Field of the invention:

The present invention relates to novel process for the preparation of (Z)-isopropyl 7-
((1R,2R, 3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-
enyl)cyclo pentyl) hept-5-enoate represented by the compound of formula-I and novel intermediates thereof.

(Z)-isopropyl 7-((lR, 2R, 3R, 5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy)but-l-enyl)cyclopentyl) hept-5-enoate generically known as " Travoprost" is a synthetic analog of prostaglandin F2,, (PGF2a ), which is a naturally occurring prostaglandin. Travoprost is approved in both U.S and Europe as a potential treatment option for the reduction of elevated intraocular pressure (IOP) in patients with open angle glaucoma or ocular hypertension. Travoprost is formulated as ophthalmic solution and is marketed under the brand name TRAVATAN®.

Background of the invention:

The synthetic derivatives of prostaglandin F20 (PGF2a) like bimatoprost, latanoprost and travoprost are usually prepared according to synthetic methods which starts from hydroxy protected corey aldehyde [(3aR,4R,5R,6aS)-5-hydroxy-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde]. (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) and its process for the preparation was first disclosed in US 4,321,275 (herein after referred as '275' patent). The process involves condensation of 2-[3-(trifluoromethyl)phenoxy]acetyl chloride (compound of formula-A) with dimethyl methylphosphonate in presence of n-butyllithium in tetrahydrofuran (THF) which provides dimethyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate (compound of formula-B) which is condensed with the p-phenylbenzoylated (PPB) corey aldehyde (compound of formula-C) in presence of n-butyllithium in dimethoxyethane to provide the unsaturated ketone (compound of formula-D). Reduction of unsaturated ketone with zinc borohydride in dimethoxyethane provides an unsaturated alcohol (compound of formula-E) which is treated with potassium carbonate to give a diastereomeric mixture of unsaturated diols, which is resolved by chromatography provides chiral unsaturated diol (compound of formula-F). The protection of chiral unsaturated diol with dihydropyran and toluene sulfonic acid (TsOH) provides the bis (tetrahydropyranyl) protected ether (compound of formula-G), which on reduction of the lactone ring with diisobutyl aluminium hydride (DIBAL-H) in THF provides the lactol (compound of formula-H). The condensation of lactol with Wittig salt in presence of sodium hydride in dimethylsulfoxide (DMSO) provides the prostenoic acid (compound of formula-I), which is esterified with isopropyl iodide in presence of 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) in acetone provides isopropyl ester (compound of formula-J). Finally, this isopropyl ester is deprotected with acetic acid in hot THF/water provides Travoprost compound of formula-I. The above process can be schematically represented in Scheme-1,

The synthetic starting materials which are used in the synthesis of prostaglandins like corey aldehyde and phosphonium ylides are very costly materials indeed. The above process involves multiple hydroxy protection and deprotection steps and chromatographic separation of intermediates which results in the loss of yield and productivity and leading to more consumption of key starting materials to get the desired quality and quantity of the product, which usually hampers the cost of the production.

There are several other processes for the preparation of synthetic derivatives of prostaglandin F2U (PGF2a ) are reported in literature references like US 7,897,795 , US 7,166,730, US 7,109,371, US2007155973, US20100010239, WO 2010/097672 , WO2011/055377 and the like.

The protection of the hydroxy groups particularly in prostaglandin synthesis is generally obtained via the formation of esters for example acetate, benzoate and p-phenyl benzoate (PPB) or silyl ethers such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS) or with tetrahydropyranyl (THP). The protection by means of the above protecting groups indicated above has considerable drawbacks, for example difficulty of final release , intermediates which are not facilitating the subsequent asymmetric synthesis steps or in the case of tetrahydropyranyl (THP) protection, the introduction of further chiral centre which entails the formation of diastereomers.

Most of the above processes disclosed in the prior art involves the usage of intermediates having two different or same protecting groups for two hydroxy functional groups. The protection of two hydroxy groups with different or same protection groups leads to the formation many impurities and additional reaction steps for deprotection of protecting groups which makes the process cumbersome and not amenable for commercial production. Hence, the usage of intermediates having dual protecting groups in prostaglandins synthesis is not suggestible in commercialization of the process.

Further added to these disadvantages, the prior art processes for the preparation of synthetic derivatives of prostaglandin F2a(PGF2a) such as travoprost involves condensation of (4-Carboxy butyl)triphenyl phosphonium bromide (Wittig salt) with bicyclic compound in presence of a strong base to provide the reaction mixture containing travoprost acid, wherein the pH of the reaction mixture is highly basic . The pH of the reaction mixture was adjusted with inorganic acids such as hydrochloric acid and organic acid such as acetic acid and citric acid, which leads to the uncontrolled formation of 15-(S)-Hydroxy epimer impurity in final API.

