TW202317527A - Synthesis intermediate for beraprost or optically active form thereof, and method for producing same - Google Patents

Abstract

The present disclosure provides: a novel synthesis intermediate for beraprost or an optically active form thereof; and a production method using the synthesis intermediate. More specifically, in the present disclosure, a compound represented by general formula (I) or (II) or an optically active form thereof is used as a synthesis intermediate in the production of beraprost or an optically active form thereof.

Description

Synthetic intermediate of beraprost or optically active substance and its production method

[Refer to related application] This patent application claims priority based on Japanese Patent Application No. 2021-107087 filed on June 28, 2021, and all disclosures in the previous patent application are cited as a part of this specification.

This disclosure relates to a synthetic intermediate of beraprost or an optically active substance and a manufacturing method thereof. More specifically, the disclosure relates to a synthetic intermediate of beraprost or an optically active substance that is a derivative of prostaglandin I ₂ , and a method for producing the same, and the beraprost or optically active substance is used as Oral drug for the treatment of essential pulmonary hypertension.

Beraprost sodium, which is a stable prostaglandin I ₂ derivative, is a compound having the following structure and is used as an oral therapeutic drug for essential pulmonary hypertension. Treprostinil (treprostinil) for injection and iloprost (iloprost) that requires an inhalation device are also known as therapeutic drugs for essential pulmonary hypertension, but beraprost sodium is an oral drug that is easy to administer Therefore, it is a general prescription. The use of beraprost sodium is gradually expanding, and its application as a reperfusion preventive drug after surgery has been studied. Further, in the case of use other than humans, it can be used as a chronic kidney disease in pet animals, especially cats. The demand for therapeutic drugs is increasing.

[chemical formula 1]

According to the Japanese Pharmacopoeia, beraprost sodium is a mixture of the following 4 stereoisomers (Monosodium(1RS, 2RS, 3aSR, 8bSR)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(1E ,3SR,4RS)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-1H-cyclopenta[b]benzofuran-5-butanoate, and Monosodium (1RS,2RS,3aSR,8bSR) -2,3,3a,8b-tetrahydro-2-hydroxy-1-[(1E,3SR,4SR)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl]-1H-cyclopenta [b]benzofuran-5-butanoate). It is known that this mixture can be produced by using 2,4-dibromocyclopentene as a starting material through multiple stages (see Patent Document 1). [chemical formula 2]

Among the above four stereoisomers of known beraprost, especially the compound (8S, 9S, 16S) represented by the above formula (A) is significantly more effective than the other three isomers (refer to non-patent literature 1), a method for selectively producing a single stereoisomer has been longed for. In addition, from the viewpoint of reducing the burden on the body of a patient, a drug substance consisting of a single optical isomer is also desired.

As a method for synthesizing a single optical isomer, a method is known, which is to convert the synthetic intermediate of beraprost into a carboxylic acid compound, and perform optical resolution by recrystallization as a salt of an optically active amine (refer to the non-patent literature 1). However, this method cannot be said to be an efficient method because the steps become lengthy and unnecessary optical isomers cannot be reused.

In addition, a synthetic method has been reported, which is to use 1-acetyloxypent-4-en-3-ol as chiral building blocks (Chiral Building Blocks), and by using the free radical ring of allyl tin Synthesizing by reaction, this method can selectively introduce an allyl group that is easily introduced into a side chain in a desired configuration while constructing a [3.3.0] bicyclooctane skeleton. It is efficient (see Patent Document 2). However, this method cannot be said to be an efficient method in view of the multi-stage reaction steps and the need for an expensive rhodium complex as a catalyst for isomerizing the introduced allyl groups.

In addition, a method has been reported to construct beraprost [3.3. 0] Bicyclooctane skeleton (see Patent Document 3). However, the reaction steps of this method are multi-stage, especially the europium catalyst used in the [4+2] cycloaddition reaction and the lavendin-3-carboxylate of the diene equivalent, which are expensive, It cannot be said to be an efficient method.

The method described in the above patent document 3 is as shown in the following scheme 1. After obtaining a diol intermediate having a [3.3.0]bicyclooctane skeleton through multiple steps, one of the diol intermediates is further selectively protected. The primary hydroxyl group is introduced into the secondary hydroxyl group with different protecting groups, and then the primary hydroxyl group is selectively deprotected to obtain the key intermediate, which is converted into the optical isomer of beraprost. [chemical formula 3]

In addition, in the above method, it is necessary to remove unreacted substances such as side reaction products and the above-mentioned diol intermediates. In addition, the production of beraprost requires multiple steps including selective protection and deprotection of the hydroxyl group of the above-mentioned diol intermediate, and thus cannot be said to be an efficient method for industrial production.

[Prior Art Literature] [Patent Document] [Patent Document 1] Japanese Unexamined Patent Publication No. 1983-124778 [Patent Document 2] Japanese PCT Publication No. 2017-520529 [Patent Document 3] Japanese Patent Laid-Open No. 2019-065015

[Non-patent literature] [Non-Patent Document 1] H. Wakita, H. Yoshiwara, H. Nishiyama, H. Nagase, Heretocycles, 53, 1085 (2000)

As a result of the incisive research carried out by the applicant of this case, it was discovered this time that: Beraprost can be efficiently produced by using the synthetic intermediate of the [3.3.0] bicyclooctane skeleton derived from a chiral structural component of a specific structure or its optically active substance. This disclosure is based on this knowledge insight.

One object of the present disclosure is to provide a novel synthetic intermediate of beraprost or its optically active substance and its production method.

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 According to an embodiment of the present disclosure, a compound represented by the following general formula (I) or an optically active substance thereof is provided. [chemical formula 4]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group).

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 Also, according to an embodiment of the present disclosure, it is a compound represented by the following general formula (II) or an optically active substance thereof. [chemical formula 5]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group).

(式中，X表示鹵素原子，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 In addition, according to an embodiment of the present disclosure, a method for producing a compound represented by general formula (I) or an optically active substance thereof is provided. The production method includes the following steps: making the compound represented by general formula (B) The compound shown or its optical active substance is cyclized to obtain the compound represented by general formula (I) or its optical active substance. [chemical formula 6]

(In the formula, X represents a halogen atom, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, may have a substituent aromatic hydrocarbon group, or a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group which may have a substituent).

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 Moreover, according to an embodiment of the present disclosure, a method for producing a compound represented by general formula (II) or an optically active substance thereof is provided, the production method comprising the following steps: reducing the compound represented by general formula (I) The compound represented by the general formula (II) or its optically active substance can be obtained. [chemical formula 7]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group).

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基，R ⁶表示矽基以外之羥基的保護基)。 Moreover, according to an embodiment of the present disclosure, there is provided a method for producing a compound represented by general formula (III) or an optically active substance thereof, the production method comprising the following steps: introducing a protecting group into the general formula ( The hydroxyl group of the compound represented by II) or its optically active substance is obtained to obtain the compound represented by general formula (III) or its optically active substance. [chemical formula 8]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or it may have a substituent and a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, and ^R6 represents a protecting group for a hydroxyl group other than a silicon group).

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基，R ⁶表示矽基以外之羥基的保護基)。 In addition, according to an embodiment of the present disclosure, there is provided a method for producing a compound represented by general formula (IV) or an optically active substance thereof, the production method comprising the following steps: obtaining The compound represented by the general formula (III) or its optically active substance is desiliconized to obtain the compound represented by the general formula (IV) or its optically active substance. [chemical formula 9]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or it may have a substituent and a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, and ^R6 represents a protecting group for a hydroxyl group other than a silicon group).

According to the present disclosure, a novel synthetic intermediate of beraprost or its optically active substance and its production method can be provided. According to the present disclosure, beraprost or its optically active substance can be efficiently produced by using a synthetic intermediate derived from a chiral building block with a specific structure, which is beneficial to industrial production.

[Specific Description of the Invention] <Definition> The terms and expressions used in this manual will be described below. The following definitions apply throughout this specification unless otherwise specified. For example, the definition of "alkyl" also applies to functional groups containing "alk" or "alkyl" (eg, aralkyl, etc.).

In this specification, for example, "C ₁ to C ₆ " means having 1 to 6 carbon atoms.

"Aliphatic hydrocarbon group" means a functional group (hydrocarbon group not having aromaticity) formed by removing a hydrogen atom from an aliphatic hydrocarbon. The "aliphatic hydrocarbon group" may refer to a monovalent or divalent functional group depending on the context, but is preferably a monovalent functional group. The aliphatic hydrocarbon group may be any of a chain shape, a ring shape, and a combination thereof. The chain may be linear or branched. The aliphatic hydrocarbon group is preferably linear or branched. The aliphatic hydrocarbon group may be saturated or unsaturated. The unsaturated bond may be a carbon-carbon double bond or a carbon-carbon triple bond.

As an aliphatic hydrocarbon group, an alkyl group, an alkenyl group, an alkynyl group etc. are mentioned, for example.

