WO2016013225A1 - Procédé de fabrication de dérivé de diphénylsulfure, et intermédiaire de production - Google Patents

Procédé de fabrication de dérivé de diphénylsulfure, et intermédiaire de production Download PDF

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Publication number
WO2016013225A1
WO2016013225A1 PCT/JP2015/003702 JP2015003702W WO2016013225A1 WO 2016013225 A1 WO2016013225 A1 WO 2016013225A1 JP 2015003702 W JP2015003702 W JP 2015003702W WO 2016013225 A1 WO2016013225 A1 WO 2016013225A1
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general formula
compound represented
carbon atoms
group
alkyl group
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PCT/JP2015/003702
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Japanese (ja)
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後藤　崇之
康則 阿部
晃一 清田
誠 牛渡
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杏林製薬株式会社
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Priority to JP2016535803A priority Critical patent/JPWO2016013225A1/ja
Publication of WO2016013225A1 publication Critical patent/WO2016013225A1/fr

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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture

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).
  • Non-Patent Document 1 a method of constructing an amino acid having a quaternary asymmetric carbon by asymmetric hydrolysis of a symmetric diester derivative using an enzyme such as porcine liver esterase and subjecting the obtained product to a rearrangement reaction is known.
  • An object of the present invention is to provide a technique relating to a novel method for producing a diphenyl sulfide derivative.
  • the present inventors have conducted asymmetric hydrolysis of a specific symmetric diester derivative using porcine liver esterase or rabbit liver esterase, thereby obtaining a compound represented by the formula (A), etc.
  • the present inventors have found that a compound represented by the general formula (5) can be obtained as a production intermediate in a method for producing a diphenyl sulfide derivative containing:
  • the gist of the present invention is as follows.
  • the manufacturing method of the compound represented by the said General formula (5) including carrying out asymmetric hydrolysis using the pig liver esterase or rabbit liver esterase.
  • the compound represented by the general formula (4) is asymmetrically hydrolyzed using the porcine liver esterase, The method of [1], wherein the optical purity of the obtained compound represented by the general formula (5) is 99% ee or more.
  • a technique relating to a novel method for producing a diphenyl sulfide derivative can be provided.
  • an alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • 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.
  • the alkyl group having 1 to 6 carbon atoms may have a substituent.
  • 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.
  • the alkyl group having 1 to 6 carbon atoms represented by R 4 is preferably an n-propyl group.
  • As the alkyl group having 1 to 6 carbon atoms represented by R 5 a methyl group, an ethyl group or a tert-butyl group is preferable, and a methyl group is particularly preferable.
  • the alkyl group having 1 to 6 carbon atoms represented by R 6 is preferably a tert-butyl group.
  • the “optionally substituted alkyl group having 1 to 6 carbon atoms” is preferably a 2-methoxyethoxymethyl group (MEM group) or a methoxymethyl group (MOM group), more preferably a methoxymethyl group. Is mentioned.
  • the “C 1-6 alkoxy group” is a linear or branched alkoxy group having 1-6 carbon atoms.
  • Examples of the alkoxy group having 1 to 6 carbon atoms include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, isopropoxy group, tert-butoxy group and hexyloxy group.
  • the “alkoxy group having 1 to 6 carbon atoms” used as R 1 is preferably an ethoxy group.
  • the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom.
  • examples of the “aralkyl group” include a benzyl group, a diphenylmethyl group, a phenethyl group, and a phenylpropyl group.
  • the aralkyl group may have a substituent.
  • 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.
  • Examples of the “aralkyl group which may have a substituent” include a benzyl group and a p-methoxybenzyl group, preferably a benzyl group.
  • R 2 is preferably an aralkyl group which may have a substituent from the viewpoint of improving crystallinity, and a benzyl group is particularly preferable.
  • pig liver esterase includes an esterase obtained using a genetic recombination technique, and is not limited to those derived from pigs.
