WO2023276983A1 - Intermédiaire de synthèse pour beraprost ou forme optiquement active de celui-ci, et son procédé de production - Google Patents

Intermédiaire de synthèse pour beraprost ou forme optiquement active de celui-ci, et son procédé de production Download PDF

Info

Publication number
WO2023276983A1
WO2023276983A1 PCT/JP2022/025651 JP2022025651W WO2023276983A1 WO 2023276983 A1 WO2023276983 A1 WO 2023276983A1 JP 2022025651 W JP2022025651 W JP 2022025651W WO 2023276983 A1 WO2023276983 A1 WO 2023276983A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
optically active
general formula
optionally substituted
compound represented
Prior art date
Application number
PCT/JP2022/025651
Other languages
English (en)
Japanese (ja)
Inventor
重信 青柳
亮 山田
Original Assignee
大内新興化学工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大内新興化学工業株式会社 filed Critical 大内新興化学工業株式会社
Priority to JP2023531963A priority Critical patent/JPWO2023276983A1/ja
Publication of WO2023276983A1 publication Critical patent/WO2023276983A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages

Definitions

  • the present disclosure relates to a synthetic intermediate of beraprost or an optically active substance and a method for producing the same. More specifically, the present disclosure relates to a synthetic intermediate of prostaglandin I2 derivative beraprost or an optically active substance used as an oral therapeutic agent for primary pulmonary hypertension and a method for producing the same.
  • Beraprost sodium a stable prostaglandin I2 derivative, is a compound with the following structure and is used as an oral treatment for primary pulmonary hypertension.
  • Treprost, an injectable drug, and iloprost, which requires an inhaler are also known as therapeutic drugs for primary pulmonary hypertension, but beraprost sodium, an easy-to-administer oral drug, is commonly prescribed.
  • beraprost sodium an easy-to-administer oral drug, is commonly prescribed.
  • beraprost sodium is expanding, and research into its application as a preventive drug for reperfusion after surgery is progressing.
  • the demand for it as a treatment for chronic kidney disease in pet animals, especially cats is increasing. .
  • beraprost sodium is a mixture of the following four stereoisomers (Monosodium (1RS, 2RS, 3aSR, 8bSR)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[( 1E,3SR,4RS)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-1H-cyclopenta[b]benzofuran-5-butanoate, and Monosodium (1RS,2RS,3aSR,8bSR) )-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(1E,3SR,4SR)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-1H- cyclopenta [b]benzofuran-5-butanoate). It is known that this mixture can be produced in multiple steps using 2,4-dibromocyclopentene as a starting material (see Patent Document 1).
  • the compounds (8S, 9S, 16S) represented by the above formula (A) are known to be significantly more effective than the other three isomers.
  • Non-Patent Document 1 a method for selectively producing a single stereoisomer is desired. Also from the viewpoint of reducing the physical burden on patients due to drug administration, a drug substance consisting of a single optical isomer is desired.
  • Non-Patent Document 1 As a method for synthesizing a single optical isomer, a method is known in which a synthetic intermediate of beraprost is converted to a carboxylic acid compound and optically resolved by recrystallization as an optically active amine salt (see Non-Patent Document 1). ). However, the process is lengthy and the unnecessary optical isomer cannot be reused, so it cannot be said to be efficient.
  • a diol intermediate having a [3.3.0]bicyclooctane skeleton is obtained through multiple steps, and then a primary diol intermediate is obtained.
  • the hydroxyl group is selectively protected, the secondary hydroxyl group is introduced with a different protective group, and the primary hydroxyl group is selectively deprotected to obtain a key intermediate, which is then converted into an optical isomer of beraprost.
  • JP-A-1983-124778 Japanese Patent Publication No. 2017-520529 JP 2019-065015 A
  • beraprost or an optically active form thereof can be efficiently produced by using a synthetic intermediate having a [3.3.0]bicyclooctane skeleton derived from a chiral building block of a specific structure. I found what I can do. The present disclosure is based on such findings.
  • One object of the present disclosure is to provide a novel synthetic intermediate of beraprost or its optically active form and a method for producing the same.
  • a compound represented by the following general formula (I) or an optically active substance thereof is provided.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • a compound represented by the following general formula (II) or an optically active substance thereof wherein, R 1 represents a silyl group represented by general formula (i), R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • the step of cyclizing the compound represented by general formula (B) or an optically active substance thereof to obtain the compound represented by general formula (I) or an optically active substance thereof A method for producing a compound represented by general formula (I) or an optically active substance thereof is provided.
  • X represents a halogen atom
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • the step of reducing the compound represented by general formula (I) or its optically active substance to obtain the compound represented by general formula (II) or its optically active substance is A method for producing a compound represented by general formula (II) or an optically active form thereof is provided.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • a compound represented by general formula (III) or its optical activity is obtained by introducing a protective group to the hydroxyl group of the compound represented by general formula (II) or its optically active substance.
  • a method for producing a compound represented by general formula (III) or an optically active form thereof, comprising a step of obtaining a compound.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents a functional group formed by combining an optionally substituted aromatic hydrocarbon group or an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group
  • R6 represents a hydroxyl - protecting group other than a silyl group.
  • the compound represented by general formula (III) obtained by the above method or its optical activity is desilylated to obtain a compound represented by general formula (IV) or its optical activity
  • a method for producing a compound represented by general formula (IV) or its optical activity comprising the step of obtaining (Wherein, R 1 represents a silyl group represented by general formula (i), R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents a functional group formed by combining an optionally substituted aromatic hydrocarbon group or an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group, R6 represents a hydroxyl - protecting group other than a silyl group. )
  • a novel synthetic intermediate of beraprost or its optically active substance and a method for producing the same can be provided.
  • synthetic intermediates derived from chiral building blocks with specific structures can be used to efficiently produce beraprost or its optically active form, which is advantageous in terms of industrial production.
