Field of the Invention:

The present invention relates to a novel process for the preparation of Isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]-cyclopentyl]-5-heptenoate represented by structural formula-1. The present invention also relates to novel intermediates for the preparation of Isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]-cyclopentyl]-5-heptenoate.

Isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]-cyclopentyl]-5-heptenoate is a prostaglandin analog/prodrug used topically to control the progression of glaucoma or ocular hypertension by reducing intraocular pressure. It is marketed by Pfizer under the trade name Xalatan.

Background of the Invention:

Isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]-cyclopentyl]-5-heptenoateis commonly known as Latanoprost.

Latanoprost and its process for preparation were first disclosed in US 7163959. The disclosed process involves the oxidation of PPB-protected corey lactone diol to provide PPB protected corey aldehyde, which is further undergoes wittig-horner reaction with dimethyl 2-oxo-4-phenylbutylphosphonate to provide (3aR,4R,5R,6aS)-2-oxo-4-((lE)-3-oxo-5-phenyl pent-1 -enyl)hexahydro-2H-cyclopenta[b]furan-5-ylbiphenyl-4-carboxylate. The obtained compound further undergoes reduction with Pd-C to provide (3aR,4R,5R,6aS)-4-(3-hydroxy-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-ylbiphenyl-4-carboxylate and further deprotected using potassium carbonate, followed by reduction using diisobutyl aluminium hydride provides (3aR,4R,5R,6aS)-4-(3-hydroxy-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2,5-diol. This compound further undergoes wittig reaction with (4- carboxybutyl)triphenylphosphonium bromide and then reacted with isopropyl iodide to provide Latanoprost.

The usage of PPB- as protecting group for hydroxyl functional group of its intermediate prevents the usage of pd-C, because pd-C may also reduce the oxo moieties present in protecting group. The reduction of (3aR,4R,5R,6aS)-2-oxo-4-((lE)-3-oxo-5-phenylpent-l-enyl)hexahydro-2H-cyclopenta[b] furan-5-ylbiphenyl-4-carboxylate using Pd-C resulted in the formation of racemic compound, which must be resolved in the subsequent steps. The intermediate (in which two hydroxyl groups are not protected), when reduced using diisobutylaluminium hydride the free hydroxyl groups may form complex with diisobutyl aluminium hydride, which in-turn requires additional equivalents of reducing agent such as diisobutyl aluminium hydride. The intermediate with free hydroxy functional groups also results in the formation of impurities. Hence the usage of intermediate with PPB-protection and also the intermediate with free hydroxy functional groups are not suggestible for the synthesis of Latanoprost.

The prior known processes reported in US 5359095, US 4739078, US 5466833, US 6689901, US6720438 and US20100010239 involves the usage of intermediates having benzyl-, benzoyl- or PPB- protecting groups. These protecting groups prevent the use of many reducing agents including diisobutyl aluminium hydride and PtO2/H2 (g). The usage of DIBAL in the reduction of lactone to lactol results in the reduction of oxo moieties present in the protecting groups. Even the usage of PtO2/H2 (g) in the reduction of C-C double bond of intermediate compound results in the deprotection of protecting groups such as benzyl protecting group. Thus, in prior art procedures wherein DIBAL or PtO2/H2 (g) employed as reducing agent, the protecting groups (benzyl, benzoyl- or PPB) present in starting materials are must be deprotected before reduction.

US 7166730 and US 6927300 were disclosed the processes for preparation of Latanoprost. The disclosed processes involve the usage of intermediates having two different protecting groups for two hydroxy functional groups. The protection of two hydroxy functional groups with two different protecting group leads to additional step with different reagent and the deprotection also lead to problems. Because both the hydroxyl functional groups may not be deprotected at the same time and required one more step for the deprotection of another protecting group which makes the process uneconomic and time consuming and resulted in the formation of product with low purity and yield. Hence the usage of two different protecting groups for two hydroxyl functional groups of its intermediate is not suggestible.

The prior known process also involves the usage of intermediates with TMS-protection. The TMS- protecting groups are sensitive towards mild acid, base and chromatographic purification on silica gel, makes their survival through multi-step operations in synthetic sequence become problematic. Hence the usage of intermediates having trimethylsilyl protecting groups in the synthesis of Latanoprost is found to be difficult.

Henceforth there is a need in the art to provide an alternative protecting group which is resistant towards mild acid, base, reduction and chromatographic purification on silica gel.

