Field of the Invention:

The present invention relates to a novel process for the preparation of (2)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[( 1 E,3 S)-3 -hydroxy-5-phenyl-1 -pentenyl]cyclopentyl] 5-iV-ethylheptenamide represented by structural formula-1.

Formula-1

(Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[( 1 E,3 S)-3-hydroxy-5-phenyl-1 -pentenyl] cyclopentyl]5-Af-ethylheptenamide is a prostaglandin analog/prodrug used topically to control the progression of glaucoma and in the management of ocular hypertension. It is marketed by Allergan under the trade name Lumigan.

Background of the Invention:

(Z)-7(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl] cyclopentyl]5-N-ethylheptenamide is commonly known as Bimatoprost.

Bimatoprost and its process for preparation were first disclosed in US 6403649. The disclosed process involves esterification of Bimatoprost acid, followed by amidation with ethyl amine.

The prior known processes disclosed in US 5359095, US 4739078, US 6689901, US6720438 and US20100010239 involves the usage of intermediates having benzoyl- or PPB-protecting groups. These protecting groups prevent the use of many reducing agents, including diisobutyl aluminium hydride and borane-DMS. The usage of DIBAL-H in the reduction of lactone to lactol and borane-DMS in combination with R-methyl CBS in the reduction of keto group present on straight chain of intermediate compound, results in the reduction of oxo moieties present in the protecting groups. Thus, in prior art procedures wherein DIBAL-H or borane-DMS employed as reducing agents, the protecting groups (benzoyl- or PPB-) present in starting materials are must be deprotected before reduction.
US 7163959 disclosed a process for the preparation of Bimatoprost intermediates which involves the presence of unprotected hydroxy functional groups in the DIBAL-H reduction step which is undesirable because each free hydroxyl group of the starting material interacts with DIBAL-H. As a result, the use of additional equivalents of DIBAL-H becomes necessary, thus makes the process uneconomic and leading to the formation of undesired impurities.

US 6720438 was disclosed a process for the preparation of Bimatoprost intermediates which involves the usage of separate protecting group for each hydroxy functional group.

Therefore, the process requires an additional step for protection and deprotection of another hydroxyl functional group. Hence, the usage of different protecting groups for each hydroxyl functional group is not advisable.

US4820836 disclosed a process for the protection of (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxy methyl)hexahydro-2H-cyclopenta[b]furan-2-one, a starting material of Bimatoprost using trimethylsilyl chloride in presence of triethylamine. However, the trimethyl silyl protecting group is sensitive towards mild acids, bases and chromatographic purification on silica gel, makes its survival through multi-step operations in synthetic sequence become problematic. The usage of intermediates having trimethylsilyl protecting groups in the synthesis of Bimatoprost is also found to be difficult.

Hence there is a need in the art to provide an alternative protecting group which are more stable towards mild acid, base, reduction and chromatographic purification.

US 7498458 was generically covered a process for the preparation of (Z)-methyl 7-((1 R,2R,3R,5S)-3,5-dihydroxy-2-(( 1 E,3S)-3-hydroxy-5-phenylpent-1 -enyl)cyclo pentyl)hept-5-enoate, which is a key intermediate in the synthesis of Bimatoprost. The disclosed process involves oxidation of (3aR,4S,5R,6aS)-5-(aryl protected hydroxy)-4-(hydroxymethyl)hexahydro-2H-cyclopenta [b]furan-2-one to provide its corresponding aldehyde, further it undergoes wittig-horner reaction with dimethyl 2-oxo-4-phenylbutylphosphonate in presence of lithium chloride along with an organic base. The obtained compound further undergoes asymmetric reduction to provide its corresponding alcohol and then deprotected to give (3aR,4R,5R,6aS)-5-hydroxy-4-((S,E)-3-hydroxy-5-phenylpent-l-enyl)hexahydro-2H-cyclopenta[b]furan-2-one, which is again protected with triethylsilyl chloride to provide its corresponding bis(triethylsilyl) protected derivative. This compound now undergoes reduction with diisobutylaluminium hydride, followed by wittig reaction with (4-carboxybutyl)triphenylphosphonium bromide in presence of potassium tertiary butoxide and then reacted with methyl iodide in presence of DBU. The obtained compound further protected using triethylsilyl chloride provides tris(triethylsilyl)protected bimatoprost methyl ester and then deprotected to give (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl) cyclopentyl)hept-5-enoate. As the said process involves repeated protection and deprotection of hydroxyl functional groups, which utilizes additional solvents and reagents and makes the process uneconomic and time consuming, which in-turn produces the final product with low yield and low purity.

Hence there is a need in the art to provide an improved and cost-effective process for the preparation of (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dmydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoate in shorter reaction time.

Summary of the Invention:

The first embodiment of the present invention relates to a novel compound, i.e.(3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-ol compound of formula-8, which is a key intermediate in the synthesis of prostaglandin derivatives such as Bimatoprost and Latanoprost. The present invention also provides the process for the preparation of compound of formula-8.

The second embodiment of the present invention is to provide an improved process for the preparation of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy) methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3, comprising of reacting (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-2 with a triethylsilylating agent in presence of a suitable base in a suitable solvent to provide the compound of formula-3.

The third embodiment of the present invention is to provide one pot process for the preparation of (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethyl silyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-6 from (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3 proceeding through (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-4.

The fourth embodiment of the present invention is to provide a novel process for the preparation of (Z)-7-(( 1 R,2R,3R,5S)-3,5-dihydroxy-2-(( 1E,3 S)-3-hydroxy-5-phenylpent-1 -enyl)cyclopentyl)hept-5-enoic acid compound of formula-10, comprising of condensing (3aR,4R,5R,6aS)-4-(( 1 E,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide the compound of formula-10.

