DESC:Field of the Invention:
This invention relates to an improved process for the preparation of 17-phenyl-18, 19, 20-trinor-PGF2a and its derivatives thereof.

Background of the Invention:
Prostaglandins are a family of biologically active compounds that are found in virtually all tissues and organs. These naturally occurring prostaglandins have extremely complex biological functions (e.g. stimulation of smooth muscles, dilation of smaller arteries and bronchi, lowering blood pressure etc.). Structurally, prostaglandins are formed of a ring and two side chains, said ring and chains being replaceable (usually hydroxyl or keto group) and optionally being partly unsaturated.
The compounds Bimatoprost, Travoprost and Latanoprost are analogues of prostaglandin F2a and used in therapy in the treatment of glaucoma, in particular to reduce high endo- ocular pressure. 17-phenyl-18, 19, 20-trinor-PGF2a and its derivatives represented by formula [I]:


wherein the bond between carbon 1 and 2 is either a single bond (C1-C2) or a double bond (C1=C2) and R4 is selected from the group consisting of alkoxy and alkylamino are synthetic structural analogs of prostaglandins.
Synthetic and relatively metabolically stable analogs of Prostaglandin F2a having therapeutic use include Latanoprost [II], Bimatoprost [III], Travoprost[IV], Fluprostenol [V] and Cloprostenol [VI].
[II]
[III]
[IV]
[V]
[VI]

The known methods for the synthesis of compounds of formula [I] are located in various patents and patent application as well as other publications like US 3,931,279; US 5,223,537; US 5,698,733; and US 5,688,819; WO95/26729, Prostaglandins, v. 9, 5 1975, J. Med. Chem., 1993, 36, 243, US 7,166,730

The prior process for preparation of prostaglandin derivatives has following disadvantages:
1) Time consuming process like column chromatography are involved in intermediate preparations reducing the yields,
2) Multiple steps involve in getting the final product from intermediate like in bimatoprost, like conversion of triol intermediate to get acid intermediate, further converting the acid intermediate to ester and then converting the same to amide , hence reducing the yields.
3) Prep HPLC required to obtain high purity prostaglandin analogs.

Hence there is a need of shorter and cost effective process for the preparation of prostaglandins.
Summary of Invention:
In one aspect, present invention provides an improved process for preparation of a compound of formula (I) with good yield and high purity.
In another aspect, present invention provides process for isolation of compound of “B” without using column chromatography.
In another aspect, present invention provides purification process of compound of formula “B” using various solvents, more preferably toluene.
In another aspect, present inventions provides the novel intermediate of compound of formula “C” and process for the preparation thereof.
In another aspect, present invention provides process for preparation of compound of formula “I” from compound of formula “C”.
Brief Description of Drawings:
Figure 1: IR spectrum of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.
Figure 2: H1 NMR of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.
Figure 3: Mass Spectrum of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.
Figure 4: IR spectrum of (3aR, 4R, 5R, 6aS)-2-hydroxy-4-((S, E)-3-((4-nitrobenzoyl)oxy)-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate.
Figure 5: H1 NMR of (3aR, 4R, 5R, 6aS)-2-hydroxy-4-((S, E)-3-((4-nitrobenzoyl)oxy)-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate.
Figure 6: Mass spectrum of (3aR, 4R, 5R, 6aS)-2-hydroxy-4-((S, E)-3-((4-nitrobenzoyl)oxy)-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate.
Figure 7: Mass spectrum of (Z)-7-((1R, 2R, 3R, 5S)-3, 5-dihydroxy-2-((S, E)-3-hydroxy-5-phenylpent-1-en-1-yl) cyclopentyl) hept-5-enoic acid.
Figure 8: H1 NMR of triol ester.
Figure 9: Mass spectrum of triol ester.

Detailed Description of the Invention:
The invention is directed to a process for the preparation of a compound of formula (I) and its derivatives. Intermediates used in the processes of this invention are also part of this invention.
In a more preferred embodiment, the invention provides a specific process for the preparation of Bimatoprost, Latanoprost and Travoprost wherein compound of formula “A” and compound of formula D could be prepared from the methods known in the art.