"Alkyl" means a monovalent functional group formed by removing one hydrogen atom from an alkane. The alkyl group may be any of a chain shape, a ring shape, and a combination thereof. In addition, cyclic alkyl is synonymous with "cycloalkyl". The chain may be linear or branched. The alkyl group is preferably linear or branched. The number of carbons in the linear alkyl group is usually 1-20, preferably 1-10, preferably 1-8, more preferably 1-6, more preferably 1-4, more preferably 1 ~3. The carbon number of the branched chain alkyl group is usually 3-20, preferably 3-10, preferably 3-8, more preferably 3-6, more preferably 3-4. The carbon number of the cyclic alkyl group is usually 3-20, preferably 3-10, more preferably 3-8, more preferably 3-6. The carbon number of the alkyl group having a linear or branched part and a cyclic part is usually 4-20, preferably 4-10, preferably 4-8, more preferably 4-6.

Examples of the alkyl group include: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, pentyl, hexyl and other C ₁ -C ₆ alkyl groups; heptyl, 1 -Methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 2,2-dimethylpentyl, 4,4-dimethylpentyl, 1-ethylpentyl, 2- Ethylpentyl, 1,1,3-trimethylbutyl, 1,2,2-trimethylbutyl, 1,3,3-trimethylbutyl, 2,2,3-trimethylbutyl Butyl, 2,3,3-trimethylbutyl, 1-propylbutyl, 1,1,2,2-tetramethylpropyl, octyl, 1-methylheptyl, 3-methyl Heptyl, 6-methylheptyl, 2-ethylhexyl, 5,5-dimethylhexyl, 2,4,4-trimethylpentyl, 1-ethyl-1-methylpentyl, nonyl Base, 1-methyloctyl, 2-methyloctyl, 3-methyloctyl, 7-methyloctyl, 1-ethylheptyl, 1,1-dimethylheptyl, 6,6 -Dimethylheptyl, decyl, 1-methylnonyl, 2-methylnonyl, 6-methylnonyl, 1-ethyloctyl, 1-propylheptyl, etc., but preferably C ₁ ~C ₆ alkyl. Suitable examples of C ₁ -C ₆ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, pentyl, or hexyl, which have straight or branched chains. Alkyl groups such as ring moieties and ring moieties, preferably methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, pentyl or hexyl.

"Alkenyl" means a monovalent functional group formed by removing one hydrogen atom from an alkene. Alkenyl has at least one carbon-carbon double bond. The alkenyl group may be any of a chain form, a cyclic form, and a combination thereof. In addition, cycloalkenyl is synonymous with "cycloalkenyl". The chain may be linear or branched. The alkenyl group is preferably linear or branched. The number of carbons in the linear alkenyl group is usually 2-20, preferably 2-10, preferably 2-8, more preferably 2-6, and more preferably 2-4. The carbon number of the branched alkenyl group is usually 3-20, preferably 3-10, preferably 3-8, more preferably 3-6, more preferably 3-4. The carbon number of the cyclic alkenyl group is usually 3-20, preferably 3-10, more preferably 3-8, more preferably 3-6. The carbon number of the alkenyl group having a linear or branched part and a cyclic part is usually 4-20, preferably 4-10, preferably 4-8, more preferably 4-6. The number of double bonds in the alkenyl group is usually 1 to 9, preferably 1 to 7, more preferably 1 to 4, more preferably 1 to 3.

Examples of alkenyl groups include vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, and 3-hexene 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonyl, 4-decenyl and other linear or branched alkenyl; cyclopropenyl , cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and other cyclic alkenyl groups; cyclopentenylmethyl, cyclopentenylethyl, cyclopentenylpropane Alkenyl groups having a linear or branched chain part and a cyclic part, such as cyclohexenylmethyl group and cyclohexenylethyl group, etc.

"Alkynyl" means a monovalent functional group formed by removing one hydrogen atom from an alkyne. An alkynyl group has at least one carbon-carbon triple bond. The alkynyl group may be any of a chain form, a cyclic form and a combination thereof. In addition, cyclic alkynyl is synonymous with "cycloalkynyl". The chain may be linear or branched. The alkynyl group is preferably linear or branched. The number of carbons in the linear alkynyl group is usually 2-20, preferably 2-10, preferably 2-8, more preferably 2-6, and more preferably 2-4. The carbon number of the branched alkynyl group is usually 4-20, preferably 4-10, more preferably 4-8, more preferably 3-6. The carbon number of the cyclic alkynyl group is usually 4-20, preferably 4-10, preferably 4-8, more preferably 4-6. The number of carbons in the alkynyl group having a linear or branched part and a cyclic part is usually 5-20, preferably 5-10, preferably 5-8, more preferably 5-6. The number of triple bonds in the alkynyl group is usually 1 to 9, preferably 1 to 7, more preferably 1 to 4, more preferably 1 to 3.

Examples of the alkynyl group include: 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl and other linear or branched alkynyl groups; cyclobutynyl Cyclopentynyl, cycloheptynyl, cyclooctynyl and other cyclic alkynyl groups; cyclopentynylmethyl, cyclopentenylethyl, cyclopentynylpropyl, cyclopentynylmethyl, An alkynyl group such as a cyclopentynylethyl group having a linear or branched part and a cyclic part, etc.

The "aromatic hydrocarbon ring group" means a functional group formed by removing a hydrogen atom from an aromatic hydrocarbon ring. Depending on the context, the "aromatic hydrocarbon ring group" may refer to a monovalent or divalent functional group, but is preferably a monovalent functional group.

As an aromatic hydrocarbon ring group, an aryl group etc. are mentioned, for example.

"Aryl" refers to a monocyclic or polycyclic (eg 2-ring or 3-ring) aromatic hydrocarbon ring group. The aryl group is usually 1-4 rings, preferably 1-3 rings, more preferably 1- or 2-ring aromatic hydrocarbon rings. The number of carbon atoms constituting the ring in the aryl group is usually 6-18, preferably 6-14, more preferably 6-10.

As a monocyclic aromatic hydrocarbon ring group, a phenyl group is mentioned, for example.

The aryl group also includes condensed polycyclic aromatic hydrocarbon ring groups and partially saturated condensed polycyclic aromatic hydrocarbon ring groups. The partially saturated condensed polycyclic aromatic hydrocarbon ring group is a condensed polycyclic aromatic hydrocarbon ring group in which a part of the constituting ring is bonded and hydrogenated. As the condensed polycyclic aromatic hydrocarbon ring group, for example: naphthyl, anthracenyl, phenanthrenyl, condensed tetraphenyl, pyrenyl and other 2-4 ring aromatic hydrocarbon ring groups, also include: Perylene, indenyl, acenaphthyl, etc. Examples of the partially saturated condensed polycyclic aromatic hydrocarbon ring group include dihydronaphthyl, dihydroindenyl, dihydroacenaphthyl and the like.

More specifically, the aryl group is preferably a monocyclic or bicyclic aromatic hydrocarbon group, preferably an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl, and more preferably a phenyl group.

"A 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 by the formula: (*)-aromatic hydrocarbon ring group - Represented by aliphatic hydrocarbon group. (*) represents a bond of an organic group, and the bond of the organic group includes a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group.

Examples of the functional group represented by the formula: (*)-aliphatic hydrocarbon group-aromatic hydrocarbon ring group include alkaryl, alkenaryl, alkynaryl and the like. The descriptions of the alkyl, alkenyl, alkynyl and aryl groups in "alkaryl", "alkenaryl" and "alkynaryl" are the same as above.

The number of alkyl groups in the alkaryl group, the number of alkenyl groups in the alkenaryl group, and the number of alkynyl groups in the alkynaryl group are usually 1 to 4, preferably 1 to 3, more preferably 1 to 2. Examples of alkaryl groups include o-methylphenyl, m-methylphenyl, p-methylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-Dimethylphenyl, 2,6-Dimethylphenyl, 3,4-Dimethylphenyl, 3,5-Dimethylphenyl, 2,4,6-Trimethylbenzene base, o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, etc. Examples of alkenyl aryl groups include alkenyl aryl groups such as o-vinylphenyl, m-vinylphenyl, and p-vinylphenyl. As an aryl group, an aryl group, such as 2-ethynyl-2-phenyl, etc. are mentioned, for example.

Examples of the functional group represented by the formula: (*)-aromatic hydrocarbon ring group-aliphatic hydrocarbon group include aralkyl, aralkenyl, and aralkynyl. The descriptions of the alkyl, alkenyl, alkynyl and aryl groups in the "aralkyl", "arylalkenyl" and "arylalkynyl" are the same as above.

The carbon number of the aralkyl group is usually 7-15, preferably 7-11. Examples of aralkyl groups include alkyl groups substituted with aryl groups such as phenyl, naphthyl, anthracenyl, phenanthrenyl, and acenaphthyl, but phenylmethyl, 2-phenylethyl, 3-phenyl Propyl, 2-phenylpropyl, 1-phenylpropyl, α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-naphthylethyl, diphenylmethyl group, triphenylmethyl group, etc., preferably triphenylmethyl group.