  • alkyl group also applies to functional groups that include “alkyl” or “alkyl groups” (eg, arylalkyl groups, etc.).
  • C 1 -C 6 means having 1 to 6 carbon atoms.
  • Aliphatic hydrocarbon group means a functional group (hydrocarbon group without aromaticity) generated by removing a hydrogen atom from an aliphatic hydrocarbon.
  • An "aliphatic hydrocarbon group” can mean a monovalent or divalent functional group, depending on the context, but is preferably a monovalent functional group.
  • the aliphatic hydrocarbon group may be linear, cyclic, or a combination thereof.
  • the chain may be linear or branched.
  • Aliphatic hydrocarbon groups are preferably linear or branched.
  • Aliphatic hydrocarbon groups may be saturated or unsaturated. The unsaturated bond may be a carbon-carbon double bond or a carbon-carbon triple bond.
  • aliphatic hydrocarbon groups examples include alkyl groups, alkenyl groups, and alkynyl groups.
  • Alkyl group means a monovalent functional group generated by removing one hydrogen atom from an alkane.
  • Alkyl groups may be linear, cyclic, or combinations thereof.
  • a cyclic alkyl group is synonymous with a "cycloalkyl group”.
  • the chain may be linear or branched.
  • Alkyl groups are preferably straight-chain or branched.
  • the linear alkyl group usually has 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, More preferably 1 to 3.
  • the branched-chain alkyl group usually has 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, still more preferably 3 to 6 carbon atoms, and still more preferably 3 to 4 carbon atoms. be.
  • the number of carbon atoms in the cyclic alkyl group is generally 3-20, preferably 3-10, more preferably 3-8, and still more preferably 3-6.
  • the number of carbon atoms in the alkyl group having a linear or branched chain portion and a cyclic portion is usually 4 to 20, preferably 4 to 10, more preferably 4 to 8, and even more preferably 4 to 6. is.
  • alkyl groups include C 1 to C 6 alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, pentyl group and hexyl group; methylhexyl group, 5-methylhexyl group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 4,4-dimethylpentyl group, 1-ethylpentyl group, 2-ethylpentyl group, 1,1, 3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,3,3-trimethylbutyl group, 2,2,3-trimethylbutyl group, 2,3,3-trimethylbutyl group, 1-propylbutyl group, 1,1,2,2-tetramethylpropyl group, octyl group, 1-methylheptyl group, 3-methylheptyl group, 6-methylheptyl group, 2-e
  • C 1 -C 6 alkyl groups are preferred.
  • Preferred examples of C 1 -C 6 alkyl groups are linear or branched moieties such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, pentyl or hexyl groups. and an alkyl group having a cyclic moiety, preferably methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, pentyl group or hexyl group.
  • Alkenyl group means a monovalent functional group generated by removing one hydrogen atom from an alkene. Alkenyl groups have at least one carbon-carbon double bond. Alkenyl groups may be linear, cyclic, or combinations thereof. A cyclic alkenyl group is synonymous with a "cycloalkenyl group".
  • the chain may be linear or branched. Alkenyl groups are preferably straight-chain or branched. The straight-chain alkenyl group usually has 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms. be.
  • the branched alkenyl group usually has 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, still more preferably 3 to 6 carbon atoms, and still more preferably 3 to 4 carbon atoms.
  • the number of carbon atoms in the cyclic alkenyl group is generally 3-20, preferably 3-10, more preferably 3-8, and still more preferably 3-6.
  • the alkenyl group having a linear or branched chain portion and a cyclic portion usually has 4 to 20 carbon atoms, preferably 4 to 10 carbon atoms, more preferably 4 to 8 carbon atoms, and still more preferably 4 to 6 carbon atoms. is.
  • the number of double bonds in the alkenyl group is generally 1-9, preferably 1-7, more preferably 1-4, and still more preferably 1-3.
  • alkenyl groups include vinyl group, 2-propenyl group, 3-butenyl group, 2-butenyl group, 4-pentenyl group, 3-pentenyl group, 2-hexenyl group, 3-hexenyl group, 2-heptenyl group, Linear or branched alkenyl groups such as 3-heptenyl group, 4-heptenyl group, 3-octenyl group, 3-nonenyl group, 4-decenyl group; cyclopropenyl group, cyclobutenyl group, cyclopentenyl group, cyclohexenyl Cyclic alkenyl groups such as groups, cycloheptenyl groups, and cyclooctenyl groups; straight-chain or branched-chain moieties and cyclic Examples include alkenyl groups having moieties and the like.
  • Alkynyl group means a monovalent functional group generated by removing one hydrogen atom from alkyne. Alkynyl groups have at least one carbon-carbon triple bond. Alkynyl groups may be linear, cyclic, or combinations thereof. A cyclic alkynyl group is synonymous with a "cycloalkynyl group". The chain may be linear or branched. Alkynyl groups are preferably straight-chain or branched. The straight-chain alkynyl group usually has 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 8 carbon atoms, still more preferably 2 to 6 carbon atoms, and still more preferably 2 to 4 carbon atoms. be.
  • the branched alkynyl group usually has 4 to 20 carbon atoms, preferably 4 to 10 carbon atoms, more preferably 4 to 8 carbon atoms, and still more preferably 3 to 6 carbon atoms.
  • the cyclic alkynyl group usually has 4 to 20 carbon atoms, preferably 4 to 10 carbon atoms, more preferably 4 to 8 carbon atoms, and still more preferably 4 to 6 carbon atoms.
  • the alkynyl group having a linear or branched chain portion and a cyclic portion usually has 5 to 20 carbon atoms, preferably 5 to 10 carbon atoms, more preferably 5 to 8 carbon atoms, and still more preferably 5 to 6 carbon atoms. is.
  • the number of triple bonds in the alkynyl group is generally 1-9, preferably 1-7, more preferably 1-4, and still more preferably 1-3.
  • alkynyl groups include 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl and 3-heptynyl groups.
  • linear or branched alkynyl groups such as groups, 4-heptynyl groups, 3-octynyl groups, 3-nonynyl groups and 4-decynyl groups; cyclic groups such as cyclobutynyl groups, cyclopentynyl groups, cycloheptynyl groups and cyclooctynyl groups alkynyl group; cyclopentynylmethyl group, cyclopentenylethyl group, cyclopentynylpropyl group, cyclopentynylmethyl group, cyclopentynylethyl group, etc. Alkynyl group having a linear or branched chain portion and a cyclic portion etc.
  • Aromatic hydrocarbon ring group means a functional group generated by removing a hydrogen atom from an aromatic hydrocarbon ring.
  • An "aromatic hydrocarbon ring group” can mean a monovalent or divalent functional group, depending on the context, but is preferably a monovalent functional group.
  • aromatic hydrocarbon ring groups examples include aryl groups.
  • Aryl group means a monocyclic or polycyclic (eg, bicyclic or tricyclic) aromatic hydrocarbon ring group.
  • the aryl group is generally a 1- to 4-ring, preferably 1- to 3-ring, more preferably 1- or 2-ring aromatic hydrocarbon ring group.
  • the number of ring-constituting carbon atoms in the aryl group is generally 6-18, preferably 6-14, more preferably 6-10.
