Field of the invention:

The present invention relates to the preparation for the preparation of prostaglandin derivatives of the formula (I) and further relates to process for the purification of prostaglandin derivatives of the formula (I) by using preparative HPLC as a purification tool.

Back ground of the invention:

Prostaglandin analogs have been reported to possess a number of therapeutic uses and are currently recognized for their ability to exhibit the intraocular pressure lowering effect and can be used for the treatment of glaucoma and related eye disorders. These prostaglandin compounds comprise a cyclopentyl ring with two hydroxyl groups in cis configuration and two side chains in trans configuration. The side chains may contain double bonds and different substituents. Among this class of compounds Latanoprost, Bimatoprost and travoprost are the most important ones that have been in current use.

The common structure for these drugs is represented by the following structural formula (I) Wherein

The bond between carbon 1 and 2 is either a single bond (C1-C2) or a double bond (C1-C2);

R1 is selected from the group consisting of alkoxy and alkyl amino;

X represents CH2 or O;

R represents phenyl optionally substituted by CF3;

A variety of methods for synthesizing prostaglandin derivatives and their purification methods using preparative HPLC have been disclosed and are known from, e.g

Tetrahedron vol. 51, No. 33, pp 9139-9135, 1995; US 7,163,959; US 20040249172 , WO93/00329 and US 2005/0209337.

US 7,163,959 patent discloses the process for the preparation of prostaglandin derivatives, of which latanoprost preparation is mentioned as an example. The process involves the PPB-protected Corey lactone (II) as starting material, which undergoes moffatt oxidation and the subsequent reaction with phosphonate carbanion affords corresponding olefin (IV). The resulting olefin is then reduced to give corresponding hydroxy compound (V), which is subsequently deprotected to give compound (VI). The lactone oxo group of compound (VI) is reduced to form the corresponding hydroxy compound (VII). A subsequent witting reaction followed by esterification yields desired PGF2a compound containing a mixture of epimeric alcohols are separated by preparative liquid chromatography using 40% CH3CN in water v/v as eluent. The foregoing method is depicted in scheme-1

Scheme-1

The process disclosed in the US 7,163,959 results very low yields in certain steps and hence there is further decline in its overall yield, which renders the process futile.

US 2004/0249172 discloses a variety of methods to produce analogs of PGF2a and further discloses the purification of prostaglandins and analogs thereof. According to one of the methods depicted in scheme-2, the protected corey-lactone (IIA) is subjected to oxidation in presence of a stable organic nitroxyl radical to obtain the corresponding aldehyde (IIIA). The compound (IIIA) undergoes modified Homer-Wadsworth-Emmons reaction and the subsequent reduction and deprotection yields compound (VIA). Double bond of compound (VIA) is cleaved by means of hydrogenation to provide (VA), which is silylated to give compound (VB). The resulting compound (VB) undergoes reduction followed by Wittig reaction yields compound (VIIIA) or compound (VIII B), subsequent deprotection and optional reaction with alkyl halide provides compound (I-A) and compound (I-B) accordingly.

US 2004/0249172 application further discloses the process for the preparation of prostaglandin derivatives and provides the purification method by preparative HPLC.

This process as depicted in the shceme-3, the silyl protected latanoprost is deprotected in presence of pyridinium p-toluene sulphonate in water, the organic volatiles are evaporated, and the residue is mixed with a mixture of ethyl acetate and brine followed by further conventional work up procedure gives latanoprost crude as a pale yellow oil. This crude compound is subjected to chromatographic purification using hexane/ethyl acetate mixture as eluent and the desired fractions are further purified by preparative HPLC using isocratic eluting system comprised a hydrocarbon, an alcohol and acetonitrile as optional solvent for the eluting system.

According to US 2004/0249172 patent application, the process involves many steps that encompass a number of protections using expensive silyl protecting groups and subsequent deprotections which renders the process more lengthy.

C. Liljebris et al. (Tetrahedron, 1995, 51(33, 9139-9154) discloses chemoselective palladium catalyzed intermolecular cyclizations of the 15R and 15S epimers of prostaglandins which produce a complex mixture of products, which have been isolated and discussed. The process further discloses the purification of prostaglandins by means of preparative HPLC, which is performed using a silica gel column (21.4x 250nm); mobile phase: 3-7% of ethanol in n-hexane; flow rate: 14 mL/min; detection: 220nm.