The carbon number of the aralkenyl group is usually 8-16, preferably 8-12. As an aralkenyl group (Aralkenyl group), a 2-styryl group, a 2-naphthyryl group etc. are mentioned, for example.

The carbon number of the aralkynyl group is usually 8-16, preferably 8-12. As an aralkinyl group (Aralkinyl group), a phenylethynyl group etc. are mentioned, for example.

The expression "may have a substituent" for certain functional groups means that one or more hydrogen atoms of the functional group can be independently replaced by other atoms or atomic groups, and this expression is synonymous with the following: may have a substituent Or there can be no substitution.

The number of substituents that the aliphatic hydrocarbon group may have can be appropriately determined according to the carbon number of the aliphatic hydrocarbon group and the like. The aliphatic hydrocarbon group may have, for example, 1 to 6 substituents, preferably 1 to 3 substituents, preferably 1 or 2 substituents at positions that can be substituted. When the hydrocarbon group has two or more substituents, the two or more substituents may be the same or different.

When the carbon number of the alkyl group is 1 to 4, the number of substituents that the alkyl group may have is usually 1 to 3, preferably 1 or 2, preferably 1. When the carbon number of the alkyl group is 5-9, the number of substituents that the alkyl group may have is usually 1-6, preferably 1-5, preferably 1-4, more preferably 1 or 2 . When the carbon number of 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, more preferably 1 or 2.

When the carbon number of the alkenyl group is 2 to 4, the number of substituents that the alkenyl group may have is usually 1 to 3, preferably 1 or 2, and preferably 1. Also, when the carbon number of the alkenyl group is 5-9, the number of substituents that the alkenyl group may have is usually 1-5, preferably 1-4, preferably 1-3, more preferably 1 or 2. Also, when the carbon number of 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, more preferably 1 to 3, more preferably 1 or 2 indivual.

When the carbon number of the alkynyl group is 2 to 4, the number of substituents that the alkynyl group may have is usually 1 to 3, preferably 1 or 2, and preferably 1. When the carbon number of the alkynyl group is 5-9, the number of substituents that the alkynyl group may have is usually 1-5, preferably 1-4, preferably 1-3, more preferably 1 or 2 . When the carbon number of the alkynyl group is 10 or more, the number of substituents that the alkynyl group may have is usually 1 to 8, preferably 1 to 4, more preferably 1 to 3, more preferably 1 or 2.

The number of substituents that the aromatic hydrocarbon ring group may have can be appropriately determined according to the carbon number, number of members, etc. of the aromatic hydrocarbon ring group. The aromatic hydrocarbon ring group may have, for example, 1 to 5 substituents, preferably 1 to 4 substituents, preferably 1 to 3 substituents, more preferably 1 or 2 substituents at positions that can be substituted. When the aromatic hydrocarbon ring group has two or more substituents, the two or more substituents may be the same or different.

When the carbon number of the aralkyl or alkaryl is 7~11, the number of substituents that the aralkyl or alkaryl can have is usually 1~5, preferably 1~4, preferably 1~ 2. When the carbon number of aralkyl or alkaryl is 12~15, the number of substituents that aralkyl or alkaryl can have is usually 1~6, preferably 1~4, preferably 1~ 2. When the carbon number of the aralkyl or alkaryl is 16 or more, the number of substituents that the aralkyl or alkaryl may have is usually 1 to 8, preferably 1 to 6, preferably 1 to 4 , more preferably 1 to 2.

When the carbon number of the aralkenyl or alkenaryl is 8-11, the number of substituents that the aralkenyl or alkenaryl can have is usually 1-5, preferably 1-4, preferably 1-4 2. When the carbon number of the aralkenyl or alkenyl is 12 to 15, the number of substituents that the aralkenyl or alkenyl can have is usually 1 to 6, preferably 1 to 4, preferably 1 to 2. When the carbon number of the aralkenyl or alkenyl is 16 or more, the number of substituents that the aralkenyl or alkenyl may have is usually 1 to 8, preferably 1 to 6, preferably 1 to 4 , more preferably 1 to 2.

As substituent, can enumerate: alkoxyl group, halogen atom, cyano group, nitro group, sulfonyl group, sulfonyl group, carboxyl group or acyl group etc., but the example of suitable substituent is C _～ C ₆ alkoxy group or Halogen atom (preferably fluorine atom or chlorine atom, etc.).

Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy, tert-butoxy, Pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, etc.

Examples of the acyl group include, for example, an acetyl group, a propionyl group, an n-butyryl group, an iso-butyryl group, an n-pentyl group, a hexyl group, and a benzoyl group.

The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom, iodine atom and the like.

The so-called "protecting group" is a well-known protecting group in the industry, and it is used with the meaning shown in Green's Protective Groups in Organic Synthesis (Wuts, Peter G.M., John WIley & Sons Inc.).

The so-called "room temperature" means 10°C~35°C.

The compounds described in this specification may also contain an asymmetric center, and therefore may also exist in the form of enantiomers. When the compounds described in this specification have two or more asymmetric centers, they may also exist in the form of diastereomers. Enantiomers and diastereoisomers are among the broader classes of stereoisomers. It is intended to include all possible isomers of the substantially pure isolated enantiomers, their racemic mixtures, and mixtures of diastereomers. In particular, the description of one isomer is applicable to any possible isomer unless otherwise stated. When no isomer composition is specified, all possible isomers are included.

In this specification, "optically active substance" means: a compound with an Enantiomeric Excess (e.e.) ratio (Enantiomeric Excess (e.e.)) of 90% or more, preferably 95%, more preferably 98%, and especially preferably 99% or more Its isomer mixture.

Synthetic intermediates of beraprost or its optically active substances According to an embodiment of the present disclosure, a compound represented by the following general formula (I) or (II) or its optically active substance is provided as a synthetic intermediate suitable for the production of beraprost or its optically active substance . The compound represented by the general formula (I) or (II) or its optically active substance can be produced using the chiral structural component of the specific structure described below. From this point of view, it can be advantageously used in the manufacture of beraprost or its optically active substance. things. In addition, when the compound represented by the general formula (I) or (II) or its optically active substance is used as a synthetic intermediate of beraprost, it is not necessary to use an expensive catalyst, and it is not necessary to undergo the process described in Patent Document 3. Generally, beraprost can be produced from the diol intermediate of [3.3.0]bicyclooctane skeleton that requires multiple stages of protection and deprotection of the hydroxyl group, which is beneficial to industrial production.

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 Compound represented by general formula (I) or its optically active substance According to an embodiment of the present disclosure, a compound represented by the following general formula (I) or its optically active substance is provided. [chemical formula 10]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group).

According to an embodiment of the present disclosure, in general formula (I), R ² , R ³ , R ⁴ , and R ⁵ are each independently an alkyl group that may have a substituent, an alkenyl group that may have a substituent, an alkenyl group that may have a substituent Alkynyl, aryl that may have substituents, aralkyl that may have substituents, aralkenyl that may have substituents, or aralkynyl that may have substituents; alkaryl that may have substituents, alkenyl group or alkyne aryl group.

According to an embodiment of the present disclosure, in general formula (I), R ² , R ³ , R ⁴ and R ⁵ are each independently an alkyl group that may have a substituent, an aryl group that may have a substituent, or an aryl group that may have a substituent The base of the aralkyl group.

According to an embodiment of the present disclosure, in the general formula (I), R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ -C ₆ alkyl group that may have a substituent, a C ₆ alkyl group that may have a substituent ~C ₁₀ aryl group or C ₇ ~C ₁₄ aralkyl group which may have a substituent.

According to an embodiment of the present disclosure, in the general formula (I), R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ -C ₄ alkyl group that may have a substituent, a C ₆ alkyl group that may have a substituent ~C ₁₀ aryl group or C ₇ ~C ₁₄ aralkyl group which may have a substituent.

According to an embodiment of the present disclosure, in the general formula (I), R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ ~C ₆ alkyl group, a C ₆ ~C ₁₀ aryl group, or a C ₇ ~C 10 aryl group. _14Aralkyl .

In a more preferred embodiment of the present disclosure, in the general formula (I), R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ -C ₆ alkyl group.

According to an embodiment of the present disclosure, in general formula (I), the functional groups represented by R ² , R ³ , R ⁴ and R ⁵ are obtained from compounds represented by formula (B) represented by formula (I). A group that does not exhibit free radical cyclization reactivity in the case of the compound.

In the general formula (I) in any of the above embodiments, the substituents having functional groups represented by R ² , R ³ , R ⁴ and R ⁵ are preferably independently alkoxy groups, halogen atoms, cyano groups, Nitro, sulfonyl, carboxyl or acyl, preferably C ₁ ~C ₆ alkoxy or halogen atom, more preferably C ₁ ~C ₃ alkoxy or halogen atom (preferably fluorine atom or chlorine atom, etc. ).