The fifth embodiment of the present invention is to provide one pot process for the preparation of (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoate compound of formula-12 from (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 proceeding through (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl) hept-5-enoic acid compound of formula-10.

The sixth embodiment of the present invention is to provide one pot process for the
preparation of (2)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[( 1 E,3 S)-3-hydroxy-5-phenyl-1 -pentenyl]cyclopentyl]-N-ethylheptenamide compound of formula-1 from (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 without proceeding through (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoate compound of formula-12.

The seventh embodiment of the present invention is to provide an improved process for
the preparation of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7 from
(3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-2.

The eighth embodiment of the present invention is to provide a novel process for the
preparation of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[( 1 E,3S)-3-hydroxy-5-phenyl-1 -pentenyl] cyclopentyl]5-N-ethylheptenamide compound of formula-1 from (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-one compound of formula-7, proceeding through (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy) hexa hydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 and (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl) hept-5-enoate compound of formula-12.

The ninth embodiment of the present invention is to provide a novel process for the
preparation of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl] cyclopentyl]5-N-ethylheptenamide compound of formula-1 from (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-one compound of formula-7 through (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta [b]furan-2-ol compound of formula-8 without proceeding through (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl) hept-5-enoate compound of formula-12.

The tenth embodiment of the present invention is to provide one pot process for the preparation of dimethyl 2-oxo-4-phenylbutylphosphonate compound of formula-5 from 4-phenyl-2-butanone compound of formula-13 through l-bromo-4-phenyl-2-butanone compound of formula-14 without conversion of compound of formula-14 into its corresponding iodide derivative.

The eleventh embodiment of the present invention is to provide a novel process for the preparation of crystalline form-I of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl] 5-iV-ethylheptenamide compound of formula-1 using a mixture of acetonitrile and methyl tertiary butyl ether.

Advantages of the Invention:

• Provides a process for the preparation of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-iV-ethylheptenamide compound of formula-1 in shorter reaction time with high yield and purity.

• Avoids the use of additional reagents and solvents by controlling repeated protection and deprotection process; and also avoids the conversion of l-bromo-4-phenyl-2-butanone into l-iodo-4-phenyl-2-butanone.

• Avoids the usage of protecting groups which are sensitive towards mild acids, bases, reduction and chromatographic purification on silica gel.

• Provides cost-effective, time saving and environmental friendly process.

Detailed description of the Invention:

As used herein the present invention, the term "suitable solvent" wherever necessary, is selected from "ester solvents" like ethyl acetate, methyl acetate, isopropyl acetate and the like; "ether solvents" like tetrahydrofuran, diethylether, diisopropyl ether, methyl tertiary butyl ether and the like; "hydrocarbon solvents" like toluene, hexane, heptane, pet.ether, cyclohexane and the like; "polar aprotic solvents" like dimethylformamide, dimethyl acetamide, dimethyl sulfoxide, acetonitrile and the like; "ketone solvents" like acetone, propanone, methyethyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" like methanol, ethanol, n-propanol, isopropanol, n-butanol, diglycol, isobutanol and the like; "chloro solvents" like dichloromethane, chloroform, carbon tetrachloride, dichloroethane and the like; and "polar solvents" like water; and also mixtures thereof.

The term "suitable base" herein the present invention is selected from inorganic bases like alkali metal and alkaline earth metal alkoxides, hydroxides, hydrides, amides, carbonates and bicarbonates such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate etc; and ammonia; and organic bases like triethylamine, tributyl amine, dimethyl aniline, N-methyl piperidine and N-methyl pyrrolidine, N-methyl morpholine, diisopropyl methylamine, diisopropyl amine, diisopropyl ethyl amine, piperidine, dimethyl amino pyridine, pyridine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, alkyl lithium such as methyl lithium, butyl lithium and the like.

The term "suitable acid" herein the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid and the like.

The term "suitable oxidizing agent" herein the present invention is selected from oxalyl chloride in combination with dimethylsulfoxide and a suitable base, trichloroisocyanuric acid in presence of TEMPO, pyridinium chlorochromate, quaternary ammonium halide-TEMPO-oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base, Dess-Martin periodinane etc.

The term "methylating agent" herein the present invention is selected from dimethyl sulfide and methyl iodide etc.

The term "suitable coupling agent" herein the present invention is selected from carbodiimides such as N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3 -(3 -dimethyl aminopropyl)carbodiimide (EDC), N,N'-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (DPPA), P2O5, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), N,N'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), (2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

The term "triethyl silylating agent" herein the present invention is selected from triethylsilyl chloride, triethylsilyl triflate and the like.

The first embodiment of the present invention relates to a novel intermediate compound, i.e.(3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 or its enantiomer, Formula-8 which is a key intermediate in the synthesis of prostaglandin derivatives such as Bimatoprost and Latanoprost.

Another embodiment of the present invention provides a process for the preparation of (3aR,4R,5R,6aS)-4-(( 1 E,3 S)-3 -hydroxy-5-phenylpent-1 -enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclo penta[b]furan-2-ol compound of formula-8, comprising of reducing the keto group of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7 with a suitable reducing agent in a suitable solvent provides compound of formula-8.