  • porcine liver esterase include PLE433 (DSM).
  • the “rabbit liver esterase” includes an esterase obtained by using a gene recombination technique, and is not limited to those derived from rabbits.
  • the optical purity (% ee) refers to the ratio of a certain compound to the sum of the compound and its optical isomers. Specifically, the optical purity can be calculated based on the area percentage of a certain compound and its optical isomer in the HPLC measurement result.
  • the production method according to this embodiment is shown in the following scheme 1. Each step shown in Scheme 1 will be described in detail below.
  • R 1 represents an alkoxy group having 1 to 6 carbon atoms
  • R 2 may have a hydrogen atom, an optionally substituted alkyl group having 1 to 6 carbon atoms, or a substituent.
  • a good aralkyl group R 3 represents a hydrogen atom or 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 a carbon number 1 to 6 alkyl groups are shown.
  • 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 the same as defined above.
  • the conversion can be performed based on, for example, a Wittig reaction, a Horner-Emmons reaction, a Peterson reaction, a TiCl 4 —CH 2 Cl 2 —Zn-based reaction, or a Többe reaction.
  • a Wittig reaction a Horner-Emmons reaction
  • a Peterson reaction a TiCl 4 —CH 2 Cl 2 —Zn-based reaction
  • a Többe reaction since the compound represented by the general formula (2) tends to decompose at a high temperature, it is preferable to perform the reaction based on the Peterson reaction in which the reaction proceeds at a relatively low temperature.
  • the Peterson reaction was obtained, for example, by reacting a Peterson reagent such as trimethylsilylmethylmagnesium chloride, trimethylsilylmethylmagnesium bromide with the compound represented by the general formula (1) in a reaction solvent such as tetrahydrofuran.
  • 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, 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.
  • 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 are mentioned, More preferably, tetrahydrofuran is mentioned.
  • the reaction solvent is preferably used in an amount that is twice or more the amount of the compound represented by the general formula (1).
  • the amount of the reaction solvent used is more preferably 2 to 7 times the amount of the compound represented by the general formula (1), particularly preferably the compound represented by the general formula (1). On the other hand, the amount is 3 times or more and 5 times or less.
  • 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.
  • a compound such as 5-alkoxy-1,3-benzoxiathiol-2-one and the like represented by the general formula (p1) 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).
  • 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.
  • 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 obtained compound represented by the general formula (p2) is mixed with metal zinc, zinc amalgam, zinc-in the presence of a reducing agent such as sodium borohydride or an acid such as hydrochloric acid or acetic acid in a reaction solvent.
  • a compound represented by general formula (1) is obtained by allowing a copper alloy or the like to act and then reacting with a compound represented by general formula (p3) in a reaction solvent (step P2).
  • 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.
  • 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.
  • 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.
  • Amides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate , Aliphatic esters such as isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, or ethyl isovalerate, ketones such as acetone, or mixtures thereof.
  • the solution of the compound represented by the general formula (2) may be added dropwise to the solution of the compound represented by the general formula (3) in terms of suppressing the formation of by-products. preferable.
  • the amount of the solvent is 2 times or more, more preferably 2 times or more and 7 times or less, More preferably, the amount is adjusted to be 3 times or more and 5 times or less.
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent to be used, but preferably 0 ° C. in that the yield of the compound represented by the general formula (4) can be improved.
  • the temperature is 100 ° C. or less, more preferably 10 ° C. or more and 45 ° C. or less, and particularly preferably 20 ° C. or more and 40 ° C. or less.
  • 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-
  • inorganic bases such as cesium carbonate and potassium carbonate
  • 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.
  • the usage-amount of a base can be used 1 equivalent or more with respect to the compound represented by General formula (2).
  • they are 1 equivalent or more and 10 equivalents or less, More preferably, they are 1 equivalent or more and 5 equivalents or less, More preferably, they are 1.1 equivalents or more and 2.8 equivalents or less, Especially preferably, 1.2 equivalents or more and 1.8 equivalents or less are mentioned.
