Method and intermediate for preparing benzoprostacyclin analogs, and benzoprostacyclin analogs prepared therefrom

Abstract

The present invention relates to a process for preparing benzoprostacyclin analogs and intermediates prepared by the process, as well as benzoprostacyclin analogs prepared therefrom. The present invention also relates to cyclopentenone intermediates in racemic or optically active form.

Description

Technical Field

[0001] The present invention relates to novel methods and intermediates for preparing benzoprostacyclin analogs, and benzoprostacyclin analogs prepared therefrom. Background Art

[0002] Since the discovery of prostacyclin, a number of chemically and metabolically stable benzoprostacyclin analogs have been developed as clinically effective antithrombotic agents. Among these, beraprost, developed by Toray Industries Inc., is one of the most notable compounds. Commercially available beraprost sodium is a racemic compound, a mixture of the following four isomers:

[0003] Beraprost sodium

[0004]

[0005] Enantiomerically pure beraprost-314d is the pharmacologically active isomer of beraprost and is currently undergoing clinical trials for the treatment of pulmonary hypertension and vascular diseases.

[0006] The synthesis of beraprost or beraprost-314d has been disclosed in the prior art, such as US5202447, CN106478572, WO2017 / 174439, US8779170, US9334255, US9765047, US8779170, Tetrahedron Lett. 1990, 31, 4493., and Org. Lett. 2017, 19, 1112, but its efficiency is quite low.

[0007] US7345181 discloses a method for synthesizing beraprost with higher efficiency via conjugate addition reaction, as shown in the following Scheme A, which starts from cyclopentenone A1 via conjugate addition to form intermediate A2 (step 1):

[0008] Process A

[0009]

[0010] As shown in Scheme A, intermediate A2 having a 9-keto group is reacted with lithium tri(sec-butyl)borohydride (L-selectride) to obtain intermediate A3 having a 9α-hydroxyl group (Step 2). Intermediate A3 then undergoes an SN2 reaction to convert the 9α-hydroxyl group into a 9β-chloro group to form intermediate A4 (Step 3). Subsequently, the methoxymethyl protecting group of the phenol group and the tert-butyldimethylsilyl protecting group of the hydroxyl group of intermediate A4 are removed (Step 4), and an intramolecular cyclization reaction is performed to obtain intermediate A6 (Step 5).

[0011] However, the method depicted in Scheme A requires at least five steps to form the tricyclic structure of benzoprostacyclin from cyclopentenone A1. Therefore, there is a need to develop and research an efficient conjugate addition method for forming the tricyclic structure of benzoprostacyclin in industry. Summary of the Invention

[0012] The main object of the present invention is to provide a more efficient conjugate addition process for producing benzoprostacyclin analogs and intermediates thereof with higher diastereomeric and enantiomeric purity, thereby forming products with high purity.

[0013] One aspect of the present invention provides a racemic or optically enriched cyclopentenone of Formula 1:

[0014]

[0015] Where P is H or P1; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 is a hydroxyl protecting group.

[0016] Another aspect of the present invention provides a process for preparing a compound of formula (R)-1″ enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess (ee),

[0017]

[0018] Where X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 Aralkyl.

[0019] Another aspect of the present invention provides a method for preparing a benzoprostacyclin analogue of formula 4,

[0020]

[0021] Wherein P is H, P1 or P2; R2 is H or C 1-4 Alkyl; R3 is C 1-7 Alkyl, C 2-7 Alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-4 Alkyl, halogen or trihalomethyl substituted; X is Cl, Br, I or -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 or P2 is a hydroxyl protecting group.

[0022] Another aspect of the present invention provides a method for preparing an optically enriched benzoprostacyclin analog of formula 4a,

[0023]

[0024] Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 and P2 are hydroxyl protecting groups.

[0025] Another aspect of the present invention provides a method for preparing a racemic benzoprostacyclin analog of formula 4b,

[0026]

[0027] Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 and P2 are hydroxyl protecting groups.

[0028] Another aspect of the present invention provides an optically enriched intermediate of formula 4a", wherein Y is Cl, Br or I, which is used to prepare beraprost-314d,

[0029]

[0030] Another aspect of the present invention provides a racemic intermediate of formula 11,15-isomeric 4b", wherein Y is Cl, Br or I, which is used to prepare beraprost and comprises at least four isomers of formula 4b"-1, formula 4b"-2, formula 4b"-3 and formula 4b"-4:

[0031] 11,15-same side 4b"

[0032] DETAILED DESCRIPTION

[0033] definition

[0034] When used in conjunction with the term "comprising" in the claims and / or the specification, the word "a" or "an" may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." Although the present invention supports definitions referring only to alternatives and "and / or," the term "or" is used in the claims to mean "and / or" unless expressly indicated as referring only to alternatives or unless the alternatives are mutually exclusive. Throughout this application, the term "about" is used to indicate a value that includes the inherent error variation resulting from variations in the device, the method used to determine the value, or the study subjects.

[0035] As used in this specification and claims, the terms "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0036] Unless otherwise specified, the term "alkyl" as used herein refers to a straight or branched chain hydrocarbon group containing 1 to 30 carbon atoms, preferably 1 to 20 carbon atoms and most preferably 1 to 12 carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl and the like; or a cyclic saturated hydrocarbon group having 3 to 20 carbon atoms and preferably 3 to 10 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and similar groups.

[0037] As used herein, unless otherwise specified, the term "alkynyl" refers to a straight or branched chain hydrocarbon group containing 2 to 30 carbon atoms, and preferably 3 to 20 carbon atoms, and one or more carbon-carbon triple bonds, such as pentynyl, propynyl, and the like; or a cyclic unsaturated hydrocarbon group having 6 to 20 carbon atoms and one or more carbon-carbon triple bonds.

[0038] As used herein, unless otherwise specified, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 30 carbon atoms, and preferably 6 to 20 carbon atoms, such as phenyl, naphthyl, anthracenyl, phenanthrenyl and the like.

[0039] As used herein, unless otherwise specified, the term "aralkyl" refers to a straight or branched chain hydrocarbon containing 1 to 20 carbon atoms and one or more aryl groups as described above, such as benzyl, benzhydryl, fluorenylmethyl, and the like.

[0040] Each of the above-mentioned alkyl, alkynyl, aryl and aralkyl groups may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, aryloxy, thioalkoxy, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl and carbonyl, or a heterocyclic group selected from the group consisting of pyridyl, thienyl, furyl, imidazolyl, morpholinyl, oxazolinyl, pyridyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl and the like.

[0041] Unless otherwise indicated, the term "hydroxy protecting group" has the meaning conventionally defined in organic synthetic chemistry, i.e., a group capable of protecting a hydroxy group or moiety of a compound from attack by chemical reactions. Examples of hydroxy protecting groups include, but are not limited to, methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, trityl, allyl, benzyl, substituted benzyl, and SiRaRbRc, wherein Ra, Rb, and Rc are each independently unsubstituted or substituted alkyl or unsubstituted or substituted aryl, such as C1-4 alkyl, phenyl, benzyl, substituted phenyl, and substituted benzyl.

[0042] In the descriptions of compounds given throughout this specification, non-wedged bold bonds ( ) or wedge-shaped bold key ( ) means a key that projects above the plane of the paper. Non-wedge-cut keys ( ) or wedge-cut key ( ) means a key that projects below the plane of the paper. Wedge-shaped bold keys ( ) and wedge-cut key ( ) for absolute configuration; non-wedge bold keys ( ) and non-wedge cutting keys ( ) indicates relative configuration and racemic character; and wavy bond ( ) means a key that projects almost half above the plane of the paper and half below the plane of the paper.

[0043] Synthesis of racemic cyclopentenone of formula 1'

[0044] The present invention provides a method for preparing a racemic cyclopentenone of formula 1':

[0045]

[0046] Where P1 is a hydroxyl protecting group, X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 Aralkyl.

[0047] According to the present invention, the compound of formula 1' can be prepared according to the reaction shown in process B. As shown in process B, the compound of formula 5 (wherein X is Cl, Br or I) reacts with lithium diisopropylamide (LDA) to convert it into an organic lithium intermediate via regioselective lithiation, and then formylated with dimethylformamide (DMF) to obtain a compound of formula 6, wherein X is as defined above (step 1). Subsequently, the compound of formula 6 is treated with 2-lithiofuran via a 1,2-addition reaction to obtain a compound of formula 7 (step 2). Thereafter, the compound of formula 7 undergoes a Piancatelli rearrangement (step 3) and isomerization (step 4) to obtain a cyclopentenone of formula 1". Finally, the secondary hydroxyl group of the compound of formula 1" is protected to obtain a compound of formula 1', wherein P1 is a hydroxyl protecting group and X is as defined above (step 5). In some embodiments, a compound of Formula 6, 7, 8, 1" or 1', wherein X is Cl, Br or I, can be subjected to a Suzuki cross-coupling reaction to form a compound of Formula 6, 7, 8, 1" or 1', wherein X is -CH2CH2CH2COOR1, and wherein R1 is C 1-7 Alkyl or C 7-11 Aralkyl,

[0048] Process B

[0049]

[0050] The present invention also provides a racemic or optically enriched compound of Formula 1:

[0051]

[0052] Where P is H or P1; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 is a hydroxyl protecting group.

[0053] Chiral analysis of racemic cyclopentenone of formula 1

[0054] According to the present invention, according to the reaction shown in Scheme C, the racemic cyclopentenone of Formula 1″ can be easily chirally resolved to form a cyclopentenone enriched in the (R)-enantiomer and having high optical purity. As shown in Scheme C, the racemic compound of Formula 1″ (wherein X is Cl, Br or I) is resolved by enantioselective esterification using a first lipase to form a mixture of unreacted alcohol of Formula (S)-1″ and ester of Formula 8 (Step 1). Subsequently, the unreacted alcohol of Formula (S)-1″ can be easily removed, for example, by separating it from the mixture through column purification, and then continuing with the Mitsunobu reaction to obtain the corresponding compound of Formula 8. Alternatively, the mixture can be directly subjected to the Mitsunobu reaction (step 2) to convert the unreacted alcohol of formula (S)-1″ into the compound of formula 8. Finally, the compound of formula 8 is deacylated by using a chemical hydrolysis reaction or an enzymatic cleavage reaction to form a compound of formula (R)-1″ that is enriched in the (R)-enantiomer and has high optical purity.

[0055] Process C

[0056]

[0057] In step 1 of Scheme C, the enantioselective esterification of a cyclopentenone of formula 1″ is carried out with an acyl donor of formula D (wherein R4 and R5 are independently H or C 1-6 alkyl) in the presence of a first lipase, wherein the acyl donor preferentially reacts with the (R) form of the cyclopentenone, thereby producing a mixture consisting essentially of a photoactive ester of formula 8 and an unreacted alcohol of formula (S)-1″,

[0058]

[0059] In some embodiments, a suitable first lipase is commercially available and can be derived from Achromobacter sp., Candida cylindracea, Alcaligenes sp., Candida antarcitica, Pseudomonas cepacia, Burkholderia cepacian, Pseudomonas stutzri, or a mixture thereof, preferably Alcaligenes sp., Candida cylindracea, Candida antarcitica, Burkholderia cepacian, Pseudomonas stutzri, or a mixture thereof, and most preferably Burkholderia cepacian. Suitable acyl donors include, but are not limited to, vinyl acetate, isopropyl acetate, vinyl valerate, isopropyl valerate, vinyl butyrate, isopropyl butyrate, and mixtures thereof, with vinyl acetate being particularly preferred. In addition, the enantioselective esterification reaction can be carried out in a single organic solvent or a mixture of organic solvents, such as hexane, cyclohexane, toluene, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, ether, isopropyl ether, methyl isopropyl ether, tert-butyl methyl ether and mixtures thereof. Suitable reaction temperatures are in the range of about 5° C. to about 50° C., preferably at ambient temperature.

[0060] Step 2 of Process C relates to the Mitsunobu reaction. Due to the different polarities of alcohols and esters, the unreacted alcohol of Formula (S)-1″ can be easily separated from the mixture obtained in Step 1 of Process C by column purification and subjected to the Mitsunobu reaction to form the ester of Formula 8. In some embodiments, it is not necessary to separate the compounds of Formula (S)-1″ and Formula 8 from the mixture, and the mixture can be directly subjected to the Mitsunobu reaction to convert the unreacted alcohol of Formula (S)-1″ into the ester of Formula 8. In this step, almost 100% of the alcohol of Formula (S)-1″ in the mixture can be converted into the ester of Formula 8.

[0061] In the Mitsunobu reaction, an acyloxy donor of the formula R4COOH (where R4 is H or C 1-6The unreacted alcohol of formula (S)-1″ is treated with an alkyl) to convert it into a compound of formula 8 in the presence of a dialkyl azodicarboxylate and a trialkylphosphine / triarylphosphine in a suitable solvent. Suitable dialkyl azodicarboxylates include, but are not limited to, dimethyl azodicarboxylate (DMAD), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DTBAD), dibenzyl azodicarboxylate (DBAD), bistrichloroethyl azodicarboxylate (BTCEAD), di-p-chlorobenzyl azodicarboxylate (DCAD), di-4-(2-methyl-2-oxo-4-oxo-3-yl)azodicarboxylate (DCTAD), di-4-(2-methyl-2-oxo-3 ... Nitrobenzyl ester (DNAD), dicyclopentyl azodicarboxylate (DCpAD), and mixtures thereof; and preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate and mixtures thereof. Suitable trialkylphosphines / triarylphosphines include, but are not limited to, tri-n-butylphosphine, triphenylphosphine and mixtures thereof; and preferably triphenylphosphine. Suitable solvents in the Mitsunobu reaction include, but are not limited to, tetrahydrofuran, toluene, benzene, dimethylformamide, diethyl ether, acetonitrile, dichloromethane and mixtures thereof. The Mitsunobu reaction is preferably carried out at a suitable temperature in the range of about -30°C to about 70°C, preferably at ambient temperature.

[0062] Step 3 of Process C is about a deacylation reaction, such as a chemical hydrolysis reaction or an enzymatic cleavage reaction. In some embodiments, the deacylation reaction is a chemical hydrolysis reaction using an acid catalyst in an alcohol system. Suitable acid catalysts include, but are not limited to, phosphoric acid, p-toluenesulfonic acid, hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, and mixtures thereof. Suitable alcohols in the alcohol system include, but are not limited to, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and mixtures thereof. For example, the chemical hydrolysis reaction of the compound of Formula 8 is carried out in the presence of sulfuric acid and methanol.

[0063] In some embodiments, the deacylation reaction in step 3 of Scheme C is an enzymatic cleavage reaction. The enzymatic cleavage reaction can be carried out in a suitable organic solvent or aqueous system in the presence of a second lipase at an appropriate temperature to obtain a compound of formula (R)-1". Suitable second lipases are commercially available and can be derived from Achromobacter, Alcaligenes, Candida antarctica, Pseudomonas cepacia, Pseudomonas stutzeri, Pseudomonas, or a mixture thereof; preferably Achromobacter, Alcaligenes, Candida antarctica, Pseudomonas, or a mixture thereof; and most preferably Candida antarctica.

[0064] According to the present invention, the deacylation reaction is monitored for the purpose of the optical purity of the resulting compound of formula (R)-1″. In some embodiments, the deacylation is monitored by HPLC using a chiral column, and is preferably stopped by removing the second lipase when the optical purity of the resulting compound decreases to about 95% ee, preferably about 99% ee, and more preferably about 99.9% ee. In some embodiments, the unreacted ester of formula 8 and its enantiomers can be removed after the deacylation reaction, such as by column chromatography. According to the present invention, the optical activity of the resulting compound of formula (R)-1″ is at least about 95% ee, preferably at least about 99% ee, and optimally at least about 99.9% ee.

[0065] Therefore, the present invention provides a process for preparing a compound of formula (R)-1″ enriched in the (R)-enantiomer and having an optical purity of at least 95% ee,

[0066]

[0067] Wherein X is Cl, Br or I, the method comprises the following steps:

[0068] (1) Enantioselective (R)-esterification of the compound of formula 1″:

[0069]

[0070] The esterification uses an acyl donor of formula D:

[0071]

[0072] Wherein R4 and R5 are independently H or C 1-6 an alkyl group, and a first lipase to form a mixture of (S)-alcohol and (R)-ester;

[0073] (2) optionally removing the (S)-alcohol; and

[0074] (3) Deacylation of the (R)-ester.

[0075] In some embodiments, a compound of formula (R)-1″, wherein X is Cl, Br, or I, can be subjected to a Suzuki cross-coupling reaction to form a compound of formula (R)-1″, wherein X is —CH 2 CH 2 CH 2 COOR 1 , and wherein R 1 is C 1-7 Alkyl or C 7-11 Aralkyl.

[0076] Preparation of Benzoprostacyclin Analogs of Formula 4

[0077] The present invention also provides a method for preparing a benzoprostacyclin analogue of formula 4:

[0078]

[0079] Wherein P is H, P1 or P2; R2 is H or C 1-4 Alkyl; R3 is C 1-7 Alkyl, C 2-7 Alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-4 Alkyl, halogen or trihalomethyl substituted; X is Cl, Br, I or -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 and P2 are hydroxyl protecting groups.

[0080] According to the present invention, the compound of formula 4 can be prepared according to the reaction shown in Scheme D. As shown in Scheme D, the synthesis of the compound of formula 4 starts with the compound of formula 1', wherein step 1 is about 1,4-addition reaction, step 2 is about reduction reaction, and step 3 is about intramolecular cyclization reaction.

[0081] Process D

[0082]

[0083] The details described subsequently can be used for any of the methods for preparing the benzoprostacyclin analogs of the present invention. In step 1 of Scheme D, a cyclopentenone of formula 2 (wherein P, X, R2 and R3 are as defined above) is prepared by coupling a cyclopentenone of formula 1' (wherein P1 and X are as defined above) with an ω side chain unit derived from a cuprate of a compound of formula L1, formula L2 or formula L3 (wherein Y is Cl, Br or I; P2, R2 and R3 are as defined above). In some embodiments, the reaction is carried out at a temperature in the range of about -100°C to about -20°C, preferably at about -80°C to about -40°C.

[0084]

[0085] Step 2 of Scheme D is about a ketone reduction reaction. In step 2, the C9-carbonyl group of the compound of Formula 2 is reduced to an α-hydroxy group using a reducing agent. Suitable reducing agents include, but are not limited to, sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium trialkylborohydride, potassium trialkylborohydride, sodium trialkylborohydride, and mixtures thereof; preferably, lithium tri-secondary butylborohydride (L-selectride), sodium tri-secondary butylborohydride (N-selectride), potassium tri-secondary butylborohydride (K-selectride), lithium tripentylborohydride, potassium tripentylborohydride, and mixtures thereof; and in this step, lithium tri-secondary butylborohydride (L-selectride) is more preferably used as a reducing agent.

[0086] As shown in step 3 of Scheme D, a benzoprostacyclin analog of Formula 4 is prepared by an intramolecular cyclization reaction of a compound of Formula 3 in the presence of suitable basic conditions. In some embodiments, the intramolecular cyclization reaction is achieved by using a suitable base in a suitable solvent at a temperature ranging from about 0°C to about 120°C. Suitable bases include, but are not limited to, sodium hydride, potassium hydride, lithium hydride, potassium tert-butoxide, butyl lithium, and mixtures thereof. Suitable solvents include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dimethylformamide, N,N'-dimethylpropylene urea, 1,2-dimethoxypropane, toluene, and mixtures thereof.

[0087] Compared to the conventional conjugate addition reaction shown in Scheme A, which requires five (5) steps to form the tricyclic structure of benzoprostacyclin, the method of the present invention requires only three (3) steps to form the tricyclic structure of benzoprostacyclin. The method of the present invention is a more efficient conjugate addition method.

[0088] In some embodiments, the obtained compound of Formula 2, 3, or 4 may be subjected to a deprotection reaction to remove the hydroxyl protecting group.

[0089] In some embodiments, a Suzuki cross-coupling reaction can be performed on a compound of Formula 2, 3, or 4, wherein X is Cl, Br, or I, to form a compound of Formula 2, 3, or 4, wherein X is -CH2CH2CH2COOR1, and wherein R1 is C 1-7 Alkyl or C 7-11 The Suzuki cross-coupling reaction is preferably carried out in the presence of an alkyl borane of the formula BR2-CH2CH2CH2COOR1 (wherein R is an alkyl group), which is prepared by 3-butenoic acid alkyl (R1) ester (wherein R1 is C 1-7 Alkyl or C 7-11The Suzuki cross-coupling reaction can also be carried out in the presence of a palladium catalyst, a ligand, and a base at a temperature ranging from about 50° C. to about 60° C. under nitrogen or argon. Suitable palladium catalysts include, but are not limited to, Pd(PPh3)4, Pd(dppf)2Cl2-DCM, Pd(dppf)2Cl2, Pd(OAc)2, Pd2(dba)2, bis(eta3-allyl-mu-chloropalladium(II), and mixtures thereof. In some embodiments, the palladium catalyst can be treated with a ligand to form a reactive palladium complex for promoting the cross-coupling reaction. Suitable ligands include, but are not limited to, PPh3, AsPh3, P(OMe)3, (n-Bu)3P, dppe, dppp, dicyclohexyl-(2,6 -dimethoxybiphenyl-2-yl)phosphine and mixtures thereof. Suitable bases can increase the reactivity of alkylboranes toward forming Pd halide complexes to promote the cross-coupling rate, including but not limited to Li2CO3, Na2CO3, K2CO3, Cs2CO3, NaOMe, K3PO4, t-BuON, t-BuOK, K3PO4, NaOH, and mixtures thereof. In some embodiments, the Suzuki cross-coupling reaction is carried out in the presence of Pd(dppf)2Cl2-DCM, AsPh3, and K3PO4 at 60°C in tetrahydrofuran solvent.

[0090] Therefore, the present invention provides a method for preparing a compound of formula 4:

[0091]

[0092] Wherein P is H, P1 or P2; R2 is H or C 1-4 Alkyl; R3 is C 1-7 Alkyl, C 2-7 Alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-4 Alkyl, halogen or trihalomethyl substituted; X is Cl, Br, I or -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 Aralkyl; and P1 and P2 are hydroxyl protecting groups, the method comprising the following steps:

[0093] (1) making the compound of formula 1':

[0094]

[0095] wherein P1 and X are as defined above, reacted with a cuprate derived from a compound of formula L1, formula L2 or formula L3:

[0096]

[0097] wherein Y is Cl, Br or I; P2, R2 and R3 are as defined above, to form a compound of formula 2:

[0098]

[0099] wherein P, X, R2 and R3 are as defined above;

[0100] (2) reducing the ketone of the compound of formula 2 to form a compound of formula 3:

[0101]

[0102] wherein P, X, R2 and R3 are as defined above;

[0103] (3) performing an intramolecular cyclization reaction on the compound of formula 3 to form a compound of formula 4:

[0104]

[0105] wherein P, X, R2 and R3 are as defined above;

[0106] (4) optionally performing a deprotection reaction to remove the hydroxy protecting group; and

[0107] (5) Optionally performing a Suzuki cross-coupling reaction of the compound of Formula 2, 3 or 4, wherein X is Cl, Br or I, to form a compound of Formula 2, 3 or 4, wherein X is -CH2CH2CH2COOR1 and R1 is as defined above.

[0108] Synthetic route for optically enriched benzoprostacyclin analogs of formula 4a

[0109] The present invention further provides a method for preparing an optically enriched compound of formula 4a:

[0110]

[0111] Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 and P2 are hydroxyl protecting groups.

[0112] As depicted in Scheme E, the synthesis of the compound of Formula 4a is similar to the synthesis of the compound of Formula 4 shown in Scheme D. The synthesis of the compound of Formula 4a begins with an optically enriched compound of Formula (R)-1′, wherein P1 and X are as defined above; and 1a 、Formula L 2a Or L 3a Optically enriched compounds,

[0113]

[0114] Wherein Y is Cl, Br or I; and P2 is a hydroxyl protecting group, Scheme E

[0115]

[0116] In step 1 of process E, an optically enriched compound of formula (R)-1′ is reacted with a compound derived from formula L 1a 、L 2a Or L 3a The compound of formula 2a is prepared by coupling the ω side chain unit of the cuprate of the optically enriched compound of formula 2a. Subsequently, the compound of formula 2a is subjected to a reduction reaction (step 2) and an intramolecular cyclization reaction (step 3) to obtain a compound of formula 4a, wherein X and P are as defined above.

[0117] In some embodiments, the obtained compound of formula 2a, 3a or 4a can be subjected to a deprotection reaction to remove the hydroxy protecting group. In some embodiments, the compound of formula 2a, 3a or 4a (wherein X is Cl, Br or I) can be converted to the compound of formula 2a, 3a or 4a via a Suzuki cross-coupling reaction, wherein X is -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 Aralkyl.

[0118] Therefore, the present invention provides a method for preparing an optically enriched compound of formula 4a:

[0119]

[0120] Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 Aralkyl; and P1 and P2 are hydroxyl protecting groups;

[0121] The method comprises the following steps:

[0122] (1) making an optically enriched compound of formula (R)-1':

[0123]

[0124] wherein P1 and X are as defined above, and are derived from the formula L 1a 、Formula L 2a Or L 3a Cuprate reactions of optically enriched compounds:

[0125]

[0126] wherein Y is Cl, Br or I; and P2 is a hydroxy protecting group, to form a compound of formula 2a:

[0127]

[0128] wherein P and X are as defined above;

[0129] (2) reducing the ketone of the compound of formula 2a to form a compound of formula 3a:

[0130]

[0131] wherein P and X are as defined above;

[0132] (3) performing an intramolecular cyclization reaction on the compound of formula 3a to form a compound of formula 4a:

[0133]

[0134] wherein P and X are as defined above;

[0135] (4) optionally performing a deprotection reaction to remove the hydroxy protecting group; and

[0136] (5) optionally performing a Suzuki cross-coupling reaction of the compound of Formula 2a, 3a or 4a, wherein X is Cl, Br or I, to form the compound of Formula 2a, 3a or 4a, wherein X is -CH2CH2CH2COOR1 and R1 is as defined above.

[0137] Synthetic route of benzoprostacyclin analogs of formula 4b

[0138] The present invention further provides a method for preparing a compound of formula 4b:

[0139]

[0140] Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 aralkyl; and P1 and P2 are hydroxyl protecting groups.

[0141] Compounds of formula 4b can be prepared according to the reaction shown in Scheme F:

[0142] Process F

[0143]

[0144] The synthetic route of the compound of formula 4b shown in Scheme F is also similar to the reaction depicted in Scheme D or E. In step 1 of Scheme F, a racemic cyclopentenone of formula 1′ is reacted with a compound comprising formula L 1b 、Formula L 2b Or L 3b Cuprates formed from racemic and diastereomeric mixtures of compounds,

[0145]

[0146] wherein Y is Cl, Br or I, and P2 is as defined above, reacts via a coupling reaction to form a compound of formula 2b (step 1). Thereafter, the compound of formula 2b is subjected to a reduction reaction (step 2) and an intramolecular cyclization reaction (step 3) to form a mixture or composition comprising a compound of formula 4b, a compound of formula 11,15-homologous side 4b and a compound of formula 11,15-trans-side 4b, wherein P and X are as defined above,

[0147]

[0148] Generally, the undesired 11,15-trans isomer of the compound of formula 4b can be obtained in about 50% amount by treating the racemic cyclopentenone of formula 1' with racemic cuprate.

[0149] However, a surprising result is that the coupling reaction of the present invention has a high selectivity for forming the 11,15-syn isomer of the compound of Formula 4b, and thus, the ratio of the compound of Formula 11,15-syn 4b to the compound of Formula 11,15-trans 4b is observed to be about 70% or more and about 30% or less, as detected by HPLC. The surprising result shows that the 11(R)-enantiomer of racemic cyclopentenone 1' and the 15(S)-enantiomer of racemic cuprate, or the 11(S)-enantiomer of racemic cyclopentenone 1' and the 15(R)-enantiomer of racemic cuprate, are a matching pair, and therefore, the coupling reaction thereof tends to form the 11,15-syn isomer. In contrast, the 11(R)-enantiomer of racemic cyclopentenone 1' and the 15(R)-enantiomer of racemic cuprate, or the 11(S)-enantiomer of racemic cyclopentenone 1' and the 15(S)-enantiomer of racemic cuprate, are mismatched pairs, and therefore their coupling reactions tend not to produce the 11,15-trans isomer. According to the present invention, the undesired 11,15-trans isomer (also known as the 15-epimer) can be separated by column chromatography or crystallization.

[0150] In some embodiments, the compound of Formula 2b, 3b or 4b, wherein P is H, can be obtained by removing the protecting group of the compound of Formula 2b, 3b or 4b, wherein P is a hydroxy protecting group.

[0151] In some embodiments, compounds of Formula 2b, 3b, or 4b, wherein X is Cl, Br, or I, can be converted to compounds of Formula 2b, 3b, or 4b, wherein X is -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 Aralkyl.

[0152] Therefore, the present invention provides a method for preparing the racemic compound of formula 4b:

[0153]

[0154] Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 Aralkyl; and P1 and P2 are hydroxyl protecting groups, the method comprising the following steps:

[0155] (1) making a racemic compound of formula 1':

[0156]

[0157] wherein P1 and X are as defined above, and are derived from the formula L 1b 、Formula L 2b Or L 3b Cuprate reaction of racemic and diastereomeric mixtures of compounds:

[0158]

[0159] wherein Y is Cl, Br or I; P2 is as defined above, to form a compound of formula 2b:

[0160]

[0161] wherein P and X are as defined above;

[0162] (2) reducing the ketone of the compound of formula 2b to form a compound of formula 3b:

[0163]

[0164] wherein P and X are as defined above;

[0165] (3) performing an intramolecular cyclization reaction on the compound of formula 3b to form a compound of formula 4b:

[0166]

[0167] wherein P and X are as defined above;

[0168] (4) optionally performing a deprotection reaction to remove the hydroxy protecting group; and

[0169] (5) optionally performing a Suzuki cross-coupling reaction of the compound of Formula 2b, 3b or 4b, wherein X is Cl, Br or I, to form a compound of Formula 2b, 3b or 4b, wherein X is -CH2CH2CH2COOR1 and R1 is as defined above.

[0170] The present invention further provides a racemic intermediate of formula 11,15-isomorphic 4b" wherein Y is Cl, Br or I, which is used to prepare beraprost

[0171] 11,15-ipsilateral 4b".

[0172] According to the present invention, the racemic intermediate of formula 11,15-homologous 4b" comprises at least four 11,15-homologous isomers of formula 4b"-1, formula 4b"-2, formula 4b"-3 and formula 4b"-4:

[0173]

[0174] wherein Y is Cl, Br or I.

[0175] The compound of formula 11,15-syn-4b" has excellent crystallinity and can therefore be easily purified by crystallization to remove the undesired 11,15-trans isomer. As a result, the amount of the undesired 11,15-trans isomer can be reduced to no more than about 5%, 1%, or 0.1% in the resulting intermediate mixture.

[0176] The present invention also provides novel optically enriched intermediates of formula 4a", wherein Y is Cl, Br or I, which are used to prepare beraprost-314d.

[0177]

[0178] According to the present invention, the compound of Formula 4a″ has excellent crystallinity and can therefore be easily crystallized by a crystallization method performed from a polar / non-polar solvent mixture. Suitable polar / non-polar solvent systems include, but are not limited to, ethyl acetate / n-hexane, ethyl acetate / n-heptane, MTBE / n-heptane, and iPrOAc / n-heptane mixtures. In addition, the impurities generated by the aforementioned reaction can be reduced to no more than about 5%, 1%, or 0.1% by repeated crystallization methods to obtain a high-purity compound.

[0179] All compounds and / or methods disclosed and claimed herein can be made and executed in accordance with the present invention without undue experimentation. Although the compounds and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied to the compositions and / or methods and to the steps or sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the present invention. All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the present invention as defined by the appended claims.

[0180] Examples

[0181] Example 1

[0182] (3-Bromo-2-fluorophenyl)(furan-2-yl)methanol

[0183]

[0184] To a solution of diisopropylamine (43.3 g, 0.43 mol) in anhydrous THF (220 mL) at -50°C under nitrogen was added dropwise 1.6 M (270 mL, 0.43 mol) of n-BuLi in THF. The reaction mixture was allowed to warm to -10°C. After one hour, the reaction mixture was cooled to -70°C. A solution of 1-bromo-2-fluorobenzene (50.0 g, 0.29 mol) in anhydrous THF (200 mL) was slowly added via a dropping funnel, maintaining the reaction temperature between -70°C and -65°C. The reaction mixture was then stirred at -70°C for 30 minutes. A solution of furfural (28.8 g, 0.30 mol) in anhydrous THF (29 mL) was then slowly added via a dropping funnel, maintaining the reaction temperature between -70°C and -65°C. The reaction was confirmed to be complete by TLC monitoring. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (400 mL). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum to give 78 g of the crude title compound.

[0185] Example 2

[0186] 5-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone

[0187]

[0188] To a solution of (2-bromo-3-fluorophenyl)(furan-2-yl)methanol (78 g, 0.29 mol, from Example 1) in a mixture of THF / H2O (780 mL, THF / H2O=8 / 1) was added p-TsOH-H2O (54.95 g, 0.29 mol), and the reaction mixture was stirred at 60°C. After the reaction was complete, the mixture was quenched with 10% aqueous NaHCO3 solution (800 mL), the reaction mixture was phase-separated, and the aqueous layer was extracted with ethyl acetate (500 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum to give 82.5 g of the crude title compound.

[0189] Example 3

[0190] 2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone

[0191]

[0192] To a solution of crude 5-(3-bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (82.5 g, from Example 2) in toluene (825 mL) was added triethylamine (30.9 g, 0.305 mol) and chloral hydrate (5.05 g, 30.5 mmol) at room temperature. The reaction was confirmed to be complete by TLC monitoring. The mixture was washed with 10% NaCl. (水溶液) The mixture was washed with 4% paraformaldehyde (800 mL) and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a gradient eluent of a mixture of hexane and ethyl acetate. The yield of the title compound was 28.81 g (45% over 3 steps).

[0193] 1 H-NMR (400MHz, CDCl3): δ7.813-7.824(m,1H),7.716-7.756(m,1H),7.512-7.552(m,1H) ,7.036-7.079(m,1H),5.099-5.114(m,1H),2.931-2.993(m,1H),2.455-2.507(dd,1H).

[0194] Example 4

[0195] 2-(3-Bromo-2-fluorophenyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-enone

[0196]

[0197] 2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (51.0 g, 143.6 mmol, from Example 3) was dissolved in dichloromethane (510 mL). Acetic acid (740 mg, 9.4 mmol) and dihydropyridine (24 g, 285.3 mmol) were then added. The reaction mixture was stirred at room temperature. The reaction was confirmed to be complete by TLC monitoring. The reaction mixture was dried over a medium temperature with 10% NaHCO 3(水溶液) The reaction mixture was quenched with 4% paraformaldehyde (510 mL) and the phases were separated. The organic layer was collected and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum to obtain the crude compound. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 52 g (79%).

[0198] 1 H-NMR (400MHz, CDCl3): δ7.891-7.944(d,1H),7.746-7.791(m,1H),7.507-7.544(t,1H),7.036-7.075(t,1H),5.019-5.050(m,1H) ),4.817-4.884(m,1H),3.870-3.960(m,1H),3.549-3.604(m,1H),2.875-2.985(m,1H),2.489-2.667(m,1H),1.539-1.862(m,6H).

[0199] Example 5

[0200] (R)-3-(3-bromo-2-fluorophenyl)-4-oxocyclopent-2-en-1-yl acetate

[0201]

[0202] 2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (25 g, 92.6 mmol, from Example 3) was diluted with toluene (250 ml) and then lipase-SL (2.5 g) and vinyl acetate (25 g) were added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was monitored for completion by chiral HPLC column. Lipase-SL was filtered from the reaction mixture, and the filtrate was concentrated to give a crude mixture (31.25 g).

[0203] Subsequently, triphenylphosphine (15.18 g, 57.8 mmol) and acetic acid (3.47 g, 57.8 mmol) were added to toluene (300 mL) containing the crude mixture. The reaction mixture was stirred at room temperature until triphenylphosphine was dissolved in the reaction mixture. Diisopropyl azodicarboxylate was then slowly added thereto. The reaction was confirmed to be complete by TLC monitoring. The reaction solvent was further removed under vacuum and the residue was suspended with a mixture of ethyl acetate (150 mL) and n-hexane (450 mL). The solid was filtered out and the filtrate was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 26.6 g (92%).

[0204] 1 H-NMR (400MHz, CDCl3): δ7.809-7.819(m,1H),7.736-7.769(m,1H),7.497-7.537(m,1H),7.02 0-7.060(m,1H),5.883-5.910(m,1H),2.964-3.028(m,1H),2.477-2.528(m,1H),2.090(s,3H).

[0205] Example 6

[0206] (R)-2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone

[0207]

[0208] Lipase-435 (3.0 g) was added to a solution of (R)-3-(3-bromo-2-fluorophenyl)-4-oxocyclopent-2-en-1-yl acetate (15 g, 48 mmol, from Example 5) in methyl isobutyl ketone (MIBK, 150 mL). The reaction mixture was stirred at room temperature for four hours. Lipase-435 was filtered from the reaction mixture, and the filtrate was concentrated to obtain the crude compound. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 10.65 g (83%).

[0209] 1 H-NMR (400MHz, CDCl3): δ7.816-7.828(m,1H),7.707-7.747(m,1H),7.509-7.549(m,1H) ),7.035-7.075(m,1H),5.103-5.118(m,1H),2.934-2.995(m,1H),2.458-2.510(m,1H).

[0210] Example 7

[0211] (4R)-2-(3-Bromo-2-fluorophenyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-enone

[0212]

[0213] (R)-2-(3-bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (10.0 g, 37 mmol, from Example 6) was dissolved in dichloromethane (100 mL). Acetic acid (145 mg, 1.85 mmol) and dihydropyridine (4.67 g, 55.5 mmol) were then added. The reaction mixture was stirred at room temperature. The reaction was confirmed to be complete by TLC monitoring. The reaction mixture was dried over a 10% NaHCO 3(水溶液) The reaction mixture was quenched with 100 mL of ethyl acetate and the phases were separated. The organic layer was collected and dried over anhydrous NaSO. The solid was filtered off and the organic solvent was evaporated under vacuum to give the crude compound. The crude product was purified by silica gel chromatography using a gradient eluent of hexane and ethyl acetate. The yield of the title compound was 10.99 g (83%).

[0214] 1 H-NMR (400MHz, CDCl3): δ7.873-7.927(m,1H),7.715-7.771(m,1H),7.503-7.524(m,1H),7.016-7.055(m,1H),5.001-5.030(m,1H),4.790 -4.868(m,1H),3.853-3.994(m,1H),3.532-3.585(m,1H),2.856-2.965(td,1H,J=6.4,18.8Hz),2.477-2.649(m,1H),1.521-1.844(m,6H).

[0215] Example 8

[0216] (R)-2-(3-Bromo-2-fluorophenyl)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone

[0217]

[0218] (R)-2-(3-bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (1.5 g, 5.53 mmol, from Example 6) was dissolved in dichloromethane (15 mL). Imidazole (0.75 g, 11.01 mmol) and tert-butyldimethylsilyl chloride (1.25 g, 8.23 mmol) were then added. The reaction mixture was stirred at room temperature. The reaction was confirmed to be complete by TLC monitoring. The reaction mixture was quenched with 10% NaHCO 3(水溶液) The reaction mixture was quenched with 100 mL of ethyl acetate and the phases were separated. The organic layer was collected and dried over anhydrous NaSO. The solid was filtered off and the organic solvent was evaporated under vacuum to give the crude compound. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 1.64 g (77%).

[0219] 1 H-NMR (400MHz, CDCl3): δ7.741-7.787(m,2H),7.509-7.550(m,1H),7.042-7.084(m,1H),5.05 1-5.078(m,1H),2.880-2.941(m,1H),2.438-2.489(m,1H),0.931(s,9H),0.157-0.176(m,6H).

[0220] Example 9

[0221] (R)-4-(3-(3-((tert-Butyldimethylsilyl)oxy-5-oxocyclo-1-en-1-yl)-2-fluorophenyl)butanoic acid methyl ester

[0222]

[0223] To a solution of methyl 3-butenoate (261 mg, 2.60 mmol) in anhydrous THF (2.6 mL) was added dropwise 0.5 M (5.2 mL, 2.60 mmol) of 9-BBN in THF at 0°C under nitrogen. The reaction mixture was allowed to warm to room temperature and stirred for three hours. Subsequently, the solution was transferred to a mixture of (R)-2-(3-bromo-2-fluorophenyl)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone (500 mg, 1.28 mmol from Example 8), Ph As (40 mg, 0.13 mmol), K PO (827 mg, 3.90 mmol) and PdCl (dppf) (95 mg, 0.13 mmol) in anhydrous THF (5 ml) under nitrogen. The reaction mixture was stirred at 60°C for three hours. The mixture was quenched with hydrogen peroxide (30% aqueous solution, 7.8 mmol) and stirred at 0°C for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 211 mg (40%).

[0224] 1 H-NMR (400MHz, CDCl3): δ7.688-7.699(m,1H),7.591-7.627(m,1H),7.150-7.184(m,1H),7.068-7.106(m,1H),5.037-5.064(m,1H),3.661(s,3H) ),2.867-2.927(m,1H),2.685-2.724(m,2H),2.429-2.480(m,1H),2.329 -2.366(m,2H),1.933-1.990(m,2H),0.931(s,9H),0.050-0.166(m,6H).

[0225] Example 10

[0226] (2SR,3RS,4RS)-2-(3-Bromo-2-fluorophenyl)-3-((E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentenone

[0227]

[0228] To a solution of (E)-tert-butyl((1-iodo-4-methyloct-1-en-6-yn-3-yl)oxy)dimethylsilane (130.0 g, 343.6 mmol) in anhydrous diethyl ether (1000 mL) was added dropwise 1.9 M (360 mL, 684 mmol) of tert-butyl lithium in pentane at -70°C and stirred at the same temperature for 2 hours. A mixture of copper iodide (65.3 g, 342.8 mmol) and n-tributylphosphine (180.7 g, 893.1 mmol) in THF (1.3 L) was cooled to -70°C and added to the reaction flask. After 1 hour, a solution of 2-(3-bromo-2-fluorophenyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-enone (91.5 g, 257.6 mmol, from Example 4) in 90 ml of THF was added thereto at -70 ° C. The reaction mixture was quenched with a saturated aqueous ammonium chloride solution (4.5 L) containing ammonium hydroxide (0.5 L). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum to give 426.6 g of the crude title compound.

[0229] Example 11

[0230] (1SR,2SR,3RS,4RS)-2-(3-Bromo-2-fluorophenyl)-3-((E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentanol

[0231]

[0232] (2SR,3RS,4RS)-2-(3-bromo-2-fluorophenyl)-3-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentenone (426.6 g, 699.7 mmol, crude product from Example 10) was diluted with anhydrous THF (4.3 L), then the solution was cooled to -70°C and 1.0 M L-selectride (258 mL, 258 mol) in hexanes was added at -70°C. After addition, the reaction was checked by TLC. The mixture was quenched with hydrogen peroxide (30% aqueous solution, 100 mL) and stirred at 0°C for 30 minutes. The reaction mixture was phase separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 99.8 g (64% over 2 steps from Example 10).

[0233] 1 H-NMR (400MHz, CDCl3): δ7.422(m,1H),7.258-7.338(m,1H),6.991-7.021(m,1H),5.364-5.553(m,2H),4.702-4.747(m,1H),3.854-4.285( m,4H),3.493-3.519(m,1H),3.116-3.221(m,2H),2.395-2.564(m,1H) ,1.541-2.110(m,14H),0.647-0.910(m,12H),-0.271~-0.026(m,6H).

[0234] Example 12

[0235] (((E)-1-((1RS,2RS,3aSR,8bSR)-5-bromo-2-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl)-4-methyloct-1-en-6-yn-3-yl)oxy)(tert-butyl)dimethylsilane

[0236]

[0237] To a solution of (1SR,2SR,3RS,4RS)-2-(3-bromo-2-fluorophenyl)-3-((E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentanol (98.3 g, 166.7 mmol, from Example 11) in toluene (5.45 L) and DMPU (115.4 g, 900.3 mmol) at 60° C. under nitrogen was added t-BuOK (64.3 g, 573.1 mmol). Completion of the reaction was confirmed by TLC monitoring. The mixture was washed with saturated aqueous ammonium chloride solution (1000 mL) and dried over anhydrous NaSO. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 79.2 g (83%).

[0238] 1 H-NMR (400MHz, CDCl3): δ7.259(m,1H),7.054(m,1H),6.686-6.714(m,1H),5. 521-5.655(m,2H),5.262-5.294(m,1H),4.603-4.662(m,1H),4.049-4.184(m, 2H),3.837-3.912(m,1H),3.411-3.689(m,2H),2.441-2.781(m,2H),1.947-2. 242(m,3H),1.209-1.785(m,10H),0.833-0.939(m,12H),0.101-0.070(m,6H).

[0239] Example 13

[0240] (1RS,2RS,3aSR,8bSR)-5-Bromo-1-((3SR,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-ol

[0241]

[0242] (((E)-1-((1RS,2RS,3aSR,8bSR)-5-bromo-2-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl)-4-methyloct-1-en-6-yn-3-yl)oxy)(tert-butyl)dimethylsilane (75.8 g, 128.5 mmol, from Example 12) was diluted with acetonitrile (758 mL), and a 3N aqueous HCl solution (76 mL) was added thereto. The reactants were stirred at room temperature and the progress of the reaction was checked by TLC. After the reaction was completed, the mixture was neutralized to pH 7-8 with a 10% aqueous NaHCO solution (760 mL) and then concentrated to remove the acetonitrile. The residue was extracted with ethyl acetate and the organic layer was dried over anhydrous NaSO. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title 11,15-homoisomer was 26.3 g (52%) and the yield of the 11,15-transisomer (15-epimer) was 11.1 g (22%). The compound was recrystallized from a solvent mixture of ethyl acetate and n-hexane to obtain a crystalline compound (22.83 g). The crystalline compound was characterized by an X-ray powder diffraction (XRPD) pattern with peaks at 6.7 ± 0.2°, 15.4 ± 0.2°, 19.5 ± 0.2°, 19.9 ± 0.2°, and 21.5 ± 0.2° 2θ.

[0243] 1 H-NMR (400MHz, CDCl3): δ7.259-7.294(m,1H),6.992-7.032(m,1H),6.698-6.7 30(m,1H),5.563-5.706(m,2H),5.186-5.235(m,1H),4.029-4.194(m,1H),3.92 4(m,1H),3.505-3.544(m,1H),2.655-2.722(m,1H),2.426-2.482(m,1H),2.235 -2.267(m,2H),2.013-2.101(m,1H),1.734-1.825(m,4H),0.977-1.019(m,3H).

[0244] Example 14

[0245] Methyl 4-((1RS,2RS,3aSR,8bSR)-2-hydroxy-1-((3SR,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoate

[0246]

[0247] To a solution of methyl 3-butenoate (2.9 g, 28.9 mmol) in anhydrous THF (30 mL) was added 0.5 M (56.2 mL, 28.1 mmol) 9-BBN in THF dropwise under nitrogen at 0° C. The reaction mixture was allowed to warm to room temperature and stirring was continued for three hours. The solution was then transferred via cannula under nitrogen to a solution of (1RS,2RS,3aSR,8bSR)-5-bromo-1-((3SR,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-ol (5.0 g, 12.8 mmol, from Example 13), PhAs (390 mg, 1.3 mmol), KPO (8.14 g, 38.3 mmol), and PdCl(dppf)-CHCl (1.04 g, 1.3 mmol) in anhydrous THF (50 mL). The reaction mixture was stirred at 60° C. for three hours. After completion of the reaction, the mixture was quenched with hydrogen peroxide (30% aqueous solution, 20 mL) and stirred at 0° C. for 30 minutes. Saturated aqueous ammonium chloride (250 mL) was then added to the reactor, the reaction mixture was phase separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 3.74 g (71%).

[0248] 1 H-NMR (400MHz, CDCl3): δ6.940(m,2H),6.758(m,1H),5.558-5.708(m,2H),5.087(m,1H),4.045-4.173(m,1H),3.913(m,1H),3.649(s,3H),3.41 1-3.454(m,1H),2.483-2.649(m,3H),2.384-2.434(m,1H),2.243-2.366 (m,5H),1.862-2.088(m,3H),1.717-1.829(m,4H),0.824-1.030(m,3H).

[0249] Example 15

[0250] 4-((1RS,2RS,3aSR,8bSR)-2-hydroxy-1-((3SR,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoic acid (Beraprost)

[0251]

[0252] Methyl 4-((1RS,2RS,3aSR,8bSR)-2-hydroxy-1-((3SR,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoate (2.38 g, 5.97 mmol) was dissolved in methanol (24 mL) and a solution of NaOH (460 mg, 11.5 mmol) in water (24 mL) was slowly added dropwise at 10 ° C. After the reaction was completed, methanol was removed from the reaction mixture in vacuo. The residue was diluted with water (25 mL) and further washed with methyl-tert-butyl ether (25 mL). The aqueous layer was acidified to pH 3-4 with 3N aqueous HCl solution and further extracted with methyl-tert-butyl ether (25 mL). The organic layer was dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was evaporated under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as a gradient eluent. The yield of the title compound was 1.78 g (77%).

[0253] 1 H-NMR (400MHz, CDCl3): δ6.892-6.942(m,2H),6.729-6.748(m,1H),5.503- 5.656(m,2H),5.038-5.056(m,1H),3.984-4.107(m,1H),3.821-3.893(m,1H ),3.214-3.390(m,1H),2.542-2.673(m,3H),2.325-2.394(m,3H),2.044-2. 238(m,2H),1.857-1.998(m,3H),1.745-1.788(m,4H),0.979-1.031(d,3H).

[0254] 13C-NMR (100MHz, CDCl3): δ178.685,157.204,134.016,133.811,133.325,132.756,129.621,1 29.576,128.908,123.200,123.169,121.856,121.811,120.551,120.513,84.223,84.132,77 .415,77.240,77.225,77.179,76.367,76.079,75.980,58.780,58.735,50.196,50.150,41.103,38.218,38.066,33.209,29.034,24.540,22.453,22.362,15.720,14.847,3.523,3.492.

[0255] Example 16

[0256] (2S,3R,4R)-2-(3-bromo-2-fluorophenyl)-3-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentenone

[0257]

[0258] 2-Thienyl(cyano)copper lithium was prepared under dry nitrogen. To a solution of thiophene (6.84 g, 81.4 mmol) in anhydrous THF (70 mL) at -10°C was added 1.6 M n-butyllithium in hexane (46.3 mL, 74.1 mmol) dropwise. After one hour, the reaction mixture was cooled to -70°C. The solution was transferred via cannula to a suspension of copper cyanide (7.3 g, 81.5 mmol) in anhydrous THF (73 mL) at -70°C and stirred for 30 minutes. Next, n-butyllithium in hexane (1.6 M, 55.5 mL, 88.8 mmol) was added dropwise to a solution of tert-butyldimethyl(((3S,4S,E)-4-methyl-1-(tributylstannyl)oct-1-en-6-yn-3-yl)oxy)silane (40.1 g, 74 mmol) at -70°C for 30 minutes. 2-Thienyl(cyano)copper lithium was added to the reaction mixture via cannula at -70°C and stirred for 30 minutes. Subsequently, a solution of (4R)-2-(3-bromo-2-fluorophenyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-enone (13.2 g, 37.1 mmol, from Example 7) was added. The reaction mixture was quenched with saturated aqueous ammonium chloride (540 mL) containing ammonium hydroxide (60 mL). The reaction mixture was phase separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous Na 2 SO 4 . The solid was filtered off and the organic solvent was evaporated under vacuum to give 60.2 g of the crude title compound.

[0259] Example 17

[0260] (1S,2S,3R,4R)-2-(3-bromo-2-fluorophenyl)-3-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentanol

[0261]

[0262] The compound was obtained from (2S,3R,4R)-2-(3-bromo-2-fluorophenyl)-3-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentenone (60.2 g from Example 16) by following the procedure of Example 11. The yield of the title compound was 13.8 g (65% over 2 steps from Example 16).

[0263] 1H-NMR (400MHz, CDCl3): δ7.422(m,1H),7.289-7.352(m,1H),7.001(m,1H),5.359-5.542(m,2H),4.699-4.743(m,1H),3.850-4.346(m,4 H),3.497-3.513(m,1H),3.130-3.265(m,2H),2.378-2.578(m,1H),1.524-2.026(m,14H),0.642-0.955(m,12H),-0.182-0.089(m,6H).

[0264] Example 18

[0265] (((3S,4S,E)-1-((1R,2R,3aS,8bS)-5-bromo-2-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl)-4-methyloct-1-en-6-yn-3-yl)oxy)(tert-butyl)dimethylsilane

[0266]

[0267] The compound was obtained from (1S,2S,3R,4R)-2-(3-bromo-2-fluorophenyl)-3-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentanol (13.8 g, 22.6 mmol, from Example 17) by following the procedure of Example 12. The yield of the title compound was 10.9 g (81%).

[0268] 1 H-NMR (400MHz, CDCl3): δ7.259(m,1H),7.014-7.055(m,1H),6.670-6.689(m,1H) ),5.481-5.654(m,2H),5.242-5.264(m,1H),4.603-4.664(m,1H),4.048-4.077( m,2H),3.818-3.912(m,1H),3.414-3.713(m,2H),2.408-2.798(m,2H),2.057-2 .233(m,3H),1.259-1.787(m,10H),0.856-0.950(m,12H),-0.007-0.095(m,6H).

[0269] Example 19

[0270] (1R,2R,3aS,8bS)-5-Bromo-1-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-ol

[0271]

[0272] By following the procedure of Example 13, the compound was obtained from (((3S,4S,E)-1-((1R,2R,3aS,8bS)-5-bromo-2-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-1-yl)-4-methyloct-1-en-6-yn-3-yl)oxy)(tert-butyl)dimethylsilane (9.9 g, 16.8 mmol, from Example 18). The yield of the title compound was 5.55 g (84%). After recrystallization, the crystalline compound was obtained (4.12 g, 75%). The crystalline compound was characterized by an X-ray powder diffraction pattern with peaks at 6.7±0.2°, 15.4±0.2°, 19.5±0.2°, 19.9±0.2°, and 21.5±0.2° 2θ.

[0273] 1 H-NMR (400MHz, CDCl3): δ7.258-7.277(m,1H),6.967-6.985(m,1H),6.681-6.720(m,1H), 5.523-5.655(m,2H),5.158-5.213(m,1H),3.989-4.024(m,1H),3.838-3.884(m,1H),3.46 3-3.508(m,1H),3.285-3.296(m,1H),2.949(s,1H),2.665-2.733(m,1H),2.343-2.407(m, 1H),2.221-2.242(m,2H),1.972-2.044(m,1H),1.715-1.853(m,4H),0.961-0.977(m,3H).

[0274] Example 20

[0275] Methyl 4-((1R,2R,3aS,8bS)-2-hydroxy-1-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoate

[0276]

[0277] By following the procedure of Example 14, the compound was obtained from (1R,2R,3aS,8bS)-5-bromo-1-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-2-ol (2.0 g, 5.1 mmol, from Example 19). The yield of the title compound was 1.47 g (70%). After recrystallization, the crystalline compound was obtained (1.11 g, 75%). The crystalline compound was characterized by an X-ray powder diffraction pattern with peaks at 8.2±0.2°, 10.8±0.2°, 18.5±0.2°, 20.9±0.2°, and 22.1±0.2° 2θ.

[0278] 1 H-NMR (400MHz, CDCl3): δ6.886-6.931(m,2H),6.711-6.748(t,1H),5.501-5.656(m,2 H),5.015-5.070(m,1H),3.969-4.007(t,1H),3.809-3.869(m,1H),3.628(s,3H),3.54 1(s,1H),3.341-3.386(t,1H),3.168(s,1H),2.564-2.677(m,3H),2.291-2.373(m,3H) ,2.168-2.220(m,2H),1.876-1.970(m,3H),1.696-1.778(m,4H),0.955-0.971(m,3H).

[0279] 13 C-NMR (100MHz, CDCl3): δ174.173,157.194,134.083,133.324,129.582,128.830,123.290,121.749,120.428,84.042,77 .279,77.150,76.285,75.882,58.843,51.458,50.129,41.211,38.175,33.416,29.173,24.710,22.358,15.694,3.474.

[0280] Example 21

[0281] 4-((1R,2R,3aS,8bS)-2-Hydroxy-1-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoic acid (Beraprost-314d)

[0282]

[0283] By following the procedure of Example 15, the compound was obtained from methyl 4-((1R,2R,3aS,8bS)-2-hydroxy-1-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoate (406 mg, 0.98 mmol, from Example 20). The yield of the title compound was 353 mg (90%). After recrystallization, the crystalline compound was obtained (251 g, 71%). The crystalline compound was characterized by an X-ray powder diffraction pattern with peaks at 6.1±0.2°, 6.6±0.2°, 7.2±0.2°, 12.1±0.2°, and 16.3±0.2° 2θ.

[0284] 1 H-NMR (400MHz, CDCl3): δ6.904-6.941(m,2H),6.722-6.759(t,1H),5.522 -5.672(m,2H),5.032-5.086(m,1H),3.996-4.033(m,1H),3.850-3.909(m ,1H),3.369-3.412(m,1H),2.536-2.668(m,3H),2.301-2.416(m,3H),2.2 29(m,2H),1.879-2.005(m,3H),1.717-1.788(m,4H),0.967-0.984(d,3H).

[0285] 13 C-NMR (100MHz, CDCl3): δ178.287,157.194,134.052,133.293,129.582,128.937,123.199,121.810,120.504,84.14 8,77.233,77.218,76.353,75.966,58.752,50.137,41.082,38.061,33.135,29.022,24.543,22.342,15.716,3.519.

[0286] Example 22

[0287] Methyl 4-((1R,2R,3aS,8bS)-2-((tert-butyldimethylsilyl)oxy)-1-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-2,3,3a,8b-tetrahydro-1H-cyclopenta[b]benzofuran-5-yl)butanoate

[0288]

[0289] The compound was obtained from methyl (R)-4-(3-(3-((tert-butyldimethylsilyl)oxy-5-oxocyclo-1-en-1-yl)-2-fluorophenyl)butanoate (10.0 g, 24.6 mmol, from Example 9) and tert-butyldimethyl(((3S,4S,E)-4-methyl-1-(tributylstannyl)oct-1-en-6-yn-3-yl)oxy)silane (39.96 g, 73.8 mmol), following the same procedures as Examples 10, 11 and 12. The yield of the title compound was 7.6 g (48% over 3 steps).

[0290] 1 H-NMR (400MHz, CDCl3): δ6.963-6.982(d,1H),6.895-6.912(d,1H),6.708-6.745(t,1H,J=7.6Hz),5.496-5.6 23(m,2H),5.073-5.126(m,1H),4.019-4.048(m,1H),3.902-3.952(m,1H),3.652(s,3H),3.433-3.473(m,1H) ,2.525-2.599(m,3H),2.417-2.484(m,1H),2.319-2.356(m,2H),2.192-2.252(m,1H),2.060-2.120(m,1H),1 .891-2.012(m,3H),1.780-1.792(m,3H),1.628-1.745(m,1H),0.758-0.941(m,21H),-0.049-0.091(m,12H).

[0291] 13C-NMR (100MHz, CDCl3): δ174.105,157.331,132.861,131.350,130.212,128.405 ,122.956,121.901,120.109,84.801,77.909,77.142,76.421,75.958,58.114,51 .412,49.962,42.380,39.746,33.568,29.302,29.234,25.887,25.674,25.629,24.756,21.940,18.168,17.819,15.542,3.458,-2.970,-3.980,-4.678,-4.875.

[0292] Although the present invention has been described with reference to illustrative examples, it should be understood that any modifications or alterations that may be easily accomplished by those skilled in the art will fall within the scope of the disclosure of the present specification and the appended claims.

Claims

1. A racemic or optically enriched compound of formula 1, wherein P is H or a hydroxy protecting group selected from the group consisting of methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, trityl, allyl, benzyl, and SiRaRbRc, wherein Ra, Rb, and Rc are each independently unsubstituted C 1-4 Alkyl, phenyl or benzyl; and X is Cl, Br, I or -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 Aralkyl.

2. The compound of claim 1 which is enriched in the (R)-enantiomer and has an optical purity of at least 95% enantiomeric excess.

3. The compound of claim 1 which is enriched in the (R)-enantiomer and has an optical purity of at least 99% enantiomeric excess.

4. The compound of claim 1 which is enriched in the (R)-enantiomer and has an optical purity of at least 99.9% enantiomeric excess.

5. A process for preparing a compound of formula (R)-1″ enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess ee, Wherein X is Cl, Br or I, the method comprises the following steps: (1) Enantioselective (R)-esterification of the compound of formula 1″: Wherein X is Cl, Br or I, The esterification uses an acyl donor of formula D: Wherein R4 and R5 are independently H or C 1-6 an alkyl group, and a first lipase derived from Achromobacterium, Candida columnaris, Alcaligenes, Candida antarctica, Pseudomonas cepacia, Burkholderia cepacia, or Pseudomonas stutzeri to form a mixture of (S)-alcohol and (R)-ester, or a mixture thereof; and (2) deacylation of the (R)-ester, wherein the deacylation comprises a chemical hydrolysis reaction or an enzymatic cleavage reaction.

6. A process for preparing a compound of formula (R)-1″ enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess ee, Wherein X is Cl, Br or I, the method comprises the following steps: (1) Enantioselective (R)-esterification of the compound of formula 1″: Wherein X is Cl, Br or I, The esterification uses an acyl donor of formula D: Wherein R4 and R5 are independently H or C 1-6 an alkyl group, and a first lipase derived from Achromobacterium, Candida columnaris, Alcaligenes, Candida antarctica, Pseudomonas cepacia, Burkholderia cepacia, or Pseudomonas stutzeri, or a mixture thereof, to form a mixture of (S)-alcohol and (R)-ester; (2) removing the (S)-alcohol; and (3) deacylation of the (R)-ester, wherein the deacylation comprises a chemical hydrolysis reaction or an enzymatic cleavage reaction.

7. The method of claim 5 or 6, wherein the acyl donor of formula D is selected from the group consisting of vinyl acetate, isopropenyl acetate, vinyl valerate, isopropenyl valerate, vinyl butyrate, isopropenyl butyrate and mixtures thereof.

8. The method of claim 5 or 6, wherein the deacylation step comprises a chemical hydrolysis reaction.

9. The method of claim 5 or 6, wherein the deacylation step comprises an enzymatic cleavage reaction using a second lipase derived from Achromobacterium, Alcaligenes, Candida antarctica, Pseudomonas, or a mixture thereof.

10. The method of claim 5 or 6, wherein the deacylation step comprises an enzymatic cleavage reaction using a second lipase derived from Achromobacterium, Alcaligenes, Candida antarctica, Pseudomonas cepacia, Pseudomonas stutzeri, or a mixture thereof.

11. The method of claim 6, wherein the step of removing the (S)-alcohol comprises converting the (S)-alcohol into the corresponding (R)-ester by reacting the (S)-alcohol with an acyloxy donor of the formula R4COOH in the presence of a dialkyl azodicarboxylate and a triarylphosphine, wherein R4 is as defined in claim 6.

12. The method of claim 11, wherein the dialkyl azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, and mixtures thereof.

13. The method of claim 11, wherein the triarylphosphine is triphenylphosphine.

14. A method for preparing a compound of formula 4, Wherein P is H, P1 or P2; R2 is H or C 1-4 Alkyl; R3 is C 1-7 Alkyl, C 2-7 Alkynyl or monocyclic or polycyclic aromatic hydrocarbon group of 6 to 20 carbon atoms, each of which is unsubstituted or C 1-4 Alkyl, halogen or trihalomethyl substitution; X is Cl, Br, I or -CH2CH2CH2COOR1, wherein R1 is C 1-7 Alkyl or C 7-11 alkyl; and P1 and P2 are hydroxy protecting groups selected from the group consisting of methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, trityl, allyl, benzyl, and SiRaRbRc, wherein Ra, Rb, and Rc are each independently an unsubstituted C 1-4 alkyl, phenyl or benzyl, the method comprising the steps of: (1) making the compound of formula 1': wherein P1 and X are as defined above, reacted with a cuprate derived from a compound of formula L1, formula L2 or formula L3: wherein Y is Cl, Br or I; P2, R2 and R3 are as defined above, to form a compound of formula 2: wherein P, X, R2 and R3 are as defined above; (2) reducing the ketone of the compound of formula 2 to form a compound of formula 3: wherein P, X, R2 and R3 are as defined above; and (3) performing an intramolecular cyclization reaction on the compound of formula 3 to form a compound of formula 4: wherein P, X, R2 and R3 are as defined above.

15. The method of claim 14, wherein the steps include: (4) A deprotection reaction is performed to remove the hydroxyl protecting group.

16. The method of claim 14 or 15, wherein the steps include: Performing a Suzuki cross-coupling reaction of the compound of Formula 2, 3 or 4, where X is Cl, Br or I, to form the compound of Formula 2, 3 or 4, where X is -CH2CH2CH2COOR1 and R1 is as defined in claim 14.

17. The method of claim 14, for preparing an optically enriched compound of formula 4a: Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 Aralkyl; and P1 and P2 are the hydroxy protecting groups, the method comprising the following steps: (1') making an optically enriched compound of formula (R)-1a': Wherein P1 and X are as defined in claim 14, and are derived from the formula L 1a 、Formula L 2a Or L 3a Cuprate reactions of optically enriched compounds: wherein Y is Cl, Br or I; and P2 is as defined in claim 14, to form a compound of formula 2a: wherein P and X are as defined in claim 14; (2') reducing the ketone of the compound of formula 2a to form a compound of formula 3a: wherein P and X are as defined in claim 14; and (3') performing an intramolecular cyclization reaction of the compound of formula 3a to form the compound of formula 4a: wherein P and X are as defined in claim 14.

18. The method of claim 17, wherein the steps include: (4') A deprotection reaction is performed to remove the hydroxyl protecting group.

19. The method of claim 17 or 18, wherein the steps include: Performing a Suzuki cross-coupling reaction of the compound of Formula 2a, 3a or 4a, where X is Cl, Br or I, to form the compound of Formula 2a, 3a or 4a, where X is -CH2CH2CH2COOR1 and R1 is as defined in claim 14.

20. The method of claim 14, for preparing a racemic compound of formula 4b: Where P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, where R1 is C 1-7 Alkyl or C 7-11 Aralkyl; and P1 and P2 are the hydroxy protecting groups, the method comprising the following steps: (1") making a racemic compound of formula 1': Wherein P1 and X are as defined in claim 14, and are derived from the formula L 1b 、Formula L 2b Or L 3b Cuprate reaction of racemic and diastereomeric mixtures of compounds: wherein Y is Cl, Br or I; and P2 is as defined in claim 14, to form a compound of formula 2b: wherein P and X are as defined in claim 14; (2") reducing the ketone of the compound of formula 2b to form a compound of formula 3b: wherein P and X are as defined in claim 14; and (3") performing an intramolecular cyclization reaction of the compound of formula 3b to form the compound of formula 4b: wherein P and X are as defined in claim 14.

21. The method of claim 20, wherein the steps include: (4") A deprotection reaction is performed to remove the hydroxyl protecting group.

22. The method of claim 20 or 21, wherein the steps include: Performing a Suzuki cross-coupling reaction of the compound of Formula 2b, 3b or 4b, where X is Cl, Br or I, to form the compound of Formula 2b, 3b or 4b, where X is -CH2CH2CH2COOR1 and R1 is as defined in claim 14.

23. An optically enriched compound of formula 4a″, wherein Y is Cl, Br or I.

24. The compound of claim 23, wherein Y is Br.

25. A racemic compound of formula 11,15-isomorphic 4b" wherein Y is Cl, Br or I.

26. The compound of claim 25, comprising four isomers of formula 4b"-1, formula 4b"-2, formula 4b"-3 and formula 4b"-4 wherein Y is Cl, Br or I.

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