  • Examples of the monocyclic aromatic hydrocarbon ring group include a phenyl group.
  • Aryl groups also include condensed polycyclic aromatic hydrocarbon ring groups and partially saturated condensed polycyclic aromatic hydrocarbon ring groups.
  • a partially saturated condensed polycyclic aromatic hydrocarbon ring group is a condensed polycyclic aromatic hydrocarbon ring group in which some of the bonds constituting the ring are hydrogenated.
  • Examples of condensed polycyclic aromatic hydrocarbon ring groups include, for example, bi- to tetracyclic aromatic hydrocarbon ring groups such as naphthyl group, anthryl group, phenanthrenyl group, tetracenyl group, pyrenyl group, and fluorenyl group. , an indenyl group, acenaphthylenyl, etc., preferably.
  • Partially saturated condensed polycyclic aromatic hydrocarbon ring groups include, for example, a dihydronaphthyl group, an indanyl group, and an acenaphthenyl group.
  • the aryl group is preferably a monocyclic or bicyclic aromatic hydrocarbon group, more preferably an aryl group having 6 to 10 carbon atoms such as a phenyl group and a naphthyl group.
  • a phenyl group is more preferred.
  • “Functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group” is represented by the formula: (*) - aliphatic hydrocarbon group - aromatic hydrocarbon ring group, or the formula: (*) - Aromatic hydrocarbon ring group - Aliphatic hydrocarbon group. (*) represents a bond of an organic group including a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group.
  • Examples of functional groups represented by the formula: (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group include alkylaryl groups, alkenylaryl groups, and alkynylaryl groups.
  • alkylaryl groups alkenylaryl groups
  • alkynylaryl groups alkynylaryl groups
  • alkyl group, alkenyl group, alkynyl group and aryl group in the "alkylaryl group", “alkenylaryl group” and “alkynylaryl group” are the same as above.
  • the number of alkyl groups in an alkylaryl group, the number of alkenyl groups in an alkenylaryl group, and the number of alkynyl groups in an alkynylaryl group are generally 1 to 4, preferably 1 to 3, more preferably 1 to 2. .
  • alkylaryl groups include o-toluyl, m-toluyl, p-toluyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3, 4-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, o-ethylphenyl, m-ethylphenyl, p-ethylphenyl and the like.
  • alkenylaryl groups include alkenylaryl groups such as o-styryl, m-styryl and p-styryl.
  • alkynylaryl groups include alkynylaryl groups such as 2-ethynyl-2-phenyl.
  • Examples of functional groups represented by the formula: (*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group include arylalkyl groups, arylalkenyl groups, and arylalkynyl groups.
  • the descriptions of the alkyl group, alkenyl group, alkynyl group and aryl group in the "arylalkyl group”, “arylalkenyl group” and “arylalkynyl group” are the same as above.
  • Arylalkyl groups include, for example, alkyl groups substituted with aryl groups such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, preferably benzyl, 2-phenylethyl, 3-phenylpropyl, 2 -phenylpropyl group, 1-phenylpropyl group, ⁇ -naphthylmethyl group, ⁇ -naphthylethyl group, ⁇ -naphthylmethyl group, ⁇ -naphthylethyl group, diphenylmethyl group, triphenylmethyl group and the like, more preferably It is a triphenylmethyl group.
  • the arylalkenyl group usually has 8 to 16 carbon atoms, preferably 8 to 12 carbon atoms.
  • the aralkenyl group includes, for example, 2-phenethenyl group, 2-nephthylethenyl group and the like.
  • the number of carbon atoms in the arylalkynyl group is usually 8-16, preferably 8-12.
  • the aralkynyl group includes, for example, a phenylethynyl group.
  • the number of substituents that the aliphatic hydrocarbon group can have can be appropriately determined according to the number of carbon atoms in the aliphatic hydrocarbon group.
  • the aliphatic hydrocarbon group can have, for example, 1 to 6, preferably 1 to 3, more preferably 1 or 2 substituents at substitutable positions.
  • the hydrocarbon group has two or more substituents, the two or more substituents may be the same or different.
  • the number of substituents that the alkyl group may have is usually 1 to 3, preferably 1 or 2, more preferably 1.
  • the number of substituents that the alkyl group may have is usually 1 to 6, preferably 1 to 5, more preferably 1 to 4, and still more preferably. is 1 or 2.
  • the number of carbon atoms in the alkyl group is 10 or more, the number of substituents that the alkyl group may have is usually 1 to 9, preferably 1 to 5, more preferably 1 to 4, still more preferably is 1 or 2.
  • the number of substituents that the alkenyl group may have is usually 1 to 3, preferably 1 or 2, more preferably 1. Further, when the alkenyl group has 5 to 9 carbon atoms, the number of substituents that the alkenyl group may have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, more One or two is more preferable. Further, when the number of carbon atoms in the alkenyl group is 10 or more, the number of substituents that the alkenyl group may have is usually 1 to 8, preferably 1 to 4, still more preferably 1 to 3, more One or two is more preferable.
  • the number of substituents that the alkynyl group may have is usually 1 to 3, preferably 1 or 2, more preferably 1.
  • the number of substituents that the alkynyl group may have is usually 1 to 5, preferably 1 to 4, more preferably 1 to 3, and more preferably 1 to 3.
  • One or two is preferred.
  • the number of substituents that the alkynyl group may have is usually 1 to 8, preferably 1 to 4, still more preferably 1 to 3, still more preferably is 1 or 2.
  • the number of substituents that the aromatic hydrocarbon ring group can have can be appropriately determined according to the number of carbon atoms, the number of members, etc. of the aromatic hydrocarbon ring group.
  • the aromatic hydrocarbon ring group can have, for example, 1 to 5, preferably 1 to 4, more preferably 1 to 3, still more preferably 1 or 2 substituents at substitutable positions. .
  • the aromatic hydrocarbon ring group has two or more substituents, the two or more substituents may be the same or different.
  • the number of substituents that the arylalkyl group or alkylaryl group may have is usually 1 to 5, preferably 1 to 4, more The number is preferably 1-2.
  • the number of substituents that the arylalkyl group or alkylaryl group may have is usually 1 to 6, preferably 1 to 4, more The number is preferably 1-2.
  • the number of substituents that the arylalkyl group or alkylaryl group may have is generally 1 to 8, preferably 1 to 6, more preferably is 1 to 4, and more preferably 1 to 2.
  • the number of substituents that the arylalkenyl group or alkenylaryl group may have is usually 1 to 5, preferably 1 to 4, more The number is preferably 1-2.
  • the number of substituents that the arylalkenyl group or alkenylaryl group may have is usually 1 to 6, preferably 1 to 4, more The number is preferably 1-2.
  • the number of substituents that the arylalkenyl group or alkenylaryl group may have is generally 1 to 8, preferably 1 to 6, more preferably. is 1 to 4, and more preferably 1 to 2.
  • substituents include alkoxy groups, halogen atoms, cyano groups, nitro groups, sulfonyl, sulfonyl groups, carboxyl groups and acyl groups. It is an atom (preferably a fluorine atom, a chlorine atom, or the like).
  • alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy groups. , an isohexyloxy group, and the like.
  • acyl groups include acetyl group, propionyl group, n-butyryl group, iso-butyryl group, n-valeryl group, caproyl group and benzoyl group.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or the like.
  • Protecting group is a protecting group known to those skilled in the art, and is used in the meaning shown in Green's Protective Groups in Organic Synthesis (Wuts, Peter GM, John Wiley & Sons Inc.).
  • Root temperature means 10°C to 35°C.
  • the compounds described herein may contain asymmetric centers and therefore may exist as enantiomers. Where the compounds described herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader class of stereoisomers. All possible isomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers, are intended to be included. Unless specifically stated otherwise, references to one isomer apply to any possible isomer. Whenever the isomeric composition is not specified, all possible isomers are included.
  • optically active substance means an enantiomeric excess (ee) of 90% or more, preferably 95%, still more preferably 98%, and further It preferably means 99% or more of the compound or its isomer mixture.
  • Synthetic intermediate of beraprost or its optically active substance represented by general formula (I) or (II) described later
  • a compound or an optically active form thereof is provided. Since the compound represented by the general formula (I) or (II) or an optically active substance thereof can be produced using a chiral building block having a specific structure described later, beraprost or an optically active substance thereof can be selectively produced. can be used to your advantage.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • R 2 , R 3 , R 4 and R 5 each independently represent an optionally substituted alkyl group, a substituent an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group, an optionally substituted an arylalkenyl group which may have a substituent, an arylakinyl group which may have a substituent, an alkylaryl group which may have a substituent, an alkenylaryl group or an alkynylaryl group.
  • R 2 , R 3 , R 4 and R 5 each independently represent an optionally substituted alkyl group, a substituent It is an optionally substituted aryl group or an optionally substituted arylalkyl group.
  • R 2 , R 3 , R 4 and R 5 are each independently C 1 -C 6 alkyl optionally having substituent(s) group, a C 6 -C 10 aryl group optionally having substituent(s) or a C 7 -C 14 arylalkyl group optionally having substituent(s).
  • R 2 , R 3 , R 4 and R 5 are each independently C 1 -C 4 alkyl optionally having substituent(s) group, a C 6 -C 10 aryl group optionally having substituent(s) or a C 7 -C 14 arylalkyl group optionally having substituent(s).
  • R 2 , R 3 , R 4 and R 5 are each independently a C 1 -C 6 alkyl group, a C 6 -C 10 aryl group or represents a C 7 -C 14 arylalkyl group.
  • R 2 , R 3 , R 4 and R 5 each independently represent a C 1 -C 6 alkyl group.
  • the functional groups represented by R 2 , R 3 , R 4 and R 5 are from the compound represented by formula (B) to It is a group that does not show radical cyclization reactivity when obtaining a compound that is represented by
  • the substituents possessed by the functional groups represented by R 2 , R 3 , R 4 and R 5 are each independently preferably an alkoxy group, a halogen atom, a cyano group, a nitro group, a sulfonyl group, a carboxyl group or an acyl group, more preferably a C1 - C6 alkoxy group or a halogen atom , still more preferably a C1 - C3 alkoxy group or a halogen atom (preferably fluorine atom, chlorine atom, etc.).
  • R 4 , R 5 and R 6 of the silyl group represented by formula (i) are preferably methyl group, ethyl group, propyl group and isopropyl group. butyl, sec-butyl, tert-butyl, pentyl, hexyl, phenyl or combinations thereof.
  • the silyl group represented by formula (i) is preferably a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, or a methyldiphenylsilyl group. , more preferably a tert-butyldimethylsilyl group.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • the compound represented by formula (II) can be obtained by reducing the carbonyl group of the compound represented by formula (I), as described below.
  • R 2 , R 3 , R 4 and R 5 are as described above, R 6 is a hydroxyl-protecting group other than a silyl group, X is a halogen atom (preferably a bromine atom or an iodine atom etc.)
  • the compound represented by the formula (IV), which is a key synthetic intermediate, can be obtained selectively and efficiently through the Furthermore, the compound represented by formula (IV) can be efficiently converted into beraprost or its optically active form according to the known method described in Patent Document 3 and the like.
  • the method of the present disclosure can produce beraprost without going through the [3.3.0] diol intermediate of the bicyclooctane skeleton, which requires multiple steps for the protection and deprotection of hydroxyl groups as described in Patent Document 3. and efficient.
  • the method of the present disclosure does not require the use of expensive heavy metal catalysts used in conventional production methods, which is advantageous for industrial production.
  • (4R)-4-hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one (B1) can be synthesized according to Scheme 3 above.
  • 4-hydroxy-2-(hydroxymethyl)-2-cyclopenten-1-one is first obtained by hydrothermal reaction of 2-deoxy-D-glucose. Then, the primary hydroxyl group of the synthesized compound is selectively silylated to obtain 4-hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one. Next, the resulting compound is optically resolved using lipase and vinyl acetate to obtain (4R)-4-acetoxy-2-(silyloxymethyl)-2-cyclopenten-1-one.
  • (4R)-4-acetoxy-2-(silyloxymethyl)-2-cyclopenten-1-one is then hydrolyzed using lipase and phosphate buffer (0.1 M, pH 7) to yield (4R )-4-hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one (B1).
  • lipase and phosphate buffer 0.1 M, pH 7
  • 4R )-4-hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one B1
  • the compound represented by general formula (B) or its optically active substance can be synthesized according to Scheme 4 below. More specifically, it can be obtained by subjecting the compound represented by the general formula (B1) and the phenol derivative (B2) to dehydration condensation through a Mitsunobu reaction.
  • azodicarboxylic acid diester The type of azodicarboxylic acid diester used in the Mitsunobu reaction is not particularly limited, and any one used in the art can be used.
  • the azodicarboxylic acid diester include dimethyl azodicarboxylate (DMAD), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), dibenzyl azodicarboxylate, di-tert-butyl azodicarboxylate, and azodicarboxylic acid.
  • Bis(2-methoxyethyl), bis(2,2,2-trichloroethyl) azodicarboxylate or 1,1-azobis(N,N-dimethylformamide) diamide can be used, but are not limited to these.
  • the amount of the azodicarboxylic acid diester used is usually in the range of 1.0 to 10.0 mol, preferably in the range of 1.0 to 5.0 mol, more preferably in the range of 1.0 to 10.0 mol, per 1 mol of the raw material compound. It ranges from 1.0 to 2.0 mol.
