WO2023127855A1

WO2023127855A1 - Cyclopentenone derivative and method for producing same

Info

Publication number: WO2023127855A1
Application number: PCT/JP2022/048119
Authority: WO
Inventors: 重信青柳; 亮山田
Original assignee: 大内新興化学工業株式会社
Priority date: 2021-12-28
Filing date: 2022-12-27
Publication date: 2023-07-06

Abstract

The present disclosure provides a novel synthetic intermediate of prostaglandin or an optically active substance thereof, and a production method that uses the same. More specifically, in the method according to the present disclosure for producing prostaglandin or an optically active substance thereof, a compound represented by any of general formulas (I) through (IV) or an optically active substance thereof is used as the synthetic intermediate.

Description

Cyclopentenone derivative and method for producing the same

Reference to Related Applications

This patent application claims priority based on Japanese Patent Application No. 2021-215326 filed on December 28, 2021, and the entire disclosure content in such earlier patent application is incorporated by reference. incorporated herein.

The present disclosure relates to cyclopentenone derivatives and methods for producing the same.

A method using an optically active cyclopentenone derivative as a chiral building building block has been previously reported as a synthetic scheme for prostaglandins. For example, as in Scheme 1, to (4R)-4-hydroxy-2-(dialkylaminomethyl)-2-cyclopenten-1-one in which the 4-position hydroxyl group is protected, an α side chain linker is conjugated and added to the α side. A method of synthesizing a prostaglandin by introducing a chain and then conjugating an ω side chain linker to the resulting endoenone to introduce an ω side chain is known as a two-component ligation method (Patent Document 1).

4-silyloxy-2-(diethylaminomethyl)-2-cyclopenten-1-one, which is the chiral building block in the two-component ligation method, can be prepared from 3-hydroxy-1,4-pentadiene as shown in Scheme 2. It is obtained through optical resolution by asymmetric epoxidation (Non-Patent Document 1). However, the manufacturing method requires multiple steps and cannot be said to be efficient.

In addition, as in Scheme 3, 4-hydroxy-2-hydroxymethyl-2-cyclopentenone was synthesized by hydrothermal reaction of D-glucal, optically resolved by high-performance liquid chromatography, and treated with lipase derived from porcine pancreas. A method is known for synthesizing optically active 4-silyloxy-2-diethylaminomethyl-2-cyclopentenone by acetylating the hydroxymethyl group at the 4-position, sequentially silyl-protecting the hydroxyl group at the 4-position, and reacting with diethylamine. (Patent Document 2). However, the racemic form of 4-hydroxy-2-hydroxymethyl-2-cyclopentenone must be optically resolved by high-performance liquid chromatography, which is extremely inefficient. In addition, the acetylation selectivity of the primary hydroxyl group of 4-hydroxy-2-hydroxymethyl-2-cyclopentenone is 36%, and lipase derived from porcine pancreas, which is a biological raw material that is concerned about virus contamination, is used. There is also a problem as a manufacturing means of the drug substance (Patent Document 2).

Further, 4-hydroxy-2-hydroxymethyl-2-cyclopentenone, which is a raw material for the production method of Scheme 3, can be obtained by solvolysis of 2-deoxy-D-glucose or triacetylglucal as shown in Scheme 4. It can be obtained by heating the resulting aqueous solution of D-glucal in a closed container (Patent Documents 3 and 4). Furandiol has been isolated as a hydrothermal intermediate (Non-Patent Documents 2, 3), and it is known that this reaction involves a Piancatelli rearrangement reaction via furandiol (Non-Patent Documents 4, 5). Therefore, the optical activity derived from glucal is lost in the course of the reaction, and the chiral pool method cannot be applied. In addition, since the product of the hydrothermal reaction is obtained as a mixture of kinetic isomers in addition to the target product, it is adsorbed on hydrous aqueous alumina and heated to isomerize to converge into a thermodynamically stable target product. There is a need (Patent Document 5). Furthermore, in the production method of Scheme 4, 2-deoxy-D-glucose and tri-O-acetyl-D-glucal, which are raw materials for 4-hydroxy-2-hydroxymethyl-2-cyclopentenone, are expensive and inexpensive. A manufacturing method using raw materials is required.

Further, as explained in Scheme 1 above, Patent Document 1 discloses that an α side chain linker is conjugated to (4R)-4-hydroxy-2-(diethylaminomethyl)-2-cyclopenten-1-one. A two-component ligation method is disclosed in which an α side chain is introduced and then an ω side chain linker is conjugated to the resulting endoenone to introduce the ω side chain and synthesize a prostaglandin. A specific two-component ligation method shown in Patent Document 1 is as shown in Scheme 5. However, the two-component ligation method requires high purity in the production of drug substances, but conventional chiral building blocks are liquid and cannot be purified by recrystallization, requiring purification by column chromatography, which is not efficient for industrial production. I can't say

JP-A-1988-140943 JP 2018-220888 A JP 2014-73987 A JP 2019-159871 A JP 2019-150578 A

As a result of intensive studies, the present inventors produced a specific raw material compound having a cyclopentenone skeleton, and further derivatized by enzymatic hydrolysis of the raw material compound, thereby efficiently producing prostaglandins. It has been found that a cyclopentenone derivative that can be used as a useful synthetic intermediate or chiral building block for the production of cyclopentenone can be efficiently produced. The present disclosure is based on such findings.

Accordingly, one object of the present disclosure is to provide a synthetic intermediate useful for efficient production of prostaglandin and a production method using the same.

According to one embodiment of the present disclosure, compounds represented by the following general formula (I) are provided.

(In general formula (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group indicates a functional group formed by combining

Moreover, according to one embodiment of the present disclosure, a compound represented by the following general formula (II) or an optically active substance thereof is provided.

(In general formula (II), R ² and R ³ are bonded to each other to form a ring structure together with the nitrogen atom to which they are bonded.)

Moreover, according to one embodiment of the present disclosure, a compound represented by the following general formula (III) or an optically active substance thereof is provided.

(In general formula (III), R ² and R ³ are bonded to each other to form a ring structure together with the nitrogen atom to which they are bonded,
R ⁴ represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic hydrocarbon ring group. )

Moreover, according to one embodiment of the present disclosure, a compound represented by the following general formula (IV) or an optically active substance thereof is provided.

(In general formula (IV), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
W represents a —SiR ⁵ R ⁶ R ⁷ group, an optionally substituted benzyl group or an acetal-type protecting group;
R ^5, R ⁶ and R ⁷ each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present.

Further, according to one embodiment of the present disclosure, there is provided an intermediate for producing a prostaglandin or an optically active substance thereof, which consists of a compound of any one of the above general formulas (I) to (IV).

Further, according to one embodiment of the present disclosure, a step of heating and refluxing the compound represented by general formula (b) in the presence of water to obtain the compound represented by general formula (I) comprises: Methods are provided for preparing compounds represented by general formula (I).

(In the general formulas (b) and (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and an aromatic Indicates a functional group formed by combining hydrocarbon ring groups.)

Further, according to one embodiment of the present disclosure, the compound represented by the general formula (I) is heated under reflux in the presence of water to obtain the compound represented by the general formula (V). A method for producing a compound represented by general formula (V) is provided.

Further, according to one embodiment of the present disclosure, the compound represented by the general formula (I) is reacted with the compound represented by the general formula (c) to obtain the compound represented by the general formula (II) A method is provided for preparing compounds represented by general formula (II), comprising the steps of:

(In general formula (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group represents a functional group formed by combining
In general formulas (c) and (II), ^R2 and ^R3 form a ring structure together with the nitrogen atom to which they are attached. )

Further, according to one embodiment of the present disclosure, the compound represented by the general formula (II) is reacted with the compound represented by the general formula (d) to obtain the compound represented by the general formula (III) There is provided a method for preparing a compound represented by general formula (III), comprising the steps of:

(In general formulas (II) and (III), R ² and R ³ are bonded to each other to form a ring structure together with the nitrogen atom to which they are bonded,
In general formulas (d) and (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent represents a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (3c). )

Further, according to one embodiment of the present disclosure, the compound represented by the formula (V) and the compound represented by the general formula (d) are reacted under basic conditions to obtain the compound represented by the general formula (VI). There is provided a method of making a compound represented by general formula (VI) comprising the step of obtaining the compound

(In general formulas (d) and (VI), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (d). )

Further, according to one embodiment of the present disclosure, the compound represented by the formula (VI) and the compound represented by the general formula (c) are reacted under basic conditions to obtain the compound represented by the general formula (III). There is provided a method of making a compound represented by general formula (III) comprising the step of obtaining a compound

(In general formulas (c) and (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formulas (VI) and (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )

Further, according to one embodiment of the present disclosure, the compound represented by the general formula (III) is optically resolved using a hydrolase to obtain an optically active form of the compound represented by the general formula (II) ( Manufacture of an optically active form (R form) of a compound represented by general formula (II), comprising a step of obtaining an optically active form (S form) of a compound represented by general formula (III). A method is provided.

(In general formulas (II) and (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formula (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituted A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. )

Further, according to one embodiment of the present disclosure, the optically active form (S form) of the compound represented by general formula (III) is solvolyzed to obtain the optical activity of the compound represented by general formula (II). Provided is a method for producing an optically active form (S form) of the compound represented by general formula (II), comprising a step of obtaining the form (S form).

Further, according to one embodiment of the present disclosure, the optically active form (S form) of the compound represented by general formula (II) is converted to the optically active form of the compound represented by general formula (II) through a Mitsunobu reaction. Provided is a method for producing an optically active form (R-form) of a compound represented by general formula (II), comprising a step of converting to the form (R-form).

(In general formula (II), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached.)

