３２８　［Ｍ＋Ｈ］＋
Figure JPOXMLDOC01-appb-C000068
 The compound (100 g) of the formula (16') was dissolved in dimethyl sulfoxide (200 mL), concentrated hydrochloric acid (26.3 mL) was added to this solution at 25 ° C. or lower, and the mixture was stirred overnight at 25 ° C. A solution containing the compound of the formula (17) was obtained. This solution is added at 15 ° C. or lower to a mixed solution of 22% aqueous sodium hydroxide solution (578 g) and 30% hydrogen peroxide solution (64.4 mL) adjusted to 5 ° C. or lower in another reaction vessel. Then, the mixture was stirred at 45 ° C. for 75 minutes and at 90 ° C. for 2 hours. After cooling the reaction solution to 5 ° C. or lower, 4M hydrochloric acid was added, and the mixture was stirred at the same temperature for 1 hour. The precipitated solid was collected by filtration, washed with a mixed solution of ethanol (250 mL) and water (250 mL) at 5 ° C., and dried by blowing nitrogen to obtain the compound (75.3 g) of the formula (1) as a solid. ..
1H NMR (600 MHz, DMSO-d6) δppm 2.54-2.20 (4H, m), 3.91 (1H, br s), 4.38 (1H, dJ = 11.1 Hz), 4 .53 (1H, dJ = 11.6 Hz), 7.12-7.17 (2H, m), 7.33-7.37 (2H, m)
MS m / z: 328 [M + H] +
　本発明の製造方法により、式（２）で示される合成中間体化合物を経ずに、式（１）に示される化合物（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の立体選択的でかつ効率的な大量生産が可能になった。 According to the production method of the present invention, the compound (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro represented by the formula (1) does not go through the synthetic intermediate compound represented by the formula (2). -Three-selective and efficient mass production of 3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid has become possible.

Claims (14)

  1. 式（１）に示される（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）－２－アミノ－６－フルオロ－３－［（４－フルオロフェニル）メトキシ］ビシクロ［３．１．０］ヘキサン－２，６－ジカルボン酸の製造方法であって、
    Figure JPOXMLDOC01-appb-C000001
     （ａ）式（３）に示される化合物から式（４）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
     （式中、Ｒ1は、置換基を有してもよいＣ１－６アルキル基、又は置換基を有してもよいアリール基を示す。）
    （ｂ）前記式（４）に示される化合物及び式（５）に示される化合物を反応させることにより式（６）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000004
     （式中、Ｒ２は、置換基を有してもよいＣ１－６アルキル基を示す。）
    Figure JPOXMLDOC01-appb-C000005
     （式中、Ｒ２は前記と同じ意味を示す。）
    （ｃ）前記式（６）に示される化合物を式（７）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000006
     （式中、Ｒ２は前記と同じ意味を示す。）
    （ｄ）前記式（７）に示される化合物を式（８）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000007
     （式中、Ｒ２は前記と同じ意味を示す。）
    （ｅ）前記式（８）に示される化合物及び式（９）に示される化合物を反応させることにより式（１０）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000008
     （式中、Ｒ３は、置換基を有してもよいＣ１－６アルキル基、又は置換基を有してもよいアリール基を示す。）
    Figure JPOXMLDOC01-appb-C000009
     （式中、Ｒ２は前記と同じ意味を示す。）
    （ｆ）前記式（１０）に示される化合物を式（１１）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000010
     （式中、Ｒ２は前記と同じ意味を示す。）
    （ｇ）前記式（１１）に示される化合物を式（１２）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000011
     （式中、Ｒ２は前記と同じ意味を示す。）
    （ｈ）前記式（１２）に示される化合物を式（１３）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000012
     （ｉ）前記式（１３）に示される化合物を式（１４）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000013
     （ｊ）前記式（１４）に示される化合物を式（１５）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000014
     （ｋ）前記式（１５）に示される化合物を式（１６）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000015
     （ｌ）前記式（１６）に示される化合物を式（１７）に示される化合物に変換する工程と、
    Figure JPOXMLDOC01-appb-C000016
     （ｍ）前記式（１７）に示される化合物を前記式（１）に示される化合物に変換する工程を含む製造方法。     (1R, 2R, 3R, 5R, 6R) -2-amino-6-fluoro-3-[(4-fluorophenyl) methoxy] bicyclo [3.1.0] hexane-2, represented by the formula (1). A method for producing 6-dicarboxylic acid.