  • phosphine The type of phosphine used in the Mitsunobu reaction is not particularly limited, and any one used in the industry can be used. Phosphines include, for example, triphenylphosphine, trihexylphosphine, tricyclohexylphosphine, isopropyldiphenylphosphine, diethylphenylphosphine, diphenyl-2-pyridylphosphine, 4-(dimethylamino)phenyldiphenylphosphine, tributylphosphine, dicyclohexylphenylphosphine, Phenoxydiphenylphosphine, tri-tert-butylphosphine, tri-n-octylphosphine can be used, but are not limited to these. The amount of phosphine used is usually in the range of 1.0 to 10.0 mol, preferably in the range of 1.0 to 5.0 mol, more
  • the type of base used in the Mitsunobu reaction is not particularly limited, and any base used in the art can be used.
  • the base include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 4-dimethylaminopyridine, and lutidine.
  • the amount of the base to be used is usually in the range of 1.0 to 10.0 mol, preferably in the range of 1.0 to 5.0 mol, more preferably 1.0 mol, per 1 mol of the raw material compound. ⁇ 2.0 molar range.
  • solvent The type of solvent used in the Mitsunobu reaction is not particularly limited, and any one used in the art can be used.
  • the solvent include toluene, benzene, tetrahydrofuran, dichloromethane, diethyl ether, and acetonitrile, but are not limited to these. Any amount of the solvent may be used as long as the reaction proceeds. A person skilled in the art can appropriately adjust the amount of solvent used in the Mitsunobu reaction.
  • reaction temperature The reaction temperature of the Mitsunobu reaction is not particularly limited. In one embodiment, the reaction temperature is in the range of -20°C to 200°C, preferably -10°C to 150°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. range, more preferably from -5°C to 120°C.
  • reaction time The reaction time of the Mitsunobu reaction is not particularly limited. In one embodiment, the reaction time is in the range of 0.5 hours to 48 hours, preferably 1 hour to 24 hours, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. range, more preferably 1 hour to 10 hours. However, the reaction time of the Mitsunobu reaction can be appropriately adjusted by those skilled in the art.
  • a general treatment for obtaining a product from the reaction solution may be performed.
  • water is added to the reaction solution after the reaction is completed to neutralize it, and an extraction operation is performed using a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like.
  • the desired product is obtained by distilling off the reaction solvent and extraction solvent from the resulting extract under reduced pressure.
  • the desired product thus obtained may, if necessary, be subjected to general purification such as silica gel column chromatography, recrystallization and the like to further increase the purity.
  • the compound represented by general formula (B) or its optically active substance can be cyclized to obtain the compound represented by general formula (I) or its optically active substance.
  • X represents a halogen atom
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • a bicyclo[3.3.0]octane skeleton is constructed by subjecting the compound represented by the general formula (B) or an optically active form thereof to a radical cyclization reaction.
  • a compound represented by formula (I) or an optically active form thereof can be obtained.
  • the radical cyclization reaction is preferably carried out by reacting the compound represented by the general formula (B) or an optically active substance thereof, an organic tin hydride, and a radical initiator.
  • organic tin hydride used in the radical cyclization reaction is not particularly limited, and any one used in the art can be used.
  • organic tin hydrides that can be used include, but are not limited to, trimethyltin hydride, triethyltin hydride, tripropyltin hydride, tributyltin hydride, dimethylphenyltin hydride, triphenyltin hydride, tritoyltin hydride, or trioctyltin hydride.
  • the amount of the organic tin hydride to be used is generally 1.0 to 10.0 mol, preferably 1.0 to 6.0 mol, more preferably 1.0 to 10.0 mol, per 1 mol of the raw material compound. It ranges from 0 to 3.0 mol.
  • Radical initiators include 2,2'-azobis(isobutyronitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2,4- dimethylvaleronitrile), 2,2′-azobis(2-methylbutyronitrile), 1,1′-azobis(cyclohexane-1-carbonitrile), 2,2′-azobis(2-(2-imidazoline-2 -yl)propane) dihydrochloride, 2,2′-azobis(2-(2-imidazolin-2-yl)propane) dihydrochloride dihydrate, 2,2′-azobis(2-(2-imidazoline) -2-yl)propane), 2,2′-azobis(2-methylpropionamidine) dihydrochloride, 2,2′-azobis(N-(carboxyethyrenethyl-N-(carboxyethyl-butyronitrile), 1,1′-azobis(cyclohex
  • solvent used in the radical cyclization reaction
  • the type of solvent used in the radical cyclization reaction is not particularly limited, and any one used in the art can be used.
  • the solvent include, but are not limited to, benzene, toluene, xylene, n-butanol, and dimethoxyethane. Any amount of the solvent may be used as long as the reaction proceeds. A person skilled in the art can appropriately adjust the amount of solvent used in the radical cyclization reaction.
  • reaction temperature The reaction temperature of the radical cyclization reaction is not particularly limited. In one embodiment, the reaction temperature is in the range of -20°C to 200°C, preferably in the range of -10°C to 150°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably in the range of -5°C to 120°C.
  • reaction time The reaction time of the radical cyclization reaction is not particularly limited. In one embodiment, the reaction time is in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, from the viewpoints of yield improvement, suppression of by-products, economic efficiency, and the like. and more preferably in the range of 1 hour to 10 hours. However, the reaction time of the radical cyclization reaction can be appropriately adjusted by those skilled in the art.
  • a general treatment for obtaining a product from the reaction solution may be performed.
  • water is added to the reaction solution after the completion of the reaction to neutralize it, and an extraction operation is performed using a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like.
  • a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like. you can go
  • the target product can be obtained by distilling off the reaction solvent and the extraction solvent from the extract obtained by such extraction treatment under reduced pressure.
  • the desired product thus obtained may, if necessary, be subjected to general purification such as silica gel column chromatography, recrystallization and the like to further increase the purity.
  • the compound represented by general formula (II) or its optically active substance is produced by reducing the compound represented by general formula (I) or its optically active substance to produce A compound represented by (II) or an optically active substance thereof can be obtained.
  • the compound represented by general formula (I) or an optically active substance thereof is reacted with a reducing agent, and the carbonyl group of the compound represented by general formula (I) or an optically active substance thereof is can be stereoselectively converted to an alcohol group by reduction.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