Also, in the general formula (I) in any one of the above-mentioned embodiments, R ⁴ , R ⁵ and R ⁶ of the silicon group represented by the formula (i) are preferably methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, tert-butyl, pentyl, hexyl, phenyl or combinations thereof.

In addition, in the general formula (I) in any of the above-mentioned embodiments, the silicon group represented by the formula (i) is preferably tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyl Diphenylsilyl, preferably tert-butyldimethylsilyl.

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 Compound represented by general formula (II) or its optically active substance According to an embodiment of the present disclosure, a compound represented by the following general formula (II) or its optically active substance is provided. [chemical formula 11]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group).

According to an embodiment of the present disclosure, the compound represented by formula (II) can be obtained by reducing the carbonyl group of the compound represented by formula (I) as described below.

Therefore, according to an implementation aspect of the present disclosure, in formula (II), the implementation aspects of R ² , R ³ , R ⁴ and R ⁵ are the same as those in formula (I).

Manufacturing method According to an embodiment of the present disclosure, as described above, beraprost or its optically active substance can be efficiently synthesized by using the compound represented by the general formula (I) or (II) as a synthesis intermediate. The following scheme 2 shows an embodiment of the production method of beraprost or its optically active substance, which is through the production method of the compound represented by the general formula (I) or (II).

(上述式中，R ²、R ³、R ⁴及R ⁵如上所述，R ⁶為矽基以外之羥基的保護基，X為鹵素原子(宜為溴原子或碘原子等))。 [chemical formula 12]

(In the above formula, R ² , R ³ , R ⁴ and R ⁵ are as above, R ⁶ is a protecting group for a hydroxyl group other than a silicon group, and X is a halogen atom (preferably a bromine atom or an iodine atom, etc.)).

Scheme 2 is from (4R)-4-hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one, and 2-bromo-6-(3-methoxycarbonylpropyl)phenol The reaction generates a compound (cyclization precursor) represented by general formula (B), and the cyclization precursor is cyclized, thereby constructing a [3.3.0] bicyclooctane skeleton to obtain a compound represented by formula (I) . Afterwards, reducing the compound shown in formula (I) to obtain the [3.3.0] bicyclooctane skeleton compound (II) with the hydroxyl and silicon substituents of the desired stereo configuration, and through compound (III) selective and The key synthetic intermediate, namely the compound represented by formula (IV), is efficiently obtained. Furthermore, the compound represented by the formula (IV) can be efficiently converted into beraprost or its optically active substance by following the known methods described in Patent Document 3 and the like. The method disclosed in this disclosure does not need to go through the [3.3.0]bicyclooctane-skeleton diol intermediate that requires multi-stage protection and deprotection of the hydroxyl group as described in Patent Document 3, to produce pequisin element, it is efficient from this point of view. In addition, according to the method of the present disclosure, it is not necessary to use the expensive heavy metal catalyst used in the conventional production method, which is beneficial to industrial production.

In the following, each step will be described in more detail regarding one embodiment of the production method of beraprost or its optically active substance shown in Flowchart 2.

Synthesis of (4R)-4-hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one (B1) [chemical formula 13]

(4R)-4-Hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one (B1) can be synthesized following Scheme 3 above. According to an embodiment, firstly, 4-hydroxy-2-(hydroxymethyl)-2-cyclopenten-1-one is obtained by hydrothermal reaction of 2-deoxy-D-glucose. Next, the primary hydroxyl group of the synthesized compound was selectively siliconized to obtain 4-hydroxy-2-(siloxanemethyl)-2-cyclopenten-1-one. Next, the obtained compound was optically isolated using lipase and vinyl acetate to obtain (4R)-4-acetyloxy-2-silyloxymethyl)-2-cyclopenten-1-one. Next, use lipase and phosphate buffer solution (0.1M, pH7) to hydrolyze (4R)-4-acetyloxy-2-(silyloxymethyl)-2-cyclopenten-1-one, then (4R)-4-Hydroxy-2-(silyloxymethyl)-2-cyclopenten-1-one (B1) is obtained. This method can be implemented according to the description of T. Kamishima, M. Suzuki, S. Aoyagi, T. Watanabe, Y. Koseki, H. Kasai, Tetrahedron Lett., 60, 1375-1378 (2019).

Synthesis of compounds represented by general formula (B) or optically active substances thereof The compound represented by the general formula (B) or its optically active substance can be synthesized according to the following Scheme 4. More specifically, it can be obtained by the Mitsunobu reaction of the compound represented by the general formula (B1) and the phenol derivative (B2), and dehydration condensation of the compounds.

[chemical formula 14]

(Azodicarboxylate diester) The kind of azodicarboxylate diester used in the Mitsunobu reaction is not particularly limited, and any one used in the industry can be used. As the diester of azodicarboxylate, for example, dimethyl azodicarboxylate (DMAD), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), ), benzhydryl azodicarboxylate, di-tert-butyl azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate, bis(2-methoxyethyl) azodicarboxylate , 2,2-trichloroethyl) ester or 1,1-azobis(N,N-dimethylformamide) diamide, but not limited thereto. The amount of azodicarboxylic acid diester used is usually in the range of 1.0-10.0 moles, preferably in the range of 1.0-5.0 moles, more preferably in the range of 1.0-2.0 moles, relative to 1 mole of the raw material compound.

(phosphine) The kind of phosphine used in the Mitsunobu reaction is not particularly limited, and any one used in the industry can be used. As the phosphine, for example, triphenylphosphine, trihexylphosphine, tricyclohexylphosphine, isopropyldiphenylphosphine, diethylphenylphosphine, diphenyl-2-pyridylphosphine, 4-(di Methylamino)phenyldiphenylphosphine, tributylphosphine, dicyclohexylphenylphosphine, phenoxydiphenylphosphine, tri-tert-butylphosphine, tri-n-octylphosphine, but not limited to wait here. The amount of phosphine used is usually in the range of 1.0-10.0 moles, preferably in the range of 1.0-5.0 moles, more preferably in the range of 1.0-2.0 moles, relative to 1 mole of the raw material compound.

(base) The type of base used in the Mitsunobu reaction is not particularly limited, and any one used in the industry can be used. As the base, for example, triethylamine, diisopropylethylamine, N-methylmorphine, imidazole, pyridine, 4-dimethylaminopyridine, lutidine can be used, but not limited thereto wait. The amount of the base used is usually in the range of 1.0-10.0 moles, preferably in the range of 1.0-5.0 moles, more preferably in the range of 1.0-2.0 moles, relative to 1 mole of the raw material compound.

(solvent) The kind of solvent used for the Mitsunobu reaction is not particularly limited, and any one used in the industry can be used. As the solvent, for example, toluene, benzene, tetrahydrofuran, dichloromethane, diethyl ether, and acetonitrile can be used, but not limited thereto. The amount of the solvent used may be any amount as long as the reaction proceeds. If you are a person in the industry, you can properly adjust the amount of solvent used in the Mitsunobu reaction.

(temperature reflex) The reaction temperature of the Mitsunobu reaction is not particularly limited. In one aspect, from the perspectives of improving yield, suppressing by-products, and economic efficiency, the above-mentioned reaction temperature can be, for example, in the range of -20°C to 200°C, preferably in the range of -10°C to 150°C. The best range is from -5°C to 120°C.

(Reaction time) The reaction time of the Mitsunobu reaction is not particularly limited. In one aspect, from the perspectives of improving yield, suppressing by-products, and economic efficiency, the above-mentioned reaction time can be, for example, in the range of 0.5 hour to 48 hours, preferably in the range of 1 hour to 24 hours, preferably 1 hour to 10 hours range. However, if you are a person in the industry, you can adjust the response time of Mitsunobu's reaction appropriately.

(post-processing) As the treatment after the Mitsunobu reaction, general treatment for obtaining a product produced from the reaction solution may be performed. For example, after the reaction, the reaction liquid is neutralized by adding water, and then extracted with common extraction solvents such as ethyl acetate, diethyl ether, dichloromethane, toluene, and hexane. The target object can be obtained by vacuum distilling the reaction solvent and the extraction solvent from the obtained extract. The target substance obtained in this way may be subjected to general purification such as silica gel column chromatography and recrystallization, if necessary, to further increase the purity.

Production of compounds represented by general formula (I) or optically active substances thereof

(式中，X表示鹵素原子，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵如上所述)。 According to an embodiment of the present disclosure, the compound represented by the general formula (B) or its optically active substance can be cyclized to obtain the compound represented by the general formula (I) or its optically active substance. [chemical formula 15]

(In the formula, X represents a halogen atom, R ¹ represents a silicon group represented by general formula (i), and R ² , R ³ , R ⁴ and R ⁵ are as described above).