US 7498458 disclosed a process for the preparation of Latanoprost. The disclosed process involves the oxidation of benzoyl protected corey lactone diol, which is then undergoes wittig-horner reaction with dimethyl 2-oxo-4-phenylbutylphosphonate, followed by asymmetric reduction with borane-DMS in combination with R-methyl CBS provides (3aR,4R,5R,6aS)-2-hydroxy-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)hexahydro-2H-cyclopenta[b]furan-5-yl benzoate. The obtained compound is further deprotected, followed by C-C double bond reduction using Pd-C to provide (3aR,4R,5R,6aS)-5-hydroxy-4-(3-hydroxy-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-2-one. This compound is again protected with triethyl silyl protecting group, followed by reduction of keto group with diisobutyl aluminium hydride and further undergoes wittig reaction with (4-carboxybutyl) triphenylphosphonium bromide, followed by reaction with isopropyl iodide and finally free hydroxy functional group again protected with triethyl silyl protecting group to provide tris(triethylsilyl) protected Latanoprost. Tris(triethylsilyl)protected Latanoprost is finally deprotected using pyridinium p-toluene sulfonate to provide Latanoprost.

The said process involves the repeated protection and deprotection process, there by utilizes additional reagents and solvents and makes the process uneconomic and time-consuming and results in the formation of final product with low purity and yield.

Henceforth, there is a need in the art to provide an improved and cost-effective process which overcome the problems of prior art to provide Latanoprost with high yield and purity in shorter reaction time.

Brief description of the Invention:

The first aspect of the present invention relates to (3aR,4R,5R,6aS)-4-((3R)-3- hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one, a novel compound of formula-3 or its isomer, which is an useful intermediate in the synthesis of prostaglandin derivatives such as Latanoprost. The present invention also provides a process for the preparation of compound of formula-3.

The second aspect of the present invention relates to (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol, a novel compound of formula-4 or its isomer, which is an useful intermediate in the synthesis of prostaglandin derivative such as Latanoprost. The present invention also provides a process for the preparation of compound of formula-4.

The third aspect of the present invention is to provide a novel process for the preparation of (Z)-7-(( lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl) cyclopentyl)hept-5-enoic acid compound of formula-6, comprising of reacting (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides compound of formula-6.

The fourth aspect of the present invention is to provide one-pot process for the preparation of Isopropyl (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenyl pentyl]cyclopentyl]-5-heptenoate compound of formula-1 from (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4, proceeding through (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid compound of formula-6.

The fifth aspect of the present invention is to provide a novel process for the preparation of Isopropyl (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenyl pentyl]cyclopentyl]-5-heptenoate compound of formula-1, comprising of:

a) Reducing the C-C double bond of (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 with a metal catalyst in a suitable solvent under hydrogen pressure to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3,

b) reducing the keto group of compound of formula-3 with a suitable reducing agent in suitable solvent to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-ol compound of formula-4,

c) reacting the compound of formula-4 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid compound of formula-6,

d) reacting the compound of formula-6 in-situ with 2-halo propane in presence of a suitable base in a suitable solvent to provide the compound of formula-1.

Advantages of the present Invention:

• Provides the process for preparation of Latanoprost compound of formula-1 in shorter reaction time with high yield and purity.

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

• Avoids the usage of additional reagents and solvents for the repeated protection and deprotection processes.

• 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 tert-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 "metal catalyst" herein the present invention is selected from Pd, Pt, Pd-C, Pt-C, Ru-C, Rh-C, palladium hydroxide, palladium acetate, palladium chloride, Pd(PPh3)4, Pd(PPh3)2C12, palladium on metal oxide, palladium on zeolites, platinum oxide (PtO2), rhodium on alumina and Raney-Ni etc.

The term "halo" herein the present invention represents fluoro-, chloro-, bromo- and iodo-.

The term "suitable reducing agent" herein the present invention is selected from diisobutyl aluminium hydride, sodium borohydride and lithium aluminium hydride etc.

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 amide, potassium amide, 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 suitable "acid" herein the present invention is selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid and hydroiodic acid etc.

The first aspect of the present invention relates to (3aR,4R,5R,6aS)-4-((3R)-3- hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one, a novel compound of formula-3 or its isomers, which is an useful intermediate in the synthesis of prostaglandin derivative such as Latanoprost.