According to C. Liljebris et al. both the 15(S) and 15(R), which are structurally similar as that of formula (I), are prepared, gives a mixture of diastereomers. There is no further purification steps employed to remove impurities after the 15(S) and 15(R) are made. Thus 15(S) and 15(R) contain corresponding trans and cis isomers with more content of trans isomer. Although preparative HPLC purification is performed, the compound thus obtained contains more content of 15(S)-cis isomer, 15(S) - trans isomer and 15(R) - trans isomer. Hence, removal of such typical impurities by this method turns out to be complicated.

vanish et al. (WO 93/00329) discloses similar process for purifying prostaglandins involves column chromatography purification of oily residue on silica gel using 20:1 mixture of methylene chloride and isopropanol as eluent and further purification by using 1:1 mixture of ethyl acetate and hexane as eluent to obtain colorless desired compound. Ivanics et al., however, did not mention the purity of the compound.

US 2005/0209337 patent application discloses the process for the purification of latanoprost and Bimatoprost, wherein latanoprost is purified by column chromatography on silica gel (heptane/isopropanol 97:3 then 80:20). The relevant fractions are combined and concentrated in vacuum. The residue is further purified by preparative HPLC on Phenomenex™ Luna CN silica gel column (heptane/isopropanol 97:3) to give latanoprost as colorless oil with 99% purity by HPLC.

Summary of the Invention

In one aspect, the present invention provides an efficient method for preparing prostaglandin derivatives (I) with desired purity, of which latanoprost preparation is the embodiment of such invention.

Yet another aspect, the present invention provides process for the purification of prostaglandins and analogs thereof of formula (I), using preparative liquid chromatography.

Further aspect of the present invention is to provide process for the purification of prostaglandins by preparative liquid chromatography employing the mixtures of any of the solvents selected from the group hydrocarbons and alcohols.

Yet another aspect of the present invention relates to a process, which comprises preparing Latanoprost that includes,

i. protecting the Corey lactone diol to obtain silyl protected compound followed by benzoyl protection of other hydroxy group and then removing the silyl protecting group and isolating the (3aR,4S,5R,6aS)-Hexahydro-4-hydroxymethyl-5-(benzoyloxy) cyclopenta [b] furan-2-one ii. oxidizing the step (i) compound followed by reaction with Dimethyl-2-oxo-4-phenyl butyl phosphonate and isolating the (3aR,4S,5R,6aS)-4-(3-oxo-5-phenyl-lE-pentenyl)-5- (benzoyloxy)-hexahydro-2H- cyclopenta[b] furan-2-one iii. reducing the step (ii) compound stereo selectively and isolating the (3ai?,4S,5R,6aS)-4-[3- S-hydroxy-5-phenyl-lE-pentenyl)-5-(benzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-
one iv. hydrogenating the step (iii) compound followed by hydrolysis and isolating the (3aR,4S,5R,6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-cyclopenta b]furan-2-one v. reducing the lactone oxo group of step (iv) compound and isolating the (3aR,4S,5R,6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-cyclopenta[b]furan-2-ol vi. reacting the step (v) compound with wittig reagent and obtaining latanoprost acid in-situ followed by esterification and isolating the latanoprost crude vii. purifying the latanoprost crude by using preparative liquid chromatography

Detailed description of the invention

The process of the present invention for the preparation of prostaglandins of formula (I),
Wherein, the bond between carbon 1 and 2 is either a single bond (C -C ) or a double bond (C =C );

R1 is selected from the group consisting of alkoxy and alkyl amino;
X represents CH2 or O;

R2 represents phenyl optionally substituted by CF3;

The like structures are indicated in connection with the structural formula of (I) are shown below of which latanoprost preparation is demonstrated as a typical example of this invention, which preparation comprises of;

i. selectively protecting the chiral corey lactone diol using tert-Butyl chloro dimethyl silane (TBDMSC1) to obtain silyl protected compound followed by benzoyl protection of other hydroxy group and then removing the silyl protecting group using tetrabutylammonium fluoride (TBAF) to obtain (3aR, 4S, 5R, 6aS)-hexahydro-4-hydroxymethyl-5-(benzoyloxy) cyclopenta [b]furan-2-one ii. Oxidizing the compound obtained from step (i) with Dess-Martin periodinane to get corresponding aldehyde, which without isolation reacting with dimethyl-2-oxo-4- phenyl butyl phosphonate in presence of lithium chloride, N,N-diisopropylethylamine (DIPEA) to obtain corresponding olefin