  • reducing agent used in the above reduction reaction is not particularly limited, and any one used in the art can be used.
  • reducing agents include sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, borane complexes, lithium tri(sec-butyl)borohydride, tri( Sodium sec-butyl)borohydride, potassium tri(sec-butyl)borohydride or lithium triethylborohydride (superhydride) can be used, but are not limited to these.
  • the amount of the reducing agent used (in terms of hydride) is usually in the range of 1.0 to 30.0 mol, preferably in the range of 1.0 to 20.0 mol, per 1 mol of the raw material compound. It is preferably in the range of 1.0 to 10.0 mol.
  • reaction solvent The type of reaction solvent used in the reduction reaction is not particularly limited, and any one used in the art can be used.
  • the reaction solvent include, but are not limited to, methanol, ethanol, THF, and mixed solvents thereof. Any amount of the solvent may be used as long as the reaction proceeds. A person skilled in the art can appropriately adjust the amount of solvent used in the reduction reaction.
  • reaction temperature The reaction temperature for the reduction reaction is not particularly limited. In one embodiment, the reaction temperature is in the range of -78°C to 100°C, preferably in the range of -40°C to 70°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably in the range of -20°C to 20°C.
  • reaction time The reaction time of the reduction reaction is not particularly limited. In one embodiment, the reaction time is in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, from the viewpoints of yield improvement, suppression of by-products, economic efficiency, and the like. and more preferably in the range of 1 hour to 10 hours. However, the reaction time of the reduction reaction can be appropriately adjusted by those skilled in the art.
  • post-processing As the post-treatment of the reduction reaction, a general treatment for obtaining a product from the reaction solution may be performed.
  • a post-treatment for example, water is added to the reaction solution after the completion of the reaction to neutralize it, and an extraction operation is performed using a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like. you can go
  • the desired product can be obtained by distilling off the reaction solvent and the extraction solvent from the extract obtained by such an extraction procedure under reduced pressure.
  • the desired product thus obtained may, if necessary, be subjected to general purification such as silica gel column chromatography, recrystallization and the like to further increase the purity.
  • a protective group is added to the hydroxyl group of the compound represented by general formula (II) or an optically active substance thereof.
  • a compound represented by the general formula (III) or an optically active substance thereof can be obtained by introduction.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, and R 6 is a hydroxyl-protecting group other than a silyl group.
  • a protecting group other than a silyl group such as an alkyl group, an alkoxycarbonyl group, and an acyl group
  • acyl group specifically acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, hexanoyl group, pivaloyl group, benzoyl group, p-methoxybenzoyl group, p-phenylbenzoyl and the like.
  • the protecting group may be substituted with a halogen atom, such a halogen atom being a fluorine atom or a chlorine atom.
  • an acyl group is introduced by reacting an acid anhydride or an acid chloride on the compound represented by the general formula (II) or an optically active form thereof in the presence of a base, and the hydroxyl group is an acyl A group-protected compound represented by general formula (III) or an optically active form thereof is obtained.
  • acid anhydride or acid chloride examples include acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, valeryl chloride, hexanoyl chloride, pivaloyl chloride, benzoyl chloride, p-methoxybenzoyl chloride, and p-chloride.
  • Phenylbenzoyl, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, hexanoic anhydride, pivalic anhydride, etc. can be used, but are not limited to these.
  • the amount of acid anhydride or acid chloride to be used is usually in the range of 1.0 to 100.0 mol, preferably in the range of 1.0 to 50.0 mol, per 1 mol of the raw material compound. It is preferably in the range of 1.0 to 30.0 mol.
  • the base used for the hydroxyl protection reaction is not particularly limited, and triethylamine, diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, and lutidine can be used, for example.
  • the amount of the base to be used is usually in the range of 1.0 to 100.0 mol, preferably in the range of 1.0 to 50.0 mol, more preferably 1.0 mol, per 1 mol of the raw material compound. ⁇ 30.0 mol range.
  • the catalyst used for the hydroxyl protection reaction is not particularly limited, and for example, 4-dimethylaminopyridine can be used.
  • the amount of the catalyst to be used is usually in the range of 0.01 to 1.0 mol, preferably in the range of 0.05 to 0.5 mol, more preferably 0.1 mol, per 1 mol of the raw material compound. ⁇ 0.3 moles.
  • reaction temperature used for the hydroxyl protection reaction is not particularly limited.
  • the reaction temperature is, for example, in the range of -78°C to 100°C, preferably -40°C to 70°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably -20°C to 20°C.
  • reaction time The reaction time of the hydroxyl protection reaction is not particularly limited. In one embodiment, the reaction time is in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, from the viewpoints of yield improvement, suppression of by-products, economic efficiency, and the like. and more preferably in the range of 1 hour to 10 hours.
  • post-processing As the post-treatment of the hydroxyl group protection reaction, a general treatment for obtaining a product from the reaction solution may be performed.
  • a post-treatment for example, water is added to the reaction solution after the completion of the reaction to neutralize it, and an extraction operation is performed using a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like. you can go
  • the desired product can be obtained by distilling off the reaction solvent and the extraction solvent from the extract obtained by such an extraction procedure under reduced pressure.
  • the desired product thus obtained may, if necessary, be subjected to general purification such as silica gel column chromatography, recrystallization and the like to further increase the purity.
  • the compound represented by the general formula (III) or its optically active substance is reacted with an acid to remove the silyl group represented by the formula (i), thereby obtaining A compound represented by (IV) or an optically active substance thereof can be obtained.
  • the type of acid used in the desilylation reaction is not particularly limited, and any organic acid or inorganic acid commonly used in the art can be used.
  • acids that can be used include, but are not limited to, hydrochloric acid, sulfuric acid, PTSA, and ion exchange resins having sulfonic acid residues. Any amount of acid may be used as long as the reaction proceeds.