The process is depicted in scheme-1

According to one aspect, the present invention provides an improved process for the preparation of compound of formula I;

wherein represents a double bond or a single bond; R4 is alkoxy or alkyl amino group; W is a residue from group consisting of substituted and unsubstituted C1-C6 alkyl, C7-C16 aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of C1-C6 alkyl, halo and CF3, and (CH2)nORa, wherein n is from 1-3 and Ra represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of C1-C6 alkyl, halo and CF3; comprising the steps of:
i) protection of compound of formula (A) using 4-nitrobenzoyl halide under basic conditions optionally in the presence of a catalyst and organic solvent to obtain compound (B),

wherein R3 is p-nitrobenzoyl (PNB) group; 3, 5-dinitrobenzoyl group and W is as defined above;
ii) reduction of compound of formula (B) using DIBAL in an organic solvent to obtain the compound of formula (C)

wherein R3 is p-nitrobenzoyl (PNB) group; 3, 5 dinitrobenzoyl group and W is as defined above;
iii) Wittig coupling of the compound of formula C with compound of formula D in the presence of base and organic solvent to achieve the desired compound of formula (I)

wherein R4 can be OH, O-R or NHEt, where R is any alkyl group.
The 4-nitrobenzoyl halide or 3,5 dinitrobenzoyl halide used in step (i) is selected from 4- nitrobenzoyl chloride, 4-nitrobenzoyl bromide, 3,5 dinitrobenzoyl chloride, 3,5 dinitrobenzoyl bromide respectively and the like; more preferably,4- nitrobenzoyl chloride, 3,5 dinitrobenzoyl chloride.
The catalyst used in step (i) is DMAP and the like; and the base used in step (i) is organic or inorganic base, selected from triethylamine, trimethylamine, dimethyl amine and tert-butyl amine; ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and more preferably, the base is triethylamine.
The reaction of step (i) is carried out at a temperature of -5°C to the reflux temperature of the solvent used.
The reducing agent used in reaction step (ii) is selected from borane-dimethyl sulfide complex, DIBAL more preferably the reducing agent is DIBAL.
The Wittig reaction in step (iii) is carried out using 4-alkoxyxybutyl triphenyl phosphonium ester, or (5-(ethylamino)-5-oxopentyl) triphenyl phosphonium bromide ,or -carboxybutyl triphenyl phosphonium bromide in presence of various strong bases.like potassium tert-butoxide, sodium hydride, potassium bis (trimethylsilyl) amide (KHMDS), sodium bis (trimethylsilyl) amide (NaHMDS), butyl lithium , hexyl lithium and more preferably, the base potassium tert-butoxide.
The Wittig reaction in step (iii) is carried out at a temperature of -70°C to reflux temperature and more preferably at a temperature of -70°C to 10°C.
One of the advantage of step (iii) involves in-situ deprotection of the protected hydroxy, hence reducing the steps to achieve final product whereby increasing the overall yield.
The organic solvent used in step (i), step (ii) and step (iii) selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or water and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methylene chloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, and/or water and mixtures thereof; and more preferably, the organic solvent is DCM, tetrahydrofuran, toluene, dimethyl sulfoxide and mixture of tetrahydrofuran and dichloromethane.
In another aspect, the invention involves the isolation of the compound of formula “B” without using the column chromatography in order to get maximum enantiomeric excess and purity. The compound of formula B is isolated using single or mixture of organic solvents to give enantiomeric excess is at least 91.7% to about 96.7%
In another aspect, the invention involves purification of compound of formula “B” using various organic solvents and combinations thereof to obtain enantiomeric excess about 99.6% and wherein unwanted isomer is less than or about 0.15%.
The organic solvent used for isolation and purification of compound “B” selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or water and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methylene chloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, and/or water and mixtures thereof; and more preferably methanol, mixture of DCM and cyclohexane; DCM and diisopropyl ether, whereas most preferred is methanol, propanol, mixture of DCM and diisopropyl ether , and toluene.
Isolation of (3aR,4R,5R,6aS)-4-((S,E)-3-((4-nitrobenzoyl)oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate: Compound of formula B ( Nitro Compound) was isolated by using different types of solvents and combination of solvents to obtain intermediate with maximum enantiomeric excess and purity.
HPLC method has been developed to analyze the percentage of unwanted isomer. Different experiments were done to isolate (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate, results are tabulated in table 1.

Table 1:- HPLC analysis of Isolated 3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate in different solvents

Sr. No Conditions of isolation Required isomer Unwanted ß-isomer Isomer ration (e,e)
1 Concentrated organic layer after work up 75.03 4.12 95.53:4.47 91.06
2 Isolation in Methanol 97.81 2.19 97.81:2.19 95.62
3 Isolation in Dichloromethane and Cyclohexane 95.61 3.10 97.37:2.63 94.74
4 Isolation in Dichloromethane and Di isopropyl ether 97.43 2.10 98.22:1.78 96.44

Further purification of 3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate isolated by using methanol is done in different solvents. Results of the purification are tabulated in table 2.

Table 2:- :- HPLC analysis of Purified 3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate in different solvent systems.

