Process for the separation of geometric isomers

Abstract

The present application is a method for separating a compound represented by formula (1) or (2) [in the formula, P 1 is a protecting group for a hydrogen atom or a hydroxyl group, R 1 is a linear or branched C 1‑6 alkyl group which can be substituted with a phenyl group, A is an alkenylene group, R 2 is a hydroxyl group, a C 1‑3 alkoxy group, a mono(C 1‑3 alkyl)amino group or a di(C 1‑3 alkyl)amino group] from its geometric isomer which is a geometric isomer of the double bond contained in A, the method comprising: treating a mixture containing the compound and its geometric isomer by chromatography using an acidic functional group-modified silica gel as a stationary phase.

Description

Technical Field

[0001] This invention relates to a method for separating geometric isomers. Background Technology

[0002] Prostaglandins (PGs) are a collective term for endogenous physiologically active substances synthesized in the body from arachidonic acid through the metabolism of cyclooxygenase. There are many types of prostaglandins, including prostaglandin H2, prostaglandin D2, prostaglandin E1, prostaglandin E2, and prostaglandin F. 2α Prostaglandins, such as prostaglandin I2, participate in a variety of physiological functions via their respective specific G protein-coupled receptors.

[0003] The chemical structure of prostaglandins is characterized by a cyclopentane ring with four asymmetric carbons and two aliphatic side chains. Therefore, they have long been a target for synthetic research or a seed for drug development, and various prostaglandin derivatives have been developed to date. The common intermediate used in their synthesis, (3aS,4R,5S,6aR)-(+)-hexahydro-5-hydroxy-4-(hydroxymethyl)-2H-cyclopentano[b]furan-2-one, is also known as "coreylactone". The chemical structures of coreylactone and representative commercially available prostaglandin derivatives are shown below.

[0004]

[0005] Existing technical documents

[0006] Patent documents

[0007] Patent Document 1: Japanese Patent No. 5209542

[0008] Patent Document 2: International Publication No. 2011 / 095990

[0009] Patent Document 3: International Publication No. 2012 / 011128

[0010] Patent Document 4: International Publication No. 2015 / 136317 Summary of the Invention

[0011] The problem that the invention aims to solve

[0012] Prostaglandins possess a functionalized cyclopentane ring at the center of their chemical structure, with long aliphatic side chains on two adjacent carbon atoms, one of which contains a carboxyl group or a carboxylic acid ester. Prostaglandins are generally produced via a co-synthetic intermediate, with subsequent steps involving the controlled oxidation of substituents. Many prostaglandins contain cis double bonds within their aliphatic side chains; therefore, eliminating their geometric isomers during chemical synthesis is a challenge. Compounds with cis double bonds are also referred to as Z-isomers, and those with trans double bonds as E-isomers.

[0013]

[0014] Therefore, the object of the present invention is to provide a method for separating a compound having a structure similar to that of prostaglandins from its geometric isomers.

[0015] Methods for solving problems

[0016] The present invention provides the following [1] to [5].

[0017] [1] A method for separating a compound represented by formula (1) or (2) from its geometric isomers, wherein the geometric isomers are geometric isomers of the double bonds contained in A, the method comprising: treating a mixture containing the compound and its geometric isomers by using a chromatographic method with acidic functional group modified silica gel as a stationary phase.

[0018]

[0019] [In the formula, P] 1 and P 2 Each is an independent protecting group for either a hydrogen atom or a hydroxyl group, R 1 It is a linear or branched C that can be substituted with phenyl groups. 1-6 Alkyl group, where A is C 3-10 Ideonyl, R 2 Hydroxyl group, C 1-3 Alkoxy, mono(C) 1-3 alkyl)amino or di(C) 1-3 alkyl)amino,

[0020]

[0021] It can be a single or double bond.

[0022] [2] According to the method described in [1], where A is

[0023]

[0024] [3] According to the method described in [1] or [2], wherein R 1 for

[0025]

[0026] [4] The method according to any one of [1] to [3], wherein P 1 It consists of a hydrogen atom or a 2-tetrahydropyranyl group.