Wherein, the suitable reducing agent for the reduction of keto group of compound of
formula-7 is selected from diisobutylaluminium hydride, sodium borohydride and lithium aluminium hydride etc; preferably diisobutyl aluminium hydride; and the suitable solvent is ether solvent such as tetrahydrofuran, diethylether, diisopropyl ether, methyl tertiary butyl ether and the like, preferably tetrahydrofuran.

The suitable reducing agent employed in the present invention for the reduction of keto group of compound of formula-8 is in molar proportions between 2 and 8 moles, preferably 3.5 moles per mole of compound of formula-8; and the solvent used in an amount ranging from 8 to 14 volumes, preferably 10 volumes to lg of compound of formula-8.

The reduction step of keto group of compound of formula-8 was carried out at a temperature ranging from -60 to -75°C, preferably -68 to -72°C.

US 7163959 disclosed a process for reduction of (3aR,4R,5R,6aS)-5-hydroxy-4-((S,E)-3-hydroxy-5-phenylpent-l-enyl)hexahydro-2H-cyclopenta[b]furan-2-one (in which two hydroxy functional groups are not protected) which provides the product with 78% yield, and US 5422369 also disclosed a process for reduction of (3aR,4R,5R,6aS)-4-((3S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-l-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (in which the two hydroxy functional groups are protected with tetrahydropyran protecting groups) which provides the product with 76% yield. Whereas the present invention involves the usage of triethylsilyl protecting groups in the reduction of (3aR,4R,5R,6aS)-5-hydroxy-4-((S,E)-3-hydroxy-5-phenylpent-l-enyl)hexahydro-2H-cyclopenta[b]furan-2-one, resulting the cleaner reaction with higher yields (95-100%). Hence the present invention is more advantageous over the prior known processes.

The second embodiment of the present invention is to provide an improved process for the preparation of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy) methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3, comprising of reacting (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-2 with a triethylsilylating agent in presence of a suitable base in a suitable solvent to provide the compound of formula-3.

Wherein, the suitable base is selected from imidazole, diisopropyl amine, diisopropylethyl amine, pyridine, triethyl amine and dimethylamino pyridine etc, preferably diisopropylethyl amine; the suitable solvent is selected from chloro solvents, ether solvents and polar aprotic solvents; and the triethyl silylating agent is selected from triethylsilyl chloride and triethylsilyl triflate etc.

US4820836 disclosed a process for the protection of (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxy methyl)hexahydro-2H-cyclopenta[b]furan-2-one using trimethylsilyl chloride in presence of triethylamine. However, the trimethylsilyl protecting group is sensitive towards mild acids, bases and chromatographic purification on silica gel, makes its survival through multi-step operations in synthetic sequence become problematic. Hence the present inventors selected an alternative protecting group which is more stable and more resistant towards mild acid, base and chromatographic purification when compared to trimethylsilyl protecting group.

The third embodiment of the present invention is to provide one pot process for the preparation of (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethyl silyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-6, comprising of:

a) Deprotective oxidation of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy) methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3 with a suitable oxidizing agent in a suitable solvent to provide (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-4-carbaldehyde compound of formula-4,

b) condensing the compound of formula-4 in-situ with dimethyl 2-oxo-4-phenylbutylphosphonate compound of formula-5 in presence of lithium hydroxide monohydrate in a suitable solvent provides the compound of formula-6.

Wherein,

in step-a) the suitable solvent is chloro solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like, preferably dichloromethane; and the suitable oxidizing agent is selected from oxalyl chloride in combination with dimethylsulfoxide and a suitable base, trichloroisocyanuric acid in presence of TEMPO, pyridinium chlorochromate, quaternary ammonium salt-TEMPO-oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base and Dess-Martin periodinane etc, in step-b) the suitable solvent is ether solvent such as diisopropyl ether, diethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like, preferably tetrahydrofuran.

In step-b), the usage of lithium chloride in presence of a base was disclosed in US 2009259066. However the cost of lithium chloride is very high when compared to lithium hydroxide mono hydrate, hence the usage of lithium hydroxide mono hydrate of the present invention makes the process cost-effective when compared to the prior reported process utilizing lithium chloride. Hence the present invention is more advantageous over the prior art.

In the present invention, the compound of formula-4 can be isolated using a suitable solvent and then condensed with dimethyl 2-oxo-4-phenylbutylphosphonate compound of formula-5 to provide compound of formula-6.

The fourth embodiment of the present invention is to provide a novel process for the preparation of (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl) cyclopentyl)hept-5-enoic acid compound of formula-10, comprising of condensing (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides the compound of formula-10.

Wherein, the suitable base is inorganic base selected from alkali metal hydrides such as
sodium hydride, potassium hydride and the like; alkali metal amides such as sodium amide, potassium amide and the like; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, potassium tertiary butoxide, sodium tertiary butoxide and the like; and organic base is alkyl lithium such as methyl lithium, n-butyl lithium and the like; preferably alkali metal alkoxide, more preferably potassium tertiary butoxide; The suitable solvent is ether solvent such as diisopropyl ether, diethyl ether, terahydrofuran, methyl tertiary butyl ether and the like, preferably tetrahydrofuran; and the suitable acid is inorganic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid and the like, preferably hydrochloric acid.

The suitable base employed for the above condensation of compound of formula-8 with
compound of formula-9 is in molar proportions of between 4 and 8 moles, preferably 6 moles per mole of compound of formula-8; and the compound of formula-9 employed is in molar proportions of between 2 and 4 moles, preferably 3 moles per mole of compound of formula-8.

The above step of condensation of compound of formula-8 with compound of formula-9 is carried out at a temperature ranging from 0-5°C, for a period of 1-6 hours, preferably 3-4 hours.

