WO2015194157A1 - Manufacturing method and manufacturing intermediate for diphenylsulfide derivative - Google Patents

Manufacturing method and manufacturing intermediate for diphenylsulfide derivative Download PDF

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WO2015194157A1
WO2015194157A1 PCT/JP2015/002985 JP2015002985W WO2015194157A1 WO 2015194157 A1 WO2015194157 A1 WO 2015194157A1 JP 2015002985 W JP2015002985 W JP 2015002985W WO 2015194157 A1 WO2015194157 A1 WO 2015194157A1
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general formula
compound represented
group
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carbon atoms
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PCT/JP2015/002985
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French (fr)
Japanese (ja)
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後藤　崇之
佐藤　正則
誠 牛渡
康則 阿部
信敬 坂本
啓太 三好
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杏林製薬株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/26—Separation; Purification; Stabilisation; Use of additives
    • C07C319/28—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/32—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/63—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing a diphenyl sulfide derivative and a technique relating to a compound that can be used as an intermediate for the production.
  • the applicant has disclosed a diphenyl sulfide derivative represented by the following formula (A) that exhibits an excellent sphingosine-1-phosphate receptor 3 (S1P3) antagonistic action (for example, Patent Document 1).
  • R a represents an alkoxy group having 1 to 6 carbon atoms
  • R b represents a propyl group or an allyl group
  • Z represents a halogen atom.
  • the compound represented by the general formula (A) can be produced, for example, by the method described in Patent Document 1.
  • One of a plurality of synthesis routes disclosed in Patent Document 1 is shown below.
  • a b is a halogen atom, a methanesulfonyloxy group, shows a typical leaving group such as p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group
  • a c is a halogen atom, a methanesulfonyloxy group
  • p R 1 represents a general leaving group such as toluenesulfonyloxy group or trifluoromethanesulfonyloxy group
  • R c represents an alkyl group having 1 to 6 carbon atoms
  • R d represents a general amino protecting group
  • R e represents a hydrogen atom or a general protecting group for a phenolic hydroxyl group
  • R a , R b and Z are the same as defined in formula (A).
  • An object of the present invention is to provide a technique relating to a novel method for producing a diphenyl sulfide derivative.
  • the gist of the present invention is as follows.
  • optical resolution column Separated, general formula (7): [Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ] And / or general formula (8): [Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
  • the compound represented by the general formula (6) is represented by the general formula (7a) as the compound represented by the general formula (7): [Wherein R 9 represents a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group; R 10 is a methyl group, an ethyl group or a tert-butyl group; R 11 is an ethyl group or a tert-butyl group; Z is a chlorine atom]
  • a compound represented by the general formula (8) as a compound represented by the general formula (8a): [Wherein R 9 , R 10 , R 11 and Z are the same as defined above.
  • Including a compound represented by The optical purity of the compound represented by the general formula (7a) to be recovered and / or the optical purity of the compound represented by the general formula (8a) to be recovered is 95% ee or more.
  • a detert-butylation reaction is carried out by reacting the compound represented by formula (5) with an organic sulfonic acid or an acidic clay mineral.
  • R 1 is an ethoxy group
  • R 2 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group
  • R 3 is a chlorine atom
  • 4 is an n-propyl group
  • R 5 is a methyl group, an ethyl group or a tert-butyl group
  • R 6 in the formula (6) is an ethyl group or a tert-butyl group
  • R 3 is bonded to the meta position with respect to the phenylthio group substituted with the R 1 and R 2 O groups.
  • R 1 in Formula (1) and Formula (2) is an ethoxy group
  • R 2 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group
  • R 3 is a chlorine atom
  • R 1 in Formula (3) 4 is an n-propyl group
  • R 5 is a methyl group, an ethyl group or a tert-butyl group
  • R 3 is bonded to the meta position with respect to the phenylthio group substituted by the R 1 and R 2 O groups.
  • a mixture containing the compound represented by A mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid.
  • a pharmaceutically acceptable salt of the compound represented by the general formula (14) is obtained by subjecting the mixture containing a hydrolyzate to a hydrolysis treatment and reacting the product of the hydrolysis treatment with an inorganic acid or an organic acid. A method involving that.
  • R 1 is an ethoxy group
  • R 2 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group
  • R 3 is a chlorine atom
  • R 4 is an n-propyl group
  • R 6 in formula (9) and formula (10) is an ethyl group or a tert-butyl group
  • those skilled in the art can naturally understand that R 3 is bonded to the meta position with respect to the phenylthio group substituted with the R 1 and R 2 O groups.
  • a mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is converted to D-(-)-
  • a D-( ⁇ )-tartrate salt of the compound represented by the general formula (13) is obtained and / or the compound represented by the general formula (10) and the general formula (12 ) Is subjected to hydrolysis treatment, and the product of the hydrolysis treatment is reacted with L-(+)-tartaric acid to produce L-- of the compound represented by the general formula (14).
  • the optical purity of the compound represented by the general formula (15) and / or the optical purity of the compound represented by the general formula (16) is 99.5% ee or more. the method of. [9]
  • R 9 represents a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group
  • R 10 represents a methyl group, an ethyl group or a tert-butyl group
  • R 11 represents an ethyl group or a tert-butyl group
  • Z represents a chlorine atom
  • R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above.
  • a compound represented by [15] General formula (17): [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms; R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent; R 3 represents a halogen atom; R 4 represents an alkyl group having 1 to 6 carbon atoms; R 7 represents an amino-protecting group; R 8 represents an alkyl group having 1 to 6 carbon atoms. ] Or general formula (18): [Wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above.
  • a compound represented by [16] General formula (4): [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms; R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent; R 3 represents a halogen atom; R 4 represents an alkyl group having 1 to 6 carbon atoms; R 5 represents an alkyl group having 1 to 6 carbon atoms. ] A detert-butylation reaction is carried out by reacting the compound represented by formula (5) with an organic sulfonic acid or an acidic clay mineral. [Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
  • a mixture containing the compound represented by formula (13) is subjected to hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid to obtain a general formula (13): [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ] And / or obtaining a pharmaceutically acceptable salt of the compound represented by formula (10): [Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above. ] And a compound represented by the general formula (12): [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • a mixture containing the compound represented by formula (14) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid to obtain a general formula (14): [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ] A pharmaceutically acceptable salt of the compound represented by the general formula (13) and / or the general formula (14). For producing a pharmaceutically acceptable salt of the compound.
  • a mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is converted to D-(-)-
  • D-(-)-tartrate of the compound represented by the general formula (13) is obtained, and / or the compound represented by the general formula (10) and the general formula (12 ) Is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with L-(+)-tartaric acid to give L- ( The method according to [17], wherein +)-tartrate is obtained.
  • a technique relating to a novel method for producing a diphenyl sulfide derivative can be provided.
  • Example 20 is an HPLC (High performance liquid chromatography) chromatogram obtained in Example 20.
  • 2 is an HPLC chromatogram obtained in Example 21.
  • 2 is an HPLC chromatogram obtained in Example 22.
  • 2 is an HPLC chromatogram obtained in Example 23.
  • 2 is an HPLC chromatogram obtained in Example 24.
  • the halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • the alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a 1-ethylpropyl group.
  • the alkoxy group having 1 to 6 carbon atoms is a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • the alkoxy group having 1 to 6 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an isopropoxy group, and a tert-butoxy group.
  • examples of the aralkyl group include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group.
  • the amino protecting group is not particularly limited as long as it is a protecting group commonly known as an amino protecting group.
  • an aralkyl group such as a benzyl group or a paramethoxybenzyl group (p-methoxybenzyl group) is used.
  • Alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, 1- (alkoxy) such as p-methoxybenzyloxycarbonyl group, aralkoxycarbonyl group such as p-nitrobenzyloxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, 1- (ethoxy) ethyl group, methoxyisopropyl group
  • acyl groups such as a kill group, an acetyl group, a trifluoroacetyl group, a propionyl group, a butyryl group, a pivaloyl group, a benzoyl group and a methylbenzoyl group.
  • the alkyl group having 1 to 6 carbon atoms and the aralkyl group may have a substituent.
  • substituents include a halogen atom, a hydroxyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 6 carbon atoms.
  • the alkyl group having 1 to 6 carbon atoms represented by R 4 is preferably an n-propyl group.
  • the alkyl group having 1 to 6 carbon atoms represented by R 5 is preferably a methyl group, an ethyl group or a tert-butyl group, and particularly preferably an ethyl group.
  • the alkyl group having 1 to 6 carbon atoms represented by R 6 is preferably a methyl group, an ethyl group or a tert-butyl group, more preferably an ethyl group or a tert-butyl group, and particularly preferably an ethyl group.
  • R 2 is an optionally substituted alkyl group having 1 to 6 carbon atoms
  • R 2 is preferably a 2-methoxyethoxymethyl group.
  • R 2 is an aralkyl group which may have a substituent
  • R 2 is preferably a benzyl group.
  • Preferred examples of the alkoxy group having 1 to 6 carbon atoms represented by R 1 include an ethoxy group.
  • An organic sulfonic acid is an organic compound containing at least one —SO 3 H group in the molecular structure.
  • an acidic clay mineral means an acidic thing (the thing which acts on the compound represented by General formula (4) as a solid acid) among the inorganic minerals which comprise clay.
  • Examples of the acidic clay mineral include montmorillonite KSF, montmorillonite K10, and montmorillonite K30.
  • R 1 represents an alkoxy group having 1 to 6 carbon atoms
  • R 2 may have a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or a substituent.
  • R 3 represents a halogen atom
  • R 4 represents an alkyl group having 1 to 6 carbon atoms
  • R 5 represents an alkyl group having 1 to 6 carbon atoms
  • R 6 represents an alkyl group having 1 to 6 carbon atoms.
  • R 7 represents an amino-protecting group
  • R 8 represents an alkyl group having 1 to 6 carbon atoms.
  • the compound represented by the general formula (2) can be obtained by converting the compound represented by the general formula (1) into a compound represented by the general formula (2).
  • R 1 , R 2 and R 3 are the same as defined above.
  • R 1 , R 2 and R 3 are as defined above.
  • the conversion can be performed based on, for example, the Wittig reaction, the Horner-Emmons reaction, the Peterson reaction, the TiCl 4 —CH 2 Cl 2 —Zn system reaction, the Thebes reaction, and the compound represented by the general formula (2) Since it tends to decompose at a high temperature, the reaction is preferably performed based on the Peterson reaction in which the reaction proceeds at a relatively low temperature.
  • a Peterson reagent such as trimethylsilylmethylmagnesium chloride or trimethylsilylmethylmagnesium bromide is allowed to act on the compound represented by the general formula (1), and then the obtained compound Can be carried out by treating with acid or base.
  • the Peterson reagent such as trimethylsilylmethyl magnesium chloride is preferably used in an amount of, for example, 1 equivalent to 5 equivalents with respect to the compound represented by the general formula (1). More preferably, it is 1 equivalent or more and 2 equivalents or less, and still more preferably 1 equivalent or more and 1.5 equivalents or less.
  • the amount of the Peterson reagent used is particularly preferably 1.2 equivalents or more and 1.5 equivalents or less with respect to the compound represented by the general formula (1).
  • the reaction temperature is usually from ⁇ 20 ° C. to the boiling point of the solvent, and preferably from 0 ° C. to 70 ° C. Furthermore, the reaction temperature is more preferably 10 ° C. or more and 70 ° C. or less, even more preferably 15 ° C. or more and 50 ° C. or less, and particularly preferably 20 ° C. or more and 35 ° C. or less in that generation of by-products is suppressed. It is done.
  • the “double amount” shown in the present specification is a value obtained by dividing the volume (mL) of the solvent by the weight (g) of the compound.
  • reaction solvent examples include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, halogenated hydrocarbons such as dichloromethane, or the like.
  • ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme
  • aromatic compounds such as benzene, toluene, or xylene
  • halogenated hydrocarbons such as dichloromethane, or the like.
  • a mixture is mentioned,
  • ethers are mentioned, More preferably, tetrahydrofuran is mentioned.
  • the compound represented by General formula (1) can be obtained based on the reaction pathway shown below, for example.
  • a compound represented by the general formula (p1) such as 5-alkoxy-1,3-benzoxiathiol-2-one is allowed to act on a base such as sodium hydroxide, and then a hydrogen peroxide solution, etc.
  • an alkyl halide such as benzyl bromide and a base such as potassium carbonate are allowed to act on the resulting product as necessary to obtain a compound represented by the general formula (p2). (Process P1).
  • the reaction solvent can be, for example, water, methanol, ethanol, or a mixture thereof, and the reaction temperature is, for example, 10 ° C. to 25 ° C. It can be set to ° C.
  • the reaction solvent can be N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, or a mixture thereof. It can be set to 20 ° C to 30 ° C.
  • the compound represented by the general formula (1) is obtained by reacting with the compound represented by the general formula (p3) in a reaction solvent (step P2).
  • a reaction solvent for example, toluene, xylene, benzene, or a mixture thereof can be used, and the reaction temperature can be set to 50 ° C. to 60 ° C., for example.
  • the reaction solvent can be, for example, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or a mixture thereof.
  • the reaction temperature can be, for example, 20 ° C. to 60 ° C.
  • Xa represents a fluoro group
  • R 1 , R 2 and R 3 are the same as defined above.
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
  • R 4 and R 5 are the same as defined above.
  • R 5 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms different from the tert-butyl group, since by-products can be suppressed in Step 3 described later.
  • the reaction can be performed, for example, by reacting the compound represented by the general formula (3) with the compound represented by the general formula (2) in the presence of a base in a reaction solvent.
  • the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like.
  • Halogenated hydrocarbons methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and other alcohols, N, N-dimethylacetamide, N-methylpyrrolidone, N, N-dimethylformamide, etc.
  • sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-acetate
  • aliphatic esters such as butyl, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate, ketones such as acetone, or mixtures thereof.
  • sulfoxides are used, and dimethyl sulfoxide is more preferable.
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent used, but impurities increase when the reaction is carried out at a temperature higher than 62 ° C. Therefore, the temperature can be preferably -70 ° C to 62 ° C, more preferably 0 ° C to 60 ° C, further preferably 5 ° C to 60 ° C, and particularly preferably 10 ° C to 55 ° C. In consideration of the suppression of the increase in impurities and the shortening of the reaction time, the reaction temperature is preferably 30 ° C. or higher and 55 ° C. or lower, more preferably 40 ° C. or higher and 55 ° C. or lower.
  • the base examples include inorganic bases such as cesium carbonate and potassium carbonate, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-.
  • organic bases such as undecene and pyridine, alkali metal alkoxides such as sodium ethoxide and potassium tert-butoxide can be used, preferably inorganic bases, more preferably cesium carbonate. Can be mentioned.
  • the amount of the base used is preferably 2 equivalents or more based on the compound represented by the general formula (2) from the viewpoint of improving the yield.
  • step 2 the compound represented by general formula (1) is represented by general formula (2) in a yield of 100%.
  • the amount of the compound represented by the general formula (1) is regarded as the amount of the compound represented by the general formula (2).
  • the compound represented by the general formula (3) is preferably used in an amount of 1 to 5 equivalents with respect to the compound represented by the general formula (2). More preferably 1.2 equivalents or more and 2 equivalents or less, and still more preferably 1.4 equivalents or more and 1.7 equivalents or less.
  • the compound represented by the general formula (5) can be obtained by subjecting the compound represented by the general formula (4) to a detert-butylation reaction.
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
  • the reaction has a general formula using, for example, an acid, preferably an organic sulfonic acid such as p-toluenesulfonic acid and methanesulfonic acid, an acidic clay mineral such as montmorillonite KSF, montmorillonite K10, and montmorillonite K30 in a reaction solvent. It can carry out by processing the compound represented by (4).
  • an acid preferably an organic sulfonic acid such as p-toluenesulfonic acid and methanesulfonic acid
  • an acidic clay mineral such as montmorillonite KSF, montmorillonite K10, and montmorillonite K30
  • the amount used is preferably 0.1 equivalent or more with respect to the compound represented by the general formula (4). More preferably, it is 0.1 equivalent or more and 0.5 equivalent or less, and still more preferably 0.1 equivalent or more and 0.3 equivalent or less.
  • the amount used is relative to the amount of the compound represented by the general formula (4), and is used as it is in step 3 without purification in steps 1 and 2.
  • the compound represented by General Formula (2) is represented by General Formula (4) in a yield of 100%.
  • the amount of the compound represented by the general formula (2) is regarded as the amount of the compound represented by the general formula (4).
  • reaction solvent examples include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like.
  • Halogenated hydrocarbons methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and other alcohols, N, N-dimethylacetamide, N-methylpyrrolidone, N, N-dimethylformamide, etc.
  • the reaction temperature can be, for example, 60 ° C. to heating reflux temperature, more preferably 80 ° C. to heating reflux temperature.
  • it is preferable to perform the said reaction using an acidic clay mineral from a viewpoint of progress of reaction and suppression of a by-product More preferably, montmorillonite KSF is mentioned. Furthermore, it is more preferable that montmorillonite KSF is used and the reaction solvent is acetonitrile.
  • the compound represented by the general formula (6) can be obtained by subjecting the compound represented by the general formula (5) to a rearrangement reaction.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above.
  • the reaction can be performed based on the Curtius rearrangement, the Schmitt rearrangement, the Rossen rearrangement, the Hoffman rearrangement, etc., but is preferably performed based on the Curtius rearrangement.
  • bis (4-methylphenyl) phosphoric azide, bis (4-chlorophenyl) phosphoric azide, diphenylphosphoric azide is added to the compound represented by the general formula (5) in the presence of a base such as triethylamine in a reaction solvent.
  • An azidation reagent such as
  • the amount of the azidation reagent used can be, for example, 1 equivalent or more, preferably 1 equivalent or more and 5 equivalents or less with respect to the compound represented by the general formula (5). More preferably, it is 1 equivalent or more and 3 equivalents or less, and still more preferably 1 equivalent or more and 1.5 equivalents or less.
  • the compound represented by General Formula (4) is represented by General Formula (5) in 100% yield.
  • the amount of the compound represented by the general formula (4) is regarded as the amount of the compound represented by the general formula (5).
  • Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and other inorganic bases, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7 -Organic bases such as undecene.
  • an organic base is preferable to use an organic base as a base in the reaction, and particularly preferable is triethylamine.
  • the amount of the base used is preferably 1 equivalent or more and 5 equivalents or less with respect to the compound represented by the general formula (5). From the viewpoint of improving the yield, it is more preferably 1.2 equivalents or more and 3 equivalents or less, and particularly preferably 1.2 equivalents or more and 2 equivalents or less.
  • reaction solvent examples include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like.
  • Halogenated hydrocarbons amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, Aliphatic such as n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate Ester, ketones such as acetone, or mixtures thereof, preferably, can be used benzene, toluene, aromatic hydrocarbon solvents such as xylene, preferably toluene.
  • the amount of the solvent is small when the azide reagent is reacted with the general formula (5) to produce an acyl azide.
  • the solvent is preferably used in an amount of 20 times or less with respect to the compound represented by the general formula (5). More preferably, the amount is 8 times or less, more preferably 6 times or less.
  • the transfer reaction proceeds preferably by heating, and isocyanate is produced. At this time, the reaction rate can be adjusted by adding the acyl azide solution to a separately heated solvent.
  • the reaction temperature is, for example, suitably from 0 ° C. to 60 ° C., preferably 20 ° C. to 55 ° C., more preferably 30 ° C. to 50 ° C., when acylazide is produced.
  • the reaction temperature is suitably 60 ° C. or more and 150 ° C. or less, for example, in the production of isocyanate, preferably 70 ° C. or more and 100 ° C. or less, more preferably 75 ° C. or more and 100 ° C. or less.
  • an alkali metal alkoxide represented by the general formula (i) is allowed to act on the obtained product.
  • M represents a sodium atom or a potassium atom
  • R 6 has the same definition as above.
  • a commercially available compound can be used, and for example, it can be prepared in a reaction solution by reacting a compound such as sodium hydride or sodium metal with an alcohol. It may be used.
  • Alkali metal alkoxides such as sodium alkoxide are preferably used in an amount of 1 to 5 equivalents relative to the compound represented by the general formula (5). From the viewpoint of improving the yield, more preferably 1.3 equivalents or more and 3 equivalents or less, and particularly preferably 1.4 equivalents or more and 1.8 equivalents or less.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above.
  • Optical resolution using an optical resolution column can be performed by high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), simulated moving bed method (SMB), or the like.
  • HPLC high performance liquid chromatography
  • SFC supercritical fluid chromatography
  • SMB simulated moving bed method
  • the optical resolution of the compound represented by the general formula (6) means that the compounds having the enantiomeric relationship in the compound represented by the general formula (6) are separated from each other.
  • the optical resolution column refers to a column filled with a filler carrying an optically active compound. Examples of the optical resolution column that can be used include, but are not limited to, normal phase polysaccharide derivative-coated chiral columns and polysaccharide derivative solvent-resistant chiral columns.
  • the normal phase polysaccharide derivative-coated chiral column is an optical resolution column that can be used for a solvent that can be used as a mobile phase in normal phase chromatography, using an amylose derivative or cellulose derivative as a chiral selector, and the amylose derivative or cellulose derivative. Means a column using a packing material coated with silica gel.
  • Examples of normal phase polysaccharide derivative-coated chiral columns include CHIRALPAK AD, CHIRALPAK AS, CHIRALCEL OD, CHIRALCEL OJ, CHIRALCEL OX, CHIRALPAK AY, CHIRALPAK AZ, and CHIRALCEL OZ.
  • the polysaccharide derivative solvent-resistant chiral column is an optical that can use all solvents that can be used in HPLC columns using silica gel as a base material, such as hexane, alcohol, ethyl acetate, tetrahydrofuran, halogenated solvents, DMSO, and the like. It is a split column, and means a column using a filler in which an amylose derivative or cellulose derivative is a chiral selector and the amylose derivative or cellulose derivative is fixed to silica gel.
  • Polysaccharide derivative solvent-resistant chiral columns include CHIRALPAK IA and CHIRALPAK Examples include IB, CHIRALPAK IC, CHIRALPAK ID, CHIRALPAK IE, and CHIRALPAK IF. Among them, from the viewpoint of separation ability, it is preferable to use CHIRALPAK AD, CHIRALCELOD, CHIRALCEL OJ, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK IB, or CHIRALPAK IC, CHIRALPAK ID.
  • optical resolution column More preferable examples of the optical resolution column include CHIRALPAK AD, CHIRALCEL OD, CHIRALCEL OJ, and CHIRALPAK AY, and particularly preferable examples include CHIRALPAK AD, CHIRALCEL OD, and CHIRALCEL OJ.
  • R 5 and R 6 in the structural formula is an alkyl group having 4 or more carbon atoms such as a tert-butyl group
  • CHIRALPAK AD or Preference is given to using CHIRALCEL OJ.
  • the inner diameter and length of the column and the particle diameter of the filler can be appropriately set according to the separation method and the compound to be separated.
  • CHIRALPAK and CHIRALCEL are registered trademarks.
  • R 5 or R 6 in the structural formula is an alkyl group having 3 or less carbon atoms such as a methyl group or an ethyl group
  • CHIRALCEL OD is It is preferred to use.
  • the eluent include alcohols such as methanol, ethanol and 2-propanol, acetonitrile, n-hexane, acetone, methyl tert-butyl ether (MTBT), chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide (DMSO).
  • 1,4-dioxane water, supercritical fluid or mixtures thereof.
  • a mixed solution of 2-propanol and n-hexane a mixed solution of 2-propanol and n-hexane, methanol, or ethanol
  • n-hexane is 7 to 11 times, more preferably 8 to 10 times, particularly preferably 9 to 2-propanol.
  • Use double amount when a mixed solution of ethanol and n-hexane is used, n-hexane is used in an amount of 7 to 11 times, more preferably 8 to 10 times, particularly preferably 9 times the amount of ethanol. .
  • CHIRALCEL OJ when CHIRALCEL OJ is used as the optical resolution column, it is preferable to use an alcohol such as methanol or ethanol as an eluent.
  • Step 6 The mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) can be obtained by reducing the compound represented by the general formula (7).
  • the mixture containing the compound represented by the general formula (10) and the compound represented by the general formula (12) can be obtained by reducing the compound represented by the general formula (8).
  • R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above.
  • R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above.
  • R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • the compound represented by the general formula (7) or the compound represented by the general formula (8) is dissolved in a reaction solvent such as tetrahydrofuran, the obtained solution is added to a reducing agent, and ethanol is further added. It can be carried out by adding alcohol such as methanol and reacting.
  • the reducing agent is aluminum hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, trimethoxylithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, lithium triethylborohydride, hydrogen
  • aluminum hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, trimethoxylithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, lithium triethylborohydride, hydrogen
  • boron hydrides such as sodium borohydride, potassium borohydride, lithium borohydride, lithium tri (sec-butyl) borohydride, potassium trihydride (sec-butyl) borohydride be able to. More preferred is a boron hydride reducing agent, and further preferred is sodium borohydride.
  • a reducing agent is 1 equivalent or more and 10 equivalents or less with respect to the compound represented by General formula (7) or the compound represented by General formula (8), for example. More preferably, it is 1 equivalent or more and 5 equivalents or less, and still more preferably 2 equivalents or more and 3.5 equivalents or less.
  • the reducing agent may be prepared and used in combination with a lithium salt such as lithium chloride, lithium bromide or lithium iodide and a boron hydride reducing agent such as sodium borohydride or potassium borohydride.
  • a lithium salt such as lithium chloride, lithium bromide or lithium iodide
  • a boron hydride reducing agent such as sodium borohydride or potassium borohydride.
  • a method using a boron hydride reducing agent in the presence of lithium chloride is used. More preferably, potassium borohydride is used in the presence of lithium chloride.
  • the preferred use amount of the lithium salt and the boron hydride-based reducing agent is the compound represented by the general formula (7) or the general formula (8). All are 1 equivalent or more and 10 equivalent or less with respect to the compound represented. More preferably, all are 1 equivalent or more and 5 equivalents or less, More preferably, all are 2 equivalents or more and 3.5 equivalents or less.
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent used, but from the viewpoint of improving yield, it is preferably 0 ° C. or higher and 55 ° C. or lower, more preferably 25 ° C. or higher and 55 ° C. or lower.
  • ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, or hydrocarbons such as hexane, heptane, or cyclohexane, Alternatively, a mixture thereof can be mentioned.
  • ethers are used, and more preferably, tetrahydrofuran is used.
  • the preferable amount of alcohol used is, for example, 0.5 to 10 times the amount of the compound represented by the general formula (7) or the compound represented by the general formula (8). From the viewpoint of improving the yield, more preferably 0.7 times or more and 2 times or less, still more preferably 0.8 times or more and 1.2 times or less.
  • Step 7 The pharmaceutically acceptable salt of the compound represented by the general formula (13) is obtained by subjecting a mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) to hydrolysis treatment.
  • the product of the hydrolysis treatment can be obtained by reacting with an inorganic acid or an organic acid.
  • the pharmaceutically acceptable salt of the compound represented by the general formula (14) is obtained by subjecting a mixture containing the compound represented by the general formula (10) and the compound represented by the general formula (12) to hydrolysis treatment.
  • the product of the hydrolysis treatment can be obtained by reacting with an inorganic acid or an organic acid.
  • R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • the hydrolysis treatment can be performed by a method usually used for ester hydrolysis.
  • a reaction when a reaction is carried out using a base, the substrate is treated at a temperature from room temperature to reflux with a strong base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide in a reaction solvent. It can be carried out.
  • the reaction temperature is preferably from 70 ° C. to the temperature of heating to reflux, more preferably from 75 ° C. to the temperature of heating to reflux, from the viewpoint of improving the yield.
  • the normal temperature means 15 to 25 ° C. as defined by the Japanese Pharmacopoeia.
  • reaction solvent examples include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, diglyme or triethylene glycol dimethyl ether, aromatic compounds such as benzene, toluene, or xylene, and nitriles such as acetonitrile or propionitrile.
  • ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, diglyme or triethylene glycol dimethyl ether
  • aromatic compounds such as benzene, toluene, or xylene
  • nitriles such as acetonitrile or propionitrile.
  • Halogenated hydrocarbons such as dichloromethane, alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol or diethylene glycol, amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide , Sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ketones such as acetone, water, or a mixture thereof. From the above viewpoint, a mixed solvent containing alcohols and water is preferable. More preferred is a mixed solvent containing ethanol and water.
  • the amount of the base in the hydrolysis is preferably 1 equivalent or more and 30 equivalents or less based on the compound represented by the general formula (7) or the compound represented by the general formula (8). From the viewpoint of yield improvement, it can be 5 equivalents or more and 20 equivalents or less, more preferably 8 equivalents or more and 15 equivalents or less.
  • preferred examples of the inorganic acid that can be used in the treatment of reacting the product of the hydrolysis treatment with an inorganic acid or an organic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • organic acid examples include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • tartaric acid is preferably used in terms of yield improvement.
  • D-( ⁇ )-tartaric acid is used for the compound represented by the general formula (13), and L is used for the compound represented by the general formula (14). It is preferable to use-(+)-tartaric acid.
  • reaction solvent examples include acetonitrile, ethanol, 2-propanol, 1,2-dimethoxyethane, water, and mixtures thereof. it can.
  • reaction temperature range from ⁇ 70 ° C. to the boiling point of the solvent used. From the viewpoint of improving the yield, the reaction temperature is preferably 0 ° C. or higher and 70 ° C. or lower, more preferably 10 ° C. or higher and 65 ° C. or lower, even more preferably. Can be 25 ° C. or more and 60 ° C. or less.
  • a solvent containing 1,2-dimethoxyethane as the reaction solvent, more preferably 1,2-dimethoxy.
  • a mixed solvent containing ethane and water is preferable to use.
  • the compound represented by the general formula (15) can be obtained by subjecting a pharmaceutically acceptable salt of the compound represented by the general formula (13) to free base formation and amino group protection.
  • the compound represented by the general formula (16) can be obtained by subjecting a pharmaceutically acceptable salt of the compound represented by the general formula (14) to free base formation and amino group protection.
  • R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above.
  • R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above.
  • the protecting group for the amino group represented by R 7 is not particularly limited as long as it protects the amino group.
  • an acyl group such as an acetyl group or an alkoxycarbonyl group such as tert-butoxycarbonyl or a benzyloxycarbonyl group
  • An aralkoxycarbonyl group such as can be used.
  • R 7 is preferably an alkoxycarbonyl group, more preferably a tert-butoxycarbonyl group.
  • reaction may be carried out by using a pharmaceutically acceptable salt of the compound represented by the general formula (13) or a pharmaceutically acceptable salt of the compound represented by the general formula (14) as a base in a reaction solvent. It can be carried out by neutralizing with a free base and reacting the resulting free base with an acid chloride or acid anhydride.
  • the base that can be used for neutralizing the pharmaceutically acceptable salt of the compound represented by the general formula (13) or the pharmaceutically acceptable salt of the general formula (14) is, for example, Inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, Organic compounds such as pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene Examples include bases.
  • Inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, 4-
  • reaction temperature range from 0 ° C. to the boiling point of the solvent to be used. From the viewpoint of improving the yield, the reaction temperature is preferably 30 ° C. or higher and 60 ° C. or lower, more preferably 35 ° C. or higher and 50 ° C. or lower.
  • reaction solvent include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, diglyme or triethylene glycol dimethyl ether, aromatic compounds such as benzene, toluene, or xylene, and nitriles such as acetonitrile or propionitrile.
  • Halogenated hydrocarbons such as dichloromethane, alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol or diethylene glycol, amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide , Sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate, ethyl acetate Aliphatic esters such as sopropyl, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate or ethyl isovalerate, ketones such as acetone, water, Alternatively, a mixture thereof may be
  • the acid chloride acetyl chloride or benzyloxycarbonyl chloride can be used.
  • acid anhydride acetic anhydride, di-tert-butyl dicarbonate or the like can be used.
  • the reaction is preferably carried out using di-tert-butyl dicarbonate.
  • di-tert-butyl dicarbonate the pharmaceutically acceptable salt of the compound represented by the general formula (13) or the compound represented by the general formula (14) is used from the viewpoint of easy progress of the reaction. It is preferable to use 1.2 equivalents or more, more preferably 1.3 equivalents or more, based on the pharmaceutically acceptable salt.
  • di-tert-butyl dicarbonate is a pharmaceutically acceptable salt of the compound represented by the general formula (13) or the compound represented by the general formula (14). It is preferable to use 1.3 equivalents or more and 2.0 equivalents or less, more preferably 1.3 equivalents or more and 1.5 equivalents or less, based on the pharmaceutically acceptable salt. From the viewpoint of suppressing by-products, it is preferable to add an amine such as 1-methylpiperazine to the reaction solution after completion of the reaction. From the viewpoint of optical purity and chemical purity, it is preferable to recrystallize the compound represented by the general formula (15) and / or the compound represented by the general formula (16).
  • Solvents used for recrystallization are, for example, water, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate, diisopropyl ether, n-hexane, n-heptane, tetrahydrofuran, toluene, 1,2-dimethoxyethane, N, N-dimethyl.
  • formamide can be used.
  • a mixed solvent containing toluene and n-heptane is preferable from the viewpoint of optical purity, chemical purity, filterability, fluidity, and recovery rate, and toluene, n-heptane, and N, N-dimethyl are preferable.
  • a mixed solvent containing formamide is more preferable.
  • Step 9 The compound represented by the general formula (17) can be obtained by reacting the compound represented by the general formula (15) with a phosphate esterification reagent.
  • the compound represented by the general formula (18) can be obtained by reacting the compound represented by the general formula (16) with a phosphate esterification reagent.
  • R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above.
  • R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above.
  • Examples of the phosphate esterification reagent include compounds represented by general formula (ii).
  • R 12 is a halogen atom
  • R 8 is the same as defined above.
  • a compound in which R 12 is a chlorine atom and R 8 is a methyl group, an ethyl group or an isopropyl group is preferable.
  • the reaction can be performed, for example, in a reaction solvent using a phosphoric esterification reagent and triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo
  • the compound represented by the general formula (15) or the general formula (16) using bases such as [4.3.0] -5-nonene and 1,8-diazabicyclo [5.4.0] -7-undecene. ) Can be carried out by phosphoric esterification.
  • the base is preferably used in an amount of 1 to 10 equivalents relative to the compound represented by the general formula (15) or the compound represented by the general formula (16). More preferable equivalents include 3 equivalents or more and 10 equivalents or less, and more preferably 5.5 equivalents or more and 7 equivalents or less.
  • Reaction solvents include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, and halogens such as dichloromethane.
  • ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, or diglyme
  • aromatic compounds such as benzene, toluene, or xylene
  • nitriles such as acetonitrile or propionitrile
  • halogens such as dichloromethane.
  • Hydrocarbons such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide
  • sulfoxides such as dimethyl sulfoxide
  • sulfones such as sulfolane
  • ethyl formate n-butyl formate
  • ethyl acetate acetic acid
  • Aliphatic esters such as n-propyl, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate Ethers
  • ketones such as acetone, or mixtures thereof.
  • the reaction solvent is preferably nitriles, aliphatic esters or ketones, and more preferably a mixture of nitriles and aliphatic esters, more preferably in terms of suppressing the formation of precipitates during the reaction. Is a mixture of ethyl acetate and acetonitrile.
  • the reaction temperature is usually in the range of -70 ° C. to the boiling point of the solvent used, but is preferably ⁇ 5 ° C. or more in view of disappearance of raw materials and 15 ° C. or less in terms of suppressing side reactions. More preferably, it is 0 degreeC or more and 15 degrees C or less, More preferably, 5 degreeC or more and 15 degrees C or less are mentioned.
  • the compound represented by the general formula (19) can be obtained by converting the compound represented by the general formula (17).
  • the compound represented by the general formula (20) can be obtained by converting the compound represented by the general formula (18).
  • R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • R 1 , R 2 , R 3 and R 4 are the same as defined above.
  • the reaction can be performed, for example, by allowing a deprotection reagent to act on the compound represented by the general formula (17) or the compound represented by the general formula (18) in a reaction solvent such as acetonitrile.
  • a deprotection reagent include trialkylsilyl halides such as trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl bromide, triethylsilyl iodide, trialkylsilyl triflate such as trimethylsilyl triflate, triethylsilyl triflate, etc. Of these, trimethylsilyl iodide is preferred.
  • Trimethylsilyl iodide may be generated in the system using trimethylsilyl chloride and sodium iodide.
  • the deprotection reagent is preferably used in an amount of 1 equivalent to 20 equivalents relative to the compound represented by the general formula (17) or the compound represented by the general formula (18). More preferably, they are 3 equivalents or more and 10 equivalents or less, More preferably, 5 equivalents or more and 8 equivalents or less are mentioned.
  • the compound represented by General Formula (15) or the compound represented by General Formula (16) is 100% yield.
  • the compound represented by the general formula (17) or the compound represented by the general formula (18) is regarded as being converted, and the compound represented by the general formula (15) or the compound represented by the general formula (16).
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent used, preferably from ⁇ 10 ° C. to the boiling point of the solvent used, more preferably from ⁇ 5 ° C. to 35 ° C. .
  • water is added to the reaction solution in which the compound represented by the general formula (17) or the compound represented by the general formula (18), trimethylsilyl halide and sodium iodide are dissolved.
  • the amount of water to be added is preferably 0.5 equivalents or more and 2 equivalents or less with respect to the compound represented by the general formula (17) or the compound represented by the general formula (18). More preferably, it is 0.9 equivalent or more and 1.1 equivalent or less, Especially preferably, 1 equivalent is mentioned.
  • the compound represented by general formula (19) or the compound represented by general formula (20) will crystallize. Therefore, it is preferable from the viewpoint of purification to add water to the reaction solution after stopping the reaction.
  • reaction solvent examples include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like.
  • Halogenated hydrocarbons formamide, N-methylpyrrolidone, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ketones such as acetone, or mixtures thereof
  • amides such as N, N-dimethylformamide
  • sulfoxides such as dimethyl sulfoxide
  • sulfones such as sulfolane
  • ketones such as acetone
  • nitriles are used, and acetonitrile is more preferable.
  • R 2 is preferably a hydrogen atom, a benzyl group, a p-methoxybenzyl group, or a 2-methoxyethoxymethyl group, more preferably benzyl. It is a group.
  • R 5 is preferably a methyl group, an ethyl group, or a tert-butyl group.
  • R 6 is preferably a methyl group, an ethyl group, or a tert-butyl group.
  • R 5 is more preferably a methyl group or an ethyl group from the viewpoint of suppressing the by-product in Step 3 (dicarboxylic acid product hydrolyzed even up to R 5 ).
  • the compound represented by the general formula (7) is more preferably a compound represented by the general formula (7a), and the compound represented by the general formula (8) is represented by the general formula (7).
  • the compound represented by 8a) is more preferable.
  • R 9 represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group or a 2-methoxyethoxymethyl group
  • R 10 represents a methyl group, an ethyl group or a tert-butyl group
  • R 11 represents a methyl group Group, ethyl group or tert-butyl group
  • Z represents a fluorine atom or a chlorine atom.
  • R 9, R 10, R 11 and Z are as defined above.
  • R 9 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group
  • R 11 is Even more preferably, the compound is an ethyl group or a tert-butyl group
  • Z is a chlorine atom.
  • the operation shown as process 5 can be performed, and the optical purity of these compounds can be 95% ee or more.
  • the compound particularly suitable as the compound represented by the formula (7a) and the compound that is an enantiomer thereof (the compound represented by the formula (8a)) include the following compounds.
  • the reaction shown as Step 7 is carried out using D-( ⁇ )-tartaric acid and / or L-(+)-tartaric acid, so that D-- of the compound represented by the general formula (13) obtained is obtained.
  • the optical purity of ( ⁇ )-tartrate and / or L-(+)-tartrate of the compound represented by the general formula (14) can be 99.0% ee or more.
  • the optical purity of the compound represented by the general formula (15) and / or the compound represented by the general formula (16) obtained by performing the reaction shown as Step 8 in the present embodiment is 99.5% ee. This can be done.
  • optical purity as used in this specification shows the value computed based on the area percentage of the said compound and its optical isomer of HPLC measured on the following conditions.
  • the novel manufacturing method of a diphenyl sulfide derivative can be provided.
  • steps 1 to 10 are described as a series of steps for obtaining a diphenyl sulfide derivative.
  • it is not limited to this, Of course, it is also possible to set it as the aspect which each performs 1 or 2 or more among each process.
  • 5-Ethoxy-1,3-benzoxiathiol-2-one (20.00 g, 102 mmol) was added to a mixture of ethanol (20 mL) and water (50 mL) to give a first reaction solution.
  • a mixed solution of sodium hydroxide (12.23 g, 306 mmol) and water (50 mL) was added to the first reaction solution at an internal temperature of 15 to 25 ° C., and the mixture was stirred at an internal temperature of 40 to 47 ° C. for 1 hour.
  • the first reaction solution was cooled, 35% aqueous hydrogen peroxide (4.95 g, 50.9 mmol) was added at an internal temperature of 12 to 20 ° C., and the mixture was stirred at an internal temperature of 20 to 24 ° C.
  • the first reaction solution was cooled, 30 mL of concentrated hydrochloric acid was added at an internal temperature of 4 to 13 ° C., and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed successively with a mixture of sodium bisulfite (20.00 g) and water (200 mL) and saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a yellow oil (15.5 g). The obtained yellow oil (15.5 g) was dissolved in N, N-dimethylformamide (100 mL) to obtain a second reaction solution.
  • 1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide (16.0 g, 30.8 mmol) was added to a mixed solution of toluene (80 mL) and concentrated hydrochloric acid (32 mL), dissolved by heating, It was set as the reaction liquid.
  • Zinc powder (5.04 g, 77.1 mmol) was added to the first reaction solution at an internal temperature of 50 to 57 ° C., and the mixture was stirred at an internal temperature of 54 to 57 ° C. for 1.5 hours.
  • the first reaction liquid was cooled, and water (48 mL) was added thereto at an internal temperature of 20 to 25 ° C. for liquid separation.
  • the second reaction liquid was heated and stirred at an internal temperature of 50 to 56 ° C. for 1 hour, and water (39 mL) was added at an internal temperature of 54 to 58 ° C.
  • the second reaction solution was cooled and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour.
  • the precipitated crystals were collected by filtration and washed with water (39 mL).
  • the precipitated crystals were dried under reduced pressure at 50 ° C. to obtain a brown powder (11.3 g).
  • Ethanol (57 mL) was added, and the mixture was suspended by heating at an internal temperature of 50 to 55 ° C. for 0.5 hour.
  • the mixture was cooled and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour.
  • the brown oil (942 g) obtained in Example 2 was dissolved in acetonitrile (5.00 L), and Montmorillonite KSF (900 g) was added with stirring at an internal temperature of 8 ° C. to obtain a reaction solution.
  • the reaction solution was heated and heated to reflux at an internal temperature of 76 to 82 ° C. for 10 hours.
  • the reaction was cooled and left overnight.
  • Montmorillonite KSF (100 g) was added to the reaction solution, heated, and heated to reflux at an internal temperature of 80 to 82 ° C. for 8 hours (during heating to reflux, 3.00 L of solvent was distilled off using a Dean-stark apparatus, and acetonitrile ( 2.60 L) was added).
  • the vessel was washed with toluene (100 mL).
  • the first reaction liquid was heated and stirred at an internal temperature of 35 to 42 ° C. for 1 hour and 25 minutes.
  • the first reaction solution was added dropwise to separately heated toluene (2.96 L) with stirring at an internal temperature of 82 to 85 ° C. over 1 hour and 13 minutes, washed with toluene (0.50 L), and the second reaction. Liquid.
  • the second reaction solution was stirred at an internal temperature of 85 ° C. for 50 minutes, then cooled and diluted with ethanol (0.89 L) at an internal temperature of 4 to 12 ° C. in a 20% sodium ethoxide ethanol solution (471 g, 1.38 mol). Was added with stirring over 25 minutes.
  • the second reaction solution was added to a mixed solution of ammonium chloride (890 g) and water (4.94 L) at an internal temperature of 10-12 ° C., Extracted with ethyl acetate (3.46 L). The organic layer was washed with water (4.94 L) and concentrated under reduced pressure to give a brown oil (645 g).
  • Ethyl 2- ⁇ 2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl ⁇ -2-ethoxycarbonylaminopentanoate (52.5 kg) was adjusted to about 80 g / L. It melt
  • the organic layer was washed with normal water (250 mL), and the organic layer and aqueous layer were separated (insufficient separation). Subsequently, sodium chloride (12.5 g) was added to the aqueous layer and mixed with the organic layer again to separate the organic layer. The organic layer was concentrated under reduced pressure at a set temperature of 40 to 50 ° C. to obtain a yellow oil (46.8 g). The obtained oil was dissolved in ethanol (100 mL) and concentrated under reduced pressure at a preset temperature of 40 to 50 ° C. to obtain a yellow oil (44.8 g). The resulting yellow oil was used in the next reaction without further purification.
  • Example 6 The yellow oil (44.8 g) obtained in Example 6 was dissolved in ethanol (300 mL), and then sodium hydroxide (32.6 g, 814 mmol) and normal water (150 mL) were added at an internal temperature of 29 ° C. The mixed solution was added to obtain a first reaction solution. The first reaction liquid was heated and refluxed at an internal temperature of 80 ° C. The first reaction liquid was cooled, normal water (300 mL) was added at an internal temperature of 17 ° C., and the mixture was stirred at an internal temperature of 8 to 10 ° C. for 10 minutes.
  • Isopropyl acetate 300 mL was added to the first reaction solution at an internal temperature of 6-8 ° C., and the mixture was stirred at an internal temperature of 5-6 ° C. for 5 minutes. After standing for 5 minutes, the organic layer was separated. The obtained organic layer was washed with a mixed solution of sodium chloride (30.0 g) and normal water (300 mL) at an internal temperature of 9 to 14 ° C., and the organic layer was separated. The obtained organic layer was washed with a mixed solution of sodium chloride (15.0 g) and normal water (300 mL) at an internal temperature of 10 to 13 ° C., and the organic layer was separated. The organic layer was concentrated under reduced pressure at a preset temperature of 40 ° C.
  • the second reaction solution was heated, and a mixed solution of D-( ⁇ )-tartaric acid (13.4 g, 89.5 mmol) and normal water (75 mL) was added dropwise at an internal temperature of 39 to 40 ° C. Stir at 40 ° C. for 30 minutes.
  • the second reaction liquid was cooled, 1,2-dimethoxyethane (250 mL) was added at an internal temperature of 12 to 13 ° C., and the mixture was stirred at an internal temperature of 12 to 15 ° C. for 1 hour.
  • the crystals were collected by filtration and washed with 1,2-dimethoxyethane (100 mL) to obtain wet crystals (65.4 g).
  • di-tert-butyl dicarbonate (20.7 g, 94.7 mmol) was added to the reaction solution at an internal temperature of 16 ° C., heated, and stirred at an internal temperature of 40-43 ° C. for 4 hours.
  • the reaction mixture was cooled, 1-methylpiperazine (7.5 mL, 67.7 mmol) was added at an internal temperature of 21-24 ° C., and the mixture was stirred at an internal temperature of 23-24 ° C. for 1 hour. After standing, the organic layer was separated. The organic layer was washed with a mixed solution of concentrated hydrochloric acid (13.2 mL) and normal water (572 mL), and the organic layer was separated.
  • the organic layer was washed with a mixed solution of sodium hydrogen carbonate (4.40 g) and normal water (88 mL), and the organic layer was separated.
  • the organic layer was washed with normal water (88 mL), and the organic layer was separated.
  • Acetone (176 mL) was added to the organic layer, and the mixture was concentrated under reduced pressure at a set temperature of 50 ° C.
  • the obtained concentrated residue was dissolved in ethyl acetate (220 mL), N, N-dimethylformamide (13.4 mL) was added, and the mixture was concentrated under reduced pressure at a set temperature of 50 ° C. to give a concentrated residue (50.8 g).
  • Toluene (176 mL) was added to the resulting concentrated residue, and then heated to dissolve.
  • the insoluble material was filtered off while hot and washed with toluene (88 mL).
  • the filtrate and the washing solution were combined and heated, and n-heptane (1.06 L) was added dropwise over 14 minutes at an internal temperature of 46 to 53 ° C.
  • the resulting mixture was cooled and stirred at an internal temperature of 6-7 ° C. for 30 minutes.
  • the crystals were collected by filtration and washed with a mixed solution of toluene (44 mL) and n-heptane (176 mL) to obtain wet crystals (41.5 g).
  • the reaction solution was cooled, and diethyl chlorophosphate (12.6 mL, 87.5 mmol) was added dropwise at an internal temperature of 7 to 10 ° C. over 30 minutes, followed by stirring at an internal temperature of 9 to 10 ° C. for 1 hour.
  • a mixture of ethyl acetate (140 mL) and n-heptane (280 mL) was added to the reaction solution at an internal temperature of 9 to 15 ° C., then concentrated hydrochloric acid (52.5 mL) and normal water (648 mL) at an internal temperature of 15 to 25 ° C.
  • the organic layer was separated.
  • the organic layer was washed with a mixed solution of concentrated hydrochloric acid (52.5 mL) and normal water (648 mL) at an internal temperature of 16 to 21 ° C., and the organic layer was separated.
  • the organic layer was washed with a mixed solution of concentrated hydrochloric acid (52.5 mL) and normal water (648 mL) at an internal temperature of 15 to 21 ° C., and the organic layer was separated.
  • the organic layer was washed with a mixed solution of sodium hydrogen carbonate (4.38 g) and normal water (87.5 mL) at an internal temperature of 20 to 21 ° C., and the organic layer was separated.
  • the organic layer was washed with a mixed solution of sodium chloride (17.5 g) and normal water (87.5 mL) at an internal temperature of 20 to 21 ° C., and the organic layer was separated.
  • the organic layer was concentrated under reduced pressure at a set temperature of 40 ° C. to obtain a slightly yellowish oil (45.2 g).
  • the obtained oil was dissolved in acetonitrile (175 mL) and concentrated under reduced pressure at a preset temperature of 40 to 50 ° C. to obtain a slightly yellow oil (43.1 g).
  • the resulting pale yellow oil was used in the next reaction without further purification.
  • the reaction mixture was cooled, and trimethylsilyl chloride (44.2 mL, 350 mmol) was added dropwise at an internal temperature of 16-24 ° C.
  • the reaction solution was heated and stirred at an internal temperature of 20 to 25 ° C. for 4.5 hours.
  • the reaction solution was cooled, and a mixed solution of sodium sulfite (8.75 g) and purified water (350 mL) was added dropwise at an internal temperature of 3 to 8 ° C. After completion of dropping, crystallization was confirmed, followed by stirring at an internal temperature of 2 to 6 ° C. for 30 minutes.
  • Purified water (350 mL) was added dropwise to the reaction solution at an internal temperature of 3-8 ° C., followed by stirring at an internal temperature of 3-8 ° C.
  • Purified water (187 mL) was added dropwise to the solution at an internal temperature of 31 to 32 ° C., and then cooled and stirred at an internal temperature of 11 to 15 ° C. for 30 minutes. The crystals were collected by filtration and washed with purified water (234 mL). Drying under reduced pressure at a set temperature of 50 ° C. gave a white powder (22.9 g). Ethanol (183 mL) was added to the obtained white powder and dissolved, and purified water (91.5 mL) was added at an internal temperature of 31 ° C. to confirm crystallization. After the mixture was dissolved by heating, the insoluble material was filtered off while hot and washed with ethanol (45.8 mL).
  • the filtrate and the washing solution were combined and dissolved by heating.
  • the solution was cooled and stirred at an internal temperature of 42-46 ° C. for 30 minutes.
  • Purified water (366 mL) was added dropwise to the solution at an internal temperature of 41 to 43 ° C., followed by cooling and stirring at an internal temperature of 11 to 15 ° C. for 30 minutes.
  • the crystals were collected by filtration and washed with purified water (114 mL).
  • Optical purity in Table 1 is a value calculated by the following formula (e1) from the area of the R-form and S-form obtained by measuring the reaction solution under the following HPLC condition A.
  • E optical purity (% ee)
  • S represents the production amount of S isomer
  • R represents the production amount of R isomer.
  • HPLC area% in Table 2 is obtained by measuring the reaction solution under HPLC condition B and calculating the area percentage (%) of the target product at the end of the reaction from the following formula (e2).
  • D represents the area percentage (%) of the target product
  • OP represents the amount of the target product generated
  • HP represents the total peak amount observed by HPLC excluding the solvent peak.
  • the target product was obtained in a yield as high as 96% when Montmorillonite KSF was used compared to the case where other acids were used.
  • the reaction proceeds and the target product can be obtained.
  • Example 20 The compounds shown in Table 3 were subjected to optical resolution in the same manner as in Example 5 using the separation conditions shown in Table 3. The results of the resolution are shown in FIG. 1 to FIG. 5 as HPLC chromatograms (Example 20: FIG. 1, Example 21: FIG. 2, Example 22: FIG. 3, Example 23: FIG. 4, Example 24: FIG. 5).
  • k′1 is a value represented by the following formula (e3), and becomes smaller as the retention time of the first peak is shorter.
  • k′1 (t1 ⁇ t0) / t0 (e3)
  • t0 represents the elution time of the component not retained on the column
  • t1 represents the retention time of the first peak
  • ⁇ ( ⁇ value) is a value represented by the following equation (e4).
  • the ⁇ value increases as the difference in retention time between the first peak and the second peak increases.
  • the ⁇ value is preferably 1.5 or more, and particularly preferably 1.7 or more.
  • k′2 in the formula (e4) is a value represented by the following formula (e5).
  • t0 represents the elution time of the component not retained on the column
  • t2 represents the retention time of the second peak.
  • the novel manufacturing method of the diphenyl sulfide derivative containing the compound disclosed in patent document 1 can be provided.
  • the optical purity of the obtained compound can be increased.
  • the optical purity of the obtained compound can be further increased by selecting the substrate and the production intermediate. Therefore, according to the present embodiment, the diphenyl sulfide derivative can be advantageously produced industrially, and a high-quality pharmaceutical product can be provided.

