Processes and intermediates for the preparation of carbaprostacyclin analogs

Abstract

To provide more efficient and selective methods for preparing carbaprostacyclin analogues, and intermediates.SOLUTION: The present invention provides a racemic or optically active compound represented by the following formula (where Y is -CH2OP or-COOR1; X is F, Cl, Br, I or -OTs; P is H or a hydroxy group protecting group; and R1 is C1-7-alkyl, aryl or aralkyl, each of which is unsubstituted or substituted by C1-4-alkyl, C2-7-alkenyl, C2-7-alkynyl, nitro, halogen or alkoxy).SELECTED DRAWING: None

Description

[Technical field]

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

[0002] Since the discovery of prostacyclin, many chemically and metabolically stable prostacyclin analogues have been developed as clinically effective antithrombotic agents. Among these, carbaprostacyclin analogues are some of the most attractive compounds. For example, iloprost and 16S-iloprost are effective in treating pulmonary hypertension and vascular diseases.

[0003] [ka] [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO2019 / 202345 [Non-patent literature]

[0005] [Non-Patent Document 1] Journal of Organic Chemistry, 1981, 46, 1954 [Non-Patent Document 2] Journal of Organic Chemistry, 1983, 48, 5341 [Non-Patent Document 3] Journal of the American Chemical Society, 2005, 127, 17910-17920 Summary of the Invention [Problem to be solved by the invention]

[0006] In the industrial field, the current methods for the mass production of carbaprostacyclin analogs, such as the methods described in Non-Patent Document 1, Non-Patent Document 2 and Patent Document 1, as shown in Scheme 1, use an expensive prostaglandin intermediate, Corey lactone, as a starting material and use a four-step reaction to convert bicyclic lactone A to bicyclic ketone B.

[0007] [ka]

[0008] However, almost none of these four steps can be considered as an efficient reaction. For example, Non-Patent Document 1 describes that in the alkylation reaction in the first step, about 20% of the starting material does not react completely, in the oxidation reaction in the second step, 29% or less of eliminated byproducts are generated, and in the intramolecular Horner-Wadworth-Emmons (HWE) reaction in the third step, a large amount of intermolecular byproducts is generated. Furthermore, Patent Document 1 describes that the yield of the hydrogenation step in the fourth step is only 23%. Therefore, the overall yield of the four-step reaction in the methods of Non-Patent Document 1 and Patent Document 1 is very low.

[0009] Furthermore, the synthesis procedure from bicyclic ketone B to carbaprostacyclin analogs, C5-C6(E)-olefins, is formed by the Wittig reaction of bicyclic ketone B, as shown in Scheme 2. However, the Wittig reaction described in Non-Patent Document 2 has very low selectivity and produces about 35% Z-type by-products (Z-isomer impurities). Patent Document 1 uses the same Wittig reaction to form C5-C6(E)-olefins, which also produces about 40% Z-type by-products (Z-isomer impurities), and it is very difficult to remove the produced Z-type by-products. Patent Document 1 describes that preparative HPLC can be used to reduce the amount of Z-type by-products to less than 0.2-0.5%. Patent Document 1 also describes that the unwanted Z-isomers can be isomerized to form a mixture of Z-isomers and E-isomers with a ratio of 1:1, but only a small amount of the desired E-isomer can be recycled from the mixture via preparative HPLC. This method is time consuming, expensive and difficult to mass produce.

[0010] [ka]

[0011] Furthermore, as shown in Scheme 3, Non-Patent Document 3 uses a short-chain chiral phosphonate represented by formula C to inhibit the production of Z-type by-products, but the chiral phosphonate represented by formula C is expensive and requires several additional reactions, which significantly increases the production cost.

[0012] [ka] [Means for solving the problem]

[0013] In view of the above, the present invention provides a more efficient and selective approach for producing carbacyclic prostacyclins such as iloprost and 16(S)-iloprost, in order to reduce production costs. In one aspect, the present invention provides a racemic or optically active cyclopentenone of formula 1:

[0014] [ka]

[0015] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an optically active cyclopentenone represented by formula (R)-1.

[0016] [ka]

[0017] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs, P is H or a hydroxyl protecting group, R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy, and the compounds have an optical purity of at least 95% enantiomeric excess. In one aspect, the present invention provides a novel method for producing an optically active cyclopentenone represented by formula (R)-1. In one aspect, the present invention provides a novel method for preparing a compound represented by formula (R)-1d.

[0018] [ka]

[0019] In the formula, X is F, Cl, Br, I or -OTs; R 4 is H or C 1-6 It is an alkyl. In one aspect, the present invention provides a method for preparing a compound of formula 4.

[0020] [ka]

[0021] In the formula, Y is -CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy; 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 - substituted by alkyl, halogen or trihalomethyl. In one aspect, the present invention provides a novel method for preparing a compound of formula 4a.

[0022] [ka]

[0023] In the formula, Y is -CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides a novel method for preparing a compound of formula 4b.

[0024] [ka]

[0025] In the formula, Y is -CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula 2 for the preparation of a carbaprostacyclin analogue.

[0026] [ka]

[0027] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy; R 2is 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 1-7 - substituted by alkyl, halogen or trihalomethyl. In one aspect, the present invention provides an intermediate of formula 2a for the preparation of a carbaprostacyclin analogue.

[0028] [ka]

[0029] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula 2b for the preparation of a carbaprostacyclin analogue.

[0030] [ka]

[0031] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7-substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula 3 for the preparation of a carbaprostacyclin analog.

[0032] [ka]

[0033] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy; 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 - substituted by alkyl, halogen or trihalomethyl. In one aspect, the present invention provides an intermediate of formula 3a for the preparation of a carbaprostacyclin analogue.

[0034] [ka]

[0035] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4-Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula 3b for the preparation of carbaprostacyclin analogs.

[0036] [ka]

[0037] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula 3' for the preparation of a carbaprostacyclin analog.

[0038] [ka]

[0039] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy; R 2 is H or C 1-4 -alkyl; R3 is C alkyl, C alkynyl, aryl or aryloxy, each of which is unsubstituted or 1-4 - substituted with alkyl, halogen or trihalomethyl. In one aspect, the present invention provides an intermediate of formula 3'a for the preparation of a carbaprostacyclin analog.

[0040] [ka]

[0041] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula 3'b for the preparation of a carbaprostacyclin analog.

[0042] [ka]

[0043] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7-substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula A2:

[0044] [ka]

[0045] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. In one aspect, the present invention provides an intermediate of formula A8:

[0046] [ka]

[0047] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] definition As used herein, unless otherwise specified, the term "alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to 30 (e.g., 1 to 10, 1 to 6, or 1 to 4) carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl, etc.; or a cyclic saturated hydrocarbon group having 3 to 10 (e.g., 3 to 8) carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, methyl, etc. An alkyl group can be unsubstituted or substituted.

[0049] The term "alkenyl," as used herein, unless otherwise indicated, refers to a straight or branched chain hydrocarbon group having 2 to 20 (e.g., 2 to 10) carbon atoms and one or more carbon-carbon double bonds, such as pentenyl, propenyl, etc.; or a cyclic unsaturated hydrocarbon group having 5 to 20 carbon atoms and one or more carbon-carbon double bonds, such as cyclopentenyl, cyclohexenyl, etc. An alkenyl group can be unsubstituted or substituted.

[0050] The term "alkynyl," as used herein, unless otherwise indicated, refers to a straight or branched chain hydrocarbon group containing 2 to 20 (e.g., 2 to 10) carbon atoms and one or more carbon-carbon triple bonds, e.g., 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. Alkynyl groups can be unsubstituted or substituted.

[0051] The term "aryl" as used herein refers to a monocyclic or polycyclic aromatic hydrocarbon group, such as phenyl, naphthyl, anthryl, phenanthryl, etc. Aryl groups can be unsubstituted or substituted.

[0052] The term "aralkyl" as used herein refers to a straight or branched chain hydrocarbon containing 1-20 (e.g., 1-10 or 1-6) carbon atoms and one or more aryl groups as described above, such as benzyl, benzhydryl, fluorenylmethyl, etc. The term "aryloxy" may be phenoxy, tolyloxy, xylyloxy, etc. The aralkyl or aryloxy group may be unsubstituted or substituted.

[0053] Each of the above alkyl, alkenyl, alkynyl, aryl and aralkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, aryloxy, thioalkoxy, 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 and the like.

[0054] The term "hydroxyl-protecting group" has its conventional meaning in synthetic organic chemistry, i.e., a group capable of protecting a functional group or moiety of a compound against attack by a chemical reaction. Protecting groups include methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl, and SiR. a R b R c These include, but are not limited to, R a , R b and R c are each independently 1-4Alkyl, aryl, aralkyl, substituted aryl or substituted benzyl, each of the aryl, benzyl and acyl being independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, aryl, alkoxy, aryloxy and the like.

[0055] TIFF0007680058000022.tif26170

[0056] Synthetic Route to Racemic or Optically Active Cyclopentenone (Formula 1) The present invention provides racemic or optically active cyclopentenones represented by formula 1.

[0057] [ka]

[0058] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy.

[0059] The compounds of formula 1 are enriched in the (R)-enantiomer and have an optical purity of at least 95%, at least 99%, or at least 99.9% enantiomeric excess.

[0060] According to the present invention, compounds of formula 1, such as racemic cyclopentenones of formula (±)-1a and (±)-1b, can be prepared according to the reaction shown in Scheme A. As shown in Scheme A, an α-bromo-α,β-unsaturated aldehyde compound of formula A2 is prepared by bromination reaction of a compound of formula A1 (step 1), and then the aldehyde compound of formula A2 is subjected to reduction reaction (step 2) to be converted to an allylic alcohol compound of formula A3. Further, a mesylation reaction (step 3) is carried out to convert the hydroxyl group in formula A3 to a mesylate group to form a compound of formula A4. The compound of formula A4 is then reacted with an organolithium compound of formula A4-1, which is prepared by reacting 2-(1,3-dithian-2-yl)furan with n-butyllithium, to form a compound of formula A5 via a substitution reaction (step 4). Compound A5 undergoes a desilylation reaction (step 5), a deprotection reaction (step 6) and a reduction reaction (step 7) to form compound A8. Compound A8 then undergoes a Piancatelli rearrangement (step 8) and an isomerization reaction (step 9) to give compound (±)-1a. Compound (±)-1a further undergoes a protection reaction (step 10) to give compound (±)-1b.

[0061] [ka]

[0062] Step 1 of Scheme A relates to a bromination reaction. In step 1, an α-bromo-α,β-unsaturated aldehyde compound represented by formula A2 is produced by treating an α,β-unsaturated aldehyde compound represented by formula A1 with a suitable reagent. Suitable reagents include, but are not limited to, a mixture of N-bromosuccinimide (NBS) and pyridine-N-oxide (PNO) in an acetonitrile system; OXONE® (KHSO) in a dichloromethane system; 5 -0.5KHSO 4 -0.5K 2 SO 4), a mixture of bromine and triethylamine; a mixture of bromine and pyridine in a dichloromethane system; a mixture of N-bromosuccinimide (NBS) and pyridine-N-oxide (PNO) preferably in an acetonitrile system; and OXONE® (KHSO 5 -0.5KHSO 4 -0.5K 2 SO 4 ), hydrobromic acid (HBr) and triethylamine. A mixture of N-bromosuccinimide (NBS) and pyridine-N-oxide (PNO) in acetonitrile system is more preferred at this stage. Surprisingly, according to the present invention, after analysis by HPLC, the novel brominated product of formula A2 is produced with a Z-selectivity of at least about 95%, at least about 99%, preferably at least about 99.5%, and most preferably at least about 99.9%. The brominated product of formula A2 is substantially free of E-isomer, does not contain more than 1.0% of E-isomer, does not contain more than 0.5% of E-isomer, or does not contain more than 0.1% of E-isomer.

[0063] As shown in Scheme B, the Z-isomer of the intermediate represented by formula A2 produced in step 1 will form the Z-isomer of the cyclopentenone represented by formula 1. The Z-isomer of the cyclopentenone represented by formula 1 will form the E-isomer of the final carbaprostacyclin. That is, the Z / E amount ratio of the isomers of the intermediate represented by formula A2 produced in step 1 completely corresponds to the amount of the final carbaprostacyclin.

[0064] [ka]

[0065] Therefore, the carbaprostacyclin synthesized from the Z-type compound represented by formula A2, which is substantially free of E-isomer, does not contain the corresponding undesired Z-isomer. In contrast, the conventional synthetic carbaprostacyclin produces a large amount of undesired Z-isomer, which can only be removed by using expensive preparative HPLC, and therefore cannot be used for mass production. The (E)-carbaprostacyclin synthesized in the present invention contains almost no Z-isomer, which can effectively reduce the cost of separating and removing undesired Z-isomer.

[0066] Step 2 of scheme A includes a reduction reaction. In step 2, the carbonyl group of the compound represented by formula A2 is reduced to a hydroxyl group with a reducing agent. Suitable reducing agents include, but are not limited to, sodium borohydride, 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(sec-butyl)borohydride (L-selectride), sodium tri(sec-butyl)borohydride (N-selectride), potassium tri(sec-butyl)borohydride (K-selectride), lithium triamylborohydride, potassium triamylborohydride and mixtures thereof, with sodium borohydride being more preferred as the reducing agent in this step.

[0067] Step 3 of Scheme A relates to a mesylation reaction. In step 3, the mesylate group as a leaving group of the compound of formula A4 can be obtained from protecting the hydroxyl group of the compound of formula A3 by using mesyl chloride and triethylamine in dichloromethane at 0°C.

[0068] Step 4 of Scheme A relates to a substitution reaction. In step 4, the compound represented by formula A5 can be produced by a substitution reaction using an organolithium compound represented by formula A4-1 prepared from 2-(1,3-dithian-2-yl)furan and n-butyllithium, preferably carried out at a temperature ranging from about -70°C to about -50°C.

[0069] Step 5 of Scheme A involves a desilylation reaction. In step 5, the desilylation reaction of the compound represented by formula A5 to form the compound represented by formula A6 is carried out by using a suitable reagent. Suitable reagents include, but are not limited to, tetra-n-butylammonium fluoride (TBAF), hydrogen chloride, and mixtures thereof. In this step, hydrogen chloride is more preferred.