Another aspect of the present invention is to provide a process for the preparation of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3, comprising of reducing the C-C double bond of (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 using a metal catalyst in a suitable solvent under hydrogen pressure to provide compound of formula-3.

Wherein, the suitable solvent is alcoholic solvent such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol and the like, preferably ethanol; and the metal catalyst is selected from Pd, Pt, Pd-C, Pt-C, Ru-C, Rh-C, palladium hydroxide, palladium acetate, palladium chloride, Pd(PPh3)4, Pd(PPh3)2C12, palladium on metal oxide, palladium on zeolites, platinum oxide, rhodium on alumina and Raney-Ni etc, preferably platinum oxide.

The metal catalyst employed in the present invention for the reduction of C-C double bond of compound of formula-2 is in the range of 0.02 to 0.08 g, preferably 0.04 g per lg of compound of formula-2; and the solvent used is in an amount ranging from 15 to 30 volumes, preferably 20 volumes per lg of compound of formula-2.

The reduction of C-C double bond was carried out at ambient temperatures for a period of 1-4 hours, preferably 2-3 hours.

The above reduction step with bis(TES) protection was carried for about 15-17 hours. Whereas with mono TES protection, the reaction was carried only in a period of 1-4 hours. Hence the present invention is more advantageous when compare to the prior known processes.

The second aspect of the present invention relates to (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol, a novel compound of formula-4 or its isomers, which is an useful intermediate in the synthesis of prostaglandin derivative such as Latanoprost.

Another aspect of the present invention is to provide a process for the preparation of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4, comprising of reducing the keto group of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H- cyclopenta[b]furan-2-one compound of formula-3 with a suitable reducing agent in a suitable solvent to provide compound of formula-4.

Wherein, the suitable solvent is ether solvent selected from diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and the like, preferably tetrahydrofuran; and the suitable reducing agent is selected from diisobutyl aluminium hydride, sodium borohydride, lithium aluminium hydride etc, preferably diisobutyl aluminium hydride.

The reducing agent used for the keto group reduction in the present invention is in the mole proportions of between 4 and 8 moles, preferably 6 moles per mole of compound of formula-3; and the solvent used in an amount ranging from 8 to 14 volumes, preferably 10 volumes per lg of compound of formula-3.

The reduction of keto group of compound of formula-3 is carried out at a temperature ranging between -60 and -75°C, preferably -68 and -72°C.

The third aspect of the present invention is to provide a novel process for the preparation of (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl) cyclopentyl)hept-5-enoic acid compound of formula-6, comprising of reacting (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4 with (4-carboxy butyl)triphenyl phosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid provides compound of formula-6.

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 selected from alkyl lithium such as methyl lithium, n-butyl lithium and the like, preferably alkali metal alkoxide such as potassium tertiary butoxide; and the suitable solvent is ether solvent such as diisopropyl ether, diethyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like; preferably tetrahydrofuran; the suitable acid is selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid and hydroiodic acid etc, preferably hydrochloric acid.

The base used in the present invention for the reaction of compound of formula-4 with compound of formula-5 is in molar proportions of between 4 and 8 moles, preferably 6 moles per mole of compound of formula-4; compound of formula-5 of present invention is used in molar proportions of between 2 and 4 moles, preferably 3 moles per mole of compound of formula-4; and the solvent used in an amount ranging from 2 to 10 volumes, preferably 6 volumes per lg of compound of formula-4.

The above step of reaction between compound of formula-4 and compound of formula-5 is carried out at a temperature ranging from 0 to 5°C for a period of 2 to 3 hours.

The fourth aspect of the present invention is to provide one pot process for the preparation of Isopropyl (Z)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenyl pentyl]-cyclopentyl]-5-heptenoate compound of formula-1, comprising of:

a) Reacting (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4 with (4-carboxy butyl)triphenyl phosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl) cyclopentyl)hept-5-enoic acid compound of formula-6,

b) reacting the compound of formula-6 in-situ with 2-halopropane in presence of a suitable base in a suitable solvent to provide compound of formula-1.

Wherein,

in step-a) the suitable base, the suitable acid and suitable solvent are same as defined in third aspect of the present invention,

in step-b) halo represents fluoro, chloro, bromo and iodo, preferably iodo; the suitable base is inorganic base such as alkali metal carbonate like potassium carbonate and sodium carbonate etc; organic base such as DBU, DBN and the like, preferably DBU; the suitable solvent is ketone solvent such as methyl ethyl ketone, acetone, propanone, methyl isobutyl ketone and the like.