[0027] [5] The method according to any one of [1] to [4], wherein the above-mentioned acidic functional group modified silica gel is silica gel obtained by modification with carboxyl or sulfonyl groups.

[0028] Invention Effects

[0029] According to the present invention, a method can be provided for separating a compound having a structure similar to that of prostaglandins from its geometric isomers. Detailed Implementation

[0030] The present invention will now be described in detail.

[0031] One embodiment of the present invention is a method for separating a compound represented by formula (1) or formula (2) from its geometric isomers, wherein the geometric isomers are geometric isomers of the double bonds contained in A, the method comprising: treating a mixture containing the above-mentioned compound and its geometric isomers by using a chromatography method with acidic functional group modified silica gel as the stationary phase.

[0032]

[0033] [In the formula, P] 1 and P 2 Each is an independent protecting group for either a hydrogen atom or a hydroxyl group, R 1 It is a linear or branched C that can be substituted with phenyl groups. 1-6 Alkyl group, where A is C 3-10 Ideonyl, R 2 Hydroxyl group, C 1-3 Alkoxy, mono(C) 1-3 alkyl)amino or di(C) 1-3 alkyl)amino,

[0034]

[0035] It can be a single or double bond.

[0036] In the method of this embodiment, the combination of two or more geometric isomers as the objects of separation is a compound represented by formula (1) or (2), in which the double bond contained in A has a relationship between cis isomers and trans isomers. In another side chain (having R...) 1 When the side chain also contains double bonds, there can be a total of four geometric isomers.

[0037]

[0038] P 1 and P 2 Each independently represents a hydrogen atom or a protecting group for a hydroxyl group. A protecting group for a hydroxyl group is a substituent used for the purpose of protecting the hydroxyl group so that it does not react with a reactant in an organic synthesis reaction. There is no particular limitation on the protecting group for a hydroxyl group, and examples thereof include: acetal protecting groups such as methoxymethyl, ethoxyethyl, benzyloxymethyl, and tetrahydropyranyl; ether protecting groups such as benzyl, p-methoxybenzyl, and p-nitrobenzyl; acyl protecting groups such as acetyl, pivaloyl, benzoyl, and p-methoxybenzoyl; and silyl protecting groups such as trimethylsilyl, triethylsilyl, tert-butyldimethyl, triphenylsilyl, and phenyldimethylsilyl.

[0039] R 1 is a linear or branched C 1-6 alkyl group that may be substituted with a phenyl group. The linear or branched C 1-6 alkyl group is an alkyl group having 1 to 6 carbon atoms. Specifically, examples thereof include: methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1,1-dimethylpropyl, 1-hexyl, 2-hexyl, 3-hexyl, and the like. R 1 may be a group in which a phenyl group is substituted on the above-mentioned linear or branched C 1-6 alkyl group.

[0040] A is a C 3-10 alkenylene group. Specifically, examples thereof include: propenylene, butenylene, pentenylene, hexenylene, heptenylene, octenylene, nonenylene, and decenylene. The position of the double bond in A is not particularly limited. According to the separation method of the present embodiment, the geometric isomers (cis isomers and trans isomers) of the double bond can be separated.

[0041] R 2 is a hydroxyl group, a C 1-3 alkoxy group, a mono(C 1-3 alkyl)amino group, or a di(C 1-3 alkyl)amino group. The C 1-3 alkoxy group is a group in which an alkyl group having 1 to 3 carbon atoms is substituted on an oxygen atom. Specifically, it is methoxy, ethoxy, 1-propoxy, or 2-propoxy. The mono(C 1-3 alkyl)amino group is a group in which one alkyl group having 1 to 3 carbon atoms is substituted on a nitrogen atom. Specifically, examples thereof include: monomethylamino, monoethylamino, mono(1-propyl)amino, mono(2-propyl)amino, and the like. The di(C 1-3Alkyl)amino is a group in which two alkyl groups with one to three carbon atoms are substituted on a nitrogen atom. Specifically, examples include: dimethylamino, diethylamino, di(1-propyl)amino, di(2-propyl)amino, ethyl(methyl)amino, etc.