Hence, there is a need in the art to provide an improved and cost-effective process which overcome the problems underlying the prior-art processes to provide synthetic derivatives of prostaglandin F2a (PGF2a) such as travoprost with high yield & purity with less reaction steps.

Surprisingly, the present inventors have developed a novel process for the preparation of synthetic derivatives of prostaglandin F2U (PGF20 ) such as travoprost, which involves the formation of intermediates with single hydroxy protecting group throughout the synthesis, which facilitates the simple work-up procedures thereby leading to the formation of travoprost with high yield and purity.

Brief description of the invention:

The first aspect of the present invention is to provide ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifiuoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one, compound of formula-Ill, which is a novel intermediate useful in the synthesis of travoprost and fluprostenol sodium.
The second aspect of the present invention is to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta [b]furan-2-one, compound of formula-IV, which is a novel intermediate useful in the synthesis of travoprost and fluprostenol sodium.

The third aspect of the present invention is to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol, compound of formula-V, which is a novel intermediate useful in the synthesis of travoprost and fluprostenol sodium.
The fourth aspect of the present invention is to provide a process for the preparation of ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill, which comprises of reacting the(3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-II with dialkyl 2-oxo-3-(3-(trifluoromethyl)phenoxy) propyl phosphonate in presence of a base in a suitable solvent.

The fifth aspect of the present invention is to provide a process for the preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyl oxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV, which comprises of reducing the ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill with an asymmetric reducing agent in a suitable solvent.

The sixth aspect of the present invention provides a process for the preparation of (3aR,4R,5R,6aS)-4-((R3)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V, which comprises of reducing (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy )hexahydro-2H-cyclopenta[b]furan-2-one with a suitable reducing agent in a suitable solvent.

The seventh aspect of the present invention is to provide a process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost), which comprises of reacting (3aR,4,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyl-oxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V with (4-carboxybutyl) triphenylphosphonium bromide in presence of a suitable base in a suitable solvent provides travoprost acid and further reacts with 2-halopropane in presence of a base in a suitable solvent to provide travoprost compound of formula-I.

The eight aspect of the present invention is to provide a process for the preparation of (Z)-isopropyl7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(rrifluoromethyl) phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) which comprises the following steps:

a) Reacting the (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-4-carbaldehyde compound of formula-II with dialkyl 2-oxo-3-(3-(trifiuoro methyl)phenoxy) propylphosphonate in presence of a suitable base in a suitable solvent to provide ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill,

b) reducing the compound of formula-Ill with a suitable asymmetric reducing agent in a suitable solvent to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV,

c) reducing the compound of formula-IV with a suitable reducing agent in a suitable solvent to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy )hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V,

d) condensing the compound of formula-V with (4-carboxybutyl)triphenylphosphonium bromide in presence of a suitable base in a suitable solvent to provide travoprost acid.

e) reacting the above obtained travoprost acid with 2-halopropane in presence of base in a suitable solvent to provide (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy) but-1 -enyl)cyclopentyl)hept-5-enoate compound of formula-I.

The ninth aspect of the present invention is to provide process for the preparation of travoprost containing less than 0.5% of 15-(S)-hydroxy epimer impurity.

The tenth aspect of the present invention is to provide the purification of travoprost by preparative high performance liquid chromatography (HPLC) using chiral HPLC column and an eluent system having the mixture of acetonitrile and one or more alcohol solvents.

The eleventh aspect of the present invention is to provide the purification of travoprost by reverse phase high performance liquid chromatography (HPLC) using HPLC column and an eluent system having the mixture of one or more hydrocarbon solvents, one or more alcohol solvents and acetonitrile.

Detailed description of the invention:

As used herein, the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; "ether solvents" such as di-tert-butyl ether, diethyl ether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran,2-methyl tetrahydrofuran and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.

As used herein, the present invention "asymmetric reducing agent" is defined as asymmetric reducing agent is a reducing agent which will convert the prochiral ketone into chiral, alcohols. The non-limiting examples of asymmetric reducing agents are (-)-B-chlorodiisopino campheylborane (DIP-C1), chiral oxazaborolidine catalyst (CBS catalyst) i.e. preferably (R)-2-alkyl-CBS or (R)-2-aryl-CBS or oxazaborolidine catalyst optionally in combination with Borane-Ligand and the ligand may be tetrahydrofuran (THF), dimethyl sulfide (DMS) or N,N-diethylaniline (DEAN) and the preferred agent may be [(R)-MeCBS]/Borane.DMS or [(R)-MeCBS]/ Borane.DEAN or chemo enzymatic reducing agents such as ketoreductase enzyme.