The compound of formula-6 in present invention can be isolated using a suitable solvent and then reacted with 2-halopropane in a suitable solvent to provide compound of formula-1.

The fifth aspect of the present invention is to provide a novel process for the preparation of Isopropyl (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenyl pentyl]cyclopentyl]-5-heptenoate compound of formula-1, comprising of:

a) Reducing the C-C double bond of (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 with a metal catalyst in a suitable solvent under hydrogen pressure to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3,

b) reducing the keto group of compound of formula-3 with a suitable reducing agent in suitable solvent to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4,

c) reacting the compound of formula-4 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid compound of formula-6,

d) reacting the compound of formula-6 in-situ with 2-halo propane in presence of a suitable base in a suitable solvent to provide compound of formula-1.

Wherein, in step-a) the metal catalyst and the suitable solvent are same as defined in the first aspect of the present invention, in step-b) the suitable reducing agent and the suitable solvent are same as defined in the second aspect of the present invention, in step-c) the suitable base, the suitable solvent and the suitable acid are same as defined in third aspect of the present invention, in step-d) the halo group, the suitable base and the suitable solvent are same as defined in step-b) of fourth aspect of the present invention.

The compound of formula-6 obtained in step-c) can be isolated using a suitable solvent and then reacted with 2-halopropane in a suitable solvent to provide compound of formula-1.

In the present invention, the compound of formula-6 is optionally converted into its amine salt compound of general formula-7 by treating with a suitable organic amine in a suitable solvent, further treated with a suitable acid to provide pure compound of formula-6, which in-turn results in the formation of pure compound of formula-1.

Wherein, the suitable organic amine is 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, phenylethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethyl benzyl amine, N-ethyl-N-methylbenzylamine, tribenzyl amine, cyclopentylamine, cyclohexyl -amine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexyl amine, N-ethyl cycloheptylamine, dicyclohexylamine, N,N-dimethylcyclo pentylamine, N,N-dimethyl cyclohexylamine, N,N-diethylcycloheptylamine and the like, preferably methyl amine, ethyl amine, tertiary butyl amine, n-butyl amine and propyl amine.

The (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 of the present invention can be prepared from (3aR,4S,5R,6aS)-5-hydroxy-4-(hydroxymethyl)hexahydro-2H-cyclopenta[b]furan-2-one, by treating with triethylsilyl chloride in tetrahydrofuran to provide (3aR,4S,5R,6aS)-5-(triethylsilyloxy)-4-((triethylsilyloxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-one. The obtained compound was oxidized with oxalyl chloride in presence of DMSO in DCM, further reacted in-situ with dimethyl 2-oxo-4-phenylbutylphosphonate in presence of aqueous lithium hydroxide in methyl tertiary butyl ether to provide (3aR,4R,5R,6aS)-4-((lE)-3-oxo-5-phenylpent-l-enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one. The obtained compound was reduced with borane-DMS in presence of R-methyl CBS in tetrahydrofuran to provide compound of formula-2.

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

The related substances of Latanoprost of the present invention are measured by using preparative HPLC with the following chromatographic conditions:

Apparatus : Preparative high performance liquid chromatography equipped with U.V. Detector
Column : chiralcelpak AD-H 250 x 30mm, 5 um (or) equivalent
Flow rate : 40 ml/min
Wavelength :215nm
Column temperature : Ambient
Injection volume : 4000 uL
Elution : Isocratic
Run time : 40 minutes
Mobile Phase : Acetonitrile:methanol (70:30)v/v
Diuent : Mobile Phase

The present invention is schematically represented as follows: Scheme-I:


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,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one(Fomrula-3)

(3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 (10 g) was dissolved in ethanol (200 ml). Platinum dioxide (0.4 g) was added to the reaction mixture. Hydrogen gas was passed into the reaction mixture at 25-35°C and then stirred for 3 hours at 25-35°C. After completion of the reaction, filtered the reaction mixture through celite bed and washed with ethanol. Distilled off the solvent from the filtrate to get the title compound. Yield: 10.0 g

Example-2: (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta [b]furan-2-ol (Formula-4)