[0070] Step 6 of scheme A relates to deprotection reaction. In step 6, deprotection reaction of compound represented by formula A6 to form compound represented by formula A7 is carried out by using a suitable reagent. Suitable reagents include, but are not limited to, bis(trifluoroacetoxy)iodobenzene (PIFA), iodine, mercuric oxide (HgO) and mixtures thereof. In this step, bis(trifluoroacetoxy)iodobenzene (PIFA) is more preferred as the deprotection agent.

[0071] Step 7 of scheme A includes a reduction reaction. In step 7, the ketone group of the compound represented by formula A7 is reduced to a hydroxyl group using a reducing agent to form a compound represented by formula A8. Suitable reducing agents include, but are not limited to, sodium borohydride, 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(sec-butyl)borohydride (L-selectride), sodium tri(sec-butyl)borohydride (N-selectride), potassium tri(sec-butyl)borohydride (K-selectride), lithium triamylborohydride, potassium triamylborohydride and mixtures thereof, with sodium borohydride being more preferred as the reducing agent in this step.

[0072] Step 8 of Scheme A involves a Piancatelli rearrangement. In step 8, the reaction is carried out in a suitable phosphate buffer solution and then heated to reflux. Suitable phosphate buffers for this step include K, K2SO4, K3SO4, K4SO4, K5SO4, K6SO4, K7SO4, K8SO4, K9SO4, K10SO4, K12SO4, K10SO4, K20SO4, K10SO4, K20SO4, K12SO4, K20SO4, K10SO4, K20SO4, K10SO4, K20SO4, K20SO4, K3 ... 2 HPO 4 and H 3 PO 4 It can be prepared using:

[0073] Step 9 of Scheme A involves an isomerization rearrangement. In step 9, the reaction can be carried out by using hydridochloral and triethylamine in tetrahydrofuran.

[0074] Step 10 of Scheme A involves a silylation reaction, which can be carried out using tert-butyldimethylsilyl chloride and imidazole in tetrahydrofuran at less than 20° C. The primary alcohol can be first protected to form a compound of formula 1b. Thus, the present invention further provides novel compounds of formula A2.

[0075] [ka]

[0076] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. The present invention further provides novel compounds of formula A8.

[0077] [ka]

[0078] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy.

[0079] Chiral resolution of cyclopentenone (formula (R)-1), Compounds of formula (R)-1, enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess, preferably at least about 99% enantiomeric excess, and most preferably at least about 99.9% enantiomeric excess, can be prepared from a starting compound of formula 1. Compounds of formula (R)-1 have the following structure:

[0080] [ka]

[0081] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P 1 is H or a hydroxyl protecting group, R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. This manufacturing method is (1) Racemic compound represented by formula 1

[0082] [ka]

[0083] (wherein Y and X are as defined above) with an acyl donor represented by formula D

[0084] [ka] (In the formula, R 4 and R 5 are independently H or C 1-6 (R)-esterification reaction of the (R)-1b′ alkyl group with a first lipase to produce an (R)-ester represented by formula (R)-1b′ and an unreacted (S)-alcohol represented by formula (S)-1.

[0085] [ka]

[0086] forming a (2) removing unreacted (S)-alcohol; and (3) Deacylation of the resulting (R)-ester Includes.

[0087] In step 1, the acyl donor represented by formula D may be vinyl acetate, isopropenyl acetate, vinyl valerate, isopropenyl valerate, vinyl butyrate, isopropenyl butyrate or mixtures thereof. The first lipase is commercially available and may be derived from Burkholderia cepacia, Candida antarcitica, Alcaligenese sp., Pseudomonas stutzri, Pseudomonas cepacia or mixtures thereof.

[0088] The removing step in (2) is carried out by reacting the (S)-alcohol with a compound of formula R in the presence of a dialkyl azodicarboxylate and a trialkyl / triaryl phosphine. 4 COOH(wherein, R 4 is H or C 1-6 The method includes converting the unreacted (S)-alcohol to the corresponding (R)-ester by reacting with an acyloxy donor represented by the formula (I) (R)-alkyl. 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-nitrobenzyl azodicarboxylate (DNAD), dicyclopentyl azodicarboxylate (DCPAD) and mixtures thereof; preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate and mixtures thereof. Suitable trialkyl / triaryl phosphines include, but are not limited to, tri-n-butylphosphine, triphenylphosphine and mixtures thereof, preferably triphenylphosphine.

[0089] The deacylation step in (3) comprises an enzymatic cleavage reaction using a second lipase derived from Candida cylindracea, Pseudomonas stutzri, Alcaligenese sp., Achromobacter sp., Burkholderia cepacia, Candida antarcitica or a mixture thereof, preferably Candida antarcitica. In some embodiments, the deacylation step in (3) is chemical hydrolysis.

[0090] Synthetic route to optically active cyclopentenone, formula (R)-1b Scheme C illustrates a method for preparing an optically active cyclopentenone of formula (R)-1b. The reaction shown in Scheme C allows chiral resolution of racemic cyclopentenone of formula (±)-1b to form a cyclopentenone enriched in the (R)-enantiomer and having high optical purity. As shown in Scheme C, the racemic compound of formula (±)-1b is resolved via enantioselective esterification (step 1) using a first lipase to form a mixture of unreacted alcohol of formula (S)-1b and compound of formula (R)-1c. The mixture can then be directly subjected to a Mitsunobu reaction (step 2) to convert the alcohol of formula (S)-1b to compound of formula (R)-1c. Finally, the compound of formula (R)-1c is deacylated to form compound of formula (R)-1b with high optical purity by using chemical hydrolysis or enzymatic cleavage (step 3).

[0091] [ka]

[0092] In step 1 of Scheme C, the enantioselective esterification of a cyclopentenone of formula (±)-1b is carried out with an acyl donor of formula D, where R 4 and R 5 are independently H or C 1-6The reaction can be carried out using a first lipase, such as an acyl donor (alkyl), in which the acyl donor reacts preferentially with the (R)-form of cyclopentenone, thereby producing a mixture of essentially the optically active ester of formula (R)-1c and unreacted alcohol of formula (S)-1b.

[0093] [ka]

[0094] In some embodiments, suitable first lipases are commercially available and may be derived from Burkholderia cepacia, Candida antarcitica, Alcaligenese sp., Pseudomonas stutzri, Pseudomonas cepacia or mixtures thereof, preferably Alcaligenese sp. or Burkholderia cepacia, 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 may be carried out in a single organic solvent, such as hexane, cyclohexane, toluene, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, ether, isopropyl ether, methyl isopropyl ether, tert-butyl methyl ether, or mixtures thereof. Suitable reaction temperatures range from about 5° C. to about 50° C., preferably ambient temperature.

[0095] Step 2 of Scheme C involves a Mitsunobu reaction. In the Mitsunobu reaction, the unreacted alcohol of formula (S)-1b is reacted with an azodicarboxylate of formula R in the presence of a dialkyl azodicarboxylate and a trialkyl / triaryl phosphine in a suitable solvent to afford an azodicarboxylate of formula R 4 COOH(wherein, R 4 is H or C 1-6(R)-1c. 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-nitrobenzyl azodicarboxylate (DNAD), dicyclopentyl azodicarboxylate (DCPAD) and mixtures thereof; preferably diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate and mixtures thereof. 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 is preferably carried out at a suitable temperature ranging from about -30°C to about 70°C, preferably at ambient temperature.

[0096] Step 3 of Scheme C relates to a deacylation reaction. In one embodiment, the deacylation reaction in step 3 of Scheme C is a chemical hydrolysis in the presence of an alcohol and a base (e.g., lithium hydroxide, sodium hydroxide, or potassium hydroxide). In another embodiment, 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 at a suitable temperature in the presence of a second lipase to obtain a compound represented by formula (R)-1b. Suitable second lipases are commercially available and are derived from Candida cylindracea, Pseudomonas stutzri, Alcaligenese sp., Achromobacter sp., Burkholderia cepacia, Candida antarcitica, or mixtures thereof; preferably Alcaligenese sp., Burkholderia cepacia, Candida antarcitica, or mixtures thereof; most preferably from Burkholderia cepacia. Suitable organic solvents and temperatures for this step are apparent to those skilled in the art.

[0097] According to the present invention, the deacylation reaction is monitored for the optical purity of the resulting compound of formula (R)-1b. In some embodiments, the deacylation reaction is monitored by HPLC using a chiral column and can be stopped by removing the enzyme when the optical purity of the resulting compound drops to preferably about 95% ee, preferably about 99% ee, more preferably about 99.9% ee. In some embodiments, the unreacted ester of formula (R)-1c and its enantiomer can be removed by column chromatography or the like after the deacylation reaction. According to the present invention, the compound of formula (R)-1b has an optical activity of at least about 95% ee, preferably at least about 99% ee, most preferably at least about 99.9% ee.

[0098] Synthetic route to optically active cyclopentenone (formula (R)-1d) Scheme D illustrates a method for preparing racemic cyclopentenone represented by formula (R)-1d. According to the reaction shown in Scheme D, racemic cyclopentenone represented by formula (±)-1a can be easily chirally resolved to form cyclopentenone enriched in the (R)-enantiomer and having high optical purity according to the reaction. As shown in Scheme D, the racemic compound represented by formula 1a is resolved by enantioselective esterification (step 1) using a first lipase to form a mixture of alcohol represented by formula (S)-1e and compound represented by formula (R)-1d. This mixture can then be directly subjected to a Mitsunobu reaction (step 2) to convert the alcohol represented by formula (S)-1e to compound represented by formula (R)-1d.

[0099] [ka]

[0100] In step 1 of Scheme D, the enantioselective esterification of a compound of formula (±)-1a is carried out by reacting a first lipase with an acyl donor of formula D in an organic solvent at a suitable temperature.

[0101] [ka]

[0102] (In the formula, R 4 and R 5 are each independently H or C 1-6 (alkyl).) to give a mixture of compounds represented by formula (R)-1d and (S)-1e.

[0103] Examples of suitable first lipases include, but are not limited to, Burkholderia cepacia, Candida antarcitica, Alcaligenese sp., Pseudomonas stutzri, Pseudomonas cepacia, and mixtures thereof, preferably Burkholderia cepacia or Alcaligenese sp., with Burkholderia cepacia being most preferred.

[0104] Examples of 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 reaction can be carried out in a single organic solvent, such as hexane, cyclohexane, toluene, tetrahydrofuran, methyl ethyl ketone, methyl isobutyl ketone, ether, isopropyl ether, methyl isopropyl ether, tert-butyl methyl ether, or mixtures thereof. Suitable reaction temperatures are about 5-50° C., particularly ambient temperature.

[0105] In step 2 of Scheme D, the compound represented by formula (S)-1e in the mixture obtained in step 1 of Scheme D can be easily removed by column purification due to the difference in polarity between the alcohol and the ester, to give the compound represented by formula (R)-1d.

[0106] In some embodiments, it is not necessary to separate the compounds of formula (R)-1d and (S)-1e from the mixture obtained in step 1 of Scheme D. Instead, a Mitsunobu conversion reaction can be carried out to convert the compound of formula (S)-1e to the corresponding (R)-ester. The unreacted compound of formula (S)-1e can be converted to the corresponding (R)-ester by the addition of a 2-methyl-2-propanediol (DMSO) to the corresponding (R)-ester. 4 COOH(wherein, R 4 is H or C 1-6(R)-1d, which is an alkyl group.) and then can be converted to a compound of formula (R)-1d in the presence of a dialkyl azodicarboxylate and a trialkyl / triaryl phosphine in a suitable solvent. Examples of suitable dialkyl azodicarboxylates include 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-nitrobenzyl azodicarboxylate (DNAD), dicyclopentyl azodicarboxylate (DCPAD) and mixtures thereof; examples of suitable trialkyl / triaryl phosphine include tri-n-butylphosphine, triphenylphosphine or mixtures thereof; triphenylphosphine is preferred. Additionally, suitable solvents for the reaction include, but are not limited to, tetrahydrofuran, toluene, benzene, dimethylformamide, diethyl ether, acetonitrile, dichloromethane, and mixtures thereof. The reaction is preferably carried out at a reaction temperature ranging from about -30°C to about 70°C, particularly at ambient temperature.

[0107] Thus, the present invention provides a method for preparing a compound of formula (R)-1d, which is enriched in the (R)-enantiomer and has an optical purity of at least 95% enantiomeric excess.

[0108] [ka]

[0109] In the formula, X is F, Cl, Br, I or -OTs; R 4 is H or C 1-6 It is an alkyl. The present manufacturing method comprises the steps of: (1) Compound represented by formula 1a

[0110] [ka]

[0111] (wherein X is F, Cl, Br, I or -OTs) with an acyl donor represented by formula D

[0112] [ka]

[0113] (In the formula, R 4 and R 5 are independently H or C 1-6 (R)-esterification is carried out enantioselectively by reaction with a first lipase to produce a mixture of a compound represented by formula (R)-1d and a compound represented by formula (S)-1e.

[0114] [ka]

[0115] forming a (2) Removal of the compound represented by formula (S)-1e Includes.

[0116] Synthetic route to optically active cyclopentenone (formula (R)-1f) As shown in Scheme E, a compound of formula (R)-1d (wherein R 4 is H or C 1-6 The cyclopentenone of formula (R)-1a is deacylated to form a compound of formula (R)-1a via an enzymatic cleavage reaction using a lipase (step 1). The hydroxyl group in the compound of formula (R)-1a is then protected to form a compound of formula (R)-1f.

[0117] [ka]

[0118] Step 1 of Scheme E is a deacylation reaction by using chemical hydrolysis or enzymatic cleavage. This reaction can be carried out via enzymatic cleavage in the presence of a commercially available lipase at a suitable temperature in a suitable organic solvent or aqueous system to obtain the compound represented by formula (R)-1a. Examples of suitable lipases include, but are not limited to, Candida antarcitica, Burkholderia cepacia, or mixtures thereof, preferably Burkholderia cepacia.

[0119] The deacylation reaction is monitored for the optical purity of the compound represented by formula (R)-1a. In some embodiments, the deacylation reaction is monitored by HPLC using a chiral column and is preferably stopped by removing the lipase when the optical purity of the resulting compound drops to about 95% ee, preferably about 99% ee, more preferably about 99.9% ee.