The fifth embodiment of the present invention is to provide one pot process for the preparation of (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclo pentyl)hept-5-enoate compound of formula-12, comprising of:

a) Condensing (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoic acid compound of formula-10,

b) reacting the compound of formula-10 in-situ with a methylating agent in presence of a suitable base in a suitable solvent to provide compound of formula-12.
Wherein, the suitable solvent, the suitable acid and suitable base used in step-a) are same as defined in fourth embodiment of the present invention; and in step-b) the suitable base is inorganic base such as alkali metal carbonate like potassium carbonate, sodium carbonate etc; (or) organic base such as DBU, DBN and the like; preferably potassium carbonate; the suitable solvent is ketone solvent such as methyl ethyl ketone, acetone, propanone, methyl isobutyl ketone and the like, preferably acetone; the methylating agent is methyl iodide and dimethyl sulfide etc.

In the present invention, the compound of formula-10 can be isolated using a suitable solvent and then reacted with a methylating agent to provide compound of formula-12.

The sixth embodiment of the present invention is to provide one pot process for the
preparation of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-iV-ethylheptenamide compound of formula-1, comprising of:

a) Condensing (3aR,4R,5R,6aS)-4-(( 1 E,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethyl silyloxy)hexa hydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides (Z)-7-((1 R,2R,3R,5S)-3,5-dihydroxy-2-(( lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)cyclopentyl)hept-5-enoic acid compound of formula-10,

b) condensing the compound of formula-10 in-situ with ethyl amine in presence of a suitable coupling agent in presence or absence of a suitable solvent provides compound of formula-1.

Wherein, the suitable solvent, the suitable acid and suitable base used in step-a) are same as defined in fourth embodiment of the present invention; and the suitable coupling agent in step-b) is selected from carbodiimides such as N,N1-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC), N,N'-dicyclohexyl carbodiimide (DCC); alkyl or aryl chloroformates such as ethyl chloroformates, benzyl chloroformates, para-nitrophenyl chloroformates; 3-hydroxy-3,4-dihydro-l,2,3-benzotriazin-4-one, diethyl phosphoraro cyanidate (DEPC), di phenylphosphoroazidate (DPPA), P2O5, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine-4(3H)-one (DEPBT), N,N'-carbonyl diimidazole. The carbodiimides can be used optionally in combination with 1-hydroxybenzotriazole (HOBt), l-hydroxy-7-azatriazole (HOAt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), N-hydroxy succinamide (HOSu), 2-(lH-benzotriazol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoro borate (TBTU), dimethylamino pyridine (DMAP). The alkyl or aryl chloroformates can be used optionally in combination with a base.

In the present invention, the compound of formula-10 can be isolated using a suitable
solvent and then condensed with ethyl amine in presence of a suitable coupling agent in a
suitable solvent to provide compound of formula-1.

The seventh embodiment of the present invention is to provide an improved process for the preparation of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl silyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7, comprising of:

a) Reacting (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta [b]furan-2-one compound of formula-2 with a triethylsilylating agent in presence of a suitable base in a suitable solvent provides (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy) methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3,

b) deprotective oxidation of the compound of formula-3 with a suitable oxidizing agent in a suitable solvent provides (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-4,

c) condensing the compound of formula-4 in-situ with dimethyl 2-oxo-4-phenylbutylphosphonate compound of formula-5 in presence of lithium hydroxide mono hydrate in a suitable solvent provides (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-6,

d) asymmetric reduction of keto group present on straight chain of compound of formula-6 with a suitable reducing agent in a suitable solvent provides (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7.

Wherein,

in step-a) the suitable base and suitable solvent are same as defined in second embodiment of the present invention,

in step-b) & step-c) the suitable solvent is same as defined in step-a) & step-b) of third embodiment of the present invention respectively; the suitable oxidizing agent in step-b) is same as defined in step-a) of third embodiment of the present invention,

in step-d) the suitable solvent is ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like, preferably tetrahydrofuran; and the suitable reducing agent is selected from p-chlorodiisopinocampheyl borane (DIP Chloride); or a reducing agent like, borane-THF or borane-DMS in combination with a chiral catalyst like (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo(l,2-c)(l,3,2) oxazaborole (herein after referred as "R-Methyl CBS") or R-Butyl CBS or R-Phenyl CBS and the like.

The compound of formula-7 of the present invention is a key intermediate in the synthesis of prostaglandin derivatives such as Bimatoprost and Latanoprost.

The eighth embodiment of the present invention is to provide a novel process for the preparation of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl] cyclo pentyl]5-N-ethylheptenamide compound of formula-1, comprising of:

a) Reducing the keto group of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7 with a suitable reducing agent in a suitable solvent provides (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8,

b) condensing the compound of formula-8 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoic acid compound of formula-10,

c) reacting the compound of formula-10 in-situ with a methylating agent in presence of a suitable base in a suitable solvent to provide (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoate compound of formula-12,

d) reacting the compound of formula-12 with ethyl amine in presence or absence of a solvent provides compound of formula-1.

The ninth embodiment of the present invention is to provide a novel process for the preparation of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl] cyclopentyl]5-N-ethyl heptenamide compound of formula-1, comprising of:

a) Reducing the keto group of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7 with a suitable reducing agent in a suitable solvent provides (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8,

b) condensing the compound of formula-8 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoic acid compound of formula-10,

c) condensing the compound of formula-10 in-situ with ethyl amine in presence of suitable coupling agent in presence or absence of a suitable solvent provides compound of formula-1.