[0042] The separation method in this embodiment includes: processing a mixture of geometric isomers by using chromatography with acidic functional group-modified silica gel as a packing material (stationary phase).

[0043] For acidic functionalized silica gels used as stationary phases in chromatography, any modified silica gel obtained by modifying silica gel with acidic functional groups is acceptable. Examples of acidic functionalized silica gels include carboxyl-modified silica gels and sulfonyl-modified silica gels. Normal-phase chromatography is preferred in the above-mentioned chromatographic method.

[0044] The shape of acid-functionalized silica gel can be spherical or fragmented, preferably spherical. Spherical silica gel has a fixed surface area and can be uniformly packed into the column, thus further improving the resolution during chromatographic separation.

[0045] The average particle size of the acid-functionalized silica gel can be 3–500 μm, preferably 5–300 μm, and more preferably 30–200 μm.

[0046] The column length can be 5–200 cm, preferably 10–150 cm, and more preferably 15–100 cm. If the column length is 15 cm or more, the separation degree is improved and the range of eluents that can be selected is wider.

[0047] The eluent (mobile phase) can be any organic solvent known to those skilled in the art. Examples of organic solvents include: aliphatic hydrocarbon solvents such as pentane, hexane, and heptane; aromatic hydrocarbon solvents such as toluene; halogenated hydrocarbon solvents such as dichloromethane and chloroform; ester solvents such as ethyl acetate and propyl acetate; and alcohol solvents such as methanol, ethanol, and 2-propanol. These solvents can be appropriately selected considering the solubility of the crude purified product to be separated, or they can be mixed in any proportion considering their miscibility. Examples of mixed solvents include: two-component mixtures such as hexane and ethanol, hexane and isopropanol, and hexane and ethyl acetate, and three-component mixtures such as hexane, methanol, and isopropanol.

[0048] In this specification, "separating the compound represented by formula (1) or (2) from its geometric isomers" means that, when the desired content of the compound is set to 100, the content of the corresponding geometric isomer is 2 or less, preferably 1 or less, and more preferably 0.5 or less. Furthermore, the purity of the separated compound represented by formula (1) or (2) can be 90% or more, preferably 95% or more, and more preferably 97%, 98%, or 99% or more.

[0049] Example

[0050] The present invention will be described in more detail below with examples and comparative examples.

[0051] Unless otherwise specified, abbreviations used in embodiments, etc., should be understood in the sense of their meaning as known to those skilled in the art. For example, the meanings of some abbreviations are shown below.

[0052] THP: 2-Tetrahydropyranyl

[0053] Ph: Phenyl

[0054] Example 1

[0055] Purification of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoic acid ((Z)-IFL-FA)

[0056]

[0057] Example 1a

[0058] The crude purified product (a mixture of E- and Z-isomers of IFL-FA, 238 mg) was dissolved in dichloromethane and purified by chromatography under the following separation conditions. Fractions in which the E-isomer was not detected under the following analytical conditions were collected to obtain the Z-isomer (yield: 206 mg, 90%).

[0059] <Separation Conditions>

[0060] Eluent: Hexane: Isopropanol = 10:1

[0061] Filler material: CROMATOREX COOH MB100-40 / 75 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size 40-75μm, fine pore size 10nm))

[0062] Dispensing volume: 1-2 mL / fraction

[0063] <Analysis Conditions>

[0064] Pillar: YMC-Pack SIL (trade name, manufactured by YMC, inner diameter: 4.6mm, length: 25cm)

[0065] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0066] Flow rate: 1 mL per minute

[0067] Detection wavelength: 215nm

[0068] Injection volume: 20μL

[0069] The proportions of each isomer before and after separation are shown in Table 1. The proportions of each isomer were calculated based on the area under the curve of the chromatogram obtained under the above analytical conditions. (E)-IFL-FA is (E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoic acid.