As used herein the present invention, the term "base" refers to inorganic or organic base. An "inorganic base" is an inorganic compound, which acts as a base. Examples of such bases include, but are not limited to, hydrides, hydroxides, carbonates, bicarbonates, oxides, and alkoxides of alkali or alkaline earth metals, such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, calcium oxide, and barium oxide or ammonium hydroxide. Mild bases like lithium halides, magnesium halides and DBU. Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and alkali metal amides such as sodium amide or potassium amide or mixtures thereof;

An "organic base" is an organic compound, which acts as a base. Examples of such bases include, but are not limited to, triethylamine, diisopropylamine, diisopropyl ethylamine, triethanolamine, tributylamine, pyridine, 2,6-lutidine, 4-dimethylaminopyridine (DMAP), diethanolamine, 4-methylmorpholine, dimethylethanolamine, tetramethylguanidine, tetramethyl ammonium hydroxide, tetraethylammonium hydroxide, N-methyl-l,5,9-triaza bicyclo[4.4.0]decene, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), dicyclohexylamine, picoline, 1,5-Diazabicyclo[4.3.0] non -5-ene (DBN) and l,4-diazabicyclo[2.2.2]octane (DABCO).

The first aspect of the present invention provides ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromemyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one, compound of formula-Ill, which is a novel intermediate used in the synthesis of anti-glaucoma agents like travoprost and fluprostenol sodium.

Wherein, -TES is triethylsilyl group.

The second aspect of the present invention provides (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta [b]furan-2-one, compound of formula-IV, which is a novel intermediate used in the synthesis of anti-glaucoma agents like travoprost and fluprostenol sodium.

wherein, -TES is triethylsilyl group.

The third aspect of the present invention provides (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-ol, compound of formula-V, which is a novel intermediate used in the synthesis of anti-glaucoma agents like travoprost and fluprostenol sodium.

wherein, -TES is triethylsilyl group.

The fourth aspect of the present invention provides a process for the preparation of ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill which comprises of, reacting the (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde compound of formula-II,
with dialkyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate having the following ctnirtiirp
wherein, 'R' may be selected from Ci - C4 straight or branched chain alkyl groups, in presence of a suitable base in a suitable solvent to provide compound of formula-Ill, Wherein the suitable base is selected from alkali metal hydrides such as sodium hydride, potassium hydride; alkali metal amides such as sodium amide or potassium amide; alkali metal alkoxides such as potassium ethoxide, sodium ethoxide, sodium methoxide, potassium tertiary butoxide and sodium tertiary butoxide; and alkali metal hydroxide like sodium hydroxide, potassium hydroxide and lithium hydroxide and lithium metal bases like n-Butyl lithium; and mild bases like lithium halides, magnesium halides and DBU; the suitable solvent is selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether or cyclic ether such as tetrahydrofuran and 2-methyltetrahydrofuran.

The preferred embodiment of the present invention provides a process for the preparation of (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy)
hexa hydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill, which comprises of, reacting the (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-4-
carbaldehyde compound of formula-II with dimethyl 2-oxo-3-(3-(trifluoromethyl) phenoxy) propylphosphonate in presence of mild base such as lithium chloride in tetrahydrofuran to provide the compound of formula-Ill.

The fifth aspect of the present invention provides a process for the preparation of (3aR, 4R, 5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy) hexa hydro-2H-cyclopenta[b]furan-2-one compound of formula-IV, which comprises of, reducing the ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill, with an asymmetric reducing agent in a suitable solvent.

wherein, the asymmetric reducing agent is (-)-B-chlorodiisopinocampheyl borane (DIP-Cl) or oxazaborolidine catalyst (CBS catalyst), preferably (R)-2-alkyl-CBS or (R)-2-aryl-CBS or oxazaborolidine catalyst (CBS catalyst) optionally in combination with a borane-ligand selected from borane-THF, borane- dimethyl sulfide (DMS) and borane-N, N-diethylaniline (DEAN) and the preferred agent may be [(R)-MeCBS]/Borane-DMS or [(R)-MeCBS]/Borane-DEAN or [(R)-MeCBS]/Borane-THF or ketoreductase enzyme; the suitable solvent is selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether or cyclic ethers such as tetrahydrofuran and 2-methyl tetrahydrofuran.