  • the amount of the compound represented by the general formula (3) is preferably 1 equivalent or more and 10 equivalents or less with respect to the compound represented by the general formula (2). More preferably, 1.6 equivalents or more and 5 equivalents or less, more preferably 2 equivalents or more and 4 equivalents or less are used.
  • 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 (5) can be obtained by reacting the compound represented by the general formula (4) with porcine liver esterase or rabbit liver esterase and performing hydrolysis (asymmetric hydrolysis).
  • asymmetric hydrolysis refers to selective hydrolysis of one of the same two alkoxycarbonyl groups bonded to a quaternary carbon to convert it into a carboxy group. Means to preferentially produce one of the compounds having an optical isomer relationship.
  • R 1 , R 2 , R 3 , R 4 and R 5 are the same as defined above.
  • any porcine liver esterase or rabbit liver esterase can be used and is not particularly limited.
  • the porcine liver esterase may be a porcine liver esterase obtained by using a gene recombination technique.
  • the rabbit liver esterase may also be a rabbit liver esterase obtained by using a gene recombination technique as described above.
  • porcine liver esterase When porcine liver esterase is used, a compound represented by general formula (5) with higher optical purity is obtained than when rabbit liver esterase is used, and the yield of the compound represented by general formula (5) is obtained. Will also improve. Therefore, the use of porcine liver esterase is preferred for the reaction.
  • the yield is a value obtained by dividing the amount of the target substance actually obtained by the amount of the target substance assumed to be theoretically obtained.
  • Porcine liver esterase or rabbit liver esterase is preferably used in an amount of 50 wt% to 500 wt% with respect to the compound represented by the general formula (4). More preferable use amount is 60 wt% or more and 300 wt% or less, and more preferable use amount is 70 wt% or more and 150 wt% or less. *
  • the preferable pH of the reaction is 8.0 or less. From the viewpoint that the reaction rate can be further increased, the more preferable pH is 3.0 or more and 8.0 or less, further preferably 5.0 or more and 7.5 or less, and particularly preferably 6.0 or more and 7.0 or less. It is.
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent to be used, but if the reaction temperature is high, the enzyme is rapidly deactivated and the yield may decrease. Accordingly, a preferable reaction temperature is 50 ° C. or lower, more preferably 45 ° C. or lower, and still more preferably 38 ° C. or lower.
  • the reaction temperature is preferably 20 ° C. or higher because the reaction rate decreases as the reaction temperature decreases. More preferably, 25 degreeC or more, Especially preferably, 30 degreeC or more is mentioned. Accordingly, the reaction temperature is preferably 20 ° C. or higher and 50 ° C. or lower, more preferably 25 ° C. or higher and 45 ° C. or lower, and particularly preferably 30 ° C. or higher and 38 ° C. or lower.
  • the enzyme reaction can be performed using, for example, a solvent.
  • a solvent examples include ethers such as tetrahydrofuran, cyclopentyl methyl ether, dioxane, dimethoxyethane, and diglyme, aromatic compounds such as benzene, toluene, and xylene, nitriles such as acetonitrile and propionitrile, and halogenated carbonization such as dichloromethane.
  • Hydrogens methanol, ethanol, 2-propanol, tert-butyl alcohol, alcohols such as ethylene glycol and diethylene glycol, amides such as formamide, N-methylpyrrolidone and N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, Examples include sulfones such as sulfolane, ketones such as acetone, water, or a mixture thereof. When acetonitrile is used as a solvent, the reaction may not easily proceed.
  • Preferable solvents include sulfoxides from the viewpoint of improving the yield, and more preferably dimethyl sulfoxide.
  • the amount of the solvent used is preferably 2 times or more and 30 times or less, more preferably 5 times or more and 20 times or less, still more preferably 7 times or more and 15 times the amount of the compound represented by the general formula (4). Double amount or less is mentioned.