Sr No Conditions of Purification Required isomer Unwanted ß-isomer Enantiomeric excess
(e,e) Yields
1 Purification in 4 volume Ethyl Acetate 99.65 0.35 99.30 76 %
2 Purification in 8 Vol. Methanol : Acetone (1:1) 99.43 0.57 98.86 80 %
3 Purification 3.5 Vol. Acetone 99.58 0.42 99.16 60 %
4 Purification in 4 volume Toluene 99.85 0.15 99.70 84 %

Purification in toluene gives good yield and unwanted isomer also gets wash out up to 0.15% in single purification.
In another aspect, the invention involves the novel intermediate of compound of formula “C”.

In another aspect, the invention involves the preparation of compound of formula C:

comprising reduction of compound of formula B using DIBAL to form compound of formula “C” wherein R3 is p-nitrobenzoyl (PNB) group; 3,5 dinitrobenzoyl group and W is as defined above.
In another aspect, the invention involves use of compound of formula C for preparation for compound formula I.

Examples:
The following examples describe the present invention in detail, but are not to be construed to be in any way limiting for the present invention.

Example 1: Preparation of (3aR, 4R, 5R, 6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.

50 gm Corey’s lactone was reacted with 66 gm Dess-Martin periodinane in 750 ml dichloromethane at 10 to 15°C. After reaction completion, the reaction mass was filtered and organic layer was washed by 750 ml solution of sodium bicarbonate 60 gm + 53 gm sodium thiosulphate pentahydrate in water. Further organic layer was washed by 250 ml water and 250 ml 20% brine solution. (Org. Layer 1)
In another flask charged 500 ml Dichloromethane and added 47.25 gm dimethyl (2-oxo-4-phenyl butyl) phosphonate under nitrogen. Added 68 ml n-Hexyl lithium 2.6 M solution at 0 to 5°C. To this solution added above organic layer (Org. Layer 1) at -15°C to -10°C and stirred till reaction completion. 10.5 ml acetic acid and 500 ml D.M. water charged to quench reaction. The reaction mass was stirred, allowed to settle and the layers were separated. Organic layer was washed with 250 ml 5% sodium bicarbonate solution followed by 3 X 500 ml water wash and finally 250 ml 20% brine sol. Distilled out dichloromethane from organic layer and taken concentrated mass in 250 ml methanol. Stirred cooled and filtered solid. Washed by 50 ml methanol and dried under vacuum.

Dry wt. = 49.5 gm.
Yield = 73 %

Example 2: Preparation of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-hydroxy-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.

Charged 4 gm of (3aR, 4R, 5R, 6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate in 40 ml tetrahydrofuran and cooled to -30°C to -35°C. Added 12 ml (-) DIP chloride (50-60% in hexane) slowly and raised temperature to 25°C. Stirred reaction for 14 Hrs. to complete reaction. Added 6 ml methanol to quench reaction. Concentrated reaction mass to 2 - 3 vol. This concentrated mass was taken in 30 ml dichloromethane and washed by 20% ammonium chloride sol. and 20 % brine solution. Organic layer was concentrated under vacuum to get oily mass. Dissolved this oily mass in 8 ml isopropanol at 50°C. Added diisopropyl ether to this. Cooled the mass to 0 to -10°C, solid was precipitated and filtered. Solid was washed by diisopropyl ether and dried under vacuum to get (3aR, 4R, 5R, 6aS)-4-((S, E)-3-hydroxy-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.
Dry wt. 2.9 gm
Yield = 72.31%

Example 3: Preparation of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate.

Dissolved 2.0 gm of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-hydroxy-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate in 20 ml dichloromethane at room temperature. Added 0.2 gm of 4-dimethyl amino pyridine and 0.75 gm triethylamine under nitrogen. Cooled mixture to 0 to 5°C. Added 1.14 gm para nitro benzoyl chloride to reaction mass and stirred at same temperature till reaction completion. After completion of reaction, added 10 ml D.M. water. Reaction mixture was stirred, allowed to settle and organic layer was separated. Organic layer was washed with 10 ml D.M. water, 10 ml 6% sodium bicarbonate. Organic layer was dried over sodium sulfate and distilled out dichloromethane completely under vacuum. Added 10 ml methanol to concentrated mass and heated to 50°C. Stirred at 50°C, cooled to room temperature and filtered the solid. The solid was washed with methanol and dried under vacuum to get 3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate.
Dry wt. = 2.4 gm
Yield = 92 %
Melting range: - 119.2°C to 120.2°C
IR: 1274.8cm-1, 1351.27 cm-1, 1536.74cm-1, 1762.51cm-1
1H-NMR (CDCl3) d: 1.60-2.09 (1H, m), 2.14-2.26 (2H, m), 2.49-2.90 (7H, m), 5.05-5.07 (1H, t), 5.24-5.28 (1H, q), 5.48-5.52 (1H, q), 5.72-5.74 (2H, - ethylene), 7.11-7.98 (14H, m), 8.05-8.07 (2H, d) 8.19-8.21(2H, d)
Mass: 631.6+18(Ammonium adduct)

Example 4: Preparation of ((3aR, 4R, 5R, 6aS)-2-hydroxy-4-((S,E)-3-((4-nitrobenzoyl)oxy)-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate.