Further, according to one embodiment of the present disclosure, the optically active form (R form) of the compound represented by general formula (II) is reacted with a protective group-introducing agent to obtain the compound represented by general formula (IV). Provided is a method for producing an optically active form (R form) of the compound represented by general formula (IV), comprising a step of obtaining an optically active form (R form) of the compound.

(In general formulas (II) and (IV), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formula (IV), W represents a —SiR ⁵ R ⁶ R ⁷ group, an optionally substituted benzyl group or an acetal-type protecting group;
R ⁵ , R ⁶ and R ⁷ each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )

Further, according to one embodiment of the present disclosure, prostaglandin or an intermediate for producing an optically active substance thereof represented by the general formula (I), (II), (III) or (IV) A use of the compound or an optically active form thereof is provided.

According to the present disclosure, it is possible to provide a cyclopentenone derivative that can be used as a useful synthetic intermediate or chiral building block for producing prostaglandins, and a method for producing the same. According to the present disclosure, the cyclopentenone derivative can efficiently produce prostaglandins by using synthetic intermediates, which is advantageous in terms of industrial production. In addition, according to the method of the present disclosure, the cyclopentenone derivative can be produced from inexpensive raw materials such as furfural and dimethylsulfoxide, which is advantageous in reducing production costs. In addition, according to the present disclosure, in the above production method, the reaction of the sulfoxide compound can be carried out in the presence of water under heating and reflux conditions for a short period of time to consume the sulfoxide compound, which is advantageous for industrial production. Moreover, according to the method of the present disclosure, there is no need to undergo a reaction step under closed conditions and pressurized conditions, which is advantageous in terms of reducing facility costs.

Specific description of the invention

<Definition>
The terms and expressions used in this specification are explained below. The following definitions apply throughout this specification unless otherwise specified. For example, the definition of "alkyl group" also applies to functional groups that include "alkyl" or "alkyl groups" (eg, arylalkyl groups, etc.).

In this specification, for example, "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.

Examples of aliphatic hydrocarbon groups 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, still more preferably 4 to 6. is.

Examples of 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-ethylhexyl group, 5,5-dimethylhexyl group, 2 , 4,4-trimethylpentyl group, 1-ethyl-1-methylpentyl group, nonyl group, 1-methyloctyl group, 2-methyloctyl group, 3-methyloctyl group, 7-methyloctyl group, 1-ethylheptyl 1,1-dimethylheptyl group, 6,6-dimethylheptyl group, decyl group, 1-methylnonyl group, 2-methylnonyl group, 6-methylnonyl group, 1-ethyloctyl group, 1-propylheptyl group, etc. are preferred, but 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. be. 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.

Examples of 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.

Examples of 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.

Examples of aromatic hydrocarbon ring groups 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.

More specifically, 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. The descriptions of the 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. . Examples of 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. Examples of alkenylaryl groups include alkenylaryl groups such as o-styryl, m-styryl and p-styryl. Examples of 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.

The number of carbon atoms in the arylalkyl group is usually 7-15, preferably 7-11. 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, α-naphthylmethyl group, α-naphthylethyl group, β-naphthylmethyl group, β-naphthylethyl group, diphenylmethyl group, triphenylmethyl group and the like, more preferably It is a triphenylmethyl group.

The number of carbon atoms in the arylalkenyl group is usually 8-16, preferably 8-12. 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 expression "optionally substituted" with respect to a functional group means that one or more hydrogen atoms of the functional group may be independently replaced with other atoms or atomic groups. is synonymous with the fact that it may have a substituent or may be unsubstituted.

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. When the hydrocarbon group has two or more substituents, the two or more substituents may be the same or different.

When the alkyl group has 1 to 4 carbon atoms, the number of substituents that the alkyl group may have is usually 1 to 3, preferably 1 or 2, more preferably 1. When the alkyl group has 5 to 9 carbon atoms, 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. When 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.

When the alkenyl group has 2 to 4 carbon atoms, 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.

When the alkynyl group has 2 to 4 carbon atoms, the number of substituents that the alkynyl group may have is usually 1 to 3, preferably 1 or 2, more preferably 1. When the alkynyl group has 5 to 9 carbon atoms, 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. When the alkynyl group has 10 or more carbon atoms, 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. . When the aromatic hydrocarbon ring group has two or more substituents, the two or more substituents may be the same or different.

When the arylalkyl group or alkylaryl group has 7 to 11 carbon atoms, 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. When the arylalkyl group or alkylaryl group has 12 to 15 carbon atoms, 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. When the arylalkyl group or alkylaryl group has 16 or more carbon atoms, 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.

When the arylalkenyl group or alkenylaryl group has 8 to 11 carbon atoms, 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. When the arylalkenyl group or alkenylaryl group has 12 to 15 carbon atoms, 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. When the arylalkenyl group or alkenylaryl group has 16 or more carbon atoms, 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.

Examples of 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).

Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, and hexyloxy groups. , an isohexyloxy group, and the like.

Examples of 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.

A "protecting group" is a protecting group known to those skilled in the art and is used in the sense given in Green's Protective Groups in Organic Synthesis (Wuts, Peter GM, John WIley & Sons Inc.).
"Room 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.

As used herein, the term "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 intermediates of prostaglandins According to one embodiment of the present disclosure, as synthetic intermediates applicable to the production of prostaglandins, compounds represented by general formulas (I) to (IV) described below or optical compounds thereof An active is provided. Moreover, according to a preferred embodiment of the present disclosure, a compound represented by general formula (I) or general formula (II) or an optically active substance thereof is provided. When synthetic intermediates including compounds represented by general formula (I) or general formula (II) are used for the production of prostaglandins, without going through multiple steps as described in Non-Patent Document 1, Prostaglandins can be produced efficiently. In addition, when synthetic intermediates such as compounds represented by general formula (I) or general formula (II) are used for the production of prostaglandins, expensive raw materials as described in Non-Patent Document 2 are used. It is advantageous in terms of industrial production because prostaglandins can be produced without

Compound Represented by General Formula (I) According to one embodiment of the present disclosure, there is provided a compound represented by the following general formula (I).

(In general formula (I), R ¹ represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic hydrocarbon ring group.)

According to one embodiment of the present disclosure, in general formula (I), R ¹ is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted optionally substituted alkynyl group, optionally substituted aryl group, optionally substituted arylalkyl group, optionally substituted arylalkenyl group or substituted an arylakinyl group which may be substituted, an alkylaryl group which may have a substituent, an alkenylaryl group or an alkynylaryl group.

According to one embodiment of the present disclosure, in general formula (I), R ¹ is an optionally substituted alkyl group or an optionally substituted alkylaryl group.

According to one embodiment of the present disclosure, in general formula (I), R ¹ is an optionally substituted C ₁ to C ₆ alkyl group or an optionally substituted C ₇ to represents a _C14 alkylaryl group.

According to an even more preferred embodiment of the present disclosure, in general formula (I), R ¹ represents a C ₁ -C ₆ alkyl group, preferably methyl.

In the general formula (I) in any of the above embodiments, the substituents possessed by the functional group represented by R ¹ 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 C ₁ -C ₆ alkoxy group or a halogen atom, still more preferably a C ₁ -C ₃ alkoxy group or a halogen atom (preferably a fluorine atom, a chlorine atom, etc.) .

Compound Represented by General Formula (II) or Optically Active Form Thereof According to one embodiment of the present disclosure, there is provided a compound represented by the following general formula (II) or an optically active form thereof.

According to one embodiment of the present disclosure, in general formula (II), the ring structure formed with the nitrogen atom to which R ² and R ³ are bonded preferably contains a heteroatom other than the nitrogen atom. It is a good C ₂ -C ₁₁ ring structure, and more preferably forms a C ₄ -C ₆ ring structure which may contain heteroatoms other than the above nitrogen atoms. Also, according to a preferred embodiment of the present disclosure, the heteroatom other than the nitrogen atom is preferably a nitrogen atom, an oxygen atom or a sulfur atom, more preferably a nitrogen atom.

Further, according to a more preferred embodiment of the present disclosure, the heteroatom other than the nitrogen atom may have a protecting group, and examples of the protecting group include a tosyl group and a Boc group. is preferred.

Further, according to an even more preferred embodiment of the present disclosure, in general formula (II), the ring structure formed with the nitrogen atom to which R ² and R ³ are bound may be a 4-tosylpiperidine structure. . Thus, according to an even more preferred embodiment of the present disclosure, R ² and R ³ together represent a 3-tosyl-3-azapentanediyl group.

Compound Represented by General Formula (III) or Optically Active Form Thereof According to one embodiment of the present disclosure, there is provided a compound represented by the following general formula (III) or an optically active form thereof.

(In general formula (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
R ⁴ represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic hydrocarbon ring group. )

Further, according to one embodiment of the present disclosure, in general formula (III), the ring structure formed with the nitrogen atom to which R ² and R ³ are bonded is the same as in general formula (II).

Further, according to one embodiment of the present disclosure, in general formula (III), R ⁴ is an optionally substituted alkyl group, an optionally substituted alkenyl group, or It is an optionally substituted alkynyl group or an optionally substituted aryl group.

According to one embodiment of the present disclosure, in general formula (III), R ⁴ is an optionally substituted C ₁ to C ₆ alkyl group or an optionally substituted phenyl group; be.

In the general formula (III) in any of the above embodiments, the substituent possessed by the functional group represented by ^R4 is 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 C ₁ -C ₆ alkoxy group or a halogen atom, still more preferably a C ₁ -C ₃ alkoxy group or a halogen atom (preferably a fluorine atom, a chlorine atom, or the like).

Further, according to one embodiment of the present disclosure, in general formula (III), R ⁴ is
CH _(3-n) X _n (where X is F, Cl or Br and n is an integer of 1 to 3), or CH ₂ OY (where Y is an alkyl group, an aryl group, or an aralkyl group).