  • the compound represented by General formula (5) can be isolate
  • 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.
  • a base such as triethylamine, azidation of bis (4-methylphenyl) phosphoric azide, bis (4-chlorophenyl) phosphoric azide, diphenylphosphoric azide, etc. into the compound represented by the general formula (5) React the reagent.
  • 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.
  • it is preferable to use an organic base and triethylamine is particularly preferable.
  • the amount of the base used is preferably 1 equivalent or more and 3 equivalents or less with respect to the compound represented by the general formula (5). From the viewpoint of improving the yield, more preferably 1 equivalent to 2 equivalents, and particularly preferably 1 equivalent to 1.5 equivalents.
  • the reaction can be performed, for example, in a reaction solvent.
  • the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, and diglyme, aromatic compounds such as benzene, toluene, and xylene, nitriles such as acetonitrile and propionitrile, and halogenation such as dichloromethane.
  • Hydrocarbons amides such as formamide, N-methylpyrrolidone, N, N-dimethylformamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, ethyl formate, n-butyl formate, ethyl acetate, n-propyl acetate , Aliphatic esters such as isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-hexyl acetate, 2-ethylhexyl acetate, ethyl propionate, n-butyl propionate, ethyl isovalerate, ketones such as acetone,
  • the mixtures thereof, preferably, benzene, toluene can be used an aromatic hydrocarbon solvent such as xylene, more preferably toluene.
  • the amount of the solvent is preferably small.
  • 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 15 times or less, more preferably 10 times or less.
  • the rearrangement reaction is preferably allowed to proceed with heating to generate isocyanate. 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 (13) 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.
  • the compound represented by the general formula (13) a commercially available compound can be used. For example, it can be prepared in a reaction solution by reacting a compound such as sodium hydride or metal sodium 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 with respect 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.
  • the reaction temperature is usually in the range from ⁇ 70 ° C. to the boiling point of the solvent used, preferably in the range from ⁇ 10 ° C. to the boiling point of the solvent used, particularly preferably from 0 to 30 ° C., more preferably A range of 10 to 30 ° C can be mentioned.
  • R 1 , R 2 , R 3 , R 4 and R 6 are the same as defined above.
  • the compound represented by the general formula (7) is dissolved in a reaction solvent such as tetrahydrofuran, the obtained solution is added to a reducing agent, and an alcohol such as ethanol or methanol is further added to react. Can be done.
  • a reaction solvent such as tetrahydrofuran
  • an alcohol such as ethanol or methanol
  • 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, still more preferred is lithium borohydride.
  • a reducing agent is 1 equivalent or more and 10 equivalent or less with respect to the compound represented by General formula (7), for example. More preferably, they are 2 equivalents or more and 8 equivalents or less, More preferably, 4 equivalents or more and 7 equivalents or less are mentioned.
  • 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 preferred is a method using potassium borohydride in the presence of lithium chloride.
  • the preferred usage amount of the lithium salt and the boron hydride-based reducing agent is 1 for each compound represented by the general formula (7).
  • the reaction temperature usually ranges from ⁇ 70 ° C. to the boiling point of the solvent used. From the viewpoint of improving the yield, it is preferably 0 ° C. or higher and 55 ° C. or lower, more preferably 25 ° C. or higher and 55 ° C. or lower. .
  • the reaction can be performed, for example, in a reaction solvent.
  • the reaction solvent include ethers such as tetrahydrofuran, cyclopentylmethyl ether, dioxane, dimethoxyethane, diglyme, aromatic compounds such as benzene, toluene, xylene, hydrocarbons such as hexane, heptane, cyclohexane, or the like.
  • 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). 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.
  • the resulting compound represented by the general formula (9) can be purified by recrystallization to remove impurities that are difficult to purify and improve the chemical purity. Furthermore, the optical purity can be further increased by the recrystallization.