  • the amount of solvent used in the desilylation reaction can be appropriately adjusted by those skilled in the art.
  • reaction solvent The type of reaction solvent used in the desilylation reaction is not particularly limited, and any solvent commonly used in the art can be used.
  • reaction solvents include diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, tert-butanol, and water. and mixtures thereof, but are not limited to these. Any amount of the solvent may be used as long as the reaction proceeds.
  • reaction temperature The reaction temperature for the desilylation reaction is not particularly limited. In one embodiment, the reaction temperature is in the range of -78°C to 150°C, preferably in the range of -40°C to 100°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably in the range of -20°C to 80°C.
  • reaction time The reaction time of the desilylation reaction is not particularly limited. In one embodiment, the reaction time is in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, from the viewpoints of yield improvement, suppression of by-products, economic efficiency, and the like. and more preferably in the range of 1 hour to 10 hours.
  • post-processing As a post-treatment of the desilylation reaction, a general treatment for obtaining a product from the reaction solution may be performed. For example, in the post-treatment, water is added to the reaction solution after the completion of the reaction to neutralize it, and an extraction operation is performed using a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane, or the like. you can go
  • the desired product can be obtained by distilling off the reaction solvent and the extraction solvent from the extract obtained by such an extraction treatment under reduced pressure.
  • the desired product thus obtained may, if necessary, be subjected to general purification such as silica gel column chromatography, distillation, recrystallization, etc. to further increase the purity.
  • the compound represented by the general formula (IV) or its optically active substance can be derivatized to obtain beraprost or its optically active form.
  • the primary hydroxy group of the compound represented by general formula (IV) or its optically active substance is oxidized to form the corresponding aldehyde, followed by the formula:
  • a compound represented by the general formula (A1) by coupling with the side chain of to form a compound of Reduction of the ketone in the side chain, removal of the remaining R2 and R6, and conversion of the terminal carboxyl group to a cation yields a compound of general formula (A): Or form its optically active form.
  • beraprost or its optically active form from the compound represented by general formula (III) or its optically active form
  • the compound represented by either general formula (I) or (II) or its optical activity can be utilized as a synthetic intermediate in the production.
  • a reagent for producing beraprost or an optically active substance thereof represented by either general formula (I) or (II) or an optically active substance thereof is provided.
  • optically active form of beraprost is represented by formula (A).
  • a compound represented by the following general formula (I) or an optically active substance thereof (Wherein, R 1 represents a silyl group represented by general formula (i), R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • R 2 , R 3 , R 4 and R 5 each independently have an optionally substituted alkyl group, an optionally substituted aryl group or a substituted group;
  • R 2 , R 3 , R 4 and R 5 each independently represent an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 6 -
  • R 2 , R 3 , R 4 and R 5 each independently represent a C 1 -C 6 alkyl group, a C 6 -C 10 aryl group or a C 7 -C 14 arylalkyl group, [1 ] to [3] or an optically active substance thereof.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • a reagent comprising the compound or optically active substance according to any one of [1] to [5], for producing beraprost or an optically active substance thereof.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • general formula (II) comprising a step of reducing the compound represented by general formula (I) or an optically active substance thereof to obtain the compound represented by general formula (II) or an optically active substance thereof; A method for producing a compound represented by or an optically active substance thereof.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents an optionally substituted aromatic hydrocarbon group, or a functional group formed by combining an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group.
  • R 10 introducing a protective group to the hydroxyl group of the compound represented by general formula (II) or an optically active substance thereof to obtain the compound represented by general formula (III) or an optically active substance thereof; A method for producing a compound represented by general formula (III) or an optically active form thereof.
  • R 1 represents a silyl group represented by general formula (i)
  • R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents a functional group formed by combining an optionally substituted aromatic hydrocarbon group or an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group
  • R6 represents a hydroxyl - protecting group other than a silyl group.
  • Step of desilylating the compound represented by general formula (III) or its optical activity obtained by the method described in [10] to obtain the compound represented by general formula (IV) or its optical activity A method for producing a compound represented by general formula (IV) or an optical activity thereof, comprising: (Wherein, R 1 represents a silyl group represented by general formula (i), R 2 , R 3 , R 4 and R 5 are each independently an optionally substituted aliphatic hydrocarbon group, represents a functional group formed by combining an optionally substituted aromatic hydrocarbon group or an optionally substituted aliphatic hydrocarbon group and an aromatic hydrocarbon cyclic group, R6 represents a hydroxyl - protecting group other than a silyl group.
  • a novel synthetic intermediate of beraprost or its optically active substance and a method for producing the same can be provided.
  • synthetic intermediates derived from chiral building blocks with specific structures can be used to efficiently produce beraprost or its optically active form, which is advantageous in terms of industrial production.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente divulgation concerne : un nouvel intermédiaire de synthèse pour beraprost ou une forme optiquement active de celui-ci ; et un procédé de production utilisant l'intermédiaire de synthèse. Plus particulièrement, dans la présente divulgation, un composé représenté par la formule générale (I) ou (II) ou une forme optiquement active de celui-ci est utilisé comme intermédiaire de synthèse dans la production de beraprost ou d'une forme optiquement active de celui-ci.
PCT/JP2022/025651 2021-06-28 2022-06-28 Intermédiaire de synthèse pour beraprost ou forme optiquement active de celui-ci, et son procédé de production WO2023276983A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2023531963A JPWO2023276983A1 (fr) 2021-06-28 2022-06-28