[0120] Step 2 of Scheme E involves a protection reaction. The protection reaction can be carried out using a suitable base reagent and tert-butyldimethylsilyl chloride at a temperature ranging from about 25° C. to about 80° C. Suitable base reagents include, but are not limited to, imidazole, triethylamine, and mixtures thereof. In this step, imidazole is more preferred as the base reagent.

[0121] Synthetic route to optically active cyclopentenone (formula (R)-1j) As shown in Scheme F, the compound of formula (R)-1d(R 4 is H or C 1-6 ) is selectively deacylated to give a cyclopentenone represented by the formula (R)-1g (R 4 is as defined above.) is obtained (Step 1). Next, the hydroxyl group of the compound represented by formula (R)-1g is oxidized to obtain a primary alcohol represented by formula (R)-1h (R 4 is as defined above. A carboxylic acid for forming a compound represented by formula (R)-1h can then be obtained (step 2). 1 OH(R1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy.) with an acid catalyst to give a compound of formula (R)-1i via deacylation and esterification (step 3). Finally, the secondary alcohol of formula (R)-1i is protected to give a compound of formula (R)-1j (step 4).

[0122] [ka]

[0123] Step 1 of Scheme F involves a selective deacylation reaction. This reaction is carried out via an enzymatic cleavage reaction in the presence of a commercially available lipase at a suitable temperature in a suitable organic solvent or aqueous system to obtain a compound of formula (R)-1g. Examples of suitable lipases include Candida Cylindracea, Pseudomonas stutzri, Alcaligenese sp., Achromobacter sp., Burkholderia Cepacia, Candida antarcitica or mixtures thereof, more preferably the lipase is from Burkholderia Cepacia or Candida antarcitica, most preferably from Candida antarcitica. Other operating conditions for this reaction are apparent in the art.

[0124] Step 2 of Scheme F involves an oxidation reaction. In this reaction, a primary alcohol represented by formula (R)-1g is oxidized under suitable oxidation conditions to give a carbonyl acid group. Suitable oxidizing agents include, but are not limited to, potassium permanganate (KMnO 4 ), Jones reagent, pyridinium chlorochromate (PCC) in dimethylformamide (DMF), ruthenium tetroxide (RuO4 ), 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), bis(acetoxy)iodobenzene (BAIB) and a mixture thereof, preferably 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) / bis(acetoxy)iodobenzene (BAIB), which form the compound represented by formula (R)-1h.

[0125] Step 3 of Scheme F relates to a one-step reaction including deacylation (at C11) and esterification (at C1) of the compound represented by formula (R)-1h. In some embodiments, the deacylation of the acyl group at C11 of the compound represented by formula (R)-1h and the esterification of the -COOH group at C1 of the compound represented by formula (R)-1h can be carried out in the presence of 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, both the deacylation and esterification of the compound represented by formula (R)-1h are carried out in the presence of sulfuric acid and methanol.

[0126] Step 3 of Scheme F also involves a stepwise reaction involving deacylation followed by esterification, which can be carried out via an enzymatic cleavage reaction in the presence of a commercially available lipase in a suitable organic solvent or aqueous system at a suitable temperature to give a compound of formula (R)-1h'.

[0127] [ka]

[0128] Suitable lipases include, but are not limited to, those derived from Candida cylindracea, Pseudomonas stutzri, Alcaligenese sp., Achromobacter sp., Burkholderia cepacia, Candida antarcitica and mixtures thereof; more preferably, Alcaligenese sp., Burkholderia cepacia, Candida antarcitica and mixtures thereof; most preferably, Burkholderia cepacia. Other operating conditions will be apparent to those skilled in the art.

[0129] Next, the compound represented by formula (R)-1h′ is reacted with a compound represented by formula R 1 OH (in the formula, R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy to give a compound of formula (R)-1i.

[0130] Step 4 of Scheme F involves a protection reaction. The protection reaction can be carried out using a suitable base reagent and tert-butyldimethylsilyl chloride at a temperature ranging from about 25° C. to about 80° C. Suitable base reagents include, but are not limited to, imidazole and triethylamine. In this step, imidazole is more preferred as the base reagent.

[0131] Preparation of Compounds of Formula 4 Starting from a compound of formula 1, a compound of formula 4 (wherein Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; P is H or a hydroxyl protecting group; R 1 is C 1-7-alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy; 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 The synthesis of carbaprostacyclin analogs represented by the formula (I) is based on the synthetic route shown in Scheme G.

[0132] [ka]

[0133] In step 1 of scheme G, a cyclopentanone represented by formula 2 (wherein P, X, Y, R 2 and R 3 is as defined above.) is a compound represented by the formula 1 and a compound represented by the formula L 1 Halides represented by formula L 2 or a vinylstannane represented by the formula L 3 Cuprates derived from alkynes represented by

[0134] [ka]

[0135] (In the formula, X 1 is Cl, Br or I, P 2 is a hydroxyl protecting group, R 2 and R 3can be prepared by a coupling reaction of the ω-side unit of (which is as defined above, as described in Chen et al. (J. Org. Chem., 1978, 43, 3450; US 4,233,231; US ​​4,415,501; and US 6,294,679, all of which are incorporated herein by reference) in a suitable solvent, which may be tetrahydrofuran, 2-methyltetrahydrofuran, ethyl ether, isopropyl ether, methylbutyl ether, dimethoxyethane, toluene, heptane or hexane or a mixture thereof, preferably at a temperature in the range of -100°C to 40°C.

[0136] Step 2 of Scheme G involves an olefination reaction. In this reaction, the carbonyl group in formula 2 is converted to a terminal double bond under olefination such as Peterson olefination, Julia olefination, Wittig olefination, Kauffmann olefination, Tebbe olefination and Nysted olefination. Preferably, the compound represented by formula 2 is treated with Nozaki-Lombardo reagent (Bull. Chem. Soc. Jpn., 53, 1698(1980)), which can be prepared from dibromomethane, zinc and titanium(IV) chloride, to give the compound represented by formula 3. This reaction can be carried out in any suitable solvent, such as selected from dichloromethane, tetrahydrofuran, ether, toluene, hexane and mixtures thereof. The reaction can be carried out at a temperature ranging from -50°C to 100°C, preferably from -20°C to room temperature. The Nozaki-Lombardo reagent can be used in an amount that allows the reactants to react completely, as monitored by thin layer chromatography (TLC). Upon completion of the reaction, the compound of formula 3 can be isolated from the reaction mixture by work-up procedures such as removal of excess reagents, extraction, drying, concentration, and the like.

[0137] In some embodiments, the methylene group can be introduced by a two-step procedure taught by Johnson (J. Am. Chem. Soc. 95, 6462 (1973)). For example, cyclopentanone of formula 2 is reacted with the anion of methylphenyl-N-methylsulfoximine in a suitable solvent, followed by treatment of the resulting crude adduct with aluminum amalgam in a solvent mixture of water-acetic acid-tetrahydrofuran to give the compound of formula 3.

[0138] This relates to the intramolecular cross-coupling reaction in step 3 of scheme G, i.e., intramolecular cyclization or intramolecular Suzuki reaction. The intramolecular cyclization reaction is an intramolecular Suzuki reaction with a boron reagent using a palladium catalyst and a base, resulting in a compound represented by formula 4. In this step, the intramolecular cross-coupling reaction includes two steps, regioselective hydroboration and Suzuki reaction, as shown in scheme G-1.

[0139] [ka]

[0140] In the first step, the compound represented by formula 3 can be treated with a borane reagent via regioselective hydroboration, and then the terminal double bond in formula 3 can be converted to an alkyl-9-borane intermediate represented by formula 3-1. Suitable boron reagents can be 9-borabicyclo[3.3.1]nonane (9-BBN), disiamylborane, diisoamylborane, catecholborane, diisopinocamphenylborane, dicyclohexylborane, bis(pinacolato)diborane, or mixtures thereof. More preferred as the boron reagent is 9-borabicyclo[3.3.1]nonane (9-BBN).

[0141] The second step involves treating the intermediate of formula 3-1 with a palladium catalyst in the presence of a base reagent at a temperature ranging from about 50° C. to about 60° C. under nitrogen or argon to form the compound of formula 4 via Suzuki cross-coupling. Suitable palladium catalysts include, but are not limited to, Pd(PPh 3 ) 4 , Pd(dppf) 2 Cl 2 -DCM, Pd(dppf) 2 Cl 2 , Pd(OAc) 2 , Pd 2 (dba) 2 , bis(η-allyl-μ-chloropalladium(II)), and mixtures thereof. Suitable base reagents can also enhance the reactivity of alkylboranes towards the formation of Pd-halide complexes to enhance the cross-coupling rate. Suitable base reagents include, but are not limited to, Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , NaOMe, K 3 PO 4 , t-BuONa, t-BuOK, K 3 PO 4 , NaOH, and mixtures thereof. In some embodiments, the Suzuki cross-coupling reaction is carried out in tetrahydrofuran solvent at 60° C. with Pd(dppf) 2 Cl 2 and Na 2 CO 3 It is carried out in the presence of

[0142] Step 3 of Scheme G relates to an intramolecular cross-coupling reaction. In some embodiments, the intramolecular cross-coupling reaction includes three steps, namely, hydroboration-oxidation (step 3-1), alkylsulfonation (step 3-2), and intramolecular cross-coupling reaction (step 3-3), as shown in Scheme G-2.

[0143] [ka]

[0144] Step 3-1 of Scheme G-2 involves a hydroboration-oxidation reaction. A compound of formula 3 is reacted with a boron reagent and then oxidized with basic hydrogen peroxide to give an alcohol compound of formula 3'. Suitable borane reagents include, but are not limited to, PY 2 BH 2 , sodium tetrahydroborate, borane·THF, borane·DMS and 9-BBN.

[0145] In step 3-2 of scheme G-2, the alcohol compound of formula 3' is further subjected to a sulfonylation reaction to obtain a compound of formula 3'' (wherein Z is a sulfonyl group consisting of alkylsulfonyl, arylsulfonyl, and aralkylsulfonyl (e.g., methanesulfonyl or p-toluenesulfonyl). The sulfonylation reaction is accomplished by using a suitable sulfonyl donor (e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride) in the presence of a base such as an amine (e.g., triethylamine).

[0146] Step 3-3 of Scheme G-2 involves an intramolecular cross-coupling reaction. Carbaprostacyclin analogs of formula 4 can be prepared by intramolecular cyclization of compounds of formula 3'' under suitable basic conditions. In some embodiments, the intramolecular cyclization is accomplished by using a suitable base in a suitable solvent at a temperature ranging from about -70°C to about -50°C. Suitable bases include, but are not limited to, n-butyllithium, sec-butyllithium, tert-butyllithium, and mixtures thereof. Suitable solvents include, but are not limited to, tetrahydrofuran, ether, toluene, and mixtures thereof. Thus, the present invention provides a method for preparing a compound of formula 4.

[0147] [ka]

[0148] In the formula, Y is -CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy; R 2 is H or C 1-4 -alkyl; R 3 is C 1-7 Alkyl, C 1-7 alkynyl, aryl or aryloxy, each of which is unsubstituted or substituted with C1-4 alkyl, halogen or trihalomethyl. This manufacturing method (1) Starting compound represented by formula 1

[0149] [ka]

[0150] (Wherein, X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; Y is as defined above; and a compound of formula L 1 , formula L 2 Or formula L 3 Starting cuprate derived from a compound represented by

[0151] [ka]

[0152] (In the formula, X 1 is Cl, Br or I; P 2 is a hydroxyl protecting group; R 2 and R 3 is as defined above.) to give a compound represented by formula 2

[0153] [ka]

[0154] (In the formula, P, X, Y, R 2 and R 3 is as defined above; (2) Methylenation of the ketone group of the compound represented by formula 2 to obtain a compound represented by the following formula 3:

[0155] [ka]

[0156] (In the formula, P, X, Y, R 2 and R 3 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

[0157] [ka]

[0158] (In the formula, P, Y, R 2 and R 3 is as defined above; and (4) P 1 and / or P 2 A deprotection reaction is optionally carried out to remove

[0159] The present invention further provides novel intermediates of formula 2.

[0160] [ka]

[0161] In the formula, Y is -CH 2 OP or -COOR1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -Alkynyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy; R 2 is H or -C 1-4 ;R 3 is C 1-7- Alkyl, C 2-7- alkynyl, aryl, or aryloxy, each of which is unsubstituted or C 1-7 - substituted with alkyl, halogen or trihalomethyl.

[0162] The present invention further provides novel intermediates of formula 3.

[0163] [ka]

[0164] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -Alkynyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy; R 2 is H or -C 1-4 ;R 3 is C 1-7 -Alkyl, C 2-7 -alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-7- substituted with alkyl, halogen or trihalomethyl. The present invention further provides novel intermediates of formula 3″.

[0165] [ka]

[0166] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy; R 2 is H or -C 1-4 ;R 3 is C 1-7 -Alkyl, C 2-7 -alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-4 - substituted by alkyl, halogen or trihalomethyl.

[0167] The intermediate of formula 3'' is preferably a compound of formula 3''a or a compound of formula 3''b. [ka]

[0168] In the formula, Y, X, Z and P are as defined above.

[0169] Synthetic Route of Formula 4a Used to Form 16S-Iloprost The synthesis of compounds of formula 4a, as shown in Scheme H, is similar to the synthesis of compounds of formula 4, as shown in Scheme G.

[0170] [ka]

[0171] The synthesis of the compound represented by formula 4a can be carried out by the synthesis of an optically enriched compound represented by formula (R)-1, where Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy; and 1a , formula L 2a Or formula L 3a Optically enriched (3S,4S)-compounds represented by

[0172] [ka]

[0173] (In the formula, X 1 is Cl, Br or I; P 2 is a hydroxyl protecting group.)

[0174] As shown in Scheme H, the compound represented by formula 2a can be prepared by the reaction of formula L 1a Halides represented by formula L 2a or a vinylstannane represented by the formula L 3aThe enantiomerically enriched ω-side unit of the cuprate derived from an alkyne of formula (R)-1 is coupled with a cyclopentenone of formula (R)-1 to give a compound of formula 2a (step 1). The compound of formula 2a is then subjected to an olefination reaction (step 2) and an intramolecular cyclization reaction (step 3) to give a compound of formula 4a. In some embodiments, the intramolecular cyclization reaction is an intramolecular Suzuki reaction with a boron reagent using a palladium catalyst and a base to give a compound of formula 4a. Thus, the present invention provides a method for preparing a compound of formula 4a.