Abstract

[Problem] To provide a technique relating to a novel manufacturing method for a diphenylsulfide derivative. [Solution] An optical resolution method for subjecting a compound represented by general formula (6) to optical resolution using an optical resolution column and collecting a separated compound represented by general formula (7) and/or a compound represented by general formula (8). Also, a compound manufacturing method comprising said optical resolution method.

Description

ジフェニルスルフィド誘導体の製造方法及び製造中間体Process for producing diphenyl sulfide derivative and production intermediate
　本発明は、ジフェニルスルフィド誘導体の製造方法及びその製造中間体として用いることができる化合物についての技術に関する。 The present invention relates to a method for producing a diphenyl sulfide derivative and a technique relating to a compound that can be used as an intermediate for the production.
　出願人により、優れたスフィンゴシン－１－リン酸レセプター３（Ｓ１Ｐ３）アンタゴニスト作用を示す以下の式（Ａ）で表されるジフェニルスルフィド誘導体が開示されている（例えば特許文献１）。 The applicant has disclosed a diphenyl sulfide derivative represented by the following formula (A) that exhibits an excellent sphingosine-1-phosphate receptor 3 (S1P3) antagonistic action (for example, Patent Document 1).
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　式（Ａ）中、Ｒａは炭素数１～６のアルコキシ基を示し、Ｒｂはプロピル基またはアリル基を示し、Ｚはハロゲン原子を示す。 In the formula (A), R a represents an alkoxy group having 1 to 6 carbon atoms, R b represents a propyl group or an allyl group, and Z represents a halogen atom.
　当該一般式（Ａ）で表される化合物は、例えば特許文献１に記載された方法で製造することができる。特許文献１において開示された複数の合成経路のうちの１つを以下に示す。 The compound represented by the general formula (A) can be produced, for example, by the method described in Patent Document 1. One of a plurality of synthesis routes disclosed in Patent Document 1 is shown below.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　上記合成経路において、Ａｂはハロゲン原子、メタンスルホニルオキシ基、パラトルエンスルホニルオキシ基またはトリフルオロメタンスルホニルオキシ基などの一般的な脱離基を示し、Ａｃはハロゲン原子、メタンスルホニルオキシ基、パラトルエンスルホニルオキシ基またはトリフルオロメタンスルホニルオキシ基などの一般的な脱離基を示し、Ｒcは炭素数１～６のアルキル基を示し、Ｒdは一般的なアミノ基の保護基を示し、Ｒeは水素原子またはフェノール性水酸基の一般的な保護基を示し、Ｒa、Ｒb及びＺは一般式（Ａ）における定義と同じである。 In the above synthetic route, A b is a halogen atom, a methanesulfonyloxy group, shows a typical leaving group such as p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, A c is a halogen atom, a methanesulfonyloxy group, p R 1 represents a general leaving group such as toluenesulfonyloxy group or trifluoromethanesulfonyloxy group, R c represents an alkyl group having 1 to 6 carbon atoms, R d represents a general amino protecting group, R e represents a hydrogen atom or a general protecting group for a phenolic hydroxyl group, and R a , R b and Z are the same as defined in formula (A).
国際公開第２０１２／０８６１８４号International Publication No. 2012/086184
　本発明は、ジフェニルスルフィド誘導体の新規な製造方法に関する技術を提供することを目的とする。 An object of the present invention is to provide a technique relating to a novel method for producing a diphenyl sulfide derivative.
　本発明者は、鋭意研究の結果、特許文献１において開示された化合物などを含むジフェニルスルフィド誘導体の新規な製造方法と、その製造方法において製造中間体として使用できる新規な化合物を見出し、本発明を完成させた。 As a result of diligent research, the present inventor has found a novel production method of a diphenyl sulfide derivative containing the compound disclosed in Patent Document 1, and a novel compound that can be used as a production intermediate in the production method. Completed.
　本発明の要旨は以下のとおりである。
［１］　一般式（６）：
Figure JPOXMLDOC01-appb-C000003
［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３は、ハロゲン原子を示し；
Ｒ４は、炭素数１～６のアルキル基を示し；
Ｒ５は、炭素数１～６のアルキル基を示し；
Ｒ６は、炭素数１～６のアルキル基を示す。］で表される化合物を、光学分割カラムによる光学分割に供し、
　分離される、一般式（７）：
Figure JPOXMLDOC01-appb-C000004
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、前記定義と同じ。］
で表される化合物、及び／または一般式（８）：
Figure JPOXMLDOC01-appb-C000005
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、前記定義と同じ。］
で表される化合物を回収する、光学分割方法。
 
［２］　前記一般式（６）で表される化合物は、前記一般式（７）で表される化合物として一般式（７ａ）：
Figure JPOXMLDOC01-appb-C000006
［式中、Ｒ９は水素原子、ベンジル基または２－メトキシエトキシメチル基であり；
Ｒ１０は、メチル基、エチル基またはｔｅｒｔ－ブチル基であり；
Ｒ１１は、エチル基またはｔｅｒｔ－ブチル基であり；
Ｚは、塩素原子である］
で表される化合物を含み、且つ前記一般式（８）で表される化合物として一般式（８ａ）：
Figure JPOXMLDOC01-appb-C000007
［式中、Ｒ９、Ｒ１０、Ｒ１１及びＺは、前記定義と同じ。］
で表される化合物を含み、
　回収される前記一般式（７ａ）で表される化合物の光学純度、及び／または回収される前記一般式（８ａ）で表される化合物の光学純度が９５％ｅｅ以上である、請求項１に記載の光学分割方法。

［３］　前記一般式（７）で表される化合物、及び／または前記一般式（８）で表される化合物の製造方法であって、
　一般式（４）：
Figure JPOXMLDOC01-appb-C000008
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、前記定義と同じ。］
で表される化合物に対し、有機スルホン酸または酸性粘土鉱物を反応させることにより、脱ｔｅｒｔ－ブチル化反応を行い、一般式（５）：
Figure JPOXMLDOC01-appb-C000009
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、前記定義と同じ。］
で表される化合物を取得し、
　前記一般式（５）で表される化合物を転位反応に供することにより、前記一般式（６）で表される化合物を取得し、
　［１］または［２］に記載の光学分割方法により、前記一般式（６）で表される化合物から前記一般式（７）で表される化合物及び／または前記一般式（８）で表される化合物を得ることを含む方法。
　なお、［２］に記載の光学分割方法により当該方法を実施する場合、
　式（４）、式（５）および式（６）におけるＲ１はエトキシ基であり、Ｒ２は水素原子、ベンジル基または２－メトキシエトキシメチル基であり、Ｒ３は塩素原子であり、Ｒ４はｎ－プロピル基であり、Ｒ５はメチル基、エチル基またはｔｅｒｔ－ブチル基であり、
　式（６）におけるＲ６はエチル基またはｔｅｒｔ－ブチル基であり、
　式（４）、式（５）および式（６）においてＲ３はＲ１およびＲ２Ｏ基で置換されたフェニルチオ基に対してメタ位に結合していることを、当業者は当然に理解できる。
 
［４］　［３］に記載の方法において、
　一般式（１）：
Figure JPOXMLDOC01-appb-C000010
［式中、Ｒ１、Ｒ２及びＲ３は、前記定義と同じ。］
で表される化合物を一般式（２）：
Figure JPOXMLDOC01-appb-C000011
［式中、Ｒ１、Ｒ２及びＲ３は、前記定義と同じ。］
で表される化合物に変換し、；
　前記一般式（２）で表される化合物を、一般式（３）：
Figure JPOXMLDOC01-appb-C000012
［式中、Ｒ４及びＲ５は、前記定義と同じ。］
で表される化合物と反応させ、前記一般式（４）で表される化合物を取得することをさらに含む方法。
　なお、［２］に記載の光学分割方法により当該方法を実施する場合、
　式（１）および式（２）におけるＲ１はエトキシ基であり、Ｒ２は水素原子、ベンジル基または２－メトキシエトキシメチル基であり、Ｒ３は塩素原子であり、式（３）におけるＲ４はｎ－プロピル基であり、Ｒ５はメチル基、エチル基またはｔｅｒｔ－ブチル基であり、
　式（１）および式（２）においてＲ３は、Ｒ１およびＲ２Ｏ基で置換されたフェニルチオ基に対して、メタ位に結合していることを、当業者は当然に理解できる。
 
［５］　一般式（１３）：
Figure JPOXMLDOC01-appb-C000013
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の薬学的に許容しうる塩、及び／または一般式（１４）：
Figure JPOXMLDOC01-appb-C000014
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の製造方法であって、
　［１］または［２］に記載の光学分割方法により、前記一般式（６）で表される化合物から前記一般式（７）で表される化合物及び／または前記一般式（８）で表される化合物を取得し、
　前記一般式（７）で表される化合物の還元を行うことにより一般式（９）：　　
Figure JPOXMLDOC01-appb-C000015
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、前記定義と同じ。］
で表される化合物及び一般式（１１）：
Figure JPOXMLDOC01-appb-C000016
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物を含む混合物を取得し、及び／または前記一般式（８）で表される化合物の還元を行うことにより一般式（１０）：
Figure JPOXMLDOC01-appb-C000017
［式中Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、前記定義と同じ。］
で表される化合物及び一般式（１２）：
Figure JPOXMLDOC01-appb-C000018
［式中Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物を含む混合物を取得し、
　前記一般式（９）で表される化合物及び前記一般式（１１）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより前記一般式（１３）で表される化合物の薬学的に許容しうる塩を取得し、及び／または前記一般式（１０）で表される化合物及び前記一般式（１２）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより前記一般式（１４）で表される化合物の薬学的に許容しうる塩を取得することを含む方法。
　なお、［２］に記載の光学分割方法により当該方法を実施する場合、
　式（９）～（１４）におけるＲ１はエトキシ基であり、Ｒ２は水素原子、ベンジル基または２－メトキシエトキシメチル基であり、Ｒ３は塩素原子であり、Ｒ４はｎ－プロピル基であり、
　式（９）および式（１０）におけるＲ６はエチル基またはｔｅｒｔ－ブチル基であり、
　式（９）～（１４）においてＲ３は、Ｒ１およびＲ２Ｏ基で置換されたフェニルチオ基に対して、メタ位に結合していることを、当業者は当然に理解できる。

［６］　前記一般式（９）で表される化合物及び前記一般式（１１）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物をＤ－（－）－酒石酸と反応させることにより前記一般式（１３）で表される化合物のＤ－（－）－酒石酸塩を取得し、及び／または前記一般式（１０）で表される化合物及び前記一般式（１２）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物をＬ－（＋）－酒石酸と反応させることにより前記一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩を取得し、
　前記一般式（１３）で表される化合物のＤ－（－）－酒石酸塩の光学純度、及び／または前記一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩の光学純度が９９．０％ｅｅ以上である、［５］に記載の製造方法。
 
［７］　一般式（１５）：
Figure JPOXMLDOC01-appb-C000019
［式中、Ｒ７はアミノ基の保護基を示し、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物、及び／または一般式（１６）：
Figure JPOXMLDOC01-appb-C000020
［式中、Ｒ７はアミノ基の保護基を示し、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の製造方法であって、
　［５］または［６］に記載の方法により得られる前記一般式（１３）で表される化合物の薬学的に許容しうる塩の遊離塩基化及びアミノ基の保護を行い、及び／または［５］または［６］に記載の方法により得られる前記一般式（１４）で表される化合物の薬学的に許容しうる塩の遊離塩基化及びアミノ基の保護を行うことを含む方法。
 
［８］　前記一般式（１５）で表される化合物の光学純度、及び／または前記一般式（１６）で表される化合物の光学純度が９９．５％ｅｅ以上である、［７］に記載の方法。
 
［９］　一般式（１９）：
Figure JPOXMLDOC01-appb-C000021
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物、及び／または一般式（２０）：
Figure JPOXMLDOC01-appb-C000022
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の製造方法であって、
　［７］または［８］に記載の方法により得られる前記一般式（１５）で表される化合物とリン酸エステル化試薬とを反応させ、一般式（１７）：
Figure JPOXMLDOC01-appb-C000023
［式中、Ｒ８は炭素数１～６のアルキル基を示し、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、前記定義と同じ。］
で表される化合物を取得し、及び／または［７］または［８］に記載の方法により得られる前記一般式（１６）で表される化合物とリン酸エステル化試薬とを反応させ、一般式（１８）：
Figure JPOXMLDOC01-appb-C000024
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、前記定義と同じ。］
で表される化合物を取得し、
　前記一般式（１７）で表される化合物を一般式（１９）で表される化合物に変換し、及び／または前記一般式（１８）で表される化合物を前記一般式（２０）で表される化合物に変換することを含む方法。
 
［１０］　一般式（７）：
Figure JPOXMLDOC01-appb-C000025
［式中、Ｒ１は炭素数１～６のアルコキシ基を示し；
Ｒ２は水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３はハロゲン原子を示し；
Ｒ４は炭素数１～６のアルキル基を示し；
Ｒ５は炭素数１～６のアルキル基を示し；
Ｒ６は炭素数１～６のアルキル基を示す。］
または、一般式（８）：
Figure JPOXMLDOC01-appb-C000026
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、前記定義と同じ。］
で表される化合物。
 
［１１］　一般式（７ａ）：
Figure JPOXMLDOC01-appb-C000027
［式中、Ｒ９は水素原子、ベンジル基、ｐ－メトキシベンジル基または２－メトキシエトキシメチル基を示し；
Ｒ１０はメチル基、エチル基、ｔｅｒｔ－ブチル基を示し；
Ｒ１１はメチル基、エチル基、ｔｅｒｔ－ブチル基を示し；
Ｚはフッ素原子または塩素原子を示す。］、または
一般式（８ａ）：
Figure JPOXMLDOC01-appb-C000028
［式中、Ｒ９、Ｒ１０、Ｒ１１及びＺは前記定義と同じ。］
で表される［１０］に記載の化合物。
 
［１２］　前記一般式（７ａ）及び一般式（８ａ）において、
Ｒ９は水素原子、ベンジル基または２－メトキシエトキシメチル基を示し；
Ｒ１０は、メチル基、エチル基またはｔｅｒｔ－ブチル基を示し；
Ｒ１１は、エチル基またはｔｅｒｔ－ブチル基を示し；
Ｚは、塩素原子を示す［１１］に記載の化合物。
 