  • Step 6 The compound represented by the general formula (11) is converted to a phosphate ester of the hydroxyl group of the compound represented by the general formula (9) using the method described in Patent Document 1, and then R 6 and R 2 . It can be obtained by deprotection and dealkylation of the phosphate group.
  • the compound represented by the general formula (5) can be produced using porcine liver esterase or rabbit liver esterase.
  • the compound represented by the general formula (5) can be used as a production intermediate in a method for producing a diphenyl sulfide derivative including, for example, the compound represented by the above formula (A). Therefore, according to this embodiment, a novel method for producing a diphenyl sulfide derivative can be provided.
  • porcine liver esterase a compound represented by the general formula (5) having high optical purity can be obtained. Therefore, it is possible to produce the final product diphenyl sulfide derivative with high optical purity.
  • 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).
  • a solution of sodium hydroxide (12.23 g, 306 mmol) in water (50 mL) was added to the mixture 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 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 reaction mixture 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).
  • 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), and dissolved by heating.
  • Zinc powder (5.04 g, 77.1 mmol) was added to the mixture 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 reaction solution was cooled, and water (48 mL) was added at an internal temperature of 20 to 25 ° C. to separate the layers.
  • the organic layer was washed with saturated brine (80 mL) and dried over anhydrous sodium sulfate.
  • Tetrahydrofuran 200 mL of 4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorobenzaldehyde (50 g, 125 mmol) in 1.0 mol / L trimethylsilylmethylmagnesium chloride tetrahydrofuran solution (163 mL, 163 mmol) under nitrogen atmosphere
  • the solution was added with stirring at an internal temperature of 27 to 28 ° C. over 32 minutes.
  • the mixture was stirred at an internal temperature of 25 to 27 ° C. for 1 hour, cooled, and concentrated hydrochloric acid (40 mL) was added at an internal temperature of 2 to 11 ° C. over 10 minutes.
  • the reaction solution was stirred at an internal temperature of 8 to 21 ° C.
  • Dimethyl sulfoxide (200 mL) was added to the brown oil (53.9 g) obtained in Example 1 and dissolved. Under a nitrogen atmosphere, dimethyl 2-propylmalonate (48.0 g, 276 mmol) was dissolved in dimethyl sulfoxide (200 mL), and cesium carbonate (61.3 g, 188 mmol) was added at 29 to 32 ° C. with stirring.
  • a dimethyl sulfoxide (200 mL) solution of the brown oil (53.9 g) obtained in Example 1 described above was added to the mixture at an internal temperature of 31 ° C. over 1 hour and 4 minutes, and the internal temperature was 29 to 31 ° C. The mixture was stirred for 6 hours and then allowed to stand overnight.
  • the reaction solution was cooled, and toluene (1.00 L) and water (1.00 L) were added at an internal temperature of 14-16 ° C.
  • the organic layer was separated, washed with a mixed solution of sodium chloride (100 g) and water (1.00 L), and dried using anhydrous sodium sulfate (100 g). After anhydrous sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure to obtain a brown oil (96.7 g). Diisopropyl ether (150 mL) was added to the brown oil obtained at an internal temperature of 25 ° C. to obtain a mixed solution.
  • Example 3 the optical purity of the obtained product was calculated based on the following formula (e1) from the areas of R-form and S-form obtained in the measurement under HPLC condition A shown below.
  • the R form means (2R) -2- ⁇ 2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl ⁇ -2-methoxycarbonylpentanoic acid.
  • the S form means (2S) -2- ⁇ 2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl ⁇ -2-methoxycarbonylpentanoic acid.
  • the reaction liquid was cooled to room temperature, 0.5 mol / L hydrochloric acid (100 mL) was added, and liquid separation was performed.
  • the organic layer was washed successively with water (100 mL), saturated sodium hydrogen carbonate solution (100 mL), and saturated brine (100 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil (11.2 g).