[0175] [ka]

[0176] In the formula, Y is -CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. The present manufacturing method comprises the steps of: (1) Optically enriched compound represented by formula (R)-1

[0177] [ka]

[0178] (Wherein, X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; Y is as defined above; and a compound of formula L 1a , formula L 2a Or formula L 3a A compound represented by

[0179] [ka]

[0180] (In the formula, X 1 is Cl, Br or I, P 2 is a hydroxyl protecting group.) to give a compound represented by formula 2a

[0181] [ka]

[0182] wherein P, X and Y are as defined above; (2) Methylenation of the ketone group of the compound represented by formula 2a to give a compound represented by formula 3a

[0183] [ka]

[0184] wherein P, X and Y are as defined above; (3) carrying out an intramolecular cyclization reaction to the compound represented by formula 3a to obtain a compound represented by formula 4a

[0185] [ka]

[0186] wherein P and Y are as defined above; and (4) Arbitrarily P 1 and / or P 2 A step of carrying out a deprotection reaction to remove Includes.

[0187] In this production method, the intramolecular cyclization reaction is (1) Hydroboration of the compound represented by formula 3a with a boron reagent, followed by oxidation with basic hydrogen peroxide to give the alcohol compound represented by formula 4a-1.

[0188] [ka]

[0189] wherein P, X and Y are as defined above; (2) In the presence of a base, a compound represented by formula 4a-1 is subjected to a sulfonylation reaction with a sulfonyl donor to obtain a compound represented by formula 4a-2.

[0190] [ka]

[0191] wherein Z is a sulfonyl group; and P, X, and Y are as defined above; and (3) Intramolecular alkylation of the compound represented by formula 4a-2 in the presence of a base to obtain a compound represented by formula 4a

[0192] [ka]

[0193] wherein Y and P are as defined above. Includes. The present invention further provides novel compounds of formula 2a, which are intermediates for compounds of formula 3a.

[0194] [ka]

[0195] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group.

[0196] Synthesis of 16S-Iloprost Scheme I shows the synthesis of 16S-iloprost from a compound of formula (R)-1' (Y is -COOR 1 and R 1 is methyl in formula (R)-1.

[0197] [ka]

[0198] As shown in Scheme I, the TBS-protected 16S-iloprost methyl ester represented by formula 4a' contains less than 0.5% of a geometric isomer (E-isomer), and the compound represented by formula (R)-1' contains less than 0.5% of a geometric isomer (E-isomer), and the compound represented by formula L 2a

[0199] [ka]

[0200] (In the formula, P 2 is a hydroxyl group protecting group.) is prepared from the cuprate derived from the optically enriched (3S,4S)-compound represented by formula 2a' via coupling reaction (Step 1). The coupling product represented by formula 2a' is reacted with TiCl 4 In the presence of Lewis acids such as CH 2 Br 2 The compound represented by formula 3a' is converted to a terminal double bond by olefination using -Zn to form a compound represented by formula 3a' (Step 2). The compound represented by formula 3a' is converted to a terminal double bond by olefination using Pd(dppf) 2 Cl 2 and Na 2 CO 3 In the presence of 1,4-dibromophenylamine, the compound is subjected to intramolecular Suzuki cross-coupling reaction with the boron reagent, 9-borabicyclo[3.3.1]nonane (9-BBN), to give a compound of formula 4a' (step 3). The TBS protecting group of compound of formula 4a' is removed using TBAF to give a compound of formula 5a' (step 4), and a hydrolysis step is carried out under alkaline conditions to give 16S-iloprost (step 5).

[0201] HPLC analysis shows that the geometric isomer (Z-isomer) of the obtained crude 16S-iloprost is less than 0.5%, which meets the quality requirement of 0.6% or less as disclosed in Patent Document 1. Therefore, compared with the conventional synthesis method of 16S-iloprost in Patent Document 1, the method of the present invention has fewer steps and higher yield, and the geometric isomer (Z-isomer) in the obtained crude 16S-iloprost can be controlled to less than 0.6%, so that expensive preparative HPLC method is not required, and therefore the cost of separating and purifying 16S-iloprost can be significantly reduced.

[0202] Synthetic Route of Formula 4b Used to Form Iloprost As shown in Scheme J, the synthesis of compounds of formula 4b is similar to the synthesis of compounds of formula 4 shown in Scheme G, or similar to the synthesis of compounds of formula 4a shown in Scheme H.

[0203] [ka]

[0204] The synthesis of the compound represented by formula (R)-1 can be carried out by reacting a compound represented by formula (R)-1 (wherein Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy; and an optically enriched compound represented by formula L 1b , formula L 2b Or formula L 3b Starting from the optically enriched (3S, 4S and 4R)-compounds represented by

[0205] [ka]

[0206] (In the formula, X 1 is Cl, Br or I; P 2 is a hydroxyl-protecting group.) can be prepared by the same method as in Scheme G or H. Compounds of formula 4b can be prepared according to the reaction shown in Scheme J via a coupling reaction to give compounds of formula 2b (Step 1). Compounds of formula 2b are then subjected to an olefination reaction (Step 2) and an intramolecular cyclization reaction (Step 3) to give compounds of formula 4b. Thus, the present invention provides a method for preparing a compound of formula 4b.

[0207] [ka]

[0208] In the formula, Y is -CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 -alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy. This manufacturing method is (1) Optically enriched compound represented by formula (R)-1

[0209] [ka]

[0210] (Wherein, X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; Y is as defined above; and a compound of formula L 1b , formula L 2b Or formula L 3b A compound represented by

[0211] [ka]

[0212] (In the formula, X 1 is Cl, Br or I, P 2 is a hydroxyl group protecting group.) to give a compound represented by formula 2b.

[0213] [ka]

[0214] wherein P, X and Y are as defined above; (2) Methylenation of the ketone group of the compound represented by formula 2b to give a compound represented by formula 3b

[0215] [ka]

[0216] wherein P, X and Y are as defined above; (3) carrying out an intramolecular cyclization reaction to a compound represented by formula 3b to obtain a compound represented by formula 4b

[0217] [ka]

[0218] wherein P and Y are as defined above; and (4) Arbitrarily P 1 and / or P 2 A step of carrying out a deprotection reaction to remove Includes.

[0219] In this method, the intramolecular cyclization reaction is: (1) Hydroboration of a compound represented by formula 3b with a boron reagent, followed by oxidation with basic hydrogen peroxide to give a compound represented by formula 4b-1

[0220] [ka]

[0221] wherein P, X and Y are as defined above; (2) sulfonylation of a compound represented by formula 4b-1 in the presence of a base and reaction with a sulfonyl donor to give a compound represented by formula 4b-2

[0222] [ka]

[0223] wherein Z is a sulfonyl group; and P, X and Y are as defined above; and (3) Intramolecular alkylation of the compound represented by formula 4b-2 in the presence of a base to give the compound represented by formula 4b

[0224] [ka]

[0225] wherein P and Y are as defined above. Includes. The present invention further provides novel intermediates of formula 2b or 3b.

[0226] [ka]

[0227] In the formula, Y is -CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group; R 1 is C 1-7-alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy.

[0228] Formula (R)-1" (wherein Y is -CH 2 OP. Synthesis of iloprost from the compound represented by As shown in Scheme J-1,

[0229] [ka]

[0230] The compound represented by formula 4b' is a compound represented by formula (R)-1" containing less than 0.5% of a geometric isomer (E-isomer) and a compound represented by formula L 2b The compound represented by formula 2b' is produced by coupling reaction with a cuprate derived from a vinyl stannane represented by formula (Step 1). The coupling product represented by formula 2b' is 2 Br 2 -Zn olefination conditions, TiCl 4 In the presence of a Lewis acid such as 9-borabicyclo[3.3.1]nonane (9-BBN), the compound represented by formula 3b' is converted to a compound represented by formula 3b' containing a terminal double bond in good yield (Step 2). The compound represented by formula 3b' is converted to a compound represented by formula 3b' by the boron reagent, 9-borabicyclo[3.3.1]nonane (9-BBN), and Pd(dppf) 2 Cl 2 and Na 2 CO 3 This is subjected to an intramolecular Suzuki cross-coupling reaction in the presence of to give a compound represented by formula 4b' (Step 3).

[0231] The compound represented by formula 3b' can also be subjected to an intramolecular cross-coupling reaction, which includes three steps, namely, hydroboration-oxidation (step 3-1), alkylsulfonation (step 3-2), and intramolecular cross-coupling reaction (step 3-3), as shown in Scheme J-2.

[0232] [ka]

[0233] Step 3-1 of Scheme J-2 involves a hydroboration-oxidation reaction. Compounds of formula 3b' are reacted with a boron reagent and then oxidized with basic hydrogen peroxide to give alcohol compounds of formula 3b'-1. Suitable boron reagents include, but are not limited to, Py 2 BH 2 , sodium borohydride, borane-THF, borane-DMS and 9-BBN.

[0234] In step 3-2 of scheme J-2, the alcohol compound of formula 3b'-1 is further subjected to a sulfonylation reaction to obtain a compound of formula 3b'-2, where Z is a sulfonyl group consisting of alkylsulfonyl, arylsulfonyl and aralkylsulfonyl, for example, methanesulfonyl or p-toluenesulfonyl. The sulfonylation reaction is accomplished by using a suitable sulfonyl donor, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride, in the presence of a base such as an amine (for example, triethylamine).

[0235] Step 3-3 of Scheme J-2 involves an intramolecular cross-coupling reaction. Carbaprostacyclin analogs of formula 4b are prepared by intramolecular cyclization of compounds of formula 3b'-2 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 ranging from about -70°C to about -50°C. Suitable bases include, but are not limited to, n-butyllithium, sec-butyllithium, tert-butyllithium, and mixtures thereof. Suitable solvents include tetrahydrofuran, ether, toluene, and mixtures thereof.

[0236] Then, as shown in Scheme K, the TBS protecting group of the primary alcohol at C1 of the compound represented by formula 4b' is removed using aluminum oxide to give the compound represented by formula 5b (step 1). Step 2 of Scheme K involves an oxidation reaction in which the primary alcohol (formula 5b) is oxidized to the protected iloprost represented by formula 6b containing a carbonyl acid group by using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) / bis(acetoxy)iodobenzene (BAIB) oxidation conditions. Thus, the TBS protecting group is removed using acids or TBAF to give iloprost (step 3).

[0237] [ka]

[0238] HPLC analysis shows that the geometric isomer (Z-isomer) of the obtained crude iloprost is less than 0.5%, which meets the quality requirement of 0.6% or less as disclosed in Patent Document 1. Therefore, compared with the synthesis method of iloprost in Patent Document 1, the method of the present invention has fewer steps and a higher yield, and can control the geometric isomer (Z-isomer) in the obtained crude iloprost to less than 0.6%, so that an expensive preparative HPLC method is not required, and the cost of separating and purifying iloprost can be significantly reduced.

[0239] Synthesis of Iloprost Scheme L shows the synthesis of iloprost from a compound of formula (R)-1' (Y is -COOR 1 and R 1 is methyl in formula (R)-1. As shown in Scheme L,

[0240] [ka]

[0241] The TBS-protected 16S iloprost methyl ester of formula 4b' is a compound of formula (R)-1' containing less than 0.5% of the geometric isomer (E-isomer) and the compound of formula L containing less than 0.2% of the (3R)-enantiomer. 2a The compound represented by formula 2b' is prepared by a coupling reaction (step 1) between a cuprate derived from a vinyl stannane represented by formula 4 In the presence of Lewis acids such as CH 2 Br 2 Under olefination conditions with -Zn, the compound represented by formula 3b' containing a terminal double bond is converted in good yield (Step 2). The compound represented by formula 3b' is reacted with the boron reagent, 9-borabicyclo[3.3.1]nonane (9-BBN), and Pd(dppf) 2 Cl 2 and Na 2 CO 3 to give the compound of formula 4b' (step 3). The TBS protecting group of the compound of formula 4b' is removed using TBAF to give the compound of formula 5b' (step 4), which is then hydrolyzed under alkaline conditions to give iloprost (step 5).

[0242] HPLC analysis shows that the geometric isomer (Z-isomer) of crude iloprost is less than 0.5%, which meets the quality requirements of 0.6% or less of Z-isomer of 16S-iloprost or 0.2% or less of 15-epi-iloprost disclosed in Patent Document 1. Therefore, compared with the conventional synthesis method of iloprost in Patent Document 1, the method of the present invention has fewer steps, higher yield, and can control the geometric isomer (Z-isomer) to less than 0.6% and 15-epi-iloprost to less than 0.2%, thereby eliminating the need for expensive preparative HPLC methods and significantly reducing the cost of separating and purifying iloprost.

[0243] All of the compounds and / or processes disclosed and claimed herein can be made and executed without undue experimentation in light of this disclosure. Although the compounds and methods of the present invention have been described with reference to preferred embodiments, it will be apparent to those skilled in the art that modifications can be applied to the compositions and / or methods described herein, and in the steps or in the order of steps, without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims. EXAMPLES

[0244] Example 1 (Z) 2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-enal (A2)

[0245] [ka]

[0246] N-Bromosuccinimide (436.1 g, 2.45 mol) was added to a mixture of (E)-7-((tert-butyldimethylsilyl)oxy)hept-2-enal (330.0 g, 1.36 mol), pyridine-N-oxide (258.9 g, 2.72 mol) and acetonitrile (1.65 L). After completion of the reaction, the reaction mixture was diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (1.6 L) and ethyl acetate (1.6 L), and then the reaction mixture was phase separated. The organic layer was collected and washed with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed under vacuum to give 783.2 g of crude compound. HPLC analysis of the crude product showed 0.35% of E-isomer. 1 H-NMR (400MHz, CDCl 3):δ 9.235(s,1H),7.189(t,1H,J=7.2 Hz),3.686-3.626(m,2H),2.615-2.483(m,2H),1.762-1.555(m,4Hz),0.944-0.920(m,9H),0.078-0.070(m,6H). 13 C-NMR (100 MHz, CDCl 3 ):δ 186.159,155.784,128.869,62.472,32.256,31.823,25.956,25.660,24.021,18.336,-5.300,-5.322.