Further, according to one embodiment of the present disclosure, in general formula (III), R ⁴ is
CH _(3-n) X _n (where X is F, Cl or Br and n is an integer from 1 to 3), or CH ₂ OY (where Y is C ₁ -C ₆ alkyl or phenyl).

Further, according to one embodiment of the present disclosure, in general formula (III), R ⁴ is a C ₁ to C ₆ alkyl group optionally having a substituent with a halogen atom or a halogen atom having a substituent is a phenyl group which may be substituted, preferably CH ₂ Cl.

(In general formula (IV), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
W represents a —SiR ⁵ R ⁶ R ⁷ group, an optionally substituted benzyl group or an acetal-type protecting group;
R ^5, R ⁶ and R ⁷ each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )

According to one embodiment of the present disclosure, in general formula (IV), W is preferably a -SiR ⁵ R ⁶ R ⁷ group.

According to one embodiment of the present disclosure, in general formula (IV), R ⁵ , R ⁶ and R ⁷ are each independently an optionally substituted alkyl group and a substituted optionally substituted alkenyl group, optionally substituted aryl group, optionally substituted arylalkyl group, 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.

According to one embodiment of the present disclosure, in general formula (IV), R ⁵ , R ⁶ and R ⁷ are each independently an optionally substituted alkyl group and a substituted is an aryl group which may be substituted or an arylalkyl group which may have a substituent.

According to one embodiment of the present disclosure, in general formula (IV), R ⁵ , R ⁶ and R ⁷ are each independently a C ₁ -C ₆ alkyl group optionally having substituent(s), substituted represents a C ₆ -C ₁₀ aryl group optionally having a group or a C ₇ -C ₁₄ arylalkyl group optionally having a substituent.

According to one embodiment of the present disclosure, in general formula (IV), R ⁵ , R ⁶ and R ⁷ are each independently a C ₁ -C ₄ alkyl group optionally having a substituent, a substituted represents a C ₆ -C ₁₀ aryl group optionally having a group or a C ₇ -C ₁₄ arylalkyl group optionally having a substituent.

According to one embodiment of the present disclosure, in general formula (IV), R ⁵ , R ⁶ and R ⁷ are each independently a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group or a C ₇ represents a _-C14 arylalkyl group.

According to an even more preferred embodiment of the present disclosure, in general formula (IV), R ⁵ , R ⁶ and R ⁷ each independently represent a C ₁ -C ₆ alkyl group.

In general formula (IV) in any of the above embodiments, the substituents possessed by the functional groups represented by R ⁵ , R ⁶ and R ⁷ 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 a fluorine atom or chlorine atom, etc.).

In general formula (IV) in any of the above embodiments, R ⁵ , R ⁶ and R ⁷ are preferably methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, tert- A butyl group, a pentyl group, a hexyl group, a phenyl group, or a combination thereof, more preferably a combination of a t-butyl group and a methyl group.

According to one embodiment of the present disclosure, preferred examples of the optionally substituted benzyl group represented by W in general formula (IV) include a methyl group, an ethyl group, a butyl group, a trifluoromethyl group, a trichloro Examples include, but are not limited to, benzyl groups optionally substituted with methyl groups, methoxy groups, and the like.

Further, according to another embodiment of the present disclosure, in general formula (IV), the acetal-type protecting group represented by W is a protecting group-introducing agent represented by -C(CHR ⁸ R ⁹ )R ¹⁰ (OR ¹¹ ) may be used. Here, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, a substituent An alkynyl group optionally having a substituent, an aryl group optionally having a substituent, an arylalkyl group optionally having a substituent, an arylalkenyl group optionally having a substituent or a substituent , an optionally substituted alkylaryl group, an alkenylaryl group or an alkynylaryl group, any one of R ⁸ and R ⁹ and R ¹¹ may together form alkylene, alkenylene or alkynylene.

According to one embodiment of the present disclosure, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ each independently have a hydrogen atom, an optionally substituted alkyl group, or a aryl group, optionally substituted alkenyl group or optionally substituted alkynyl group, provided that any one of R ⁸ and R ⁹ and R ¹¹ Together they may form an alkylene.

According to one embodiment of the present disclosure, R ⁸ , R ⁹ and R ¹⁰ and R ¹¹ are each independently a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₆ -C ₁₀ aryl group, a C ₇ - may be a C ₁₄ alkenyl group or a C ₇ -C ₁₄ alkynyl group, provided that either one of R ^{8 and R 9} ^{and R 11} ^together form a C ₃ -C ₁₀ alkylene good.

According to one embodiment of the present disclosure, R ⁸ , R ⁹ and R ¹⁰ and R ¹¹ may each independently be a hydrogen atom or a C ₁ -C ₆ alkyl group, provided that R ⁸ and R Either one of ⁹ and R ¹¹ may together form a C ₃ -C ₁₀ alkylene.

According to one embodiment of the present disclosure, suitable examples of the acetal-type protecting group represented by W in general formula (IV) include a tetrahydropyranyl (THP) group, —CH(CH ₃ )OCH ₂ CH ₃ , Examples include, but are not limited to, -C(CH ₃ ) ₂ OCH ₂ CH ₃ , -CH ₂ OCH ₂ Ph and the like.

Production Method According to one embodiment of the present disclosure, as described above, prostaglandins can be efficiently synthesized using the compounds represented by general formulas (I) to (IV) as synthetic intermediates. The scheme below illustrates one embodiment of a method for preparing chiral building blocks (VI) for prostaglandin synthesis via compounds of general formula (I) or (II).

In Scheme 6, compound (b) is synthesized from furfural (a ₁ ) and sulfoxide compound (a ₂ ), and this is converted to compound (I) by Piancatelli rearrangement, and then reacted with a secondary amine to give a racemate. A racemic compound (III) can be synthesized by acylating the hydroxyl group at the 4-position of the compound (II). Further, compound I can be converted to diol compound (V) by a decomposition reaction, and after acylation to form diester compound (VI), racemic compound (III) can be synthesized by reacting it with a secondary amine. The racemic compound (III) can be optically resolved using a hydrolase to obtain a 4R-configured alcohol compound (II)-(R-isomer) and a 4S-configured ester compound (III)-(S-isomer). be done. Ester compound (III)-(S-form) is converted to 4S-configured alcohol compound (II)-(S-form) by solvolysis, and then converted to 4R-configured ester compound (III)-(R-form) by Mitsunobu reaction, The 4R configuration alcohol compound (II)-(R form) can be obtained by solvolysis. By protecting the hydroxyl group at the 4-position with a silyl group, compound (II)-(R form) can be converted to compound (VI), which is a key intermediate in prostaglandin synthesis.

One embodiment of the method for producing prostaglandin shown in Scheme 6 will be described below in more detail for each step. In the series of schemes shown below, specific examples and combinations of functional groups R ¹ to R ⁷ in each compound are the same as specific examples and combinations of functional groups R ¹ to R ⁷ in each embodiment above. .

Synthesis step of compound (b) Compound (b) can be synthesized by reacting sulfoxide compound (a ₂ ) with a base to generate an anion and reacting it with furfural compound (a ₁ ).

The amount of the sulfoxide compound (a ₂ ) to be used is generally 0.2 to 10 equivalents, preferably 0.5 to 2 equivalents, more preferably 0.8 to 1.2 equivalents, per 1 mol of the furfural compound (a ₁ ). is. Specific embodiments and combinations of R ¹ in sulfoxide compound (a ₂ ) are the same as specific embodiments and combinations of functional group R ¹ in compound (I) above.

(base)
The type of base is not particularly limited, and any base used in the art can be used. Examples of the base include lithium hydride, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, sodium-tert-butoxide, potassium-tert-butoxide, n-butyllithium, sec-butyllithium, tert. -Butyllithium can be used, but is not limited to these.
The amount of the base to be used is usually in the range of 0.2 to 10.0 mol, preferably in the range of 0.5 to 5.0 mol, more preferably 0.8 mol, per 1 mol of the raw material compound. ~1.2 mol range.

(solvent)
The type of solvent is not particularly limited, and any one used in the technical field can be used. Examples of the solvent include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide, but are not limited to these. do not have. Dimethyl sulfoxide, which is a reaction reagent, can also be used as a solvent. 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 reaction.

(reaction temperature)
The reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. range, more preferably -20°C to 30°C.

(reaction time)
The reaction time 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 can be adjusted appropriately by those skilled in the art.

Synthesis step of compound (I) Compound (b) can be converted to compound (I) by a hydrothermal reaction.

(solvent)
Water or a mixture of water and a water-soluble solvent can be used as solvent. The type of water-soluble solvent is not particularly limited, and any one used in the technical field can be used. Examples of the water-soluble solvent include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, n-propanol, 2-propanol, Non-limiting examples include n-butanol, 2-butanol, tert-butanol. 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 reaction.

(pH)
In the step of synthesizing compound (I), the reaction solution is acidic, preferably pH 2-7, more preferably pH 2-4.

(Reaction solution concentration)
In the step of synthesizing compound (I), the reaction solution concentration is preferably 0.02 to 1.0 mol/L, more preferably 0.1 to 0.3 mol/L.

(reaction temperature)
In the step of synthesizing compound (I), the reaction temperature is 20 to 200°C, preferably 50 to 180°C, more preferably 80 to 130°C.

(reaction time)
In the synthesis step of compound (I), the reaction time is 1 to 48 hours, preferably 2 to 36 hours, more preferably 3 to 24 hours. The reaction time can be arbitrarily set depending on the temperature conditions.

Synthetic Step of Compound (II) By reacting compound (I) with secondary amine compound (c), the primary ester is converted to an amino group to give compound (II). Here, specific embodiments and combinations of R ² and R ³ in compound (c) are the same as specific embodiments and combinations of functional groups R ² and R ³ in compound (II) above.

