WO2015194157A1 - Procédé de fabrication et intermédiaire de fabrication de dérivé diphénylsulfure - Google Patents

Procédé de fabrication et intermédiaire de fabrication de dérivé diphénylsulfure 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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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 Table
    • 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.

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Abstract

L'invention vise à procurer une technique qui se rapporte à un nouveau procédé de fabrication d'un dérivé diphénylsulfure. L'invention concerne un procédé de résolution optique consistant à soumettre un composé représenté par la formule générale (6) à une résolution optique à l'aide d'une colonne de résolution optique et à recueillir un composé séparé représenté par la formule générale (7) et/ou un composé représenté par la formule générale (8). L'invention concerne également un procédé de fabrication de composé comprenant ledit procédé de résolution optique.
PCT/JP2015/002985 2014-06-16 2015-06-15 Procédé de fabrication et intermédiaire de fabrication de dérivé diphénylsulfure WO2015194157A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018427A1 (fr) * 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
WO2009099174A1 (fr) * 2008-02-07 2009-08-13 Kyorin Pharmaceutical Co., Ltd. Agent thérapeutique ou agent préventif pour maladie inflammatoire des intestins contenant un dérivé d'alcool aminé comme composant actif
WO2011004604A1 (fr) * 2009-07-09 2011-01-13 杏林製薬株式会社 Dérivés de sulfure de diphényle et médicaments les contenant comme principe actif
WO2012086184A1 (fr) * 2010-12-21 2012-06-28 杏林製薬株式会社 Dérivés de sulfure de diphényle, et médicaments les contenant en tant que principe actif

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018427A1 (fr) * 2006-08-08 2008-02-14 Kyorin Pharmaceutical Co., Ltd. Dérivé d'ester de l'acide aminophosphorique et modulateur du récepteur s1p contenant ledit dérivé en tant que principe actif
WO2009099174A1 (fr) * 2008-02-07 2009-08-13 Kyorin Pharmaceutical Co., Ltd. Agent thérapeutique ou agent préventif pour maladie inflammatoire des intestins contenant un dérivé d'alcool aminé comme composant actif
WO2011004604A1 (fr) * 2009-07-09 2011-01-13 杏林製薬株式会社 Dérivés de sulfure de diphényle et médicaments les contenant comme principe actif
WO2012086184A1 (fr) * 2010-12-21 2012-06-28 杏林製薬株式会社 Dérivés de sulfure de diphényle, et médicaments les contenant en tant que principe actif

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHINO,M. ET AL.: "An efficient total synthesis of a sphingosine-1-phosphate receptor agonist KRP- 203", TETRAHEDRON, vol. 64, no. 17, 2008, pages 3859 - 3866, XP022520419 *

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