[0247] Example 2 (Z) 2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-ol (A3)

[0248] [ka]

[0249] (Z) 2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-enal (668.3 g, crude product from Example 1) was diluted with dry THF (3.4 L), then the solution was cooled to 0° C., followed by the addition of 2.0 M sodium borohydride (340 mL, 0.68 mol) at 0° C. After the addition, the reaction was monitored by TLC. The reaction was cooled to 0° C. with 10% NH 4 The mixture was quenched with aqueous solution (3 L) and stirred at the same temperature for 10 min. The reaction mixture was phase-separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with anhydrous Na 2 SO 4 The mixture was dried at 40° C. 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 276.8 g (63%, 2 steps starting from Example 1). 1 H-NMR (400MHz, CDCl 3):δ 5.996(t,1H,J=7.2 Hz),4.242-4.228(m,2H),3.612(t,2H,J=6 Hz),2.241-2.188(q,2H,J=7.6Hz),1.575-1.424(m,4H),0.908-0.887(m,9H),0.091-0.041(m,6H). Example 3 (Z) 2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl methanesulfonate (A4)

[0250] [ka]

[0251] (Z) 2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-ol (270 g, 835 mmol, from Example 2) was dissolved in dichloromethane (2.7 L) and the solution was then cooled to 0° C. Triethylamine (101.4 g, 1 mol) and methanesulfonyl chloride (105.2 g, 918 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (3 L) and the phases were separated. The organic layer was collected and washed with anhydrous Na 2 SO 4 The solid was filtered off, and the organic solvent was removed under vacuum to give 367 g of crude compound.

[0252] Example 4 (Z)-((6-bromo-7-(2-(furan-2-yl)-1,3-dithian-2-yl)hept-5-en-1-yl)oxy)(tert-butyl)dimethylsilane (A5)

[0253] [ka]

[0254] A 1.6M solution of n-butyllithium (658mL, 1.05mol) in hexane was added dropwise to a solution of 2-(1,3-dithian-2-yl)furan (226.4g, 1.21mol) in dry THF (1.13L) at -70°C and stirred at the same temperature for 30 minutes. A solution of (Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-ylmethanesulfonic acid (325.2g, 810mmol, from Example 3) in THF (813mL) was added to the reaction flask at -70°C. The reaction was warmed to 0°C and continued to stir at the same temperature for 1 hour. Completion of the reaction was confirmed by TLC. The reaction mixture was diluted with 10% NH 4 The reaction mixture was quenched with water (3 L) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4 The solid was filtered off, and the organic solvent was removed under vacuum to give 531 g of crude compound. 1 H-NMR (400 MHz, CDCl 3 ):δ 7.430-7.428(m,1H),6.554-6.546(m,1H),6.344-6.331(m,1H),5.541(t,1H,J=7.2Hz),3.581(t,2H,J=6 Hz),3.230(s,2H),2.911-2.840(m,2H),2.728-2.674(m,2H),2.109-1.876(m,4H),1 .521-1.452(m,2H),1.392-1.335(m,2H),0.942-0.855(m,9H),0.049-0.005(m,6H). 13 C-NMR (100 MHz, CDCl 3 ):δ 152.338,142.273,135.253,117.947,112.331,110.623,62.889,52.984,51.9 37,32.188,31.398,27.899,25.994,25.721,25.083,24.438,18.351,-5.239.

[0255] Example 5 (Z)-6-Bromo-7-(2-(furan-2-yl)-1,3-dithian-2-yl)hept-5-en-1-ol (A6)

[0256] [ka]

[0257] (Z)-((6-bromo-7-(2-(furan-2-yl)-1,3-dithian-2-yl)hept-5-en-1-yl)oxy)(tert-butyl)dimethylsilane (531 g, crude product from Example 4) was diluted with THF (5.3 L) and 1N hydrochloric acid (1.08 L) was added thereto. The reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with 10% NaHCO 3 The reaction mixture was neutralized to pH 7-8 with aqueous solution (5.3 L), and the phases of the reaction mixture were separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 174.1 g (55%, 3 steps from Example 3). 1 H-NMR (400 MHz, CDCl 3 ):δ 7.425(s,1H),6.546-6.537(m,1H),6.341-6.328(m,1H),5.550(t,1H,J=6.8 Hz),3.607(t,2H,J=6.8 Hz),3.225(s,2H),2.903-2.831(m,2H),2.724-2.669(m,2H),2.124-2.015(m,4H),1.657-1.497(m,2H),1.423-1.347(m,2H). Example 6 (Z)-3-Bromo-1-(furan-2-yl)-8-hydroxyoct-3-en-1-one (A7)

[0258] [ka]

[0259] To a solution of (Z)-6-bromo-7-(2-(furan-2-yl)-1,3-dithian-2-yl)hept-5-en-1-ol (172.2 g, 456 mmol) in methanol (3.4 L) and water (86 mL) was added PIFA (196.2 g, 456 mmol) at room temperature. The reaction was confirmed to be complete by TLC. After completion of the reaction, the mixture was concentrated to remove methanol. Ethyl acetate and 20% Na 2 S 2 O 3 The mixture was extracted with aqueous solution (4 L) and the phases were separated. The organic layer was collected and diluted with 10% NaHCO 3 The organic layer was collected and extracted with anhydrous Na 2 SO 4 The solid was filtered off, and the organic solvent was removed under vacuum to give 261.3 g of crude compound. 1 H-NMR (400MHz, CDCl 3 ):δ 7.593-7.590(s,1H),7.245-7.235(m,1H),6.542-6.530(m,1H),5.865(t,1H,J=7.2 Hz),3.949(s,2H),3.637-3.606(m,2H),2.248-2.194(m,2H),1.615-1.453(m,4H). 13 C-NMR (100 MHz, CDCl 3 ):δ 184.459,152.186,146.896,134.023,118.251,117.932,112.536,62.495,50.168,32.013,31.224,24.370. Example 7 (Z)-3-Bromo-1-(furan-2-yl)oct-3-ene-1,8-diol (A8)

[0260] [ka]

[0261] (Z) 3-Bromo-1-(furan-2-yl)-8-hydroxyoct-3-en-1-one (261.3 g, crude product from Example 6) was diluted with dry THF (2.6 L) and the solution was cooled to 0° C., after which 1.0 M sodium borohydride (456 mL, 456 mmol) was added at 0° C. After the addition, the reaction was monitored by TLC. 4 The organic layer was quenched by adding aqueous Cl (4 L). 3 The organic layer was extracted with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 85.75 g (65%, 2 steps from Example 6). 1 H-NMR (400MHz, CDCl 3 ):δ 7.392-7.389(s,1H),6.343-6.330(m,1H),6.281-6.273(m,1H),5.787(t,1H,J=7.2 Hz),5.062-5.028(m,1H),3.631(t,2H,J=6.4Hz),2.953-2.934(m,2H),2.232-2.178(m,2H),1.578-1.447(m,4H). 13 C-NMR (100 MHz, CDCl 3 ):δ 155.085,142.175,132.482,123.002,110.183,106.623,77.379,65.379,62.540,47.717,31.914,31.011,24.408. Example 8 (Z)-5-(2-bromo-7-hydroxyhept-2-en-1-yl)-4-hydroxycyclopent-2-enone (A9)

[0262] [ka]

[0263] 1.0 mM K2 HPO 4 (1.7 L, 1.7 mmol) was added to a solution of (Z)-3-bromo-1-(furan-2-yl)oct-3-ene-1,8-diol (83.3 g, 288 mmol, from Example 7) in THF (125 mL), heated to reflux, and stirred. Completion of the reaction was confirmed by TLC. After completion of the reaction, the reaction solution was extracted with ethyl acetate (2 L) and phase-separated. The organic layer was collected and washed with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed under vacuum to give 81.2 g of the crude title compound.

[0264] Example 9 (Z)-2-(2-Bromo-7-hydroxyhept-2-en-1-yl)-4-hydroxycyclopent-2-enone (1a)

[0265] [ka]

[0266] To a solution of crude (Z)-5-(2-bromo-7-hydroxyhept-2-en-1-yl)-4-hydroxycyclopent-2-enone (81.2 g, crude product from Example 8) in THF (810 mL) was added triethylamine (28.4 g, 280 mol) and chloral hydrate (4.65 g, 28.1 mmol) at room temperature. The reaction was complete as confirmed by TLC. 10% NH 4 Wash with aqueous solution (800 mL) of anhydrous Na 2 SO 4 The mixture was dried at rt. 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 42.1 g (51%, 2 steps). 1 H-NMR (400MHz, CDCl 3):δ 7.332-7.277(m,1H),5.824(t,1H,J=7.2 Hz),4.981-4.967(m,1H),3.641(t,2H,J=6 Hz),3.335(s,2H),2.871-2.809(m,1H),2.366-2.315(m,1H),2.234-2.181(m,2H),1.608-1.469(m,4H). 13 C-NMR (100 MHz, CDCl 3 ):δ 205.445,158.478,143.753,131.791,122.501,77.379,68.377,62.570,44.688,36.757,31.967,31.049,24.431.

[0267] Example 9-1 (Z)-2-(2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-hydroxycyclopent-2-enone (1b, Scheme A, Step 10)

[0268] [ka]

[0269] (Z)-2-(2-Bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-hydroxycyclopent-2-enone (54.3 g, 188 mmol, from Example 12) was dissolved in ethyl acetate (540 mL). Imidazole (28.12 g, 411 mmol) and tert-butyldimethylsilyl chloride (28.25 g, 188 mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC. The reaction mixture was diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (600 mL) and the phases were separated. The organic layer was collected and washed with anhydrous Na 2 SO 4The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 42.8 g (56%). 1 H-NMR (400 MHz, CDCl 3 ):δ 7.313-7.305(m,1H),5.833-5.798(m,1H),4.984(m,1H),3.626-3.597(m,2H),3.329(m,2H),2.872-2.810(m, 1H),2.360-2.308(m,1H),2.206-2.170(m,2H),1.552-1.433(m,4H),0.918-0.886(m,9H),0.053-0.010(m,6H)

[0270] Example 9-2 (R,Z)-3-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetic acid ((R)-1c), and (S,Z)-2-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-hydroxycyclopent-2-enone ((S)-1b) (S)-1b and (R)-1c, Scheme C, Step 1)

[0271] [ka]

[0272] (Z)-2-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-hydroxycyclopent-2-enone (42.8 g, 106 mmol, from Example 9-1) was dissolved in hexane (430 mL), and then vinyl acetate (43 mL) and lipase SL (2.1 g, 5 wt%) were added thereto. The reaction mixture was stirred at room temperature. Completion of the reaction was confirmed by HPLC analysis, where the reaction conversion was close to 50%. The conversion was 50±3% or more. The reaction mixture was filtered, and the filtrate was concentrated to obtain 45.21 g of a crude mixture.

[0273] Example 9-3 (R,Z)-3-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-oxocyclopent-2-en-1-ylacetic acid ((R)-1c, Scheme C, Step 2)

[0274] [ka]

[0275] A mixture of (R,Z)-3-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-oxocyclopent-2-en-1-ylacetic acid ((R)-1c) and (S,Z)-2-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-hydroxycyclopent-2-enone ((S)-1b) (45.21 g, crude product from Example 9-2) in toluene (450 mL). Triphenylphosphine (14.7 g, 56 mmol) was added thereto, and stirring was continued until triphenylphosphine solid was dissolved in toluene, then cooled to -10 ° C. and stirred at the same temperature. Acetic acid (3.36 g, 56 mmol) and diisopropyl azodicarboxylate (11.3 g, 56 mmol) were added thereto. The reaction mixture was stirred at -10 °C. The reaction was complete by TLC. The reaction mixture was concentrated and 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 42.27 g (89.5%, 2 steps). HPLC analysis of the product showed 0.63% of the enantiomer. 1 H-NMR (400MHz, CDCl 3 ):δ 7.305-7.298(m,1H),5.835-5.800(m,2H),3.607(t,2H,J=6.4Hz),3.346-3.344(m,2H),2.908-2.846(m,1H),2.396 -2.344(m,1H),2.184-2.166(m,2H),2.082(s,3H),1.529-1.453(m,4H),0.892-0.878(m,9H),0.046-0.032(m,6H).

[0276] Example 9-4 (R,Z)-2-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-hydroxycyclopent-2-enone ((R)-1b, Scheme C, Step 3)

[0277] [ka]

[0278] (R,Z)-3-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-oxocyclopent-2-en-1-ylacetic acid (42.27 g, from Example 9-3) was dissolved in acetone (20 mL) and phosphate buffer (420 mL), and 3M NaOH aqueous solution was added to adjust the pH value to 8.5. Lipase SL (4.2 g, 10 wt%) was added thereto, and the reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by HPLC analysis that the enantiomeric excess of the title compound was more than 99.0%. Then, it was filtered to remove the lipase resin. The filtrate was concentrated, and the crude product was purified by silica gel chromatography using a hexane-ethyl acetate mixture as a gradient eluent. The yield of the title compound was 37.09 g (96.8%). HPLC analysis of the product detected 0.28% of the enantiomer. 1 H-NMR (400MHz, CDCl 3 ):δ 7.309(m,1H),5.815(t,1H,J=6.4Hz),4.988(m,1H),3.610(t,2H,J=6.4Hz),3.326(m,2H),2.874-2.812(m,1H),2.36 2-2.357(m,1H),2.315-2.150(m,2H),2.072-2.057(m,1H),1.550-1.429(m,4H),0.888(m,9H),0.044-0.009(m,6H). 13 C-NMR (100 MHz, CDCl 3 ):δ 204.917,157.728,144.088,132.126,122.092,77.324,68.557,62.872,44.6 93,36.708,32.260,31.971,31.167,25.967,25.353,24.431,18.354,-5.275.

[0279] Example 10 (R,Z)-3-(7-acetoxy-2-bromohept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetic acid ((R)-1b), and (S,Z)-6-Bromo-7-(3-hydroxy-5-oxocyclopent-1-en-1-yl)hept-5-en-1-yl acetic acid ((S)-1c) (1a to (R)-1b and (S)-1c)

[0280] [ka]

[0281] (Z) 2-(2-Bromo-7-hydroxyhept-2-en-1-yl)-4-hydroxycyclopent-2-enone (42.1 g, 145.6 mmol, from Example 9) was dissolved in methyl isobutyl ketone (420 mL), and then vinyl acetate (41.3 g, 479 mmol) and lipase SL (2.11 g, 5 wt%) were added thereto. The reaction mixture was stirred at room temperature. Completion of the reaction was confirmed by HPLC as the reaction conversion was close to 50%. The conversion was 50±3% or more. The reaction mixture was filtered, and the filtrate was concentrated to obtain 55.1 g of a crude mixture.