Dissolved 5 gm of (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate in 20 ml dichloromethane and 60 ml tetrahydrofuran under nitrogen. Cooled mixture to -75 to -78°C. To this slowly added 18 ml of diisobutylaluminium hydride (25% in toluene) using dropping funnel while monitoring reaction on TLC. After reaction completion added 15 ml methanol to quench excess diisobutylaluminium hydride. Raised temperature to 0°C and added solution of 20 gm sodium potassium tartarate in 80 ml water. Stirred settled and separated layers. Aqueous layer was extracted by 2 X 70 ml dichloromethane. Organic layers were combined and washed by 45 ml D.M water and 50 ml of 20% brine solution. Organic layer was dried on sodium sulfate and dichloromethane was distilled out completely under vacuum to get oily mass 5.5 gm. The oily was cooled overnight in freezer, to obtain solid (3aR, 4R, 5R, 6aS)-2-hydroxy-4-((S,E)-3-((4-nitrobenzoyl)oxy)-5-phenylpent-1-en-1-yl)hexahydro-2H-cyclopenta[b]furan-5-yl [1,1'-biphenyl]-4-carboxylate.
Melting range: 52 to 60°C
Mass: - 633.6 + 18 (Ammonium adduct).
1H-NMR (CDCl3) d: 1.69-2.18 (5H, m), 2.58-2.68 (5H, m), 2.7 (1H, Ex.) 4.63-4.64 (1H, q), 5.17-5.19 (1H, q), 5.47-5.52 (1H, q), 5.64-5.81 (3H, - m), 7.08-8.05 (14H, m), 8.11-8.13 (2H, d), 8.16-8.18(2H, d).

IR: 1274cm-1 ,1348cm-1, 1526 cm-1, 3415cm-1

Example 5:- Preparation of (Z)-7-((1R, 2R, 3R, 5S)-3, 5-dihydroxy-2-((S,E)-3-hydroxy-5-phenylpent-1-en-1-yl)cyclopentyl)hept-5-enoic acid.

Experimental Procedure:-
Added 10 gm of 4-carboxybutyl triphenyl phosphonium bromide to 50 ml dry tetrahydrofuran. The solution was stirred and cooled to -5°C to -10°C under nitrogen. Added 47 ml Potassium tert-butoxide (1 M sol in THF) in three lots at interval of 10 min to get orange red dyestuff. Stirred mixture for additional 45 min at -5 to 5°C to check consistency of Wittig reagent. Added solution of 3.5gm (3aR, 4R, 5R, 6aS)-4-((S, E)-3-((4-nitrobenzoyl) oxy)-5-phenylpent-1-en-1-yl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate in 15 ml tetrahydrofuran. Stirred reaction at -5°C to 5°C till completion of reaction. Reaction mass was quenched by adding 100 ml D.M. water at 0 to 5°C. Raised temperature of reaction mass to RT, stirred and washed with 100 ml dichloromethane. The aqueous layer was acidified to pH = 4 by citric acid solution and extracted with dichloromethane 2 X 100 ml. Organic layer was washed by 50 ml D.M. water and 50 ml 20% brine solution. Dried organic layer over sodium sulfate and distilled out dichloromethane completely under vacuum. Degassed concentrated oily mass under vacuum.
Oily mass wt. = 4.0 gm
Used this oily mass as it is for further reaction
Product Identification:-
Product is identified by Mass analysis.
Mass: 406.3 (M+18 ammonium adduct)

Example 6:- Preparation of Triol Ester

Above prepared crude triol acid 3.5 gm was added to 35 ml dimethylformamide. Cesium carbonate3.5 gm (1:1 w/w) was added and this reaction mixture was cooled to 0°C to 4°C. To this methyl iodide 2 gm was added and reaction mixture was stirred at same temperature till completion. After completion of the reaction 30 ml D.M water was added and reaction mass was acidified to pH = 3 using citric acid solution. Reaction mass was extracted by 3 X 30ml ethyl acetate. Organic layer was washed with 25 ml 5% sodium bicarbonate solution and organic layer was dried on sodium sulfate. Ethyl acetate was distilled out completely under vacuum to obtain crude triol ester as oily mass. Purification of this triol ester was done by column chromatography using ethyl acetate and cyclohexane.
Yield = 1.0 gm
Mass: 461.4 (M-1+60 acetate adduct).
1H-NMR (CDCl3) d: 1.68-1.71 (2H, m),1.80-1.86(4H, m), 1.91-2.17 (7H, m), 2.31-2.34 (4H, m), 2.71-2.74 (2H, m), 3.67 (3H, s), 3.99 (1H,m), 4.13-4.14(1H, m) 4.21 (1H, m), 4.41-5.63 (4H, - ethylene),7.21-7.31 (5H,m).