Wherein,

in step-a) of eighth & ninth embodiments of the present invention, the suitable solvent and suitable reducing agent are same as defined in first embodiment of the present invention,

in step-b) of eighth & ninth embodiments of the present invention, the suitable solvent, the suitable acid and suitable base are same as defined in step-a) of fourth embodiment of the present invention,

in step-c) of eighth embodiment of the present invention, the suitable solvent, the suitable base and methylating agent are same as defined in step-b) of fifth embodiment of the present invention,

in step-c) of ninth embodiment of the present invention, the suitable coupling agent is same as defined in step-b) of sixth embodiment of the present invention.

The compound of formula-10 of the present invention is optionally converted into its acid halide and then treated with ethyl amine to provide compound of formula-1.

In the present invention, the compound of formula-10 can be optionally converted into its amine salts compound of formula-11 by treating with a suitable organic amine in a suitable solvent, followed by treating with a base to provide pure compound of formula-10, which in-turn results in the formation of pure compound of formula-1.

Wherein, the suitable organic amine can be selected from methyl amine, ethyl amine, n-propyl amine, isopropyl amine, n-butyl amine, tertiary butyl amine, (+/-)-sec-butyl amine, octyl amine, 2-ethyl hexylamine, benzyl amine, a-methyl-benzylamine, phenyl ethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcyclo heptylamine and the like, preferably methyl amine, ethyl amine, tertiary butyl amine, n-butyl amine and propyl amine.

The tenth embodiment of the present invention is to provide an improved process for the preparation of dimethyl 2-oxo-4-phenylbutylphosphonate compound of formula-5, comprising of:

a) Brominating the 4-phenyl-2-butanone compound of formula-13 with bromine in a suitable solvent to provide l-bromo-4-phenyl-2-butanone compound of formula-14,

b) reacting the compound of formula-14 in-situ with trimethyl phosphite in a suitable solvent to provide compound of formula-5.

Wherein, the suitable solvent used in step-a) is alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and the like, preferably methanol,
in step-b) is polar aprotic solvent such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and acetonitrile etc, preferably acetonitrile.

US6720438 disclosed a process for the preparation of dimethyl 2-oxo-4-phenylbutyl phosphonate. The disclosed process involves the bromination of 4-phenyl-2-butanone, and then converted into its corresponding iodo substituted compound. The obtained compound further treated with trimethyl phosphite. The additional step utilizes additional reagents and solvents and makes the process uneconomic and time consuming. Whereas, the present invention involves the direct conversion of bromo substituted compound into dimethyl 2-oxo-4-phenylbutyl phosphonate without proceeding through its iodo substituted compound. Hence the present invention is more advantageous over the prior art.

The eleventh embodiment of the present invention is to provide a novel process for the preparation of crystalline form-I of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-1-pentenyl] cyclopentyl] 5-N-ethylheptenamide compound of formula-1, comprising of:

a) Dissolving (Z)-7[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl] cyclo pentyl]5-N-ethylheptenamide compound of formula-1 in a mixture of acetonitrile and methyl tertiary butyl ether by heating,

b) stirring the reaction mixture at 50-80°C,

c) cooling the reaction mixture to 0-10°C,

d) stirring the reaction mixture at 0-10°C,

e) filtering the solid and washing with methyl tertiary butyl ether,

f) drying the solid to get crystalline form-I of compound of formula-1.

Wherein, acetonitrile used in amount ranging from 1 to 4 volumes, preferably 1.5 to 3 volumes, more preferably 2.5 volumes to lg of compound of formula-1; and methyl tertiary butyl ether is used in amount ranging from 10 to 30 volumes, preferably 20 volumes to lg compound of formula-1.

Further, the Bimatoprost of the present invention can be used as a medicament for the treatment of ocular hypertension and glaucoma.

The related substances of bimatoprost measured by using HPLC with the following chromatographic conditions: Apparatus: A liquid chromatographic system is equipped with radiable wavelength detector or multi wavelength detector; Column: stainless steel column packed with octadecylsilane silica gel for chromatography, C-18, 25 cm x 4.6 mm, 5 urn (hypersil hypurity is suitable); Flow rate: 1.5 ml/min; Wave length: 210 nm; Column temperature: 25°C; Injection volume: 10 μ l; Run time: 40 minutes; Elution: Isocratic; Mobile phase: Buffer: acetonitrile: methanol (72:23:5 by volume); Diluent: Mobile phase; Needle wash: Diluent Buffer preparation: Take 1.8822 g of 1-hexane sulphonate sodium in 10000ml of water and adjust the pHto 3.0 with dilute phosphoric acid solution.

The present invention is schematically represented as follows:

The process described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not construed as limitation of the scope of invention. Examples:

Example-1: Preparation of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy) methyl)hexahydro-2H-cyclopenta [b]furan-2-one (Formula-3)

A mixture of (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta [b]furan-2-one compound of formula-2 (25 g) and tetrahydrofuran (400 ml) was cooled to 10-15°C. Diisoproylethylamine (101 ml) was added slowly to the reaction mixture at 10-15°C over a period of 15 minutes, followed by triethylsilyl chloride (73 ml) at 10-15°C over a period of 45 minutes. The reaction mixture was stirred for 4 hours at 10-15°C.