(Secondary amine compound (c))
The type of the secondary amine compound (c) used in the reaction is not particularly limited, and any one used in the technical field can be used. Examples of the secondary amine compound (c) that can be used include pyrrolidine, piperidine, homopiperidine, morpholine, isoindoline, N-methylpiperazine, N-ethylpiperazine, N-phenylpiperazine and N-tosylpiperazine. is not limited to The amount of the secondary amine compound (c) used in the reaction is usually in the range of 2.0 to 10.0 mol, preferably in the range of 2.0 to 5.0 mol, per 1 mol of the raw material compound. and more preferably in the range of 2.0 to 3.0 mol.

(solvent)
In the step of synthesizing compound (II), the type of solvent is not particularly limited, and any one used in the art can be used. Examples of the solvent include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide and N,N-dimethylacetamide, but are not limited to these. do not have. The reaction can also be carried out by adding water to these solvents at any ratio. 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 reaction.

(reaction temperature)
In the step of synthesizing compound (II), the reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably -20°C to 30°C.

(reaction time)
In the step of synthesizing compound (II), the reaction time 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. and more preferably a range of 1 hour to 10 hours. However, the reaction time can be adjusted appropriately by those skilled in the art.

Synthetic Step of Compound (III) Compound (III) can also be synthesized by esterifying the 4-position hydroxyl group of compound (II).

(Acylating agent)
In the step of synthesizing compound (III), as compound (d), an acid chloride or acid anhydride of a carboxylic acid having an electron-withdrawing substituent at the α-position can be used as an acylating agent for the reaction. The type of carboxylic acid is not particularly limited, and any one used in the technical field can be used. Here, specific embodiments and combinations of R ⁴ in compound (d) are the same as specific embodiments and combinations of functional group R ⁴ in compound (III) above.

Examples of the carboxylic acid include fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, dibromoacetic acid, tribromoacetic acid, methoxyacetic acid, phenoxyacetic acid, and their asymmetric acid anhydrides. can be used, but are not limited to these. The amount of the acylating agent to be used is usually in the range of 0.5 to 10.0 mol, preferably in the range of 0.8 to 5.0 mol, more preferably 1 mol, per 1 mol of the raw material compound. .0 to 2.0 moles.

(base)
In the step of synthesizing compound (III), the type of base used in the reaction is not particularly limited, and any base used in the art can be used. Examples of the base include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 4-dimethylaminopyridine, and lutidine. A person skilled in the art can appropriately adjust the amount of the base used in the reaction.

(solvent)
In the step of synthesizing compound (III), the type of solvent is not particularly limited, and any one used in the art can be used. Examples of the solvent include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide, but are not limited to these. do not have. Bases can also be used as solvents. 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 reaction.

(reaction temperature)
In the step of synthesizing compound (III), the reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. range, more preferably -20°C to 30°C.

(reaction time)
In the step of synthesizing compound (III), the reaction time 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 can be adjusted appropriately by those skilled in the art.

Synthesis step 1 of compound (V)
Compound (I) can be converted to compound (V) by thermal decomposition.

(solvent)
Water or a mixture of water and a water-soluble solvent can be used as a solvent in the step of synthesizing compound (V). The type of water-soluble solvent is not particularly limited, and any one used in the technical field can be used. Examples of the water-soluble solvent include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, ethanol, n-propanol, 2-propanol, Non-limiting examples include n-butanol, 2-butanol, tert-butanol. 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 reaction.

(pH)
In the step of synthesizing compound (V), the reaction solution is neutral to acidic, preferably pH 2-7, more preferably pH 5-7.

(reaction temperature)
In the step of synthesizing compound (V), the reaction temperature is 20 to 200°C, preferably 50 to 180°C, more preferably 80 to 130°C.

(reaction time)
In the step of synthesizing compound (V), the reaction time is 1 to 48 hours, preferably 2 to 36 hours, more preferably 3 to 24 hours. The reaction time can be arbitrarily set depending on the temperature conditions.

Synthesis step 2 of compound (V)
Compound (V) can also be produced in one pot from compound (b).

(pH)
In the step of synthesizing compound (V), the reaction solution is acidic, preferably pH 2-7, more preferably pH 2-4.

(Reaction solution concentration)
In the step of synthesizing compound (V), the reaction solution concentration is preferably 0.02 to 1.0 mol/L, more preferably 0.1 to 0.3 mol/L.

Synthesis step of compound (VI) Compound (VI) can be converted to compound (VI) by reacting compound (V) with acylating agent compound (d) and a base.

(Acylating agent compound (d))
In the step of synthesizing compound (VI), an acid chloride or acid anhydride of a carboxylic acid having an electron-withdrawing substituent at the α-position can be used as the acylating agent compound (d) used in the reaction. The type of carboxylic acid is not particularly limited, and any one used in the technical field can be used. Examples of the carboxylic acid include fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, dibromoacetic acid, tribromoacetic acid, methoxyacetic acid, phenoxyacetic acid, and their asymmetric acid anhydrides. It can be, but is not limited to. The amount of the acylating agent to be used is usually in the range of 0.5 to 10.0 mol, preferably in the range of 0.8 to 5.0 mol, more preferably 1 mol, per 1 mol of the raw material compound. .0 to 2.0 moles.

(base)
In the step of synthesizing compound (VI), the type of base used in the reaction is not particularly limited, and any base used in the art can be used. Examples of the base include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 4-dimethylaminopyridine, and lutidine. A person skilled in the art can appropriately adjust the amount of the base used in the reaction.

(solvent)
In the step of synthesizing compound (VI), the type of solvent is not particularly limited, and any one used in the art can be used. Examples of the solvent include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide and N,N-dimethylacetamide, but are not limited to these. do not have. Bases can also be used as solvents. 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 reaction.

(reaction temperature)
In the step of synthesizing compound (VI), the reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably -20°C to 30°C.

(reaction time)
In the step of synthesizing compound (VI), the reaction time 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. and more preferably a range of 1 hour to 10 hours. However, the reaction time can be adjusted appropriately by those skilled in the art.

Synthetic Step of Compound (III) By reacting compound (VI) with secondary amine compound (c), the primary ester is converted to an amino group to give compound (III).

(Secondary amine)
In the step of synthesizing compound (III), the type of secondary amine compound (c) used in the reaction is not particularly limited, and any one used in the art can be used. Examples of the secondary amine include pyrrolidine, piperidine, homopiperidine, morpholine, isoindoline, N-methylpiperazine, N-ethylpiperazine, N-phenylpiperazine, and N-tosylpiperazine, but are limited to these. not a thing The amount of the secondary amine used in the reaction 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 5.0 mol, per 1 mol of the raw material compound. is in the range of 1.0 to 3.0 mol.

(solvent)
In the step of synthesizing the solvent compound (III), the type of medium is not particularly limited, and any medium used in the art can be used. Examples of the solvent include diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, N,N-dimethylformamide and N,N-dimethylacetamide, but are not limited to these. do not have. The reaction can also be carried out by adding water to these solvents at any ratio. 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 reaction.

(reaction temperature)
In the step of synthesizing compound (III), the reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. and more preferably -20°C to 30°C.

Compound (II)-(R-form) and/or compound (III)-(S-form) synthesis step Compound (III) is dissolved in a phosphate buffer and a hydratable solvent and reacted with a hydrolase, Compound (II)-(R form) and compound (III)-(S form) are obtained. These can be separated by column chromatography.

(hydrolase)
In the step of synthesizing compound (II)-(R form) and/or compound (III)-(S form), the hydrolase (lipase) used includes, for example, a commercially available hydrolase lipase AK (Amano ), Lipase PS (manufactured by Amano), Lipase PS Amano SD (manufactured by Amano), Lipase AYS (manufactured by Amano), Lipase G Amano 50 (manufactured by Amano), Lipase PSIM (manufactured by Amano), Lipase F- AP15 (manufactured by Amano), CHIRAZYME L-6 (manufactured by Roche), Lipase-OML (manufactured by Meito Sangyo), Lipase TL (manufactured by Meito Sangyo), Lipase-MY-30 (manufactured by Meito Sangyo) , Lipase-SL (manufactured by Meito Sangyo Co., Ltd.), Lipase A-10D (manufactured by Nagase ChemteX Corporation), KM-109 (manufactured by Nagase ChemteX Corporation), Immobilizedlipase (manufactured by Toyobo Co., Ltd.) can be used, preferably Lipase PS Amano SD (manufactured by Amano Corporation) may be mentioned, but is not limited to these. Various forms of hydrolase can be used, such as purified enzymes, those adsorbed on diatomaceous earth and the like, and those immobilized on bead glass and the like.

(buffer)
The step of synthesizing compound (II)-(R form) and/or compound (III)-(S form) can be suitably carried out in a phosphate buffer. As the phosphate buffer, for example, a phosphate buffer having a concentration of 0.1 M and a pH of about 7 can be used, but the present invention is not limited to this.

(solvent)
In the step of synthesizing compound (II)-(R-form) and/or compound (III)-(S-form), the reaction may be carried out by adding an organic solvent in addition to the buffer, and the solvent may be acetone. , dimethyl sulfoxide, dibutyl ethers and the like, either singly or as a mixture. The amount used can be appropriately adjusted by those skilled in the art.

(reaction temperature and reaction time)
In the step of synthesizing compound (II)-(R form) and/or compound (III)-(S form), the reaction temperature is usually 10 to 50° C., and the reaction time is usually 0.5 to 50 hours. is.