Example 7:- Preparation of Bimatoprost

Purified Methyl ester of triol acid 0.7 gm was then stirred in mixture of 3.5 ml (5 vol.) methanol and 3.5 ml (5 vol.) 70% Ethyl amine solution for 72 Hrs. After reaction completion added 40 volume ethyl acetate and 40 vol. water. Stirred reaction mass and layers were separated. Aqueous layer was extracted with 20 vol. ethyl acetate. Combined organic layer was washed with 20 vol. 6% sodium bicarbonate twice. Organic layer was dried over sodium sulfate and distilled out ethyl acetate completely under vacuum. The distilled mass was stripped with acetone and added four volume of acetone further stirred to dissolve material. Added 15 volume cyclohexane slowly under stirring. Filtered out precipitated Bimatoprost and washed with cyclohexane.
Yield = 80%
Mass: 416.5 (M +1)

Example 8: Preparation of (3aR, 4R, 5R, 6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate (2).

This synthesis was carried out in two steps. Step1: Corey’s lactone (50 g) was reacted with dess-Martin periodinane (66 g) in dichloromethane (750 mL) at 10 to 15°C. After reaction completion, reaction mass was filtered and organic layer was washed by solution of sodium bicarbonate (60 g) + sodium thiosulphate pentahydrate (53 g) in water (750 mL). Further organic layer was washed by water (250 mL) and 20% brine solution (250 mL). Organic layer was separated and used for next step
Step 2: In another flask charged dichloromethane (500 mL) and added dimethyl (2-oxo-4-phenyl butyl) phosphonate (47.25 g) under nitrogen. Added 2.6 M n-Hexyl lithium solution (68 mL) at 0°C to 5°C. To this solution added above organic layer of step 1 at -15°C to -10°C and stirred till reaction completion. Acetic acid (10.5 mL) and D.M. water (500 mL) was added to quench reaction. The reaction mass was stirred, allowed to settle and organic layer was separated. This organic layer was washed with 5% sodium bicarbonate solution (250 mL) followed by water (3 X 500 mL) and finally with 20% brine solution (250 mL). Dichloromethane was distilled out from separated organic layer to obtain concentrated mass. This concentrated mass was taken in methanol (250 mL) stirred, cooled to room temperature and solid was filtered. Washed this solid by methanol (50 mL) and dried under vacuum at 45°C. (49.5 g, 72.60 % yield)
IR: 1277cm-1 ,1692cm-1,1713cm-1, 1757cm-1.
1H-NMR (400 MHz, CDCl3) d: 2..44-2.78 (3H, m), 2.97-3.09(7H, m), 5.22-5.25 (1H, m), 5.42-5.46 (1H, m), 6.34-6.38 (1H, d), 6.77-6.82 (1H, dd), 7.31-7.829 (12H,m), 8.17-8.19(2H, d),
13C NMR (400 MHz, CDCl3): d ppm 29.89, 34.90, 37.77, 42.47, 42.51, 126.18, 127.20, 127.25, 127.81, 128.24, 128.35, 128.49, 128.92, 130.19, 131.38, 139.75, 140.80, 142.99, 146.21, 165.71, 175.83, 198.63.
MS: m/z 498.3 (M+18 ammonium adduct).

Example 9: Preparation of (Prost- 2/ Latano -2):- (3aR,4R,5R6aS)-2-oxo-4-(3-oxo-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4-carboxylate.

In autoclave pot charged (3aR, 4R, 5R, 6aS)-2-oxo-4-((E)-3-oxo-5-phenylpent-1-en-1-yl) hexahydro-2H-cyclopenta[b]furan-5-yl [1, 1’-biphenyl]-4-carboxylate 2 (10 g) and ethyl acetate (300 ml). Added 50 % wet palladium on carbon (Pd/C, 2.5 g). Boxed up assembly and applied 2 Kg hydrogen pressure art room temperature. Stirred reaction mass for 3 Hrs. to complete reaction. Released hydrogen pressure and filled out palladium on carbon. Distilled out ethyl acetate under vacuum and n-hexane to concentrated mass under stirring. Cooled to 5-10°C and filtered solid, washed by n-hexane (30 ml) dried under vacuum. (9.25 g, 92.5%)

IR: 1281cm-1 ,1607cm-1,1705cm-1, 1764cm-1.