[0070] [Table 1]

[0071] Before separation After separation (Z)-IFL-FA 74.0％ 82.0％ (E)-IFL-FA 1.1％ 0.0％

[0072] Example 1b

[0073] The crude purified product (a mixture of E- and Z-isomers of IFL-FA, 224 mg) was dissolved in dichloromethane and purified by chromatography under the following separation conditions. Fractions in which the E-isomer was not detected under the following analytical conditions were collected to obtain the Z-isomer (yield: 142 mg, yield: 68%).

[0074] <Separation Conditions>

[0075] Eluent: Hexane: Isopropanol = 10:1

[0076] Filler material: CROMATOREX SO3H MB 100-40 / 75 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size 40-75μm, fine pore size 10nm))

[0077] Dispensing volume: 1-2 mL / fraction

[0078] <Analysis Conditions>

[0079] Pillar: YMC-Pack SIL (trade name, manufactured by YMC, inner diameter: 4.6mm, length: 25cm)

[0080] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0081] Flow rate: 1 mL per minute

[0082] Detection wavelength: 215nm

[0083] Injection volume: 20μL

[0084] The proportions of each isomer before and after separation are shown in Table 2. The proportions of each isomer were calculated based on the area under the curve of the chromatogram obtained under the above analytical conditions. The content of the E-isomer was 0.0%, and the Z-isomer could be obtained with high purity.

[0085] [Table 2]

[0086] Before separation After separation (Z)-IFL-FA 74.0％ 99.2％ (E)-IFL-FA 1.1％ 0.0％

[0087] Example 2

[0088] Purification of (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]hept-5-enoic acid ((Z)-IFL-PPF)

[0089]

[0090] The crude purified product (392 mg of the EZ mixture of IFL-PPF) was dissolved in a mixture of hexane and ethyl acetate. Purification was performed by chromatography under the following separation conditions. The fraction containing less than 0.5% E-isomer was collected under the following analytical conditions to obtain the Z-isomer (yield: 99 mg, 68%). It should be noted that approximately 0.1 mL of the fraction was concentrated, the residue was dissolved in 1 mL of 2-propanol, a catalyst amount of p-toluenesulfonic acid monohydrate was added, and the reaction was carried out at room temperature for approximately 2 hours to deprotect and derivatize to IFL-FA (refer to Example 1), followed by analysis.

[0091] <Separation Conditions>

[0092] Eluent: Hexane: Ethyl acetate = 3:1 to 3:7

[0093] Filler material: CROMATOREXSO3H MB100-40 / 75 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size: 40-75μm, fine pore size: 10nm))

[0094] Dispensing volume: 1-2 mL / fraction

[0095] <Analysis Conditions>

[0096] Pillar: YMC-Pack SIL (trade name, manufactured by YMC, inner diameter: 4.6mm, length: 25cm)

[0097] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0098] Flow rate: 1 mL per minute

[0099] Detection wavelength: 215nm

[0100] Injection volume: 20μL

[0101] The proportions of each isomer before and after separation are shown in Table 3. The proportions of each isomer were calculated based on the area under the curve of the chromatogram. (E)-IFL-PPF is (E)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]hept-5-enoic acid. Under the above analytical conditions, the Z-isomer contained 0.2% of the E-isomer after separation. It was also possible to separate triphenylphosphine, which was present in large quantities in the crude purified product.

[0102] [Table 3]

[0103] Before separation After separation (Z)-IFL-PPF 17.3％ 992％ (E)-IFL-PPF 2.0％ 0.2％ Triphenylphosphine oxide 78.0％ 0.5％

[0104] Example 3

[0105] Purification of propane-2-yl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoate ((Z)-latanoprost)

[0106]

[0107] Example 3a

[0108] The crude purified product (200 mg of latanoprost EZ mixture) was dissolved in a mixture of hexane and ethyl acetate. The product was purified by chromatography under the following separation conditions. Fractions with E-isomer content below 0.5% were collected under the following analytical conditions to obtain the Z-isomer (yield: 94 mg, yield: 47%).