After completion of the reaction, the reaction mixture was quenched with water and raised the temperature of the reaction mixture to 25-30°C. The reaction mixture was extracted with ethyl acetate. Dried the ethyl acetate layer with sodium sulfate and then distilled to get crude title compound. The obtained compound was further purified by column chomatography using pet.ether and ethyl acetate as eluent. Yield: 60.0 g
Example-2: Preparation of (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta [b] furan-2-one (Formula-6)

Step-a) Preparation of (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta (b]furan-4-carbaldehyde(Formula-4)

A mixture of dichloromethane (400 ml) and dimethylsulfoxide (20.3 ml) was cooled to -
67 to -73 °C and oxalyl chloride (18.2 ml) was added to it over a period of 45 minutes at -67 to -73 °C. The reaction mixture was stirred for 30 minutes at the same temperature. A solution of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3 (40 g) in dichloromethane (200 ml) was added drop wise to the reaction mixture at -70°C over a period of 45 minutes and then stirred for 4 hours at -65 to -70°C. The temperature of the reaction mixture was raised to -40°C and then stirred for 5 minutes at -40°C. After completion of the reaction, the reaction mixture was cooled to -65 to -70°C and triethyl amine (80 ml) was added to the reaction mixture at -60 to -65°C and stirred for 30 minutes at the same temperature.

Water was added to the reaction mixture and both organic and aqueous layers were separated, and the aqueous layer was extracted with dichloromethane. Both the organic layers were combined and then distilled off the solvent to get the title compound as a residue. The obtained compound was taken to the next step without isolation.

Step-b) Preparation of (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one(Formula-6) Methyl tertiary butyl ether (400 ml), lithium hydroxide mono hydrate (4 g) and dimethyl 2-oxo-
4-phenylbutylphosphonate (25.5 g) were taken into a clean and dry RBF under nitrogen
atmosphere. The reaction mixture was stirred for 1 hour at 20-25°C and then cooled to 0-5°C.

(3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta [b]furan-4-carbaldehyde compound of formula-4 obtained in step-a) was dissolved in methyl tertiary butyl ether (100 ml) and then added to the reaction mixture at 0-5°C over a period of 10 minutes. Water (15 ml) was added to the reaction mixture and stirred for 45 minutes at 0-5°C. After completion the reaction, the reaction mixture was quenched with water and both organic and aqueous layers were separated, the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, dried with sodium sulfate and then distilled off the solvent to get title compound. The obtained compound was further purified by column chromatography using cyclohexane and ethyl acetate as eluent. Yield: 18 g

Example-3: (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl
silyloxy)hexahydro-2H-cyclopenta [b] furan-2-one (Formula-7)

Tetrahydrofuran (330 ml), (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-6 (33 g) and R-methyl CBS (1M in toluene) (39.7 ml) were taken into a clean and dry RBF at 25-35°C and then cooled to -20 to -25°C. Borane-DMS (5.6 ml) was added to the reaction mixture slowly over a period of 30 minutes at the same temperature and then stirred for 4 hours at -20 to -25°C. Temperature of the reaction mixture was raised to -5 to 0°C. After completion of the reaction, the reaction mixture was quenched with methanol.

Ammonium chloride solution (200 g of ammonium chloride dissolved in 200 ml of water) was added to the reaction mixture at below -15°C. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Both the organic layers were combined, dried over sodium sulfate and then distilled off the solvent to get title compound. The obtained compound was further purified by column chromatography using pet.ether and ethyl acetate as eluent. Yield: 21.0 g.

Example-4: (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl
silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol(Formula-8)

(3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7 (15 g) was dissolved in tetrahydrofuran (150 ml) and the reaction mixture was cooled to -68 to -72°C. Diisobutylaluminium hydride (25% in toluene) (71.6 ml) was added slowly to the reaction mixture over a period of 1 hour at -68 to -72°C and then stirred for 30 minutes at -65 to -70°C. After completion of the reaction, the reaction mixture was quenched with methanol. Water was added to the reaction mixture followed by ethyl acetate at -40°C.

Temperature of the reaction mixture was raised to 25-35°C and stirred for 45 minutes at the same temperature. Filtered the reaction mixture through celite bed and washed with ethyl acetate. The filtrate was washed with water and the ethyl acetate and aqueous layers were separated. Distilled off the solvent from ethyl acetate layer to get title compound.

Yield: 14.6 g.

Examplc-5: (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent -l-enyl)cyclopentyl)hept-5-enoate(formula-12)

Step-a) (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl) cyclopentyl)hept-5-enoic acid (Formula-10)

(4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 (44.4 g) was taken into a clean and dry RBF and then heated to 100-110°C for about 7 hours under reduced pressure. The obtained pure compound of formula-9 was taken into a clean RBF and tetrahydrofuran (180 ml) was added to it under nitrogen atmosphere. Potassium tertiary butoxide (22.4 g) was added to the reaction mixture at 25-35°C and stirred for 40 minutes at 30-35°C. The reaction mixture was cooled to 0-5°C, (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 solution (prepared by dissolving 14g of compound of formula-8 in 30 ml of tetrahydrofuran) was added to it and then stirred for 4 hours at 0-5°C. After completion of the reaction, the reaction mixture was quenched with water at 10-15°C and pH of the reaction mixture was adjusted to 3.5 by using sodium bisulfate solution (prepared by dissolving 20g of sodium bisulfate in 50ml of water at 10-15°C). The compound was extracted with ethyl acetate and then treated with sodium hydroxide followed by hydrochloric acid. The ethyl acetate layer was distilled under reduced pressure. Methyl tertiary butyl ether (70 ml) was added to the obtained residue at 25-35°C. The reaction mixture was cooled to 0-5°C and stirred for 45 minutes at 0-5°C. Filtered the reaction mixture, washed with methyl tertiary butyl ether and then distilled off the solvent from the filtrate to get title compound as a residue. The obtained compound was taken to the next step without isolation.