The preferred embodiment of the present invention is to provide novel process for the preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV, comprises of reducing the compound of formula-Ill with [(R)-MeCBS]/Borane-DMS in THF to provide compound of formula-IV.
The sixth aspect of the present invention provides a process for the preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V, which comprises of, reducing the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula -IV, tetrahydrofuran and hydrocarbon solvents such as toluene, xylenes, n-hexane and the like.

The preferred embodiment of the present invention is to provide novel process for the preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyl oxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V, which comprises of, reducing the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) with a suitable reducing agent in a suitable solvent.

wherein, the suitable reducing agent may be selected from hydride reagents such as sodium borohydride, potassium borohydride, diisobutyl aluminium hydride (DIBAL-H), lithium aluminium hydride (LAH) and the like; the suitable solvent may be selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether or cyclic ethers such as tetrahydrofuran and hydrocarbon solvents such as toluene, xylenes, n-hexane and the like.

The preferred embodiment of the present invention is to provide novel process for the preparation of (3 aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyl oxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V, which comprises of, reducing the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-(triethylsilyl oxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula -IV with diisobutyl aluminum hydride (DIBAL-H) in tetrahydrofuran to provide the compound of formula-V.

The seventh aspect of the present invention provides a process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy) but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) which comprises of,

a) Reacting (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V, with (4-carboxybutyl)triphenylphosphonium bromide in presence of a suitable base in a suitable solvent to provide travoprost acid,

b) reacting the travoprost acid in-situ with 2-halopropane in presence of a base in a suitable solvent to provide travoprost of formula-I.

wherein, in step-a), the suitable base is selected from alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide and alkali amide bases like sodium amide or potassium amide and the like; the suitable solvent may be selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether or cyclic ethers such as tetrahydrofuran and hydrocarbon solvents such as toluene, xylenes, n-hexane and the like.

wherein, in step-b) the suitable base is selected from bases like alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate and alkali bicarbonates such as sodium bicarbonate, potassium bicarbonate and N-methyl-l,5,9-triazabicyclo[4.4.0]decene, 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN) and l,4-diazabicyclo[2.2.2]octane (DABCO); and the suitable solvent may be selected from ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone and nitrile solvents such as acetonitrile an polar aprotic solvents such as dimethyl formamide and dimethyl acetamide; and the 2-halopropane is preferably 2-iodopropane.

The preferred embodiment of the present invention is to provide a novel process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy) but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) which comprises of,

a) Reacting (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V with (4-carboxybutyl)triphenylphosphonium bromide (Wittig salt) in presence of potassium tert.butoxide in THF to provide the travoprost acid compound,

b) reacting the above obtained travoprost acid with 2-Iodopropane in presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to provide travoprost compound of formula-1.
The eighth aspect of the present invention provides a process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy) but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) which comprises of the following steps,

a) Reacting the (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-4-carbaldehyde compound of formula-II,

with dialkyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate in presence of a suitable base in a suitable solvent to provide ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta [b]furan-2-one compound of formula-Ill,

b) reducing the compound of formula-Ill with a suitable asymmetric reducing agent in a suitable solvent to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-IV,
c) reducing the compound of formula-IV with a suitable reducing agent in a suitable solvent to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V,

d) condensing the compound of formula-V with (4-Carboxybutyl)triphenyl phosphonium bromide (Wittig salt) in presence of a suitable base in a suitable solvent to provide travoprost acid,

e) reacting the above obtained travoprost acid with 2-halopropane in presence of base in a suitable solvent to provide (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) compound of formula-I.

The preferred embodiment of the present invention to provide novel process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoro methyl) phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate (Travoprost) which comprises the following steps,

a) Reacting the (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-4-carbaldehyde compound of formula-II with dimethyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate in presence of lithium chloride in tetrahydrofuran to provide ((3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl) phenoxy)but-1 -enyi)-5-(triethylsilyl oxy)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-Ill,

b) reducing the compound of formula-Ill with [(R)-MeCBS]/borane-dimethyl sulfide in tetrahydrofuran to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV,

c) reducing the compound of formula-IV with diisobutyl aluminium hydride in tetrahydrofuran to provide (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V,

d) condensing the compound of formula-V with (4-carboxybutyl) triphenylphosphonium bromide (Wittig salt) in presence of potassium tertiary butoxide in tetrahydrofuran to provide travoprost acid,

e) reacting the above obtained travoprost acid with 2-iodopropane in presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone solvent provides (Z)-isopropyl 7-
((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate compound of formula-I.