[0282] Example 11 (R,Z)-3-(7-acetoxy-2-bromohept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetate ((R)-1b and (S)-1C to (R)-1d)

[0283] [ka]

[0284] A mixture of (R,Z)-3-(7-acetoxy-2-bromohept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetic acid ((R)-1b) and (S,Z)-6-bromo-7-(3-hydroxy-5-oxocyclopent-1-en-1-yl)hept-5-en-1-yl acetic acid ((S)-1c) (55.1 g, crude product from Example 10) was dissolved in toluene (551 mL). Triphenylphosphine (21.82 g, 83 mmol), acetic acid (5.0 g, 83 mmol) and diisopropyl azodicarboxylate (16.82 g, 83 mmol) were added thereto. The reaction mixture was stirred at room temperature. Completion of the reaction was confirmed by TLC. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography using a hexane-ethyl acetate mixture as gradient eluent. The yield of the title compound was 43.5 g (80%, 2 steps). HPLC analysis of the product showed no enantiomers. 1 H-NMR (400 MHz, CDCl 3 ):δ 7.311-7.305(m,1H),5.829-5.774(m,2H),4.056(t,2H,J=6.8 Hz),3.348-3.343(m,2H),2.912-2.850(m,1H),2.402-2.350(m,1H),2.215-2.16 1(m,2H),2.085(s,3H),2.038(s,3H),1.668-1.606(m,2H),1.504-1.428(m,2H).

[0285] Example 12 (R,Z)-2-(2-Bromo-7-hydroxyhept-2-en-1-yl)-4-hydroxycyclopent-2-enone ((R)-1d to (R)-1E)

[0286] [ka]

[0287] (R,Z)-3-(7-acetoxy-2-bromohept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetate (11.2 g, from Example 11) was dissolved in acetone (11 mL) and phosphate buffer (112 mL), and the pH value was adjusted to 8.5 by adding 1N NaOH aqueous solution. Novozym 435 (5.6 g, 50 wt%) was added thereto, and the reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by HPLC analysis, and the lipase resin was removed during filtration. The filtrate was concentrated, and the crude product was purified by silica gel chromatography using a hexane-ethyl acetate mixture as a gradient eluent. The yield of the title compound was 6.16 g (71%). 1 H-NMR (400 MHz, CDCl 3 ):δ 7.334-7.329(m,1H),5.813(t,1H,J=7.2 Hz),4.966-4.950(m,1H),3.624(t,2H,J=6.4Hz),3.323(s,2H),2.857-2.7 96(m,1H),2.354-2.303(m,1H),2.224-2.170(m,2H),1.612-1.437(m,4H). 13 C-NMR (100 MHz, CDCl 3 ):δ 205.680,158.759,143.647,131.769,122.516,68.286,62.502,44.673,36.757,31.929,31.041,24.431.

[0288] Example 13 (R,Z)-2-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone ((R)-1e to (R)-1f)

[0289] [ka]

[0290] (R,Z)-2-(2-Bromo-7-hydroxyhept-2-en-1-yl)-4-hydroxycyclopent-2-enone (2.76 g, 9.5 mmol, from Example 12) was dissolved in ethyl acetate (28 mL). Then, imidazole (3.9 g, 57 mmol) and tert-butyldimethylsilyl chloride (4.32 g, 28.7 mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC. The reaction mixture was diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (30 mL) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 4.1 g (83%). 1 H-NMR (400 MHz, CDCl 3 ):δ 7.191-7.188(m,1H),5.798(t,1H,J=6.8 Hz),4.932-4.918(m,1H),3.610(t,2H,J=6.4Hz),3.378-3.251(q,2H,16.4Hz),2.795-2.734(dd,1H,J=6,18.4Hz),2.317-2.266(dd,1H,J= 2,18.4Hz),2.206-2.152(q,2H,7.6 Hz),1.597-1.430(m,4H),0.906-0.889(m,18H),0.129-0.036(m,12H).

[0291] Example 14 (R,Z)-3-(2-bromo-7-hydroxyhept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetic acid ((R)-1d to (R)-1g)

[0292] [ka]

[0293] (R,Z)-3-(7-acetoxy-2-bromohept-2-en-1-yl)-4-oxocyclopent-2-en-1-ylacetic acid (54.1 g, crude product from Example 11) was dissolved in methyl tert-butyl ether (541 mL) and methanol (54 mL). Novozym 435 (5.6 g, 50 wt%) was added thereto and the reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by HPLC analysis and the lipase resin was removed during filtration. The filtrate was concentrated and the crude product was purified by silica gel chromatography using a hexane-ethyl acetate mixture as gradient eluent. The yield of the title compound was 27.5 g (57%). 1 H-NMR (400MHz, CDCl 3 ):δ 7.314-7.309(m,1H),5.823(t,1H,J= 7.2 Hz),5.782-5.766(m,1H),3.643(t,2H,J= 6.4Hz),3.343(m,2H),2.909-2.847(dd,1H,J=6,18.8 Hz),2.403-2.351(dd,1H,J= 2,18.8 Hz),2.218-2.164(q,2H),2.085(s,3H),1.602-1.462(m,4H).

[0294] Example 15 (R,Z)-7-(3-acetoxy-5-oxocyclopent-1-en-1-yl)-6-bromohept-5-enoic acid ((R)-1g to (R)-1h)

[0295] [ka]

[0296] To a solution of (R,Z)-3-(2-bromo-7-hydroxyhept-2-en-1-yl)-4-oxocyclopent-2-en-1-yl acetate (27.2 g, crude product from Example 14) in a mixture of acetonitrile and water (544 mL, v / v=1 / 1), diacetoxyiodobenzene (88.26 g, 274 mmol) and 2,2,6,6-tetramethylpiperidine-1-oxyl (3.89 g, 24.9 mmol) were added and stirred at room temperature. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with 1M Na 2 S 2 O 3 The reaction mixture was quenched with aqueous solution (600 mL) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 28 g (98%). 1 H-NMR (400MHz, CDCl 3 ):δ 7.320-7.315(m,1H),5.834-5.777(m,2H),3.354(m,2H),2.919-2.856(dd,1H,J= 6.4,18.8 Hz),2.410-2.357(m,3H),2.260-2.206(m,2H),2.092(s,3H),1.795-1.739(m,2H).

[0297] Example 16 (R,Z)-Methyl 6-bromo-7-(3-hydroxy-5-oxocyclopent-1-en-1-yl)hept-5-enoate ((R)-1h to (R)-1i)

[0298] [ka]

[0299] (R,Z)-7-(3-acetoxy-5-oxocyclopent-1-en-1-yl)-6-bromohept-5-enoic acid (27.1 g, 78.5 mmol, from Example 15) was dissolved in methanol (220 mL) and cooled to 0° C. Then, dilute sulfuric acid (27.1 g) in methanol (55 mL) was added thereto. The reaction mixture was allowed to warm to room temperature and kept stirring at the same temperature for 2 hours. The completion of the reaction was confirmed by TLC. Ice water (200 mL) was slowly added to quench the reaction, followed by 10% NaHCO 3 Aqueous solution (450 mL) was added. Methanol was removed from the reaction mixture under reduced pressure, and then ethyl acetate (600 mL) was added to the mixture for extraction. The reaction mixture was phase separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 20.75 g (82%). HPLC analysis of the product showed 0.71% of the enantiomer. 1 H-NMR (400 MHz, CDCl 3 ):δ 7.330-7.325(m,1H),5.799(t,1H,J=7.2 Hz),4.982(m,1H),3.669(s,3H),3.327(s,2H),2.866-2.760(m,3H),2.366-2.314(m,3H),2.234-2.179(m,2H),1.778-1.722(m,2H). 13 C-NMR (100 MHz, CDCl 3 ): 205.286,173.977,158.372,143.624,130.805,123.237,68.430,51.694,44.666,36.711,33.318,30.730,23.520.

[0300] Example 17 (R,Z)-Methyl 6-bromo-7-(3-((tert-butyldimethylsilyl)oxy)-5-oxocyclopent-1-en-1-yl)hept-5-enoate ((R)-1i to (R)-1j)

[0301] [ka]

[0302] (R,Z)-Methyl 6-bromo-7-(3-hydroxy-5-oxocyclopent-1-en-1-yl)hept-5-enoate (20.0 g, 63 mmol, from Example 16) was dissolved in ethyl acetate (200 mL). Then, imidazole (12.88 g, 189 mmol) and tert-butyldimethylsilyl chloride (19.0 g, 126 mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC. The reaction mixture was diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (300 mL) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 26.02 g (95%). GC analysis of the product showed 0.43% E-isomer. 1 H-NMR (400MHz, CDCl 3 ):δ 7.220-7.211(m,1H),5.804(t,1H,J=6.8 Hz),4.953-4.937(m,1H),3.683(s,3H),3.400-3.275(m,2H),2.811-2.751(m,1H),2 .366-2.203(m,4H),1.798-1.724(m,2H),0.930-0.906(m,9H),0.155-0.082(m,6H). 13 C-NMR (100 MHz, CDCl 3 ): 205.035,173.749,158.888,142.850,130.645,123.420,68.976,51.557,45.318,36.749,33.296,30.753,25.789,23.565,18.123,-4.639.

[0303] Example 18 (Z) 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-oxocyclopentyl)hept-5-enoic acid ((R)-1j to 2a)

[0304] [ka]

[0305] To a solution of thiophene (640 mg, 7.62 mmol) in dry THF (6.4 mL) at −20° C. was added 1.6 M (4.4 mL, 6.93 mmol) n-butyllithium in hexanes dropwise and the reaction mixture was stirred for 1 h at −20° C. After 1 h, the solution was transferred via cannula to a slurry of CuCN (2.9 g, 7.62 mmol) and dry THF (29 mL) at −40° C., then the reaction mixture was stirred for 1 h at −40° C. to give a 2-thienyl(cyano)copper lithium solution. To a solution of tert-butyldimethyl(((3S,4S,E)-4-methyl-1-(tributylstannyl)oct-1-en-6-yn-3-yl)oxy)silane (3.77 g, 6.96 mmol) in dry THF (37.7 mL), a 1.6 M solution of n-butyllithium (4.4 mL, 6.93 mmol) in n-hexane was added dropwise at -70°C and stirred at the same temperature for 30 minutes. The 2-thienyl(cyano)copper lithium solution was cooled to -70°C and added to the reaction flask. After 1 hour, a solution of (R,Z)-methyl 6-bromo-7-(3-((tert-butyldimethylsilyl)oxy)-5-oxocyclopent-1-en-1-yl)hept-5-enoate (1.0 g, 2.32 mmol, from Example 17) in THF (10 mL) was added thereto at -70°C. The reaction was complete as determined by TLC, and then the reaction mixture was quenched with saturated aqueous ammonium chloride solution (67.5 mL) containing ammonium hydroxide (7.5 mL). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with anhydrous Na2 SO 4 The solid was filtered off and the organic solvent was removed under vacuum to give the crude title 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 1.32 g (83%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.695(t,1H,J=6.8 Hz),5.534-5.502(m,2H),4.157-4.143(m,1H),4.013-3.985(m,1H),3.670(s,3H),2. 784-2.145(m,13H),1.784-1.613(m,5H),0.910-0.860(m,21H),0.068-0.005(m,12H) 13 C-NMR (100 MHz, CDCl 3 ): 216.117,173.787,133.545,130.425,130.182,128.452,128.323,126.418,77.750,77.219,76.528,75.747,73.758,51.853,51.550,50.988,47.360,41.576,39.565,33.288,30.662,25.880,25.766,25.744,23.672,22.017,18.154,17.971,15.383,3.474,-3.987,-4.700,-4.738,-4.852.

[0306] Example 19 (Z) 7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-enoic acid (2a to 3a)

[0307] [ka]

[0308] To a slurry of activated zinc powder (330 mg, 5.04 mmol), dibromomethane (292 mg, 1.68 mmol) and dry THF (15 mL) was added titanium tetrachloride (224 mg, 1.18 mmol) at -40°C, then the temperature of the reaction mixture was warmed to 5°C and stirred at the same temperature for 3 days. After 3 days, (Z)-6-methylbromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-oxocyclopentyl)hept-5-enoic acid (1.15 g, 1.68 mmol, from Example 18) in dry THF (12 mL) was added. The reaction mixture was stirred at room temperature. The reaction was confirmed to be complete by TLC. The reaction mixture was diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (200 mL) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 0.53 g (46%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.644(t,1H,J=7.2 Hz),5.448-5.417(m,2H),4.910-4.830(m,2H),3.970-3.902(m,2H),3.666(s,3H),2. 643-2.062(m,12H),1.779-1.629(m,6H),0.912-0.862(m,21H),0.070-0.006(m,12H) 13 C-NMR (100 MHz, CDCl 3): 173.833,151.047,132.505,131.966,129.014,128.551,108.103,78.009,76.308,76.043,55.755,51.519,46.859,44.954,42.631,39.649,33.394,30.654,25.903,25.865,23.725,22.032,18.154,18.032,15.421,3.474,1.008,-3.926,-4.601,-4.662,-4.890.

[0309] Example 20 (E) 5-(((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-(((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoate (3a to 4a)

[0310] [ka]

[0311] 9-BBN in THF (0.5 M, 4.38 mL, 2.19 mmol) was added to a dry THF solution of (Z)-methyl 6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-enoic acid (500 mg, 0.73 mmol, from Example 19) at 0° C. and stirred at the same temperature for 2 h. After 2 h, Pd(dppf)Cl 2 (54 mg, 0.073 mmol) and 1M Na 2 CO 3 Aqueous solution (2.2 mL, 2.2 mmol) was added and stirred at 60° C. for 1 h. The reaction was confirmed to be complete by TLC. The reaction mixture was extracted with water (25 mL) and ethyl acetate (25 mL) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 209 mg (47%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.532-5.357(m,2H),5.207-5.172(m,1H),3.974-3.943(m,1H),3.768-3.706(m,1H ),3.661(s,3H),2.374-1.156(m,21H),0.916-0.862(m,21H),0.0640.000(m,12H). 13 C-NMR (100 MHz, CDCl 3 ): 174.280,143.131,132.717,131.632,120.384,78.312,78.122,77.325,76.202,56.051,51.443,44.445,42.571,39.816,38.252,37.698,35.998,33.501,28.780,25.911,25.076,22.062,18.169,18.100,15.436,3.474,1.008,-3.933,-4.450,-4.601,-4.950.