According to a suitable embodiment of the disclosure, a free radical cyclization reaction can be carried out in the compound represented by the general formula (B) or its optically active substance, thereby constructing a bicyclo[3.3.0]octane skeleton to obtain the general formula The compound represented by (I) or an optically active substance thereof. More specifically, the above-mentioned radical cyclization reaction is preferably carried out by reacting a compound represented by general formula (B) or an optically active substance thereof, an organotin hydride, and a radical initiator.

(organotin hydride) The type of organotin hydride used in the radical cyclization reaction is not particularly limited, and any one used in the industry can be used. As organotin hydrides, for example, trimethyltin hydride, triethyltin hydride, tripropyltin hydride, tributyltin hydride, dimethylphenyltin hydride, triphenyltin hydride, tricresyl tin hydride or trioctyl tin hydride, but not limited thereto. The amount of organotin hydride used is usually in the range of 1.0-10.0 moles, preferably in the range of 1.0-6.0 moles, more preferably in the range of 1.0-3.0 moles, relative to 1 mole of the raw material compound.

(free radical initiator) The kind of the radical initiator used in the radical cyclization reaction is not particularly limited, and any one used in the industry can be used. As a radical initiator, for example, 2,2'-azobis(isobutyronitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-Azobis(2,4-Dimethylvaleronitrile), 2,2'-Azobis(2-methylbutyronitrile), 1,1'-Azobis(cyclohexane- 1-carbonitrile), 2,2'-azobis(2-(2-imidazol-2-yl)propane) dihydrochloride, 2,2'-azobis(2-(2-imidazol- 2-yl)propane) dihydrochloride dihydrate, 2,2'-azobis(2-(2-imidazol-2-yl)propane), 2,2'-azobis(2-methyl 2-methylpropionamidine) dihydrochloride, 2,2'-azobis(N-(carboxyethyl)-2-methylpropionamidine) n-hydrate, 2,2'-azobis(2-methyl -N-(2-hydroxyethyl)propionamide), 2,2'-azobis(N-(2-propenyl)-2-methylpropionamide), 2,2'-azobis (N-butyl-2-methylpropionamide) or 2,2'-azobis(isobutyric acid) dimethyl 4,4'-azobis(4-cyanovaleric acid), but not limited wait here. The usage amount of the radical initiator is usually in the range of 0.01-1.0 mole, preferably in the range of 0.1-0.5 mole, more preferably in the range of 0.1-0.3 mole, relative to 1 mole of the raw material compound.

(solvent) The type of solvent used in the radical cyclization reaction is not particularly limited, and any one used in the industry can be used. As the solvent, for example, benzene, toluene, xylene, n-butanol, or dimethoxyethane can be used, but not limited thereto. The amount of the solvent used may be any amount as long as the reaction proceeds. If you are a person in the industry, you can properly adjust the amount of solvent used in the radical cyclization reaction.

(temperature reflex) The reaction temperature of the radical cyclization reaction is not particularly limited. In one aspect, from the perspectives of increasing yield, suppressing by-products, and economic efficiency, the reaction temperature can be, for example, in the range of -20°C to 200°C, preferably in the range of -10°C to 150°C, preferably It is in the range of -5°C~120°C.

(Reaction time) The reaction time of the radical cyclization reaction is not particularly limited. In one aspect, from the perspectives of improving yield, suppressing by-products, and economic efficiency, the reaction time can be, for example, in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, preferably 1 hour. The range of hours to 10 hours. However, those in the industry can appropriately adjust the reaction time of the radical cyclization reaction.

(post-processing) As the treatment after the radical cyclization reaction, general treatment for obtaining the product produced from the reaction solution may be performed. For example, in post-treatment, water can also be added to the reaction liquid after the reaction to neutralize, and general extraction solvents such as ethyl acetate, diethyl ether, dichloromethane, toluene, hexane, etc. can be used for extraction operations . The target product can be obtained by vacuum distilling the reaction solvent and the extraction solvent from the extract obtained by such extraction treatment. The target substance obtained in this way may be subjected to general purification such as silica gel column chromatography and recrystallization, if necessary, to further increase the purity.

Production of compounds represented by general formula (II) or optically active substances thereof Moreover, according to an embodiment of the present disclosure, the compound represented by the general formula (I) or its optically active substance can be reduced to obtain the compound represented by the general formula (II) or its optically active substance.

(式中，R ¹、R ²、R ³、R ⁴及R ⁵係如上所述)。 According to a suitable embodiment of the present disclosure, the reducing agent can act on the compound represented by the general formula (I) or its optically active substance to reduce the carbonyl group of the compound represented by the general formula (I) or its optically active substance, so that It is stereoselectively converted to the alcohol group. [chemical formula 16]

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as above).

(reducing agent) The kind of reducing agent used in the above reduction reaction is not particularly limited, and any one used in the industry can be used. For example, as a reducing agent, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetyloxyborohydride, borane complex, lithium tris(sec-butyl)borohydride, Sodium tri(sec-butyl)borohydride, lithium tri(sec-butyl)borohydride, or lithium triethylborohydride (superhydride), but not limited thereto. The amount of the reducing agent used (calculated as a hydride) is usually in the range of 1.0-30.0 moles, preferably in the range of 1.0-20.0 moles, more preferably in the range of 1.0-10.0 moles, relative to 1 mole of the raw material compound.

(reaction solvent) The kind of the reaction solvent used for the reduction reaction is not particularly limited, and any one used in the industry can be used. As a reaction solvent, for example, methanol, ethanol, THF, and a mixed solvent of these can be used, but not limited thereto. The amount of the solvent used may be any amount as long as the reaction proceeds. If you are a person in the industry, you can properly adjust the amount of solvent used in the reduction reaction.

(temperature reflex) The reaction temperature of the reduction reaction is not particularly limited. In one aspect, from the perspectives of increasing yield, suppressing by-products, and economic efficiency, the reaction temperature can be, for example, in the range of -78°C to 100°C, preferably in the range of -40°C to 70°C, preferably It is in the range of -20℃~20℃.

(Reaction time) The reaction time of the reduction reaction is not particularly limited. In one aspect, from the perspectives of improving yield, suppressing by-products, and economic efficiency, the reaction time can be, for example, in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, preferably 1 hour. The range of hours to 10 hours. However, those in the industry can appropriately adjust the reaction time of the reduction reaction.

(post-processing) As the treatment after the reduction reaction, general treatment for obtaining the product produced from the reaction solution may be performed. As a post-treatment, for example, water can be added to the reaction solution after the reaction to neutralize it, and a general extraction solvent such as ethyl acetate, diethyl ether, dichloromethane, toluene, hexane, etc. can be used for extraction operation. The target object can be obtained by vacuum distilling the reaction solvent and the extraction solvent from the extract obtained by such an extraction operation. The target substance obtained in this way may be subjected to general purification such as silica gel column chromatography and recrystallization, if necessary, to further increase the purity.

(式中，R ¹、R ²、R ³、R ⁴及R ⁵係如上所述，R ⁶為矽基以外之羥基的保護基)。 Production of the compound represented by general formula (III) or its optically active substance. According to an embodiment of the present disclosure, a protecting group can be introduced into the hydroxyl group of the compound represented by general formula (II) or its optically active substance, and A compound represented by the general formula (III) or an optically active substance thereof is obtained. [chemical formula 17]

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as above, and R ⁶ is a protecting group for a hydroxyl group other than a silicon group).

(protecting group for hydroxyl group) As a protecting group for the hydroxyl group, from the viewpoint of selectively deprotecting the silicon group represented by the formula (i), it is a protecting group other than the silicon group, and examples include an alkyl group, an alkoxycarbonyl group, an acyl group, etc. The protective group is preferably an acyl group, specifically, acetyl, propionyl, butyryl, isobutyryl, pentyl, hexyl, trimethylacetyl, benzoyl, p -methoxybenzoyl, p-phenylbenzoyl and the like. The above-mentioned protecting group may also be substituted with a halogen atom, and the halogen atom is a fluorine atom or a chlorine atom.

According to a suitable implementation aspect of the present disclosure, an acid anhydride or an acid chloride is reacted in the presence of a base, thereby introducing an acyl group into the compound represented by the general formula (II) or its optically active substance, and obtaining a general method in which the hydroxyl group is protected by an acyl group. A compound represented by formula (III) or an optically active substance thereof.

(acid anhydride or acid chloride) As an acid anhydride or acyl chloride used in the protection reaction of the hydroxyl group, for example, acetyl chloride, acryl chloride, butyryl chloride, isobutyryl chloride, pentyl chloride, hexyl chloride, Trimethylacetyl, benzoyl chloride, p-methoxybenzoyl chloride, p-phenylbenzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, valeric anhydride, hexanoic anhydride Anhydride, trimethylacetic anhydride, etc., but not limited thereto. The amount of acid anhydride or acid chloride used is usually in the range of 1.0-100.0 mol, preferably 1.0-50.0 mol, more preferably 1.0-30.0 mol, relative to 1 mol of the raw material compound.