［１３］ 一般式（１３）：
Figure JPOXMLDOC01-appb-C000029
  
［式中、Ｒ１は炭素数１～６のアルコキシ基を示し；
Ｒ２は水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３はハロゲン原子を示し；
Ｒ４は炭素数１～６のアルキル基を示す。］
または一般式（１４）：
Figure JPOXMLDOC01-appb-C000030
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は前記定義と同じ。］
で表される化合物の薬学的に許容しうる塩。
 
［１４］　一般式（１５）：
Figure JPOXMLDOC01-appb-C000031
［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３は、ハロゲン原子を示し；
Ｒ４は、炭素数１～６のアルキル基を示し；
Ｒ７はアミノ基の保護基を示す。］
または一般式（１６）：
Figure JPOXMLDOC01-appb-C000032
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、前記定義と同じ。］
で表される化合物。
 
［１５］　一般式（１７）：
Figure JPOXMLDOC01-appb-C000033
［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３は、ハロゲン原子を示し；
Ｒ４は、炭素数１～６のアルキル基を示し；
Ｒ７はアミノ基の保護基を示し；
Ｒ８は、炭素数１～６のアルキル基を示す。］
または一般式（１８）：
Figure JPOXMLDOC01-appb-C000034
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、前記定義と同じ。］
で表される化合物。
 
［１６］　一般式（４）：
Figure JPOXMLDOC01-appb-C000035
［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３は、ハロゲン原子を示し；
Ｒ４は、炭素数１～６のアルキル基を示し；
Ｒ５は、炭素数１～６のアルキル基を示す。］
で表される化合物に対し、有機スルホン酸または酸性粘土鉱物を反応させることにより、脱ｔｅｒｔ－ブチル化反応を行い、一般式（５）：
Figure JPOXMLDOC01-appb-C000036
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、前記定義と同じ。］
で表される化合物を取得することを含む、前記一般式（５）で表される化合物の製造方法。
 
［１７］　一般式（９）
Figure JPOXMLDOC01-appb-C000037
［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を表し；
Ｒ３は、ハロゲン原子を示し；
Ｒ４は、炭素数１～６のアルキル基を示し；
Ｒ６は、炭素数１～６のアルキル基を示す。］
で表される化合物と一般式（１１）：
Figure JPOXMLDOC01-appb-C000038
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより一般式（１３）：

［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の薬学的に許容しうる塩を取得すること、及び／または
一般式（１０）：
Figure JPOXMLDOC01-appb-C000040
［式中Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、前記定義と同じ。］
で表される化合物及び一般式（１２）：
Figure JPOXMLDOC01-appb-C000041
［式中Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより一般式（１４）：
Figure JPOXMLDOC01-appb-C000042
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の薬学的に許容しうる塩を取得することを含む、前記一般式（１３）で
表される化合物の薬学的に許容しうる塩及び／または前記一般式（１４）で表される化合物の薬学的に許容しうる塩の製造方法。
 
［１８］　一般式（１３）：
Figure JPOXMLDOC01-appb-C000043
［式中、Ｒ１は炭素数１～６のアルコキシ基を示し；
Ｒ２は水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を表し；
Ｒ３はハロゲン原子を示し；
Ｒ４は炭素数１～６のアルキル基を示す。］
で表される化合物の薬学的に許容しうる塩の遊離塩基化及びアミノ基の保護を行い、一般式（１５）：
Figure JPOXMLDOC01-appb-C000044
［式中、Ｒ７はアミノ基の保護基を示し、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物を取得すること、及び／または
一般式（１４）：
Figure JPOXMLDOC01-appb-C000045
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物の薬学的に許容しうる塩の遊離塩基化及びアミノ基の保護を行い、一般式（１６）：
Figure JPOXMLDOC01-appb-C000046
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、前記定義と同じ。］で表される化合物を取得することを含む、前記一般式（１５）で表される化合物及び／または前記一般式（１６）で表される化合物の製造方法。
 
［１９］　一般式（１７）：
Figure JPOXMLDOC01-appb-C000047
［式中、Ｒ１は炭素数１～６のアルコキシ基を示し；
Ｒ２は水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を表し；
Ｒ３はハロゲン原子を示し；
Ｒ４は炭素数１～６のアルキル基を示し；
Ｒ７はアミノ基の保護基を表し；
Ｒ８は炭素数１～６のアルキル基を示す。］
で表される化合物を一般式（１９）：
Figure JPOXMLDOC01-appb-C000048
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物に変換すること、及び／または
　一般式（１８）：
Figure JPOXMLDOC01-appb-C000049
［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、前記定義と同じ。］
で表される化合物を一般式（２０）：
Figure JPOXMLDOC01-appb-C000050
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
で表される化合物に変換することを含む、前記一般式（１９）で表される化合物及び／または前記一般式（２０）で表される化合物の製造方法。
 
［２０］　前記一般式（９）で表される化合物と前記一般式（１１）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物をＤ－（－）－酒石酸と反応させることにより前記一般式（１３）で表される化合物のＤ－（－）－酒石酸塩を取得する、及び／または前記一般式（１０）で表される化合物及び前記一般式（１２）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物をＬ－（＋）－酒石酸と反応させることにより一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩を取得する［１７］に記載の方法。
 
［２１］　前記一般式（１３）で表される化合物のＤ－（－）－酒石酸塩の遊離塩基化及びアミノ基の保護を行い、前記一般式（１５）で表される化合物を取得する、及び／または前記一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩の遊離塩基化及びアミノ基の保護を行い、前記一般式（１６）で表される化合物を取得する［１８］に記載の方法。
 
［２２］ 一般式（１３ａ）：
Figure JPOXMLDOC01-appb-C000051
［式中、Ｒ１は炭素数１～６のアルコキシ基を示し；
Ｒ２は水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
Ｒ３はハロゲン原子を示し；
Ｒ４は炭素数１～６のアルキル基を示す。］
または一般式（１４ａ）：
Figure JPOXMLDOC01-appb-C000052
［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は前記定義と同じ。］
で表される化合物。
  The gist of the present invention is as follows.
[1] General formula (6):
Figure JPOXMLDOC01-appb-C000003
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 5 represents an alkyl group having 1 to 6 carbon atoms;
R 6 represents an alkyl group having 1 to 6 carbon atoms. The compound represented by the above is subjected to optical resolution by an optical resolution column,
Separated, general formula (7):
Figure JPOXMLDOC01-appb-C000004
[Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
And / or general formula (8):
Figure JPOXMLDOC01-appb-C000005
[Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
The optical resolution method which collect | recovers the compound represented by these.

[2] The compound represented by the general formula (6) is represented by the general formula (7a) as the compound represented by the general formula (7):
Figure JPOXMLDOC01-appb-C000006
[Wherein R 9 represents a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group;
R 10 is a methyl group, an ethyl group or a tert-butyl group;
R 11 is an ethyl group or a tert-butyl group;
Z is a chlorine atom]
And a compound represented by the general formula (8) as a compound represented by the general formula (8a):
Figure JPOXMLDOC01-appb-C000007
[Wherein R 9 , R 10 , R 11 and Z are the same as defined above. ]
Including a compound represented by
The optical purity of the compound represented by the general formula (7a) to be recovered and / or the optical purity of the compound represented by the general formula (8a) to be recovered is 95% ee or more. The optical resolution method described.

[3] A method for producing a compound represented by the general formula (7) and / or a compound represented by the general formula (8),
General formula (4):
Figure JPOXMLDOC01-appb-C000008
[Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above. ]
A detert-butylation reaction is carried out by reacting the compound represented by formula (5) with an organic sulfonic acid or an acidic clay mineral.
Figure JPOXMLDOC01-appb-C000009
[Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above. ]
To obtain a compound represented by
The compound represented by the general formula (6) is obtained by subjecting the compound represented by the general formula (5) to a rearrangement reaction,
From the compound represented by the general formula (6) to the compound represented by the general formula (7) and / or the general formula (8) by the optical resolution method described in [1] or [2]. Obtaining a compound.
In addition, when carrying out the method by the optical resolution method described in [2],
In the formula (4), formula (5) and formula (6), R 1 is an ethoxy group, R 2 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group, R 3 is a chlorine atom, 4 is an n-propyl group, R 5 is a methyl group, an ethyl group or a tert-butyl group,
R 6 in the formula (6) is an ethyl group or a tert-butyl group,
In the formula (4), the formula (5) and the formula (6), those skilled in the art understand that R 3 is bonded to the meta position with respect to the phenylthio group substituted with the R 1 and R 2 O groups. it can.

[4] In the method according to [3],
General formula (1):
Figure JPOXMLDOC01-appb-C000010
[Wherein R 1 , R 2 and R 3 are the same as defined above. ]
A compound represented by the general formula (2):
Figure JPOXMLDOC01-appb-C000011
[Wherein R 1 , R 2 and R 3 are the same as defined above. ]
Converted to a compound represented by:
The compound represented by the general formula (2) is represented by the general formula (3):
Figure JPOXMLDOC01-appb-C000012
[Wherein, R 4 and R 5 are the same as defined above. ]
The method further comprising obtaining the compound represented by the general formula (4) by reacting with the compound represented by formula (4).
In addition, when carrying out the method by the optical resolution method described in [2],
R 1 in Formula (1) and Formula (2) is an ethoxy group, R 2 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group, R 3 is a chlorine atom, and R 1 in Formula (3) 4 is an n-propyl group, R 5 is a methyl group, an ethyl group or a tert-butyl group,
In the formula (1) and formula (2), those skilled in the art can naturally understand that R 3 is bonded to the meta position with respect to the phenylthio group substituted by the R 1 and R 2 O groups.

[5] General formula (13):
Figure JPOXMLDOC01-appb-C000013
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or the general formula (14):
Figure JPOXMLDOC01-appb-C000014
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A process for producing a compound represented by
From the compound represented by the general formula (6) to the compound represented by the general formula (7) and / or the general formula (8) by the optical resolution method described in [1] or [2]. Obtain a compound
By reducing the compound represented by the general formula (7), the general formula (9):
Figure JPOXMLDOC01-appb-C000015
[Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above. ]
And a compound represented by the general formula (11):
Figure JPOXMLDOC01-appb-C000016
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or reducing the compound represented by the general formula (8) to obtain the mixture represented by the general formula (10):
Figure JPOXMLDOC01-appb-C000017
[Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above. ]
And a compound represented by the general formula (12):
Figure JPOXMLDOC01-appb-C000018
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
To obtain a mixture containing the compound represented by
A mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid. To obtain a pharmaceutically acceptable salt of the compound represented by the general formula (13) and / or the compound represented by the general formula (10) and the compound represented by the general formula (12). A pharmaceutically acceptable salt of the compound represented by the general formula (14) is obtained by subjecting the mixture containing a hydrolyzate to a hydrolysis treatment and reacting the product of the hydrolysis treatment with an inorganic acid or an organic acid. A method involving that.
In addition, when carrying out the method by the optical resolution method described in [2],
In the formulas (9) to (14), R 1 is an ethoxy group, R 2 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group, R 3 is a chlorine atom, and R 4 is an n-propyl group. And
R 6 in formula (9) and formula (10) is an ethyl group or a tert-butyl group,
In the formulas (9) to (14), those skilled in the art can naturally understand that R 3 is bonded to the meta position with respect to the phenylthio group substituted with the R 1 and R 2 O groups.

[6] A mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is converted to D-(-)- By reacting with tartaric acid, a D-(−)-tartrate salt of the compound represented by the general formula (13) is obtained and / or the compound represented by the general formula (10) and the general formula (12 ) Is subjected to hydrolysis treatment, and the product of the hydrolysis treatment is reacted with L-(+)-tartaric acid to produce L-- of the compound represented by the general formula (14). Acquire (+)-tartrate,
Optical purity of D-(−)-tartrate salt of the compound represented by the general formula (13) and / or optical purity of L-(+)-tartrate salt of the compound represented by the general formula (14) The production method according to [5], wherein is 99.0% ee or more.

[7] General formula (15):
Figure JPOXMLDOC01-appb-C000019
[Wherein R 7 represents an amino-protecting group, and R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or general formula (16):
Figure JPOXMLDOC01-appb-C000020
[Wherein R 7 represents an amino-protecting group, and R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A process for producing a compound represented by
Free basification and amino group protection of a pharmaceutically acceptable salt of the compound represented by the general formula (13) obtained by the method according to [5] or [6], and / or [5 Or a free basification of a pharmaceutically acceptable salt of the compound represented by the general formula (14) obtained by the method of [6] and protection of an amino group.

[8] The optical purity of the compound represented by the general formula (15) and / or the optical purity of the compound represented by the general formula (16) is 99.5% ee or more. the method of.

[9] General formula (19):
Figure JPOXMLDOC01-appb-C000021
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or general formula (20):
Figure JPOXMLDOC01-appb-C000022
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A process for producing a compound represented by
The compound represented by the general formula (15) obtained by the method according to [7] or [8] is reacted with a phosphoric acid esterification reagent, and the general formula (17):
Figure JPOXMLDOC01-appb-C000023
[Wherein R 8 represents an alkyl group having 1 to 6 carbon atoms, and R 1 , R 2 , R 3 , R 4 and R 7 are as defined above. ]
And / or reacting the compound represented by the general formula (16) obtained by the method described in [7] or [8] with a phosphate esterification reagent, (18):
Figure JPOXMLDOC01-appb-C000024
[Wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above. ]
To obtain a compound represented by
The compound represented by the general formula (17) is converted into the compound represented by the general formula (19), and / or the compound represented by the general formula (18) is represented by the general formula (20). Converting to a compound.

[10] General formula (7):
Figure JPOXMLDOC01-appb-C000025
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aralkyl group;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 5 represents an alkyl group having 1 to 6 carbon atoms;
R 6 represents an alkyl group having 1 to 6 carbon atoms. ]
Or general formula (8):
Figure JPOXMLDOC01-appb-C000026
[Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
A compound represented by

[11] General formula (7a):
Figure JPOXMLDOC01-appb-C000027
[Wherein R 9 represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group or a 2-methoxyethoxymethyl group;
R 10 represents a methyl group, an ethyl group, or a tert-butyl group;
R 11 represents a methyl group, an ethyl group, or a tert-butyl group;
Z represents a fluorine atom or a chlorine atom. Or general formula (8a):
Figure JPOXMLDOC01-appb-C000028
[Wherein R 9 , R 10 , R 11 and Z are as defined above. ]
The compound as described in [10] represented by these.

[12] In the general formula (7a) and the general formula (8a),
R 9 represents a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group;
R 10 represents a methyl group, an ethyl group or a tert-butyl group;
R 11 represents an ethyl group or a tert-butyl group;
The compound according to [11], wherein Z represents a chlorine atom.

[13] General formula (13):
Figure JPOXMLDOC01-appb-C000029
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aralkyl group;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms. ]
Or general formula (14):
Figure JPOXMLDOC01-appb-C000030
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A pharmaceutically acceptable salt of the compound represented by:

[14] General formula (15):
Figure JPOXMLDOC01-appb-C000031
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 7 represents an amino-protecting group. ]
Or general formula (16):
Figure JPOXMLDOC01-appb-C000032
[Wherein R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above. ]
A compound represented by

[15] General formula (17):
Figure JPOXMLDOC01-appb-C000033
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 7 represents an amino-protecting group;
R 8 represents an alkyl group having 1 to 6 carbon atoms. ]
Or general formula (18):
Figure JPOXMLDOC01-appb-C000034
[Wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above. ]
A compound represented by

[16] General formula (4):
Figure JPOXMLDOC01-appb-C000035
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 5 represents an alkyl group having 1 to 6 carbon atoms. ]
A detert-butylation reaction is carried out by reacting the compound represented by formula (5) with an organic sulfonic acid or an acidic clay mineral.
Figure JPOXMLDOC01-appb-C000036
[Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above. ]
The manufacturing method of the compound represented by the said General formula (5) including obtaining the compound represented by these.

[17] General formula (9)
Figure JPOXMLDOC01-appb-C000037
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 6 represents an alkyl group having 1 to 6 carbon atoms. ]
And a compound represented by the general formula (11):
Figure JPOXMLDOC01-appb-C000038
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A mixture containing the compound represented by formula (13) is subjected to hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid to obtain a general formula (13):

[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or obtaining a pharmaceutically acceptable salt of the compound represented by formula (10):
Figure JPOXMLDOC01-appb-C000040
[Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above. ]
And a compound represented by the general formula (12):
Figure JPOXMLDOC01-appb-C000041
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A mixture containing the compound represented by formula (14) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid to obtain a general formula (14):
Figure JPOXMLDOC01-appb-C000042
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A pharmaceutically acceptable salt of the compound represented by the general formula (13) and / or the general formula (14). For producing a pharmaceutically acceptable salt of the compound.

[18] General formula (13):
Figure JPOXMLDOC01-appb-C000043
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aralkyl group;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms. ]
The compound represented by general formula (15):
Figure JPOXMLDOC01-appb-C000044
[Wherein R 7 represents an amino-protecting group, and R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or general formula (14):
Figure JPOXMLDOC01-appb-C000045
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
The compound represented by general formula (16):
Figure JPOXMLDOC01-appb-C000046
[Wherein R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above. A method for producing a compound represented by the general formula (15) and / or a compound represented by the general formula (16).

[19] General formula (17):
Figure JPOXMLDOC01-appb-C000047
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aralkyl group;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms;
R 7 represents an amino-protecting group;
R 8 represents an alkyl group having 1 to 6 carbon atoms. ]
A compound represented by the general formula (19):
Figure JPOXMLDOC01-appb-C000048
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
And / or general formula (18):
Figure JPOXMLDOC01-appb-C000049
[Wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above. ]
A compound represented by the general formula (20):
Figure JPOXMLDOC01-appb-C000050
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
The manufacturing method of the compound represented by the said general formula (19) and / or the compound represented by the said General formula (20) including converting into the compound represented by these.

[20] A mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is converted to D-(-)- By reacting with tartaric acid, D-(-)-tartrate of the compound represented by the general formula (13) is obtained, and / or the compound represented by the general formula (10) and the general formula (12 ) Is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with L-(+)-tartaric acid to give L- ( The method according to [17], wherein +)-tartrate is obtained.

[21] Free-basification of D-(-)-tartrate of the compound represented by the general formula (13) and protection of the amino group to obtain the compound represented by the general formula (15). And / or free-basification of the L-(+)-tartrate salt of the compound represented by the general formula (14) and protection of the amino group to obtain the compound represented by the general formula (16) [ 18].