The ninth aspect of the present invention provides a process for the preparation of travoprost containing less than 0.5% of 15-(S)-hydroxy epimer impurity having the structure which comprising of,

a) reacting (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl) -5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V with (4-carboxybutyl) triphenylphosphonium bromide in presence of potassium tert.butoxide in tetrahydrofuran to form a reaction mixture,

b) quenching the reaction mixture and followed by adjusting the pH of the reaction mixture by using aqueous sodium bisulfate,

c) extracting the above reaction mixture into a solvent and concentrate the organic layer to provide travoprost acid and,

d) reacting the travoprost acid with 2-haloproane in presence of a base in a solvent to provide the crude travoprost,

e) purifying the crude travoprost by column chromatography to provide travoprost containing less than 0.5% of 15-(S)-hydroxy epimer impurity.

The tenth aspect of the present invention provides a purification process of travoprost by preparative HPLC using a chiral HPLC column and an eluent system containing mixture of acetonitrile and one or more alcohol solvents (90-98 : 10-2 v/v) to provide the travoprost containing substantially free of 5,6-trans impurity and 15-(S)-hydroxy epimer impurity having the following structures:

Now it is possible to separate the substantially pure travoprost by using the preparative HPLC with the following chromatographic conditions;

Apparatus: Preparative high performance liquid chromatography equipped with U.V detector; Column: Chiralpak AD-H (Daicel), 250 mm X 30 mm, 5um; Flow rate: 20 ml/min; Wave length: 210 nm;Column temperature: ambient; Injection volume: 2000ul (2.0 ml); Elution: Isocratic; Mobile phase: acetonitrile: methanol (95: 5) v/v; Diluent : Mobile phase.

Preparation of sample solution : weigh accurately 500 mg of sample and transfer into a 10 ml volumetric flask, add about a 5 ml of diluent and sonicate to dissolve and make up to the volume.

Procedure: Inject 2.0 ml of sample solution and collect the pure fraction.

The eleventh aspect of the present invention is to provide the purification of travoprost by reverse phase high performance liquid chromatography (HPLC) using HPLC column and an eluent system having the mixture of one or more hydrocarbon solvents, one or more alcohol solvents and acetonitrile (80-98: 1-15: 1-5 v/v) to provide the travoprost containing substantially free of 5,6-trans impurity and 15-(S)-hydroxy epimer impurity.

In the above aspect, the hydrocarbon solvents are selected from heptane, hexane; and alcohol solvents are selected from methanol, ethanol and isopropanol.

Now it is possible to separate the substantially pure travoprost by using the preparative HPLC with the following chromatographic conditions;

Apparatus: Preparative high performance liquid chromatography equipped with U.V detector; Column: SunFire CI8 OBD Prep Column (Waters), 250 mm X 50 mm, lOum; Flow rate: 35 ml/min; Wave length: 210 nm; Column temperature: ambient; Injection volume: 4 to 4.5 ml; Elution: Isocratic; Run Time: 35 min; mobile phase: heptane: alcohol: acetonitrile (90: 7: 3) v/v; Diluent: Mobile phase.

Preparation of sample solution : weigh accurately 500 mg of sample and transfer into a 10 ml volumetric flask, add about a 5 ml of diluent and sonicate to dissolve and make up to the volume.

Procedure: Inject 4.0 ml of sample solution and collect the pure fraction. 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 the invention.

Examples:
Example-1: Preparation of (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclo penta[b]furan-4-carbaldehyde compound of formula-II.

3.2 ml of oxalyl chloride was added to the mixture of dimethylsulfoxide (3.5 ml) and dichloromethane (70 ml) at -65°C to -70°C and stirred the reaction mixture for 30 minutes at -65°C to -70°C. A solution of (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy) methyl)hexahydro-2H-cyclopenta[b]furan-2-one (7.0 gm) in dichloromethane (20 ml) was added dropwise to the reaction mixture at -65°C to -70°C under nitrogen atmosphere. The reaction mixture was stirred for 4 hrs at -65°C to -70°C and raised the temperature of the reaction mixture to -40°C to -45°C and stirred for 10 minutes at the same temperature.

The reaction mixture was again cooled to -65°C to -70°C and triethylamine (13.8 ml) was added to the reaction mixture at -65°C to -70°C under nitrogen atmosphere and stirred the reaction mixture for 30 minutes at -60°C to -65°C. After completion of the reaction, water was added to the reaction mixture and then allowed the reaction mixture to room temperature and both the organic and aqueous layers were separated. Extract the aqueous layer with dichloromethane and dried the organic layer with sodium sulfate and completely distilled off the organic layer to provide the residue of compound of formula-II. Yield: 7 gm

Example-2: Preparation of (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyI)phenoxy) but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill.