  • Tetrahydrofuran 60 mL was added to potassium borohydride (4.85 g, 90.0 mmol), lithium chloride (3.82 g, 90.0 mmol) was added at room temperature, and the resulting mixture was heated at an internal temperature of 40 ° C. for 22 hours.
  • the reaction solution was extracted with ethyl acetate (100 mL), and the organic layer was washed successively with 1 mol / L potassium hydroxide (100 mL) twice and saturated brine (50 mL).
  • the organic layer was dried using anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • Toluene (30 mL) was added to the residue, heated, and stirred at 55 ° C. for 15 minutes. After hot filtration, the filtrate was stirred at 55 ° C. for 15 minutes, and then heptane (240 mL) was added. The filtrate to which heptane was added was cooled, stirred at 38 ° C.
  • Example 5 by recrystallization with toluene and heptane, crystals having excellent fluidity and filterability can be obtained with high yield.
  • Example 5 the optical purity of the obtained product was calculated based on the following formula (e2) from the areas of R-form and S-form obtained in the measurement under HPLC condition B shown below.
  • the R form means (2R) -2- ⁇ 2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl ⁇ -2- (1,1-dimethylethoxycarbonyl). Means amino) pentanol.
  • the S form is (2S) -2- ⁇ 2- [4- (2-benzyloxy-5-ethoxyphenylthio) -2-chlorophenyl] ethyl ⁇ -2- (1,1-dimethylethoxycarbonylamino) pen Means Tanol.
  • 5-Ethoxy-1,3-benzoxiathiol-2-one (10.00 g, 51.0 mmol) was added to a mixture of ethanol (10 mL) and water (50 mL).
  • Sodium hydroxide (6.12 g, 153 mmol) was added to the mixture at an internal temperature of 12 to 28 ° C.
  • the mixture was stirred at an internal temperature of 40 to 48 ° C. for 1.5 hours.
  • the reaction mixture was cooled, 35% aqueous hydrogen peroxide (2.25 mL, 25.5 mmol) was added at an internal temperature of 10 to 28 ° C., and the mixture was stirred at an internal temperature of 20 to 28 ° C. for 2 hours.
  • the reaction mixture was cooled, 15 mL of concentrated hydrochloric acid was added at an internal temperature of 10 to 18 ° C., and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed sequentially with 10% sodium bisulfite (100 mL) and saturated brine (100 mL). The organic layer was dried using anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a brown oil (8.18 g). The obtained brown oil (8.18 g) was dissolved in tetrahydrofuran (30 mL).
  • N, N-diisopropylethylamine (16.5 g, 127 mmol) was added at an internal temperature of 25 ° C.
  • chloromethyl methyl ether (7.7 mL, 101 mmol) was added at an internal temperature of 25-37 ° C.
  • the mixture was stirred at an internal temperature of 55-62 ° C. for 4 hours.
  • a saturated ammonium chloride solution (75 mL) and water (25 mL) were added to the reaction solution at an internal temperature of 11 to 26 ° C.
  • the reaction solution was extracted with ethyl acetate (100 mL) and ethyl acetate (50 mL).
  • the reaction solution was cooled, and water (53 mL) was added at an internal temperature of 15 to 25 ° C., and a mixed solution of ammonium chloride (10.5 g) and water (53 mL) was added at an internal temperature of 20 to 25 ° C. Extracted twice with diisopropyl ether (53 mL). The organic layers were combined and extracted with a mixture of sodium hydroxide (2.64 g) and water (54 mL), a mixture of sodium hydroxide (1.32 g) and water (27 mL). The aqueous layers were combined, and concentrated hydrochloric acid (8.4 mL) was added at an internal temperature of 15 to 20 ° C.