[22] General formula (13a):
Figure JPOXMLDOC01-appb-C000051
[Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
R 2 represents a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or an optionally substituted aralkyl group;
R 3 represents a halogen atom;
R 4 represents an alkyl group having 1 to 6 carbon atoms. ]
Or general formula (14a):
Figure JPOXMLDOC01-appb-C000052
[Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
A compound represented by
　本発明によれば、ジフェニルスルフィド誘導体の新規な製造方法に関する技術を提供することができる。 According to the present invention, a technique relating to a novel method for producing a diphenyl sulfide derivative can be provided.
実施例２０で得られたＨＰＬＣ(High performance liquid chromatography)クロマトグラムである。2 is an HPLC (High performance liquid chromatography) chromatogram obtained in Example 20. 実施例２１で得られたＨＰＬＣクロマトグラムである。2 is an HPLC chromatogram obtained in Example 21. 実施例２２で得られたＨＰＬＣクロマトグラムである。2 is an HPLC chromatogram obtained in Example 22. 実施例２３で得られたＨＰＬＣクロマトグラムである。2 is an HPLC chromatogram obtained in Example 23. 実施例２４で得られたＨＰＬＣクロマトグラムである。2 is an HPLC chromatogram obtained in Example 24.
　以下、本発明の実施形態の１つについて詳細に説明する。
　なお、以下において、一般式が有する官能基の定義については、すでに記載した定義を引用してその説明を省略することがある。引用している定義は、以下に記載する実施形態の説明中に記載した定義を指しており、先行技術についての記載において説明した官能基についての定義を引用するものではないことは、当然に理解できる。 Hereinafter, one embodiment of the present invention will be described in detail.
In the following description, the definition of the functional group of the general formula may be omitted with reference to the definition already described. It should be understood that the definitions cited refer to the definitions set forth in the description of the embodiments described below and do not refer to the definitions for the functional groups described in the description of the prior art. it can.
　なお、本明細書において、ハロゲン原子とは、フッ素原子、塩素原子、臭素原子またはヨウ素原子を表す。
　また、炭素数１～６のアルキル基とは、直鎖または分岐鎖状の炭素数１～６のアルキル基である。炭素数１～６のアルキル基としては、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、１－エチルプロピル基、２－エチルプロピル基、ヘキシル基などを挙げることができる。
　また、炭素数１～６のアルコキシ基とは、直鎖または分岐鎖状の炭素数１～６のアルコキシ基である。炭素数１～６のアルコキシ基としては、例えばメトキシ基、エトキシ基、ｎ－プロポキシ基、ｎ－ブトキシ基、イソプロポキシ基またはｔｅｒｔ－ブトキシ基などを挙げることができる。
　また、アラルキル基としては、ベンジル基、ジフェニルメチル基、フェネチル基、フェニルプロピル基などを挙げることができる。
　また、アミノ基の保護基とは、アミノ基の保護基として通常知られている保護基であれば特に制限はなく、例えばベンジル基、パラメトキシベンジル基（ｐ－メトキシベンジル基）などのアラルキル基、メトキシカルボニル基、エトキシカルボニル基、ｎ－プロピルオキシカルボニル基、イソプロピルオキシカルボニル基、ｎ－ブチルオキシカルボニル基、イソブチルオキシカルボニル基、ｔｅｒｔ－ブトキシカルボニル基などの、アルコキシカルボニル基、ベンジルオキシカルボニル基、ｐ－メトキシベンジルオキシカルボニル基、ｐ－ニトロベンジルオキシカルボニル基などのアラルコキシカルボニル基、メトキシメチル基、メトキシエトキシメチル基、１－（エトキシ）エチル基、メトキシイソプロピル基などの１－（アルコキシ）アルキル基、アセチル基、トリフルオロアセチル基、プロピオニル基、ブチリル基、ピバロイル基、ベンゾイル基、メチルベンゾイル基などのアシル基等が挙げられ、特にアルコキシカルボニル基が好ましく、更に好ましくは、ｔｅｒｔ－ブトキシカルボニル基である。 In this specification, the halogen atom represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Further, the alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, and a 1-ethylpropyl group. , 2-ethylpropyl group, hexyl group and the like.
Further, the alkoxy group having 1 to 6 carbon atoms is a linear or branched alkoxy group having 1 to 6 carbon atoms. Examples of the alkoxy group having 1 to 6 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an isopropoxy group, and a tert-butoxy group.
Moreover, examples of the aralkyl group include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group.
The amino protecting group is not particularly limited as long as it is a protecting group commonly known as an amino protecting group. For example, an aralkyl group such as a benzyl group or a paramethoxybenzyl group (p-methoxybenzyl group) is used. , Alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, n-propyloxycarbonyl group, isopropyloxycarbonyl group, n-butyloxycarbonyl group, isobutyloxycarbonyl group, tert-butoxycarbonyl group, benzyloxycarbonyl group, 1- (alkoxy) such as p-methoxybenzyloxycarbonyl group, aralkoxycarbonyl group such as p-nitrobenzyloxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, 1- (ethoxy) ethyl group, methoxyisopropyl group A And acyl groups such as a kill group, an acetyl group, a trifluoroacetyl group, a propionyl group, a butyryl group, a pivaloyl group, a benzoyl group and a methylbenzoyl group. An alkoxycarbonyl group is particularly preferable, and a tert-butoxycarbonyl is more preferable. It is a group.
　また、明示する場合、炭素数１～６のアルキル基及びアラルキル基は置換基を有していてもよい。当該置換基としては、ハロゲン原子、ヒドロキシル基、シアノ基、炭素数１～６のアルコキシ基、及び炭素数１～６のアルコキシ基で置換されていてもよい炭素数１～６のアルコキシ基、からなる群から選ばれた１～５個の置換基などが挙げられる。 In addition, when clearly indicated, the alkyl group having 1 to 6 carbon atoms and the aralkyl group may have a substituent. Examples of the substituent include a halogen atom, a hydroxyl group, a cyano group, an alkoxy group having 1 to 6 carbon atoms, and an alkoxy group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 6 carbon atoms. And 1 to 5 substituents selected from the group.
　Ｒ４として表される炭素数１～６のアルキル基として、好ましくはｎ－プロピル基が挙げられる。
　Ｒ５として表される炭素数１～６のアルキル基として、好ましくはメチル基、エチル基またはtｅｒｔ－ブチル基が挙げられ、特に好ましくはエチル基が挙げられる。
　Ｒ６として表される炭素数１～６のアルキル基として、好ましくはメチル基、エチル基またはtｅｒｔ－ブチル基、より好ましくは、エチル基またはtｅｒｔ－ブチル基、特に好ましくはエチル基が挙げられる。
　Ｒ２が置換基を有してもよい炭素数１～６のアルキル基である場合、当該Ｒ２として好ましくは２－メトキシエトキシメチル基が挙げられる。Ｒ２が置換基を有してもよいアラルキル基である場合、当該Ｒ２として好ましくはベンジル基が挙げられる。
　Ｒ１として表される炭素数１～６のアルコキシ基として、好ましくはエトキシ基が挙げられる。
　また、有機スルホン酸とは、－ＳＯ３Ｈ基を分子構造中に少なくとも１つ含む有機化合物である。有機スルホン酸としては、例えばメタンスルホン酸、エタンスルホン酸、プロパンスルホン酸、２－プロパンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸またはナフタレンスルホン酸等が挙げられる。
　また、酸性粘土鉱物とは、粘土を構成する無機鉱物のうち酸性のもの（固体酸として一般式（４）で表される化合物に作用するもの）を意味する。酸性粘土鉱物としては、モンモリロナイトＫＳＦ、モンモリロナイトＫ１０またはモンモリロナイトＫ３０等が挙げられる。 The alkyl group having 1 to 6 carbon atoms represented by R 4 is preferably an n-propyl group.
The alkyl group having 1 to 6 carbon atoms represented by R 5 is preferably a methyl group, an ethyl group or a tert-butyl group, and particularly preferably an ethyl group.
The alkyl group having 1 to 6 carbon atoms represented by R 6 is preferably a methyl group, an ethyl group or a tert-butyl group, more preferably an ethyl group or a tert-butyl group, and particularly preferably an ethyl group.
When R 2 is an optionally substituted alkyl group having 1 to 6 carbon atoms, R 2 is preferably a 2-methoxyethoxymethyl group. When R 2 is an aralkyl group which may have a substituent, R 2 is preferably a benzyl group.
Preferred examples of the alkoxy group having 1 to 6 carbon atoms represented by R 1 include an ethoxy group.
An organic sulfonic acid is an organic compound containing at least one —SO 3 H group in the molecular structure. Examples of the organic sulfonic acid include methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, 2-propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid.
Moreover, an acidic clay mineral means an acidic thing (the thing which acts on the compound represented by General formula (4) as a solid acid) among the inorganic minerals which comprise clay. Examples of the acidic clay mineral include montmorillonite KSF, montmorillonite K10, and montmorillonite K30.
　本実施形態に係る製造方法の一例である、以下に表す反応経路を詳細に説明する。 DETAILED DESCRIPTION OF THE INVENTION The following reaction route, which is an example of a production method according to this embodiment, will be described in detail.
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　当該反応経路において、Ｒ１は炭素数１～６のアルコキシ基を示し、Ｒ２は水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を表し、Ｒ３はハロゲン原子を示し、Ｒ４は炭素数１～６のアルキル基を示し、Ｒ５は炭素数１～６のアルキル基を示し、Ｒ６は炭素数１～６のアルキル基を示し、Ｒ７はアミノ基の保護基を示し、Ｒ８は炭素数１～６のアルキル基を示す。 In the reaction pathway, R 1 represents an alkoxy group having 1 to 6 carbon atoms, and R 2 may have a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or a substituent. R 3 represents a halogen atom, R 4 represents an alkyl group having 1 to 6 carbon atoms, R 5 represents an alkyl group having 1 to 6 carbon atoms, and R 6 represents an alkyl group having 1 to 6 carbon atoms. R 7 represents an amino-protecting group, and R 8 represents an alkyl group having 1 to 6 carbon atoms.
（工程１）
　一般式（２）で表される化合物は、一般式（１）で表される化合物を一般式（２）で表される化合物に変換することにより得ることができる。 (Process 1)
The compound represented by the general formula (2) can be obtained by converting the compound represented by the general formula (1) into a compound represented by the general formula (2).
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　式（１）中、Ｒ１、Ｒ２及びＲ３は、上記定義と同じである。 In formula (1), R 1 , R 2 and R 3 are the same as defined above.
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　式（２）中、Ｒ１、Ｒ２及びＲ３は、上記定義と同である。 In formula (2), R 1 , R 2 and R 3 are as defined above.
　当該変換は、例えば、ウィッティヒ反応、ホーナー・エモンズ反応、ピーターソン反応、ＴｉＣｌ４－ＣＨ２Ｃｌ２－Ｚｎ系反応、テーベ反応に基づき行うことができるが、一般式（２）で表される化合物が高温で分解する傾向があるため、比較的低い温度で反応が進行する、ピーターソン反応に基づき行うことが好ましい。ピーターソン反応は、例えば、テトラヒドロフランなどの反応溶媒中において、塩化トリメチルシリルメチルマグネシウム、臭化トリメチルシリルメチルマグネシウムなどのピーターソン試薬を一般式（１）で表される化合物に作用させ、次いで得られた化合物を酸または塩基で処理することにより行うことができる。塩化トリメチルシリルメチルマグネシウム等のピーターソン試薬は、一般式（１）で表される化合物に対して、例えば１当量以上５当量以下用いることが好ましい。より好ましくは１当量以上２当量以下、さらにより好ましくは１当量以上１．５当量以下が挙げられる。また、副生成物の生成を抑制するという点で、塩化トリメチルシリルメチルマグネシウム等のピーターソン試薬は、一般式（１）で表される化合物に対して、１．２当量以上を用いることが好ましい。従って、ピーターソン試薬の使用量として、特に好ましくは、一般式（１）で表される化合物に対して、１．２当量以上１．５当量以下が挙げられる。
　反応温度は、通常－２０℃以上溶媒の沸点以下が挙げられ、好ましくは０℃以上７０℃以下が挙げられる。さらに、副生成物の生成が抑制されるという点で、反応温度は１０℃以上７０℃以下がより好ましく、さらにより好ましくは１５℃以上５０℃以下、特に好ましくは２０℃以上３５℃以下が挙げられる。 The conversion can be performed based on, for example, the Wittig reaction, the Horner-Emmons reaction, the Peterson reaction, the TiCl 4 —CH 2 Cl 2 —Zn system reaction, the Thebes reaction, and the compound represented by the general formula (2) Since it tends to decompose at a high temperature, the reaction is preferably performed based on the Peterson reaction in which the reaction proceeds at a relatively low temperature. In the Peterson reaction, for example, in a reaction solvent such as tetrahydrofuran, a Peterson reagent such as trimethylsilylmethylmagnesium chloride or trimethylsilylmethylmagnesium bromide is allowed to act on the compound represented by the general formula (1), and then the obtained compound Can be carried out by treating with acid or base. The Peterson reagent such as trimethylsilylmethyl magnesium chloride is preferably used in an amount of, for example, 1 equivalent to 5 equivalents with respect to the compound represented by the general formula (1). More preferably, it is 1 equivalent or more and 2 equivalents or less, and still more preferably 1 equivalent or more and 1.5 equivalents or less. Moreover, it is preferable to use 1.2 equivalents or more of Peterson reagents such as trimethylsilylmethyl magnesium chloride with respect to the compound represented by the general formula (1) in terms of suppressing the formation of by-products. Accordingly, the amount of the Peterson reagent used is particularly preferably 1.2 equivalents or more and 1.5 equivalents or less with respect to the compound represented by the general formula (1).
The reaction temperature is usually from −20 ° C. to the boiling point of the solvent, and preferably from 0 ° C. to 70 ° C. Furthermore, the reaction temperature is more preferably 10 ° C. or more and 70 ° C. or less, even more preferably 15 ° C. or more and 50 ° C. or less, and particularly preferably 20 ° C. or more and 35 ° C. or less in that generation of by-products is suppressed. It is done.
　本件明細書中に示される「倍量」とは、溶媒の容積（ｍＬ）を化合物の重量（ｇ）で除した値である。 The “double amount” shown in the present specification is a value obtained by dividing the volume (mL) of the solvent by the weight (g) of the compound.
　反応溶媒としては、例えば、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、またはジグライム等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、ジクロロメタン等のハロゲン化炭化水素類、あるいはこれらの混合物が挙げられ、好ましくは、エーテル類、さらに好ましくはテトラヒドロフランが挙げられる。 Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, halogenated hydrocarbons such as dichloromethane, or the like. A mixture is mentioned, Preferably, ethers are mentioned, More preferably, tetrahydrofuran is mentioned.
　なお、一般式（１）で表される化合物は、例えば以下に示す反応経路に基づき得ることができる。
　具体的には、５－アルコキシ－１，３－ベンゾキサチオール－２－オンなどの一般式（ｐ１）で表される化合物について水酸化ナトリウムなどの塩基を作用させた後、過酸化水素水などの酸化剤を作用させ、次に得られた生成物に必要に応じて臭化ベンジルなどのハロゲン化アルキル、及び炭酸カリウムなどの塩基を作用させ、一般式（ｐ２）で表される化合物を得る（工程Ｐ１）。塩基及び酸化剤を一般式（ｐ１）で表される化合物に順次作用させるとき、反応溶媒は、例えば水、メタノール、エタノール、またはこれらの混合物とすることができ、反応温度は例えば１０℃～２５℃とすることができる。また、ハロゲン化アルキル及び塩基を用いた反応においては、反応溶媒は、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、テトラヒドロフラン、またはこれらの混合物とすることができ、また、反応温度は例えば２０℃～３０℃とすることができる。
　次に、得られた一般式（ｐ２）で表される化合物に、反応溶媒中、水素化ホウ素ナトリウム等の還元剤、もしくは塩酸や酢酸などの存在下、金属亜鉛や亜鉛アマルガム、亜鉛－銅合金などを作用させ、次いで、反応溶媒中で一般式（ｐ３）で表される化合物と反応させることにより、一般式（１）で表される化合物を得る（工程Ｐ２）。金属亜鉛などを用いる反応において、反応溶媒は、例えば、トルエン、キシレン、ベンゼン、またはこれらの混合物を用いることができ、また反応温度は例えば５０℃～６０℃とすることができる。また、一般式（ｐ３）で表される化合物を用いる反応において、反応溶媒は、例えば、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、テトラヒドロフランまたはそれらの混合物とすることができる。また、反応温度は、例えば２０℃～６０℃とすることができる。 In addition, the compound represented by General formula (1) can be obtained based on the reaction pathway shown below, for example.
Specifically, a compound represented by the general formula (p1) such as 5-alkoxy-1,3-benzoxiathiol-2-one is allowed to act on a base such as sodium hydroxide, and then a hydrogen peroxide solution, etc. Then, an alkyl halide such as benzyl bromide and a base such as potassium carbonate are allowed to act on the resulting product as necessary to obtain a compound represented by the general formula (p2). (Process P1). When a base and an oxidizing agent are allowed to act sequentially on the compound represented by the general formula (p1), the reaction solvent can be, for example, water, methanol, ethanol, or a mixture thereof, and the reaction temperature is, for example, 10 ° C. to 25 ° C. It can be set to ° C. In the reaction using an alkyl halide and a base, the reaction solvent can be N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, or a mixture thereof. It can be set to 20 ° C to 30 ° C.
Next, in the obtained compound represented by the general formula (p2), metal zinc, zinc amalgam, zinc-copper alloy in the presence of a reducing agent such as sodium borohydride or hydrochloric acid or acetic acid in a reaction solvent. Then, the compound represented by the general formula (1) is obtained by reacting with the compound represented by the general formula (p3) in a reaction solvent (step P2). In the reaction using metal zinc or the like, as the reaction solvent, for example, toluene, xylene, benzene, or a mixture thereof can be used, and the reaction temperature can be set to 50 ° C. to 60 ° C., for example. In the reaction using the compound represented by the general formula (p3), the reaction solvent can be, for example, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran or a mixture thereof. The reaction temperature can be, for example, 20 ° C. to 60 ° C.
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　工程Ｐ１及び工程Ｐ２に関する当該反応経路においてＸａはフルオロ基を示し、Ｒ１、Ｒ２及びＲ３は、上記定義と同じである。 In the reaction pathway relating to Step P1 and Step P2, Xa represents a fluoro group, and R 1 , R 2 and R 3 are the same as defined above.
（工程２）
　一般式（４）で表される化合物は、一般式（２）で表される化合物と一般式（３）で表される化合物とを反応させることにより得ることができる。 (Process 2)
The compound represented by the general formula (4) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (3).
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　式（４）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、上記定義と同じである。 In formula (4), R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　式（３）中、Ｒ４及びＲ５は、上記定義と同じである。なお、Ｒ５はｔｅｒｔ－ブチル基とは異なる直鎖または分岐鎖状の炭素数１～６のアルキル基であることが、後述する工程３において副生成物を抑制できるため、好ましい。 In formula (3), R 4 and R 5 are the same as defined above. R 5 is preferably a linear or branched alkyl group having 1 to 6 carbon atoms different from the tert-butyl group, since by-products can be suppressed in Step 3 described later.
　反応は、例えば、反応溶媒中、塩基の存在下、一般式（２）で表される化合物に一般式（３）で表される化合物を作用させることにより行うことができる。反応溶媒は、例えば、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、またはジグライム等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、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、エチレングリコール、またはジエチレングリコール等のアルコール類、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、ギ酸エチル、ギ酸ｎ－ブチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ｎ－ブチル、酢酸イソブチル、酢酸ｓｅｃ－ヘキシル、酢酸２－エチルヘキシル、プロピオン酸エチル、プロピオン酸ｎ－ブチル、またはイソ吉草酸エチル等の脂肪族エステル類、アセトン等のケトン類、あるいはこれらの混合物が挙げられ、好ましくは、スルホキシド類、さらに好ましくはジメチルスルホキシドが挙げられる。 The reaction can be performed, for example, by reacting the compound represented by the general formula (3) with the compound represented by the general formula (2) in the presence of a base in a reaction solvent. Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like. Halogenated hydrocarbons, methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and other alcohols, N, N-dimethylacetamide, N-methylpyrrolidone, N, N-dimethylformamide, etc. Amides, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-acetate And aliphatic esters such as butyl, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate, ketones such as acetone, or mixtures thereof. Preferably, sulfoxides are used, and dimethyl sulfoxide is more preferable.
　反応温度は、通常－７０℃から使用する溶媒の沸点の範囲が挙げられるが、６２℃より高い温度で反応を行うと不純物が増加する。このため、好ましくは－７０℃から６２℃以下、より好ましくは０℃以上６０℃以下、さらに好ましくは５℃以上６０℃以下、特に好ましくは、１０℃以上５５℃以下とすることができる。また、不純物の増加抑制に加えて反応時間の短縮という点も考慮すると、反応温度は、３０℃以上５５℃以下が好ましく、さらに好ましくは４０℃以上５５℃以下が挙げられる。 The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used, but impurities increase when the reaction is carried out at a temperature higher than 62 ° C. Therefore, the temperature can be preferably -70 ° C to 62 ° C, more preferably 0 ° C to 60 ° C, further preferably 5 ° C to 60 ° C, and particularly preferably 10 ° C to 55 ° C. In consideration of the suppression of the increase in impurities and the shortening of the reaction time, the reaction temperature is preferably 30 ° C. or higher and 55 ° C. or lower, more preferably 40 ° C. or higher and 55 ° C. or lower.
　また、塩基としては、例えば炭酸セシウム、炭酸カリウムなどの無機塩基類、１，５－ジアザビシクロ［４．３．０］－５－ノネン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン、ピリジンなどの有機塩基類、ナトリウムエトキシド、カリウム　ｔｅｒｔ－ブトキシドなどのアルカリ金属アルコキシドなどのうち１種または２種以上を用いることができ、好ましくは、無機塩基類、さらに好ましくは炭酸セシウムが挙げられる。塩基の使用量は、収率向上という観点から、一般式（２）で表される化合物に対し、２当量以上用いることが好ましい。より好ましくは、２．２当量以上５当量以下、さらに好ましくは２．５当量以上３．５当量以下が挙げられる。工程１の粗生成物をさらなる精製をせずに、そのまま工程２に用いている場合は、一般式（１）で表される化合物が１００％の収率で、一般式（２）で表される化合物に変換されたとみなし、一般式（１）で表される化合物の使用量を、一般式（２）で表される化合物の使用量とみなす。 Examples of the base include inorganic bases such as cesium carbonate and potassium carbonate, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-. One or more of organic bases such as undecene and pyridine, alkali metal alkoxides such as sodium ethoxide and potassium tert-butoxide can be used, preferably inorganic bases, more preferably cesium carbonate. Can be mentioned. The amount of the base used is preferably 2 equivalents or more based on the compound represented by the general formula (2) from the viewpoint of improving the yield. More preferably, it is 2.2 equivalents or more and 5 equivalents or less, and more preferably 2.5 equivalents or more and 3.5 equivalents or less. When the crude product of step 1 is used as it is in step 2 without further purification, the compound represented by general formula (1) is represented by general formula (2) in a yield of 100%. The amount of the compound represented by the general formula (1) is regarded as the amount of the compound represented by the general formula (2).
　一般式（３）で表される化合物は、一般式（２）で表される化合物に対し、１当量以上５当量以下用いることが好ましい。より好ましくは１．２当量以上２当量以下、さらに好ましくは１．４当量以上１．７当量以下用いられることが好ましい。 The compound represented by the general formula (3) is preferably used in an amount of 1 to 5 equivalents with respect to the compound represented by the general formula (2). More preferably 1.2 equivalents or more and 2 equivalents or less, and still more preferably 1.4 equivalents or more and 1.7 equivalents or less.
（工程３）
　一般式（５）で表される化合物は、一般式（４）で表される化合物について脱ｔｅｒｔ－ブチル化反応を行うことにより得ることができる。 (Process 3)
The compound represented by the general formula (5) can be obtained by subjecting the compound represented by the general formula (4) to a detert-butylation reaction.
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　式（５）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、上記定義と同じである。 In formula (5), R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
　当該反応は、例えば、反応溶媒中、酸、好ましくはｐ－トルエンスルホン酸、メタンスルホン酸などの有機スルホン酸や、モンモリロナイトＫＳＦ、モンモリロナイトＫ１０、モンモリロナイトＫ３０のような酸性粘土鉱物などを用いて一般式（４）で表される化合物を処理することにより行うことができる。
　酸を反応に使用する場合、その使用量は一般式（４）で表される化合物に対して例えば０．１当量以上用いることが好ましい。より好ましくは、０．１当量以上０．５当量以下、さらにより好ましくは０．１当量以上０．３当量以下が挙げられる。
　酸性粘土鉱物を反応に使用する場合、その使用量は一般式（４）で表される化合物の使用量に対して、また工程１及び２において精製をせずにそのまま工程３に用いている場合は、一般式（１）で表される化合物の使用重量に対して、例えば０．５倍量（ｗ／ｗ）以上用いることが好ましい。より好ましくは、０．５倍量（ｗ／ｗ）以上５倍量（ｗ／ｗ）以下、さらにより好ましくは０．８倍量（ｗ／ｗ）以上３倍量（ｗ／ｗ）以下が挙げられる。 The reaction has a general formula using, for example, an acid, preferably an organic sulfonic acid such as p-toluenesulfonic acid and methanesulfonic acid, an acidic clay mineral such as montmorillonite KSF, montmorillonite K10, and montmorillonite K30 in a reaction solvent. It can carry out by processing the compound represented by (4).
When an acid is used in the reaction, the amount used is preferably 0.1 equivalent or more with respect to the compound represented by the general formula (4). More preferably, it is 0.1 equivalent or more and 0.5 equivalent or less, and still more preferably 0.1 equivalent or more and 0.3 equivalent or less.
When acidic clay minerals are used in the reaction, the amount used is relative to the amount of the compound represented by the general formula (4), and is used as it is in step 3 without purification in steps 1 and 2. Is preferably used in an amount of 0.5 times (w / w) or more, for example, with respect to the weight of the compound represented by the general formula (1). More preferably, it is 0.5 times (w / w) or more and 5 times (w / w) or less, and still more preferably 0.8 times (w / w) or more and 3 times (w / w) or less. Can be mentioned.
　工程２の粗生成物をさらなる精製をせずに、そのまま工程３に用いている場合は、一般式（２）で表される化合物が１００％の収率で、一般式（４）で表される化合物に変換されたとみなし、一般式（２）で表される化合物の使用量を、一般式（４）で表される化合物の使用量とみなす。 When the crude product of Step 2 is used in Step 3 as it is without further purification, the compound represented by General Formula (2) is represented by General Formula (4) in a yield of 100%. The amount of the compound represented by the general formula (2) is regarded as the amount of the compound represented by the general formula (4).
　反応溶媒としては、例えばテトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、またはジグライム等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、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、エチレングリコール、またはジエチレングリコール等のアルコール類、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、あるいはこれらの混合物を挙げることができ、反応の進みやすさと副生成物の抑制の観点から、好ましくはアセトニトリルが挙げられる。反応温度は、例えば、６０℃～加熱還流の温度、より好ましくは８０℃～加熱還流の温度とすることができる。
　このうち、当該工程３においては、反応の進みやすさと副生成物の抑制の観点から、酸性粘土鉱物を用いて当該反応を行うことが好ましく、より好ましくはモンモリロナイトＫＳＦが挙げられる。さらに、モンモリロナイトＫＳＦを用いるとともに反応溶媒をアセトニトリルとすることがより好ましい。 Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like. Halogenated hydrocarbons, methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and other alcohols, N, N-dimethylacetamide, N-methylpyrrolidone, N, N-dimethylformamide, etc. Amides, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, or a mixture thereof. From this, acetonitrile is preferable. The reaction temperature can be, for example, 60 ° C. to heating reflux temperature, more preferably 80 ° C. to heating reflux temperature.
Among these, in the said process 3, it is preferable to perform the said reaction using an acidic clay mineral from a viewpoint of progress of reaction and suppression of a by-product, More preferably, montmorillonite KSF is mentioned. Furthermore, it is more preferable that montmorillonite KSF is used and the reaction solvent is acetonitrile.
（工程４）
　一般式（６）で表される化合物は、一般式（５）で表される化合物を転位反応に供することにより得ることができる。
Figure JPOXMLDOC01-appb-C000060
 (Process 4)
The compound represented by the general formula (6) can be obtained by subjecting the compound represented by the general formula (5) to a rearrangement reaction.
Figure JPOXMLDOC01-appb-C000060
　式（６）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、上記定義と同じである。 In formula (6), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above.
　当該反応は、クルチウス転位、シュミット転位、ロッセン転位、ホフマン転位等に基づき行うことができるが、クルチウス転位に基づき行うことが好ましい。例えば、反応溶媒中、トリエチルアミン等の塩基存在下において、一般式（５）で表される化合物にビス（４－メチルフェニル）リン酸アジド、ビス（４－クロロフェニル）リン酸アジド、ジフェニルリン酸アジド等のアジド化試薬を作用させる。 The reaction can be performed based on the Curtius rearrangement, the Schmitt rearrangement, the Rossen rearrangement, the Hoffman rearrangement, etc., but is preferably performed based on the Curtius rearrangement. For example, bis (4-methylphenyl) phosphoric azide, bis (4-chlorophenyl) phosphoric azide, diphenylphosphoric azide is added to the compound represented by the general formula (5) in the presence of a base such as triethylamine in a reaction solvent. An azidation reagent such as
　アジド化試薬の使用量は、例えば一般式（５）で表される化合物に対して１当量以上とすることができ、好ましくは、１当量以上５当量以下用いられる。より好ましくは１当量以上３当量以下、さらにより好ましくは１当量以上１．５当量以下が挙げられる。工程３の粗生成物をさらなる精製をせずに、そのまま工程４に用いている場合は、一般式（４）で表される化合物が１００％の収率で、一般式（５）で表される化合物に変換されたとみなし、一般式（４）で表される化合物の使用量を、一般式（５）で表される化合物の使用量とみなす。 The amount of the azidation reagent used can be, for example, 1 equivalent or more, preferably 1 equivalent or more and 5 equivalents or less with respect to the compound represented by the general formula (5). More preferably, it is 1 equivalent or more and 3 equivalents or less, and still more preferably 1 equivalent or more and 1.5 equivalents or less. When the crude product of Step 3 is used as it is in Step 4 without further purification, the compound represented by General Formula (4) is represented by General Formula (5) in 100% yield. The amount of the compound represented by the general formula (4) is regarded as the amount of the compound represented by the general formula (5).
　塩基としては、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、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基類、トリエチルアミン、ジイソプロピルエチルアミン、４－メチルモルホリン、４－エチルモルホリン、ピリジン、１－メチルイミダゾール、１，２－ジメチルイミダゾール、１，５－ジアザビシクロ［４．３．０］－５－ノネン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセンなどの有機塩基類等が挙げられる。このうち、有機塩基を当該反応における塩基として用いることが好ましく、特に好ましくはトリエチルアミンが挙げられる。塩基の使用量は、一般式（５）で表される化合物に対し、１当量以上５当量以下用いることが好ましい。収率向上という観点から、さらに好ましくは１．２当量以上３当量以下、特に好ましくは１．２当量以上２当量以下が挙げられる。 Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and other inorganic bases, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7 -Organic bases such as undecene. Among these, it is preferable to use an organic base as a base in the reaction, and particularly preferable is triethylamine. The amount of the base used is preferably 1 equivalent or more and 5 equivalents or less with respect to the compound represented by the general formula (5). From the viewpoint of improving the yield, it is more preferably 1.2 equivalents or more and 3 equivalents or less, and particularly preferably 1.2 equivalents or more and 2 equivalents or less.
　反応溶媒は、例えば、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、またはジグライム等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、ホルムアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、ギ酸エチル、ギ酸ｎ－ブチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ｎ－ブチル、酢酸イソブチル、酢酸ｓｅｃ－ヘキシル、酢酸２－エチルヘキシル、プロピオン酸エチル、プロピオン酸ｎ－ブチル、またはイソ吉草酸エチル等の脂肪族エステル類、アセトン等のケトン類、あるいはこれらの混合物が挙げられ、好ましくは、ベンゼンや、トルエン、キシレン等の芳香族炭化水素系溶媒を用いることができ、好ましくはトルエンである。収率向上という観点から、一般式（５）にアジド化試薬を反応させ、アシルアジドを生成させる際には、溶媒量が少ないことが好ましい。溶媒は、一般式（５）で表される化合物に対し、２０倍量以下用いることが好ましい。より好ましくは８倍量以下、より好ましくは６倍量以下が挙げられる。アシルアジドが生成した後、好ましくは加熱することで転移反応が進行し、イソシアネートが生成する。この際、アシルアジドの溶液を、別途加熱した溶媒に加えることで、反応速度を調節することができる。 Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like. Halogenated hydrocarbons, amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, Aliphatic such as n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate Ester, ketones such as acetone, or mixtures thereof, preferably, can be used benzene, toluene, aromatic hydrocarbon solvents such as xylene, preferably toluene. From the viewpoint of improving the yield, it is preferable that the amount of the solvent is small when the azide reagent is reacted with the general formula (5) to produce an acyl azide. The solvent is preferably used in an amount of 20 times or less with respect to the compound represented by the general formula (5). More preferably, the amount is 8 times or less, more preferably 6 times or less. After the acyl azide is produced, the transfer reaction proceeds preferably by heating, and isocyanate is produced. At this time, the reaction rate can be adjusted by adding the acyl azide solution to a separately heated solvent.
　反応温度は、アシルアジドの生成の際は、例えば、０℃以上６０℃以下が適当であり、好ましくは２０℃以上５５℃以下、より好ましくは３０℃以上５０℃以下が挙げられる。反応温度は、イソシアネートの生成の際は、例えば、６０℃以上１５０℃以下が適当であり、好ましくは７０℃以上１００℃以下、より好ましくは７５℃以上１００℃以下が挙げられる。 The reaction temperature is, for example, suitably from 0 ° C. to 60 ° C., preferably 20 ° C. to 55 ° C., more preferably 30 ° C. to 50 ° C., when acylazide is produced. The reaction temperature is suitably 60 ° C. or more and 150 ° C. or less, for example, in the production of isocyanate, preferably 70 ° C. or more and 100 ° C. or less, more preferably 75 ° C. or more and 100 ° C. or less.
　次に、得られた生成物に一般式（ｉ）で表されるアルカリ金属アルコキシド類などを作用させる。 Next, an alkali metal alkoxide represented by the general formula (i) is allowed to act on the obtained product.
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　式（i）中、Ｍはナトリウム原子またはカリウム原子を示し、Ｒ６は上記定義と同じである。一般式（i）で表される化合物は、市販のものを使用することができるほか、例えば、水素化ナトリウムまたは金属ナトリウム等の化合物と、アルコールを反応させることにより、反応液中で調製して用いても良い。 In formula (i), M represents a sodium atom or a potassium atom, and R 6 has the same definition as above. As the compound represented by the general formula (i), a commercially available compound can be used, and for example, it can be prepared in a reaction solution by reacting a compound such as sodium hydride or sodium metal with an alcohol. It may be used.
　ナトリウムアルコキシドなどのアルカリ金属アルコキシド類は、一般式（５）で表される化合物に対して１当量以上５当量以下用いることが好ましい。収率向上という観点から、さらに好ましくは１．３当量以上３当量以下、特に好ましくは１．４当量以上１．８当量以下が挙げられる。 Alkali metal alkoxides such as sodium alkoxide are preferably used in an amount of 1 to 5 equivalents relative to the compound represented by the general formula (5). From the viewpoint of improving the yield, more preferably 1.3 equivalents or more and 3 equivalents or less, and particularly preferably 1.4 equivalents or more and 1.8 equivalents or less.
（工程５）
　一般式（７）で表される化合物及び／または一般式（８）で表される化合物は、一般式（６）で表される化合物を、光学分割カラムを用いた光学分割に供し、分離された一般式（７）で表される化合物及び／または一般式（８）で表される化合物を回収することにより得ることができる。 (Process 5)
The compound represented by the general formula (7) and / or the compound represented by the general formula (8) is separated by subjecting the compound represented by the general formula (6) to optical resolution using an optical resolution column. In addition, it can be obtained by recovering the compound represented by the general formula (7) and / or the compound represented by the general formula (8).
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　式（７）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、上記定義と同じである。 In formula (7), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above.
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　式（８）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、上記定義と同じである。 In formula (8), R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above.
　光学分割カラムを用いた光学分割は、高速液体クロマトグラフィー（ＨＰＬＣ）、超臨界流体クロマトグラフィー（ＳＦＣ）、または擬似移動床法（ＳＭＢ）などにより行うことができる。
　ここで、本明細書において、一般式（６）で表される化合物の光学分割とは、一般式（６）で表される化合物中のエナンチオマーの関係にある化合物をそれぞれ分離することをいう。また、光学分割カラムとは、光学活性化合物を担持させた充填剤が充填されているカラムをいう。使用できる光学分割カラムとしては、特に限定されないが、順相用多糖誘導体コーティング型キラルカラムや多糖誘導体耐溶剤型キラルカラムを挙げることができる。
　順相用多糖誘導体コーティング型キラルカラムとは、順相クロマトグラフィーにおいて移動相として使用可能な溶媒に対して使用できる光学分割カラムのうち、アミロース誘導体又はセルロース誘導体をキラルセレクターとし、当該アミロース誘導体又はセルロース誘導体がシリカゲルにコーティングされている充填剤を使用しているカラムを意味する。順相用多糖誘導体コーティング型キラルカラムとしては、ＣＨＩＲＡＬＰＡＫ　ＡＤ、ＣＨＩＲＡＬＰＡＫ　ＡＳ、ＣＨＩＲＡＬＣＥＬ　ＯＤ、ＣＨＩＲＡＬＣＥＬ　ＯＪ、ＣＨＩＲＡＬＣＥＬ　ＯＸ、ＣＨＩＲＡＬＰＡＫ　ＡＹ、ＣＨＩＲＡＬＰＡＫ　ＡＺ及びＣＨＩＲＡＬＣＥＬ　ＯＺ等を挙げることができる。
　また、多糖誘導体耐溶剤型キラルカラムとは、ヘキサン、アルコール、酢酸エチル、テトラヒドロフラン、ハロゲン系溶媒、ＤＭＳＯなど、シリカゲルを充填剤の基材とするＨＰＬＣ用カラムに使用可能な全ての溶媒を使用できる光学分割カラムであり、アミロース誘導体又はセルロース誘導体をキラルセレクターとし、当該アミロース誘導体又はセルロース誘導体がシリカゲルに固定されている充填剤を使用しているカラムを意味する。多糖誘導体耐溶剤型キラルカラムとしては、ＣＨＩＲＡＬＰＡＫ　ＩＡ、ＣＨＩＲＡＬＰＡＫ
　ＩＢ、ＣＨＩＲＡＬＰＡＫ　ＩＣ、ＣＨＩＲＡＬＰＡＫ　ＩＤ、ＣＨＩＲＡＬＰＡＫ　ＩＥ、及びＣＨＩＲＡＬＰＡＫ　ＩＦ等を挙げることができる。
　そのうち、分離能力という観点から、ＣＨＩＲＡＬＰＡＫ　ＡＤ、ＣＨＩＲＡＬＣＥＬＯＤ、ＣＨＩＲＡＬＣＥＬ　ＯＪ、ＣＨＩＲＡＬＰＡＫ　ＡＹ、ＣＨＩＲＡＬＰＡＫ　ＩＡ、ＣＨＩＲＡＬＰＡＫ　ＩＢ、またはＣＨＩＲＡＬＰＡＫ　ＩＣ、ＣＨＩＲＡＬＰＡＫ　ＩＤを使用するのが好ましい。
　さらに好ましい光学分割カラムとしては、ＣＨＩＲＡＬＰＡＫ　ＡＤ、ＣＨＩＲＡＬＣＥＬ　ＯＤ、ＣＨＩＲＡＬＣＥＬ　ＯＪ、またはＣＨＩＲＡＬＰＡＫ　ＡＹが挙げられ、特に好ましくは、ＣＨＩＲＡＬＰＡＫ　ＡＤ、ＣＨＩＲＡＬＣＥＬ　ＯＤ、またはＣＨＩＲＡＬＣＥＬ　ＯＪが挙げられる。
　一般式（６）で表される化合物において、構造式中のＲ５またはＲ６のいずれか一方または両方が、ｔｅｒｔ－ブチル基のような炭素数４以上のアルキル基である場合、ＣＨＩＲＡＬＰＡＫ　ＡＤまたはＣＨＩＲＡＬＣＥＬ　ＯＪを使用するのが好ましい。
　なお、使用する光学分割カラムは、分離方法、分離対象の化合物に応じて、カラムの内径、長さ、充填剤の粒子径を適宜設定できる。また、「ＣＨＩＲＡＬＰＡＫ」「ＣＨＩＲＡＬＣＥＬ」は登録商標である。
　一方、一般式（６）で表される化合物において、構造式中のＲ５またはＲ６のいずれもが、メチル基またはエチル基のような炭素数３以下のアルキル基である場合、ＣＨＩＲＡＬＣＥＬ　ＯＤを使用するのが好ましい。
　また、溶離液としては、例えばメタノール、エタノール、２－プロパノール等のアルコール、アセトニトリル、ｎ－ヘキサン、アセトン、メチル－ｔｅｒｔ－ブチルエーテル（ＭＴＢＴ）、クロロホルム、ジクロロメタン、テトラヒドロフラン、酢酸エチル、ジメチルスルホキシド（ＤＭＳＯ）、１，４－ジオキサン、水、超臨界流体またはそれらの混合物を挙げることができる。このうち、分離能力という観点から、２－プロパノール及びｎ－ヘキサンの混合液、エタノール及びｎ－ヘキサンの混合液、メタノール、または、エタノールが挙げられる。２－プロパノール及びｎ－ヘキサンの混合液を用いる場合、ｎ－ヘキサンを２－プロパノールに対して、７倍量以上１１倍量以下、より好ましくは８倍量以上１０倍量以下、特に好ましくは９倍量を用いる。
　エタノール及びｎ－ヘキサンの混合液を用いる場合、ｎ－ヘキサンをエタノールに対して、７倍量以上１１倍量以下、より好ましくは８倍量以上１０倍量以下、特に好ましくは９倍量を用いる。 Optical resolution using an optical resolution column can be performed by high performance liquid chromatography (HPLC), supercritical fluid chromatography (SFC), simulated moving bed method (SMB), or the like.
Here, in this specification, the optical resolution of the compound represented by the general formula (6) means that the compounds having the enantiomeric relationship in the compound represented by the general formula (6) are separated from each other. The optical resolution column refers to a column filled with a filler carrying an optically active compound. Examples of the optical resolution column that can be used include, but are not limited to, normal phase polysaccharide derivative-coated chiral columns and polysaccharide derivative solvent-resistant chiral columns.
The normal phase polysaccharide derivative-coated chiral column is an optical resolution column that can be used for a solvent that can be used as a mobile phase in normal phase chromatography, using an amylose derivative or cellulose derivative as a chiral selector, and the amylose derivative or cellulose derivative. Means a column using a packing material coated with silica gel. Examples of normal phase polysaccharide derivative-coated chiral columns include CHIRALPAK AD, CHIRALPAK AS, CHIRALCEL OD, CHIRALCEL OJ, CHIRALCEL OX, CHIRALPAK AY, CHIRALPAK AZ, and CHIRALCEL OZ.
In addition, the polysaccharide derivative solvent-resistant chiral column is an optical that can use all solvents that can be used in HPLC columns using silica gel as a base material, such as hexane, alcohol, ethyl acetate, tetrahydrofuran, halogenated solvents, DMSO, and the like. It is a split column, and means a column using a filler in which an amylose derivative or cellulose derivative is a chiral selector and the amylose derivative or cellulose derivative is fixed to silica gel. Polysaccharide derivative solvent-resistant chiral columns include CHIRALPAK IA and CHIRALPAK
Examples include IB, CHIRALPAK IC, CHIRALPAK ID, CHIRALPAK IE, and CHIRALPAK IF.
Among them, from the viewpoint of separation ability, it is preferable to use CHIRALPAK AD, CHIRALCELOD, CHIRALCEL OJ, CHIRALPAK AY, CHIRALPAK IA, CHIRALPAK IB, or CHIRALPAK IC, CHIRALPAK ID.
More preferable examples of the optical resolution column include CHIRALPAK AD, CHIRALCEL OD, CHIRALCEL OJ, and CHIRALPAK AY, and particularly preferable examples include CHIRALPAK AD, CHIRALCEL OD, and CHIRALCEL OJ.
In the compound represented by the general formula (6), when one or both of R 5 and R 6 in the structural formula is an alkyl group having 4 or more carbon atoms such as a tert-butyl group, CHIRALPAK AD or Preference is given to using CHIRALCEL OJ.
In the optical resolution column to be used, the inner diameter and length of the column and the particle diameter of the filler can be appropriately set according to the separation method and the compound to be separated. “CHIRALPAK” and “CHIRALCEL” are registered trademarks.
On the other hand, in the compound represented by the general formula (6), when either R 5 or R 6 in the structural formula is an alkyl group having 3 or less carbon atoms such as a methyl group or an ethyl group, CHIRALCEL OD is It is preferred to use.
Examples of the eluent include alcohols such as methanol, ethanol and 2-propanol, acetonitrile, n-hexane, acetone, methyl tert-butyl ether (MTBT), chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, dimethyl sulfoxide (DMSO). 1,4-dioxane, water, supercritical fluid or mixtures thereof. Among these, from the viewpoint of separation ability, a mixed solution of 2-propanol and n-hexane, a mixed solution of ethanol and n-hexane, methanol, or ethanol can be mentioned. When a mixed solution of 2-propanol and n-hexane is used, n-hexane is 7 to 11 times, more preferably 8 to 10 times, particularly preferably 9 to 2-propanol. Use double amount.