    Figure JPOXMLDOC01-appb-C000001
     (A) A step of converting the compound represented by the formula (3) to the compound represented by the formula (4), and
    Figure JPOXMLDOC01-appb-C000002
    Figure JPOXMLDOC01-appb-C000003
     (In the formula, R 1 indicates a C 1-6 alkyl group which may have a substituent or an aryl group which may have a substituent.)
    (B) A step of converting the compound represented by the formula (4) and the compound represented by the formula (5) into the compound represented by the formula (6) by reacting the compound.
    Figure JPOXMLDOC01-appb-C000004
     (In the formula, R 2 represents a C 1-6 alkyl group which may have a substituent.)
    Figure JPOXMLDOC01-appb-C000005
     (In the formula, R 2 has the same meaning as described above.)
    (C) A step of converting the compound represented by the formula (6) into the compound represented by the formula (7), and
    Figure JPOXMLDOC01-appb-C000006
     (In the formula, R 2 has the same meaning as described above.)
    (D) A step of converting the compound represented by the formula (7) into the compound represented by the formula (8), and
    Figure JPOXMLDOC01-appb-C000007
     (In the formula, R 2 has the same meaning as described above.)
    (E) A step of converting the compound represented by the formula (8) and the compound represented by the formula (9) into the compound represented by the formula (10) by reacting the compound.
    Figure JPOXMLDOC01-appb-C000008
     (In the formula, R 3 indicates a C 1-6 alkyl group which may have a substituent or an aryl group which may have a substituent.)
    Figure JPOXMLDOC01-appb-C000009
     (In the formula, R 2 has the same meaning as described above.)
    (F) A step of converting the compound represented by the formula (10) into the compound represented by the formula (11), and
    Figure JPOXMLDOC01-appb-C000010
     (In the formula, R 2 has the same meaning as described above.)
    (G) A step of converting the compound represented by the formula (11) into the compound represented by the formula (12), and
    Figure JPOXMLDOC01-appb-C000011
     (In the formula, R 2 has the same meaning as described above.)
    (H) A step of converting the compound represented by the formula (12) into the compound represented by the formula (13), and
    Figure JPOXMLDOC01-appb-C000012
     (I) A step of converting the compound represented by the formula (13) into the compound represented by the formula (14), and
    Figure JPOXMLDOC01-appb-C000013
     (J) A step of converting the compound represented by the formula (14) into the compound represented by the formula (15), and
    Figure JPOXMLDOC01-appb-C000014
     (K) A step of converting the compound represented by the formula (15) into the compound represented by the formula (16), and
    Figure JPOXMLDOC01-appb-C000015
     (L) A step of converting the compound represented by the formula (16) into the compound represented by the formula (17), and
    Figure JPOXMLDOC01-appb-C000016
     (M) A production method comprising a step of converting the compound represented by the formula (17) into the compound represented by the formula (1).
  2. 　式（４）に示される化合物。
    Figure JPOXMLDOC01-appb-C000017
     （式中、Ｒ１は前記と同じ意味を示す。）     The compound represented by the formula (4).
    Figure JPOXMLDOC01-appb-C000017
     (In the formula, R 1 has the same meaning as described above.)
  3. 　式（６）に示される化合物。
    Figure JPOXMLDOC01-appb-C000018
     （式中、Ｒ２は前記と同じ意味を示す。）     The compound represented by the formula (6).
    Figure JPOXMLDOC01-appb-C000018
     (In the formula, R 2 has the same meaning as described above.)
  4. 　式（７）に示される化合物。
    Figure JPOXMLDOC01-appb-C000019
     （式中、Ｒ２は前記と同じ意味を示す。）     The compound represented by the formula (7).