A solution of above obtained residue compound (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyl oxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde in tetrahydrofuran (20 ml) was slowly added to a solution of dimethyl 2-oxo-3-(3-(trifluoromethyl) phenoxy)propylphosphonate (5.6 gm) and lithium chloride (0.7 gm) in THF (50 ml) at 10-15 °C and stirred the reaction mixture for 6 hrs at the same temperature . After completion of the reaction, mixture of water and ethyl acetate was added to the reaction mixture and both the organic and aqueous layers were separated. Extract the aqueous layer with ethyl acetate and wash the organic layer with water and combined the organic layers and distilled off the organic layer to provide the residue compound of formula-Ill. Further, the obtained residue was purified by column hromatography by using petroleum ether and ethyl acetate as eluents. Yield: 2.4 gm, 'H NMR 300 MHz (CDCI3), 5 in ppm: 0.512-0.589 (6H, q), 0.890-0.942 (9H, t), 1.991-2.070 (1H, m), 2.322-2.493 (2H, m), 2.570-2.641 (1H, dd), 2.693-2.822 (2H,m), 4.031-4.093 (1H, q), 4.729 (2H, s), 4.929-4.983 (1H, m), 6.487-6.540 (1H,
d), 6.806-6.886 (1H, m), 7.053-7.124 (2H, m), 7.266-7.287 (1H, d), 7.396-7.449 (1H, t).

Example-3: Preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyI)-5-(triethylsily!oxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV.

To a solution of above obtained (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl) phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one (2.0 gm) compound of formula-Ill and (R)-MeCBS (0.6 ml) in tetrahydrofuran (20 ml) was slowly added borane.dimethyl sulfide (0.3 ml) at -25°C to -30°C. Stirred the reaction mixture for 4 hrs at -25°C to -30°C and raised the temperature of the reaction mixture to 0°C - 5°C. After completion of the reaction, the reaction mixture was quenched by adding methanol and then ammonium chloride solution was slowly added to the reaction mixture. Both organic and aqueous layers were separated and extract the aqueous layer with ethyl acetate and distilled off the solvent from organic layer to provide the residue of compound of formula-IV. The obtained residue was purified by column chromatography by using cyclohexane and ethyl acetate as eluents. Yield: 1.3 gm; 'H NMR 300 MHz (CDC13), 5 in ppm: 0.570-0.622 (6H, q), 0.922-0.974 (9H, t), 1.236-1.284 (2H, m), 1.955-2.773 (5H, m), 2.806 (1H, m), 3.861-4.157 (4H, m), 5.614-5.769 (2H, m), 7.069-7.584 (4H, m)

ExampIe-4: Preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-ol compound of formula-V.

(3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one (1.2 gm) was dissolved in tetrahydrofuran (12 ml) and cooled the reaction mixture to -65°C to -70°C. Diisobutyl aluminium hydride (4.8 ml) was slowly added to the reaction mixture at -65°C to -70°C for and stirred the reaction mixture at -65°C to -70°C for 30 minutes. After completion of the reaction, the reaction mixture was quenched with methanol at -45°C to -50°C. Water and ethyl acetate were added to the reaction mixture at -40°C to -45 °C and the temperature of the reaction mixture was raised to 25°C - 30°C. Stirred the reaction mixture for 40 min at 25°C - 30°C and filtered the reaction mixture through celite bed and washed the bed with ethyl acetate. Dried the organic layer with sodium sulfate and completely distilled of the solvent from organic layer to provide the compound of formula-V as a residue.

Yield: 1.2 gm, 'H NMR 300 MHz (CDC13), 6 in ppm: 0.535-0.660 (6H, q), 0.918-0.992 (9H, t), 1.256-2.486 (6H, m), 2.796-2.870 (1H, m), 3.829-4.406 (3H, m), 4.555-4.626 (3H, m), 5.490-5.831 (3H, m), 7.073-7.585 (4H, m).

Example-5 : Preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)cyclopentyl)hept-5-enoate(Travoprost).