Step-b) (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenyl pent-1-enyl) cyclopentyl)hept-5-enoate (formula-12)

The compound obtained in step-a) was dissolved in acetone (125 ml) and the reaction mixture was cooled to 0-5°C. Potassium carbonate (24.4 g) was added to the reaction mixture at 0-5°C, followed by methyl iodide (18.2 ml). Temperature of the reaction mixture was raised to 20-25°C and stirred for 12 hours at 20-25°C. After completion of the reaction, filtered the reaction mixture and distilled off the solvent from filtrate to get title compound as a residue. The residue was dissolved in dichloromethane and then water was added to it. Both the organic and aqueous layers were separated and the organic layer was dried with sodium sulfate and then distilled off the solvent to get the title compound. The obtained compound was further purified by column chromatography using dichloromethane and methanol as eluent. Yield: 6.2 g.

Example-6: Preparation of (Z)-7[ (1 R,2R,3R,5S) -3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-N-ethylheptenamide(Formula-l)

A mixture of (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dmydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-1-enyl) cyclopentyl)hept-5-enoate compound of formula-12 (5 g) and ethyl amine (25 ml) was stirred for 36 hours at 25-30°C. After completion of the reaction, the reaction mixture was quenched with water and the compound was extracted with dichloromethane. The dichloromethane layer was dried with sodium sulfate and then distilled off the solvent to get the title compound as a residue. The title compound was further isolated using methyl tertiary butyl ether (25 ml). Filtered the solid, washed with methyl tertiary butyl ether and then dried to get title compound. Yield: 3.0 g

Example-7: Preparation of crystalline form-I of (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-Af-ethylheptenamide(FormuIa-l)

To (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[( 1 E,3S)-3-hydroxy-5-phenyl-1 -pentenyl] cyclopentyl]5-Nethylheptenamide compound of formula-1 (5 g), acetonitrile (6.25 ml) followed by methyl tertiary butyl ether (100 ml) were added at 25-35°C. The reaction mixture was heated to 60-70°C. The reaction mixture was stirred for 45 minutes at 60-70°C and the reaction mixture was cooled to 0-5°C. The reaction mixture was stirred for 45 minutes at 0-5°C. Filtered the solid, washed with methyl tertiary butyl ether and then dried to get the title compound. The same process repeated twice to get pure crystalline form-I of compound of formula-1.

Purity by HPLC: 99.945 %; Trans impurity: 0.055%.

Example-8: Preparation of Dimethyl 2-oxo-4-phenylbutylphosphonate(Formula-5)
Step-a) l-bromo-4-phenyl-2-butanone (Formula-14)

A mixture of 4-phenyl-2-butanone compound of formula-13 (50 g) and methanol (350 ml) was cooled to 0-5°C. Bromine solution (prepared from 19.1 ml of bromine and 150 ml of methanol) was added slowly to the reaction mixture for about 1 hour at 0-5 °C. The reaction mixture was stirred for 4 hours at 0-5°C and then for 1 hour at 15-20°C. After completion of the reaction, the reaction mixture was quenched with water. The compound was extracted into dichloromethane. The organic layer was washed with water, dried with sodium sulfate and distilled off the solvent to get title compound as a liquid. Methyl tertiary butyl ether (500 ml) was added to the reaction mixture and stirred for 40 minutes at -25 to -30°C. Filtered the compound, washed with methyl tertiary butyl ether to get the title compound. The obtained wet compound was taken to the next step without isolation.

Step-b) Preparation of Dimethyl 2-oxo-4-phenylbutylphosphonate (Formula-5)

The obtained wet compound from step-a) was dissolved in acetonitrile (250 ml) and trimethyl phosphite (47.74 ml) was added slowly to the reaction mixture over a period of 30 minutes at 25-35°C. The reaction mixture was heated to reflux temperature and stirred for 3 hours at the same temperature. After completion of the reaction, the solvent was distilled off completely under reduced pressure and then distilled off trimethyl phosphite completely by high vacuum distillation. The obtained compound was further purified by column chromatography by using pet.ether and ethyl acetate. Yield: 36.0 g.

We claim:

1. A compound of formula and its isomers

2. A novel process for the preparation of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8, comprising of reducing the keto group of (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclo penta[b]furan-2-one compound of formula-7 Formula-7 with a suitable reducing agent in a suitable solvent.

3. A process for the preparation of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-
4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3, Formula-3 comprising of reacting (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2
Formula-2 with a triethylsilylating agent in presence of a suitable base in a suitable solvent to provide compound of formula-3.

4. A process for the preparation of (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-4, Formula-4 comprising of deprotective oxidation of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3 with a suitable oxidizing agent in a suitable solvent to provide compound of formula-4.

5. An improved process for the preparation of (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-6, Formula-6 comprising of condensing (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-4 with dimethyl 2-oxo-4-phenylbutyl phosphonate compound of formula-5
Formula-5 in presence of lithium hydroxide monohydrate in a suitable solvent provides compound of formula-6.

6. A novel process for the preparation of (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoic acid compound of formula-10, comprising of condensing (3aR,4R,5R,6aS)-4-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-9 Formula-9 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides compound of formula-10.

7. An improved process for the preparation of dimethyl 2-oxo-4-phenylbutylphosphonate compound of formula-5, comprising of reacting l-bromo-4-phenyl-2-butanone compound of formula-14 Formula-14 with trimethylphosphite in a suitable solvent provides compound of formula-5.