When a mixed solution of ethanol and n-hexane is used, n-hexane is used in an amount of 7 to 11 times, more preferably 8 to 10 times, particularly preferably 9 times the amount of ethanol. .
　さらに、光学分割カラムとして、ＣＨＩＲＡＬＣＥＬ　ＯＪを用いた場合は、メタノールやエタノール等のアルコールを溶離液として使用するのが好ましい。 Furthermore, when CHIRALCEL OJ is used as the optical resolution column, it is preferable to use an alcohol such as methanol or ethanol as an eluent.
　光学分割カラムとして、ＣＨＩＲＡＬＣＥＬ　ＯＤを用いた場合は、２－プロパノールとｎ－ヘキサンの混合液、または、エタノールとｎ－ヘキサンの混合液を溶離液として使用するのが好ましく、より好ましくは２－プロパノールとｎ－ヘキサンの混合液、さらに好ましくは、２－プロパノール／ｎ－ヘキサン＝９／１の混合液が挙げられる。 When CHIRALCEL OD is used as the optical resolution column, it is preferable to use a mixed solution of 2-propanol and n-hexane or a mixed solution of ethanol and n-hexane as an eluent, more preferably 2-propanol. And a mixed solution of n-hexane, more preferably a mixed solution of 2-propanol / n-hexane = 9/1.
　光学分割カラムとして、ＣＨＩＲＡＬＰＡＫ　ＡＤを用いた場合は、２－プロパノールとｎ－ヘキサンの混合液、または、メタノールを溶離液として使用するのが好ましく、より好ましくは、２－プロパノール／ｎ－ヘキサン＝９／１の混合液、またはメタノールが挙げられる。 When CHIRALPAK AD is used as the optical resolution column, it is preferable to use a mixed solution of 2-propanol and n-hexane or methanol as an eluent, more preferably 2-propanol / n-hexane = 9. / 1 liquid mixture or methanol.
（工程６）
　一般式（９）で表される化合物と一般式（１１）で表される化合物とを含む混合物は、一般式（７）で表される化合物を還元することにより得ることができる。一般式（１０）で表される化合物と一般式（１２）で表される化合物とを含む混合物は、一般式（８）で表される化合物を還元することにより得ることができる。 (Step 6)
The mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) can be obtained by reducing the compound represented by the general formula (7). The mixture containing the compound represented by the general formula (10) and the compound represented by the general formula (12) can be obtained by reducing the compound represented by the general formula (8).
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　式（９）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、上記定義と同じである。 In formula (9), R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above.
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　式（１０）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、上記定義と同じである。 In formula (10), R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above.
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　式（１１）中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、上記定義と同じである。 In formula (11), R 1 , R 2 , R 3 and R 4 are the same as defined above.
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　式（１２）中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、上記定義と同じである。 In formula (12), R 1 , R 2 , R 3 and R 4 are the same as defined above.
　当該還元処理は、例えば、一般式（７）で表される化合物または一般式（８）で表される化合物をテトラヒドロフランなどの反応溶媒に溶解し、得られた溶液を還元剤に加え、さらにエタノールやメタノールなどのアルコールを加えて反応させることで行うことができる。
　還元剤は、水素化リチウムアルニミウム、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウム、水素化トリメトキシリチウムアルミニウム、水素化アルミニウム、水素化ジイソブチルアルミニウム等のアルミニウムハイドライド系、水素化トリエチルホウ素リチウム、水素化ホウ素ナトリウム、水素化ホウ素カリウム、水素化ホウ素リチウム、水素化トリ（ｓｅｃ－ブチル）ホウ素リチウム、水素化トリ（ｓｅｃ－ブチル）ホウ素カリウム等のホウ素ハイドライド系のうち１種または２種以上を用いることができる。より好ましくはホウ素ハイドライド系還元剤であり、さらに好ましくは、水素化ホウ素ナトリウムが挙げられる。還元剤は、一般式（７）で表される化合物または一般式（８）で表される化合物に対して、例えば１当量以上１０当量以下であることが好ましい。より好ましくは１当量以上５当量以下、さらにより好ましくは２当量以上３．５当量以下が挙げられる。 In the reduction treatment, for example, the compound represented by the general formula (7) or the compound represented by the general formula (8) is dissolved in a reaction solvent such as tetrahydrofuran, the obtained solution is added to a reducing agent, and ethanol is further added. It can be carried out by adding alcohol such as methanol and reacting.
The reducing agent is aluminum hydride such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, trimethoxylithium aluminum hydride, aluminum hydride, diisobutylaluminum hydride, lithium triethylborohydride, hydrogen Use one or more of boron hydrides such as sodium borohydride, potassium borohydride, lithium borohydride, lithium tri (sec-butyl) borohydride, potassium trihydride (sec-butyl) borohydride be able to. More preferred is a boron hydride reducing agent, and further preferred is sodium borohydride. It is preferable that a reducing agent is 1 equivalent or more and 10 equivalents or less with respect to the compound represented by General formula (7) or the compound represented by General formula (8), for example. More preferably, it is 1 equivalent or more and 5 equivalents or less, and still more preferably 2 equivalents or more and 3.5 equivalents or less.
　還元剤は、塩化リチウム、臭化リチウム、ヨウ化リチウムなどのリチウム塩と、水素化ホウ素ナトリウム、水素化ホウ素カリウムなどのホウ素ハイドライド系還元剤とを組み合わせて調製して用いるようにしてもよい。好ましくは、塩化リチウム存在下ホウ素ハイドライド系還元剤を用いる方法が挙げられる。より好ましくは、塩化リチウム存在下、水素化ホウ素カリウムを用いる。 The reducing agent may be prepared and used in combination with a lithium salt such as lithium chloride, lithium bromide or lithium iodide and a boron hydride reducing agent such as sodium borohydride or potassium borohydride. Preferably, a method using a boron hydride reducing agent in the presence of lithium chloride is used. More preferably, potassium borohydride is used in the presence of lithium chloride.
　リチウム塩とホウ素ハイドライド系還元剤とを組み合わせて還元剤を調製する場合、リチウム塩とホウ素ハイドライド系還元剤の好ましい使用量は、一般式（７）で表される化合物または一般式（８）で表される化合物に対して、いずれも１当量以上１０当量以下である。より好ましくはいずれも１当量以上５当量以下、さらにより好ましくはいずれも２当量以上３．５当量以下が挙げられる。 When a reducing agent is prepared by combining a lithium salt and a boron hydride-based reducing agent, the preferred use amount of the lithium salt and the boron hydride-based reducing agent is the compound represented by the general formula (7) or the general formula (8). All are 1 equivalent or more and 10 equivalent or less with respect to the compound represented. More preferably, all are 1 equivalent or more and 5 equivalents or less, More preferably, all are 2 equivalents or more and 3.5 equivalents or less.
　反応温度は、通常－７０℃から使用する溶媒の沸点の範囲が挙げられるが、収率向上という観点から、好ましくは０℃以上５５℃以下、より好ましくは２５℃以上５５℃以下が挙げられる。 The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used, but from the viewpoint of improving yield, it is preferably 0 ° C. or higher and 55 ° C. or lower, more preferably 25 ° C. or higher and 55 ° C. or lower.
　反応溶媒としては、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、若しくはジグライム等のエーテル類、ベンゼン、トルエン、若しくはキシレン等の芳香族化合物類、または、ヘキサン、ヘプタン、若しくはシクロヘキサン等の炭化水素類、あるいはこれらの混合物が挙げられる。好ましくは、エーテル類が挙げられ、更に好ましくは、テトラヒドロフランが挙げられる。 As a reaction solvent, ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, or hydrocarbons such as hexane, heptane, or cyclohexane, Alternatively, a mixture thereof can be mentioned. Preferably, ethers are used, and more preferably, tetrahydrofuran is used.
　アルコールの好ましい使用量は、一般式（７）で表される化合物または一般式（８）で表される化合物に対して、例えば０．５倍量以上１０倍量以下が挙げられる。収率向上という観点から、より好ましくは０．７倍量以上２倍量以下、さらにより好ましくは０．８倍量以上１．２倍量以下が挙げられる。 The preferable amount of alcohol used is, for example, 0.5 to 10 times the amount of the compound represented by the general formula (7) or the compound represented by the general formula (8). From the viewpoint of improving the yield, more preferably 0.7 times or more and 2 times or less, still more preferably 0.8 times or more and 1.2 times or less.
（工程７）
　一般式（１３）で表される化合物の薬学的に許容しうる塩は、一般式（９）で表される化合物及び一般式（１１）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより得ることができる。一般式（１４）で表される化合物の薬学的に許容しうる塩は、一般式（１０）で表される化合物及び一般式（１２）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより得ることができる。 (Step 7)
The pharmaceutically acceptable salt of the compound represented by the general formula (13) is obtained by subjecting a mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) to hydrolysis treatment. The product of the hydrolysis treatment can be obtained by reacting with an inorganic acid or an organic acid. The pharmaceutically acceptable salt of the compound represented by the general formula (14) is obtained by subjecting a mixture containing the compound represented by the general formula (10) and the compound represented by the general formula (12) to hydrolysis treatment. The product of the hydrolysis treatment can be obtained by reacting with an inorganic acid or an organic acid.
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　式（１３）中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、上記定義と同じである。 In formula (13), R 1 , R 2 , R 3 and R 4 are the same as defined above.
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　式（１４）中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、上記定義と同じである。 In formula (14), R 1 , R 2 , R 3 and R 4 are the same as defined above.
　加水分解処理は、エステルの加水分解反応に通常用いられる方法により行うことができる。例えば、塩基を用いて反応を行う場合、反応溶媒中、水酸化ナトリウム、水酸化カリウム、水酸化リチウムまたは水酸化バリウムなどの強塩基を用いて常温から加熱還流の温度で基質を処理することにより行うことができる。また、反応温度は、収率向上という観点から、好ましくは７０℃から加熱還流の温度、より好ましくは７５℃から加熱還流の温度が挙げられる。
　なお、本明細書において、常温とは、日本薬局方にて定義されている１５～２５℃を意味する。
　反応溶媒は、例えばテトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、ジグライムまたはトリエチレングリコールジメチルエーテル等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、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、エチレングリコール、またはジエチレングリコール等のアルコール類、ホルムアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、アセトン等のケトン類、水あるいはこれらの混合物が挙げられ、収率向上の観点から好ましくは、アルコール類及び水を含む混合溶媒が好ましい。より好ましくはエタノール及び水を含む混合溶媒が挙げられる。
　加水分解における塩基の量は、一般式（７）で表される化合物または一般式（８）で表される化合物に対し１当量以上３０当量以下用いることが好ましい。収率向上の観点から５当量以上２０当量以下、より好ましくは８当量以上１５当量以下とすることができる。
　また、加水分解処理の生成物に無機酸又は有機酸を反応させる処理において、使用できる無機酸の好適な例としては、塩酸、臭化水素酸、硝酸、硫酸、リン酸などが挙げられる。有機酸の好適な例としては、ギ酸、酢酸、トリフルオロ酢酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸などが挙げられる。このうち、収率向上という点で酒石酸を用いることが好ましい。さらに、光学純度の向上という点で、一般式（１３）で表される化合物に対してはＤ－（－）－酒石酸、また、一般式（１４）で表される化合物に対しては、Ｌ－（＋）－酒石酸を用いることが好ましい。
　また、加水分解処理の生成物に無機酸又は有機酸を反応させる処理においては、反応溶媒として、例えばアセトニトリル、エタノール、２－プロパノール、１，２－ジメトキシエタン、水またはそれらの混合物を挙げることができる。反応温度は、例えば－７０℃から使用する溶媒の沸点の範囲が挙げられるが、収率向上という観点から、好ましくは０℃以上７０℃以下、より好ましくは１０℃以上６５℃以下、さらにより好ましくは２５℃以上６０℃以下とすることできる。
　酒石酸塩を用いる当該工程により、得られる化合物の光学純度及び収率を高めることができる。なお、化学純度の観点から、加水分解処理の生成物に酒石酸を反応させる処理においては、反応溶媒として、１，２－ジメトキシエタンを含む溶媒を用いることが好ましく、より好ましくは１，２－ジメトキシエタンと水とを含む混合溶媒である。 The hydrolysis treatment can be performed by a method usually used for ester hydrolysis. For example, when a reaction is carried out using a base, the substrate is treated at a temperature from room temperature to reflux with a strong base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or barium hydroxide in a reaction solvent. It can be carried out. The reaction temperature is preferably from 70 ° C. to the temperature of heating to reflux, more preferably from 75 ° C. to the temperature of heating to reflux, from the viewpoint of improving the yield.
In the present specification, the normal temperature means 15 to 25 ° C. as defined by the Japanese Pharmacopoeia.
Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, diglyme or triethylene glycol dimethyl ether, aromatic compounds such as benzene, toluene, or xylene, and nitriles such as acetonitrile or propionitrile. Halogenated hydrocarbons such as dichloromethane, alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol or diethylene glycol, amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide , Sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ketones such as acetone, water, or a mixture thereof. From the above viewpoint, a mixed solvent containing alcohols and water is preferable. More preferred is a mixed solvent containing ethanol and water.
The amount of the base in the hydrolysis is preferably 1 equivalent or more and 30 equivalents or less based on the compound represented by the general formula (7) or the compound represented by the general formula (8). From the viewpoint of yield improvement, it can be 5 equivalents or more and 20 equivalents or less, more preferably 8 equivalents or more and 15 equivalents or less.
In addition, preferred examples of the inorganic acid that can be used in the treatment of reacting the product of the hydrolysis treatment with an inorganic acid or an organic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of the organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Etc. Of these, tartaric acid is preferably used in terms of yield improvement. Furthermore, in terms of improvement in optical purity, D-(−)-tartaric acid is used for the compound represented by the general formula (13), and L is used for the compound represented by the general formula (14). It is preferable to use-(+)-tartaric acid.
In the treatment of reacting the hydrolysis treatment product with an inorganic acid or an organic acid, examples of the reaction solvent include acetonitrile, ethanol, 2-propanol, 1,2-dimethoxyethane, water, and mixtures thereof. it can. Examples of the reaction temperature range from −70 ° C. to the boiling point of the solvent used. From the viewpoint of improving the yield, the reaction temperature is preferably 0 ° C. or higher and 70 ° C. or lower, more preferably 10 ° C. or higher and 65 ° C. or lower, even more preferably. Can be 25 ° C. or more and 60 ° C. or less.
By the process using tartrate, the optical purity and yield of the resulting compound can be increased. From the viewpoint of chemical purity, in the treatment of reacting tartaric acid with the product of the hydrolysis treatment, it is preferable to use a solvent containing 1,2-dimethoxyethane as the reaction solvent, more preferably 1,2-dimethoxy. A mixed solvent containing ethane and water.
（工程８）
　一般式（１５）で表される化合物は、一般式（１３）で表される化合物の薬学的に許容しうる塩について遊離塩基化及びアミノ基の保護を行うことにより得ることができる。一般式（１６）で表される化合物は、一般式（１４）で表される化合物の薬学的に許容しうる塩について遊離塩基化及びアミノ基の保護を行うことにより得ることができる。 (Process 8)
The compound represented by the general formula (15) can be obtained by subjecting a pharmaceutically acceptable salt of the compound represented by the general formula (13) to free base formation and amino group protection. The compound represented by the general formula (16) can be obtained by subjecting a pharmaceutically acceptable salt of the compound represented by the general formula (14) to free base formation and amino group protection.
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　式（１５）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、上記定義と同じである。 In formula (15), R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above.
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
  式（１６）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、上記定義と同じである。 In formula (16), R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above.
　Ｒ７として表されるアミノ基の保護基としては、アミノ基を保護するものであれば特に限定されないが、例えばアセチル基などのアシル基またはｔｅｒｔ－ブトキシカルボニルなどのアルコキシカルボニル基若しくはベンジルオキシカルボニル基などのアラルコキシカルボニル基を用いることができる。Ｒ７としてアルコキシカルボニル基が好ましく、更に好ましくは、ｔｅｒｔ－ブトキシカルボニル基である。 The protecting group for the amino group represented by R 7 is not particularly limited as long as it protects the amino group. For example, an acyl group such as an acetyl group or an alkoxycarbonyl group such as tert-butoxycarbonyl or a benzyloxycarbonyl group An aralkoxycarbonyl group such as can be used. R 7 is preferably an alkoxycarbonyl group, more preferably a tert-butoxycarbonyl group.
　当該反応は、例えば、反応溶媒中で、一般式（１３）で表される化合物の薬学的に許容しうる塩または一般式（１４）で表される化合物の薬学的に許容しうる塩を塩基で中和して遊離塩基とするとともに、生じた遊離塩基に酸塩化物または酸無水物を作用させることで行うことができる。一般式（１３）で表される化合物の薬学的に許容しうる塩または一般式（１４）の薬学的に許容しうる塩で表される化合物の中和に用いることができる塩基は、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、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基類、トリエチルアミンや、ジイソプロピルエチルアミン、４－メチルモルホリン、４－エチルモルホリン、ピリジン、１－メチルイミダゾール、１，２－ジメチルイミダゾール、１，５－ジアザビシクロ［４．３．０］－５－ノネン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセン等の有機塩基類などを挙げることができる。反応温度は、例えば０℃～使用する溶媒の沸点の範囲が挙げられるが、収率向上という観点から、好ましくは３０℃以上６０℃以下、より好ましくは３５℃以上５０℃以下とすることができる。反応溶媒は、例えばテトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、ジグライムまたはトリエチレングリコールジメチルエーテル等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、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、エチレングリコール、またはジエチレングリコール等のアルコール類、ホルムアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、ギ酸エチル、ギ酸ｎ－ブチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ｎ－ブチル、酢酸イソブチル、酢酸ｓｅｃ－ヘキシル、酢酸２－エチルヘキシル、プロピオン酸エチル、プロピオン酸ｎ－ブチル、またはイソ吉草酸エチル等の脂肪族エステル類、アセトン等のケトン類、水、あるいはこれらの混合物が挙げられ、水及び酢酸エチルの混合溶媒が好ましい。また、酸塩化物は、塩化アセチル若しくは塩化ベンジルオキシカルボニルなどを用いることができる。また、酸無水物は、無水酢酸若しくは二炭酸ジ－ｔｅｒｔ－ブチルなどを用いることができる。このうち二炭酸ジ－ｔｅｒｔ－ブチルを用いて反応を行うことが好ましい。
　二炭酸ジ－ｔｅｒｔ－ブチルを用いる場合、反応の進みやすさの観点から、一般式（１３）で表される化合物の薬学的に許容しうる塩または一般式（１４）で表される化合物の薬学的に許容しうる塩に対して１．２当量以上を用いることが好ましく、１．３当量以上を用いることがより好ましい。また、副生成物の抑制も考慮すると、二炭酸ジ－ｔｅｒｔ－ブチルは、一般式（１３）で表される化合物の薬学的に許容しうる塩または一般式（１４）で表される化合物の薬学的に許容しうる塩に対して１．３当量以上２．０当量以下、より好ましくは１．３当量以上１．５当量以下を用いることが好ましい。
　また、副生成物の抑制の観点から、反応終了後、反応溶液中に１－メチルピペラジンのようなアミンを加えることが好ましい。
　また、光学純度及び化学純度の観点から、得られた一般式（１５）で表される化合物及び／または一般式（１６）で表される化合物について、再結晶を行うことが好ましい。再結晶に用いる溶媒は、例えば水、エタノール、２－プロパノール、アセトン、アセトニトリル、酢酸エチル、ジイソプロピルエーテル、ｎ－ヘキサン、ｎ－ヘプタン、テトラヒドロフラン、トルエン、１、２－ジメトキシエタン、Ｎ，Ｎ－ジメチルホルムアミドなどのうち１種または２種以上とすることができる。再結晶に用いる溶媒として、光学純度、化学純度、ろ過性、流動性、及び回収率の観点から、トルエン、ｎ－ヘプタンを含む混合溶媒が好ましく、トルエン、ｎ－ヘプタン、及びＮ，Ｎ－ジメチルホルムアミドを含む混合溶媒がより好ましい。当該精製により、精製困難な副生成物を除去し、純度を向上することができる。 For example, the reaction may be carried out by using a pharmaceutically acceptable salt of the compound represented by the general formula (13) or a pharmaceutically acceptable salt of the compound represented by the general formula (14) as a base in a reaction solvent. It can be carried out by neutralizing with a free base and reacting the resulting free base with an acid chloride or acid anhydride. The base that can be used for neutralizing the pharmaceutically acceptable salt of the compound represented by the general formula (13) or the pharmaceutically acceptable salt of the general formula (14) is, for example, Inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, Organic compounds such as pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo [4.3.0] -5-nonene, 1,8-diazabicyclo [5.4.0] -7-undecene Examples include bases. Examples of the reaction temperature range from 0 ° C. to the boiling point of the solvent to be used. From the viewpoint of improving the yield, the reaction temperature is preferably 30 ° C. or higher and 60 ° C. or lower, more preferably 35 ° C. or higher and 50 ° C. or lower. . Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, diglyme or triethylene glycol dimethyl ether, aromatic compounds such as benzene, toluene, or xylene, and nitriles such as acetonitrile or propionitrile. Halogenated hydrocarbons such as dichloromethane, alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, ethylene glycol or diethylene glycol, amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide , Sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate, ethyl acetate Aliphatic esters such as sopropyl, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate or ethyl isovalerate, ketones such as acetone, water, Alternatively, a mixture thereof may be mentioned, and a mixed solvent of water and ethyl acetate is preferable. As the acid chloride, acetyl chloride or benzyloxycarbonyl chloride can be used. As the acid anhydride, acetic anhydride, di-tert-butyl dicarbonate or the like can be used. Of these, the reaction is preferably carried out using di-tert-butyl dicarbonate.
When di-tert-butyl dicarbonate is used, the pharmaceutically acceptable salt of the compound represented by the general formula (13) or the compound represented by the general formula (14) is used from the viewpoint of easy progress of the reaction. It is preferable to use 1.2 equivalents or more, more preferably 1.3 equivalents or more, based on the pharmaceutically acceptable salt. In consideration of suppression of by-products, di-tert-butyl dicarbonate is a pharmaceutically acceptable salt of the compound represented by the general formula (13) or the compound represented by the general formula (14). It is preferable to use 1.3 equivalents or more and 2.0 equivalents or less, more preferably 1.3 equivalents or more and 1.5 equivalents or less, based on the pharmaceutically acceptable salt.
From the viewpoint of suppressing by-products, it is preferable to add an amine such as 1-methylpiperazine to the reaction solution after completion of the reaction.
From the viewpoint of optical purity and chemical purity, it is preferable to recrystallize the compound represented by the general formula (15) and / or the compound represented by the general formula (16). Solvents used for recrystallization are, for example, water, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate, diisopropyl ether, n-hexane, n-heptane, tetrahydrofuran, toluene, 1,2-dimethoxyethane, N, N-dimethyl. One or more of formamide can be used. As a solvent used for recrystallization, a mixed solvent containing toluene and n-heptane is preferable from the viewpoint of optical purity, chemical purity, filterability, fluidity, and recovery rate, and toluene, n-heptane, and N, N-dimethyl are preferable. A mixed solvent containing formamide is more preferable. By the purification, by-products that are difficult to purify can be removed and the purity can be improved.
（工程９）
　一般式（１７）で表される化合物は、一般式（１５）で表される化合物をリン酸エステル化試薬と反応させることにより得ることができる。一般式（１８）で表される化合物は、一般式（１６）で表される化合物をリン酸エステル化試薬と反応させることにより得ることができる。 (Step 9)
The compound represented by the general formula (17) can be obtained by reacting the compound represented by the general formula (15) with a phosphate esterification reagent. The compound represented by the general formula (18) can be obtained by reacting the compound represented by the general formula (16) with a phosphate esterification reagent.
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　式（１７）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、上記定義と同じである。 In formula (17), R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above.
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　式（１８）中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、上記定義と同じである。 In formula (18), R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above.
　リン酸エステル化試薬としては、例えば一般式（ｉｉ）で表さる化合物を挙げることができる。 Examples of the phosphate esterification reagent include compounds represented by general formula (ii).
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　式（ｉｉ）中、Ｒ１２はハロゲン原子であり、Ｒ８は、上記定義と同じである。入手が容易という観点から、Ｒ１２が塩素原子であり、Ｒ８が、メチル基、エチル基またはイソプロピル基である化合物が好ましい。リン酸エステル化試薬の使用量は、収率向上という観点から、一般式（１５）で表される化合物または一般式（１６）で表される化合物に対し、１当量以上用いることが好ましい。より好ましくは、１．１当量以上、さらに好ましくは１．３当量以上３当量以下、特に好ましくは１．３当量以上２当量以下が挙げられる。 In formula (ii), R 12 is a halogen atom, and R 8 is the same as defined above. From the viewpoint of easy availability, a compound in which R 12 is a chlorine atom and R 8 is a methyl group, an ethyl group or an isopropyl group is preferable. From the viewpoint of improving the yield, it is preferable to use 1 equivalent or more of the phosphate esterifying reagent with respect to the compound represented by the general formula (15) or the compound represented by the general formula (16). More preferably, 1.1 equivalent or more, still more preferably 1.3 equivalent or more and 3 equivalent or less, and particularly preferably 1.3 equivalent or more and 2 equivalent or less.
　反応は、例えば、反応溶媒中、リン酸エステル化試薬とトリエチルアミンや、ジイソプロピルエチルアミン、４－メチルモルホリン、４－エチルモルホリン、ピリジン、１－メチルイミダゾール、１，２－ジメチルイミダゾール、１，５－ジアザビシクロ［４．３．０］－５－ノネン、１，８－ジアザビシクロ［５．４．０］－７－ウンデセンなどの塩基類を用いて一般式（１５）で表される化合物または一般式（１６）で表される化合物をリン酸エステル化することにより行うことができる。塩基は、一般式（１５）で表される化合物または一般式（１６）で表される化合物に対し、１当量以上１０当量以下を用いることが好ましい。より好ましい当量として、３当量以上１０当量以下、さらに好ましくは、５．５当量以上７当量以下が挙げられる。 The reaction can be performed, for example, in a reaction solvent using a phosphoric esterification reagent and triethylamine, diisopropylethylamine, 4-methylmorpholine, 4-ethylmorpholine, pyridine, 1-methylimidazole, 1,2-dimethylimidazole, 1,5-diazabicyclo The compound represented by the general formula (15) or the general formula (16) using bases such as [4.3.0] -5-nonene and 1,8-diazabicyclo [5.4.0] -7-undecene. ) Can be carried out by phosphoric esterification. The base is preferably used in an amount of 1 to 10 equivalents relative to the compound represented by the general formula (15) or the compound represented by the general formula (16). More preferable equivalents include 3 equivalents or more and 10 equivalents or less, and more preferably 5.5 equivalents or more and 7 equivalents or less.
　反応溶媒は、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、またはジグライム等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、またはホルムアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、ギ酸エチル、ギ酸ｎ－ブチル、酢酸エチル、酢酸ｎ－プロピル、酢酸イソプロピル、酢酸ｎ－ブチル、酢酸イソブチル、酢酸ｓｅｃ－ヘキシル、酢酸２－エチルヘキシル、プロピオン酸エチル、プロピオン酸ｎ－ブチル、またはイソ吉草酸エチル等の脂肪族エステル類、アセトン等のケトン類、あるいはこれらの混合物が挙げられる。反応溶媒として、好ましくはニトリル類、脂肪族エステル類又はケトン類が挙げられ、反応中に析出物が生じるのを抑制するという点で、さらに好ましくはニトリル類と脂肪族エステル類の混合物、さらに好ましくは酢酸エチルとアセトニトリルの混合物が挙げられる。 Reaction solvents include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, and halogens such as dichloromethane. Hydrocarbons, amides such as formamide, N-methylpyrrolidone, or N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, acetic acid Aliphatic esters such as n-propyl, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate Ethers, ketones such as acetone, or mixtures thereof. The reaction solvent is preferably nitriles, aliphatic esters or ketones, and more preferably a mixture of nitriles and aliphatic esters, more preferably in terms of suppressing the formation of precipitates during the reaction. Is a mixture of ethyl acetate and acetonitrile.
　また、反応温度は、通常－７０℃から使用する溶媒の沸点の範囲が挙げられるが、原料の消失が認められるという点で－５℃以上、副反応を抑えるという点で１５℃以下が好ましい。より好ましくは０℃以上１５℃以下、さらにより好ましくは５℃以上１５℃以下が挙げられる。 The reaction temperature is usually in the range of -70 ° C. to the boiling point of the solvent used, but is preferably −5 ° C. or more in view of disappearance of raw materials and 15 ° C. or less in terms of suppressing side reactions. More preferably, it is 0 degreeC or more and 15 degrees C or less, More preferably, 5 degreeC or more and 15 degrees C or less are mentioned.
（工程１０）
　一般式（１９）で表される化合物は、一般式（１７）で表される化合物を変換することにより得ることができる。一般式（２０）で表される化合物は、一般式（１８）で表される化合物を変換することにより得ることができる。 (Process 10)
The compound represented by the general formula (19) can be obtained by converting the compound represented by the general formula (17). The compound represented by the general formula (20) can be obtained by converting the compound represented by the general formula (18).
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　式（１９）中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、上記定義と同じである。 In formula (19), R 1 , R 2 , R 3 and R 4 are the same as defined above.
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　式（２０）中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、上記定義と同じである。 In formula (20), R 1 , R 2 , R 3 and R 4 are the same as defined above.
　当該反応は、例えば、アセトニトリルなどの反応溶媒中、脱保護試薬を一般式（１７）で表される化合物または一般式（１８）で表される化合物に対し作用させることにより行うことができる。脱保護試薬として、例えばトリメチルシリルブロミド、トリメチルシリルヨージド、トリエチルシリルブロミド、トリエチルシリルヨージド等のトリアルキルシリルハライド、トリメチルシリルトリフレート、トリエチルシリルトリフレート等のトリアルキルシリルトリフレート等を挙げることができ、このうち、トリメチルシリルヨージドが好ましい。トリメチルシリルヨージドは、トリメチルシリルクロリドとヨウ化ナトリウム等を用いて系中で発生させてもよい。脱保護試薬は、一般式（１７）で表される化合物または一般式（１８）で表される化合物に対し、１当量以上２０当量以下を用いることが好ましい。より好ましくは、３当量以上１０当量以下、さらに好ましくは、５当量以上８当量以下が挙げられる。工程９の粗生成物をさらなる精製をせずにそのまま工程１０に用いている場合は、一般式（１５）で表される化合物または一般式（１６）で表される化合物が１００％の収率で、一般式（１７）で表される化合物または一般式（１８）で表される化合物に変換されたとみなし、一般式（１５）で表される化合物または一般式（１６）で表される化合物の使用量を、一般式（１７）で表される化合物または一般式（１８）で表される化合物の使用量とみなす。反応温度は、通常－７０℃から使用する溶媒の沸点の範囲が挙げられるが、好ましくは－１０℃から使用する溶媒の沸点の範囲、より好ましくは－５℃以上３５℃以下の範囲が挙げられる。
　また、反応促進の観点から、一般式（１７）で表される化合物または一般式（１８）で表される化合物と、トリメチルシリルハライドとヨウ化ナトリウムとが溶解している反応溶液中に水を加えることが好ましい。添加する水の使用量は、一般式（１７）で表される化合物または一般式（１８）で表される化合物に対し、０．５当量以上２当量以下が好ましい。より好ましくは、０．９当量以上１．１当量以下、特に好ましくは１当量が挙げられる。
　また、亜硫酸ナトリウムを用いて反応を停止させた後、水を反応溶液中に加えると、一般式（１９）で表される化合物または一般式（２０）で表される化合物が結晶化する。そのため、反応停止後には、水を反応溶液中に加えることが、精製の観点から好ましい。 The reaction can be performed, for example, by allowing a deprotection reagent to act on the compound represented by the general formula (17) or the compound represented by the general formula (18) in a reaction solvent such as acetonitrile. Examples of the deprotection reagent include trialkylsilyl halides such as trimethylsilyl bromide, trimethylsilyl iodide, triethylsilyl bromide, triethylsilyl iodide, trialkylsilyl triflate such as trimethylsilyl triflate, triethylsilyl triflate, etc. Of these, trimethylsilyl iodide is preferred. Trimethylsilyl iodide may be generated in the system using trimethylsilyl chloride and sodium iodide. The deprotection reagent is preferably used in an amount of 1 equivalent to 20 equivalents relative to the compound represented by the general formula (17) or the compound represented by the general formula (18). More preferably, they are 3 equivalents or more and 10 equivalents or less, More preferably, 5 equivalents or more and 8 equivalents or less are mentioned. When the crude product of Step 9 is directly used in Step 10 without further purification, the compound represented by General Formula (15) or the compound represented by General Formula (16) is 100% yield. Therefore, the compound represented by the general formula (17) or the compound represented by the general formula (18) is regarded as being converted, and the compound represented by the general formula (15) or the compound represented by the general formula (16). Is used as the amount of the compound represented by the general formula (17) or the compound represented by the general formula (18). The reaction temperature usually ranges from −70 ° C. to the boiling point of the solvent used, preferably from −10 ° C. to the boiling point of the solvent used, more preferably from −5 ° C. to 35 ° C. .
From the viewpoint of promoting the reaction, water is added to the reaction solution in which the compound represented by the general formula (17) or the compound represented by the general formula (18), trimethylsilyl halide and sodium iodide are dissolved. It is preferable. The amount of water to be added is preferably 0.5 equivalents or more and 2 equivalents or less with respect to the compound represented by the general formula (17) or the compound represented by the general formula (18). More preferably, it is 0.9 equivalent or more and 1.1 equivalent or less, Especially preferably, 1 equivalent is mentioned.
Moreover, after stopping reaction using sodium sulfite, when water is added in the reaction solution, the compound represented by general formula (19) or the compound represented by general formula (20) will crystallize. Therefore, it is preferable from the viewpoint of purification to add water to the reaction solution after stopping the reaction.
　反応溶媒として、例えば、テトラヒドロフラン、シクロペンチルメチルエーテル、ジオキサン、ジメトキシエタン、またはジグライム等のエーテル類、ベンゼン、トルエン、またはキシレン等の芳香族化合物類、アセトニトリル、またはプロピオニトリル等のニトリル類、ジクロロメタン等のハロゲン化炭化水素類、ホルムアミド、Ｎ－メチルピロリドン、またはＮ，Ｎ－ジメチルホルムアミドなどのアミド類、ジメチルスルホキシド等のスルホキシド類、スルホランなどのスルホン類、アセトン等のケトン類あるいはこれらの混合物が挙げられ、好ましくはニトリル類、さらに好ましくはアセトニトリルが挙げられる。 Examples of the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, or diglyme, aromatic compounds such as benzene, toluene, or xylene, nitriles such as acetonitrile or propionitrile, dichloromethane, and the like. Halogenated hydrocarbons, formamide, N-methylpyrrolidone, amides such as N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ketones such as acetone, or mixtures thereof Preferably, nitriles are used, and acetonitrile is more preferable.
　なお、本実施形態において、得られる化合物の光学純度なども考慮すると、Ｒ２は水素原子、ベンジル基、ｐ－メトキシベンジル基、または２－メトキシエトキシメチル基であることが好ましく、より好ましくはベンジル基である。同様な理由から、Ｒ５はメチル基、エチル基、ｔｅｒｔ－ブチル基であることが好ましい。また、同様な理由から、Ｒ６はメチル基、エチル基、ｔｅｒｔ－ブチル基であることが好ましい。Ｒ５に関しては、工程３における副生成物（Ｒ５までも加水分解されたジカルボン酸体）の抑制の観点から、メチル基またはエチル基であることがさらに好ましい。
　さらに、光学純度の観点から、一般式（７）で表される化合物は一般式（７ａ）で表される化合物であることがより好ましく、一般式（８）で表される化合物は一般式（８ａ）で表される化合物であることがより好ましい。 In this embodiment, considering the optical purity of the resulting compound, R 2 is preferably a hydrogen atom, a benzyl group, a p-methoxybenzyl group, or a 2-methoxyethoxymethyl group, more preferably benzyl. It is a group. For the same reason, R 5 is preferably a methyl group, an ethyl group, or a tert-butyl group. For the same reason, R 6 is preferably a methyl group, an ethyl group, or a tert-butyl group. R 5 is more preferably a methyl group or an ethyl group from the viewpoint of suppressing the by-product in Step 3 (dicarboxylic acid product hydrolyzed even up to R 5 ).
Furthermore, from the viewpoint of optical purity, the compound represented by the general formula (7) is more preferably a compound represented by the general formula (7a), and the compound represented by the general formula (8) is represented by the general formula (7). The compound represented by 8a) is more preferable.
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　式（７ａ）中、Ｒ９は水素原子、ベンジル基、ｐ－メトキシベンジル基または２－メトキシエトキシメチル基を示し、Ｒ１０はメチル基、エチル基またはｔｅｒｔ－ブチル基を示し、Ｒ１１はメチル基、エチル基またはｔｅｒｔ－ブチル基を示し、Ｚは、フッ素原子または塩素原子を示す。
Figure JPOXMLDOC01-appb-C000078
 In the formula (7a), R 9 represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group or a 2-methoxyethoxymethyl group, R 10 represents a methyl group, an ethyl group or a tert-butyl group, and R 11 represents a methyl group Group, ethyl group or tert-butyl group, Z represents a fluorine atom or a chlorine atom.
Figure JPOXMLDOC01-appb-C000078
　式（８ａ）中、Ｒ９、Ｒ１０、Ｒ１１及びＺは、上記定義と同じである。 Wherein (8a), R 9, R 10, R 11 and Z are as defined above.
　式（７ａ）で表される化合物及びそのエナンチオマーである化合物（式（８ａ）で表される化合物）として、Ｒ９は水素原子、ベンジル基または２－メトキシエトキシメチル基であり、Ｒ１１は、エチル基またはｔｅｒｔ－ブチル基であり、Ｚは、塩素原子である化合物がさらにより好ましい。当該化合物においては、工程５として示す操作を行うことによりこれら化合物の光学純度を９５％ｅｅ以上とすることができる。
　式（７ａ）で表される化合物及びそのエナンチオマーである化合物（式（８ａ）で表される化合物）として特に好適である化合物として、以下の化合物が挙げられる。
（２Ｓ）－２－（２－｛４－［２－（２－メトキシエトキシ）メチルオキシ－５－エトキシフェニルチオ］－２－クロロフェニル｝エチル）－２－（ｔｅｒｔ－ブトキシカルボニル）アミノペンタン酸ｔｅｒｔ－ブチル
（２Ｒ）－２－（２－｛４－［２－（２－メトキシエトキシ）メチルオキシ－５－エトキシフェニルチオ］－２－クロロフェニル｝エチル）－２－（ｔｅｒｔ－ブトキシカルボニル）アミノペンタン酸ｔｅｒｔ－ブチル
（２Ｓ）－２－｛２－［４－（２－ヒドロキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（ｔｅｒｔ－ブトキシカルボニル）アミノペンタン酸メチル（２Ｒ）－２－｛２－［４－（２－ヒドロキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（ｔｅｒｔ－ブトキシカルボニル）アミノペンタン酸メチル
（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（ｔｅｒｔ－ブトキシカルボニル）アミノペンタン酸ｔｅｒｔ－ブチル
（２Ｒ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（ｔｅｒｔ－ブトキシカルボニル）アミノペンタン酸ｔｅｒｔ－ブチル
（２Ｓ）－２－（２－｛４－［２－（２－メトキシエトキシ）メチルオキシ－５－エトキシフェニルチオ］－２－クロロフェニル｝エチル）－２－エトキシカルボニルアミノペンタン酸エチル
（２Ｒ）－２－（２－｛４－［２－（２－メトキシエトキシ）メチルオキシ－５－エトキシフェニルチオ］－２－クロロフェニル｝エチル）－２－エトキシカルボニルアミノペンタン酸エチル
（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチル
（２Ｒ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチル As a compound represented by the formula (7a) and a compound which is an enantiomer thereof (a compound represented by the formula (8a)), R 9 is a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group, and R 11 is Even more preferably, the compound is an ethyl group or a tert-butyl group, and Z is a chlorine atom. In the said compound, the operation shown as process 5 can be performed, and the optical purity of these compounds can be 95% ee or more.
Examples of the compound particularly suitable as the compound represented by the formula (7a) and the compound that is an enantiomer thereof (the compound represented by the formula (8a)) include the following compounds.
(2S) -2- (2- {4- [2- (2-methoxyethoxy) methyloxy-5-ethoxyphenylthio] -2-chlorophenyl} ethyl) -2- (tert-butoxycarbonyl) aminopentanoic acid tert -Butyl (2R) -2- (2- {4- [2- (2-methoxyethoxy) methyloxy-5-ethoxyphenylthio] -2-chlorophenyl} ethyl) -2- (tert-butoxycarbonyl) aminopentane Acid tert-butyl (2S) -2- {2- [4- (2-hydroxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (tert-butoxycarbonyl) aminopentanoic acid methyl ester (2R) -2- {2- [4- (2-hydroxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (ter -Butoxycarbonyl) aminopentanoic acid methyl (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (tert-butoxycarbonyl) aminopentane Acid tert-butyl (2R) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (tert-butoxycarbonyl) aminopentanoic acid tert-butyl (2S) -2- (2- {4- [2- (2-methoxyethoxy) methyloxy-5-ethoxyphenylthio] -2-chlorophenyl} ethyl) -2-ethoxycarbonylaminopentanoic acid ethyl (2R)- 2- (2- {4- [2- (2-methoxyethoxy) methyloxy-5-ethoxyphenylthio] -2 Chlorophenyl} ethyl) -2-ethoxycarbonylaminopentanoic acid ethyl (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylamino Ethyl pentanoate (2R) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoate ethyl
　また、本実施形態において工程７として示す反応をＤ－（－）－酒石酸及び／またはＬ－（＋）－酒石酸用いて行うことにより、得られる一般式（１３）で表される化合物のＤ－（－）－酒石酸塩及び／または一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩の光学純度を９９．０％ｅｅ以上とすることができる。
　また、本実施形態において工程８として示す反応を行うことにより、得られる一般式（１５）で表される化合物及び／または一般式（１６）で表される化合物の光学純度を９９．５％ｅｅ以上とすることができる。 In the present embodiment, the reaction shown as Step 7 is carried out using D-(−)-tartaric acid and / or L-(+)-tartaric acid, so that D-- of the compound represented by the general formula (13) obtained is obtained. The optical purity of (−)-tartrate and / or L-(+)-tartrate of the compound represented by the general formula (14) can be 99.0% ee or more.
In addition, the optical purity of the compound represented by the general formula (15) and / or the compound represented by the general formula (16) obtained by performing the reaction shown as Step 8 in the present embodiment is 99.5% ee. This can be done.
　なお、本明細書でいう光学純度とは、以下の条件で測定されたＨＰＬＣの、当該化合物及びその光学異性体の面積百分率に基づき算出された値を示す。 In addition, the optical purity as used in this specification shows the value computed based on the area percentage of the said compound and its optical isomer of HPLC measured on the following conditions.
式（７ａ）で表される化合物及び式（８ａ）で表される化合物
カラム：ダイセル ＣＨＩＲＡＬＣＥＬ ＯＤ－Ｈ, ５μｍ, ４．６ｍｍＩ.Ｄ.×２５０ ｍｍ
移動相：ヘキサン／２－プロパノール＝９０／１０（ｖ／ｖ）
カラム温度：４０℃
流速：１．０ ｍＬ／ｍｉｎ
検出波長：２５４ｎｍ
注入量：２μＬ
 