In the step of synthesizing compound (II)-(R-form) and/or compound (III)-(S-form), the reaction transition can be determined using, for example, liquid chromatography equipped with a packing material for optically active compounds. It can be monitored by measuring the optical purities of (II)-(R-isomer) and compound (III)-(S-isomer), and the reaction endpoint can be determined by this. In addition, the ratio of compound (II)-(R form) and compound (III)-(S form) is measured by conventional (not necessarily for optically active compounds) liquid chromatography or the like, and the ratio is The reaction end point can also be set when the ratio becomes approximately 1:1. After completion of the reaction, if necessary, a solvent such as chloroform, ethyl acetate, or ethyl ether is added to the reaction mass, for example, the enzyme is filtered off, and the filtrate is concentrated to obtain compound (II)-(R form) and compound ( A mixture of III)-(S forms) can be obtained. Furthermore, it can be separated into compound (II)-(R-form) and compound (III)-(S-form) by subjecting it to, for example, normal chromatography.

Synthetic step of compound (II)-(S-isomer) By appropriately selecting the 4-position ester of compound (III)-(S-isomer), compound (III)-(S-isomer) is solvolyzed to give compound ( II)-(S form) can be obtained.

(reaction substrate)
(4S)-4-acyloxy-2-aminomethyl-2-cyclopenten-1-one having an electron-withdrawing substituent at the α-position can be used in the step of synthesizing compound (II)-(S form). The acetyl group having an electron-withdrawing substituent at the α-position includes a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a dichloroacetyl group, a trichloroacetyl group, a bromoacetyl group, a dibromoacetyl group, and a tribromo Acetyl, methoxyacetyl, and phenoxyacetyl groups can be used, but are not limited to these.

(base)
In the step of synthesizing compound (II)-(S form), the type of base used in the reaction is not particularly limited, and any base used in the art can be used. Examples of the base include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 4-dimethylaminopyridine, and lutidine. A person skilled in the art can appropriately adjust the amount of the base used in the reaction.

(solvent)
In the step of synthesizing compound (II)-(S form), the type of solvent is not particularly limited, and any alcohol used in the art can be used. Examples of the solvent include, but are not limited to, methanol, ethanol, n-propanol, 2-propanol, and n-butanol. 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 reaction.

(reaction temperature)
In the step of synthesizing compound (II)-(S form), the reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. range, more preferably -20°C to 30°C.

(reaction time)
In the step of synthesizing compound (II)-(S form), the reaction time 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 can be adjusted appropriately by those skilled in the art.

Synthesis step of compound (III)-(R form) Compound (II)-(S form) can be converted to compound (III)-(R form) by Mitsunobu reaction.

(carboxylic acid)
A carboxylic acid having an electron-withdrawing substituent at the α-position can be used in the step of synthesizing compound (III)-(R form). Examples of the carboxylic acid that can be used include fluoroacetic acid, difluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, bromoacetic acid, dibromoacetic acid, tribromoacetic acid, methoxyacetic acid, phenoxyacetic acid, and the like, but are limited to these. not to be The amount of carboxylic acid to be used is usually in the range of 0.5 to 10.0 mol, preferably in the range of 0.8 to 5.0 mol, more preferably 1.0 mol, per 1 mol of the raw material compound. It ranges from 0 to 2.0 mol.

(Azodicarboxylic acid diester)
In the step of synthesizing compound (III)-(R form), 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. Examples of 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)
In the step of synthesizing compound (III)-(R form), the type of phosphine used in the Mitsunobu reaction is not particularly limited, and any one used in the art 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 preferably 1.0 mol, per 1 mol of the raw material compound. ~2.0 molar range.

(solvent)
In the step of synthesizing compound (III)-(R form), the type of solvent used in the Mitsunobu reaction is not particularly limited, and any solvent used in the art can be used. Examples of 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)
In the step of synthesizing compound (III)-(R form), 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)
In the step of synthesizing compound (III)-(R form), 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.

(post-processing)
In the step of synthesizing compound (III)-(R form), post-treatment of the Mitsunobu reaction may be a general treatment for obtaining a product from the reaction solution. For example, 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.

Synthetic step of compound (IV)-(R-form) Compound (II)-(R-form) is reacted with a protecting group-introducing agent to introduce a protecting group to the 4-position hydroxyl group of compound (II)-(R-form). By doing so, compound (IV)-(R form) can be obtained.

The protecting group-introducing agent includes a silylating agent, a benzyl-type protecting group-introducing agent, or an acetal-type protecting group-introducing agent for introducing a protecting group for hydroxyl groups, and is preferably a silylating agent.

According to one embodiment of the present disclosure, the protecting group-introducing agent has the general formula (e) WX (W is an optionally substituted benzyl group, silyl group or acetal-type protecting group, X is F, Cl , Br or I).

(silylating agent)
When the silylating agent is represented by general formula (e) WX, a suitable example of the optionally substituted silyl group represented by W is -SiR ⁵ R ⁶ R ⁷ group. R ⁵ , R ⁶ and R ⁷ are each independently an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group , an aryl group optionally having substituents, an arylalkyl group optionally having substituents, an arylalkenyl group optionally having substituents or an arylalkyl group optionally having substituents It is a nyl group, an optionally substituted alkylaryl group, an alkenylaryl group or an alkynylaryl group.

More specifically, in the step of synthesizing compound (IV)-(R form), the type of silylating agent is not particularly limited, and any one used in the art can be used in the method of the present invention. For example, trialkylsilyl halide compounds, monoalkyldiarylsilyl halide compounds, triarylsilyl halide compounds, and the like can be used. When the silyl halide compound has an alkyl group, the alkyl group may be, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, or tert-butyl group. etc. can be used. Among these, a methyl group or an ethyl group is preferred. When the silyl halide compound has an aryl group, a phenyl group or the like can be used. As the halogen atom constituting the silyl halide compound, a chlorine atom, a bromine atom, an iodine atom, or the like can be used, and a chlorine atom is preferably used. More specifically, the silyl halide compound includes trimethylsilyl chloride (sometimes referred to as trimethylchlorosilane; the same applies to the following compounds), triethylsilyl chloride, tert-butyldimethylsilyl chloride, and tert-butyldiphenylsilyl chloride. , triphenylsilyl chloride and the like.

(Benzyl-type protective group-introducing agent)
When the benzyl-type protecting group-introducing agent is represented by the general formula (e) WX, preferred examples of the optionally substituted benzyl group represented by W include a methyl group, an ethyl group, a butyl group, and a trifluoromethyl group. , a trichloromethyl group, a benzyl group optionally substituted with a methoxy group and the like, but are not limited thereto.

(Acetal-type protective group-introducing agent)
When the acetal-type protecting group-introducing agent is represented by the general formula (e) WX, preferred examples of the acetal-type protecting group represented by W include a tetrahydropyranyl (THP) group, —CH(CH ₃ )OCH ₂ CH ₃ , -C(CH ₃ ) ₂ OCH ₂ CH ₃ , -CH ₂ OCH ₂ Ph and the like, but are not limited thereto.

Further, according to another embodiment of the present disclosure, as the acetal-type protecting group-introducing agent, a protecting group-introducing agent represented by the general formula (f) R ⁸ R ⁹ C=CR ¹⁰ OR ¹¹ may be used. good. Here, R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, a substituent An alkynyl group optionally having a substituent, an aryl group optionally having a substituent, an arylalkyl group optionally having a substituent, an arylalkenyl group optionally having a substituent or a substituent , an optionally substituted alkylaryl group, an alkenylaryl group or an alkynylaryl group, any one of R ⁸ and R ⁹ and R ¹¹ may together form alkylene, alkenylene or alkynylene.

(base)
According to one embodiment of the present disclosure, in the step of synthesizing compound (IV)-(R form), protective group introduction is carried out in the presence of a base. The type of base used in the reaction is not particularly limited, and any base used in the art can be used. Examples of the base include, but are not limited to, triethylamine, diisopropylethylamine, N-methylmorpholine, imidazole, pyridine, 4-dimethylaminopyridine, and 2,6-lutidine. A person skilled in the art can appropriately adjust the amount of the base used in the reaction.

(solvent)
In the step of synthesizing compound (IV)-(R form), the type of solvent is not particularly limited, and any aprotic polar solvent used in the art can be used. Examples of the solvent include ethers (e.g., tetrahydrofuran (THF), diisopropyl ether, dibutyl ether, cyclopentyl methyl ether (CPME), methyl-tert-butyl ether, more preferably tetrahydrofuran (THF)), amides (e.g., N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diethylacetamide, N-methylpyrrolidone (NMP) and the like, preferably N,N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), N-methylpyrrolidone (NMP), more preferably N,N-dimethylformamide (DMF)), sulfoxides (eg, dimethylsulfoxide (DMSO), etc. can be used, but are limited to these. The amount of solvent used may be any amount as long as the reaction proceeds, and the amount of solvent used in the reaction can be appropriately adjusted by those skilled in the art.

(reaction temperature)
In the step of synthesizing compound (IV)-(R form), the reaction temperature is not particularly limited. In one embodiment, the reaction temperature is in the range of -80°C to 100°C, preferably -40°C to 50°C, from the viewpoints of yield improvement, suppression of by-products, and economic efficiency. range, more preferably -20°C to 30°C.

(reaction time)
In the step of synthesizing compound (IV)-(R form), the reaction time 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 can be adjusted appropriately by those skilled in the art.

Synthetic process of prostaglandin According to Patent Document 1, as shown in Scheme 19, (4R)-(4-tert-butyldimethylsilyl)hydroxy-2- corresponding to compound (IV)-(R form) Aminomethyl-2-cyclopenten-1-one can be used to efficiently produce prostaglandins. A prostaglandin can be obtained by applying the method described in Patent Document 1 to compound (IV)-(R form).

Synthetic intermediate/use
Production of a prostaglandin or an optically active substance thereof from a compound represented by general formula (III) or an optically active substance thereof As described above , a compound represented by any one of general formulas (I) to (VI) or its optically active substance An optically active form can advantageously utilize a prostaglandin as a synthetic intermediate in its production.