(base) The base used in the protection reaction of the hydroxyl group is not particularly limited, and for example, triethylamine, diisopropylethylamine, N-methylmorphine, imidazole, pyridine, and lutidine can be used. The amount of base used is usually in the range of 1.0-100.0 moles, preferably in the range of 1.0-50.0 moles, more preferably in the range of 1.0-30.0 moles, relative to 1 mole of the raw material compound.

(catalyst) The catalyst used for the protection reaction of the hydroxyl group is not particularly limited, for example, 4-dimethylaminopyridine can be used. The amount of the catalyst used is usually in the range of 0.01-1.0 mol, preferably in the range of 0.05-0.5 mol, more preferably in the range of 0.1-0.3 mol, relative to 1 mol of the raw material compound.

(temperature reflex) The reaction temperature used for the protection reaction of the hydroxyl group is not particularly limited. In one aspect, from the perspectives of increasing yield, suppressing by-products, and economic efficiency, the reaction temperature is, for example, in the range of -78°C to 100°C, preferably in the range of -40°C to 70°C, preferably The range of -20℃~20℃.

(Reaction time) The reaction time of the hydroxyl group protection reaction is not particularly limited. In one aspect, from the perspectives of increasing yield, suppressing by-products, and economic efficiency, the reaction time is in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, preferably in the range of 1 hour to 24 hours. 10 hours range.

(post-processing) As the post-treatment of the protection reaction of the hydroxyl group, a general treatment for obtaining a product produced from the reaction solution may be performed. As a post-treatment, for example, water can be added to the reaction solution after the reaction to neutralize it, and a general extraction solvent such as ethyl acetate, diethyl ether, dichloromethane, toluene, hexane, etc. can be used for extraction operation. The target object can be obtained by vacuum distilling the reaction solvent and the extraction solvent from the extract obtained by such an extraction operation. The target substance obtained in this way may be subjected to general purification such as silica gel column chromatography and recrystallization, if necessary, to further increase the purity.

(式中，R ¹、R ²、R ³、R ⁴、R ⁵及R ⁶如上所述)。 Synthesis of the compound represented by the general formula (III) or its optically active substance According to an embodiment of the present disclosure, the compound represented by the general formula (III) or its optically active substance obtained by the above method is desiliconized , to obtain a compound represented by general formula (IV) or an optically active substance thereof. [chemical formula 18]

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as above).

According to a suitable embodiment of the present invention, the compound represented by the general formula (III) or its optically active substance can be made to act on the acid to remove the silicon group represented by the formula (i), thereby obtaining the compound represented by the general formula (IV). compounds or their optically active substances.

(acid) The kind of acid used for the desilication reaction is not particularly limited, and any of organic acids and inorganic acids generally used in this technical field can be used. As the acid, for example, hydrochloric acid, sulfuric acid, PTSA, and an ion exchange resin having a sulfonic acid residue can be used, but not limited thereto. The acid can be used in any amount as long as the reaction proceeds. If you are a person in the industry, you can properly adjust the amount of solvent used in the desilication reaction.

(reaction solvent) The type of the reaction solvent used for the desilication reaction is not particularly limited, and any one can be used as long as it is commonly used in the technical field. As a reaction solvent, for example, diethyl ether, THF, 1,4-dioxane, 1,2-dimethoxyethane, methanol, ethanol, 1-propanol, 2-propanol, 1 -butanol, 2-butanol, tert-butanol, water and mixtures thereof, but not limited thereto. The amount of the solvent used may be any amount as long as the reaction proceeds.

(temperature reflex) The reaction temperature of the desilication reaction is not particularly limited. In one aspect, from the perspectives of increasing yield, suppressing by-products, and economic efficiency, the reaction temperature is in the range of -78°C to 150°C, preferably in the range of -40°C to 100°C, preferably - The range of 20℃~80℃.

(Reaction time) The reaction time of the desilication reaction is not particularly limited. In one aspect, from the perspectives of increasing yield, suppressing by-products, and economic efficiency, the reaction time is in the range of 0.5 hours to 48 hours, preferably in the range of 1 hour to 24 hours, preferably in the range of 1 hour to 24 hours. 10 hours range.

(post-processing) As the treatment after the desilication reaction, general treatment for obtaining the product produced from the reaction solution may be performed. For example, in the post-treatment, you can also add water to the reaction solution after the reaction to neutralize, and use a general extraction solvent, such as: ethyl acetate, diethyl ether, dichloromethane, toluene, hexane, etc. for extraction operations . The target object can be obtained by vacuum distilling the reaction solvent and the extraction solvent from the extract obtained by such an extraction operation. The target substance obtained in this way may be subjected to general purification such as silica gel column chromatography, distillation, recrystallization, etc., if necessary, to further increase the purity.

Manufacture of beraprost or its optically active substance from a compound represented by general formula (III) or its optically active substance According to an embodiment of the present invention, beraprost or its optically active substance can be obtained by derivatizing the compound represented by general formula (IV) or its optically active substance.

， 形成通式(A1)所示之化合物： [化學式20]

， 將上述側鏈中之酮還原，去除殘留的R ²及R ⁶，並將末端羧基轉換為陽離子，而形成通式(A)所示之化合物或其光學活性物： [化學式21]

。 According to a suitable embodiment of the present invention, the primary hydroxyl group of the compound represented by the general formula (IV) or its optically active substance is oxidized to form the corresponding aldehyde, and then coupled with the side chain of the following formula: [Chemical formula 19]

, form the compound shown in general formula (A1): [chemical formula 20]

, reducing the ketone in the above side chain, removing the residual R ² and R ⁶ , and converting the terminal carboxyl group into a cation to form a compound represented by general formula (A) or its optically active substance: [Chemical formula 21]

.

The above method of derivatizing the compound represented by the general formula (IV) or its optically active substance to obtain beraprost or its optically active substance can be carried out according to the method described in Patent Document 3.

Synthetic intermediates/use Manufacture of beraprost or its optically active substance from a compound represented by general formula (III) or its optically active substance As described above, the compound represented by any one of the general formula (I) or (II) or its optically active substance can be advantageously utilized as a synthetic intermediate in the production of beraprost or its optically active substance.

Therefore, according to a suitable aspect of the present invention, there is provided a reagent for producing beraprost or its optically active substance, which comprises any one of general formula (I) or (II) or its optically active substance made.

Also, according to a suitable aspect of the present invention, there is provided a use of a compound represented by any one of the general formula (I) or (II) or an optically active substance thereof, and the use is to use the compound or an optically active substance thereof as Reagents for the manufacture of beraprost or its optically active substances.

Also, according to a preferred aspect of the present invention, the optically active substance of the above-mentioned beraprost is represented by formula (A). [chemical formula 22]

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 [2]如[1]之化合物或其光學活性物，其中R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之烷基、可具有取代基之芳基或可具有取代基之芳烷基。 [3]如[1]或[2]之化合物或其光學活性物，其中R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之C ₁~C ₆烷基、可具有取代基之C ₆~C ₁₀芳基或可具有取代基之C ₇~C ₁₄芳烷基。 [4]如[1]至[3]中任一項之化合物或其光學活性物，其中R ²、R ³、R ⁴及R ⁵各自獨立表示C ₁~C ₆烷基、C ₆~C ₁₀芳基或C ₇~C ₁₄芳烷基。 [5]一種下述通式(II)所示之化合物或其光學活性物： [化學式24]

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 [6]一種試劑，係用以製造貝前列素或其光學活性物、且由如[1]至[5]中任一項之化合物或光學活性物所構成者。 [7]如[6]之試劑，其中上述貝前列素之光學活性物係式(A)所示者： [化學式25]

。 [8]一種製造通式(I)所示之化合物或其光學活性物之方法，係包含下述步驟而成：使通式(B)所示之化合物或其光學活性物環化，而獲得通式(I)所示之化合物或其光學活性物； [化學式26]

(式中，X表示鹵素原子，R ¹表示通式(i)所示之矽基， R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 [9] 一種製造通式(II)所示之化合物或其光學活性物之方法，係包含下述步驟而成：還原通式(I)所示之化合物或其光學活性物，而獲得通式(II)所示之化合物或其光學活性物； [化學式27]

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基)。 [10]一種製造通式(III)所示之化合物或其光學活性物之方法，係包含下述步驟而成：導入保護基至通式(II)所示之化合物或其光學活性物之羥基，而獲得通式(III)所示之化合物或其光學活性物； [化學式28]

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基，R ⁶表示矽基以外之羥基的保護基)。 [11] 一種製造通式(IV)所示之化合物或其光學活性物之方法，係包含下述步驟而成：將藉由如[10]之方法而得之通式(III)所示之化合物或其光學活性物去矽化，而獲得通式(IV)所示之化合物或其光學活性物。 [化學式29]