[0312] Example 21 (E)-Methyl 5-(((3aS,4R,5R,6aS)-5-hydroxy-4-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoate (4a to 16(S)-iloprost methyl ester)

[0313] [ka]

[0314] (Z) 6-Bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,4S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-enoic acid (183 mg, 0.303 mmol, from Example 20) was diluted with THF (1.8 mL) and 1M TBAF (1.8 mL, 1.818 mmol) was added thereto. The reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with 10% NaHCO 3 The reaction mixture was neutralized with aqueous solution (5 mL) and the phases were separated. The organic layer was washed with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 109 mg (96%). 1 H-NMR (400MHz, CDCl 3 ):δ 5.496-5.477(m,2H),5.222-5.188(m,1H),3.936-3.912(m,1H),3.723-3.655(m,4H),2.445-1.117(m,21H),0.934-0.917(m,3H). 13 C-NMR (100 MHz, CDCl 3 ): 174.311,142.653,134.956,132.968,120.816,77.492,77.083,76.916,76.324,57.242,51.519,45.174,41.447,38.168,38.002,37.493,35.854,33.501,28.719,25.061,22.275,15.649,3.528.

[0315] Example 22 (E)-5-((3aS,4R,5R,6aS)-5-hydroxy-4-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (16(S)-iloprost)

[0316] [ka]

[0317] (E)-Methyl 5-((3aS,4R,5R,6aS)-5-hydroxy-4-((3S,4S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (100 mg, 0.267 mmol, from Example 21) was dissolved in methanol (1 mL), and a solution of sodium hydroxide (23.5 mg, 0.587 mmol) in water (1 mL) was slowly added dropwise at 10°C. After the reaction was completed, methanol was distilled off from the reaction mixture under reduced pressure. The residue was diluted with water (5 mL) and further washed with methyl tert-butyl ether (5 mL). The aqueous layer was acidified to pH 3-4 with 3N hydrochloric acid and further extracted with methyl tert-butyl ether (5 mL). The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. 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 acetonitrile and water as gradient eluent. The yield of the title compound was 77 mg (80%). HPLC analysis of the product showed 0.42% of the Z-isomer. 1 H-NMR (400MHz, CDCl 3 ):δ 5.524-5.506(m,2H),5.225(m,1H),3.974-3.961(m,1H),3.748-3.682( m,1H),2.469-1.666(m,23H),1.205-1.156(m,1H),0.954-0.937(m,3H).

[0318] Example 23 (Z)-Methyl 6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-oxocyclopentyl)hept-5-enoate ((R)-1j to 2b)

[0319] [ka]

[0320] This compound was obtained from (R,Z)-methyl 6-bromo-7-(3-((tert-butyldimethylsilyl)oxy)-5-oxocyclopent-1-en-1-yl)hept-5-enoic acid (40.0 g, 92.7 mmol, from Example 17) and tert-butyldimethyl(((3S,E)-4-methyl-1-(tributylstannyl)oct-1-en-6-yn-3-yl)oxy)silane (165.7 g, 306 mmol) according to the procedure of Example 18. The yield of the title compound was 57.88 g (91%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.693(t,1H,J=6.8 Hz),5.543-5.501(m,2H),4.155-4.000(m,2H),3.668(s,3H),2.781-2.182 (m,13H),1.776-1.579(m,5H),0.919-0.874(m,21H),0.066-0.002(m,12H).

[0321] Example 24 (Z)-Methyl 6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-enoate (2b to 3b)

[0322] [ka]

[0323] This compound was obtained from (Z)-methyl 6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,E)-3-(tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-oxocyclopentyl)hept-5-enoic acid (56.0 g, 81.9 mmol, from Example 23) according to the procedure of Example 19. The yield of the title compound was 29.77 g (53%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.645(t,1H,J=6.4Hz),5.458-5.418(m,2H),4.910-4.831(m,2H),4.114-3.889(m,2H),3.669( s,3H),2.677-2.063(m,12H),1.777-1.634(m,6H),0.921-0.870(m,21H),0.038-0.007(m,12H).

[0324] Example 25 (E)-Methyl 5-((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (3b to 4b)

[0325] [ka]

[0326] This compound was obtained from (Z)-methyl 6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-enoate (29.0 g, 42.5 mmol, from Example 24) according to the procedure of Example 20. The yield of the title compound was 14.63 g (57%). 1 H-NMR (400MHz, CDCl 3 ):δ 5.527-5.353(m,2H),5.185(m,1H),4.101-3.937(m,1H),3.762-3.700(m,1H),3.659(s,3H),2.355-1.908(m ,14H),1.787(s,3H),1.707-1.653(m,3H),1.224-1.151(m,1H),0.926-0.856(m,21H),0.061-0.007(m,12H).

[0327] Example 26 (E)-Methyl 5-(((3aS,4R,5R,6aS)-5-hydroxy-4-((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (4b to iloprost methyl ester)

[0328] [ka]

[0329] This compound was obtained from (E)-methyl 5-((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (12.0 g, 19.9 mmol, from Example 25) according to the procedure of Example 21. The yield of the title compound was 6.3 g (84%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.539-5.510(m,2H),5.215(m,1H),4.076-3.960(m,1H),3.751-3.685(m,1H), 3.661(s,3H),2.450-1.638(m,20H),1.204-1.129(m,1H),0.996-0.930(m,3H).

[0330] Example 27 (E)-5-((3aS,4R,5R,6aS)-5-hydroxy-4-((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (iloprost)

[0331] [ka]

[0332] This compound was prepared from (E)-methyl 5-(((3aS,4R,5R,6aS)-5-hydroxy-4-(((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (3.0 g, 8 mmol, from Example 26) according to the procedure of Example 22. The yield of the title compound was 2.31 g (80%). HPLC analysis of the product showed 0.41% of the Z-isomer and no 15-epimer. 1 H-NMR (400 MHz, CDCl 3 ):δ 5.528-5.499(m,2H),5.220-5.203(m,1H),4.069-3.939(m,1H),3.739-3.6 74(m,1H),2.457-1.661(m,23H),1.201-1.126(m,1H),1.017-0.935(m,3H).

[0333] Example 28 (2R,3R,4R)-2-((Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)-3-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)cyclopentanone ((R)-1f to 2b')

[0334] [ka]

[0335] This compound was obtained from (R,Z)-2-(2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)cyclopent-2-enone (10.0 g, 19.3 mmol, from Example 13) and tert-butyldimethyl(((3S,E)-4-methyl-1-(tributylstannyl)oct-1-en-6-yn-3-yl)oxy)silane (31.4 g, 58 mmol) according to the procedure of Example 18. The yield of the title compound was 10.41 g (70%). 1 H-NMR (400MHz, CDCl 3 ):δ 5.699(m,1H),5.566-5.462(m,2H),4.158-3.990(m,2H),3.609(m,2H),2.807-1.901(m ,10H),1.772(s,3H),1.707-1.418(m,5H),1.040-0.727(m,30H),0.118-0.000(m,18H).

[0336] Example 29 (((Z)-6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-en-1-yl)oxy)(tert-butyl)dimethylsilane (2b' to 3b')

[0337] [ka]

[0338] This compound was obtained from (2R,3R,4R)-2-((Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)-3-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)cyclopentanone (11.0 g, 14.3 mmol, from Example 28) according to the procedure of Example 19. The yield of the title compound was 8.47 g (77%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.660(t,1H,J=6.8),5.463-5.418(m,2H),4.907-4.845(m,2H),4.106-3.894(m,2H),3.627-3.596(t,2H,J=5.6 Hz),2.642-1.263(m,15H),1.778(s,3H),0.927-0.873(m,30H),0.043-0.003(m,18H).

[0339] Example 30 ((E)-5-(((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentyl)oxy)dimethylsilane (3b' to 4b')

[0340] [ka]

[0341] This compound was obtained from ((Z)-6-bromo-7-((1R,2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-en-1-yl)oxy)(tert-butyl)dimethylsilane (4.0 g, 5.2 mmol, from Example 29) according to the procedure of Example 20. The yield of the title compound was 2.01 g (56%). 1 H-NMR (400MHz, CDCl 3 ):δ 5.486-5.397(m,2H),5.217(m,1H),4.094-3.962(m,1H),3.746-3.728(m,1H),3.620-3.58 7(m,2H),2.331-1.205(m,18H),1.780(s,3H),0.933-0.863(m,30H),0.067-0.001(m,18H). 13 C-NMR (100 MHz, CDCl 3 ):δ 141.910,132.824,132.331,132.073,131.549,121.636,78.470,78.379,76.238,75.29 7,63.168,56.086,56.033,44.594,44.495,42.590,40.146,39.835,38.233,38.173,37. 725, 36.017, 35.987, 32.495, 29.193, 26.104, 25.983, 25.914, 22.430, 22.074, 18.362, 18.187, 18.164, 18.096, 15.424, 14.430, 3.485, 3.454, -4.447, -4.599, -4.978, -5.252.

[0342] Example 31 ((2S,3R,4R)-2-((Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)-3-(((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)cyclopentyl)methanol (3b' to 3')

[0343] [ka]

[0344] To a solution of 9-BBN in THF (0.5 M, 242 mL, 121 mmol), a solution of ((Z)-6-bromo-7-((1R,2R,3R)-3-(tert-butyldimethylsilyl)oxy)-2-(((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)-5-methylenecyclopentyl)hept-5-en-1-yl)oxy)(tert-butyl)dimethylsilane (31 g, 40.3 mmol, from Example 29) in THF (310 mL) was added at 0° C., and the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled and stirred at −10° C., followed by the addition of 31% hydrogen peroxide (40.85 mL) at −10° C. After 10 min, aqueous sodium hydroxide (3M, 121 mL, 363 mmol) was added at the same temperature. The reaction mixture was then warmed to 0° C. and stirred for 30 min. The reaction was complete as determined by TLC. The reaction mixture was quenched with 10% brine (1 L) and the reaction mixture was phase separated. The organic layer was washed with anhydrous Na 2 SO 4 The mixture was dried at rt. The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 17.76 g (56%). 1 H-NMR (400 MHz, CDCl 3):δ 5.743(m,1H),5.458-5.341(m,2H),4.119-3.999(m,2H),3.769-3.449(m,4H),2.740-2.00 7(m,7H),1.770(s,3H),1.675-1.420(m,9H),0.945-0.720(m,30H),0.078-0.013(m,18H).

[0345] Example 32 ((1S,2S,3R,4R)-2-((Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)-3-(((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)cyclopentyl)methyl 4-methylbenzenesulfonate(3' to 3")

[0346] [ka]

[0347] ((2S,3R,4R)-2-((Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-(((tert-butyldimethylsilyl)oxy)-3-(((3S,E)-3-(tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)cyclopentyl)methanol (37.34 g, 47.5 mmol, Example 31) was dissolved in dichloromethane (380 mL). Then, triethylamine (14.4 g, 142 mmol), DMAP (0.58 g, 47.5 mmol) and 4-toluenesulfonyl chloride (22.64 g, 118.7 mmol) were added thereto. The reaction mixture was heated to reflux. The completion of the reaction was confirmed by TLC. The reaction mixture was cooled to room temperature and diluted with 10% NaHCO 3 The reaction mixture was quenched with aqueous solution (450 mL) and the phases were separated. The organic layer was collected and washed with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed under vacuum to give 45.51 g of the crude compound.

[0348] Example 33 tert-Butyl (((E)-5-(((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentyl)oxy)dimethylsilane (3" to 4')

[0349] [ka]

[0350] A solution of ((1S,2S,3R,4R)-2-((Z)-2-bromo-7-((tert-butyldimethylsilyl)oxy)hept-2-en-1-yl)-4-((tert-butyldimethylsilyl)oxy)-3-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)cyclopentyl)methyl 4-methylbenzenesulfonic acid (45.0 g, 47.8 mmol, from Example 32) in dry THF (450 mL) was added dropwise to a solution of 1.9 M tert-butyllithium (60 mL, 114 mmol) in pentane at -70°C, and the mixture was stirred at the same temperature for 1 h. The reaction was complete as confirmed by TLC. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (450 mL). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. Combine the organic layers and wash with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed under vacuum to give the crude title 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 24.0 g (73%).

[0351] Example 34 (E)-5-((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentan-1-ol

[0352] [ka]

[0353] tert-Butyl (((E)-5-(((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentyl)oxy)dimethylsilane (2.43 g, 3.5 mmol, from Example 33) was dissolved in n-hexane (370 mL). Aluminum oxide (250 g, H 2 To it was added 1,2-dichloromethane (containing 1,2-dimethyl-2,4-tetrahydrofuran). The suspension of the reaction mixture was stirred at room temperature. Completion of the reaction was confirmed by TLC. The aluminum oxide 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 1.6 g (80%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.490-5.391(m,2H),5.209(m,1H),4.089-3.958(m,1H),3.742-3.725(m,1H),3.636-3.60 6(m,2H),2.209-1.156(m,16H),1.769(s,3H),0.923-0.855(m,21H),0.032-0.007(m,12H).

[0354] Example 35 (E)-5-((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid

[0355] [ka]

[0356] (E)-5-((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy)-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentan-1-ol (1.1 g, 1.9 mmol, from Example 34) was dissolved in dichloromethane (11 mL) and water (11 mL). Then, 2,2,6,6-tetramethylpiperidine-1-oxyl (60 mg, 0.38 mmol) and (diacetoxyiodo)benzene (1.54 g, 0.48 mmol) were added thereto. The reaction mixture was stirred at room temperature. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched with 20% aqueous sodium thiosulfate solution (22 mL). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed under vacuum to give the crude title 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 0.8 g (72%). 1 H-NMR (400 MHz, CDCl 3 ):δ 5.497-5.379(m,2H),5.211-5.195(m,1H),4.144-3.980(m,1H),3.752-3.734(m,1H),2.18 1-1.612(m,17H),1.777(s,3H),1.269(m,1H),0.931-0.861(m,21H),0.063-0.001(m,12H).