(3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexa hydro-2H-cyclopenta[b]furan-2-one compound of formula-3 (10.0 g) was dissolved in tetrahydrofuran (100 ml). The reaction mixture was cooled to -68 to -72°C and added diisobutyl aluminium hydride (25% in toluene) (81.5 ml). The reaction mixture was stirred for 30 minutes at -70°C. After completion of the reaction, the reaction mixture was quenched with methanol and then water was added to the reaction mixture, followed by ethyl acetate. The temperature of the reaction mixture was raised to 25-35°C and stirred for 45 minutes at 25-35°C. Filtered the reaction mixture through the celite bed and washed with ethyl acetate. Distilled off the solvent from the filtrate to get title compound. Yield: 10.0 g

Example-3: Preparation of isopropyl-(Z) 7[(lR,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclo pentyl]-5-heptenoate (Formula-1)

Step-a) Preparation of (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl) cyclopentyl)hept-5-enoic acid (Formula-6)

(4-carboxybutyl)triphenylphosphonium bromide compound of fromula-5 (31.5 g) was heated to 100-110°C for about 7 hours under reduced pressure and then cooled to 25-35°C. To the reaction mixture, tetrahydrofuran (40 ml) followed by potassium tertiary butoxide (16.0 g) were added and the reaction mixture was stirred for 40 minutes at 30-35°C. The reaction mixture was cooled to 0-5°C and added a solution of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4 (10.0 g) in tetrahydrofuran (20 ml) at 0-5°C. The reaction mixture was stirred for 4 hours at 0-5 °C. After completion of the reaction, the reaction mixture was quenched with water and the pH of the reaction mixture was adjusted to 1.5 using hydrochloric acid solution (prepared from hydrochloric acid and water). The compound was extracted with ethyl acetate and then treated with sodium hydroxide solution followed by hydrochloric acid solution. The ethyl acetate layer was dried with sodium sulfate and then distilled off the solvent to get the title compound as a residue. Methyl tertiary butyl ether was added to the reaction mixture at 25-35°C and then cooled to 0-5°C. The reaction mixture was stirred for 45 minutes at 0-5 °C. Filtered the reaction mixture and distilled off the solvent from the filtrate to get title compound. This compound without isolation can be utilized for the next step.

Step-b) Preparation of isopropyl-(Z) 7[(lR,2R,3R,5S)3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate(Formula-l)

Dissolved the compound obtained in step-a) in acetone (125 ml) and the reaction mixture was cooled to 0-5°C. DBU (80 ml) was added to the reaction mixture, followed by 2-iodo propane (60 ml) at 0-5 °C. The temperature of the reaction mixture was raised to 20-25°C and then stirred for 20 hours at 20-25°C. After completion of the reaction, filtered the reaction mixture through the celite bed and washed with acetone. The solvent from the filtrate was distilled off under reduced pressure to get crude title compound. The crude compound was dissolved in dichloromethane (200 ml) and washed with citric acid solution (prepared from citric acid and water). Both dichloromethane and aqueous layers were separated and the dichloromethane layer was dried with sodium sulfate & distilled off the solvent under reduced pressure to get title compound. Further, the compound was purified by column chromatography using dichloromethane and methanol as eluents. Yield: 6.2 g.

We claim:

1. A compound of formula and its isomers.

2. A compound of formula and its isomers.

3. A process for the preparation of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5- (triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3, comprising of reducing the C-C double bond of (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy- 5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 with a metal catalyst in a suitable solvent under hydrogen pressure to provide the compound of formula-3.

4. A process for the preparation of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4, comprising of reducing the keto group of (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3 with a suitable reducing agent in a suitable solvent to provide the compound of formula-4.

5. A process for the preparation of (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid compound of formula-6, comprising of reacting (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4 with (4-carboxybutyl)triphenyl phosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide the compound of formula-6.

6. One pot process for the preparation of Isopropyl (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2- [(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate compound of formula-1, comprising of:

a) Reacting (3 aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4 with (4-carboxy butyl)triphenyl phosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl) cyclopentyl)hept-5-enoic acid compound of formula-6, b) reacting the compound of formula-6 in-situ with 2-halopropane in presence of a suitable base in a suitable solvent to provide compound of formula-1.

7. A novel process for the preparation of Isopropyl (Z)-7[(lR,2R,3R,5S)-3,5-dihydroxy-2- [(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate compound of formula-1, comprising of:

a) Reducing the C-C double bond of (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 with a metal catalyst in a suitable solvent under hydrogen pressure to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-3,

b) reducing the keto group of compound of formula-3 with a suitable reducing agent in a suitable solvent to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethyl silyloxy)hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4,

c) reacting the compound of formula-4 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-5 in presence of a suitable base in a suitable solvent, followed by treatment with a suitable acid to provide (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid compound of formula-6,

d) reacting the compound of formula-6 in-situ with 2-halopropane in presence of a suitable base in a suitable solvent to provide the compound of formula-1.