式（１３）で表される化合物のＤ－（－）－酒石酸塩及び式（１４）で表される化合物のＬ－（＋）－酒石酸塩
カラム：ダイセル ＣＨＩＲＡＬＰＡＫ ＡＤ－３, ３μｍ, ４．６ｍｍＩ.Ｄ.×２５０ ｍｍ
移動相：ヘキサン／エタノール／２－アミノエタノール＝９０／１０／０．１（ｖ／ｖ）流速：１．０ ｍＬ／ｍｉｎ
カラム温度：２５℃
検出波長：２３０ｎｍ
注入量：２μＬ
 
式（１５）で表される化合物及び式（１６）で表される化合物
カラム：ダイセル ＣＨＩＲＡＬＰＡＫ ＩＤ, ５μｍ, ４．６ｍｍＩ.Ｄ.×２５０ｍｍ
移動相：アセトニトリル／薄めたリン酸溶液（１→１０００）＝６３／３７（ｖ／ｖ）
流速：１．０ ｍＬ／ｍｉｎ
カラム温度：４０℃
検出波長：２１０ｎｍ
注入量：２μＬ Compound represented by formula (7a) and compound column represented by formula (8a): Daicel CHIRALCEL OD-H, 5 μm, 4.6 mm ID × 250 mm
Mobile phase: hexane / 2-propanol = 90/10 (v / v)
Column temperature: 40 ° C
Flow rate: 1.0 mL / min
Detection wavelength: 254 nm
Injection volume: 2 μL

D-(-)-tartrate of the compound represented by formula (13) and L-(+)-tartrate column of the compound represented by formula (14): Daicel CHIRALPAK AD-3, 3 μm, 4.6 mmI .D. × 250 mm
Mobile phase: hexane / ethanol / 2-aminoethanol = 90/10 / 0.1 (v / v) Flow rate: 1.0 mL / min
Column temperature: 25 ° C
Detection wavelength: 230 nm
Injection volume: 2 μL

Compound represented by formula (15) and compound column represented by formula (16): Daicel CHIRALPAK ID, 5 μm, 4.6 mm ID × 250 mm
Mobile phase: acetonitrile / diluted phosphoric acid solution (1 → 1000) = 63/37 (v / v)
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Detection wavelength: 210 nm
Injection volume: 2 μL
　以上、本実施形態によれば、ジフェニルスルフィド誘導体の新規な製造方法を提供することができる。なお、本実施形態においては工程１～１０をジフェニルスルフィド誘導体を得る一連の工程として説明している。但し、これに限定されるものではなく、各工程のうち１つまたは２つ以上をそれぞれ行う態様とすることも、もちろん可能である。 As mentioned above, according to this embodiment, the novel manufacturing method of a diphenyl sulfide derivative can be provided. In the present embodiment, steps 1 to 10 are described as a series of steps for obtaining a diphenyl sulfide derivative. However, it is not limited to this, Of course, it is also possible to set it as the aspect which each performs 1 or 2 or more among each process.
　以下実施例により本発明をさらに詳しく説明するが、本発明は実施例のみに限られるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.
（参考例１）１，２－ビス（２－ベンジルオキシ－５－エトキシフェニル）ジスルフィドの合成 Reference Example 1 Synthesis of 1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　エタノール（２０ｍＬ）と水（５０ｍＬ）の混液に５－エトキシ－１，３－ベンゾキサチオール－２－オン（２０．００ｇ，１０２ｍｍｏｌ）を加え、第１の反応液とした。第１の反応液に内温１５～２５℃で水酸化ナトリウム（１２．２３ｇ，３０６ｍｍｏｌ）と水（５０ｍＬ）の混合液を加え、内温４０～４７℃で１時間撹拌した。第１の反応液を冷却し、内温１２～２０℃で３５％過酸化水素水（４．９５ｇ、５０．９ｍｍｏｌ）を加え、内温２０～２４℃で１時間撹拌した。第１の反応液を冷却し、内温４～１３℃で濃塩酸３０ｍＬを加え、酢酸エチル（３００ｍＬ）で抽出した。有機層を亜硫酸水素ナトリウム（２０．００ｇ）と水（２００ｍＬ）の混合液、飽和食塩水（２００ｍＬ）で順次洗浄した後、無水硫酸ナトリウムを用いて乾燥した。無水硫酸ナトリウムをろ過により除去した後、ろ液を減圧濃縮し、黄色オイル（１５．５ｇ）を得た。
　得た黄色オイル（１５．５ｇ）をＮ，Ｎ－ジメチルホルムアミド（１００ｍＬ）に溶解し、第２の反応液とした。第２の反応液に内温２１℃で炭酸カリウム（１６．９０ｇ，１２２ｍｍｏｌ）、内温２１～２７℃で臭化ベンジル（１７．４３ｇ、１０２ｍｍｏｌ）を加え、内温２４～２７℃で２．５時間撹拌した。第２の反応液に内温２４～３３℃で水（１６０ｍＬ）を加え、内温２５～３０℃で３０分間撹拌した。析出晶をろ取し、水（６０ｍＬ）、ジイソプロピルエーテル（６０ｍＬ）で洗浄した。当該析出晶を４０℃で減圧乾燥し、１，２－ビス（２－ベンジルオキシ－５－エトキシフェニル）ジスルフィド（１８．１９ｇ，６９％収率）を得た。
１Ｈ　ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）δ１．２９（６Ｈ，ｔ、Ｊ＝６．９Ｈｚ），３．８７（４Ｈ，ｑ，Ｊ＝６．９Ｈｚ），５．１１（４Ｈ，ｓ），６．８１（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．１６（２Ｈ，ｄ，Ｊ＝３．１Ｈｚ），７．３０－７．３３（２Ｈ，ｍ），７．３７－７．４０（４Ｈ，ｍ），７．４８－７．５０（４Ｈ，ｍ） 5-Ethoxy-1,3-benzoxiathiol-2-one (20.00 g, 102 mmol) was added to a mixture of ethanol (20 mL) and water (50 mL) to give a first reaction solution. A mixed solution of sodium hydroxide (12.23 g, 306 mmol) and water (50 mL) was added to the first reaction solution at an internal temperature of 15 to 25 ° C., and the mixture was stirred at an internal temperature of 40 to 47 ° C. for 1 hour. The first reaction solution was cooled, 35% aqueous hydrogen peroxide (4.95 g, 50.9 mmol) was added at an internal temperature of 12 to 20 ° C., and the mixture was stirred at an internal temperature of 20 to 24 ° C. for 1 hour. The first reaction solution was cooled, 30 mL of concentrated hydrochloric acid was added at an internal temperature of 4 to 13 ° C., and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed successively with a mixture of sodium bisulfite (20.00 g) and water (200 mL) and saturated brine (200 mL), and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a yellow oil (15.5 g).
The obtained yellow oil (15.5 g) was dissolved in N, N-dimethylformamide (100 mL) to obtain a second reaction solution. To the second reaction solution, potassium carbonate (16.90 g, 122 mmol) was added at an internal temperature of 21 ° C., and benzyl bromide (17.43 g, 102 mmol) was added at an internal temperature of 21-27 ° C. Stir for 5 hours. Water (160 mL) was added to the second reaction solution at an internal temperature of 24-33 ° C., and the mixture was stirred at an internal temperature of 25-30 ° C. for 30 minutes. The precipitated crystals were collected by filtration and washed with water (60 mL) and diisopropyl ether (60 mL). The precipitated crystals were dried at 40 ° C. under reduced pressure to obtain 1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide (18.19 g, 69% yield).
1 H NMR (500 MHz, CDCl 3 ) δ 1.29 (6H, t, J = 6.9 Hz), 3.87 (4H, q, J = 6.9 Hz), 5.11 (4H, s), 6. 81 (2H, d, J = 8.8 Hz), 7.16 (2H, d, J = 3.1 Hz), 7.30-7.33 (2H, m), 7.37-7.40 (4H , M), 7.48-7.50 (4H, m)
（参考例２）４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロベンズアルデヒドの合成 Reference Example 2 Synthesis of 4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　トルエン（８０ｍＬ）と濃塩酸（３２ｍＬ）の混合液に１，２－ビス（２－ベンジルオキシ－５－エトキシフェニル）ジスルフィド（１６．０ｇ，３０．８ｍｍｏｌ）を加え、加熱溶解し、第１の反応液とした。第１の反応液に内温５０～５７℃で亜鉛粉末（５．０４ｇ，７７．１ｍｍｏｌ）を加え、内温５４～５７℃で１．５時間撹拌した。第１の反応液を冷却し、内温２０～２５℃で水（４８ｍＬ）を加え、分液した。有機層を飽和食塩水（８０ｍＬ）洗浄した後、無水硫酸ナトリウムを用いて乾燥した。無水硫酸ナトリウムをろ過により除去した後、ろ液を減圧濃縮し、黄色オイル（１６．６ｇ）を得た。
　得た黄色オイル（８．０９ｇ）をＮ，Ｎ－ジメチルホルムアミド（３９ｍＬ）に溶解し、第２の反応液とした。第２の反応液に内温２５～２７℃で２－クロロ－４－フルオロベンズアルデヒド（４．７６ｇ，３０．０ｍｍｏｌ）、内温２５～３０℃で炭酸カリウム（６．２２ｇ，４５．０ｍｍｏｌ）を加えた。第２の反応液を加熱し、内温５０～５６℃で１時間撹拌した後、内温５４～５８℃で水（３９ｍＬ）を加えた。第２の反応液を冷却し、内温０～１０℃で０．５時間撹拌した。析出晶をろ取し、水（３９ｍＬ）で洗浄した。当該析出晶を５０℃で減圧乾燥し、褐色粉末（１１．３ｇ）を得た。エタノール（５７ｍＬ）を加え、内温５０～５５℃で０．５時間加熱懸濁した。冷却し、内温０～１０℃で０．５時間撹拌した。析出晶をろ取し、エタノール（３４ｍＬ）で洗浄した。析出晶を５０℃で減圧乾燥し、４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロベンズアルデヒド（１０．５ｇ、８８％収率）を得た。ＭＳ（ＦＩ＋）：ｍ/ｚ ３９８ [Ｍ]＋ 1,2-bis (2-benzyloxy-5-ethoxyphenyl) disulfide (16.0 g, 30.8 mmol) was added to a mixed solution of toluene (80 mL) and concentrated hydrochloric acid (32 mL), dissolved by heating, It was set as the reaction liquid. Zinc powder (5.04 g, 77.1 mmol) was added to the first reaction solution at an internal temperature of 50 to 57 ° C., and the mixture was stirred at an internal temperature of 54 to 57 ° C. for 1.5 hours. The first reaction liquid was cooled, and water (48 mL) was added thereto at an internal temperature of 20 to 25 ° C. for liquid separation. The organic layer was washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a yellow oil (16.6 g).
The obtained yellow oil (8.09 g) was dissolved in N, N-dimethylformamide (39 mL) to obtain a second reaction solution. To the second reaction solution, 2-chloro-4-fluorobenzaldehyde (4.76 g, 30.0 mmol) was added at an internal temperature of 25-27 ° C., and potassium carbonate (6.22 g, 45.0 mmol) was added at an internal temperature of 25-30 ° C. added. The second reaction liquid was heated and stirred at an internal temperature of 50 to 56 ° C. for 1 hour, and water (39 mL) was added at an internal temperature of 54 to 58 ° C. The second reaction solution was cooled and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration and washed with water (39 mL). The precipitated crystals were dried under reduced pressure at 50 ° C. to obtain a brown powder (11.3 g). Ethanol (57 mL) was added, and the mixture was suspended by heating at an internal temperature of 50 to 55 ° C. for 0.5 hour. The mixture was cooled and stirred at an internal temperature of 0 to 10 ° C. for 0.5 hour. The precipitated crystals were collected by filtration and washed with ethanol (34 mL). The precipitated crystals were dried at 50 ° C. under reduced pressure to give 4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde (10.5 g, 88% yield). MS (FI +): m / z 398 [M] +
（参考例３）１，１－ジメチルエチル　エチル　２－プロピルマロネートの合成
　１，１－ジメチルエチル　エチル　マロネート（１．００ｇ，５．３１ｍｍｏｌ）をＮ，Ｎ－ジメチルホルムアミド（３．００ｍＬ）に溶解し、炭酸カリウム（２．２０ｇ，１５．９ｍｍｏｌ）を加え、反応液とした。反応液を加熱し、内温４２℃でヨウ化プロピル（８１２ｍｇ，４．７８ｍｍｏｌ）を加えた。反応液を内温４２～４４℃で２時間撹拌した。反応液に２０％塩化アンモニウム溶液（１０ｍＬ）、酢酸エチル（１０ｍＬ）、２０％塩化アンモニウム溶液（１０ｍＬ）を加えた。分液し、有機層を２０％塩化アンモニウム溶液（５ｍＬ）、水（５ｍＬ）、飽和食塩水（５ｍＬ）で順次洗浄し、無水硫酸ナトリウムを用いて乾燥した。無水硫酸ナトリウムをろ過により除去した後、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（Ｓｉ６０Ｎ，ヘキサン／酢酸エチル＝２０／１）で精製し、１，１－ジメチルエチル　エチル　２－プロピルマロネート（９６６ｍｇ，７９％）を得た。
ＭＳ（ＦＩ＋）：ｍ／ｚ　２３１　［Ｍ＋Ｈ］＋ Reference Example 3 Synthesis of 1,1 -dimethylethyl ethyl 2-propyl malonate 1,1-dimethylethyl ethyl malonate (1.00 g, 5.31 mmol) was dissolved in N, N-dimethylformamide (3.00 mL). And potassium carbonate (2.20 g, 15.9 mmol) was added to obtain a reaction solution. The reaction solution was heated, and propyl iodide (812 mg, 4.78 mmol) was added at an internal temperature of 42 ° C. The reaction solution was stirred at an internal temperature of 42 to 44 ° C. for 2 hours. 20% ammonium chloride solution (10 mL), ethyl acetate (10 mL), and 20% ammonium chloride solution (10 mL) were added to the reaction solution. The organic layer was separated, washed successively with 20% ammonium chloride solution (5 mL), water (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Si60N, hexane / ethyl acetate = 20/1) to obtain 1,1-dimethylethyl ethyl 2-propylmalonate (966 mg, 79%).
MS (FI +): m / z 231 [M + H] +
（実施例１）２－ベンジルオキシ－５－エトキシフェニル　３－クロロ－４－ビニルフェニルスルフィドの合成の合成（工程１） Example 1 Synthesis of synthesis of 2-benzyloxy-5-ethoxyphenyl 3-chloro-4-vinylphenyl sulfide (step 1)
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　窒素雰囲気下、１．０ｍｏｌ／Ｌトリメチルシリルマグネシウムクロリドテトラヒドロフラン溶液（１．６３Ｌ，１．６３ｍｏｌ）に４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロベンズアルデヒド（５００ｇ，１．２５ｍｏｌ）のテトラヒドロフラン（２．００Ｌ）溶液を撹拌下、内温２０～２８℃で１時間３８分かけて加え、反応液とした。反応液を内温２１～２６℃で１時間撹拌した後、反応液を冷却し、内温３～２２℃で濃塩酸（４００ｍＬ）を２０分間かけて加えた。反応液を内温２０～２５℃で１時間撹拌した後、内温２４～２９℃で水（１．００Ｌ）、酢酸エチル（５．００Ｌ）、水（４．００Ｌ）を順次加えた。分液し、有機層を水（５．００Ｌ）、炭酸水素ナトリウム（２５０ｇ）と水（５．００Ｌ）の混合液、食塩（５００ｇ）と水（５．００Ｌ）の混合液、食塩（５００ｇ）と水（５．００Ｌ）の混合液で順次洗浄した。有機層に４－ｔｅｒｔ－ブチルピロカテコール（５．００ｇ）を加え、溶解を確認後、無水硫酸ナトリウム（１．２５ｋｇ）を加えた。当該有機層を室温で３０分間撹拌した後、無水硫酸ナトリウムをろ過により除去し、ろ液を外温４０℃で減圧濃縮した。得られた茶色オイル（４９８ｇ）は更なる精製を行わず、次の反応に用いた。 4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde (500 g, 1.25 mol) was added to a 1.0 mol / L trimethylsilylmagnesium chloride tetrahydrofuran solution (1.63 L, 1.63 mol) under a nitrogen atmosphere. Of tetrahydrofuran (2.00 L) was added with stirring at an internal temperature of 20 to 28 ° C. over 1 hour and 38 minutes to obtain a reaction solution. After the reaction solution was stirred at an internal temperature of 21 to 26 ° C. for 1 hour, the reaction solution was cooled, and concentrated hydrochloric acid (400 mL) was added over 20 minutes at an internal temperature of 3 to 22 ° C. After the reaction solution was stirred at an internal temperature of 20 to 25 ° C. for 1 hour, water (1.00 L), ethyl acetate (5.00 L), and water (4.00 L) were sequentially added at an internal temperature of 24 to 29 ° C. The organic layer was separated, and the organic layer was mixed with water (5.00 L), a mixture of sodium bicarbonate (250 g) and water (5.00 L), a mixture of sodium chloride (500 g) and water (5.00 L), sodium chloride (500 g). And sequentially washed with a mixed solution of water and 5.00 L. 4-tert-Butylpyrocatechol (5.00 g) was added to the organic layer, and after confirming dissolution, anhydrous sodium sulfate (1.25 kg) was added. The organic layer was stirred at room temperature for 30 minutes, then anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. The resulting brown oil (498 g) was used in the next reaction without further purification.
（実施例２）（２ＲＳ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－プロピルマロン酸１，１－ジメチルエチル　エチルの合成（工程２） Example 2 (2RS) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate 1,1-dimethylethyl Synthesis (Step 2)
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　実施例１で得られた茶色オイル（４９８ｇ）にジメチルスルホキシド（２．００Ｌ）を加えて溶解した。
　窒素雰囲気下、ジメチルスルホキシド（２．００Ｌ）に１，１－ジメチルエチル　エチル　２－プロピルマロネート（４３３ｇ，１．８８ｍｏｌ）を溶解し、撹拌下、内温１７～１８℃で炭酸セシウム（１．２３ｋｇ，３．７６ｍｏｌ）を加え、反応液とした。反応液を加熱し、内温５０～５３℃で、上述の、実施例１で得られた茶色オイル（４９８ｇ）のジメチルスルホキシド（２．００Ｌ）溶液を１時間５１分間かけて加えた。反応液を内温５３℃で１時間３３分撹拌した後、冷却し、内温１０～３２℃でトルエン（１０．０Ｌ）、水（１０．０Ｌ）を加えた。分液し、有機層を食塩（１．００ｋｇ）と水（１０．０Ｌ）の混合液で洗浄し、無水硫酸ナトリウム（１．００ｋｇ）を用いて乾燥した。無水硫酸ナトリウムをろ過により除去した後、ろ液を減圧濃縮し、茶色オイル（９４２ｇ）を得た。得られた茶色オイルは更なる精製を行わず、次の反応に用いた。 Dimethyl sulfoxide (2.00 L) was added to the brown oil (498 g) obtained in Example 1 and dissolved.
Under a nitrogen atmosphere, 1,1-dimethylethyl ethyl 2-propylmalonate (433 g, 1.88 mol) was dissolved in dimethyl sulfoxide (2.00 L), and cesium carbonate (1. 23 kg, 3.76 mol) was added to obtain a reaction solution. The reaction solution was heated, and the above-described brown oil (498 g) obtained in Example 1 in dimethyl sulfoxide (2.00 L) was added at an internal temperature of 50 to 53 ° C. over 1 hour and 51 minutes. The reaction solution was stirred at an internal temperature of 53 ° C. for 1 hour and 33 minutes, then cooled, and toluene (10.0 L) and water (10.0 L) were added at an internal temperature of 10 to 32 ° C. The organic layer was separated, washed with a mixed solution of sodium chloride (1.00 kg) and water (10.0 L), and dried using anhydrous sodium sulfate (1.00 kg). After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a brown oil (942 g). The resulting brown oil was used in the next reaction without further purification.
（実施例３）（２ＲＳ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルペンタン酸の合成（工程３） Example 3 Synthesis of (2RS) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylpentanoic acid (Step 3)
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　実施例２で得られた茶色オイル（９４２ｇ）をアセトニトリル（５．００Ｌ）に溶解し、内温８℃でＭｏｎｔｍｏｒｉｌｌｏｎｉｔｅ　ＫＳＦ（９００ｇ）を撹拌下、加え、反応液とした。反応液を加熱し、内温７６～８２°Ｃで１０時間加熱還流した。反応液を冷却し、一晩放置した。反応液にＭｏｎｔｍｏｒｉｌｌｏｎｉｔｅ　ＫＳＦ（１００ｇ）を加え、加熱し、内温８０～８２℃で８時間加熱還流した（加熱還流時、Ｄｅａｎ－ｓｔａｒｋ装置を用いて３．００Ｌの溶媒を留去し、アセトニトリル（２．６０Ｌ）を加えた）。反応液を冷却した後、内温３０℃で不溶物をろ過し、当該不溶物をアセトニトリル（１．５０Ｌ）で洗浄した。ろ液と洗浄液を合一し、減圧濃縮した。残渣を酢酸エチル（５．００Ｌ）に溶解し、炭酸水素ナトリウム（１５０ｇ）と水（２．５０Ｌ）の混合液、濃塩酸（１００ｍＬ）と水（２．５０Ｌ）の混合液、食塩（５００ｇ）と水（２．５０Ｌ）の混合液で順次洗浄し、無水硫酸ナトリウム（２５０ｇ）を用いて乾燥した。無水硫酸ナトリウムをろ過により除去し、ろ液を減圧濃縮した。得られた残渣にトルエン（２．００Ｌ）を加え、外温４０℃で溶解し、撹拌下、内温２５～２９℃でヘプタン（５．００Ｌ）を３５分間で加えた。当該溶液を内温２５℃で５分間撹拌した後、晶析を確認した。更に当該混液を内温２４～２６℃で２時間撹拌した。析出晶をろ取し、トルエン（１５０ｍＬ）とヘプタン（１．５０Ｌ）の混合液で洗浄した。析出晶を５０℃で４時間減圧乾燥し、２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルペンタン酸（４９４ｇ、６９％収率）を得た。　ＭＳ（ＥＳＩ＋）：ｍ／ｚ　５７１　［Ｍ＋Ｈ］＋ The brown oil (942 g) obtained in Example 2 was dissolved in acetonitrile (5.00 L), and Montmorillonite KSF (900 g) was added with stirring at an internal temperature of 8 ° C. to obtain a reaction solution. The reaction solution was heated and heated to reflux at an internal temperature of 76 to 82 ° C. for 10 hours. The reaction was cooled and left overnight. Montmorillonite KSF (100 g) was added to the reaction solution, heated, and heated to reflux at an internal temperature of 80 to 82 ° C. for 8 hours (during heating to reflux, 3.00 L of solvent was distilled off using a Dean-stark apparatus, and acetonitrile ( 2.60 L) was added). After cooling the reaction solution, insoluble matter was filtered at an internal temperature of 30 ° C., and the insoluble matter was washed with acetonitrile (1.50 L). The filtrate and washings were combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5.00 L), a mixture of sodium hydrogen carbonate (150 g) and water (2.50 L), a mixture of concentrated hydrochloric acid (100 mL) and water (2.50 L), sodium chloride (500 g) Washed sequentially with a mixture of water and water (2.50 L) and dried over anhydrous sodium sulfate (250 g). Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. Toluene (2.00 L) was added to the resulting residue, dissolved at an external temperature of 40 ° C., and heptane (5.00 L) was added over 35 minutes with stirring at an internal temperature of 25-29 ° C. After the solution was stirred at an internal temperature of 25 ° C. for 5 minutes, crystallization was confirmed. Further, the mixture was stirred at an internal temperature of 24 to 26 ° C. for 2 hours. The precipitated crystals were collected by filtration and washed with a mixed solution of toluene (150 mL) and heptane (1.50 L). The precipitated crystals were dried under reduced pressure at 50 ° C. for 4 hours to give 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylpentanoic acid (494 g, 69 % Yield). MS (ESI +): m / z 571 [M + H] +
（実施例４）（２ＲＳ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチルの合成（工程４） Example 4 Synthesis of ethyl (2RS) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoate (Step 4) )
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　窒素雰囲気下、トルエン（１．３８Ｌ）に内温９～１５℃で２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルペンタン酸（４９４ｇ，０．８６５ｍｏｌ）を加え、第１の反応液とした。第１の反応液に撹拌下、内温９～１６℃でトリエチルアミン（１３１ｇ，１．３０ｍｏｌ）を加えた。続いて撹拌下、第１の反応液に、内温１６～２５℃でジフェニルリン酸アジド（２６２ｇ，０．９５１ｍｏｌ）を加えた。容器をトルエン（１００ｍＬ）で洗い込んだ。第１の反応液を加熱し、内温３５～４２℃で１時間２５分撹拌した。第１の反応液を別途加熱したトルエン（２．９６Ｌ）に撹拌下、内温８２～８５°Ｃで１時間１３分かけて滴下し、トルエン（０．５０Ｌ）で洗い込み、第２の反応液とした。第２の反応液を内温８５℃で５０分間撹拌した後、冷却し、内温４～１２℃でエタノール（０．８９Ｌ）で希釈した２０％ナトリウムエトキシドエタノール溶液（４７１ｇ，１．３８ｍｏｌ）を撹拌下、２５分間で加えた。第２の反応液を内温１０～１２℃で５０分間撹拌した後、第２の反応液を内温１０～１２℃で塩化アンモニウム（８９０ｇ）と水（４．９４Ｌ）の混合液に加え、酢酸エチル（３．４６Ｌ）で抽出した。有機層を水（４．９４Ｌ）で洗浄、減圧濃縮し、茶色オイル（６４５ｇ）を得た。当該茶色オイルにヘプタン（６９２ｍＬ）、酢酸エチル（３４６ｍＬ）を加え溶解し、シリカゲル(球状６０Ｎ，４９４ｇ)を用いてろ過し、不溶物をヘプタン（１．６８Ｌ）と酢酸エチル（８４０ｍＬ）の混合液で洗浄した。ろ液と洗浄液を合一した後、減圧濃縮し、２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチル（５５４ｇ）を茶色オイルとして得た。
ＭＳ（ＥＳＩ＋）：ｍ/ｚ ６１４ [Ｍ＋Ｈ]＋ 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonyl in toluene (1.38 L) at an internal temperature of 9-15 ° C. under a nitrogen atmosphere Pentanoic acid (494 g, 0.865 mol) was added to make a first reaction solution. Triethylamine (131 g, 1.30 mol) was added to the first reaction solution with stirring at an internal temperature of 9 to 16 ° C. Subsequently, diphenylphosphoric acid azide (262 g, 0.951 mol) was added to the first reaction solution with stirring at an internal temperature of 16 to 25 ° C. The vessel was washed with toluene (100 mL). The first reaction liquid was heated and stirred at an internal temperature of 35 to 42 ° C. for 1 hour and 25 minutes. The first reaction solution was added dropwise to separately heated toluene (2.96 L) with stirring at an internal temperature of 82 to 85 ° C. over 1 hour and 13 minutes, washed with toluene (0.50 L), and the second reaction. Liquid. The second reaction solution was stirred at an internal temperature of 85 ° C. for 50 minutes, then cooled and diluted with ethanol (0.89 L) at an internal temperature of 4 to 12 ° C. in a 20% sodium ethoxide ethanol solution (471 g, 1.38 mol). Was added with stirring over 25 minutes. After stirring the second reaction solution at an internal temperature of 10-12 ° C. for 50 minutes, the second reaction solution was added to a mixed solution of ammonium chloride (890 g) and water (4.94 L) at an internal temperature of 10-12 ° C., Extracted with ethyl acetate (3.46 L). The organic layer was washed with water (4.94 L) and concentrated under reduced pressure to give a brown oil (645 g). Heptane (692 mL) and ethyl acetate (346 mL) are added to the brown oil and dissolved, and the mixture is filtered through silica gel (spherical 60N, 494 g), and the insoluble matter is mixed with heptane (1.68 L) and ethyl acetate (840 mL). Washed with. The filtrate and the washing solution were combined and concentrated under reduced pressure to obtain ethyl 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoate. (554 g) was obtained as a brown oil.
MS (ESI +): m / z 614 [M + H] +
（実施例５）（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチルの合成（工程５） Example 5 Synthesis of ethyl (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoate (Step 5) )
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチル（５２．５ｋｇ）を約８０ｇ／Ｌとなるように移動相に溶解し、０．５μｍＰＴＦＥメンブレンフィルターを用いてろ過した。下記の条件で光学分取を行った。
 
ＳＭＢ分取条件
カラム：ＣＨＩＲＡＬＣＥＬ　ＯＤ（２０μｍ）
サイズ：５ｃｍＩ．Ｄ．×１０ｃｍＬ×８本
移動相：ノルマルヘキサン／２－プロパノール＝９０／１０（ｖ／ｖ）
温度：４０℃
ゾーン構成：２－３－２－１
Ｆｅｅｄ流量：１１．７ｍＬ／ｍｉｎ．
Ｅｌｕｅｎｔ流量：１３５．５ｍＬ／ｍｉｎ．
Ｒａｆｆｉｎａｔｅ流量：４１．０ｍＬ／ｍｉｎ．
Ｅｘｔｒａｃｔ流量：１０６．２ｍＬ／ｍｉｎ．
Ｒｅｃｙｃｌｅ流量：２５２．５ｍＬ／ｍｉｎ．
Ｐｅｒｉｏｄ　ｔｉｍｅ：１．８ｍｉｎ．
分取装置；少量分取装置　ＳＭＢ－Ｂ系列（株式会社ダイセル）
 
　Ｅｘｔｒａｃｔ吐出口から第２ピーク成分フラクションを採取し、設定温度３０℃で減圧濃縮した。（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチル（２８．０ｋｇ，＞９８％ｅｅ）を得た。 Ethyl 2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoate (52.5 kg) was adjusted to about 80 g / L. It melt | dissolved in the mobile phase and filtered using the 0.5 micrometer PTFE membrane filter. Optical fractionation was performed under the following conditions.