(式中，R ¹表示通式(i)所示之矽基，R ²、R ³、R ⁴及R ⁵各自獨立表示可具有取代基之脂肪族烴基、可具有取代基之芳香族烴基、或可具有取代基且組合脂肪族烴基及芳香族烴環基而形成之官能基，R ⁶表示矽基以外之羥基的保護基)。 [12]如[8]至[11]中任一項之方法，其係用以製造貝前列素或其光學活性物。 [13]如[12]之方法，其中上述貝前列素之光學活性物係式(A)所示者： [化學式30]

。 [14]一種如[1]至[5]中任一項之通式(I)或(II)所示之化合物或其光學活性物之用途，該化合物或其光學活性物係作為用以製造貝前列素或其光學活性物之試劑。 [15]如[14]之用途，其中上述貝前列素之光學活性物係式(A)所示者： [化學式31]

。 Moreover, according to one aspect of this invention, the following is provided. [1] A compound represented by the following general formula (I) or an optically active substance thereof: [Chemical formula 23]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group). [2] The compound according to [1] or an optically active substance thereof, wherein each of R ² , R ³ , R ⁴ and R ⁵ independently represents an alkyl group that may have a substituent, an aryl group that may have a substituent, or an optional substituted group Aralkyl. [3] The compound or optically active substance according to [1] or [2], wherein R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ -C ₆ alkyl group that may have a substituent, may have a substituent A C ₆ -C ₁₀ aryl group or a C ₇ -C ₁₄ aralkyl group which may have a substituent. [4] The compound or optically active substance according to any one of [1] to [3], wherein R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ ~C ₆ alkyl group, a C ₆ ~C ₁₀ aryl or C ₇ ~C ₁₄ aralkyl. [5] A compound represented by the following general formula (II) or an optically active substance thereof: [Chemical formula 24]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group). [6] A reagent for producing beraprost or its optically active substance, which is composed of the compound or optically active substance according to any one of [1] to [5]. [7] The reagent according to [6], wherein the optically active substance of the above-mentioned beraprost is represented by formula (A): [Chemical formula 25]

. [8] A method for producing a compound represented by general formula (I) or an optically active substance thereof, comprising the following steps: cyclizing a compound represented by general formula (B) or an optically active substance thereof to obtain A compound represented by general formula (I) or an optically active substance thereof; [Chemical formula 26]

(In the formula, X represents a halogen atom, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, may have a substituent aromatic hydrocarbon group, or a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group which may have a substituent). [9] A method for producing a compound represented by general formula (II) or its optically active substance, comprising the following steps: reducing the compound represented by general formula (I) or its optically active substance to obtain the compound represented by general formula (I) The compound shown in (II) or its optically active substance; [Chemical formula 27]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group). [10] A method for producing a compound represented by general formula (III) or an optically active substance thereof, comprising the following steps: introducing a protecting group to a hydroxyl group of a compound represented by general formula (II) or an optically active substance thereof , to obtain a compound represented by general formula (III) or an optically active substance thereof; [chemical formula 28]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or it may have a substituent and a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, and ^R6 represents a protecting group for a hydroxyl group other than a silicon group). [11] A method for producing a compound represented by general formula (IV) or an optically active substance thereof, comprising the steps of: preparing the compound represented by general formula (III) obtained by the method of [10] The compound or its optically active substance is desiliconized to obtain the compound represented by general formula (IV) or its optically active substance. [chemical formula 29]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or it may have a substituent and a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, and ^R6 represents a protecting group for a hydroxyl group other than a silicon group). [12] The method according to any one of [8] to [11], which is used for producing beraprost or an optically active substance thereof. [13] The method according to [12], wherein the optically active substance of the above-mentioned beraprost is represented by formula (A): [Chemical formula 30]

. [14] Use of a compound represented by general formula (I) or (II) or an optically active substance thereof as described in any one of [1] to [5], as a compound or an optically active substance for the manufacture of Reagents of beraprost or its optically active substances. [15] The use according to [14], wherein the optically active substance of the above-mentioned beraprost is represented by formula (A): [Chemical formula 31]

.

[Examples] The present disclosure will be described in more detail below with reference to examples, but the present disclosure is not limited by these examples. In addition, each physical property of an Example and a reference example was measured using the following apparatus. ¹ H nuclear magnetic resonance spectroscopy ( ¹ H NMR), ¹³ C nuclear magnetic resonance spectroscopy ( ¹³ C NMR): JNM-AL400 (manufactured by JEOL) Internal standard substance: tetramethylsilane.

Production of synthetic intermediates of beraprost or its optically active substances Follow the following scheme 5 to manufacture the synthetic intermediate of beraprost or its optically active substance. In the following scheme 5, compounds 1 to 7 correspond to compounds represented by general formulas (B1), (B2), (B), (I), (II), (III), and (IV) respectively. Also, as described above, compound 7 corresponding to the compound represented by the general formula (IV) is a synthetic intermediate that can be converted into beraprost or its optically active substance by following the method described in Patent Document 3. Each reaction will be described below.

[chemical formula 32]

Example 1: (4S)-4-(2-bromo-6-(3-(methoxycarbonylpropyl)phenoxy)-2-((tert-butyldimethylsilyl)oxymethyl-2 -Manufacture of cyclopenten-1-one (compound 3) [chemical formula 33]

Compound 1 (0.91g, 3.7mmol, enantiomer excess rate 99.5%) was dissolved in toluene under nitrogen atmosphere, and compound 2: 1.0g (3.7mmol), triphenylphosphine were added sequentially at room temperature 1.18g (4.5mmol), and 0.46g (4.5mmol) of triethylamine. The obtained reaction solution was cooled to 0° C., 2.0 mL of DEAD (2.2 mol/L toluene solution) was added, stirred at room temperature for 2 hours, and then refluxed for 3 hours. The resulting reaction solution was cooled to room temperature, and concentrated. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane:acid ethyl=8:1) to obtain Compound 3 (1.58 g, yield 85%) as a yellow oily substance.

(Compound 3) Pale yellow oil ¹ H NMR (CDCl ₃ ): δ: 0.071(s,3H),0.084(s,3H),0.90(s,9H),1.88-1.95(m,2H),2.30(t ,J=7.6Hz,2H),2.61-2.76(m,2H),2.82(dd,J=18.6,2.4Hz,1H),2.93(dd,J=18.6,6.0Hz,1H),3.65(s, 3H),4.40-4.43(m,2H),5.36-5.39(m,1H),6.98(t,J=7.8Hz,1H),7.18(d,J=7.8Hz,1H),7.44-7.46(m ,2H). ¹³ CNMR (CDCl ₃ ): δ: -5.5, -5.4, 17.7, 24.8, 25.3, 29.7, 32.7, 42.7, 51.0, 57.4, 78.5, 116.9, 120.8, 125.2, 129.2, 131.4, 136.4, 148.4, 152.8, 173 .1 , 203.1.

Example 2: 4-((1S,2R,3aS,8bS)-1-(tert-butyldimethylsilyl)oxymethyl-2-oxo-2,3,3a,8b-tetrahydro- Production of methyl 1H-cyclopenta[b]benzofuran-5-yl)butanoate (compound 4) [Chemical formula 34]

Compound 3 (1.58 g, yield 3.2 mmol) obtained in Example 1 was dissolved in 30 mL of toluene and refluxed. To the obtained solution, 1.2 ml (4.2 mmol) of tributyltin hydride and 68 mg (0.42 mmol) of azoisobutyronitrile in 10 mL of toluene were added over 1 hour. After cooling the reaction mixture to room temperature, 20 ml of a KF saturated aqueous solution was added to stop the reaction. Thereafter, Celite filtration was performed, and AcOEt/H ₂ O was used for liquid separation. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was removed by rotary evaporator. After that, it was purified by column chromatography (hexane:ethyl acetate=9:1) to obtain compound 4 (0.88g, yield 66%, enantiomer excess rate 99.4%) as a light yellow oily substance .

(Compound 4) ¹ H NMR (CDCl ₃ ): δ: 0.06(s,3H),0.09(s,3H),0.91(s,9H),1.91-1.98(m,2H),2.33(t,J= 7.6Hz, 2H), 2.45-2.48(m, 1H), 2.61(td, J=7.6, 2.8Hz, 2H), 2.67(dd, J=20.0, 3.6Hz, 1H), 2.75(dd, J=20.0 ,6.5Hz,1H),3.65(s,3H),3.84(dd,J=9.6,3.8Hz,1H),4.03(dd,J=9.6,3.8Hz,1H),4.08(dd,J=8.4, 4.4Hz,2H),5.34(td,J=7.2,4.0Hz,1H),6.82(t,J=7.6Hz,1H),6.97(d,J=7.3Hz,1H),7.04(d,J= 7.3Hz, 1H).

¹³ CNMR (CDCl ₃ ): δ: -5.65, -5.61, 18.2, 24.7, 25.8, 29.1, 33.4, 45.7, 47.2, 51.5, 57.6, 63.1, 83.0, 121.1, 122.4, 123.7, 129.1, 130.0, 157.3, 174 .0 , 217.6.