    Figure JPOXMLDOC01-appb-C000019
     (In the formula, R 2 has the same meaning as described above.)
  5. 　式（８）に示される化合物。
    Figure JPOXMLDOC01-appb-C000020
     （式中、Ｒ２は前記と同じ意味を示す。）     The compound represented by the formula (8).
    Figure JPOXMLDOC01-appb-C000020
     (In the formula, R 2 has the same meaning as described above.)
  6. 　式（９）に示される化合物。
    Figure JPOXMLDOC01-appb-C000021
     （式中、Ｒ３は前記と同じ意味を示す。）     The compound represented by the formula (9).
    Figure JPOXMLDOC01-appb-C000021
     (In the formula, R 3 has the same meaning as described above.)
  7. 　式（１０）に示される化合物。
    Figure JPOXMLDOC01-appb-C000022
     （式中、Ｒ２は前記と同じ意味を示す。）     The compound represented by the formula (10).
    Figure JPOXMLDOC01-appb-C000022
     (In the formula, R 2 has the same meaning as described above.)
  8. 　式（１１）に示される化合物。
    Figure JPOXMLDOC01-appb-C000023
     （式中、Ｒ２は前記と同じ意味を示す。）     The compound represented by the formula (11).
    Figure JPOXMLDOC01-appb-C000023
     (In the formula, R 2 has the same meaning as described above.)
  9. 　式（１２）に示される化合物。
    Figure JPOXMLDOC01-appb-C000024
     （式中、Ｒ２は前記と同じ意味を示す。）     The compound represented by the formula (12).
    Figure JPOXMLDOC01-appb-C000024
     (In the formula, R 2 has the same meaning as described above.)
  10. 　式（１３）に示される化合物。
    Figure JPOXMLDOC01-appb-C000025
         The compound represented by the formula (13).
    Figure JPOXMLDOC01-appb-C000025
  11. 　式（１４）に示される化合物。
    Figure JPOXMLDOC01-appb-C000026
         The compound represented by the formula (14).
    Figure JPOXMLDOC01-appb-C000026
  12. 　式（１５）に示される化合物。
    Figure JPOXMLDOC01-appb-C000027
         The compound represented by the formula (15).
    Figure JPOXMLDOC01-appb-C000027
  13. 　式（１６）に示される化合物。
    Figure JPOXMLDOC01-appb-C000028
         The compound represented by the formula (16).
    Figure JPOXMLDOC01-appb-C000028
  14. 　式（１７）に示される化合物。
    Figure JPOXMLDOC01-appb-C000029
         The compound represented by the formula (17).
    Figure JPOXMLDOC01-appb-C000029
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Citations (4)

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WO2011137516A1 (en) * 2010-05-03 2011-11-10 The Royal Institution For The Advancement Of Learning / Mcgill University Flavonoid dimers and their use
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WO2003061698A1 (en) * 2001-12-27 2003-07-31 Taisho Pharmaceutical Co.,Ltd. 6-fluorobicyclo[3.1.0]hexane derivatives
JP2004339199A (en) * 2003-04-23 2004-12-02 Taisho Pharmaceut Co Ltd Group ii metabotropic glutamic acid receptor antagonist
WO2011137516A1 (en) * 2010-05-03 2011-11-10 The Royal Institution For The Advancement Of Learning / Mcgill University Flavonoid dimers and their use
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ATSURO NAKAZATO, KAZUNARI SAKAGAMI, AKITO YASUHARA, HIROSHI OHTA, RYOKO YOSHIKAWA, MANABU ITOH, MASATO NAKAMURA, AND SHIGEYUKI CHA: "Synthesis, in Vitro Pharmacology, Structure-Activity Relationships, and Pharmacokinetics of 3-Alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Derivatives as Potent and Selective Group II Metabotropic Glutamate Receptor Antagonists", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 47, no. 18, 26 August 2004 (2004-08-26), US , pages 4570 - 4587, XP008157980, ISSN: 0022-2623, DOI: 10.1021/jm0400294 *
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