8. A process according to claim 7, wherein

in step-a) the reducing agent for C-C double bond reduction is used in range of 0.02 to 0.08 g, preferably 0.04 g per lg of compound of formula-2; the solvent used in an amount ranging from 15 to 30 volumes, preferably 20 volumes per lg of compound of formula-2; and the reaction was carried out at ambient temperatures for a period of 1 to 4 hours, preferably 2-3 hours;

in step-b) the reducing agent for keto group reduction is used in molar proportions ranging between 3 and 8 moles, preferably 6 moles per mole of compound of formula-3; the solvent is used in an amount ranging from 8 to 14 volumes, preferably 10 volumes per lg of compound of formula-3; and the reaction was carried out at a temperature ranging from -60 to -75°C, preferably -68 to -72°C; in step-c) the base used in molar proportions ranging from 4 to 8 moles, preferably 6 moles per mole of compound of formula-4; the compound of formula-5 is used in molar proportions between 2 to 4 moles, preferably 3 moles per mole of compound of formula-4; the solvent is used in amount ranging from 2 to 10 volumes, preferably 6 volumes per lg of compound of formula-4; and the reaction was carried at a temperature of 0-5°C for a period of 1-5 hours, preferably 3-4 hours.

9. A process according to claim 7, wherein

in step-a) the metal catalyst is selected from Pd, Pt, Pd-C, Pt-C, Ru-C, Rh-C, palladium hydroxide, palladium acetate, palladium chloride, Pd(PPh3)4, Pd(PPh3)2Cl2, palladium on metal oxide, palladium on zeolites, platinum oxide, rhodium on alumina and Raney-Ni, preferably platinum oxide; and the suitable solvent is selected from alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, butanol and isobutanol, preferably ethanol;

in step-b) the reducing agent for reduction of keto group is selected from diisobutyl aluminium hydride, sodium borohydride and lithium aluminium hydride etc, preferably diisobutyl aluminium hydride; and the suitable solvent is selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran and the like, preferably tetrahydrofuran;

in step-c) 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 selected from alkyl lithium such as methyl lithium, n-butyl lithium and the like, preferably alkali metal alkoxide such as potassium tertiary butoxide; the suitable solvent is selected from ether solvents such as diethyl ether, diisoproyl ether, tetrahydrofuran, methyl tertiary butyl ether and the like, preferably tetrahydrofuran; and the suitable acid is selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid and hydroiodic acid, preferably hydrochloric acid;

in step-d) the suitable base is inorganic base such as alkali metal carbonates like potassium carbonate and sodium carbonate etc; organic bases such as DBU, DBN and the like; preferably DBU; and the suitable solvent is selected from ketone solvents such as acetone, propanone, methyl ethyl ketone and methyl isobutyl ketone, preferably acetone; the term halo represents chloro-, bromo-, iodo- and fiuoro-, preferably iodo-.

10. A process according to claim 7, for the preparation of Isopropyl (Z)-7[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3 -hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate compound of formula-1, comprising of:

a) Reducing the C-C double bond of (3aR,4R,5R,6aS)-4-((3S,lE)-3-hydroxy-5-phenylpent-l-enyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b]furan-2-one compound of formula-2 with platinum oxide in ethanol to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy)hexahydro-2H-cyclopenta[b] furan-2-one compound of formula-3,

b) reducing the keto group of compound of formula-3 with DIBAL-H in tetrahydrofuran to provide (3aR,4R,5R,6aS)-4-((3R)-3-hydroxy-5-phenylpentyl)-5-(triethylsilyloxy) hexahydro-2H-cyclopenta[b]furan-2-ol compound of formula-4,

c) reacting the compound of formula-4 with (4-carboxybutyl)triphenylphosphonium bromide compound of formula-5 in presence of potassium tertiary butoxide in tetrahydrofuran, followed by treatment with hydrochloric acid to provide (Z)-7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((3R)-3-hydroxy-5-phenylpentyl)cyclopentyl)hept-5-enoic acid compound of formula-6,

d) reacting the compound of formula-6 in-situ with 2-iodopropane in presence of DBU in acetone to provide the compound of formula-1.