[0109] <Separation Conditions>

[0110] Eluent: Hexane: Ethyl acetate = 3:1 to 3:7

[0111] Filler material: CROMATOREXCOOH MB100-40 / 75 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size: 40-75μm, fine pore size: 10nm))

[0112] Dispensing volume: 1-2 mL / fraction

[0113] <Analysis Conditions>

[0114] Column: Spherisorb Silica (trade name, manufactured by Waters, inner diameter: 4.6mm, length: 25cm)

[0115] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0116] Flow rate: 1 mL per minute

[0117] Detection wavelength: 215nm

[0118] Injection volume: 20μL

[0119] The proportions of each isomer before and after separation are shown in Table 4. The proportions of each isomer were calculated based on the area under the curve of the chromatogram. (E)-Latanprost is propane-2-yl(E)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoate. Under the above analytical conditions, the proportion of the E-isomer was 0.4%, and the Z-isomer could be obtained with high purity.

[0120] [Table 4]

[0121] Before separation After separation (Z)-Lactamprost 96.3％ 98.7％ (E)-Lactamprost 1.5％ 0.4％

[0122] Example 3b

[0123] The crude purified product (200 mg of IFL EZ mixture) was dissolved in a mixture of hexane and ethyl acetate. The product was purified by chromatography under the following separation conditions. Fractions with E-isomer content below 0.5% were collected under the following analytical conditions to obtain the Z-isomer (yield: 64 mg, yield: 32%).

[0124] <Separation Conditions>

[0125] Eluent: Hexane: Ethyl acetate = 3:1 to 2:3

[0126] Filler material: CROMATOREXSO3H MB100-40 / 75 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size: 40-75μm, fine pore size: 10nm))

[0127] Dispensing volume: 1-2 mL / fraction

[0128] <Analysis Conditions>

[0129] Column: Spherisorb Silica (trade name, manufactured by Waters, inner diameter: 4.6mm, length: 25cm)

[0130] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0131] Flow rate: 1 mL per minute

[0132] Detection wavelength: 215nm

[0133] Injection volume: 20μL

[0134] The proportions of each isomer before and after separation are shown in Table 5. The proportion of each isomer was calculated based on the area under the curve of the chromatogram. The proportion of the E-isomer was 0.5%, and the Z-isomer could be obtained with high purity.

[0135] [Table 5]

[0136] Before separation After separation (Z)-Lactamprost 98.2％ 99.5％ (E)-Lactamprost 1.6％ 0.5％

[0137] Example 4

[0138] Purification of (Z)-7-((1R,2R,3R)-3-hydroxy-2-((3S,5S,E)-3-hydroxy-5-methylnon-1-en-1-yl)-5-oxocyclopentyl)hept-2-enoic acid ((Z)-IEL)

[0139]

[0140] The crude purified product (IEL EZ mixture, 33 mg) was dissolved in dichloromethane and purified by chromatography under the following separation conditions. Fractions in which the E-isomer was not detected under the following analytical conditions were collected to obtain the E-isomer (yield: 13 mg, yield: 56%).

[0141] <Separation Conditions>

[0142] Eluent: Hexane: Ethanol = 10:1

[0143] Filler material: CROMATOREX COOH SMB100-10 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size: 10μm, fine pore size: 10nm))

[0144] Dispensing volume: 1-2 mL / fraction

[0145] <Analysis Conditions>

[0146] Column: Develosil ODS-5 (trade name, manufactured by Nomura Chemicals, inner diameter: 4.6mm, length: 15cm)

[0147] Mobile phase: 0.02M potassium dihydrogen phosphate buffer: acetonitrile: 2-propanol = 9:5:2

[0148] Flow rate: 1 mL per minute

[0149] Detection wavelength: 215nm

[0150] Injection volume: 20μL

[0151] The proportions of each isomer before and after separation are shown in Table 6. The proportion of each compound was calculated based on the area under the curve of the chromatogram. (Z)-IEL is (Z)-7-((1R,2R,3R)-3-hydroxy-2-((3S,5S,E)-3-hydroxy-5-methylnon-1-en-1-yl)-5-oxocyclopentyl)hept-2-enoic acid, and AT-IEL is (E)-7-((1R,2S)-2-((3S,5S,E)-3-hydroxy-5-methylnon-1-en-1-yl)-5-oxocyclopentyl-3-en-1-yl)hept-2-enoic acid. The proportion of the Z-isomer in the separated E-isomer was 0.0% under the above analytical conditions. In addition, AT-IEL, which was present in large quantities in the crude purified product, could also be separated.

[0152] [Table 6]

[0153] Before separation After separation (E)-IEL 74.8％ 93.6％ (Z)-IEL 1.6％ 0.0％ AT-IEL 10.0％ 0.4％

[0154] Comparative Example 1

[0155] Purification of (Z)-7-[(1R,2R,3R,5S)-5-hydroxy-2-[(3R)-5-phenyl-3-[(tetrahydro-2H-pyran-2-yl)oxy]pentyl]-3-[(tetrahydro-2H-pyran-2-yl)oxy]cyclopentyl]hept-5-enoic acid ((Z)-IFL-PPF)

[0156]

[0157] The crude purified product (EZ mixture, 75.8 g) was dissolved in a mixed solvent of hexane and ethyl acetate and purified by chromatography under the following separation conditions to obtain the (Z) fraction (yield: 45.3 g, 96%). (E)-latanoprost was detected in all recovered fractions and could not be separated. It should be noted that approximately 0.1 mL of the fraction was concentrated, the residue was dissolved in 1 mL of 2-propanol, a catalyst amount of p-toluenesulfonic acid monohydrate was added, and the reaction was carried out at room temperature for approximately 2 hours to deprotect and derivatize to IFL-FA (refer to Example 1), which was then analyzed.

[0158] <Separation Conditions>

[0159] Eluent: Hexane: Ethyl acetate = 3:2

[0160] Filler material: BW-300S (trade name, manufactured by Fuji Silicon Chemicals, fragmented silica gel (average particle size: 38-75 μm, fine pore size: 6 nm))

[0161] Dispensing volume: 20–50 mL / fraction

[0162] <Analysis Conditions>

[0163] Pillar: YMC-Pack SIL (trade name, manufactured by YMC, inner diameter: 4.6mm, length: 25cm)

[0164] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0165] Flow rate: 1 mL per minute

[0166] Detection wavelength: 215nm

[0167] Injection volume: 20μL

[0168] The proportions of each isomer before and after separation are shown in Table 7. The proportions of each isomer were calculated based on the area under the curve of the chromatogram.

[0169] [Table 7]

[0170] Before separation After separation (Z)-IFL-PPF 63％ 97.2％ (E)-IFL-PPF 1.9％ 1.9％

[0171] Comparative Example 2

[0172] Purification of propane-2-yl(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]hept-5-enoate ((Z)-latanoprost)

[0173] The crude purified product (a mixture of E and Z latanoprost, 17.3 g) was dissolved in a mixture of hexane and ethyl acetate and purified by chromatography under the following separation conditions to give (Z)-latanoprost (yield: 14.6 g, 88%). In all fractions containing (Z)-latanoprost, (E)-latanoprost was detected under the following analytical conditions and could not be separated.