SMB preparative condition column: CHIRALCEL OD (20 μm)
Size: 5 cmI. D. × 10 cmL × 8 mobile phases: normal hexane / 2-propanol = 90/10 (v / v)
Temperature: 40 ° C
Zone configuration: 2-3-2-1
Feed flow rate: 11.7 mL / min.
Eluent flow rate: 135.5 mL / min.
Raffinate flow rate: 41.0 mL / min.
Extract flow rate: 106.2 mL / min.
Recycle flow rate: 252.5 mL / min.
Period time: 1.8 min.
Sorting device; Small volume sorting device SMB-B series (Daicel)

The second peak component fraction was collected from the Extract outlet and concentrated under reduced pressure at a set temperature of 30 ° C. (2S) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoic acid ethyl ester (28.0 kg,> 98% ee) Got.
（実施例６）（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタノール及び（２Ｓ）－４－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－４－プロピル－１，３－オキサゾリジン－２－オンの合成（工程６） Example 6 (2S) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanol and (2S) -4 Synthesis of — {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -4-propyl-1,3-oxazolidin-2-one (Step 6)
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　窒素雰囲気下、テトラヒドロフラン（１５０ｍＬ）に、内温１９℃で水素化ホウ素カリウム（１３．２ｇ，２４４ｍｍｏｌ）及び塩化リチウム（１０．４ｇ，２４４ｍｍｏｌ）を順次投入した。混液を加熱し、内温３５～３９℃で３時間撹拌した。混液を冷却し、内温１８～３０℃で１４．５時間静置した。混液を加熱し、内温４０℃で（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－エトキシカルボニルアミノペンタン酸エチル（５１．２ｇ，８１．４ｍｍｏｌ）のテトラヒドロフラン（１５０ｍＬ）混合液を加え、反応液とした。反応液に内温４０～４２℃でエタノール（５０ｍＬ）を３時間かけて滴下した。反応液を内温４０℃で３０分間撹拌した。反応液を冷却した後、内温１～１０℃で濃塩酸（３４ｍＬ）と常水（２３７ｍＬ）の混合液を滴下した。反応液を加熱して内温４５～５５℃で１時間撹拌した。内温５℃まで冷却し、内温５℃で酢酸エチル（５００ｍＬ）で抽出した。有機層を水酸化カリウム（１４．０ｇ）と常水（２５０ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を水酸化カリウム（１４．０ｇ）と常水（２５０ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を常水（２５０ｍＬ）で洗浄し、有機層と水層を分層した(分離不十分)。続いて、水層に塩化ナトリウム（１２．５ｇ）を加えて再度有機層と混ぜて、有機層を分取した。有機層を設定温度４０～５０℃で減圧濃縮し、黄色油状物（４６．８ｇ）を得た。得られた油状物をエタノール（１００ｍＬ）に溶解し、設定温度４０～５０℃で減圧濃縮し、黄色油状物（４４．８ｇ）を得た。得られた黄色油状物は更なる精製を行わず、次の反応に用いた。 In a nitrogen atmosphere, potassium borohydride (13.2 g, 244 mmol) and lithium chloride (10.4 g, 244 mmol) were sequentially added to tetrahydrofuran (150 mL) at an internal temperature of 19 ° C. The mixture was heated and stirred at an internal temperature of 35 to 39 ° C. for 3 hours. The mixed solution was cooled and allowed to stand at an internal temperature of 18-30 ° C. for 14.5 hours. The mixture was heated and ethyl (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-ethoxycarbonylaminopentanoate at an internal temperature of 40 ° C. (51.2 g, 81.4 mmol) in tetrahydrofuran (150 mL) was added to give a reaction solution. Ethanol (50 mL) was added dropwise to the reaction mixture over 3 hours at an internal temperature of 40 to 42 ° C. The reaction solution was stirred at an internal temperature of 40 ° C. for 30 minutes. After cooling the reaction solution, a mixed solution of concentrated hydrochloric acid (34 mL) and normal water (237 mL) was added dropwise at an internal temperature of 1 to 10 ° C. The reaction solution was heated and stirred at an internal temperature of 45 to 55 ° C. for 1 hour. The mixture was cooled to an internal temperature of 5 ° C. and extracted with ethyl acetate (500 mL) at an internal temperature of 5 ° C. The organic layer was washed with a mixed solution of potassium hydroxide (14.0 g) and normal water (250 mL), and the organic layer was separated. The organic layer was washed with a mixed solution of potassium hydroxide (14.0 g) and normal water (250 mL), and the organic layer was separated. The organic layer was washed with normal water (250 mL), and the organic layer and aqueous layer were separated (insufficient separation). Subsequently, sodium chloride (12.5 g) was added to the aqueous layer and mixed with the organic layer again to separate the organic layer. The organic layer was concentrated under reduced pressure at a set temperature of 40 to 50 ° C. to obtain a yellow oil (46.8 g). The obtained oil was dissolved in ethanol (100 mL) and concentrated under reduced pressure at a preset temperature of 40 to 50 ° C. to obtain a yellow oil (44.8 g). The resulting yellow oil was used in the next reaction without further purification.
（実施例７）（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール　Ｄ－（－）－酒石酸塩の合成（工程７） Example 7 (2S) -2-Amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} pentanol D-(-)-tartrate Synthesis (step 7)
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　実施例６で得られた黄色油状物（４４．８ｇ）を、エタノール（３００ｍＬ）に溶解させた後、内温２９℃にて水酸化ナトリウム（３２．６ｇ，８１４ｍｍｏｌ）と常水（１５０ｍＬ）の混合溶液を加え、第１の反応液とした。第１の反応液を加熱し、内温８０℃で還流した。第１の反応液を冷却し、内温１７℃で常水（３００ｍＬ）を投入した後、内温８～１０℃で１０分間撹拌した。第１の反応液に内温６～８℃で酢酸イソプロピル（３００ｍＬ）を投入し、内温５～６℃で５分間撹拌した。５分間静置後、有機層を分取した。得られた有機層を内温９～１４℃で塩化ナトリウム（３０．０ｇ）と常水（３００ｍＬ）の混合液で洗浄し、有機層を分取した。得られた有機層を内温１０～１３℃で塩化ナトリウム（１５．０ｇ）と常水（３００ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を設定温度４０℃で減圧濃縮し、黄色油状物（４６．３ｇ）を得た。得られた油状物を酢酸イソプロピル（２５０ｍＬ）に溶解後、不溶物をろ別し、酢酸イソプロピル（５０．０ｍＬ）で洗浄した。ろ液と洗浄液を合一し、設定温度４０℃で減圧濃縮して、黄色油状物（４２．６ｇ）を得た。
　得られた黄色油状物に１，２－ジメトキシエタン（７５０ｍＬ）を投入し、内温２８℃で溶解し、第２の反応液とした。第２の反応液を加熱し、内温３９～４０℃でＤ－（－）－酒石酸（１３．４ｇ，８９．５ｍｍｏｌ）と常水（７５ｍＬ）の混合液を滴下した後、内温３９～４０℃で３０分間撹拌した。第２の反応液を冷却し、内温１２～１３℃で１,２－ジメトキシエタン（２５０ｍＬ）を投入した後、内温１２～１５℃で１時間撹拌した。結晶をろ取し、１,２－ジメトキシエタン（１００ｍＬ）で洗浄して、湿潤結晶（６５．４ｇ）を得た。設定温度５０℃で２４時間減圧乾燥して、白色粉末の（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール　Ｄ－（－）－酒石酸塩（４５．７ｇ，８６％収率，９９．６％ｅｅ）を得た。
ＭＳ（ＥＳＩ＋）：ｍ／ｚ ５００ （ｆｒｅｅ）［Ｍ＋Ｈ］＋
（光学純度測定条件）
カラム：ダイセル ＣＨＩＲＡＬＰＡＫ ＡＤ－３, ５μｍ, ４．６ｍｍＩ.Ｄ.×２５０ ｍｍ
移動相：液体クロマトグラフィー用ヘキサン：（エタノール（９９．５）：２－アミノエタノール混液（１００：１）)混液＝９：１（アイソクラティック）
流速：１．０ ｍＬ／ ｍｉｎ
カラム温度：２５℃
検出波長：２３０ｎｍ
保持時間：（Ｒ）体; ２４．５ｍｉｎ, （Ｓ）体; ２６．４ｍｉｎ The yellow oil (44.8 g) obtained in Example 6 was dissolved in ethanol (300 mL), and then sodium hydroxide (32.6 g, 814 mmol) and normal water (150 mL) were added at an internal temperature of 29 ° C. The mixed solution was added to obtain a first reaction solution. The first reaction liquid was heated and refluxed at an internal temperature of 80 ° C. The first reaction liquid was cooled, normal water (300 mL) was added at an internal temperature of 17 ° C., and the mixture was stirred at an internal temperature of 8 to 10 ° C. for 10 minutes. Isopropyl acetate (300 mL) was added to the first reaction solution at an internal temperature of 6-8 ° C., and the mixture was stirred at an internal temperature of 5-6 ° C. for 5 minutes. After standing for 5 minutes, the organic layer was separated. The obtained organic layer was washed with a mixed solution of sodium chloride (30.0 g) and normal water (300 mL) at an internal temperature of 9 to 14 ° C., and the organic layer was separated. The obtained organic layer was washed with a mixed solution of sodium chloride (15.0 g) and normal water (300 mL) at an internal temperature of 10 to 13 ° C., and the organic layer was separated. The organic layer was concentrated under reduced pressure at a preset temperature of 40 ° C. to obtain a yellow oil (46.3 g). The obtained oil was dissolved in isopropyl acetate (250 mL), the insoluble material was filtered off, and washed with isopropyl acetate (50.0 mL). The filtrate and washings were combined and concentrated under reduced pressure at a preset temperature of 40 ° C. to give a yellow oil (42.6 g).
1,2-Dimethoxyethane (750 mL) was added to the obtained yellow oil and dissolved at an internal temperature of 28 ° C. to obtain a second reaction solution. The second reaction solution was heated, and a mixed solution of D-(−)-tartaric acid (13.4 g, 89.5 mmol) and normal water (75 mL) was added dropwise at an internal temperature of 39 to 40 ° C. Stir at 40 ° C. for 30 minutes. The second reaction liquid was cooled, 1,2-dimethoxyethane (250 mL) was added at an internal temperature of 12 to 13 ° C., and the mixture was stirred at an internal temperature of 12 to 15 ° C. for 1 hour. The crystals were collected by filtration and washed with 1,2-dimethoxyethane (100 mL) to obtain wet crystals (65.4 g). (2S) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} was dried as a white powder at a set temperature of 50 ° C. under reduced pressure for 24 hours. Pentanol D-(−)-tartrate (45.7 g, 86% yield, 99.6% ee) was obtained.
MS (ESI +): m / z 500 (free) [M + H] +
(Optical purity measurement conditions)
Column: Daicel CHIRALPAK AD-3, 5 μm, 4.6 mm ID × 250 mm
Mobile phase: hexane for liquid chromatography: (ethanol (99.5): 2-aminoethanol mixture (100: 1)) mixture = 9: 1 (isocratic)
Flow rate: 1.0 mL / min
Column temperature: 25 ° C
Detection wavelength: 230 nm
Retention time: (R) isomer; 24.5 min, (S) isomer; 26.4 min
（実施例８）（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（１，１－ジメチルエトキシカルボニルアミノ）ペンタノールの合成（工程８） Example 8 (2S) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonylamino) pen Synthesis of tanol (process 8)
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　酢酸エチル（３５２ｍＬ）に内温１６℃で（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール　Ｄ－（－）－酒石酸塩（４４．０ｇ，６７．７ｍｍｏｌ）を加え、反応液とした。反応液に内温１５～１７℃で炭酸水素ナトリウム（１４．２ｇ，１６９ｍｍｏｌ）と常水（１７６ｍＬ）の混合液を加えた。続いて、反応液に内温１６℃で二炭酸ジ－ｔｅｒｔ－ブチル（２０．７ｇ，９４．７ｍｍｏｌ）を加え、加熱して、内温４０～４３℃で４時間撹拌した。反応液を冷却し、内温２１～２４℃で１－メチルピペラジン（７．５ｍＬ，６７．７ｍｍｏｌ）を加えた後、内温２３～２４℃で１時間撹拌した。静置した後、有機層を分取した。有機層を濃塩酸（１３．２ｍＬ）と常水（５７２ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を炭酸水素ナトリウム（４．４０ｇ）と常水（８８ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を常水（８８ｍＬ）で洗浄し、有機層を分取した。有機層にアセトン（１７６ｍＬ）を加えて、設定温度５０℃で減圧濃縮した。得られた濃縮残留物を酢酸エチル（２２０ｍＬ）に溶解し、Ｎ,Ｎ－ジメチルホルムアミド（１３．４ｍＬ）を加えた後、設定温度５０℃で減圧濃縮して、濃縮残留物（５０．８ｇ）を得た。
　得られた濃縮残留物にトルエン（１７６ｍＬ）を加えた後、加熱して、溶解した。不溶物を熱時ろ別し、トルエン（８８ｍＬ）で洗浄した。ろ液と洗浄液を合一して、加熱し、内温４６～５３℃でｎ－ヘプタン（１．０６Ｌ）を１４分かけて滴下した。得られた混液を冷却し、内温６～７℃で３０分間撹拌した。結晶をろ取し、トルエン（４４ｍＬ）及びｎ－ヘプタン（１７６ｍＬ）の混合液で洗浄して、湿潤結晶（４１．５ｇ）を得た。得られた湿潤結晶を設定温度５０℃で３時間減圧乾燥して、白色粉末の（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（１，１－ジメチルエトキシカルボニルアミノ）ペンタノール（３６．５ｇ，９０％収率，９９．９％ｅｅ）を得た。
ＭＳ（ＥＳＩ＋）：ｍ／ｚ ６００［Ｍ＋Ｈ］＋
（光学純度測定条件）
カラム：ダイセル ＣＨＩＲＡＬＰＡＫ ＩＤ, ５μｍ, ４．６ｍｍＩ.Ｄ.×２５０ｍｍ
移動相：液体クロマトグラフィー用アセトニトリル：薄めたリン酸溶液（１→１０００）＝６３：３７（アイソクラティック）
流速：１．０ ｍＬ／ ｍｉｎ
カラム温度：４０℃
検出波長：２１０ｎｍ
保持時間：(Ｒ)体; １９．８ ｍｉｎ, (Ｓ)体; ２１．１ｍｉｎ (2S) -2-Amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} pentanol in ethyl acetate (352 mL) at an internal temperature of 16 ° C. D- (−)-Tartrate (44.0 g, 67.7 mmol) was added to give a reaction solution. A mixed solution of sodium hydrogen carbonate (14.2 g, 169 mmol) and normal water (176 mL) was added to the reaction solution at an internal temperature of 15 to 17 ° C. Subsequently, di-tert-butyl dicarbonate (20.7 g, 94.7 mmol) was added to the reaction solution at an internal temperature of 16 ° C., heated, and stirred at an internal temperature of 40-43 ° C. for 4 hours. The reaction mixture was cooled, 1-methylpiperazine (7.5 mL, 67.7 mmol) was added at an internal temperature of 21-24 ° C., and the mixture was stirred at an internal temperature of 23-24 ° C. for 1 hour. After standing, the organic layer was separated. The organic layer was washed with a mixed solution of concentrated hydrochloric acid (13.2 mL) and normal water (572 mL), and the organic layer was separated. The organic layer was washed with a mixed solution of sodium hydrogen carbonate (4.40 g) and normal water (88 mL), and the organic layer was separated. The organic layer was washed with normal water (88 mL), and the organic layer was separated. Acetone (176 mL) was added to the organic layer, and the mixture was concentrated under reduced pressure at a set temperature of 50 ° C. The obtained concentrated residue was dissolved in ethyl acetate (220 mL), N, N-dimethylformamide (13.4 mL) was added, and the mixture was concentrated under reduced pressure at a set temperature of 50 ° C. to give a concentrated residue (50.8 g). Got.
Toluene (176 mL) was added to the resulting concentrated residue, and then heated to dissolve. The insoluble material was filtered off while hot and washed with toluene (88 mL). The filtrate and the washing solution were combined and heated, and n-heptane (1.06 L) was added dropwise over 14 minutes at an internal temperature of 46 to 53 ° C. The resulting mixture was cooled and stirred at an internal temperature of 6-7 ° C. for 30 minutes. The crystals were collected by filtration and washed with a mixed solution of toluene (44 mL) and n-heptane (176 mL) to obtain wet crystals (41.5 g). The obtained wet crystals were dried under reduced pressure at a set temperature of 50 ° C. for 3 hours to give (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] as white powder. Ethyl} -2- (1,1-dimethylethoxycarbonylamino) pentanol (36.5 g, 90% yield, 99.9% ee) was obtained.
MS (ESI +): m / z 600 [M + H] +
(Optical purity measurement conditions)
Column: Daicel CHIRALPAK ID, 5 μm, 4.6 mm ID × 250 mm
Mobile phase: acetonitrile for liquid chromatography: diluted phosphoric acid solution (1 → 1000) = 63: 37 (isocratic)
Flow rate: 1.0 mL / min
Column temperature: 40 ° C
Detection wavelength: 210 nm
Retention time: (R) isomer; 19.8 min, (S) isomer; 21.1 min
（実施例９）リン酸　（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（１，１－ジメチルエトキシカルボニルアミノ）ペンチル　ジエチルの合成（工程９） Example 9 Phosphoric acid (2S) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- (1,1-dimethylethoxycarbonylamino ) Synthesis of pentyl diethyl (step 9)
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　アセトニトリル（１７．５ｍＬ）に内温１９℃で１－メチルイミダゾール（２７．６ｍＬ，３５０ｍｍｏｌ）を加えた。続いて、得られた溶液に内温１５～１９℃で（２Ｓ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－（１，１－ジメチルエトキシカルボニルアミノ）ペンタノール（３５．０ｇ，５８．３ｍｍｏｌ）を加え、反応液とした。内温２５℃で溶解を確認した後、反応液に内温２６℃で酢酸エチル（１７．５ｍＬ）を加えた。反応液を冷却し、内温７～１０℃でクロロリン酸ジエチル（１２．６ｍＬ，８７．５ｍｍｏｌ）を３０分かけて滴下した後、内温９～１０℃で１時間撹拌した。反応液に内温９～１５℃で酢酸エチル（１４０ｍＬ）とｎ－ヘプタン（２８０ｍＬ）の混合液を加えた後、内温１５～２５℃で濃塩酸（５２．５ｍＬ）と常水（６４８ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を内温１６～２１℃で濃塩酸（５２．５ｍＬ）と常水（６４８ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を内温１５～２１℃で濃塩酸（５２．５ｍＬ）と常水（６４８ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を内温２０～２１℃で炭酸水素ナトリウム（４．３８ｇ）と常水（８７．５ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を内温２０～２１℃で塩化ナトリウム（１７．５ｇ）と常水（８７．５ｍＬ）の混合液で洗浄し、有機層を分取した。有機層を設定温度４０℃で減圧濃縮し、微帯黄色油状物（４５．２ｇ）を得た。得られた油状物をアセトニトリル（１７５ｍＬ）に溶解し、設定温度４０～５０℃で減圧濃縮し、微黄色油状物（４３．１ｇ）を得た。得られた微黄色油状物は更なる精製を行わず、次の反応に用いた。 1-methylimidazole (27.6 mL, 350 mmol) was added to acetonitrile (17.5 mL) at an internal temperature of 19 ° C. Subsequently, (2S) -2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2- ( 1,1-dimethylethoxycarbonylamino) pentanol (35.0 g, 58.3 mmol) was added to give a reaction solution. After confirming dissolution at an internal temperature of 25 ° C., ethyl acetate (17.5 mL) was added to the reaction solution at an internal temperature of 26 ° C. The reaction solution was cooled, and diethyl chlorophosphate (12.6 mL, 87.5 mmol) was added dropwise at an internal temperature of 7 to 10 ° C. over 30 minutes, followed by stirring at an internal temperature of 9 to 10 ° C. for 1 hour. A mixture of ethyl acetate (140 mL) and n-heptane (280 mL) was added to the reaction solution at an internal temperature of 9 to 15 ° C., then concentrated hydrochloric acid (52.5 mL) and normal water (648 mL) at an internal temperature of 15 to 25 ° C. The organic layer was separated. The organic layer was washed with a mixed solution of concentrated hydrochloric acid (52.5 mL) and normal water (648 mL) at an internal temperature of 16 to 21 ° C., and the organic layer was separated. The organic layer was washed with a mixed solution of concentrated hydrochloric acid (52.5 mL) and normal water (648 mL) at an internal temperature of 15 to 21 ° C., and the organic layer was separated. The organic layer was washed with a mixed solution of sodium hydrogen carbonate (4.38 g) and normal water (87.5 mL) at an internal temperature of 20 to 21 ° C., and the organic layer was separated. The organic layer was washed with a mixed solution of sodium chloride (17.5 g) and normal water (87.5 mL) at an internal temperature of 20 to 21 ° C., and the organic layer was separated. The organic layer was concentrated under reduced pressure at a set temperature of 40 ° C. to obtain a slightly yellowish oil (45.2 g). The obtained oil was dissolved in acetonitrile (175 mL) and concentrated under reduced pressure at a preset temperature of 40 to 50 ° C. to obtain a slightly yellow oil (43.1 g). The resulting pale yellow oil was used in the next reaction without further purification.
（実施例１０）リン酸　２水素　（２Ｓ）－２－アミノ－２－｛２－［２－クロロ－４－（５－エトキシ－２－ヒドロキシフェニルチオ）フェニル］エチル｝ペンチルの合成（工程１０）
　実施例９で得られた微黄色油状物（４３．１ｇ）にアセトニトリル（１７５ｍＬ）及び精製水（１．０５ｍＬ，５８．３ｍｍｏｌ）を加え、反応液とした。続いて、反応液に内温２０～２６℃でヨウ化ナトリウム（８７．４ｇ，５８３ｍｍｏｌ）を加えた。反応液を冷却し、内温１６～２４℃でトリメチルシリルクロリド（４４．２ｍＬ，３５０ｍｍｏｌ）を滴下した。反応液を加熱し、内温２０～２５℃で４．５時間撹拌した。反応液を冷却し、内温３～８℃で亜硫酸ナトリウム（８．７５ｇ）と精製水（３５０ｍＬ）の混合液を滴下した。滴下終了後、晶析を確認した後、内温２～６℃で３０分間撹拌した。反応液に内温３～８℃で精製水（３５０ｍＬ）を滴下した後、内温３～８℃で３０分間撹拌した。結晶をろ取し、精製水（３５０ｍＬ）及びジイソプロピルエーテル（３５０ｍＬ）で順次洗浄して、湿潤粗結晶である白色粉末（８６．４ｇ）を得た。
　内温１６～２２℃で湿潤粗結晶（８６．４ｇ）をジイソプロピルエーテル（２１０ｍＬ）に加え１０分撹拌した。結晶をろ取し、ジイソプロピルエーテル（１４０ｍＬ）で洗浄し、室温で一日放置して湿潤粗結晶である白色粉末（５６．５ｇ）得た。
　得られた湿潤粗結晶（５６．５ｇ）にエタノール（２８０ｍＬ）を加えた。次いで、得られた混液に内温２１℃で亜硫酸アンモニウム一水和物（１４．０ｇ）と精製水（１０５ｍＬ）の混合液を滴下し、溶解を確認した。溶液を加熱し、内温５０～５４℃で３０分間撹拌した。溶液を冷却し、内温２０～２５℃で水酸化ナトリウム（１４．０ｇ）及び精製水（１７５ｍＬ）の混合液を滴下した後、内温２０～２５℃で１０分間撹拌した。溶液に内温２０～２４℃で濃塩酸（４５．５ｍＬ）と精製水（４５．５ｍＬ）の混合液を滴下した。溶液を加熱し、内温３０～３８℃で精製水（４５５ｍＬ）を滴下した。晶析を確認後、滴下を中断して内温３５～３７℃で３０分間撹拌し、内温３４～３７℃で残りの精製水を滴下した。当該混液を冷却し、内温７～１５℃で３０分間撹拌した。結晶をろ取し、精製水（３５０ｍＬ）で洗浄して、湿潤結晶（６４．４ｇ）を得た。設定温度５０℃で２４時間減圧乾燥して、白色粉末の粗結晶（２５．９ｇ）を得た。
　エタノール（１３０ｍＬ）及び酢酸エチル（１３０ｍＬ）を加えて、溶解を確認した。加温加熱し、内温５６～５９℃でジイソプロピルエーテル（３８９ｍＬ）を滴下した後、内温５７～６１℃で３０分間撹拌した。冷却し、内温４～１０℃で３０分間撹拌した。結晶をろ取し、エタノール（２５．９ｍＬ）とジイソプロピルエーテル（７７．７ｍＬ）の混合液で洗浄した。設定温度５０℃で３時間減圧乾燥して、白色粉末の粗結晶（２３．４ｇ）得た。
　得られた粗結晶にエタノール（１１７ｍＬ）及び精製水（４６．７ｍＬ）を加えた。得られた混液に内温２７℃で濃塩酸（１．９９ｍＬ）を加えた。混液を加温し、内温５１℃で溶解を確認した。溶液を冷却し、内温２９～３４℃で３０分間撹拌した。溶液に内温３１～３２℃で精製水（１８７ｍＬ）を滴下した後、冷却し、内温１１～１５℃で３０分間撹拌した。結晶をろ取し、精製水（２３４ｍＬ）で洗浄した。設定温度５０℃で減圧乾燥し、白色粉末（２２．９ｇ）を得た。
　得られた白色粉末にエタノール（１８３ｍＬ）を加え、溶解し、内温３１℃で精製水（９１．５ｍＬ）を加え、晶析を確認した。混液を加熱溶解した後、不溶物を熱時ろ別し、エタノール（４５．８ｍＬ）で洗浄した。ろ液と洗液を合一し、加熱溶解した。溶液を冷却し、内温４２～４６℃で３０分間撹拌した。溶液に内温４１～４３℃で精製水（３６６ｍＬ）を滴下した後、冷却し、内温１１～１５℃で３０分間撹拌した。結晶をろ取し、精製水（１１４ｍＬ）で洗浄した。結晶を設定温度５０℃で減圧乾燥し、白色粉末のリン酸　２水素　（２Ｓ）－２－アミノ－２－｛２－［２－クロロ－４－（５－エトキシ－２－ヒドロキシフェニルチオ）フェニル］エチル｝ペンチル（２２．８ｇ，８０％収率)を得た。
ＭＳ(ＥＳＩ＋)：ｍ/ｚ ４９０ [Ｍ＋Ｈ]＋ Example 10 Synthesis of dihydrogen phosphate (2S) -2-amino-2- {2- [2-chloro-4- (5-ethoxy-2-hydroxyphenylthio) phenyl] ethyl} pentyl (Step 10) )
Acetonitrile (175 mL) and purified water (1.05 mL, 58.3 mmol) were added to the slightly yellow oil (43.1 g) obtained in Example 9 to obtain a reaction solution. Subsequently, sodium iodide (87.4 g, 583 mmol) was added to the reaction solution at an internal temperature of 20 to 26 ° C. The reaction mixture was cooled, and trimethylsilyl chloride (44.2 mL, 350 mmol) was added dropwise at an internal temperature of 16-24 ° C. The reaction solution was heated and stirred at an internal temperature of 20 to 25 ° C. for 4.5 hours. The reaction solution was cooled, and a mixed solution of sodium sulfite (8.75 g) and purified water (350 mL) was added dropwise at an internal temperature of 3 to 8 ° C. After completion of dropping, crystallization was confirmed, followed by stirring at an internal temperature of 2 to 6 ° C. for 30 minutes. Purified water (350 mL) was added dropwise to the reaction solution at an internal temperature of 3-8 ° C., followed by stirring at an internal temperature of 3-8 ° C. for 30 minutes. The crystals were collected by filtration and washed successively with purified water (350 mL) and diisopropyl ether (350 mL) to obtain white powder (86.4 g) as wet crude crystals.
Wet crude crystals (86.4 g) were added to diisopropyl ether (210 mL) at an internal temperature of 16-22 ° C. and stirred for 10 minutes. The crystals were collected by filtration, washed with diisopropyl ether (140 mL), and allowed to stand at room temperature for 1 day to obtain white powder (56.5 g) as wet crude crystals.
Ethanol (280 mL) was added to the obtained wet crude crystals (56.5 g). Subsequently, a mixed solution of ammonium sulfite monohydrate (14.0 g) and purified water (105 mL) was dropped into the obtained mixed solution at an internal temperature of 21 ° C., and dissolution was confirmed. The solution was heated and stirred at an internal temperature of 50 to 54 ° C. for 30 minutes. The solution was cooled, and a mixed solution of sodium hydroxide (14.0 g) and purified water (175 mL) was added dropwise at an internal temperature of 20-25 ° C., followed by stirring at an internal temperature of 20-25 ° C. for 10 minutes. To the solution was added dropwise a mixture of concentrated hydrochloric acid (45.5 mL) and purified water (45.5 mL) at an internal temperature of 20 to 24 ° C. The solution was heated, and purified water (455 mL) was added dropwise at an internal temperature of 30 to 38 ° C. After confirming crystallization, the dropping was interrupted and stirred for 30 minutes at an internal temperature of 35 to 37 ° C., and the remaining purified water was added dropwise at an internal temperature of 34 to 37 ° C. The mixture was cooled and stirred at an internal temperature of 7 to 15 ° C. for 30 minutes. The crystals were collected by filtration and washed with purified water (350 mL) to obtain wet crystals (64.4 g). It was dried under reduced pressure at a set temperature of 50 ° C. for 24 hours to obtain white crystals of crude crystals (25.9 g).
Ethanol (130 mL) and ethyl acetate (130 mL) were added to confirm dissolution. The mixture was heated and heated, and diisopropyl ether (389 mL) was added dropwise at an internal temperature of 56 to 59 ° C., followed by stirring at an internal temperature of 57 to 61 ° C. for 30 minutes. The mixture was cooled and stirred at an internal temperature of 4 to 10 ° C. for 30 minutes. The crystals were collected by filtration and washed with a mixed solution of ethanol (25.9 mL) and diisopropyl ether (77.7 mL). Drying under reduced pressure at a preset temperature of 50 ° C. for 3 hours gave crude crystals (23.4 g) of white powder.
Ethanol (117 mL) and purified water (46.7 mL) were added to the resulting crude crystals. Concentrated hydrochloric acid (1.99 mL) was added to the resulting mixture at an internal temperature of 27 ° C. The mixture was heated and dissolution was confirmed at an internal temperature of 51 ° C. The solution was cooled and stirred at an internal temperature of 29-34 ° C. for 30 minutes. Purified water (187 mL) was added dropwise to the solution at an internal temperature of 31 to 32 ° C., and then cooled and stirred at an internal temperature of 11 to 15 ° C. for 30 minutes. The crystals were collected by filtration and washed with purified water (234 mL). Drying under reduced pressure at a set temperature of 50 ° C. gave a white powder (22.9 g).
Ethanol (183 mL) was added to the obtained white powder and dissolved, and purified water (91.5 mL) was added at an internal temperature of 31 ° C. to confirm crystallization. After the mixture was dissolved by heating, the insoluble material was filtered off while hot and washed with ethanol (45.8 mL). The filtrate and the washing solution were combined and dissolved by heating. The solution was cooled and stirred at an internal temperature of 42-46 ° C. for 30 minutes. Purified water (366 mL) was added dropwise to the solution at an internal temperature of 41 to 43 ° C., followed by cooling and stirring at an internal temperature of 11 to 15 ° C. for 30 minutes. The crystals were collected by filtration and washed with purified water (114 mL). The crystals were dried under reduced pressure at a set temperature of 50 ° C., and white powder dihydrogen phosphate (2S) -2-amino-2- {2- [2-chloro-4- (5-ethoxy-2-hydroxyphenylthio) phenyl Ethyl} pentyl (22.8 g, 80% yield) was obtained.
MS (ESI +): m / z 490 [M + H] +
（工程７についての検討）
　（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノールの塩化について、種々の酸を用いた場合の製造方法の比較結果を表１に示す。なお、９６．２％ｅｅの（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノールを、原料として反応に用いた。当該原料は、実施例８の生成物を脱Ｂｏｃ化して、（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノールへと変換した後、同様に合成したエナンチオマー（（２Ｒ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール）を、添加することで調製した。 (Examination about process 7)
Preparation of (2S) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} pentanol using various acids The comparison results of the methods are shown in Table 1. Reaction was performed using 96.2% ee (2S) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} pentanol as a raw material. Used for. The raw material was obtained by de-Bocating the product of Example 8 to produce (2S) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl. } Enantiomeric ((2R) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl) synthesized in the same manner after conversion to pentanol (Pentanol) was prepared by adding.
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１における「光学純度」とは、以下に示すＨＰＬＣ条件Ａで反応液を測定し、得られたＲ体とＳ体の面積より、以下の式（ｅ１）により算出した値である。 “Optical purity” in Table 1 is a value calculated by the following formula (e1) from the area of the R-form and S-form obtained by measuring the reaction solution under the following HPLC condition A.
 