1H-NMR (400 MHz, CDCl3) d: 1.70 -1.89 (2H, m), 2.21-2.22 (1H, m), 2.46-2.64 (3H, m), 2.70-2.80(3H, m), 2.88-2.92 (2H, m), 2.97-2.3.06 (3H, m), 5.22-5.25 (1H, m), 5.32-5.33(1H, m), 7.28-7.41 (5H, m), 7.51-7.62 (3H, m), 7.74-7.76 (2H, d),7.79-7.81 (2H, d), 8.16-8.18(2H, d)
13C NMR (400 MHz, CDCl3): d ppm 26.67, 29.67, 36.20, 37.58, 40.54, 43.74, 44.33, 52.32, 79.73, 84.36, 126.13, 127.18, 127.24, 128.16, 128.28, 128.47, 128.89, 130.12, 139.82, 140.78, 146.01, 165.86, 176.73, 208.97.

MS: m/z 500.3 (M+18 ammonium adduct).

Example 10: Synthesis of (Latano – 3 / Prost – 3): (3aR, 4R, 5R, 6aS)-4-((R)-3-hydroxy-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4-carboxylate.

To reaction flask charged R- CBS (1M sol, 1 ml) in dichloromethane (50 ml). To this added boron DMS (3.5 ml) and stirred mixture for 30 min at room temperature under nitrogen atmosphere. Cooled the reaction mixture and to -5 to -10°C and slowly added solution of (3aR,4R,5R6aS)-2-oxo-4-(3-oxo-5-phenylpentyl)hexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4carboxylate (4.0 gm) in dichloromethane (40 ml) in 60 min. Stirred reaction mass till reaction completion and added dilute hydrochloric acid to make pH acidic of the reaction mass. Precipitated solid was filtered out and aqueous layer was separated from organic layer. Water wash was given to organic layer (2 X 25 ml). Organic layer was dried over sodium sulfate and dichloromethane was distilled out completely to get oily mass (4.3 gm)
Product is identified by Mass analysis.
Mass: 484.5 + 18 (Ammonium adduct)

Example 11: Synthesis of Latano – 4: (p- nitro benzoyl protected)
(3aR, 4R, 5R, 6aS)-4-((R)-3-((4-nitrobenzoyl) oxy)-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1-biphenyl]-4carboxylate.

Dissolved (3aR, 4R, 5R, 6aS)-4-((R)-3-hydroxy-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [1, 1-biphenyl]-4carboxylate (16.0 g) in dichloromethane (160 mL) at room temperature. Added of 4-dimethyl amino pyridine (1.7 g) and trimethylamine (6.0 g) under nitrogen. Cooled mixture to 0 to 5°C. Added para nitro benzoyl chloride (9.2 g) to reaction mass and stirred at same temperature till reaction completion. After reaction completion added D.M. water (80 mL). Stirred reaction mixture, allowed to settle and separated organic layer. Organic layer was washed with 6% sodium bicarbonate solution (80 mL) and D.M. water (50 mL). Organic layer was separated and dried over sodium sulfate. Distilled out dichloromethane under vacuum from organic layer to obtain concentrated mass. Triturated concentrated oily mass by methanol (50 ml) at 45 to 50°C. Added methanol (80 mL) to concentrated mass and heated to 50°C. Stirred mixture at 50°C, cooled to 0 to 10°C and stirred at this temperature till solid precipitate. Filtered the solid and with methanol (20 mL) and dried under vacuum at 40°C to get intermediate (9 g, 43.26% yield).
Melting range: 65.2°C to 68.3°C

IR: 1276 cm-1, 1348 cm-1, 1526 cm-1, 1716 cm-1,1772 cm-1

1H-NMR (400 MHz, CDCl3) d (ppm): 1.37-1.55 (2H, m), 1.81-1.92 (2H, m), 1.97-2.15 (3H, m),2.33-2.52 (3H, m), 2.65-2.77(3H, m), 2.87-2.95 (1H, m), 5.08-5.09 (1H, m), 5.24-5.25 (1H, m), 7.13-7.67 (12H, m), 8.01-8.04(2H, t), 8.12-8.16(2H, t), 8.24-8.28(2H, t)
MS: m/z 633.6 + 18 (Ammonium adduct)

Example 12: Synthesis of Latano- 4 (3,5 di nitro benzoyl protected)
(3aR, 4R, 5R, 6aS)-4-((R)-3-((3,5-nitrobenzoyl)oxy)-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4carboxylate.