Example 3: 4-((1S,2R,3aS,8bS)-1-(tert-butyldimethylsilyl)oxymethyl-2-hydroxy-2,3,3a,8b-tetrahydro-1H- Production of methyl cyclopenta[b]benzofuran-5-yl)butyrate (compound 5) [Chemical formula 35]

Compound 4 (0.88 g, 2.1 mmol) was dissolved in MeOH: 10 ml and cooled with ice. NaBH ₄ : 0.12 g (3.2 mmol) dissolved in MeOH: 15 ml was dropped into the resulting solution, and stirred for 2 hours. Acetone was added to the obtained reaction liquid to stop the reaction, and the obtained solution was concentrated. Ethyl acetate was added to the obtained residue, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed from the resulting mixture by filtration, and the solvent was removed by a rotary evaporator, followed by purification by silica gel column chromatography (hexane:ethyl acetate=8:1~4:1) to obtain a light yellow oily substance. Compound 5 (0.56 g, yield 63%, enantiomer excess 99.4%).

(Compound 5) ¹ H NMR (CDCl ₃ ): δ: 0.09(s,3H),0.10(s,3H),0.91(s,9H),1.87-2.08(m,3H),2.12-2.18(m, 1H),2.32(t,J=7.7Hz,2H),2.35(d,J=3.6Hz,1H),2.53-2.62(m,3H),3.41(dd,J=8.0,6.8Hz,1H), 3.65(s,3H),3.72(dd,J=10.0,7.2Hz,1H),3.91(dd,J=10.0,5.2Hz,1H),4.10-4.11(m,1H),5.10-5.15(m, 1H), 6.78(t, J=7.7Hz, 1H), 6.94(d, J=7.0Hz, 1H), 7.01(d, J=7.7Hz, 1H).

¹³ CNMR (CDCl ₃ ): δ: -5.55, -5.51, 18.2, 24.7, 25.8, 29.1, 33.3, 41.9, 47.5, 51.5, 56.8, 65.1, 75.9, 85.7, 120.5, 121.9, 123.3, 128.7, 130.4, 157. 0 , 174.1.

Example 4: 4-((1S,2R,3aS,8bS)-2-Acetyloxy-1-(tert-butyldimethylsilyl)oxymethyl-2,3,3a,8b-tetrahydro Production of -1H-cyclopenta[b]benzofuran-5-yl)butyric acid methyl ester (compound 6) [chemical formula 36]

Compound 5 (0.32 g, 0.76 mmol) was dissolved in pyridine 1.3 mL, and DMAP 19 mg (0.15 mmol) was added. While cooling 1.36 g (15 mmol) of acetic anhydride with ice, this was dropped, and stirred at room temperature for 2 hours. After completion of the reaction, 300 mL of saturated aqueous sodium bicarbonate solution was added to stop the reaction. Ethyl acetate was added, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was removed by rotary evaporator. Afterwards, it was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain compound 6 (0.30 g, yield 85%) as a light yellow oily substance.

(Compound 6) ¹ H NMR (CDCl ₃ ): δ: 0.08(m,3H),0.09(m,3H),0.91(s,9H),1.71(s,3H),1.90-1.97(m,2H) ,2.10-2.16(m,1H),2.32-2.39(m,3H),2.47-2.66(m,3H),3.60(s,3H),3.68-3.74(m,3H),4.99-5.02(m, 1H), 5.21-5.25(m, 1H), 6.70(t, J=7.7Hz, 1H), 6.84(d, J=7.0Hz, 1H), 6.92(d, J=7.7Hz, 1H).

¹³ CNMR(CDCl ₃ )：δ：-5.5,18.2,20.8,24.9,25.8,29.2,33.4,39.8,48.4,51.4,55.5,63.4,77.8,86.8,120.3,122.0,122.8,128.5,130.7,157.4, 170.7, 174.1.

Example 5: 4-((1S,2R,3aS,8bS)-2-Acetyloxy-1-hydroxymethyl-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran Production of -5-yl) methyl butyrate (compound 7) [chemical formula 37]

Compound 6 (0.3g, 6.5mmol) was dissolved in methanol 5ml, and Amberlyst15 (30mg) was added to reflux for 5 hours. After removing the ion exchange resin by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain compound 7 (0.19 g, yield 84%, enantiomer surpassing rate 99.3%).

(Compound 7) ¹ H NMR (CDCl ₃ ): δ: 1.85 (3H, s), 1.92-1.96 (2H, m), 2.09-2.27 (4H, m), 2.34-2.63 (4H, m), 3.66 ( 3H,s),3.68-3.74(2H,m),5.07(1H,q,J=6.0Hz),5.17-5.19(1H,m),6.78(1H,t,J=7.2Hz),6.94(1H ,d,J=7.6Hz),7.03(1H,d,J=7.2Hz).

¹³ CNMR (CDCl ₃ ): δ: 20.9, 24.8, 29.1, 33.3, 38.9, 47.8, 51.3, 55.4, 62.2, 75.6, 85.8, 120.3, 121.9, 122.8, 128.5, 130.3, 157.2, 171.2, 174.0.

According to the present disclosure, a novel synthetic intermediate of beraprost or its optically active substance and its production method can be provided. According to the present disclosure, beraprost or its optically active substance can be efficiently produced by using a synthetic intermediate derived from a chiral building block of a specific structure, which is beneficial to industrial production.

(none)

Claims (15)

A compound represented by the following general formula (I) or an optically active substance thereof: [Chemical Formula 1]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group). A compound or an optically active substance thereof as claimed in claim 1, wherein each of R ² , R ³ , R ⁴ and R ⁵ independently represents an alkyl group that may have a substituent, an aryl group that may have a substituent, or an aralkyl group that may have a substituent base. The compound or its optically active substance as claimed in item 1 or 2, wherein R ² , R ³ , R ⁴ and R ⁵ each independently represent a C ₁ ~C ₆ alkyl group that may have a substituent, a C 6 ~C ₆ group that may have a substituent A C ₁₀ aryl group or a C ₇ -C ₁₄ aralkyl group which may have a substituent. The compound or optically active substance as claimed in item 1 or 2, wherein R ² , R ³ , R ⁴ and R ⁵ each independently represent C ₁ ~C ₆ alkyl, C ₆ ~C ₁₀ aryl or C ₇ ~C ₁₄ Aralkyl. A compound represented by the following general formula (II) or an optically active substance thereof: [Chemical Formula 2]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group). A reagent is used to manufacture beraprost or its optically active substance, and is composed of the compound or optically active substance according to claim 1 or 5. The reagent as in claim 6, wherein the optically active substance of the aforementioned beraprost is represented by formula (A): [Chemical formula 3]

. A method for producing a compound represented by general formula (I) or its optically active substance, comprising the following steps: cyclizing the compound represented by general formula (B) or its optically active substance to obtain the general formula ( I) the compound shown in or its optical active substance; [chemical formula 4]

(In the formula, X represents a halogen atom, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, may have a substituent aromatic hydrocarbon group, or a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group which may have a substituent). A method for producing a compound represented by general formula (II) or its optically active substance, comprising the following steps: reducing the compound represented by general formula (I) or its optically active substance to obtain general formula (II) The shown compound or its optical active substance; [Chemical formula 5]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or a functional group that may have a substituent and is formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group). A method for producing a compound represented by general formula (III) or its optically active substance, comprising the following steps: introducing a protecting group to the hydroxyl group of the compound represented by general formula (II) or its optically active substance to obtain A compound represented by general formula (III) or an optically active substance thereof; [Chemical formula 6]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or it may have a substituent and a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, and ^R6 represents a protecting group for a hydroxyl group other than a silicon group). A method for producing a compound represented by general formula (IV) or an optically active substance thereof, comprising the following steps: the compound represented by general formula (III) obtained by the method as claimed in item 10 or its The optically active substance is desiliconized to obtain the compound represented by the general formula (IV) or its optically active substance; [Chemical Formula 7]

(wherein, R ¹ represents a silicon group represented by general formula (i), R ² , R ³ , R ⁴ and R ⁵ each independently represent an aliphatic hydrocarbon group that may have a substituent, an aromatic hydrocarbon group that may have a substituent, Or it may have a substituent and a functional group formed by combining an aliphatic hydrocarbon group and an aromatic hydrocarbon ring group, and ^R6 represents a protecting group for a hydroxyl group other than a silicon group). The method according to any one of claims 8 to 11, which is used to manufacture beraprost or its optically active substance. The method of claim 12, wherein the optically active substance of the aforementioned beraprost is represented by formula (A): [Chemical formula 8]

. A use of the compound represented by the general formula (I) or (II) of claim 1 or 5 or its optically active substance, the compound or its optically active substance is used as a compound for the manufacture of beraprost or its optically active substance reagent. Such as the use of claim 14, wherein the optically active substance of the aforementioned beraprost is represented by formula (A): [Chemical formula 9]

.