Therefore, according to a preferred embodiment of the present invention, a prostaglandin represented by any one of general formulas (I) to (VI) or comprising an optically active substance thereof, for producing a prostaglandin or an optically active substance thereof Reagents are provided.

Further, according to a preferred embodiment of the present invention, a compound represented by any one of general formulas (I) to (VI) or an optically active substance thereof as a reagent for producing a prostaglandin or an optically active substance thereof is provided for use.

Also, according to a preferred aspect of the present invention, the prostaglandin is represented by formula (A).

Also, according to one embodiment of the present invention, the following are provided.
[1]
A compound represented by the following general formula (I).

(In general formula (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group indicates a functional group formed by combining
[2]
A compound according to claim 1, wherein R ¹ is a C ₁ -C ₆ alkyl group.
[3]
A compound represented by the following general formula (II) or an optically active form thereof.

(In general formula (II), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached.)
[4]
A compound represented by the following general formula (III) or an optically active form thereof.

(In general formula (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
R ⁴ represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic hydrocarbon ring group. )
[5]
^R4 is
CH _(3-n) X _n (where X is F, Cl or Br and n is an integer of 1 to 3), or CH ₂ OY (where Y is an alkyl group, an aryl group, or an aralkyl group).
[6]
The compound of [5], wherein R ⁴ is CH ₂ Cl.
[7]
A compound represented by the following general formula (IV) or an optically active substance thereof.

In general formula (IV), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
W represents a —SiR ⁵ R ⁶ R ⁷ group, an optionally substituted benzyl group or an acetal-type protecting group;
R ^5, R ⁶ and R ⁷ each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )
[8]
The compound according to [7], wherein R ^{5 ,} R ⁶ and R ⁷ 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.
[9]
A compound according to [8], wherein R ² and R ³ together represent a 3-tosyl-3-azapentanediyl group.
[10]
An intermediate for producing a prostaglandin or an optically active substance thereof, comprising the compound according to any one of [1] to [9].
[11]
The intermediate according to [10], wherein the prostaglandin or its optically active substance is represented by the following formula (A).

[12]
Manufacture of a compound represented by general formula (I), comprising a step of obtaining a compound represented by general formula (I) by heating under reflux a compound represented by general formula (b) in the presence of water how to.

(In the general formulas (b) and (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and an aromatic Indicates a functional group formed by combining hydrocarbon ring groups.)
[13]
Manufacture of a compound represented by general formula (V), comprising a step of obtaining a compound represented by general formula (V) by heating under reflux a compound represented by general formula (I) in the presence of water how to.

(In general formula (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group indicates a functional group formed by combining
[14]
of general formula (II), comprising a step of reacting a compound of general formula (I) with a compound of general formula (c) to obtain a compound of general formula (II); Methods of making the represented compounds.

(In general formula (I), R ¹ is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group represents a functional group formed by combining
In general formulas (c) and (II), ^R2 and ^R3 form a ring structure together with the nitrogen atom to which they are attached. )
[15]
In general formula (III), comprising a step of reacting a compound represented by general formula (II) with a compound represented by general formula (d) to obtain a compound represented by general formula (III) Methods of making the represented compounds.

(In general formulas (II) and (III), R ² and R ³ are bonded to each other to form a ring structure together with the nitrogen atom to which they are bonded,
In general formulas (d) and (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent represents a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (d). )
[16]
reacting a compound represented by formula (V) with a compound represented by general formula (d) under basic conditions to obtain a compound represented by general formula (VI); A method for producing a compound represented by (VI).

(In general formulas (d) and (VI), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (d). )
[17]
reacting a compound of formula (VI) with a compound of general formula (c) under basic conditions to obtain a compound of general formula (III); A method for producing a compound represented by (III).

(In general formulas (c) and (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formulas (VI) and (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )
[18]
The compound represented by the general formula (III) is optically resolved using a hydrolase to obtain the optically active form (R form) of the compound represented by the general formula (II) and the compound represented by the general formula (III). A method for producing an optically active form (R form) of a compound represented by general formula (II), comprising a step of obtaining an optically active form (S form) of the compound represented by formula (II).

(In general formulas (II) and (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formula (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituted A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. )
[19]
The method of [18], wherein the hydrolase is lipase.
[20]
A step of solvolyzing an optically active form (S form) of the compound represented by general formula (III) to obtain an optically active form (S form) of the compound represented by general formula (II). , a method for producing an optically active form (S form) of a compound represented by general formula (II).

(In general formulas (II) and (III), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formula (III), R ⁴ is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituted A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. )
[21]
The method of [20], wherein the solvolysis is solvolysis with methanol and a tertiary amine.
[22]
a step of converting an optically active form (S form) of the compound represented by general formula (II) into an optically active form (R form) of the compound represented by general formula (II) by Mitsunobu reaction; A method for producing an optically active form (R form) of a compound represented by general formula (II).

(In general formula (II), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached.)
[23]
A step of reacting an optically active form (R form) of a compound represented by general formula (II) with a protecting group-introducing agent to obtain an optically active form (R form) of a compound represented by general formula (IV) A method for producing an optically active form (R form) of a compound represented by general formula (IV), comprising:

(In general formulas (II) and (IV), R ² and R ³ form a ring structure together with the nitrogen atom to which they are attached,
In general formulas (e) and (IV), W represents a —SiR ⁵ R ⁶ R ⁷ group, an optionally substituted benzyl group or an acetal-type protecting group;
R ⁵ , R ⁶ and R ⁷ each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent represents a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (e). )
[24]
The method according to any one of [12] to [23] for producing prostaglandin or its optically active form.
[25]
The method of [24], wherein the optically active form of prostaglandin is represented by formula (A).

[26]
General formula (I), (II), (III) or (IV) according to any one of [1] to [9] as an intermediate for producing a prostaglandin or an optically active substance thereof Use of the represented compound or its optically active form.
[27]
The use according to [26], wherein the optically active form of prostaglandin is represented by formula (A).

EXAMPLES The present disclosure will be described in more detail with examples below, but the present disclosure is not limited to these examples. The following instruments were used to measure physical properties in Examples and Reference Examples.
¹ H nuclear magnetic resonance spectrum ( ¹ H NMR) and ¹³ C nuclear magnetic resonance spectrum ( ¹³ C NMR): JNM-ECZ400S (manufactured by JEOL)
Internal standard substance: tetramethylsilane.

Production of Prostaglandin Synthetic Intermediate A prostaglandin synthetic intermediate was produced according to the following scheme. Each step will be described below.

Example 1: Synthesis of 2-((2-methylsulfenyl-1-hydroxy)ethyl)furan (compound 2)

2.0 g of 60% sodium hydride oil dispersion was weighed into a 100 mL four-necked flask purged with nitrogen, and 40 mL of hexane was added and stirred. Hexane was removed by decantation, and 200 mL of dimethylsulfoxide was added and stirred. If the mixture is gradually heated, foaming becomes vigorous at around 50°C, so this temperature was maintained for 1 hour. When the sodium hydride was dispersed in the solution and the bubbles became fine, the temperature was gradually raised and maintained at around 55°C for 1 hour. After stirring at 65 to 70° C. for 1 hour, sodium hydride was consumed and foaming ceased to obtain a uniform solution. After cooling to 20° C., 4.3 g (45 mmol) of furfural was added at 30° C. or lower and stirred at room temperature for 1 hour. Then, 29 mL of water was added with cooling and neutralized with 1M hydrochloric acid (approximately 44 mL). Next, after removing water with a rotary evaporator, the aspirator was replaced with a vacuum pump to distill off dimethyl sulfoxide to obtain a reaction mixture containing the desired product. Next, a mixture of the desired product and dimethylsulfoxide (molar ratio 2:3) was obtained by column chromatography (ethyl acetate). Distillation of dimethyl sulfoxide with a Kugelrohr distillation gave 4.2 g (54%) of compound 2 as a diastereomeric mixture.

¹ H NMR (CDCl ₃ ) δ 2.69 (1.5 H, s), 2.72 (1.5 H, s), 3.02 (0.5 H, dd, J = 13.2, 2.4 Hz), 3.16 (0.5H, dd, J = 13.2, 4.4Hz), 3.22 (0.5H, dd, J = 13.2, 8.8Hz), 3.29 (0.5H, dd, J = 13.2, 10.0Hz), 3.82 (0.5H, brs), 3.94 (0.5H, brs), 5.36-5.42 (1H, m), 7. 40 (1H, m)

¹³ C NMR (CDCl ₃ ) δ 38.8, 39.3, 57.3, 58.9, 62.1, 63.5, 106.5, 107.0, 110.4 (overlap), 142.36, 142.42, 154.0, 154.3.

Example 2: Synthesis of 2-((2-methylsulfenyl-1-hydroxy)ethyl)furan (compound 2)

40 g (360 mmol) of potassium-tert-butoxide was weighed into a 1 L four-necked flask purged with nitrogen, and 600 mL of dimethylsulfoxide was added and stirred to dissolve. After gradually adding 50 g (520 mmol) of furfural at 30° C. or lower, the mixture was stirred at room temperature for 3 hours. After neutralizing with 2M hydrochloric acid while cooling, water was removed with a rotary evaporator, and the aspirator was replaced with a vacuum pump to distill off dimethylsulfoxide to obtain a reaction mixture containing the desired product. A Kiriyama funnel was covered with silica gel for column chromatography, and the ethyl acetate solution of the reaction mixture was filtered by suction to obtain a mixture of the desired product and dimethyl sulfoxide (molar ratio 2:3). After concentrating with a rotary evaporator, the aspirator was replaced with a vacuum pump to distill off dimethylsulfoxide to obtain 73.2 g (81%) of compound 2 as a diastereomeric mixture.