Potassium tertiary butoxide (1.6 gm) was added to a solution of (4-carboxybutyl) triphenylphosphonium bromide (3.2 gm) in tetrahydrofuran (13 ml) at 30°C - 35°C and stirred the reaction mixture at the same temperature for 30 minutes under nitrogen atmosphere and cooled the reaction mixture to 0°C-5°C. A solution of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromemyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol (1.2 gm) in tetrahydrofuran (5 ml) was added to the reaction mixture at 0°C - 5°C and stirred the reaction mixture for 4 hrs at 0°C - 5°C under the nitrogen atmosphere. After completion of the reaction, the reaction mixture was quenched with cold water and adjusted the pH of the reaction mixture using the solution of sodium bisulfate. The reaction mixture was extracted with ethyl acetate and both the aqueous and organic layers were separated. The organic layer was dried with sodium sulfate and distilled off the solvent from organic layer to provide the travoprost acid as a residue. The obtained residue was dissolved in acetone (15 ml) and cooled the reaction mixture to 0-5°C. DBU (5 ml) and 2-iodopropane (7 ml) were added to the reaction mixture at 0-5 °C and raised the temperature of the reaction mixture to 25 °C - 30°C and stirred the reaction mixture for 16 hrs at 25°C - 30°C. After completion of the reaction, filtered the reaction mixture and wash the unwanted solid with acetone. Distilled off the solvent completely from the filtrate under reduced pressure to provide the residue. Dichloromethane was added to the obtained residue and washed the reaction mixture with water then followed by citric acid solution (dissolve 5 gm citric acid in 10 ml water). Dried the organic layer with sodium sulfate and distilled off the organic layer to provide crude travoprost. Further, the obtained crude
travoprost was purified by column chromatography by using methanol and dichloromethane as
eluents.

Yield: 600 mg,
Purity by HPLC: 95.5%; 5, 6-trans impurity: 3.0%; 15-(S)-hydroxyl epimer impurity: 0.3%.

Example-6: HPLC separation of travoprost and isomers
HPLC separation of travoprost was carried out using a Daicel Chiralpak AD-H silica gel column. The isocratic eluent system comprised acetonitrile: methanol in volume/volume ranges (90-98:10-2).
The following results are shown for HPLC separation of travoprost using acetonitrile: methanol as eluent system in the volume ratio of 95vol: 5vol. The relative retention times (RRT's) of travoprost, 15-(S)-hydroxy epimer and 5, 6-trans isomers are obtained at 1.0, 0.90 and 1.16 respectively.

The above results indicate that an excellent degree of separation of travoprost from the undesired isomers can be achieved by using an eluent system comprising acetonitrile: methanol.

Example-7: HPLC separation of travoprost and isomers
HPLC separation of travoprost was carried out using Waters SunFire C18 OBD Prep silica gel column. The isocratic eluent system comprised hydrocarbon: alcohol: acetonitrile in volume/volume ranges (80-98: 1-15: 1-5).

The following results are shown for HPLC separation of travoprost using heptane: ethanol: acetonitrile as eluent system in the volume ratio of 90vol: 7vol: 3vol. The relative retention times (RRT's) of travoprost, 15-(S)-hydroxy epimer and 5, 6-trans isomers are obtained at 1.0, 0.90 and 1.16 respectively.
The above results indicate that an excellent degree of separation of travoprost from the undesired isomers can be achieved by using an eluent system comprising heptane: ethanol: acetonitrile.

We Claim:

1. Compounds having the following structural formulas:

2. A process for the preparation of (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl) phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill comprising of,
reacting the (3aR,4R,5R,6aS)-2-oxo-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-4-carbaldehyde compound of formula-II,

with dialkyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate having the following structure,

wherein 'R' may be selected from C1 - C4 straight or branched chain alkyl groups;

in presence of a base selected from alkali metal hydrides, alkali metal amides, alkali metal alkoxides, alkali metal hydroxides and mild bases like lithium halides, magnesium halides and DBU in a suitable solvent selected from ether solvents, hydrocarbon solvents, keto solvents or mixtures thereof to provide the (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-Ill.

3. A process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy) but-l-enyl)cyclopentyl)hept-5-enoate compound of formula-I comprising of,
a) Reacting the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy) but-1-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V,
wherein, -TES is triethylsilyl group;

with (4-carboxybutyl) triphenylphosphonium bromide in presence of a base selected from alkali metal amides, alkali metal alkoxides and alkali metal hydroxides in a suitable solvent selected from ether solvents, hydrocarbon solvents, keto solvents or mixtures thereof to provide travoprost acid, b) reacting the above obtained travoprost acid in-situ with 2-halopropane in presence of a base selected from alkali metal carbonates, alkali bicarbonates, N-methyl-l,5,9-triaza bicyclo[4.4.0]decene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo [4.3.0]non-5-ene (DBN) and l,4-iazabicyclo[2.2.2]octane (DABCO); and the suitable solvent is selected from ketone solvents, nitrile solvents, polar aprotic solvents or mixtures thereof to provide travoprost compound of formula-I.