iii. Subjecting the olefin obtained form step (ii) to asymmetric reduction using (-)-DIP chloride in tetrahydrofuran (THF) followed by column chromatography to get (3aR, 4S, 5R, 6aS)-4-[3-S-hydroxy-5-phenyl-lE-pentenyl)-5-(benzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one

iv. Reducing the resulting 3S-hydroxy compound of step (iii) in presence of 10% Pd/C in ethanol to obtain (3aR, 4S, 5R, 6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(benzoyloxy)-hexahydro-2H-yclopenta[b]furan-2-one, which without isolation undergoes hydrolysis under basic conditions using potassium carbonate and methanol to get (3aR, 4S, 5R, 6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-cyclopenta[b] furan-2 –one

v. Reacting the compound of step (iv) with diisobutylaluminium hydride (DIBAL-H) in THF to yield (3aR, 4S, 5R, 6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-cyclopenta[b]furan-2-ol

vi. Reacting the compound of step (v) with (4-carboxybutyl)-triphenyl phosphonium bromide in presence of t-BuOK in THF to yield latanoprost acid in-situ and esterfying the obtained acid with isopropyl iodide in presence of 1, 8-diazabicyclo [5.4.0] undec-7-en (DBU) in acetone followed by purifying the obtained residue by column chromatography over silica gel using a mixture of methanol and dichloromethane as the eluent to obtain Latanoprost crude.

vii. Purifying the step (vi) latanoprost crude by preparative liquid chromatography using the mixture of solvents selected from the group hydrocarbons and alcohols.

The above mentioned method of this present invention is depicted in the scheme-4 The present invention further provides a process for the purification of prostaglandins represented by the general formula (I), which include the drugs Latanoprost, Bimatoprost and Travaprost, by using preparative liquid chromatography. Furthermore, the present HPLC purification system involves the use of non-chiral column thus avoiding the expensive chiral columns while separation of latanoprost from the 15(S)-cis-, 15-(S)-trans-, 15(R) -trans isomers of latanoprost. Accordingly, this invention further provides the process for the purification of latanoprost by HPLC comprising the use of an eluent, which is selected from the group hydrocarbons and alkanols or the mixtures thereof. The preferred hydrocarbon in the present eluent system is a C5 to C8 straight chain, branched or cyclic, preferably n-alkane, especially hexane or heptane are preferred. The preferred alkanols in the present eluent system are C1 to C8 straight chain, branched or cyclic alkanols, preferably C1 to C5 alkanols, especially methanol, ethanol, 1-propanol, isopropanol, 1-butanol and 2-butanol are being preferred. The chromatographic conditions and procedure are set forth clearly under this as well as in examples.

The purification process involves a single step process for the purification by using normal phase chromatography with isocratic elution.

Wherein the sample is prepared in ethanol and n-heptane in the concentration of 200mg/mL.

A preparative LC system equipped with high pressure binary gradient pump and a UV detector (eg. Agilentl200 series having G136A prep pump, G2260A Prep Auto sampler, G1365D Multiwavelength detector and G1364B Prep Fraction collector).

The chromatographic conditions used are:
Column : Inertsil Silica (250 x 50) mm,
Mobile phase : A: C5-C8 hydrocarbon: B: C1-C5 alcohols: C: C1-C5 alcohols
(95:02:03) (v/v/v)
Flow rate : 80 mL/min
Detection :210nm
Sample Concentration : 200 mg/mL
Injection volume : 1500μL
Load on column : 250 mg
Mobile phase - A used is hydrocarbon and mobile phase-B is C1-C5 alcohols and mobile phase-C is C1-C5 alkanols. The hydrocarbon used is n-hexane or n-heptane. The C1-C5 alkanols used are ethanol or isoproanol. The mobile phase composition is in the ratio of 95% of pump A, 02% of pump B with and 03% of pump C with an isocratic elution at a flow rate of 80mL/min.