Example 3: Synthesis of 4-hydroxy-2-methylsulphenylmethyl-2-cyclopenten-1-one (compound 3) and 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one (compound 6)

1.0 g of dipotassium hydrogen phosphate was dissolved in 1 L of water, and phosphoric acid was added to adjust the pH to 3. 20.0 g (115 mmol) of compound 2 was dissolved in the prepared phosphoric acid aqueous solution and refluxed for 24 hours. After cooling to room temperature, water was removed with a rotary evaporator. 100 mL of 2-propanol was added to the residue and the mixture was refluxed, cooled to room temperature, and insoluble matter was removed by suction filtration using celite. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography to give 6.1 g (42%) of a diastereomer mixture of compound 3 (ethyl acetate:methanol=10:1) and compound 6 (ethyl acetate:methanol=4 : 6.4 g (32%) of 1) were obtained.

Compound 3 (less polar diastereomer)
1H NMR ( _CDCl3 ) δ 2.42 (1H, dd, J = 18.8, 2.0 Hz), 2.92 (1H, dd, J = 18.8, 6.4 Hz), 2.91 (3H, s), 3.96 (2H, s), 5.08 (1H, brs), 7.79 (1H, s).

Compound 3 (highly polar diastereomer)
¹ H NMR (CDCl ₃ ) δ 2.38 (1H, dd, J = 18.8, 2.2 Hz), 2.80 (1H, dd, J = 18.8, 6.4 Hz), 3.49 (3H , s), 4.41 (2H, s), 5.03 (1 H, s), 7.38 (1 H, s).
^13C NMR ( _CDCl3 ) d 45.1, 50.8, 57.0, 68.5, 146.3, 157.0, 206.0.

compound 6
¹ H NMR (DMSO-d ₆ ) δ 2.10 (1H, dd, J = 18.4, 1.6 Hz), 2.69 (1H, dd, J = 18.4, 6.0 Hz), 4.05 (2H, d, J = 4.8Hz), 4.75 (1H, br), 5.01-5.04 (1H, m), 5.35-5.37 (1H, m), 7.29 -7.30 (1H, m).
¹³ C NMR (DMSO-d ₆ ) δ 45.3, 55.2, 67.1, 146.4, 158.1, 205.3

Example 4: Synthesis of 4-hydroxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound rac-4)

1.0 g (5.7 mmol) of compound 3 is dissolved in 20 mL of THF and cooled with ice. After adding 2.8 g (11.6 mmpl) of N-tosylpiperazine, the mixture is stirred at room temperature for 5 hours. The filtrate is concentrated under reduced pressure using a rotary evaporator and purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 1.5 g (75%) of compound rac-4 as a powder.

Compound rac-4
mp: 182°C
¹ H NMR (CDCl ₃ ) δ 2.32 (dd, 1H, J=18.4, 2.0 Hz), 2.44 (s, 3H), 2.53-2.55 (m, brm), 2. 82 (dd, 1H, J=18.4, 6.0Hz), 3.02 (brs, 4H), 3.26 (s, 2H), 4.96-4.98 (m, 1H), 7. 26 (s, 1H), 7.33 (d, 2H, J=8.0Hz), 7.62 (d, 2H, J=8.0Hz).
^13C NMR ( _CDCl3 ) δ 21.5, 44.9, 45.9, 51.5, 52.2, 68.4, 127.8, 129.7, 132.3, 143.2, 143.8 , 158.9, 205.2.

Example 5: Synthesis of 4-chloroacetoxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound rac-5)

3.0 g (8.6 mmol) of the compound rac-4 was dissolved in 200 mL of THF, 3.0 g (18 mmol) of chloroacetic anhydride was added, and the mixture was ice-cooled. 1 mL of pyridine was added thereto, and after stirring at room temperature for 14 hours, water was added to terminate the reaction. The extract was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Next, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a mixture containing the desired product. Then, purification by silica gel column chromatography (ethyl acetate) gave 3.5 g (96%) of compound rac-5 as a pale yellow oily substance.

Example 6: Synthesis of 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one (compound 6)

1.0 g of dipotassium hydrogen phosphate was dissolved in 1 L of water, and phosphoric acid was added to adjust the pH to 3. 20.0 g (115 mmol) of compound 3 was dissolved in the prepared phosphoric acid aqueous solution, placed in a SUS cylindrical reaction vessel, sealed, and heated at 120° C. for 24 hours. After cooling to room temperature, water was removed with a rotary evaporator. 100 mL of 2-propanol was added to the residue and the mixture was refluxed, cooled to room temperature, and insoluble matter was removed by suction filtration using celite. The filtrate was concentrated with a rotary evaporator and subjected to silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 7.1 g (48%) of compound 6.

Example 7: Conversion of 4-hydroxy-2-methylsulphenylmethyl-2-cyclopenten-1-one (compound 4) to 4-hydroxy-2-hydroxymethyl-2-cyclopenten-1-one (compound 6)

500 mg (2.87 mmol) of compound 3 was weighed into a flask, dissolved by adding 20 mL of water, and refluxed for 48 hours. After cooling to room temperature, water is removed on a rotary evaporator. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 210 mg (57%) of compound 6.

Example 8: Synthesis of 4-chloroacetoxy-2-chloroacetoxymethyl-2-cyclopenten-1-one (compound 7)

7.1 g (55 mmol) of compound 6 was dissolved in 80 mL of THF, 9 mL (112 mmol) of pyridine was added, and the solution was ice-cooled. A solution of 9 mL (113 mmol) of chloroacetyl chloride in 20 mL of THF was added dropwise thereto over 1 hour. Next, after stirring at room temperature for 1 hour, water was added to stop the reaction. The extract was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. Next, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a mixture containing the desired product. Then, it was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to obtain 10.6 g (69%) of compound 7 as a pale yellow oil. It was also recrystallized from hexane and ethyl acetate to give pale yellow crystals.

compound 7
mp: 63°C
¹ H NMR (CDCl ₃ ) δ 2.50 (dd, 1H, J = 18.6, 2.2 Hz), 2.98 (dd, 1H, J = 18.6, 5.8 Hz), 4.10 (s , 2H), 4.13 (s, 2H), 4.94 (t, 2H, J = 1.6Hz), 5.90-5.93 (m, 1H), 7.44-7.46 (m , 1H).
¹³ C NMR (CDCl ₃ ) δ 40.7, 40.5, 41.1, 59.0, 71.8, 144.1, 152.9, 166.7, 166.9, 201.5.

Example 9: Synthesis of 4-chloroacetoxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound rac-5)

1.7 g (6.0 mmol) of compound 7 was dissolved in 10 mL of THF and cooled with ice. After adding 1.5 g (6.2 mmol) of N-tosylpiperazine thereto, the mixture was stirred at room temperature for 5 hours. Next, the filtrate was concentrated under reduced pressure using a rotary evaporator and purified by silica gel column chromatography (ethyl acetate) to obtain 1.8 g (70%) of compound rac-5 as a pale yellow oil.

Compound rac-5
¹ H NMR (CDCl ₃ ) δ 2.43 (1H, dd, J = 18.8, 2.6 Hz), 2.44 (3H, s), 2.64 (4H, br.t, J = 5.0 Hz ), 2.90 (1H, dd, J=48.8, 6.4 Hz), 3.02 (4H, br), 3.18 (2H, s), 4.07 (2H, s), 5. 84-5.85 (1H, m), 7.27 (s, 1H), 7.34 (2H, d, J=8.0 Hz), 7.63 (2H, d, J=8.0 Hz).
^13C NMR ( _CDCl3 ) δ 21.0, 40.4, 40.8, 45.5, 51.2, 51.7, 71.6, 127.3, 129.3, 131.6, 143.4 , 145.4, 153.0, 166.5, 202.9.

Example 10: (4R)-4-hydroxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound (4R)-4) and (4S)-4-chloro Synthesis of acetoxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound (4S)-5)

2.7 g (6.3 mmol) of compound rac-5 was dissolved in 80 mL of acetone. 80 mL of 0.1 M phosphate buffer (pH 7) and 800 mg of lipase PS (manufactured by Amano) were added thereto and stirred at room temperature for 12 hours. The suspension after the reaction was filtered under reduced pressure using celite as a filter aid and washed with acetone. After the filtrate was concentrated under reduced pressure using a rotary evaporator, the residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a mixture containing the desired product. When purified by silica gel column chromatography, compound (4S)-5 (ethyl acetate) 0.9 g (yield 34%) was obtained as a pale yellow oily substance, compound (4R)-4 (ethyl acetate:methanol=10:1)1 0 g (40% yield, enantiomeric excess 87.4% ee) was obtained as colorless crystals (mp: 204° C.).

Example 11: Solvolysis of (4S)-4-chloroacetoxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound (4S)-5)

900 mg (2.1 mmol) of compound (4S)-5 obtained in Example 10 was dissolved in 20 mL of methanol, 2 mL of triethylamine was added, and the mixture was stirred at room temperature for 5 hours. The suspension was suction filtered and washed with methanol to give 423 mg of compound (4S)-4 (yield 57%, enantiomeric excess 88.6% ee) as colorless crystals (mp: 204°C).