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2021-107087 2021-06-28
JP2021107087 2021-06-28

Publications (1)

Publication Number Publication Date
WO2023276983A1 true WO2023276983A1 (fr) 2023-01-05

Family

ID=84689918

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2022/025651 WO2023276983A1 (fr) 2021-06-28 2022-06-28 Intermédiaire de synthèse pour beraprost ou forme optiquement active de celui-ci, et son procédé de production

Country Status (3)

Country Link
JP (1) JPWO2023276983A1 (fr)
TW (1) TW202317527A (fr)
WO (1) WO2023276983A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58124778A (ja) * 1982-01-20 1983-07-25 Toray Ind Inc ５，６，７−トリノル−４，８−インタ−ｍ−フエニレンＰＧＩ↓２誘導体
JPH08225561A (ja) * 1989-02-27 1996-09-03 Toray Ind Inc ５，６，７−トリノル−４，８−インターｍ−フェニレンＰＧＩ２ 誘導体の中間体及びその製造方法
JP2003055368A (ja) * 2001-07-30 2003-02-26 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt ケミカルプロセス
HU227158B1 (en) * 2001-07-30 2010-09-28 Chinoin Gyogyszer Es Vegyeszet Production of beraprost ester by selective reduction
WO2013040068A2 (fr) * 2011-09-12 2013-03-21 Irix Pharmaceuticals, Inc. Procédé de préparation de prostacyclines synthétiques
CN103509044A (zh) * 2012-06-21 2014-01-15 上海天伟生物制药有限公司 贝前列素钠中间体及其制备方法
WO2020059646A1 (fr) * 2018-09-18 2020-03-26 国立大学法人東北大学 Dérivés de cyclopenténone optiquement actifs

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58124778A (ja) * 1982-01-20 1983-07-25 Toray Ind Inc ５，６，７−トリノル−４，８−インタ−ｍ−フエニレンＰＧＩ↓２誘導体
JPH08225561A (ja) * 1989-02-27 1996-09-03 Toray Ind Inc ５，６，７−トリノル−４，８−インターｍ−フェニレンＰＧＩ２ 誘導体の中間体及びその製造方法
JP2003055368A (ja) * 2001-07-30 2003-02-26 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt ケミカルプロセス
HU227158B1 (en) * 2001-07-30 2010-09-28 Chinoin Gyogyszer Es Vegyeszet Production of beraprost ester by selective reduction
WO2013040068A2 (fr) * 2011-09-12 2013-03-21 Irix Pharmaceuticals, Inc. Procédé de préparation de prostacyclines synthétiques
CN103509044A (zh) * 2012-06-21 2014-01-15 上海天伟生物制药有限公司 贝前列素钠中间体及其制备方法
WO2020059646A1 (fr) * 2018-09-18 2020-03-26 国立大学法人東北大学 Dérivés de cyclopenténone optiquement actifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAREDLA KESAVA REDDY, BODDURI VENKATA DURGA VIJAYKUMAR, SRIVARI CHANDRASEKHAR: "Formal Synthesis of Antiplatelet Drug, Beraprost", ORGANIC LETTERS, AMERICAN CHEMICAL SOCIETY, US, vol. 14, no. 1, 6 January 2012 (2012-01-06), US , pages 299 - 301, XP055285477, ISSN: 1523-7060, DOI: 10.1021/ol203060v *

Also Published As

Publication number Publication date
JPWO2023276983A1 (fr) 2023-01-05
TW202317527A (zh) 2023-05-01

Similar Documents

Publication Publication Date Title
CA2701534C (fr) Intermediaires et procedes pour la synthese d'analogues d'halichondrine b
JP4521185B2 (ja) ヘキサヒドロ−フロ［２，３−ｂ］フラン−３−オールの製造法
US7582779B2 (en) Processes and intermediates for the preparations of prostaglandins
KR101301200B1 (ko) 엔테카비르의 신규한 제조방법 및 이에 사용되는 중간체
JP7116384B2 (ja) 高収率の血管漏出遮断薬の調製方法
WO2023276983A1 (fr) Intermédiaire de synthèse pour beraprost ou forme optiquement active de celui-ci, et son procédé de production
JP7109029B2 (ja) Ｐｇｅ１コアブロック誘導体およびその製造方法
CN113024489A (zh) 一种奥司他韦合成工艺杂质的制备方法
KR101433690B1 (ko) 프로스타글란딘 제조를 위한 방법 및 중간체
JP4742239B2 (ja) ビシクロ［３．１．０］ヘキサン誘導体およびその中間体の製造方法
WO2023127855A1 (fr) Dérivé de cyclopenténone et son procédé de production
KR101529963B1 (ko) 에베로리무스의 제조방법 및 이의 중간체
US5332840A (en) Method for preparing a benzaldehyde intermediate
CN111556861A (zh) 茉莉酸酯化合物的制备方法
KR100457732B1 (ko) 광학합성의 비대칭 푸로푸란리그난 화합물의 신규 제조방법
EP1990334B1 (fr) Utilisation de poly-3-hydroxyalcanoates pour la préparation de composés de beta-lactame
US20090281301A1 (en) Manufacturing Process of 2' ,2' - Difluoronucleoside and Intermediate
KR102572714B1 (ko) Sglt 저해제의 합성에 유용한 중간체 및 이를 이용한 sglt 저해제의 제조 방법
KR100741310B1 (ko) 젬시타빈의 합성에 유용한 신규한나프탈렌-2-카르복실레이트 유도체와 그의 제조방법
JP3632979B6 (ja) ２―アミノマロン酸誘導体及び２―アミノ―１，３―プロパンジオール誘導体の製造方法
KR101821685B1 (ko) 베라프로스트 제조 중간체의 제조방법
JP3632979B2 (ja) ２―アミノマロン酸誘導体及び２―アミノ―１，３―プロパンジオール誘導体の製造方法
JP2019513808A (ja) ビマトプロストの調製方法
CA2796240C (fr) Procede de preparation de derives d'isoserine
CN115197115A (zh) 一种手性5-氧代吡咯烷-3-甲酸的制备方法与应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22833130

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2023531963

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE