Processes and intermediates for the preparation of benzoprostacyclin analogs, and benzoprostacyclin analogs prepared therefrom - Patents.com

Abstract

To provide: a process for preparing benzoprostacyclin analogues; intermediates prepared by a process; benzoprostacyclin analogues prepared by them; and cyclopentenone intermediates in racemic or optically active forms.SOLUTION: The invention provides racemic or optically active cyclopentenone intermediates represented by formula 1 in the figure, where P is H or a protective group for hydroxyl groups; and X is Cl, Br, I, or -CH2CH2CH2COOR1, where R1 is C1-7-alkyl or C7-11-aralkyl.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to novel processes and intermediates for the preparation of benzoprostacyclin analogs, and the benzoprostacyclin analogs prepared therefrom. [Background technology]

[0002] Since the discovery of prostacyclin, several chemically and metabolically stable benzoprostacyclin analogues have been developed as clinically effective antithrombotic agents. Among them, beraprost, developed by Toray Industries, Inc., is one of the most attractive compounds. Commercially available beraprost sodium is a racemate, i.e., a mixture of the following four isomers:

[0003] [ka]

[0004] Enantiomerically pure beraprost-314d is the pharmacologically active isomer of beraprost, which is currently in clinical trials for the treatment of pulmonary hypertension and vascular disease.

[0005] The syntheses of beraprost or beraprost-314d have been disclosed in the prior art, such as Patent Documents 1 to 7 and Non-Patent Document 1, but they are linear and somewhat inefficient.

[0006] Patent Document 8 describes a more efficient synthetic route to beraprost by conjugate addition reaction, as shown in the following scheme A, in which intermediate A2 is obtained from cyclopentenone A1 by conjugate addition (step 1).

[0007] [ka]

[0008] As shown in Scheme A, intermediate A2 having a 9-keto group is reacted with L-selectride to give intermediate A3 having a 9α-hydroxyl group (Step 2). N Through two reactions, the 9α-hydroxyl group is converted to a 9β-chloro group to give intermediate A4 (step 3). Next, intermediate A4 undergoes removal of the phenol protecting group, the methoxymethyl group, and the hydroxyl protecting group, the tert-butyldimethylsilyl group (step 4), followed by intramolecular cyclization to give intermediate A6 (step 5).

[0009] However, this approach, described in Scheme A, requires at least five steps to form the tricyclic structure of benzoprostacyclin from cyclopentenone A1. Therefore, it is necessary to discover and develop an efficient conjugate addition approach to industrially form the tricyclic structure of benzoprostacyclin. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] US Patent No. 5,202,447 [Patent Document 2] China Patent Publication No. 106478572 [Patent Document 3] International Publication No. 2017 / 174439 Brochure [Patent Document 4] US Patent No. 8779170 [Patent Document 5] US Patent No. 9334255 [Patent Document 6] US Patent No. 9765047 [Patent Document 7] US Patent No. 8779170 [Patent Document 8] US Patent No. 7345181 [Non-patent literature]

[0011] [Non-Patent Document 1] Tetrahedron Lett.1990, 31, 4493. [Non-Patent Document 2] Org.Lett.2017, 19, 1112. DISCLOSURE OF THEINVENTION [Problem to be solved by the invention]

[0012] It is an object of the present invention to produce benzoprostacyclin analogs and intermediates thereof with higher diastereomeric and enantiomeric purity, thereby providing a more efficient conjugate addition approach to form products with high purity. [Means for solving the problem]

[0013] In one aspect, the present invention provides a compound of formula 1

[0014] [ka]

[0015] Racemic or optically active cyclopentenone represented by the formula: 11 -aralkyl; P1 is a protecting group for the hydroxyl group.

[0016] In another aspect, the present invention provides a compound of formula (R)-1" that is enriched in the (R)-enantiomer and has an optical purity of at least 95% enantiomeric excess (ee).

[0017] [ka]

[0018] wherein X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl).

[0019] In another aspect, the present invention provides a compound of formula 4

[0020] [ka]

[0021] wherein P is H, P1 or P2; R2 is H or C1-4-alkyl; R3 is C1-7-alkyl, C2-7-alkynyl, aryl or aryloxy, each of which is unsubstituted or substituted by C1-4-alkyl, halogen or trihalomethyl; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 or P2 is a protecting group for a hydroxyl group).

[0022] In another aspect, the present invention provides a compound of formula 4a

[0023] [ka]

[0024] wherein P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for the hydroxyl groups).

[0025] In another aspect, the present invention provides a compound of formula 4b

[0026] [ka]

[0027] wherein P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for the hydroxyl groups).

[0028] In another aspect, the present invention provides a compound of formula 4a″, which is used in the preparation of beraprost-314d.

[0029] [ka]

[0030] wherein Y is Cl, Br or I.

[0031] In yet another aspect, the present invention provides a compound of formula 11,15-syn 4b″

[0032] [ka]

[0033] wherein Y is Cl, Br or I, which can be used to prepare beraprost, and is represented by the formula 4b''-1, 4b''-2, 4b''-3 and 4b''-4.

[0034] [ka]

[0035] The compound includes at least four isomers represented by the following formula: BEST MODE FOR CARRYING OUT THEINVENTION

[0036] definition When used in conjunction with the term "comprising" in the claims and / or this specification, the use of the word "a" or "an" can mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one." The use of the term "or" in the claims is used to mean "and / or" unless expressly indicated to refer to alternatives only or the alternatives are not mutually exclusive, but the present disclosure supports the definition and "and / or" to refer to alternatives only. Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of error for the device, method being used to determine the value, or the variation that exists among study subjects.

[0037] As used in this specification and the claims, the words "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.

[0038] Unless otherwise specified, the term "alkyl," as used herein, refers to a straight-chain or branched 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, etc.; or a cyclic saturated hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, menthyl, etc.

[0039] Unless otherwise specified, the term "alkynyl" as used herein refers to a straight-chain or branched hydrocarbon group containing 2 to 30 carbon atoms, preferably 3 to 20 carbon atoms and one or more carbon-carbon triple bonds, such as pentynyl, propynyl, etc.; or a cyclic unsaturated hydrocarbon group having 6 to 20 carbon atoms and one or more carbon-carbon triple bonds.

[0040] Unless otherwise specified, the term "aryl" as used herein refers to monocyclic or polycyclic aromatic hydrocarbon groups having 6 to 30 carbon atoms, preferably 6 to 20 carbon atoms, such as phenyl, naphthyl, anthryl, phenanthryl, and the like.

[0041] 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, etc.

[0042] Each of the above alkyl, alkynyl, aryl and aralkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxyl, aryloxy, thioalkoxyl, thioaryloxy, alkylamino, arylamino, cyano, alkoxycarbonyl, arylcarbonyl, arylaminocarbonyl, alkylaminocarbonyl and carbonyl, or a heterocyclic group selected from the group consisting of pyridinyl, thiophenyl, furanyl, imidazolyl, morpholinyl, oxazolinyl, piperidinyl, piperazinyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, etc.

[0043] Unless otherwise specified, the term "protecting group for a hydroxyl group" has the meaning conventionally defined in organic synthetic chemistry, i.e., a group capable of protecting a hydroxyl group or moiety of a compound from attack by a chemical reaction. Examples of protecting groups for a hydroxyl group include methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substituted benzyl, and SiR a R b R c (In the formula, R a , R b and R c are each independently unsubstituted or substituted alkyl or unsubstituted or substituted aryl, such as C1-4 alkyl, phenyl, benzyl, substituted phenyl, and substituted benzyl.

[0044] [ka]

[0045] Synthetic route to racemic cyclopentenone represented by formula 1' The present invention relates to a compound represented by formula 1'

[0046] [ka]

[0047] wherein P1 is a protecting group for a hydroxyl group, X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl).

[0048] In the present invention, the compound of formula 1' can be prepared according to the reaction shown in Scheme B. As shown in Scheme B, the compound of formula 5 (wherein X is Cl, Br or I) is reacted with lithium diisopropylamide (LDA) to convert it into an organolithium intermediate by regioselective lithiation, followed by formylation with dimethylformamide (DMF) to obtain the compound of formula 6 (wherein X is as defined above) (Step 1). The compound of formula 6 is then treated with 2-lithiofuran by 1,2-addition reaction to provide the compound of formula 7 (Step 2). The compound of formula 7 then undergoes Piankatelli rearrangement (Step 3) and isomerization (Step 4) to give the cyclopentenone of formula 1". Finally, the secondary hydroxyl group of the compound of formula 1" is protected to obtain the compound of formula 1' (wherein P1 is a protecting group for the hydroxyl group and X is as defined above) (Step 5). In some embodiments, a compound of formula 6, 7, 8, 1" or 1', where X is Cl, Br or I, is subjected to a Suzuki cross coupling reaction to give a compound of formula 6, 7, 8, 1" or 1', where X is -CH2CH2CH2COOR1 and R1 is C1-7-alkyl or C7- 11 -aralkyl).

[0049] [ka]

[0050] The present invention also relates to a compound of formula 1 [ka]

[0051] In one embodiment, the present invention provides a racemic or optically active compound represented by the formula: 11 -aralkyl; P1 is a protecting group for a hydroxyl group).

[0052] Chiral resolution of racemic cyclopentenone represented by formula 1"

[0053] In the present invention, according to the reaction shown in Scheme C, racemic cyclopentenones of formula 1″ can be easily chirally resolved to form cyclopentenones enriched in the (R)-enantiomer and with high optical purity. As shown in Scheme C, racemic compounds of formula 1″ (wherein X is Cl, Br, or I) are resolved by enantioselective esterification using a first lipase to form a mixture of unreacted alcohols of formula (S)-1″ and esters of formula 8 (Step 1). The unreacted alcohols of formula (S)-1″ can then be easily removed by isolating them from the mixture, for example, by column purification, and then proceeded to undergo Mitsunobu reaction to give the corresponding compounds of formula 8. Alternatively, the mixture can directly undergo Mitsunobu reaction (step 2) to convert the unreacted alcohol of formula (S)-1″ to the compound of formula 8. Finally, the compound of formula 8 is deacylated using chemical hydrolysis or enzymatic cleavage to form the compound of formula (R)-1″ enriched in the (R)-enantiomer and with high optical purity.

[0054] [ka]

[0055] In step 1 of Scheme C, enantioselective esterification of a cyclopentenone of formula 1″ is carried out with an acyl donor of formula D, in the presence of a first lipase, where R4 and R5 are independently H or C1-6 alkyl, which preferentially reacts with the (R)-form of the cyclopentenone, thereby producing a mixture consisting essentially of an optically active ester of formula 8 and an unreacted alcohol of formula (S)-1″.

[0056] [ka]

[0057] In some embodiments, suitable first lipases are commercially available and may be derived from Achromobacter spp., Candida cylindracea, Alcaligenes spp., Candida antarcitica, Pseudomonas cepacia, Burkholderia cepacian, Pseudomonas stutzri or mixtures thereof, preferably Alcaligenes spp., Candida cylindracea, Candida antarctica, Burkholderia cepacia or Pseudomonas stutzri, most preferably Burkholderia cepacia. Suitable acyl donors include, but are not limited to, vinyl acetate, isopropenyl acetate, vinyl valerate, isopropenyl valerate, vinyl butyrate, isopropenyl butyrate, and mixtures thereof, with vinyl acetate being particularly preferred. Furthermore, 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 from about 5°C to about 50°C, preferably room temperature.

[0058] Step 2 of Scheme C involves Mitsunobu reaction. The unreacted alcohol of formula (S)-1″ can be easily separated from the mixture obtained from step 1 of Scheme C by column purification due to the different polarities of the alcohol and ester, and undergo Mitsunobu reaction to form the ester of formula 8. In some embodiments, it is not necessary to separate the compounds represented by formula (S)-1″ and formula 8 from the mixture, and the mixture can directly undergo Mitsunobu reaction to convert the unreacted alcohol of formula (S)-1″ to the ester of formula 8. In this step, almost 100% of the alcohol of formula (S)-1″ in the mixture can be converted to the ester of formula 8.

[0059] In the Mitsunobu reaction, the unreacted alcohol of formula (S)-1" can be converted to a compound of formula 8 by treatment with an acyloxy donor of formula R4COOH, where R4 is H or C1-6 alkyl, in the presence of a dialkyl azodicarboxylate and a trialkyl / triaryl phosphine in a suitable solvent. Suitable dialkyl azodicarboxylates include dimethyl azodicarboxylate (DMAD), diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DTBAD), dibenzyl azodicarboxylate (DBAD), bis-trichloroethyl azodicarboxylate (BTCEAD), di-p-chlorobenzyl azodicarboxylate (DCAD), di-4-nitrobenzyl azodicarboxylate (DNAD), azodicarboxylate (CDAD), di-methyl-1,1-diphenyl-2,2-tetramethyl-1 ... Suitable trialkyl / triaryl phosphines include, but are not limited to, tri-n-butylphosphine, triphenylphosphine, and mixtures thereof; 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 can be carried out at a suitable temperature, preferably from about -30°C to about 70°C, preferably at room temperature.

[0060] Step 3 of Scheme C relates to 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 an 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 represented by formula 8 can be carried out in the presence of sulfuric acid and methanol.

[0061] 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 the presence of a second lipase at a suitable temperature in a suitable organic solvent or aqueous system to provide a compound represented by formula (R)-1". Suitable second lipases are commercially available and may be derived from Achromobacter spp., Alcaligenes spp., Candida Antarctica, Pseudomonas cepacia, Pseudomonas stutzeri, Psudomonas spp., or mixtures thereof; preferably, Achromobacter spp., Alcaligenes spp., Candida Antarctica, Pseudomonas spp., or mixtures thereof; most preferably, Candida Antarctica.

[0062] In the present invention, the deacylation reaction is monitored for the optical purity of the resulting compound represented by 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 is about 95% ee, preferably about 99% ee, more preferably about 99.9% ee. In some embodiments, the unreacted ester of formula 8 and its enantiomer can be removed after the deacylation reaction by column chromatography or the like. In the present invention, the compound represented by formula (R)-1" is produced with an optical activity of at least about 95% ee, preferably at least about 99% ee, most preferably at least about 99.9% ee.

[0063] Thus, the present invention provides a compound of formula (R)-1" that is enriched in the (R)-enantiomer and has an optical purity of at least 95% ee.

[0064] [ka]

[0065] wherein X is Cl, Br or I, (1) Formula 1”

[0066] [ka]

[0067] wherein R4 and R5 are independently H or C1-6 alkyl, and a first lipase to form a mixture of (S)-alcohols and (R)-esters; (2) optionally removing the (S)-alcohol; (3) deacylation of the (R)-ester; The present invention provides a process including:

[0068] In some embodiments, a Suzuki cross-coupling reaction is carried out on a compound of formula (R)-1″, where X is Cl, Br or I, to give a compound of formula (R)-1″, where X is —CH2CH2CH2COOR1 and R1 is C1-7-alkyl or C7- 11 -aralkyl).

[0069] Preparation of benzoprostacyclin analogs represented by formula 4

[0070] The present invention also relates to a compound of formula 4

[0071] [ka]

[0072] wherein P is H, P1 or P2; R2 is H or C1-4-alkyl; R3 is C1-7-alkyl, C2-7-alkynyl, aryl or aryloxy, each of which is unsubstituted or substituted by C1-4-alkyl, halogen or trihalomethyl; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for the hydroxyl groups).

[0073] In the present invention, the compound represented by formula 4 can be prepared according to the reaction shown in Scheme D. As shown in Scheme D, the synthesis of the compound represented by formula 4 starts from the compound represented by formula 1', step 1 involves a 1,4-addition reaction, step 2 involves a reduction reaction, and step 3 involves an intramolecular cyclization reaction.

[0074] [ka]

[0075] The details described thereafter can be used for any of the processes for the preparation of the benzoprostacyclin analogs of the present invention. In step 1 of scheme D, a cyclopentenone of formula 2, where P, X, R2 and R3 are as defined above, is prepared by coupling reaction of a cyclopentenone of formula 1', where P1 and X are as defined above, with the ω-side chain unit of a copper salt derived from a compound of formula L1, L2 or L3, where 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 of about -100°C to about -20°C, preferably about -80°C to about -40°C.

[0076] [ka]

[0077] Step 2 of Scheme D involves a keto-reduction reaction. In step 2, the C9-carbonyl group of the compound represented by formula 2 is reduced to an α-hydroxyl group by a reducing agent. Suitable reducing agents include sodium bis(2-methoxyethoxy)aluminum hydride, diisobutylaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium trialkylborohydride, potassium trialkylborohydride, sodium trialkylborohydride and mixtures thereof; preferably, but not limited to, lithium tri(sec-butyl)borohydride (L-Selectride), sodium tri(sec-butyl)borohydride (N-Selectride), sodium tri(sec-butyl)borohydride (K-Selectride), lithium triamylborohydride, potassium triamylborohydride and mixtures thereof; more preferably, lithium tri(sec-butyl)borohydride (L-Selectride) is the reducing agent in this step.

[0078] As shown in step 3 of Scheme D, benzoprostacyclin analogs of formula 4 are prepared by intramolecular cyclization of a compound of formula 3 in the presence of suitable base conditions. In some embodiments, the intramolecular cyclization is accomplished by using a suitable base in a suitable solvent at a temperature of 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, glyme, dimethylformamide, N,N'-dimethylpropyleneurea, 1,2-dimethoxypropane, toluene, and mixtures thereof.

[0079] Compared with the conventional conjugate addition reaction shown in Scheme A, which requires five steps to form the tricyclic structure of benzoprostacyclin, the process of the present invention requires only three steps to form the tricyclic structure of benzoprostacyclin, which is a more efficient conjugate addition approach.

[0080] In some embodiments, the resulting compound of formula 2, 3 or 4 can be subjected to a deprotection reaction to remove the protecting group for the hydroxyl group.

[0081] In some embodiments, a Suzuki cross-coupling reaction is carried out on a compound of formula 2, 3 or 4, where X is Cl, Br or I, to give a compound of formula 2, 3 or 4, where X is -CH2CH2CH2COOR1 and R1 is C1-7-alkyl or C7- 11The Suzuki cross-coupling reaction can be preferably carried out with a borane reagent such as 9-borabicyclo[3.3.1]nonane (9-BBN), disiamylborane, diisoamylborane, catecholborane, diisopinocamylborane, dicyclohexylborane, bis(pinacolato)diborane, and mixtures thereof to form alkyl(R1)3-butenoates (wherein R1 is C1-7-alkyl or C7- 11 -aralkyl). The Suzuki cross-coupling reaction can also be carried out in the presence of a palladium catalyst, a ligand, and a base at a temperature of 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(eta-3-allyl-mu-chloropalladium(II), and mixtures thereof. In some embodiments, the palladium catalyst can be treated with a ligand to form a palladium complex to promote the reactivity of the cross-coupling reaction. Suitable ligands include PPh3, AsPh3, P(OMe)3, (n-Bu)3P, dppe, dppp, dicyclohexyl-(2,6-dimethoxybiphenyl-2yl)phosphide, bis(eta-3-allyl-mu-chloropalladium(II), and mixtures thereof. Suitable bases include, but are not limited to, alkylboranes, alkoxysilanes, methyl ethers, ethyl ...

[0082] Thus, the present invention relates to a compound of formula 4

[0083] [ka]

[0084] wherein P is H, P1 or P2; R2 is H or C1-4-alkyl; R3 is C1-7-alkyl, C2-7-alkynyl, aryl or aryloxy, each of which is unsubstituted or substituted by C1-4-alkyl, halogen or trihalomethyl; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for hydroxyl groups, (1) Formula 1'

[0085] [ka]

[0086] (wherein P1 and X are as defined above) is reacted with a compound represented by formula L1, formula L2 or formula L3

[0087] [ka]

[0088] (wherein Y is Cl, Br or I; P2, R2 and R3 are as defined above) to form a copper salt of the compound of formula 2

[0089] [ka]

[0090] wherein P, X, R2 and R3 are as defined above; (2) Reducing the ketone of the compound represented by formula 2 to obtain a compound represented by formula 3

[0091] [ka]

[0092] wherein P, X, R2 and R3 are as defined above; (3) carrying out an intramolecular cyclization reaction of the compound represented by formula 3 to obtain formula 4

[0093] [ka]

[0094] wherein P, X, R2 and R3 are as defined above; (4) optionally carrying out a deprotection reaction to remove the protecting groups for the hydroxyl groups; (5) optionally performing a Suzuki cross-coupling reaction of a compound of formula 2, 3 or 4, where X is Cl, Br or I, to form a compound of formula 2, 3 or 4, where X is -CH2CH2CH2COOR1 and R1 is as defined above; The present invention provides a process including:

[0095] Synthetic Route to Optically Active Benzoprostacyclin Analogues of Formula 4a

[0096] The present invention further relates to a compound of formula 4a

[0097] [ka]

[0098] (wherein P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, R1 is C1-7-alkyl or C7- 11-aralkyl; P1 and P2 are protecting groups for the hydroxyl groups.

[0099] As depicted in Scheme E, the synthesis of the compound represented by formula 4a is similar to the synthesis of the compound represented by formula 4 as depicted in Scheme D. The synthesis of the compound represented by formula 4a can be carried out by reacting an optically active compound represented by formula (R)-1′ (wherein P1 and X are as defined above) with an optically active compound represented by formula L 1a , formula L 2a or formula L 3a

[0100] [ka]

[0101] The method begins with an optically active compound represented by the formula: where Y is Cl, Br or I; P2 is a protecting group for the hydroxyl group.

[0102] [ka]

[0103] In step 1 of scheme E, the compound represented by formula 2a is prepared by reacting the compound represented by formula L 1a , L 2a or L 3a The compound of formula 2a is then subjected to a reduction reaction (step 2) and an intramolecular cyclization (step 3) to obtain a compound of formula 4a, where X and P are as defined above.

[0104] In some embodiments, the resulting compound of formula 2a, 3a or 4a can be subjected to a deprotection reaction to remove the protecting group for the hydroxyl group. In some embodiments, the compound of formula 2a, 3a or 4a (wherein X is Cl, Br or I) can be converted to a compound of formula 2a, 3a or 4a (wherein X is -CH2CH2CH2COOR1 and R1 is C1-7-alkyl or C7-alkyl) by Suzuki cross-coupling reaction. 11 -aralkyl).

[0105] Thus, the present invention relates to a compound of formula 4a

[0106] [ka]

[0107] (wherein P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for hydroxyl groups, (1) Formula (R)-1'

[0108] [ka]

[0109] (wherein P1 and X are as defined above) is treated with an optically active compound represented by the formula L 1a , formula L 2a or formula L 3a

[0110] [ka]

[0111] (wherein Y is Cl, Br or I; P2 is a protecting group for a hydroxyl group) to obtain a copper salt of the optically active compound of formula 2a

[0112] [ka]

[0113] wherein P and X are as defined above; (2) reducing the ketone of the compound represented by formula 2a to obtain a compound represented by formula 3a

[0114] [ka]

[0115] wherein P and X are as defined above; (3) Intramolecular cyclization of the compound represented by formula 3a to form a compound represented by formula 4a

[0116] [ka]

[0117] wherein P and X are as defined above; (4) optionally carrying out a deprotection reaction to remove the protecting groups for the hydroxyl groups; (5) optionally performing a Suzuki cross-coupling reaction of a compound of formula 2a, 3a or 4a, where X is Cl, Br or I, to form a compound of formula 2a, 3a or 4a, where X is -CH2CH2CH2COOR1 and R1 is as defined above; The present invention provides a process including:

[0118] Synthetic Route to Benzoprostacyclin Analogues of Formula 4b

[0119] The present invention further relates to a compound of formula 4b

[0120] [ka]

[0121] (wherein P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for the hydroxyl groups.

[0122] Compounds of formula 4b can be prepared according to the reactions depicted in Scheme F.

[0123] [ka]

[0124] The synthetic route of the compound represented by formula 4b shown in Scheme F is also similar to the reaction described in Scheme D or E. In step 1 of Scheme F, racemic cyclopentenone of formula 1′ is converted to a compound represented by formula L by a coupling reaction. 1b , formula L 2b or formula L 3b

[0125] [ka]

[0126] (wherein Y is Cl, Br or I, and P2 is as defined above) to form a compound of formula 2b (Step 1). The compound of formula 2b is then subjected to a reduction reaction (Step 2) and an intramolecular cyclization reaction (Step 3) to form a mixture or composition containing a compound of formula 4b, a compound of formula 11,15-syn-4b, and a compound of formula 11,15-anti-4b (wherein P and X are as defined above).

[0127] [ka]

[0128] Generally, the undesired 11,15-anti isomer of the compound of formula 4b may be obtained in an amount of about 50% by treatment of the racemic cyclopentenone of formula 1′ with a racemic copper salt.

[0129] However, the unexpected result occurs that the coupling reaction of the present invention has high selectivity for the formation of the 11,15-syn isomer of the compound represented by formula 4b, and thus the ratio of the compound represented by formula 11,15-syn 4b and the compound represented by formula 11,15-anti 4b is observed to be about 70% or more and about 30% or less as detected by HPLC. This unexpected result indicates that the 11(R)-enantiomer of racemic cyclopentenone 1' and the 15(S)-enantiomer of the racemic copper salt, or the 11(S)-enantiomer of racemic cyclopentenone 1' and the 15(R)-enantiomer of the racemic copper salt are matched pairs, so these coupling reactions tend to form the 11,15-syn isomer. In contrast, the 11(R)-enantiomer of racemic cyclopentenone 1' and the 15(R)-enantiomer of the racemic copper salt, or the 11(S)-enantiomer of racemic cyclopentenone 1' and the 15(S)-enantiomer of the racemic copper salt, are mismatched pairs, so these coupling reactions do not tend to produce the 11,15-anti isomer. In the present invention, the unwanted 11,15-anti isomer (also called the 15-epimer) can be separated by column chromatography or crystallization.

[0130] In some embodiments, the compound represented by formula 2b, 3b or 4b (wherein P is H) can be obtained by deprotection of the protecting group of the compound represented by formula 2b, 3b or 4b (wherein P is a protecting group for a hydroxyl group).

[0131] In some embodiments, a compound represented by formula 2b, 3b, or 4b, where X is Cl, Br, or I, can be converted to a compound represented by formula 2b, 3b, or 4b, where X is -CH2CH2CH2COOR1, where R1 is C1-7-alkyl or C7- 11 -aralkyl).

[0132] Thus, the present invention relates to a compound of formula 4b

[0133] [ka]

[0134] (wherein P is H, P1 or P2; X is Cl, Br, I or -CH2CH2CH2COOR1, and R1 is C1-7-alkyl or C7- 11 -aralkyl; P1 and P2 are protecting groups for hydroxyl groups, (1) Formula 1'

[0135] [ka]

[0136] wherein P1 and X are as defined above, are reacted with a racemic compound represented by formula L 1b , formula L 2b or formula L 3b

[0137] [ka]

[0138] (wherein Y is Cl, Br or I; P2 is as defined above), to give a copper salt derived from a racemic and diastereomeric mixture containing a compound represented by formula 2b

[0139] [ka]

[0140] wherein P and X are as defined above; (2) reducing the ketone of the compound represented by formula 2b to obtain a compound represented by formula 3b

[0141] [ka]

[0142] wherein P and X are as defined above; (3) Intramolecular cyclization of the compound represented by formula 3b to form a compound represented by formula 4b

[0143] [ka]

[0144] wherein P and X are as defined above; (4) optionally carrying out a deprotection reaction to remove the protecting groups for the hydroxyl groups; (5) optionally performing a Suzuki cross-coupling reaction of a compound of formula 2b, 3b or 4b, where X is Cl, Br or I, to form a compound of formula 2b, 3b or 4b, where X is -CH2CH2CH2COOR1 and R1 is as defined above; The present invention provides a process including:

[0145] The present invention further relates to a compound of formula 11,15-syn 4b″, which is used for the preparation of beraprost.

[0146] [ka]

[0147] wherein Y is Cl, Br or I.

[0148] In the present invention, the racemic intermediate represented by the formula 11,15-syn 4b″ is represented by the formula 4b″-1, the formula 4b″-2, the formula 4b″-3 and the formula 4b″-4.

[0149] [ka]

[0150] The compound includes at least four 11,15-syn isomers represented by the formula:

[0151] 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-anti isomer. Thus, the amount of the undesired 11,15-anti isomer can be reduced to about 5%, 1% or 0.1% or less in the resulting intermediate mixture.

[0152] The present invention also relates to a compound of formula 4a″, which is used in the preparation of beraprost-314d.

[0153] [ka]

[0154] The present invention provides a novel optically active intermediate represented by the formula:

[0155] In the present invention, the compound represented by formula 4a″ has excellent crystallinity and can be easily crystallized by a crystallization process carried out 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. Furthermore, by repeating the crystallization process, the impurities generated from the preceding reaction can be reduced to about 5%, 1%, or 0.1% or less to produce a high purity compound.

[0156] All of the compounds and / or processes disclosed and claimed herein can be made and carried out without undue experimentation in light of this disclosure.Although the compounds and processes of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the art that modifications may be made to the compositions and / or methods described herein, and in the steps or sequence of steps of the methods, without departing from the concept, spirit and scope of the invention.Any similar substitutions and modifications that are apparent to those skilled in the art are considered to be within the spirit, scope and concept of the invention as defined by the appended claims. EXAMPLES

[0157] Example 1

[0158] (3-Bromo-2-fluorophenyl)(furan-2-yl)methanol

[0159] [ka]

[0160] To a solution of diisopropylamine (43.3 g, 0.43 mol) in dry THF (220 mL) was added dropwise n-BuLi (1.6 M (270 mL, 0.43 mol) in THF) under nitrogen at -50°C. The reaction mixture was warmed to -10°C. After 1 hour, the reaction mixture was cooled to -70°C. A solution of 1-bromo-2-fluorobenzene (50.0 g, 0.29 mol) in dry THF (200 mL) was added slowly thereto through a dropping funnel, and the reaction temperature was maintained between -70°C and -65°C. The reaction mixture was then stirred at -70°C for 30 minutes. Next, a solution of furfural (28.8 g, 0.30 mol) in dry THF (29 mL) was added slowly thereto through a dropping funnel, and the reaction temperature was maintained between -70°C and -65°C. The completion of the reaction was confirmed by TLC monitoring. The reaction mixture was quenched with saturated aqueous ammonium chloride (400 mL). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate (200 mL). The combined organic layers were dried over anhydrous Na2SO4. The solids were filtered off and the organic solvent was removed in vacuo to give 78 g of the crude title compound. Example 2

[0161] 5-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone

[0162] [ka]

[0163] p-TsOH-H2O (54.95 g, 0.29 mol) was added 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) and the reaction mixture was stirred at 60°C. After completion of the reaction, the mixture was quenched with 10% aqueous NaHCO3 (800 mL), the reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were dried over anhydrous Na2SO4. The solids were filtered off and the organic solvent was removed under vacuum to give 82.5 g of the crude title compound. Example 3

[0164] 2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone

[0165] [ka]

[0166] 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 completed by TLC monitoring. The mixture was washed with 10% aqueous NaCl (800 mL) and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 28.81 g (45%, 3 steps).

[0167] 1 H-NMR (400 MHz, CDCl3): δ 7.813-7.824 (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). Example 4

[0168] 2-(3-Bromo-2-fluorophenyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-enone

[0169] [ka]

[0170] 2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (51.0 g, 143.6 mmol, from Example 3) was dissolved in dichloromethane (510 mL). Then, acetic acid (740 mg, 9.4 mmol) and dihydropyridine (24 g, 285.3 mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC monitoring. The reaction mixture was quenched with 10% NaHCO3 aqueous solution (510 mL) and the reaction mixture was phase separated. The combined organic layer was dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 52 g (79%).

[0171] 1 H-NMR (400 MHz, CDCl3): δ 7.891-7.944 (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) Example 5

[0172] (R)-3-(3-bromo-2-fluorophenyl)-4-oxocyclopent-2-en-1-yl acetate

[0173] [ka]

[0174] 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 thereto. The reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was monitored by a chiral HPLC column. Lipase-SL was filtered from the reaction mixture, and the filtrate was concentrated to obtain a crude mixture (31.25 g).

[0175] Then, triphenylphosphine (15.18 g, 57.8 mmol) and acetic acid (3.47 g, 57.8 mmol) were added to the crude mixture in toluene (300 mL). The reaction mixture was stirred at room temperature until triphenylphosphine was dissolved in the reaction mixture. Then, diisopropyl azodicarboxylate was slowly added thereto. The completion of the reaction was confirmed by TLC monitoring. Further, the reaction solvent was distilled off under vacuum and the residue was suspended in a mixture of ethyl acetate (150 mL) and n-hexane (450 mL). The solid was filtered and the filtrate was distilled off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 26.6 g (92%).

[0176] 1 H-NMR (400 MHz, CDCl3): δ 7.809-7.819 (m, 1H), 7.736-7.769(m, 1H), 7.497-7.537(m, 1H), 7.020-7.060(m, 1H), 5.883-5.910(m, 1H), 2.964-3.028(m, 1H), 2.477-2.528(m, 1H), 2.090(s, 3H). Example 6

[0177] (R)-2-(3-Bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone

[0178] [ka]

[0179] 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 4 hours. Lipase-435 was filtered from the reaction mixture and the filtrate was concentrated to give the crude compound. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 10.65 g (83%).

[0180] 1 H-NMR (400 MHz, CDCl3): δ 7.816-7.828 (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). Example 7

[0181] (4R)-2-(3-bromo-2-fluorophenyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)cyclopent-2-enone

[0182] [ka]

[0183] (R)-2-(3-bromo-2-fluorophenyl)-4-hydroxycyclopent-2-enone (10.0 g, 37 mmol, from Example 6) was dissolved in dichloromethane (100 mL). Then, acetic acid (145 mg, 1.85 mmol) and dihydropyridine (4.67 g, 55.5 mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC monitoring. The reaction mixture was quenched with 10% aqueous NaHCO3 (100 mL) and the reaction mixture was phase separated. The organic layer was collected and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 10.99 g (83%).

[0184] 1 H-NMR (400 MHz, CDCl3): δ 7.873-7.927 (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, 18.8 Hz), 2.477-2.649 (m, 1H), 1.521-1.844 (m, 6H) Example 8

[0185] (R)-2-(3-bromo-2-fluorophenyl)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone

[0186] [ka]

[0187] (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). Then imidazole (0.75 g, 11.01 mmol) and tert-butyldimethylsilyl chloride (1.25 g, 8.23 ​​mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC monitoring. The reaction mixture was quenched with 10% aqueous NaHCO3 (100 mL) and the reaction mixture was phase separated. The combined organic layer was dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 1.64 g (77%).

[0188] 1 H-NMR (400 MHz, CDCl3): δ 7.741-7.787 (m, 2H), 7.509-7.550 (m, 1H), 7.042-7.084 (m, 1H), 5.051-5.078 (m, 1H), 2.880-2.941 (m, 1H), 2.438-2.489 (m, 1H), 0.931 (s, 9H), 0.157-0.176 (m, 6H) Example 9

[0189] (R)-Methyl 4-(3-(3-((tert-butyldimethylsilyl)oxy)-5-oxocyclopent-1-en-1-yl)-2-fluorophenyl)butanoate

[0190] [ka]

[0191] To a solution of methyl 3-butenoate (261 mg, 2.60 mmol) in dry THF (2.6 mL) was added 0.5 M (5.2 mL, 2.60 mmol) 9-BBN in THF dropwise under nitrogen at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 h. The solution was then transferred via cannula into a mixture of (R)-2-(3-bromo-2-fluorophenyl)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone (500 mg, 1.28 mmol, from Example 8), Ph3As (40 mg, 0.13 mmol), K3PO4 (827 mg, 3.90 mmol) and PdCl2(dppf) (95 mg, 0.13 mmol) in dry THF (5 mL) under nitrogen. The reaction mixture was stirred at 60° C. for 3 h. The mixture was quenched with hydrogen peroxide (30% aqueous solution, 7.8 mmol) and stirred at 0° C. for 30 min. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. The solids were filtered off and the organic solvent was removed in vacuo. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 211 mg (40%).

[0192] 1 H-NMR (400 MHz, CDCl3): δ 7.688-7.699 (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). Example 10

[0193] (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

[0194] [ka]

[0195] 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 dry diethyl ether (1000 mL) was added dropwise 1.9 M (360 mL, 684 mmol) tert-butyllithium in pentane at -70°C and stirred for 2 h at the same temperature. 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 THF was added thereto at -70°C. The reaction mixture was quenched with saturated aqueous ammonium chloride (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 combined organic layers were dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed in vacuo to give 426.6 g of the crude title compound. Example 11

[0196] (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

[0197] [ka]

[0198] (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)cyclopentanone (426.6 g, 699.7 mmol, crude product of Example 10) was diluted with dry THF (4.3 L) and the solution was then cooled to -70°C, followed by the addition of 1.0 M L-selectride in hexanes (258 mL, 258 mol) at -70°C. After the 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 min. The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed in vacuo. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 99.8 g (64%, 2 steps starting from Example 10).

[0199] 1 H-NMR (400 MHz, CDCl3): δ 7.422 (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). Example 12

[0200] (((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

[0201] [ka]

[0202] 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) was added t-BuOK (64.3 g, 573.1 mmol) at 60° C. under nitrogen. The reaction was completed by TLC monitoring. The mixture was washed with saturated aqueous ammonium chloride solution (1000 mL) and dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed in vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 79.2 g (83%).

[0203] 1H-NMR (400 MHz, CDCl3): δ 7.259 (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). Example 13

[0204] (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

[0205] [ka]

[0206] (((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 3N hydrochloric acid (76 mL) was added thereto. The reaction was stirred at room temperature and the progress of the reaction was checked by TLC. After completion of the reaction, the mixture was neutralized to pH 7-8 with 10% NaHCO3 aqueous solution (760 mL) and then concentrated to remove acetonitrile. The residue was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solid was filtered off and the organic solvent was removed under vacuum. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title 11,15-syn isomer was 26.3 g (52%) and the yield of the 11,15-anti isomer (15-epi isomer) was 11.1 g (22%). The compound was recrystallized from a solvent mixture of ethyl acetate and n-hexane to give 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.

[0207] 1 H-NMR (400 MHz, CDCl3): δ 7.259-7.294 (m, 1H), 6.992-7.032 (m, 1H), 6.698-6.730 (m, 1H), 5.563-5.706 (m, 2H), 5.186-5.235 (m, 1H), 4.029-4.194 (m, 1H), 3.924 (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). Example 14

[0208] 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

[0209] [ka]

[0210] To a solution of methyl 3-butenoate (2.9 g, 28.9 mmol) in dry 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 continued stirring for 3 h. The solution was then transferred via cannula into a mixture 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), Ph3As (390 mg, 1.3 mmol), K3PO4 (8.14 g, 38.3 mmol) and PdCl2(dppf)-CHCl2 (1.04 g, 1.3 mmol) in dry THF (50 mL) under nitrogen. The reaction mixture was stirred at 60° C. for 3 h. After completion of the reaction, the mixture was quenched with hydrogen peroxide (30% aqueous solution, 20 mL) and continued to stir at 0° C. for 30 min. After addition of saturated aqueous ammonium chloride (250 mL) to the reactor, the reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. The solids were filtered off and the organic solvent was removed in vacuo. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 3.74 g (71%).

[0211] 1H-NMR (400 MHz, CDCl3): δ 6.940 (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), 3.411-3.454 (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) Example 15

[0212] 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)

[0213] [ka]

[0214] 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 thereto at 10° C. After completion of the reaction, methanol was removed from the reaction mixture in vacuum. 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 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 removed in vacuo. The crude product was purified by silica gel chromatography using a mixture of hexane and ethyl acetate as gradient eluent. The yield of the title compound was 1.78 g (77%).

[0215] 1 H-NMR (400 MHz, CDCl3): δ 6.892-6.942 (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).

[0216] 13C-NMR (100 MHz, CDCl3): δ 178.685, 157.204, 134.016, 133.811, 133.325, 132.756, 129.621, 129.576, 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. Example 16

[0217] (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)cyclopentanone

[0218] [ka]

[0219] 2-Thienyl(cyano)copper lithium was prepared under dry nitrogen. To a solution of thiophene (6.84 g, 81.4 mmol) in dry THF (70 mL) was added 1.6 M n-butyllithium in hexane (46.3 mL, 74.1 mmol) dropwise at -10°C. After 1 h, the reaction mixture was cooled to -70°C. The solution was transferred via cannula into a suspension of copper cyanide (7.3 g, 81.5 mmol) in dry THF (73 mL) at -70°C and stirred for 30 min. 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 via cannula to the reaction mixture at −70° C. and stirred for 30 minutes. Then, 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 thereto. 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 combined organic layers were dried over anhydrous Na2SO4. The solids were filtered off and the organic solvent was removed in vacuo to give 60.2 g of the crude title compound. Example 17

[0220] (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

[0221] [ka]

[0222] Following the same procedure as in Example 11, 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). The yield of the title compound was 13.8 g (65%, 2 steps from Example 16).

[0223] 1 H-NMR (400 MHz, CDCl3): δ 7.422 (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, 4H), 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). Example 18

[0224] (((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

[0225] [ka]

[0226] Following the same procedure as in Example 12, 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). The yield of the title compound was 10.9 g (81%).

[0227] 1 H-NMR (400 MHz, CDCl3): δ 7.259 (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). Example 19

[0228] (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

[0229] [ka]

[0230] Following the same procedure as in 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.

[0231] 1 H-NMR (400 MHz, CDCl3): δ 7.258-7.277 (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), 3.463-3.508 (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). Example 20

[0232] 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

[0233] [ka]

[0234] Following a procedure similar to that 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, a 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.

[0235] 1 H-NMR (400 MHz, CDCl3): δ 6.886-6.931 (m, 2H), 6.711-6.748 (t, 1H), 5.501-5.656 (m, 2H), 5.015-5.070 (m, 1H), 3.969-4.007 (t, 1H), 3.809-3.869 (m, 1H), 3.628 (s, 3H), 3.541 (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).

[0236] 13C-NMR (100 MHz, CDCl3): δ 174.173, 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. Example 21

[0237] 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)

[0238] [ka]

[0239] Following a procedure similar to that of Example 15, a 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, a crystalline compound was obtained (251 mg, 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.

[0240] 1H-NMR (400 MHz, CDCl3): δ 6.904-6.941 (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), 2.229 (m, 2H), 1.879-2.005 (m, 3H), 1.717-1.788 (m, 4H), 0.967-0.984 (d, 3H).

[0241] 13 C-NMR (100 MHz, CDCl3): δ 178.287, 157.194, 134.052, 133.293, 129.582, 128.937, 123.199, 121.810, 120.504, 84.148, 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. Example 22

[0242] 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

[0243] [ka] Following the same procedure as in Examples 10, 11 and 12, the compound was obtained from (R)-methyl 4-(3-(3-((tert-butyldimethylsilyl)oxy)-5-oxocyclopent-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). The yield of the title compound was 7.6 g (48%, 3 steps).

[0244] 1 H-NMR (400 MHz, CDCl3): δ 6.963-6.982 (d, 1H), 6.895-6.912 (d, 1H), 6.708-6.745 (t, 1H, J= 7.6 Hz), 5.496-5.623 (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).

[0245] 13C-NMR (100 MHz, CDCl3): δ 174.105, 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.

Claims

1. Formula 1 【Chemistry 1】 (wherein P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substituted benzyl, and SiR a R b R c (In the formula, R a , R b and R c are each independently an unsubstituted or substituted alkyl or an unsubstituted or substituted aryl; X is Cl, Br, I, or -CH 2 CH 2 CH 2 COOR 1 and R 1 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. Formula (R)-1″, enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess (ee), 【Chemistry 2】 wherein X is Cl, Br or I, (1) Formula 1” 【Chemistry 3】 The compound represented by formula D 【Chemistry 4】 (wherein R 4 and R 5 are independently H or C 1 ~ 6 enantioselectively (R)-esterifying the (S)-alcohol with a first lipase derived from Achromobacter spp., Candida cylindracea, Alcaligenes spp., Candida antarctica, Pseudomonas cepacia, Burkholderia cepacia, or Pseudomonas stutzeri, or a mixture thereof, to form a mixture of (S)-alcohols and (R)-esters; (2) optionally removing the (S)-alcohol; (3) deacylation of the (R)-ester; A process including.

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

7. 6. The process of claim 5, wherein the deacylation step comprises a chemical hydrolysis reaction.

8. 6. The process of claim 5, wherein the deacylation step comprises an enzymatic cleavage reaction using a second lipase derived from Achromobacter spp., Alcaligenes spp., Candida Antarctica, Pseudomonas cepacia, Pseudomonas stutzeri, Pseudomonas spp., or a mixture thereof.

9. The step of removing the (S)-alcohol comprises reacting the (S)-alcohol with a compound of formula R in the presence of a dialkyl azodicarboxylate and a triarylphosphine. 4 COOH acyloxy donor (wherein R 4 is as defined in claim 5, converting the (S)-alcohol to the corresponding (R)-ester by reacting with

10. 10. The process of claim 9, wherein the dialkyl azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, and mixtures thereof.

11. 10. The process of claim 9, wherein the triarylphosphine is triphenylphosphine.

12. Formula 4 【Chemistry 5】 (wherein P is H, P 1 Or P 2 and R 2 is H or C 1 ~ 4 -alkyl; R 3 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; X is Cl, Br, I or -CH 2 CH 2 CH 2 COOR 1 and R 1 is C 1 ~ 7 -Alkyl or C 7 ~ 11 -aralkyl; P 1 and P 2 is methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substituted benzyl, and SiR a R b R c (In the formula, R a , R b and R c are protecting groups for a hydroxyl group selected from the group consisting of: (1) Formula 1' 【Chemistry 6】 A compound represented by the formula: 1 and X are as defined above) with the formula L 1 Or formula L 2 【Chemistry 7】 (wherein Y is Cl, Br or I; P 2 , R 2 and R 3 is as defined above) to form a compound of formula 2 【Chemistry 8】 A compound represented by the formula: 2 and R 3 where x is as defined above; (2) Reducing the ketone of the compound represented by formula 2 to obtain a compound represented by formula 3 【Chemistry 9】 A compound represented by the formula: 2 and R 3 where x is as defined above; (3) carrying out an intramolecular cyclization reaction of the compound represented by formula 3 to obtain a compound represented by formula 4 【Chemistry 10】 A compound represented by the formula: 2 and R 3 where x is as defined above; (4) optionally performing a deprotection reaction to remove the protecting groups for the hydroxyl groups; (5) Optionally carrying out a Suzuki cross-coupling reaction of a compound of formula 2, 3 or 4, where X is Cl, Br or I, to give a compound of formula 2, 3 or 4, where X is -CH 2 CH 2 CH 2 COOR 1 and R 1 where x is as defined above; A process including.

13. Formula 4a 【Chemistry 11】 An optically active compound represented by the formula: 1 Or P 2 and X is Cl, Br, I or -CH 2 CH 2 CH 2 COOR 1 and R 1 is C 1 ~ 7 -Alkyl or C 7 ~ 11 -aralkyl; P 1 and P 2 is methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substituted benzyl, and SiR a R b R c (In the formula, R a , R b and R c wherein each independently is an unsubstituted or substituted alkyl or an unsubstituted or substituted aryl; (1') Formula (R)-1a' 【Chemistry 12】 An optically active compound represented by the formula: 1 and X are as defined above) with the formula L 1a Or formula L 2a 【Chemistry 13】 (wherein Y is Cl, Br or I; P 2 is as defined above) to give a copper salt of formula 2a 【Chemistry 14】 wherein P and X are as defined above; (2') reducing the ketone of the compound represented by formula 2a to obtain a compound represented by formula 3a 【Chemistry 15】 wherein P and X are as defined above; (3') Intramolecular cyclization of the compound represented by formula 3a to obtain a compound represented by formula 4a 【Chemistry 16】 wherein P and X are as defined above; (4') optionally carrying out a deprotection reaction to remove the protecting groups for the hydroxyl groups; (5') Optionally carrying out a Suzuki cross-coupling reaction of a compound of formula 2a, 3a or 4a, where X is Cl, Br or I, to give a compound of formula 2a, 3a or 4a, where X is -CH 2 CH 2 CH 2 COOR 1 and R 1 where x is as defined above; A process including.

14. Equation 4b 【Chemistry 17】 A racemic compound represented by the formula: 1 Or P 2 and X is Cl, Br, I or -CH 2 CH 2 CH 2 COOR 1 and R 1 is C 1 ~ 7 -Alkyl or C 7 ~ 11 -aralkyl; P 1 and P 2 is methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, benzyl, substituted benzyl, and SiR a R b R c (In the formula, R a , R b and R c wherein each independently is an unsubstituted or substituted alkyl or an unsubstituted or substituted aryl; (1'') Equation 1' 【Chemistry 18】 A racemic compound represented by the formula: 1 and X are as defined above) with the formula L 1b Or formula L 2b 【Chemistry 19】 (wherein Y is Cl, Br or I; P 2 is as defined above), to give a copper salt derived from a racemic and diastereomeric mixture of 【Chemistry 20】 wherein P and X are as defined above; (2″) reducing the ketone of the compound represented by formula 2b to obtain a compound represented by formula 3b 【Chemistry 21】 wherein P and X are as defined above; (3″) Intramolecular cyclization of the compound represented by formula 3b to give formula 4b 【Chemistry 22】 wherein P and X are as defined above; (4″) optionally carrying out a deprotection reaction to remove the protecting groups for the hydroxyl groups; (5″) Optionally carrying out a Suzuki cross-coupling reaction of a compound of formula 2b, 3b or 4b, where X is Cl, Br or I, to give a compound of formula 2b, 3b or 4b, where X is —CH 2 CH 2 CH 2 COOR 1 and R 1 where x is as defined above; A process including.

15. Formula 4a'' 【Chemistry 23】 (wherein Y is Cl, Br or I)

16. 16. The compound of claim 15, wherein Y is Br.

17. Formula 11,15-syn 4b'' 【Chemistry 24】 (wherein Y is Cl, Br or I).

18. Formula 4b''-1, Formula 4b''-2, Formula 4b''-3 and Formula 4b''-4 【Chemistry 25】 18. The compound according to claim 17, including four isomers represented by the formula:

Images