Reference Example 1: Synthesis of (4S)-4-hydroxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound (4S)-4)

According to the literature (Tetrahedron Letters, 60, 1375-1378 (2019)), 500 mg (2.1 mmol) of compound 9 (99.9% ee) with a defined absolute configuration synthesized according to the literature was dissolved in 5 mL of methanol, and 10 mg of Amberlyst 15 was added. Stir at room temperature for 14 hours. The ion exchange resin was removed by suction filtration, and the filtrate was concentrated by a rotary evaporator to obtain compound (4S)-6. This was dissolved in 10 mL of THF, 500 mL (6.4 mmol) of pyridine was added, and the solution was ice-cooled. 500 L (6.3 mmol) of chloroacetyl chloride was added thereto, and the mixture was stirred at room temperature for 1 hour, and then water was added to terminate the reaction. The extract was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a mixture containing the desired product. Purification by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) gave 318 mg of compound (4S)-7 as a pale yellow oil. After dissolving this in 10 mL of THF and adding 550 mg (2.3 mmol) of piperazine and stirring at room temperature, 10 mL of methanol and 2 mL of triethylamine were added and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated by a rotary evaporator, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain 235 mg (33%) of compound (4S)-4 as crystals. Recrystallization from methanol gave 176 mg of colorless crystals. No enantiomeric peak was detected by HPLC and the retention time was consistent with the compound obtained in Example 11.
mp: 204°C

Example 12 Synthesis of (4R)-4-chloroacetoxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (compound (4R)-5)

423 mg (1.21 mmol) of compound (4S)-4 (enantiomeric excess 88.6% ee) obtained in Example 11, 479 mg (1.83 mmol) of triphenylphosphine and 173 mg (1.83 mmol) of chloroacetic acid were dissolved in 20 mL of THF. and cooled with ice. A toluene solution (2.2 M, 830 μL) of diethyl azodicarboxylate was added at 0° C., stirred for 30 minutes, and then stirred at room temperature for 3 hours. The reaction solution was concentrated with a rotary evaporator, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 510 mg (yield 99%) of compound (4R)-5 as a brown viscous substance. .

Example 13: Synthesis of (4R)-4-hydroxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopenten-1-one (Compound (4R)-4)

510 mg (1.19 mmol) of compound (4R)-5 obtained in Example 12 was dissolved in 18 mL of acetone. 18 mL of 0.1 M phosphate buffer (pH 7) and 180 mg of lipase PS (manufactured by Amano) were added thereto and stirred at room temperature for 8 hours. The suspension after the reaction was filtered under reduced pressure using celite as a filter aid and washed with acetone. After the filtrate was concentrated under reduced pressure using a rotary evaporator, the residue was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a mixture containing the desired product. Purification by silica gel column chromatography yielded 66 mg (yield 13%) of compound (4R)-5 (ethyl acetate) as a pale yellow oily substance, and 252 mg (yield) of compound (4R)-4 (ethyl acetate:methanol=10:1). yield 60%, enantiomeric excess 99.6% ee) were obtained as colorless crystals (mp: 204°C).

Example 14: Synthesis of (4R)-4-(tert-butyldimethylsilyl)oxy-2-(3-tosyl-3-azapentanediyl)aminomethyl-2-cyclopentenone (compound (4R)-8)

340 mg (0.97 mmol) of compound (4R)-4 (enantiomeric excess 88.6% ee) was dissolved in 5 mL of DMF and cooled with ice. 300 μL of triethylamine and 200 mg (1.33 mmol) of tert-butyldimethylsilyl chloride were added thereto and stirred at room temperature for 5 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure using a rotary evaporator to obtain a mixture containing the desired product. Purification by silica gel column chromatography (hexane:ethyl acetate=2:1) gave 330 mg (74%) of the desired product (enantiomeric excess 88.6% ee) as pale yellow crystals. 20 mL of hexane and 2 mL of ethyl acetate are added to the total amount of crystals and dissolved by refluxing. After cooling to room temperature, the precipitated crystals were filtered by suction to obtain 240 mg of (4R)-8 (yield 73%). No enantiomer was detected by HPLC.

mp: 108°C
¹ H NMR (CDCl ₃ ) δ 0.10 (s, 3H), 0.11 (s, 3H), 0.89 (s, 9H), 2.27 (dd, 1H, J = 18.2, 2. 2Hz), 2.44 (s, 3H), 2.52-2.54 (br, m, 4H), 2.74 (dd, 1H, J = 18.2, 6.0Hz), 3.03 ( brs, 4H), 3.14 (s, 2H), 4.88-4.89 (m, 1H), 7.16 (s, 1H), 7.32 (d, 2H, J=8.4Hz) , 7.63(d,2H,J=8.4Hz).
^13C NMR ( _CDCl3 ) δ 4.7, 18.1, 21.5, 25.7, 43.5, 45.9, 51.6, 52.2, 68.9, 127.9, 129.6 , 132.4, 142.3, 143.7, 159.8, 205.4.

Claims

A compound represented by the following general formula (I).

(In general formula (I), R 1 is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group indicates a functional group formed by combining
A compound according to claim 1, wherein R 1 is a C 1 -C 6 alkyl group.
A compound represented by the following general formula (II) or an optically active form thereof.

(In general formula (II), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached.)
A compound represented by the following general formula (III) or an optically active form thereof.

(In general formula (III), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached,
R 4 represents an optionally substituted aliphatic hydrocarbon group or an optionally substituted aromatic hydrocarbon ring group. )
R4 is
CH (3-n) X n (where X is F, Cl or Br and n is an integer of 1 to 3), or CH 2 OY (where Y is an alkyl group, an aryl group, or an aralkyl group).
6. The compound of claim 5, wherein R4 is CH2Cl .
A compound represented by the following general formula (IV) or an optically active substance thereof.

(In general formula (IV), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached,
W represents a —SiR 5 R 6 R 7 group, an optionally substituted benzyl group or an acetal-type protecting group;
R 5, R 6 and R 7 each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )
A compound according to claim 7, wherein R 5 , R 6 and R 7 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.
9. A compound according to claim 8, wherein R 2 and R 3 together represent a 3-tosyl-3-azapentanediyl group.
An intermediate for producing a prostaglandin or an optically active substance thereof, comprising the compound according to any one of claims 1 to 9.
11. The intermediate according to claim 10, wherein said prostaglandin or its optically active substance is represented by the following formula (A).
Manufacture of a compound represented by general formula (I), comprising a step of obtaining a compound represented by general formula (I) by heating under reflux a compound represented by general formula (b) in the presence of water how to.

(In the general formulas (b) and (I), R 1 is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and an aromatic Indicates a functional group formed by combining hydrocarbon ring groups.)
Manufacture of a compound represented by general formula (V), comprising a step of obtaining a compound represented by general formula (V) by heating under reflux a compound represented by general formula (I) in the presence of water how to.

(In general formula (I), R 1 is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group indicates a functional group formed by combining
of general formula (II), comprising a step of reacting a compound of general formula (I) with a compound of general formula (c) to obtain a compound of general formula (II); Methods of making the represented compounds.

(In general formula (I), R 1 is an optionally substituted aliphatic hydrocarbon group, or an optionally substituted aliphatic hydrocarbon group and aromatic hydrocarbon ring group represents a functional group formed by combining
In general formulas (c) and (II), R2 and R3 form a ring structure together with the nitrogen atom to which they are attached. )
In general formula (III), comprising a step of reacting a compound represented by general formula (II) with a compound represented by general formula (d) to obtain a compound represented by general formula (III) Methods of making the represented compounds.

(In general formulas (II) and (III), R 2 and R 3 are bonded to each other to form a ring structure together with the nitrogen atom to which they are bonded,
In general formulas (d) and (III), R 4 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent represents a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (d). )
reacting a compound represented by formula (V) with a compound represented by general formula (d) under basic conditions to obtain a compound represented by general formula (VI); A method for producing a compound represented by (VI).

(In general formulas (d) and (VI), R 4 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may have
X is F, Cl, Br or I in general formula (d). )
reacting a compound of formula (VI) with a compound of general formula (c) under basic conditions to obtain a compound of general formula (III); A method for producing a compound represented by (III).

(In general formulas (c) and (III), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached,
In general formulas (VI) and (III), R 4 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )
The compound represented by the general formula (III) is optically resolved using a hydrolase to obtain the optically active form (R form) of the compound represented by the general formula (II) and the compound represented by the general formula (III). A method for producing an optically active form (R form) of a compound represented by general formula (II), comprising a step of obtaining an optically active form (S form) of the compound represented by formula (II).

(In general formulas (II) and (III), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached,
In general formula (III), R 4 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituted A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. )
The method according to claim 18, wherein the hydrolase is lipase.
A step of solvolyzing an optically active form (S form) of the compound represented by general formula (III) to obtain an optically active form (S form) of the compound represented by general formula (II). , a method for producing an optically active form (S form) of a compound represented by general formula (II).

(In general formulas (II) and (III), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached,
In general formula (III), R 4 is an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon ring group, or a substituted A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group. )
The method according to claim 20, wherein the solvolysis is solvolysis using methanol and a tertiary amine.
A step of converting an optically active form (S form) of the compound represented by general formula (II) into an optically active form (R form) of the compound represented by general formula (II) via a Mitsunobu reaction. A method for producing an optically active form (R form) of a compound represented by general formula (II).

(In general formula (II), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached.)
A step of reacting an optically active form (R form) of a compound represented by general formula (II) with a protecting group-introducing agent to obtain an optically active form (R form) of a compound represented by general formula (IV) A method for producing an optically active form (R form) of a compound represented by general formula (IV), comprising:

(In general formulas (II) and (IV), R 2 and R 3 form a ring structure together with the nitrogen atom to which they are attached,
In general formula (IV), W represents a —SiR 5 R 6 R 7 group, an optionally substituted benzyl group or an acetal-type protecting group;
R 5 , R 6 and R 7 each independently represent an optionally substituted aliphatic hydrocarbon group, an optionally substituted aromatic hydrocarbon cyclic group, or a substituent A functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, which may be present. )
The method according to any one of claims 12 to 23, for producing prostaglandin or its optically active form.
25. The method according to claim 24, wherein the optically active form of prostaglandin is represented by formula (A).
In the general formula (I), (II), (III) or (IV) according to any one of claims 1 to 9, as an intermediate for producing a prostaglandin or an optically active substance thereof Use of the represented compound or its optically active form.
The use according to claim 26, wherein the optically active form of prostaglandin is represented by formula (A).