[0357] Example 36 (E)-5-((3aS,4R,5R,6aS)-5-hydroxy-4-((3S,E)-3-hydroxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidenepentanoic acid (iloprost)

[0358] [ka]

[0359] (E)-5-((3aS,4R,5R,6aS)-5-((tert-butyldimethylsilyl)oxy)-4-((3S,E)-3-((tert-butyldimethylsilyl)oxy-4-methyloct-1-en-6-yn-1-yl)hexahydropentalen-2(1H)-ylidene)pentanoic acid (800 mg, 1.35 mmol, from Example 35) was diluted with THF (8 mL) and 1M TBAF solution (5.4 mL, 5.4 mmol) was added thereto. The reaction was stirred at room temperature and the progress of the reaction was monitored by TLC. After completion of the reaction, it was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted by adding ethyl acetate (20 mL). The reaction mixture was then phase separated. The organic layer was washed with anhydrous Na 2 SO 4 The solid was filtered off and the organic solvent was removed 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 gradient eluent. The yield of the title compound was 420 mg (86%).

Claims

1. Racemic or optically active compound represented by formula 1 【Chemistry 1】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl and SiR a R b R c (R a , R b and R c are each independently 1-4 R is a hydroxyl-protecting group selected from the group consisting of alkyl, aryl, aralkyl, substituted aryl, or substituted benzyl, wherein the substituents of the substituted benzyl, substituted acyl, and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, and aryloxy; 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy.

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. 2. 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 compound of formula (R)-1, enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess. 【Chemistry 2】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl and SiR a R b R c (R a , R b and R c are each independently 1-4 R is a hydroxyl-protecting group selected from the group consisting of alkyl, aryl, aralkyl, substituted aryl, or substituted benzyl, wherein the substituents of the substituted benzyl, substituted acyl, and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, and aryloxy; 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted with alkynyl, nitro, halogen or alkoxy, comprising the steps of: (1) Compound represented by formula 1 【Chemistry 3】 (wherein Y and X are as defined above) with an acyl donor represented by formula D 【Chemistry 4】 (In the formula, R 4 and R 5 are independently H or C 1-6 (R)-esterification with a first lipase to form an (R)-ester of formula (R)-1b′ and an unreacted (S)-alcohol of formula (S)-1; 【Chemistry 5】 (2) removing unreacted (S)-alcohol; and (3) Deacylation of the resulting (R)-ester A manufacturing method comprising:

6. 6. The method of claim 5, 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.

7. 6. The method of claim 5, wherein the first lipase is derived from Burkholderia cepacia, Candida antarcitica, Alcaligenese sp., Pseudomonas stutzri, Pseudomonas cepacia, or a mixture thereof.

8. 6. The method of claim 5, wherein (i) the deacylation step (3) comprises an enzymatic cleavage reaction using a second lipase derived from Candida cylindracea, Pseudomonas stutzri, Alcaligenese sp., Achromobacter sp., Burkholderia cepacia, Candida antarcitica, or a mixture thereof; or (ii) the deacylation step (3) is chemical hydrolysis.

9. The method of claim 8 , wherein the second lipase is derived from Candida antarcitica.

10. The removing step (2) comprises converting the (S)-alcohol into a compound represented by the formula R in the presence of a dialkyl azodicarboxylate and a trialkyl / triaryl phosphine. 4 COOH (R 4 is as defined in claim 5. The method of claim 5, comprising converting the unreacted (S)-alcohol to the corresponding (R)-ester by reacting it with an acyloxy donor of the formula

11. 11. The method of claim 10, wherein the dialkyl azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, and mixtures thereof, and the trialkyl / triaryl phosphine is selected from the group consisting of tri-n-butylphosphine, triphenylphosphine, and mixtures thereof.

12. Compound of formula (R)-1d, enriched in the (R)-enantiomer and having an optical purity of at least 95% enantiomeric excess. 【Chemistry 6】 (wherein X is F, Cl, Br, I or -OTs; R 4 is H or C 1-6 a) a substituted or unsubstituted alkyl group; (1) Compound represented by formula 1a 【Chemistry 7】 (wherein X is F, Cl, Br, I or -OTs) with an acyl donor of formula D 【Chemistry 8】 (In the formula, R 4 and R 5 are independently H or C 1-6 (R)-esterification with a first lipase to obtain a mixture of a compound represented by formula (R)-1d and a compound represented by formula (S)-1e. 【Chemistry 9】 obtaining (2) Removal of the compound represented by formula (S)-1e A manufacturing method comprising:

13. 13. The method of claim 12, 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.

14. 13. The method of claim 12, wherein the first lipase is derived from Burkholderia cepacia, Candida antarcitica, Alcaligenese sp., Pseudomonas stutzri, Pseudomonas cepacia, or a mixture thereof.

15. The removing step (2) comprises reacting a compound represented by formula (S)-1e with a compound represented by formula R 4 COOH (R 4 is as defined in claim 12. The method of claim 12, comprising converting the compound of formula (S)-1e to the corresponding (R)-ester by reacting with an acyloxy donor of formula (S)-1e

16. 16. The method of claim 15, wherein the dialkyl azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate, diisopropyl azodicarboxylate, dibenzyl azodicarboxylate, and mixtures thereof, and the trialkyl / triaryl phosphine is selected from the group consisting of tri-n-butylphosphine, triphenylphosphine, and mixtures thereof.

17. Compound represented by formula 4 【Chemistry 10】 (Wherein, Y is —CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy; R 2 is H or C 1-4 -alkyl; R 3 is C 1-7 -Alkyl, C 1-7 -alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-7 -substituted by alkyl, halogen or trihalomethyl, (1) Starting compound represented by formula 1 【Chemistry 11】 (Wherein, X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; and Y is as defined above. 1 , formula L 2 Or formula L 3 A compound represented by 【Chemistry 12】 (In the formula, X 1 is Cl, Br or I; P 2 is a hydroxyl protecting group; R 2 and R 3 is as defined above.) to give a compound represented by formula 2 【Chemistry 13】 (In the formula, P, X, Y, R 2 and R 3 is as defined above; (2) Methylenation of the ketone group of the compound represented by formula 2 to obtain a compound represented by formula 3 【Chemistry 14】 (In the formula, P, X, Y, R 2 and R 3 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 15】 (In the formula, P, Y, R 2 and R 3 is as defined above; and (4) Optionally P 1 and / or P 2 A step of carrying out a deprotection reaction to remove (The hydroxyl-protecting group is methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl, and SiR a R b R c (R a , R b and R c are each independently 1-4 alkyl, aryl, aralkyl, substituted aryl or substituted benzyl, and the substituents of the substituted benzyl, substituted acyl and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy and aryloxy.

18. 18. The method of claim 17, wherein the intramolecular cyclization reaction is an intramolecular Suzuki reaction with a boron reagent using a palladium catalyst and a base to form a compound of formula 4.

19. Intramolecular cyclization reaction (a) hydroborating a compound represented by formula 3 with a boron reagent, followed by oxidation with basic hydrogen peroxide to obtain an alcohol compound represented by formula 3'; 【Chemistry 16】 (In the formula, P, X, Y, R 2 and R 3 is as defined in claim 17; (b) sulfonylation of the compound represented by formula 3' with a sulfonyl donor in the presence of a base to obtain a compound represented by formula 3'' 【Chemistry 17】 (Wherein, Z is a sulfonyl group; P, X, Y, R 2 and R 3 is as defined above; and (c) intramolecular alkylation of a compound of formula 3 in the presence of a base to form a compound of formula 4. The method of claim 17, comprising:

20. Compound represented by formula 4a 【Chemistry 18】 (Wherein, Y is —CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy, comprising the steps of: (1') Optically enriched compound represented by formula (R)-1 【Chemistry 19】 (Wherein, X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; and Y is as defined above. 1a , formula L 2a Or formula L 3a A compound represented by 【Chemistry 20】 (In the formula, X 1 is Cl, Br or I, P 2 is a hydroxyl-protecting group.) to give a compound represented by formula 2a 【Chemistry 21】 wherein P, X and Y are as defined above; (2') Methylenation of the ketone group of the compound represented by formula 2a to obtain a compound represented by formula 3a 【Chemical 22】 wherein P, X and Y are as defined above; (3') carrying out an intramolecular cyclization reaction of the compound represented by formula 3a to obtain a compound represented by formula 4a 【Chemistry 23】 wherein P and Y are as defined above; and (4') optionally P 1 and / or P 2 A step of carrying out a deprotection reaction to remove The method of claim 17, comprising:

21. The process according to claim 20, wherein the intramolecular cyclization reaction is an intramolecular Suzuki reaction with a boron reagent using a palladium catalyst and a base to form a compound represented by formula 4a.

22. Intramolecular cyclization reaction (a) hydroborating a compound represented by formula 3a with a boron reagent, followed by oxidation with basic hydrogen peroxide to give an alcohol compound represented by formula 4a-1; 【Chemistry 24】 wherein P, X and Y are as defined in claim 20; (b) a compound represented by formula 4a-1 is subjected to a sulfonylation reaction with a sulfonyl donor in the presence of a base to give a compound represented by formula 4a-2 【Chemistry 25】 wherein Z is a sulfonyl group; and P, X and Y are as defined above; and (c) intramolecular alkylation of a compound of formula 4a-2 in the presence of a base to form a compound of formula 4a. The method of claim 20, comprising:

23. Compounds represented by formula 4b 【Chemistry 26】 (Wherein, Y is —CH 2 OP or -COOR 1 P is H or a hydroxyl protecting group; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy, comprising the steps of: (1''') Optically enriched compound represented by formula (R)-1 【Chemical 27】 (Wherein, X is F, Cl, Br, I or -OTs; P 1 is a hydroxyl protecting group; and Y is as defined above; and a compound of formula L 1b , formula L 2b Or formula L 3b A compound represented by 【Chemistry 28】 (In the formula, X 1 is Cl, Br or I, P 2 is a hydroxyl-protecting group.) to give a compound represented by formula 2b 【Chemical 29】 wherein P, X and Y are as defined above; (2''') Methylenation of the ketone group of the compound represented by formula 2b to obtain a compound represented by formula 3b 【Chemistry 30】 wherein P, X and Y are as defined above; (3''') carrying out an intramolecular cyclization reaction to the compound represented by formula 3b to obtain a compound represented by formula 4b 【Chemistry 31】 wherein P and Y are as defined above; and (4'') Optionally, P 1 and / or P 2 A step of carrying out a deprotection reaction to remove The method of claim 17, comprising:

24. 24. The process according to claim 23, wherein the intramolecular cyclization reaction is an intramolecular Suzuki reaction with a boron reagent using a palladium catalyst and a base to form a compound represented by formula 4b.

25. Intramolecular cyclization reaction (a) hydroborating a compound represented by formula 3b with a boron reagent, followed by oxidation with basic hydrogen peroxide to obtain a compound represented by formula 4b-1 【Chemistry 32】 wherein P, X and Y are as defined in claim 23; (b) A compound represented by formula 4b-2 is obtained by a sulfonylation reaction of a compound represented by formula 4b-1 with a sulfonyl donor in the presence of a base. 【Chemical 33】 wherein Z is a sulfonyl group; and P, X and Y are as defined above; and (c) intramolecularly alkylating a compound of formula 4b-2 in the presence of a base to form a compound of formula 4b. The method of claim 23, comprising:

26. Compound represented by formula 2a 【Chemistry 35】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl and SiR a R b R c (R a , R b and R c are each independently 1-4 R is a hydroxyl-protecting group selected from the group consisting of alkyl, aryl, aralkyl, substituted aryl, or substituted benzyl, wherein the substituents of the substituted benzyl, substituted acyl, and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, and aryloxy; 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy.

27. Compounds represented by formula 2b 【Chemical 36】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl and SiR a R b R c (R a , R b and R c are each independently 1-4 R is a hydroxyl-protecting group selected from the group consisting of alkyl, aryl, aralkyl, substituted aryl, or substituted benzyl, wherein the substituents of the substituted benzyl, substituted acyl, and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, and aryloxy; 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy.

28. Compound represented by formula 3 【Chemical 37】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl and SiR a R b R c (R a , R b and R c are each independently 1-4 R is a hydroxyl-protecting group selected from the group consisting of alkyl, aryl, aralkyl, substituted aryl, or substituted benzyl, wherein the substituents of the substituted benzyl, substituted acyl, and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, and aryloxy; 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -Alkynyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy; R 2 is H or -C 1-4 and R 3 is C 1-7 -Alkyl, C 2-7 -alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-7 - substituted by alkyl, halogen or trihalomethyl.

29. Compounds represented by formula 3a 【Chemical 38】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group as defined above; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy.

30. Compounds represented by formula 3b 【Chemical 39】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; P is H or a hydroxyl protecting group as defined above; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy.

31. Compounds represented by formula 3″ 【Chemistry 40】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or methoxymethyl, methoxythiomethyl, 2-methoxyethoxymethyl, bis(2-chloroethoxy)methyl, tetrahydropyranyl, tetrahydrothiopyranyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydrothiofuranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, triphenylmethyl, allyl, acetyl, benzyl, substituted benzyl, acyl, substituted acyl, and SiR a R b R c (R a , R b and R c are each independently 1-4 R is a hydroxyl-protecting group selected from the group consisting of alkyl, aryl, aralkyl, substituted aryl, or substituted benzyl, wherein the substituents of the substituted benzyl, substituted acyl, and substituted aryl are each independently one or more selected from the group consisting of halogen, alkyl, aryl, alkoxy, and aryloxy; 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 - substituted by alkynyl, nitro, halogen or alkoxy; R 2 is H or -C 1-4 and R 3 is C 1-7 -Alkyl, C 2-7 -alkynyl, aryl or aryloxy, each of which is unsubstituted or C 1-4 - substituted by alkyl, halogen or trihalomethyl.

32. Compound represented by formula 3'a 【Chemistry 41】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or a hydroxyl-protecting group as defined above; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy.

33. Compound represented by formula 3'b 【Chemistry 42】 (Wherein, Y is —CH 2 OP or -COOR 1 X is F, Cl, Br, I or -OTs; Z is H or a sulfonyl group; P is H or a hydroxyl-protecting group as defined above; R 1 is C 1-7 - alkyl, aryl or aralkyl, each of which is unsubstituted or C 1-4 -Alkyl, C 2-7 -Alkenyl, C 2-7 -substituted by alkynyl, nitro, halogen or alkoxy.

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