By using the foregoing chromatographic conditions, the system is equilibrated and the sample is injected into the chromatographic system. The retention time window for prostaglandin is 35 min to 50 min and subsequent collection of preparative mLs.
Results:

The major impurities and their approximate content present after the single purification are as follows:
Impurity %Area
15 (R)-Trans isomer 0.10
15(S)-Cis isomer 0.11
15(S)-Trans isomer 1.14

The total invention is illustrated by means of the following non-limitative examples;
Example 1: Preparation of (3aR, 4S,5R,6aS)-Hexahydro-4-hydroxymethyl-5-(benzoyloxy) cyclopenta [b] furan -2-one
Procedure:

Dimethyl formamide (200 ml), Corey lactone diol (100 g), N,N-Dimethylarnino pyridine (1 g) and imidazole (60 g) were charged in to a reaction vessel at 25-30°C and cooled to -10 to -15° C. tert-butyldimethylchlorosilane(100.5 g) in Dimethyl formamide (300 ml) was added to the reaction mass the temperature of the reaction mass was raised to -2° to +2°C.

After checking the disappearance of Corey lactone diol on TLC, DM Water (1 Lt) was charged in to the reaction mass and the temperature rose to 20-30°C. Extracted with ethylacetate (2x1 lit). Extracted the combined organic layers with (4x1 Lt) of DM water, brine solution (1 Lt of 10%) and dried over anhydrous sodium sulphate, filtered organic layer was distilled under vacuum at 35-45°C to get monoprotected coreylactone.

Dichloromethane (850 ml), Triethylamine (223 g), N,N-Dimethylamino pyridine (1 g) was charged in to a reaction vessel containing the monoprotected coreylactone obtained above. Cooled the reaction mass to 0-5°C and benzoyl chloride (90 ml) was added in to reaction mass and maintained at 45-50°C. After the disappearance of Monoprotected coreylactone as checked by TLC, methanol (7 ml) was added at 25-30°C to reaction mass, DM water (1.19 Lt) was charged and extracted with Dichloro methane (2 x 350 ml).

The combined organic layers were extracted with DM water (1.19 Lt), dried over anhydrous sodium sulphate (170 g), filtered and concentrated. Tetrahydrofuran (520 ml) was charged to the residue obtained above and cooled to 0-5°C. Tetrabutylamrnonium fluoride solution (350 ml, 1M solution in THF) was added in to reaction mass at 0-5°C and maintained at 25-30°C. After the disappearance of diprotected coreylactone as seen on TLC, DM water (1 Lt) was charged in to the reaction mass at 20- 30°C and extracted with ethyl acetate (2 x 1 Lt). Combined organic layers were extracted with 10% brine solution (1 Lt) dried over anhydrous sodium sulphate (200 g), filtered and concentrated. Compound was crystallized from ethyl acetate and n-Hexane.
Yield obtained: 100.2 g

Example 2: Preparation of (3aR,4S,5R,6aS)-4-(3-oxo-5-phenyl-lE-pentenyl)-5-(benzovloxy) - hexahydro-2H-cyclopenta[b]furan-2-one Procedure:

Dichloromethane (1.84 Lt), Dess-martin (184 g) were charged in to a reaction vessel and cooled to 0-5°C. Stage-1 (100 g) was charged in to the reaction mass at 0 -5°C and maintained at 20-25°C for 1 hr. The reaction mass was added to a solution formed by mixing sodium thiosulphate (216 g) and sodium bicarbonate (80 g) in DM water (1.4 Lt). Extracted the aqueous layer with Dichloromethane (2x1 Lt). Washed the combined organic layers with saturated Sodium bicarbonate solution (1 Lt, 10%) brine solution (1 Lt, 10%), dried over Sodium sulphate (200 g) and filtered.

In other reactor Acetonitrile (1 Lt), Dimethyl-2-oxo-4-phenyl butyl phosphonate (89 g) and Lithium chloride (92 g) were charged and cooled the reaction mass to -8 to -12°C. N,N-Di isopropyl ethyl amine (137 g) was charged to reaction mass at -8 to -12°C and raised the temperature of the reaction mass to 23-25°C and maintained for lhr at 23-25°C. The reaction mass was cooled to -8 to -12°C and the organic layer obtained in the earlier step was charged in to reaction mass over a period of 1 hr. The temperature of reaction mass was raised to 10-15°C. DM water (200 ml) was added to the reaction mass. After distilling the reaction mass under vacuum at 40-45°C until 300 ml volume remains in the flask, Dichloromethane (1.0 Lt) was charged. The organic layer was washed with DM water. Combined organic layers were washed with 10% brine solution (1 Lt), and dried over anhydrous sodium sulphate (200 g) and filtered and distilled. The residue was recrystallized from Methanol (380 ml).