  • Table 1 shows that various enzymes were used for hydrolysis of dimethyl 2- ⁇ 2- [4- (5-ethoxy-2-methoxymethoxyphenylthio) -2-chlorophenyl] ethyl ⁇ -2-propylmalonate. The comparison result is shown.
  • the “conversion rate” described in Table 1 is a value calculated based on the following formula (e3) from the area percentage (%) of the obtained raw material and target product after measuring the reaction solution under the HPCL condition C shown below. It is.
  • the target product includes both the compound (R form) represented by the formula (15) and the enantiomer (S form) of the compound represented by the formula (15).
  • Optical purity described in Table 1 is a value calculated based on the following formula (e4) from the areas of the R-form and S-form obtained by measuring the reaction solution under the HPLC condition D shown below. .
  • Example 7 2- ⁇ 2- [4- (2-methoxymethoxy-5-ethoxyphenylthio) -2-chlorophenyl was added to a mixed solution of Esterase from Porcine Liver (10.0 mg) and phosphate buffer (pH 7.0, 1.0 mL). Ethyl ⁇ -2-propylmalonate dimethyl (10.0 mg) in dimethyl sulfoxide (100 ⁇ L) was added. The mixture was stirred at a set temperature of 40 ° C. for 24 hours. When the reaction solution was measured under HPLC condition D, the optical purity of the compound represented by the formula (15) was 99.5% ee.
  • Example 8 The conditions were the same as in Example 7 except that the ester from Rabbit river was used. When measured under HPLC condition D, the optical purity of the compound represented by formula (15) was 69.7% ee.
  • Comparative Examples 1 to 26 The same operation as in Example 7 was performed except that the enzymes shown in Table 1 were used. In Comparative Examples 1 to 26, the hydrolysis reaction did not proceed.
  • the hydrolysis reaction proceeds when the esterase porcine liver, which is a porcine liver esterase, or the esterase rabbit ribase, which is a rabbit liver esterase, but other enzymes are used. When used, the reaction does not proceed at all. In particular, when Esterase from Porcine liver was used, the compound represented by the formula (15) was obtained with higher optical purity.
  • a novel method for producing a diphenyl sulfide derivative containing the compound disclosed in Patent Document 1 can be provided.
  • the production method of the present embodiment is inexpensive and a compound with high optical purity can be obtained. 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

[Problème] Fournir un nouveau procédé de production d'un dérivé de diphénylsulfure. [Solution] Un procédé de production d'un composé représenté par la formule générale (5) par hydrolyse asymétrique d'un composé représenté par la formule générale (4) à l'aide d'une estérase de foie de porc ou de foie de lapin, et un procédé de production du composé comprenant l'hydrolyse asymétrique.
PCT/JP2015/003702 2014-07-24 2015-07-23 Procédé de fabrication de dérivé de diphénylsulfure, et intermédiaire de production WO2016013225A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041015A1 (fr) * 2004-10-12 2006-04-20 Kyorin Pharmaceutical Co., Ltd. Dérivé d’aminoalcool, sel d’addition dudit dérivé, et agent immunosuppresseur
WO2009142194A1 (fr) * 2008-05-19 2009-11-26 杏林製薬株式会社 Procédé de production d’un dérivé d’aminoalcool optiquement 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 (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041015A1 (fr) * 2004-10-12 2006-04-20 Kyorin Pharmaceutical Co., Ltd. Dérivé d’aminoalcool, sel d’addition dudit dérivé, et agent immunosuppresseur
WO2009142194A1 (fr) * 2008-05-19 2009-11-26 杏林製薬株式会社 Procédé de production d’un dérivé d’aminoalcool optiquement 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
IOSUB, VIOLETA ET AL.: "Enantioselective Synthesis of alpha-Quaternary Amino Acid Derivatives by Sequential Enzymatic Desymmetrization and Curtius Rearrangement of alpha,alpha-Disubstituted Malonate Diesters", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 75, 2010, pages 1612 - 1619, ISSN: 1520-6904 *

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