Dissolved (3aR, 4R,5R,6aS)-4-((R)-3-hydroxy-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4carboxylate (8.6 g) in dichloromethane (85 mL) at room temperature. Added of 4-dimethyl amino pyridine (1.08 g) and trimethylamine (3.23 g) under nitrogen. Cooled mixture to 0 to 5°C. Added para nitro benzoyl chloride (6.12 g) to reaction mass and stirred at same temperature till reaction completion. After reaction completion added D.M. water (50 mL). Stirred reaction mixture, allowed to settle and separated organic layer. Organic layer was washed water (45 ml), followed by 6% sodium bicarbonate solution (45 mL) and D.M. water (45 mL). Organic layer was separated and dried over sodium sulfate. Distilled out dichloromethane under vacuum from organic layer and given striping twice by methanol (30 ml) to concentrated mass. Added methanol (20 ml) to concentrated mass stirred for 30 min and decanted. Added fresh methanol (60 mL) to concentrated mass and stirred mixture. Cooled mixture to 0 to 10°C and stirred at this temperature till solid precipitate. Filtered the solid and with methanol (10 mL) and dried under vacuum at 40°C to get intermediate Obtained intermediate Latano – 4 (Prost- IV) is solid in nature with Melting range: 77.5 to 88.5°C

1H-NMR (400 MHz, CDCl3) d: 1.41 -1.1.55 (2H, m), 1.90-1.95 (2H, m), 2.05-2.21 (3H, m), 2.37-2.40(2H, m), 2.45-2.52 (2H, m), 2.65-2.74(3H, m ), 2.87-2.96 (1H, m), 5.08-5.10(1H, m), 5.24-5.30 (1H,m), 7.03-7.21 (5H, m), 7.37-7.48 (3H, m), 7.59-7.66 (4H, m),7.99-8.02 (2H, d), 8.99-9.00(2H, t), 9.16-9.17 (1H, t)

13C NMR (400 MHz, CDCl3): d ppm28.97, 29.18, 31.98, 32.04, 32.26, 32.36, 35.18, 35.30, 36.20, 37.72, 43.46, 52.41, 52.53, 79.78, 84.23, 122.35, 126.05, 127.18, 127.25, 128.11, 128.23, 128.56, 128.95, 129.30, 130.12, 133.67, 139.76, 140.70, 146.09, 148.52, 162.20,165.86, 176.54.

MS: m/z 678.68 +18 (Ammonium adduct)

Example 12: Synthesis of Latano -5 (Lactol):
(3aR, 4R, 5R, 6aS)-4-((R)-3-((3, 5-nitrobenzoyl) oxy)-5-phenylpentyl)-2-hydroxyhexahydro-2H-cyclopenta[b]furan-5-yl [1,1-biphenyl]-4-carboxylate.

Dissolved (3aR, 4R, 5R, 6aS)-4-((R)-3-((3,5-nitrobenzoyl)oxy)-5-phenylpentyl)-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4carboxylate (30 g) in dichloromethane (20 mL) and tetrahydrofuran (90 mL) under nitrogen. Cooled mixture to -70 to -78°C. To this slowly added 25% solution of diisobutylaluminium hydride in toluene (23 mL) using dropping funnel while monitoring reaction on TLC. After reaction completion added methanol (15 mL) to quench excess diisobutylaluminium hydride. Raised temperature to 0°C and added 25 % solution of sodium potassium tartarate in water (125 mL). Stirred reaction mass, settled and separated layers. Aqueous layer was extracted by dichloromethane (2 X 70 mL). Organic layers were combined and washed by D.M water (100 mL) and 20% brine solution (100 mL). Separated layers and organic layer was dried on sodium sulfate. Distilled out dichloromethane from organic layer completely to get solid (7.5 g).
Melting range of obtained solid is 64.43°C to 87.68°C.

IR: 1344cm-1 ,1544cm-1,1712cm-1, 2926cm-1, 3411cm-1.

1H-NMR (400 MHz, CDCl3) d: 1.41 -1.1.55 (2H, m), 1.90-1.95 (2H, m), 2.05-2.21 (3H, m), 2.37-2.40(2H, m), 2.45-2.52 (2H, m), 2.65-2.74(3H, m ), 2.87-2.96 (1H, m), 5.08-5.10(1H, m), 5.24-5.30 (1H,m), 7.03-7.21 (5H, m), 7.37-7.48 (3H, m), 7.59-7.66 (4H, m),7.99-8.02 (2H, d), 8.99-9.00(2H, t), 9.16-9.17 (1H, t)

13C NMR (400 MHz, CDCl3): d ppm 28.97, 29.18, 31.98, 32.04, 32.26, 32.36, 35.18, 35.30, 36.20, 37.72, 43.46, 52.41, 52.53, 79.78, 84.23, 122.35, 126.05, 127.18, 127.25, 128.11, 128.23, 128.56, 128.95, 129.30, 130.12, 133.67, 139.76, 140.70, 146.09, 148.52, 162.20,165.86, 176.54.
MASS m/z: 680.2+18 (ammonium adduct)

Example 13: Preparation of Latano Triol acid:-
(Z)-7((1R, 3R, 5S)-3, 5-dihydroxy-2-((R)-3-hydroxy-5-phenylpentyl) cyclopentyl) hept-5-enoic acid.