4. A process for the preparation of (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV comprising of,

wherein, -TES is triethylsilyl group;
reducing the (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill with an asymmetric reducing agent selected from (-)-B-chlorodiisopinocampheyl borane (DIP-C1) or oxazaborolidine catalyst (CBS catalyst), preferably (R)-2-alkyl-CBS or (R)-2-aryl-CBS or oxazaborolidine catalyst (CBS catalyst) optionally in combination with a borane-ligand selected from borane-THF, borane-dimethyl sulfide (DMS) and borane-N, N-diethylaniline (DEAN) in an organic solvent selected from ether solvents, hydrocarbon solvents, keto solvents or mixture of to provide the compound of formula-IV.

5. A process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy)but-1 -enyl)cyclopentyl)hept-5-enoate (Travoprost) compound of formula-I comprising of,

a) Condensing the compound of formula-II with dialkyl 2-oxo-3-(3-(trifluoromethyl)phenoxy)propylphosphonate in presence of a suitable base in a suitable solvent to provide the (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-Ill,

b) reducing the compound of formula-Ill with an asymmetric reducing agent in a suitable solvent to provide the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl) phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]fiiran-2-one compound of formula-IV,

c) reducing the compound of formula-IV with a suitable reducing agent in a suitable solvent or mixture of solvents to provide the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-ol, compound of formula-V,

d) condensing the compound of formula-V with (4-carboxybutyl)triphenyl phosphonium bromide in presence of a base in a suitable solvent or mixture of solvents to provide travoprost acid,

e) reacting the above obtained travoprost acid with 2-halopropane in presence of a base in a suitable solvent to provide travoprost compound of formula-I.

6. A process for the preparation of (Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy)but-1 -enyl)cyclopentyl)hept-5-enoate (Travoprost) compound of formula-I comprising of,

a) Condensing the compound of formula-II with dimethyl 2-oxo-3-(3-(trifluoromethyl) phenoxy)propylphosphonate in presence of lithium chloride in tetrahydrofuran to provide the (3aR,4R,5R,6aS)-4-((E)-3-oxo-4-(3-(trifluoromethyl) phenoxy)but-1 -enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-III,

b) reducing the compound of formula-Ill with (R)-methyl oxazaborolidine catalyst (CBS catalyst) in combination with borane-dimethyl sulfide in tetrahydrofuran to provide the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-IV,

c) reducing the compound of formula-IV with a diisobutylaluminium hydride (DIBAL-H) in tetrahydrofuran to provide the (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy)but-1 -enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-ol, compound of formula-V,

d) condensing the compound of formula-V with (4-carboxybutyl)triphenylphosphonium bromide in presence of potassium tertiary butoxide (KOBt) in tetrahydrofuran to provide travoprost acid,

e) reacting the above obtained travoprost acid with 2-iodopropane in presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to provide travoprost compound of formula-I.

7. A process for the preparation of travoprost containing less than 0.5% of 15-(S)-hydroxy epimer impurity having the structure:
comprising of,

a) reacting (3aR,4R,5R,6aS)-4-((R,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-V with (4-carboxybutyl)triphenylphosphonium bromide in presence of potassium tert.butoxide in tetrahydrofuran to form a reaction mixture,

b) quenching the reaction mixture and followed by adjusting the pH of the reaction mixture by using aqueous sodium bisulfate,

c) extracting the above reaction mixture into a solvent and concentrate the organic layer to provide travoprost acid and,

d) reacting the travoprost acid with 2-halopropane in presence of a base in a solvent to provide the crude travoprost,

e) purifying the crude travoprost by column chromatography to provide travoprost containing less than 0.5% of 15-(S)-hydroxy epimer impurity.

8. A process for the purification of travoprost by HPLC by using the eluent, comprising of a mixture of acetonitrile and one or more alcohol solvents.

9. A process for the purification of travoprost by HPLC by using the eluent, comprising of a mixture of acetonitrile and methanol.

10. A process for the purification of travoprost by HPLC by using the eluent system comprising of, a mixture of one or more hydrocarbon solvents, one or more alcohol solvents and acetonitrile, wherein hydrocarbon solvents are selected from heptane, hexane or mixtures thereof, and alcohol solvents are selected from methanol, ethanol, isopropanol or mixtures thereof.