8. A novel process for the preparation of (Z)-7[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-N-ethylheptenamide compound of formula-1, comprising of:

a) Reacting (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta [b]furan-2-one compound of formula-2 with a triethylsilylating agent in presence of a suitable base selected from diisopropyl amine, diisopropylethyl amine, pyridine, triethyl amine and dimethylamino pyridine in a suitable solvent selected from chloro solvents, ether solvents and polar aprotic solvents provides (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3,

b) deprotective oxidation of the compound of formula-3 with a suitable oxidizing agent selected from oxalyl chloride in combination with dimethylsulfoxide and a suitable base, trichloroisocyanuric acid in presence of TEMPO, pyridinium chlorochromate, quaternary ammonium salt-TEMPO-oxone, N-chloro succinamide in combination with dimethylsulfide and a suitable base and Dess-Martin periodinane in a suitable solvent
selected from chloro solvent provides (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-4,

c) condensing the compound of formula-4 in-situ with dimethyl 2-oxo-4-phenylbutyl phosphonate compound of formula-5 in presence of lithium hydroxide mono hydrate in a suitable solvent selected from ether solvent provides (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-6,

d) asymmetric reduction of keto group present on straight chain of compound of formula-6 with a suitable reducing agent selected from p-chlorodiisopinocampheyl borane (DIP Chloride), borane-THF or borane-DMS in combination with a chiral catalyst like (R)-tetrahydro-l-methyl-3,3-diphenyl-lH,3H-pyrrolo(l,2-c)(l,3,2)oxazaborole(R-Methyl CBS) or R-Butyl CBS or R-Phenyl CBS in a suitable solvent selected from ether solvent provides (3aR,4R,5R,6aS)-4-(( 1 E,3 S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7,

e) reducing the keto group of compound of formula-7 with a suitable reducing agent selected from diisobutylaluminium hydride, sodium borohydride and lithium aluminium hydride in a suitable solvent selected from ether solvent provides (3aR,4R,5R,6aS)-4-((1 E,3 S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta [b]furan-2-ol compound of formula-8,

f) condensing the compound of formula-8 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 in presence of a suitable base selected from alkali metal hydrides, alkali metal amides, alkali metal alkoxides and organic bases like alkyl lithium in a suitable solvent seleted from ether solvent, followed by treatment with a suitable acid selected from inorganic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid and the like provides (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoic acid compound of formula-10,

g) reacting the compound of formula-10 in-situ with a methylating agent in presence of a suitable base selected from alkali metal carbonate (or) organic base such as DBU, DBN and the like in a suitable solvent selected from ketone solvents to provide (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-
enyl)cyclopentyl)hept-5-enoate compound of formula-12, Formula-12 h) reacting the compound of formula-12 with ethyl amine in the presence (or) absence of a solvent provides compound of formula-1.

9. A novel process for the preparation of (Z)-7[(1R,2R,3R,5S)-3,5-dihydioxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-A/-ethyl heptenamide compound of formula-1, comprising of:

a) Reacting (3 aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta [b]furan-2-one compound of formula-2 with triethylsilyl chloride in presence of a diisopropylethylamine in tetrahydrofuran provides (3aR,4S,5R,6aS)-5-(triethyl silyloxy)-4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3,

b) deprotective oxidation of the compound of formula-3 with oxalyl chloride in presence of dimethyl sulfoxide and triethylamine in dichloromethane provides (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-4-carbaldehyde compound of formula-4,

c) condensing the compound of formula-4 in-situ with dimethyl 2-oxo-4-phenylbutyl phosphonate compound of formula-5 in presence of lithium hydroxide mono hydrate in methyl tertiary butyl ether provides (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-6,

d) asymmetric reduction of keto group present on straight chain of compound of formula-6 with borane-DMS in presence of R-methyl-CBS in tetrahydrofuran provides (3aR,4R,5R,6aS)-4-(( 1 E,3 S)-3 -hydroxy-5-phenylpent-1 -enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-7,

e) reducing the keto group of compound of formula-7 with diisobutyl aluminium hydride in tetrahydrofuran provides (3aR,4R,5R,6aS)-4-(( 1 E,3S)-3-hydroxy-5-phenylpent-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-8,

f) condensing the compound of formula-8 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-9 in presence of potassium tertiary butoxide in tetrahydrofuran, followed by treatment with hydrochloric acid provides (Z)-7-((1 R,2R,3R,5S)-3,5-dihydroxy-2-(( 1 E,3 S)-3-hydroxy-5-phenylpent-1 -enyl)cyclo pentyl)hept-5-enoic acid compound of formula-10,

g) reacting the compound of formula-10 in-situ with methyl iodide in presence of potassium carbonate in acetone to provide (Z)-methyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((lE,3S)-3-hydroxy-5-phenylpent-l-enyl)cyclopentyl)hept-5-enoate compound of formula-12,
h) reacting the compound of formula-12 with ethyl amine in absence of a solvent provides compound of formula-1.

10. A novel process for the preparation of crystalline form-I of (Z)-7[(1 R,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]5-Af-ethyl heptenamide compound of formula-1, comprising of:

a) Dissolving (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl] cyclopentyl]5-N-ethylheptenamide compound of formula-1 in a mixture of acetonitrile and methyl tertiary butyl ether by heating,

b) stirring the reaction mixture at 50-80°C,

c) cooling the reaction mixture to 0-10°C,

d) stirring the reaction mixture at 0-10°C,

e) filtering the solid and washing with methyl tertiary butyl ether,

f) drying the solid to get crystalline form-I of compound of formula-1.