Added of 4-carboxybutyl triphenyl phosphonium bromide (10 g) to dry tetrahydrofuran (50 mL). Solution was stirred and cooled to -5°C to -10°C under nitrogen. Added 1 M solution of Potassium tert-butoxide in tetrahydrofuran (47 ml) in three lots at interval of 10 min to get orange red dyestuff. Stirred reaction mixture for additional 45 min at -5 to 5°C to check consistency of Wittig reagent. To this added solution of (3aR,4R,5R,6aS)-4-((R)-3-((3,5-nitrobenzoyl)oxy)-5-phenylpentyl)-2-hydroxyhexahydro-2H-cyclopenta[b]furan-5-yl[1,1-biphenyl]-4carboxylate (3.0 g) in tetrahydrofuran (15 mL). Stirred reaction at -5°C to 5°C till completion of reaction. Reaction mass was quenched by adding D.M. water (100 mL) at 0 to 5°C. Raised temperature of reaction mass to room temperature. Washed reaction mass by dichloromethane (100 mL). Reaction mass was then acidified to pH = 4 by citric acid solution and extracted with dichloromethane (2 X 100 mL). Separated layers and washed combine organic layer by D.M. water (50 ml) and 20% brine solution (50 ml). Dried organic layer over sodium sulfate, distilled out dichloromethane under vacuum from organic layer to obtain oily mass of intermediate 10 (4.0 gm). Used this oily mass as it is for further reaction.
Product is identified by MASS analysis. Mass: 389.2 (M-1) ES

Example 14: Preparation of Latanoprost

Latano triol acid (4 g) was dissolved in acetone (20 ml). Cooled the mixture under nitrogen at 5 to -5°C. To this added 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (6.25 g) slowly under nitrogen. Stirred reaction mixture for 30 min at -5 to 5°C. Slowly added isopropyl iodide (10.5 g) at 5 to -5°C within 30 min. Heated reaction mass at temperature 40-45°C and stirred till reaction completion. After reaction completion cooled reaction mass and water was added to quench reaction. Reaction mixture was extracted with ethyl acetate three times. Combined ethyl acetate layer was washed with water, 5% citric acid solution then with 5% sodium bicarbonate solution and finally with 20% brine. Washed ethyl acetate layer was dried on sodium sulfate and distilled out under vacuum to obtain concentrated oily mass.
Product Identification:-
Product is identified by MASS analysis.
Mass: 449 (M-1+17 ammonium adduct) ES
,CLAIMS:1. An improved process for preparation of prostaglandin of formula I:

wherein represents a double bond or a single bond;R4 is alkoxy or alkyl amino group; W is a residue from group consisting of substituted and unsubstituted C1-C6 alkyl, C7-C16 aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of C1-C6 alkyl, halo and CF3, and (CH2)nORa, wherein n is from 1-3 and Ra represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of C1-C6 alkyl, halo and CF3; comprising the steps of :
i) protection of compound of formula (A) using 4-nitrobenzoyl halide or 3,5 dinitrobenzoyl halide to obtain compound (B);

ii) reduction of compound of formula (B) using DIBAL obtain the compound of formula (C);

iii) Wittig coupling of the compound of formula C with compound of formula D.

2. The process according to claim 1, wherein 4-nitrobenzoyl halide or 3, 5 dinitrobenzoyl halide used in step 1 is selected from 4-nitrobenzoyl chloride, 4-nitrobenzoyl bromide, 3, 5 dinitrobenzoyl chloride, 3,5 dinitrobenzoyl bromide more preferably 4-nitrobenzoyl chloride, 3,5 dinitrobenzoyl chloride.
3. The process according to claim 1, the step i) can be carried out in the presence of base and catalyst.
4. The process according to claim 3 the catalyst used is DMAP and the base used in is either organic base or inorganic base.
5. The process according to claim 4, the base is selected from trimethylamine, dimethyl amine and tert-butyl amine, ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
6. The process according to claim 1, reaction step (iii) is carried out in the presence of base selected from potassium tert-butoxide, sodium hydride, potassium bis (trimethylsilyl) amide (KHMDS), sodium bis (trimethylsilyl) amide (NaHMDS), butyl lithium, hexyl lithium.
7. The process according to claim 1, solvent used in step (i) , (ii) and (iii) selected from dichloromethane, tetrahydrofuran ,toluene, dimethyl sulfoxide and mixtures thereof.

8. Intermediate of compound of formula ‘C’;

wherein represents a double bond or a single bond; W is a residue from group consisting of substituted and unsubstituted C1-C6 alkyl, C7-C16 aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of C1-C6 alkyl, halo and CF3, and (CH2)nORa, wherein n is from 1-3 and Ra represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of C1-C6 alkyl, halo and CF3. R3 is p-nitrobenzoyl (PNB) group; 3, 5 dinitrobenzoyl group.
9. Use of the compound of formula “C” for the preparation of compound of formula I.