Output: 100.5 g

Example 3: Preparation of (3aR,4S,5R,6aS)-4-[3-S-hydroxy-5-phenyl-lE-pentenyl)-5-(benzoyloxy)-hexahydro-2H-cyclopenta[b]furan-2-one Procedure:

Tetrahydrofuran (1 Lt), Stage-2 (100 g) were charged in to a reaction vessel and cooled to -28 to -32°C. (-)Dip Chloride was added to the reaction mass at -28 to -32°C over a period of 2 hrs and maintained for 2 hrs at -28 to -32°C. The reaction mass was quenched with methanol (30 ml) at -28 to -32°C. Reaction mass temperature was raised to 25-30°C and distilled up to 500 ml volume remains in the flask.

DM water (1 Lt) was added to the resulting mass at 25-30°C and extracted with ethyl acetate (2 x 500 ml). The organic layer was washed with 20% ammonium chloride (2 x 500 ml), 10% brine solution (1 Lt), dried over anhydrous sodium sulphate (200 g) and filtered and evaporated. The residue was purified over silica gel column using a mixture of ethyl acetate and hexane as the eluent. Output: 70 g

Example 4: Preparation of (3aR,4S,5R,6aiS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-cyclopenta [b] furan-2-one Procedure:

Ethanol (1.5 Lt), Stage-3 (100 g) were charged in autoclave under nitrogen at 25-30°C, followed by 10% Pd/C (40 g) and DM water (200 ml). The reaction mass was cooled to 10-15°C and 25-30 Psi hydrogen pressure till the reaction complies. Reaction mass was filtered through Celite bed and washed with Ethanol (500 ml). Solvent was distilled off under vacuum at below 50°C to get crude product. Methanol (1.0 Lt) was charged into the reaction vessel followed by anhydrous potassium carbonate (25.3 g). The reaction mass was stirred for 4hrs at 25-30°C and checked for saturated enol content by HPLC.

After HPLC complies the pH was adjusted to 4 by the slow addition of IN Hydrochloric acid. The mass was distilled under vacuum at 40-45°C until 300 ml volume remains in the flask. Dichloromethane (1.0 Lt), DM water (1.0 Lt) were charged to the reaction mass at 25-30°C, extracted and the layers were separated. The aqueous layer was washed with mixture of IPA (50 ml) and Dichloromethane (450 ml). The combined organic layers were washed with 10% brine solution dried over anhydrous sodium sulphate (250 g) and filtered. The crude obtained after distillation was purified by column chromatography over silica gel using a mixture of ethyl acetate and hexane as eluent.
Output: 40 g

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

Tetrahydrofuran (3.0 Lt) and stage-4 (100 g) were charged into the reaction vessel at 25-30°C and cooled to -76 to -80°C. DIBAL solution (1.32 Lt) was charged into the reaction mass at -76 to -80°C over a period of 2 hrs and maintained for 3 hrs. The reaction mass was quenched with methanol (40 ml) by slow addition at -76 to -80°C. After raising the temperature of reaction mass to 25-30°C, 20% Sodium potassium tartarate (1.0 Lt) was added. The mixture was stirred for 30-40 min and extracted with ethyl acetate (3x1 Lt). The combined organic layers were washed with 10% brine solution (2.0 Lt) dried over anhydrous sodium sulphate (500 g) and filtered. After distilling the solvent the gummy mass crystallized from a mixture of acetone and ethyl acetate.

Output: 60 g

Example 6: Synthesis of Latanoprost Procedure:

THF (750 ml) and 4-carboxybutyl triphenylphosphonium bromide in (290 g) were charged in to a reaction vessel under nitrogen atmosphere at 25-30°C and cooled to -8 to -12°C. Potassium tert-butoxide solution (1.31 Lt) was added to the reaction mass at -8 to -12°C over a period of 30-40 min and the temperature raised to -5 to 5 °C. Cooled the reaction mass to -8 to -12°C and Stage 5 (50 g) in THF (250 ml) was added to reaction mass at -8 to -12°C over a period of 30 min. The reaction mass was stirred at 5 to l0°C for 2h. DM water (1.0 Lt) was charged in to the reaction mass at 5 to 10°C. The mixture was extracted with diethyl ether (2 x 1.0 Lt) and the organic layer was discarded. The pH of the aqueous layer was adjusted to 4 by the slow addition of 20% citric acid solution and extracted with ethyl acetate (3x 1.0 Lt). The combined organic layers were washed with 10% sodium chloride solution (1.0 Lt), dried and filtered. To the gummy material obtained after solvent evaporation, acetone (2.0 Lt) was added and stirred. The precipitated solids were filtered and to the washings, Diazabicyclo undecene (390 ml) was added at 0 to 5°C over a period of 30 min. The temperature of reaction mass was raised to 25 to 30°C and isopropyl iodide (220 ml) was added at 25 to 30°C over a period of 15 min. The reaction mass was stirred for 12 hrs at 25 to 30°C. The solvent was distilled under vacuum at 40-45°C until (250 ml) volume remained in the flask. DM water (1.0 Lt) was charged to the resulting mass at 25-30°C and extracted with ethyl acetate (2 x 1.0 Lt). The combined organic layers were washed withl0% citric acid solution (1.75 Lt), saturated sodium bicarbonate solution (1.75 Lt) and 10% sodium chloride solution (1.75 Lt). The organic layer was dried over anhydrous sodium sulphate (250 g) and filtered. The gummy material obtained after solvent evaporation was purified by column chromatography over silica gel using mixture of methanol and dichloromethane as the eluent. Output: 45 g

Example 7: HPLC Purification of Latanoprost

Purification of crude Latanoprost was carried out by preparative HPLC on Inertsil Silica column of dimensions 250 x 50 mm. The eluent comprised of a mixture of n-heptane, Isopropyl alcohol and ethanol in 95:02:03 volume percent respectively in isocratic elution mode. The flow rate was set to 80 mL/min and the eluent was monitored at 210 nm.
The results of typical HPLC runs using the above eluent system are shown below:

We claim;

1. A process for preparing Latanoprost comprising the steps of;

a. protecting the Corey lactone diol to obtain silyl protected compound followed by
benzoyl protection of other hydroxy group and then removing the silyl protecting
group and isolating the (3aR,4S,5R,6aS)-Hexahydro-4-hydroxymethyl-5-
(benzoyloxy) cyclopenta [b] furan-2-one

b. oxidizing the step (a) compound followed by reaction with Dimethyl-2-oxo-4-
phenyl butyl phosphonate and isolating the (3aR,4S,5i?,6aS)-4-(3-oxo-5-phenyl-
1 E-pentenyl)-5-(benzoyloxy)-hexahydro-2H- cyclopenta[b]furan-2-one

c. reducing the step (b) compound stereo selectively and isolating the
(3aR,4S,5R,6aS)-4-[3-S-hydroxy-5-phenyl-lE-pentenyl)-5-(benzoyloxy)-
hexahydro-2H-cyclopenta[b]furan-2-one

d. hydrogenating the step (c) compound followed by hydrolysis and isolating the
(3aR,4S,5R,6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-
cyclopenta [b]furan-2-one

e. reducing the lactone oxo group of step (d) compound and isolating the
(3aR,4S,5R,6aS)-4-[3-R-hydroxy-5-phenylpentyl)-5-(hydroxy)-hexahydro-2H-
cyclopenta[b]furan-2-ol

f. reacting the step (e) compound with Wittig reagent and obtaining latanoprost acid
in-situ followed by esterification and isolating the latanoprost crude

g. purifying the latanoprost crude by using preparative liquid chromatography

2. A process for the purification of prostaglandins represented by the general formula (I) using preparative liquid chromatography comprising an eluent, which is a mixture of one or more hydrocarbons and one or more alkanols.

3. The process as claimed in claim 2, wherein the hydrocarbon is a C5 to C8 straight chain, branched or cyclic hydrocarbon

4. The process as claimed in claim 3, wherein the preferable hydrocarbon is selected from hexane, heptane and a mixture thereof.

5. The process as claimed in claim 2, wherein the alkanol is C1 to C8 straight chain, branched or cyclic alkanols.

6. The process as claimed in claim 5, wherein the preferred alkanol is selected from methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol and mixtures thereof.

7. The process as claimed in claim 2, wherein the prostaglandin includes latanoprost, bimatoprost or travoprost.