Ｅ＝（Ｓ－Ｒ）／（Ｓ＋Ｒ）×１００（％）　　　（ｅ１）
 
E = (S−R) / (S + R) × 100 (%) (e1)
　式（ｅ１）中、Ｅは光学純度（％ｅｅ）を示し、ＳはＳ体の生成量を示し、ＲはＲ体の生成量を示す。 In the formula (e1), E represents optical purity (% ee), S represents the production amount of S isomer, and R represents the production amount of R isomer.
（ＨＰＬＣ条件Ａ）
カラム：ＣＨＩＲＡＬＰＡＫ　ＡＤ－３（４．６ｍｍＩＤ×２５０ｍｍ）
移動相：ノルマルヘキサン／エタノール／２－アミノエタノール＝９０／１０／０．１
流速：１．０ｍＬ／ｍｉｎ．
カラム温度：２５℃
検出波長：２３０ｎｍ
保持時間：３０．９９ｍｉｎ．（Ｒ体），３２．８３ｍｉｎ．（Ｓ体） (HPLC condition A)
Column: CHIRALPAK AD-3 (4.6 mm ID × 250 mm)
Mobile phase: normal hexane / ethanol / 2-aminoethanol = 90/10 / 0.1
Flow rate: 1.0 mL / min.
Column temperature: 25 ° C
Detection wavelength: 230 nm
Holding time: 30.99 min. (R-form), 32.83 min. (S body)
（実施例１１）
　（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール（４９．６ｍｇ，０．０９９２ｍｍｏｌ）にアセトニトリル（０．７５ｍＬ）を加え、設定温度６０℃で加熱溶解し、反応液とした。反応液にマレイン酸（１１．５ｍｇ，０．０９９１ｍｍｏｌ）とアセトニトリル（０．２５ｍＬ）の混合液を加えた。反応液を氷水冷却下、３０分撹拌した後、析出晶をろ取し、アセトニトリル（２．０ｍＬ）で洗浄した。析出晶を設定温度７０℃で減圧乾燥し、（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール　マレイン酸塩（３９．８ｍｇ、６５％収率、９８．３％ｅｅ）を得た。
　他の酸を用いた場合（実施例１２～１６）も、同様の操作で化合物を調製した。 (Example 11)
(2S) -2-Amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} pentanol (49.6 mg, 0.0992 mmol) in acetonitrile (0 .75 mL) was added and dissolved by heating at a set temperature of 60 ° C. to obtain a reaction solution. A mixed solution of maleic acid (11.5 mg, 0.0991 mmol) and acetonitrile (0.25 mL) was added to the reaction solution. The reaction solution was stirred for 30 minutes under cooling with ice water, and then the precipitated crystals were collected by filtration and washed with acetonitrile (2.0 mL). Precipitated crystals were dried under reduced pressure at a set temperature of 70 ° C., and (2S) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} pentanol malein The acid salt (39.8 mg, 65% yield, 98.3% ee) was obtained.
When other acids were used (Examples 12 to 16), the compounds were prepared in the same manner.
　実施例１１～１６の結果を表１に示す。酸としてマレイン酸やカンファースルホン酸を使用した場合、収率が７０％以下であったが、酒石酸を使用した場合は、８５％以上と高い収率で反応が進行した。さらに、Ｄ－（－）－酒石酸を使用した場合は、９９％ｅｅ以上の高い光学純度で、（２Ｓ）－２－アミノ－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝ペンタノール　Ｄ－(－)－酒石酸が得られた。 The results of Examples 11 to 16 are shown in Table 1. When maleic acid or camphorsulfonic acid was used as the acid, the yield was 70% or less, but when tartaric acid was used, the reaction proceeded with a high yield of 85% or more. Further, when D-(−)-tartaric acid is used, (2S) -2-amino-2- {2- [4- (2-benzyloxy-5-ethoxy) has a high optical purity of 99% ee or higher. Phenylthio) -2-chlorophenyl] ethyl} pentanol D-(-)-tartaric acid was obtained.
（参考例４）（２ＲＳ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－プロピルマロン酸１，１－ジメチルエチル　メチルの合成Reference Example 4 (2RS) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonate 1,1-dimethylethyl Composition
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　１，１－ジメチルエチル　エチル　２－プロピルマロネートの代わりに、１，１－ジメチルエチル　メチル　２－プロピルマロネートを用い、実施例２と同様の操作で合成した。
１Ｈ　ＮＭＲ（５００ＭＨｚ，ＣＤＣｌ３）δ０．９６（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ），１．２１－１．３１（２Ｈ，ｍ），１．３５（３Ｈ，ｔ，Ｊ＝６．９Ｈｚ），１．４７（９Ｈ，ｓ），１．９０－１．９３（２Ｈ，ｍ），２．０７－２．１２（２Ｈ，ｍ），２．５７－２．６１（２Ｈ，ｍ），３．７３（３Ｈ，ｓ），３．９１（２Ｈ，ｑ，Ｊ＝６．９Ｈｚ），５．０５（２Ｈ，ｓ），６．７３－６．７５（２Ｈ，ｍ），６．８５－６．８７（１Ｈ，ｍ），７．１１－７．１８（２Ｈ，ｍ），７．２８－７．３４（６Ｈ，ｍ） Synthesis was performed in the same manner as in Example 2, except that 1,1-dimethylethyl methyl 2-propyl malonate was used instead of 1,1-dimethylethyl ethyl 2-propyl malonate.
1H NMR (500 MHz, CDCl3) δ 0.96 (3H, t, J = 7.3 Hz), 1.21-1.31 (2H, m), 1.35 (3H, t, J = 6.9 Hz), 1.47 (9H, s), 1.90-1.93 (2H, m), 2.07-2.12 (2H, m), 2.57-2.61 (2H, m), 3. 73 (3H, s), 3.91 (2H, q, J = 6.9 Hz), 5.05 (2H, s), 6.73-6.75 (2H, m), 6.85-6. 87 (1H, m), 7.11-7.18 (2H, m), 7.28-7.34 (6H, m)
（工程３についての検討）
　以下に、（２ＲＳ）－２－｛２－［４－（２－ベンジルオキシ－５－エトキシフェニルチオ）－２－クロロフェニル］エチル｝－２－プロピルマロン酸　１，１－ジメチルエチル　メチルの脱ｔｅｒｔ－ブチル化反応について、種々の酸を用いた場合の製造方法の比較結果を示す。下記表の実施例及び比較例は実施例３の方法と同様に行った。 (Examination about process 3)
(2RS) -2- {2- [4- (2-Benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl} -2-propylmalonic acid 1,1-dimethylethyl -Shows the results of a comparison of production methods using various acids for the butylated reaction. The examples and comparative examples in the following table were carried out in the same manner as in Example 3.
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２における「ＨＰＬＣ面積％」とは、反応液をＨＰＬＣ条件Ｂで測定し、反応終了時における目的物の面積百分率（％）を、以下の式（ｅ２）から算出したものである。 “HPLC area%” in Table 2 is obtained by measuring the reaction solution under HPLC condition B and calculating the area percentage (%) of the target product at the end of the reaction from the following formula (e2).
 
Ｄ＝（ＯＰ）／（ＨＰ）×１００　　　（ｅ２）
 
D = (OP) / (HP) × 100 (e2)
　式（ｅ２）中、Ｄは目的物の面積百分率（％）を示し、ＯＰは目的物の生成量を示し、ＨＰはＨＰＬＣで観測されるピークの総和量のうち溶媒ピークを除いたものを示す。 In the formula (e2), D represents the area percentage (%) of the target product, OP represents the amount of the target product generated, and HP represents the total peak amount observed by HPLC excluding the solvent peak. .
（ＨＰＬＣ条件Ｂ）
プレカラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３（４．０ｍｍＩＤ×１０ｍｍ）
本カラム：Ｉｎｅｒｔｓｉｌ　ＯＤＳ－３（４．６ｍｍＩＤ×１５０ｍｍ）
移動相：アセトニトリル／薄めたリン酸（１→１０００）＝９０：１０
流速：１．０ｍＬ／ｍｉｎ．
カラム温度：４０℃
検出波長：２１０ｎｍ
保持時間：４．５６ｍｉｎ．（目的物），１２．６２ｍｉｎ．（原料） (HPLC condition B)
Precolumn: Inertsil ODS-3 (4.0 mm ID × 10 mm)
This column: Inertsil ODS-3 (4.6 mm ID × 150 mm)
Mobile phase: acetonitrile / diluted phosphoric acid (1 → 1000) = 90: 10
Flow rate: 1.0 mL / min.
Column temperature: 40 ° C
Detection wavelength: 210 nm
Holding time: 4.56 min. (Target product), 12.62 min. (material)
　表２の結果から分かる通り、Ｍｏｎｔｍｏｒｉｌｌｏｎｉｔｅ　ＫＳＦを用いた場合に、その他の酸を使用した場合に比べ、９６％と高い収率で、目的物が得られた。また、ｐ－トルエンスルホン酸やメタンスルホン酸を用いた場合も、反応が進行し、目的物を得ることができる。 As can be seen from the results in Table 2, the target product was obtained in a yield as high as 96% when Montmorillonite KSF was used compared to the case where other acids were used. In addition, when p-toluenesulfonic acid or methanesulfonic acid is used, the reaction proceeds and the target product can be obtained.
（工程５についての検討）
　表３に記載の化合物について、表３に記載の分離条件を用いて、実施例５と同様に光学分割を行った。分割結果を、ＨＰＬＣクロマトグラムとして図１～図５に示す（実施例２０：図１、実施例２１：図２、実施例２２：図３、実施例２３：図４、実施例２４：図５）
表３中ｋ’１は以下の式（ｅ３）で表される値であり、第一ピークの保持時間が短い程、小さな値となる。 (Examination about process 5)
The compounds shown in Table 3 were subjected to optical resolution in the same manner as in Example 5 using the separation conditions shown in Table 3. The results of the resolution are shown in FIG. 1 to FIG. 5 as HPLC chromatograms (Example 20: FIG. 1, Example 21: FIG. 2, Example 22: FIG. 3, Example 23: FIG. 4, Example 24: FIG. 5). )
In Table 3, k′1 is a value represented by the following formula (e3), and becomes smaller as the retention time of the first peak is shorter.
 
ｋ’１＝（ｔ１－ｔ０）／ｔ０　　　（ｅ３）
 
k′1 = (t1−t0) / t0 (e3)
　式（ｅ３）中、ｔ０はカラムに保持されない成分の溶出時間を示し、ｔ１は第１ピークの保持時間を示す。 In formula (e3), t0 represents the elution time of the component not retained on the column, and t1 represents the retention time of the first peak.
　表３中、α（α値）とは以下の式（ｅ４）で表される値である。α値は、第一ピークと第二ピークの保持時間の差が大きい程大きな値となる。第一ピークと第二ピークを光学分割するという点で、α値は１．５以上であることが好ましく、特に好ましくは１．７以上が挙げられる。 In Table 3, α (α value) is a value represented by the following equation (e4). The α value increases as the difference in retention time between the first peak and the second peak increases. In terms of optically dividing the first peak and the second peak, the α value is preferably 1.5 or more, and particularly preferably 1.7 or more.

α＝ｋ’２／ｋ’１　　　（ｅ４）
α = k′2 / k′1 (e4)
　なお、式（ｅ４）中のｋ’２は以下の式（ｅ５）で表される値である。 In addition, k′2 in the formula (e4) is a value represented by the following formula (e5).

ｋ’２＝（ｔ２－ｔ０）／ｔ０　　　（ｅ５）
 
k′2 = (t2−t0) / t0 (e5)
　式（ｅ５）中、ｔ０はカラムに保持されない成分の溶出時間を示し、ｔ２は第２ピークの保持時間を示す。 In formula (e5), t0 represents the elution time of the component not retained on the column, and t2 represents the retention time of the second peak.
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　図１～図５の結果から分かる通り、実施例２０～２４において、第一ピークと第二ピークが完全に分離しており、光学分割が可能である。 As can be seen from the results of FIGS. 1 to 5, in Examples 20 to 24, the first peak and the second peak are completely separated, and optical resolution is possible.
　本実施形態によれば、特許文献１において開示された化合物を含むジフェニルスルフィド誘導体の新規な製造方法を提供することができる。
　本実施形態の製造方法により、得られる化合物の光学純度を高めることができる。また、本実施形態の製造法によれば、基質及び製造中間体を選択することで、得られる化合物の光学純度をさらに高めることも可能である。
　よって、本実施形態によれば、ジフェニルスルフィド誘導体を工業的に有利に製造することができ、高品質の医薬品を提供することが可能となる。 According to this embodiment, the novel manufacturing method of the diphenyl sulfide derivative containing the compound disclosed in patent document 1 can be provided.
By the production method of the present embodiment, the optical purity of the obtained compound can be increased. Moreover, according to the production method of the present embodiment, the optical purity of the obtained compound can be further increased by selecting the substrate and the production intermediate.
Therefore, according to the present embodiment, the diphenyl sulfide derivative can be advantageously produced industrially, and a high-quality pharmaceutical product can be provided.

Claims (15)

  1. 　一般式（６）：
    Figure JPOXMLDOC01-appb-C000094
    ［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
    Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を表し；
    Ｒ３は、ハロゲン原子を示し；
    Ｒ４は、炭素数１～６のアルキル基を示し；
    Ｒ５は、炭素数１～６のアルキル基を示し；
    Ｒ６は、炭素数１～６のアルキル基を示す。］で表される化合物を、光学分割カラムによる光学分割に供し、
    　分離される、一般式（７）：
    Figure JPOXMLDOC01-appb-C000095
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、前記定義と同じ。］
    で表される化合物、及び／または一般式（８）：
    Figure JPOXMLDOC01-appb-C000096
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、前記定義と同じ。］
    で表される化合物を回収する、光学分割方法。     General formula (6):
    Figure JPOXMLDOC01-appb-C000094
    [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
    R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent, or an aralkyl group which may have a substituent;
    R 3 represents a halogen atom;
    R 4 represents an alkyl group having 1 to 6 carbon atoms;
    R 5 represents an alkyl group having 1 to 6 carbon atoms;
    R 6 represents an alkyl group having 1 to 6 carbon atoms. The compound represented by the above is subjected to optical resolution by an optical resolution column,
    Separated, general formula (7):
    Figure JPOXMLDOC01-appb-C000095
    [Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
    And / or general formula (8):
    Figure JPOXMLDOC01-appb-C000096
    [Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
    The optical resolution method which collect | recovers the compound represented by these.
  2. 　前記一般式（６）で表される化合物は、前記一般式（７）で表される化合物として一般式（７ａ）：
    Figure JPOXMLDOC01-appb-C000097
    ［式中、Ｒ９は水素原子、ベンジル基または２－メトキシエトキシメチル基であり；
    Ｒ１０は、メチル基、エチル基またはｔｅｒｔ－ブチル基であり；
    Ｒ１１は、エチル基またはｔｅｒｔ－ブチル基であり；
    Ｚは、塩素原子である］
    で表される化合物を含み、且つ前記一般式（８）で表される化合物として一般式（８ａ）：
    Figure JPOXMLDOC01-appb-C000098
    ［式中、Ｒ９、Ｒ１０、Ｒ１１及びＺは、前記定義と同じ。］
    で表される化合物を含み、
    　回収される前記一般式（７ａ）で表される化合物の光学純度、及び／または回収される前記一般式（８ａ）で表される化合物の光学純度が９５％ｅｅ以上である、請求項１に記載の光学分割方法。     The compound represented by the general formula (6) is represented by the general formula (7a) as the compound represented by the general formula (7):
    Figure JPOXMLDOC01-appb-C000097
    [Wherein R 9 represents a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group;
    R 10 is a methyl group, an ethyl group or a tert-butyl group;
    R 11 is an ethyl group or a tert-butyl group;
    Z is a chlorine atom]
    And a compound represented by the general formula (8) as a compound represented by the general formula (8a):
    Figure JPOXMLDOC01-appb-C000098
    [Wherein R 9 , R 10 , R 11 and Z are the same as defined above. ]
    Including a compound represented by
    The optical purity of the compound represented by the general formula (7a) to be recovered and / or the optical purity of the compound represented by the general formula (8a) to be recovered is 95% ee or more. The optical resolution method described.
  3. 　前記一般式（７）で表される化合物、及び／または前記一般式（８）で表される化合物の製造方法であって、
    　一般式（４）：
    Figure JPOXMLDOC01-appb-C000099
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、前記定義と同じ。］
    で表される化合物に対し、有機スルホン酸または酸性粘土鉱物を反応させることにより、脱ｔｅｒｔ－ブチル化反応を行い、一般式（５）：
    Figure JPOXMLDOC01-appb-C000100
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５は、前記定義と同じ。］
    で表される化合物を取得し、
    　前記一般式（５）で表される化合物を転位反応に供することにより、前記一般式（６）で表される化合物を取得し、
    　請求項１または２に記載の光学分割方法により、前記一般式（６）で表される化合物から前記一般式（７）で表される化合物及び／または前記一般式（８）で表される化合物を得ることを含む方法。     A method for producing a compound represented by the general formula (7) and / or a compound represented by the general formula (8),
    General formula (4):
    Figure JPOXMLDOC01-appb-C000099
    [Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above. ]
    A detert-butylation reaction is carried out by reacting the compound represented by formula (5) with an organic sulfonic acid or an acidic clay mineral.
    Figure JPOXMLDOC01-appb-C000100
    [Wherein R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above. ]
    To obtain a compound represented by
    The compound represented by the general formula (6) is obtained by subjecting the compound represented by the general formula (5) to a rearrangement reaction,
    The compound represented by the general formula (7) and / or the compound represented by the general formula (8) from the compound represented by the general formula (6) by the optical resolution method according to claim 1 or 2. A method involving obtaining.
  4. 　請求項３に記載の方法において、
    　一般式（１）：
    Figure JPOXMLDOC01-appb-C000101
    ［式中、Ｒ１、Ｒ２及びＲ３は、前記定義と同じ。］
    で表される化合物を一般式（２）：
    Figure JPOXMLDOC01-appb-C000102
    ［式中、Ｒ１、Ｒ２及びＲ３は、前記定義と同じ。］
    で表される化合物に変換し、；
    　前記一般式（２）で表される化合物を、一般式（３）：
    Figure JPOXMLDOC01-appb-C000103
    ［式中、Ｒ４及びＲ５は、前記定義と同じ。］
    で表される化合物と反応させ、前記一般式（４）で表される化合物を取得することをさらに含む方法。     The method of claim 3, wherein
    General formula (1):
    Figure JPOXMLDOC01-appb-C000101
    [Wherein R 1 , R 2 and R 3 are the same as defined above. ]
    A compound represented by the general formula (2):
    Figure JPOXMLDOC01-appb-C000102
    [Wherein R 1 , R 2 and R 3 are the same as defined above. ]
    Converted to a compound represented by:
    The compound represented by the general formula (2) is represented by the general formula (3):
    Figure JPOXMLDOC01-appb-C000103
    [Wherein, R 4 and R 5 are the same as defined above. ]
    The method further comprising obtaining the compound represented by the general formula (4) by reacting with the compound represented by formula (4).
  5. 　一般式（１３）：
    Figure JPOXMLDOC01-appb-C000104
    ［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物の薬学的に許容しうる塩、及び／または一般式（１４）：
    Figure JPOXMLDOC01-appb-C000105
    ［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物の薬学的に許容しうる塩の製造方法であって、
    　請求項１または２に記載の光学分割方法により、前記一般式（６）で表される化合物から前記一般式（７）で表される化合物及び／または前記一般式（８）で表される化合物を取得し、
    　前記一般式（７）で表される化合物の還元を行うことにより一般式（９）：
    Figure JPOXMLDOC01-appb-C000106
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、前記定義と同じ。］
    で表される化合物及び一般式（１１）：
    Figure JPOXMLDOC01-appb-C000107
    ［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物を含む混合物を取得し、及び／または前記一般式（８）で表される化合物の還元を行うことにより一般式（１０）：
    Figure JPOXMLDOC01-appb-C000108
    ［式中Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ６は、前記定義と同じ。］
    で表される化合物及び一般式（１２）：
    Figure JPOXMLDOC01-appb-C000109
    ［式中Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物を含む混合物を取得し、
    　前記一般式（９）で表される化合物及び前記一般式（１１）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより前記一般式（１３）で表される化合物の薬学的に許容しうる塩を取得し、及び／または前記一般式（１０）で表される化合物及び前記一般式（１２）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物を無機酸又は有機酸と反応させることにより前記一般式（１４）で表される化合物の薬学的に許容しうる塩を取得することを含む方法。     General formula (13):
    Figure JPOXMLDOC01-appb-C000104
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    And / or the general formula (14):
    Figure JPOXMLDOC01-appb-C000105
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    A process for producing a pharmaceutically acceptable salt of a compound represented by:
    The compound represented by the general formula (7) and / or the compound represented by the general formula (8) from the compound represented by the general formula (6) by the optical resolution method according to claim 1 or 2. Get
    By reducing the compound represented by the general formula (7), the general formula (9):
    Figure JPOXMLDOC01-appb-C000106
    [Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above. ]
    And a compound represented by the general formula (11):
    Figure JPOXMLDOC01-appb-C000107
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    And / or reducing the compound represented by the general formula (8) to obtain the mixture represented by the general formula (10):
    Figure JPOXMLDOC01-appb-C000108
    [Wherein R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above. ]
    And a compound represented by the general formula (12):
    Figure JPOXMLDOC01-appb-C000109
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    To obtain a mixture containing the compound represented by
    A mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to a hydrolysis treatment, and the product of the hydrolysis treatment is reacted with an inorganic acid or an organic acid. To obtain a pharmaceutically acceptable salt of the compound represented by the general formula (13) and / or the compound represented by the general formula (10) and the compound represented by the general formula (12). A pharmaceutically acceptable salt of the compound represented by the general formula (14) is obtained by subjecting the mixture containing a hydrolyzate to a hydrolysis treatment and reacting the product of the hydrolysis treatment with an inorganic acid or an organic acid. A method involving that.
  6. 　前記一般式（９）で表される化合物及び前記一般式（１１）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物をＤ－（－）－酒石酸と反応させることにより前記一般式（１３）で表される化合物のＤ－（－）－酒石酸塩を取得し、及び／または前記一般式（１０）で表される化合物及び前記一般式（１２）で表される化合物を含む混合物を加水分解処理に供し、当該加水分解処理の生成物をＬ－（＋）－酒石酸と反応させることにより前記一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩を取得し、
    　前記一般式（１３）で表される化合物のＤ－（－）－酒石酸塩の光学純度、及び／または前記一般式（１４）で表される化合物のＬ－（＋）－酒石酸塩の光学純度が９９．０％ｅｅ以上である、請求項５に記載の方法。     A mixture containing the compound represented by the general formula (9) and the compound represented by the general formula (11) is subjected to hydrolysis treatment, and the product of the hydrolysis treatment is reacted with D-(−)-tartaric acid. To obtain a D-(−)-tartrate salt of the compound represented by the general formula (13) and / or the compound represented by the general formula (10) and the general formula (12). The mixture containing the compound is subjected to hydrolysis treatment, and the product of the hydrolysis treatment is reacted with L-(+)-tartaric acid to give L-(+) of the compound represented by the general formula (14). -Get tartrate,
    Optical purity of D-(−)-tartrate salt of the compound represented by the general formula (13) and / or optical purity of L-(+)-tartrate salt of the compound represented by the general formula (14) The method according to claim 5, wherein is 99.0% ee or more.
  7. 　一般式（１５）：
    Figure JPOXMLDOC01-appb-C000110
    ［式中、Ｒ７はアミノ基の保護基を示し、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物、及び／または一般式（１６）：
    Figure JPOXMLDOC01-appb-C000111
    ［式中、Ｒ７はアミノ基の保護基を示し、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物の製造方法であって、
    　請求項５または６に記載の方法により得られる前記一般式（１３）で表される化合物の薬学的に許容しうる塩の遊離塩基化及びアミノ基の保護を行い、及び／または請求項５または６に記載の方法により得られる前記一般式（１４）で表される化合物の薬学的に許容しうる塩の遊離塩基化及びアミノ基の保護を行うことを含む方法。     Formula (15):
    Figure JPOXMLDOC01-appb-C000110
    [Wherein R 7 represents an amino-protecting group, and R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    And / or general formula (16):
    Figure JPOXMLDOC01-appb-C000111
    [Wherein R 7 represents an amino-protecting group, and R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    A process for producing a compound represented by
    7. Free basification of a pharmaceutically acceptable salt of the compound represented by the general formula (13) obtained by the method according to claim 5 or 6 and protection of an amino group, and / or A method comprising free basification of a pharmaceutically acceptable salt of the compound represented by the general formula (14) obtained by the method according to 6 and protection of an amino group.
  8. 　前記一般式（１５）で表される化合物の光学純度、及び／または前記一般式（１６）で表される化合物の光学純度が９９．５％ｅｅ以上である、請求項７に記載の方法。 The method according to claim 7, wherein the optical purity of the compound represented by the general formula (15) and / or the optical purity of the compound represented by the general formula (16) is 99.5% ee or higher.
  9. 　一般式（１９）：
    Figure JPOXMLDOC01-appb-C000112
    ［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物、及び／または一般式（２０）：
    Figure JPOXMLDOC01-appb-C000113
    ［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は、前記定義と同じ。］
    で表される化合物の製造方法であって、
    　請求項７または８に記載の方法により得られる前記一般式（１５）で表される化合物とリン酸エステル化試薬とを反応させ、一般式（１７）：
    Figure JPOXMLDOC01-appb-C000114
    ［式中、Ｒ８は炭素数１～６のアルキル基を示し、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、前記定義と同じ。］
    で表される化合物を取得し、及び／または請求項７または８に記載の方法により得られる前記一般式（１６）で表される化合物とリン酸エステル化試薬とを反応させ、一般式（１８）：
    Figure JPOXMLDOC01-appb-C000115
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、前記定義と同じ。］
    で表される化合物を取得し、
    　前記一般式（１７）で表される化合物を一般式（１９）で表される化合物に変換し、及び／または前記一般式（１８）で表される化合物を前記一般式（２０）で表される化合物に変換することを含む方法。     General formula (19):
    Figure JPOXMLDOC01-appb-C000112
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    And / or general formula (20):
    Figure JPOXMLDOC01-appb-C000113
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    A process for producing a compound represented by
    A compound represented by the general formula (15) obtained by the method according to claim 7 or 8 is reacted with a phosphate esterifying reagent, and the general formula (17):
    Figure JPOXMLDOC01-appb-C000114
    [Wherein R 8 represents an alkyl group having 1 to 6 carbon atoms, and R 1 , R 2 , R 3 , R 4 and R 7 are as defined above. ]
    And / or reacting the compound represented by the general formula (16) obtained by the method according to claim 7 or 8 with a phosphate esterification reagent, to obtain a general formula (18 ):
    Figure JPOXMLDOC01-appb-C000115
    [Wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above. ]
    To obtain a compound represented by
    The compound represented by the general formula (17) is converted into the compound represented by the general formula (19), and / or the compound represented by the general formula (18) is represented by the general formula (20). Converting to a compound.
  10. 　一般式（７）：
    Figure JPOXMLDOC01-appb-C000116
    ［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
    Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
    Ｒ３は、ハロゲン原子を示し；
    Ｒ４は、炭素数１～６のアルキル基を示し；
    Ｒ５は、炭素数１～６のアルキル基を示し；
    Ｒ６は、炭素数１～６のアルキル基を示す。］、または
    　一般式（８）：
    Figure JPOXMLDOC01-appb-C000117
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及びＲ６は、前記定義と同じ。］
    で表される化合物。     General formula (7):
    Figure JPOXMLDOC01-appb-C000116
    [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
    R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
    R 3 represents a halogen atom;
    R 4 represents an alkyl group having 1 to 6 carbon atoms;
    R 5 represents an alkyl group having 1 to 6 carbon atoms;
    R 6 represents an alkyl group having 1 to 6 carbon atoms. Or general formula (8):
    Figure JPOXMLDOC01-appb-C000117
    [Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are the same as defined above]. ]
    A compound represented by
  11. 　一般式（７ａ）：
    Figure JPOXMLDOC01-appb-C000118
    ［式中、Ｒ９は、水素原子、ベンジル基、ｐ－メトキシベンジル基または２－メトキシエトキシメチル基を示し；
    Ｒ１０は、メチル基、エチル基、ｔｅｒｔ－ブチル基を示し；
    Ｒ１１は、メチル基、エチル基、ｔｅｒｔ－ブチル基を示し；
    Ｚは、フッ素原子または塩素原子を示す。］、または
    　一般式（８ａ）：
    Figure JPOXMLDOC01-appb-C000119
    ［式中、Ｒ９、Ｒ１０、Ｒ１１及びＺは前記定義と同じ。］
    で表される請求項１０に記載の化合物。     General formula (7a):
    Figure JPOXMLDOC01-appb-C000118
    Wherein, R 9 represents a hydrogen atom, a benzyl group, p- methoxybenzyl group or a 2-methoxyethoxymethyl group;
    R 10 represents a methyl group, an ethyl group, or a tert-butyl group;
    R 11 represents a methyl group, an ethyl group, or a tert-butyl group;
    Z represents a fluorine atom or a chlorine atom. Or general formula (8a):
    Figure JPOXMLDOC01-appb-C000119
    [Wherein R 9 , R 10 , R 11 and Z are as defined above. ]
    The compound of Claim 10 represented by these.
  12. 　前記一般式（７ａ）及び一般式（８ａ）において、
    Ｒ９は、水素原子、ベンジル基または２－メトキシエトキシメチル基を示し；
    Ｒ１０は、メチル基、エチル基またはｔｅｒｔ－ブチル基を示し；
    Ｒ１１は、エチル基またはｔｅｒｔ－ブチル基を示し；
    Ｚは、塩素原子を示す請求項１１に記載の化合物。     In the general formula (7a) and the general formula (8a),
    R 9 represents a hydrogen atom, a benzyl group or a 2-methoxyethoxymethyl group;
    R 10 represents a methyl group, an ethyl group or a tert-butyl group;
    R 11 represents an ethyl group or a tert-butyl group;
    The compound according to claim 11, wherein Z represents a chlorine atom.
  13. 　一般式（１３）：
    Figure JPOXMLDOC01-appb-C000120
    ［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
    Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
    Ｒ３は、ハロゲン原子を示し；
    Ｒ４は、炭素数１～６のアルキル基を示す。］、または
    　一般式（１４）：
    Figure JPOXMLDOC01-appb-C000121
    ［式中、Ｒ１、Ｒ２、Ｒ３及びＲ４は前記定義と同じ。］
    で表される化合物の薬学的に許容しうる塩。     General formula (13):
    Figure JPOXMLDOC01-appb-C000120
    [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
    R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
    R 3 represents a halogen atom;
    R 4 represents an alkyl group having 1 to 6 carbon atoms. Or general formula (14):
    Figure JPOXMLDOC01-appb-C000121
    [Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above. ]
    A pharmaceutically acceptable salt of the compound represented by:
  14. 　一般式（１５）：
    Figure JPOXMLDOC01-appb-C000122
    ［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
    Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
    Ｒ３は、ハロゲン原子を示し；
    Ｒ４は、炭素数１～６のアルキル基を示し；
    Ｒ７は、アミノ基の保護基を示す。］
    または一般式（１６）：
    Figure JPOXMLDOC01-appb-C000123
      
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ７は、前記定義と同じ。］
    で表される化合物。     Formula (15):
    Figure JPOXMLDOC01-appb-C000122
    [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
    R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
    R 3 represents a halogen atom;
    R 4 represents an alkyl group having 1 to 6 carbon atoms;
    R 7 represents a protecting group for an amino group. ]
    Or general formula (16):
    Figure JPOXMLDOC01-appb-C000123
    [Wherein R 1 , R 2 , R 3 , R 4 and R 7 are the same as defined above. ]
    A compound represented by
  15. 　一般式（１７）：
    Figure JPOXMLDOC01-appb-C000124
    ［式中、Ｒ１は、炭素数１～６のアルコキシ基を示し；
    Ｒ２は、水素原子、置換基を有してもよい炭素数１～６のアルキル基または置換基を有してもよいアラルキル基を示し；
    Ｒ３は、ハロゲン原子を示し；
    Ｒ４は、炭素数１～６のアルキル基を示し；
    Ｒ７は、アミノ基の保護基を示し；
    Ｒ８は、炭素数１～６のアルキル基を示す。］、または
    　一般式（１８）：
    Figure JPOXMLDOC01-appb-C000125
    ［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ７及びＲ８は、前記定義と同じ。］
    で表される化合物。
          Formula (17):
    Figure JPOXMLDOC01-appb-C000124
    [Wherein R 1 represents an alkoxy group having 1 to 6 carbon atoms;
    R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms which may have a substituent or an aralkyl group which may have a substituent;
    R 3 represents a halogen atom;
    R 4 represents an alkyl group having 1 to 6 carbon atoms;
    R 7 represents an amino-protecting group;
    R 8 represents an alkyl group having 1 to 6 carbon atoms. Or general formula (18):
    Figure JPOXMLDOC01-appb-C000125
    [Wherein R 1 , R 2 , R 3 , R 4 , R 7 and R 8 are the same as defined above. ]
    A compound represented by
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Citations (4)

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WO2011004604A1 (en) * 2009-07-09 2011-01-13 杏林製薬株式会社 Diphenyl sulfide derivatives and medicines containing same as active ingredient
WO2012086184A1 (en) * 2010-12-21 2012-06-28 杏林製薬株式会社 Diphenyl sulfide derivative and pharmaceutical product which contains same as active ingredient

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018427A1 (en) * 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Aminophosphoric acid ester derivative and s1p receptor modulator containing the same as active ingredient
WO2009099174A1 (en) * 2008-02-07 2009-08-13 Kyorin Pharmaceutical Co., Ltd. Therapeutic agent or preventive agent for inflammatory bowel disease containing amino alcohol derivative as active ingredient
WO2011004604A1 (en) * 2009-07-09 2011-01-13 杏林製薬株式会社 Diphenyl sulfide derivatives and medicines containing same as active ingredient
WO2012086184A1 (en) * 2010-12-21 2012-06-28 杏林製薬株式会社 Diphenyl sulfide derivative and pharmaceutical product which contains same as active ingredient

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