[0174] <Separation Conditions>

[0175] Eluent: Hexane: Ethyl acetate = 3:2

[0176] Filler material: High-purity silica gel 60 (trade name, manufactured by Kanto Chemicals)

[0177] Dispensing volume: 20–50 mL / fraction

[0178] <Analysis Conditions>

[0179] Column: Spherisorb Silica (trade name, manufactured by Waters, inner diameter: 4.6mm, length: 25cm)

[0180] Mobile phase: hexane: ethanol: acetic acid = 91:9:0.05

[0181] Flow rate: 1 mL per minute

[0182] Detection wavelength: 215nm

[0183] Injection volume: 20μL

[0184] The proportions of each isomer before and after separation are shown in Table 8. The proportions of each isomer were calculated based on the area under the curve of the chromatogram.

[0185] [Table 8]

[0186] Before separation After separation (Z)-Lactamprost 95.5％ 98.1％ (E)-Lactamprost 1.9％ 1.9％

[0187] Reference Example 1

[0188] Purification of (Z)-7-((1R,2R,3R)-3-hydroxy-2-((S,E)-3-hydroxyoct-1-en-1-yl)-5-oxocyclopentyl)hept-5-enoic acid (PGE2, dinoprostone)

[0189] The crude purified product (a mixture of PGE2 and PGA2, 35 mg) was dissolved in dichloromethane and purified by chromatography under the following separation conditions. The fraction that did not contain PGA2 under the following analytical conditions was collected to obtain PGE2 (yield: 20 mg, yield: 100%).

[0190] <Separation Conditions>

[0191] Eluent: Hexane: Ethanol = 10:1

[0192] Filler material: CROMATOREX COOH SMB100-10 (trade name, manufactured by Fuji Silicon Chemicals, spherical silica gel (average particle size: 10μm, fine pore size: 10nm))

[0193] Dispensing volume: 1-2 mL / fraction

[0194] The proportions of each isomer before and after separation are shown in Table 9. The proportions of each isomer were calculated based on the area under the curve of the chromatogram obtained under the analytical conditions described below.

[0195] <Analysis Conditions>

[0196] Column: L-Column 2ODS (trade name, manufactured by Chemical Substance Evaluation Institute, inner diameter: 4.6mm, length: 25cm)

[0197] Mobile phase: Methanol: 0.2 vol% aqueous acetic acid = 58:42

[0198] Flow rate: 1 mL per minute

[0199] Detection wavelength: 210nm

[0200] Injection volume: 20μL

[0201] [Table 9]

[0202] Before separation After separation <![CDATA[PGE2]]> 71.2％ 93.6％ <![CDATA[PGA2]]> 13.5％ 1.1％

Claims

1. A method for separating a compound represented by formula (1) or (2) from its geometric isomers, wherein, The geometric isomer is the geometric isomer of the double bond contained in A. The method includes: treating a mixture containing the compound and its geometric isomers using chromatography with acid-functionalized silica gel as the stationary phase. In the formula, P 1 and P 2 Each is an independent protecting group for either a hydrogen atom or a hydroxyl group, R 1 It is a linear or branched C that can be substituted with phenyl groups. 1-6 Alkyl group, where A is C 3-10 Ideonyl, R 2 Hydroxyl group, C 1-3 Alkoxy, mono(C) 1-3 alkyl)amino or di(C) 1-3 alkyl)amino, It can be a single bond or a double bond.

2. The method according to claim 1, wherein, A is 3. The method according to claim 1 or 2, wherein, R 1 for 4. The method according to claim 1 or 2, wherein, P 1 It consists of a hydrogen atom or a 2-tetrahydropyranyl group.

5. The method according to claim 3, wherein, P 1 It consists of a hydrogen atom or a 2-tetrahydropyranyl group.

6. The method according to any one of claims 1, 2, and 5, wherein, The acidic functional group modified silica gel is a silica gel obtained by modification with carboxyl or sulfonyl groups.

7. The method according to claim 3, wherein, The acidic functional group modified silica gel is a silica gel obtained by modification with carboxyl or sulfonyl groups.

8. The method according to claim 4, wherein, The acidic functional group modified silica gel is a silica gel obtained by modification with carboxyl or sulfonyl groups.

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