FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2001
COMPLETE SPECIFICATION
(See section 10, rule 13)

1. Title of the invention
"Process for preparation of Prostaglandin Derivatives"
2. Applicant(s)
Name Nationality Address
USV LIMITED Indian company incorporated B.S.D. Marg, Station Road Govandi, Mumbai- 400 088
under Companies Act, 1956 Maharashtra India
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to an improved process for preparation and purification of Prostaglandins and analogues thereof.
Background of the invention:
Chronic glaucoma is an eye disease characterized by increased intraocular pressure (IOP), glaucomatous extraction, reduction of visual field that can ultimately cause blindness. Prostaglandins are generally characterized by substituents on the cyclopentyl ring. The PGF2α analogues generally have two hydroxyl groups in cis configuration relative to the cyclopentane ring and two side chains in a trans configuration relative to each other. Several Prostaglandin analogues are presently known for their ability to reduce intraocular pressure and can be used for treatment of glaucoma and related diseases of the eye. Among these, Bimatoprost (US5688819), Latanoprost (US4599353, US5296504, US5422368) and Travoprost (US5631287, US5849792, US5889052, US601I062) are mentioned as important ones in current use and have the chemical structure as given below,
Lumigan™ (Active ingredient: Bimatoprost), namely, (Z)-7-[(lR,2R,3R,5S)-3,5-Dihydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl]-5-N-ethyl heptenamide

Travatan™ (Active ingredient: Travoprost), namely, Isopropyl (Z)-7-[(IR,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3R)-3-hydroxy-4-[(α,α,α-trifluoro-m-tolyl)oxy]-l- butenyl]cyclopentyl] -5-heptenoate

and
Xalatan™ (Active ingredient: Latanoprost), namely isopropyl-(Z)-7 [(1R,2R,3R,5S)3,5-
dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5- heptenoate


There are various processes disclosed in US3931279, US5223537, US5698733, US5688819, EP544899, W095/26729 and J. Med. Chem., 1993, 36, 243. The process for preparation of Prostaglandin analogues as disclosed in the prior art is represented in Scheme 1 which comprises reaction of Corey aldehyde with phosphonate under Horner-Wadsworth-Emmons reaction conditions to yield enone compound. The reduction of keto group in enone compound generates fifth chiral center in the molecule. The unwanted isomer is separated from the desired compound by column chromatography. Then the C1=C2 bond in the compound is optionally reduced by catalytic hydrogenation, followed by OH-protection/deprotection procedures and reduction of lactone to lactol with diisobutylaluminium hydride at temperature -70 to -80 °C. Lactol is then reacted with 4-carboxybutyltriphenylphosphonium bromide in presence of base to obtain acid which (optionally after deprotecting the hydroxyl groups) is converted to the desired compound.
The process of the prior art has the following disadvantages:
1. The process disclosed in EP544899 provides only moderate or low yields. The low yields at the outset result in difficulties in purifying the intermediates as well as loss of valuable and expensive starting materials.
2. In the synthesis described in J. Med. Chem., 1993, 36, 243, the reduction of enone is carried out using lithium tri-sec-butylborohydride at -120°C giving low diastereomeric purity.
3. The reduction of unprotected lactone to lactol is undesirable because each free hydroxyl group coordinates with DIBAL-H (diisobutyl aluminium hydride). This difficulty becomes a serious problem when the synthesis is carried out on a large scale.


Scheme 1
wherein R = -OC6H4CF3-m or -CH2C6H5; R1 = alkoxy or alkylamino group and ™ is either a single bond or double bond.
Therefore, there exists a need for an improved process for preparing Prostaglandins which is suitable for industrial scale.
Object of the invention:
An object of the present invention is to provide simple and high yielding process for preparation of Prostaglandins of structure 1 in commercial quantities.

wherein R = -OC6H4CF3-m or -CH2C6H5; R1 = alkoxy or alkylamino group and = is either a single bond or double bond.

Another object of the present invention is to provide process for preparation of Bimatoprost, Latanoprost and Travoprost.
Summary of the invention:
According to one aspect of the present invention, there is provided a process for preparation of compound 13, a key intermediate in the preparation of prostaglandins comprising the steps of,
a) oxidizing Corey lactone alcohol (4) in presence of oxidizing agent to yield Corey lactone aldehyde (5);
b) reacting the obtained Corey lactone aldehyde (5) with a β-ketophosphonate compound to yield enone (6);

where R = -OC6H4CF3-m or -CH2C6H5 c) reducing enone (6) with a chiral reducing agent to get allylic alcohol (7) along with unwanted isomer;

d) separating unwanted isomer by chromatography to get pure allylic alcohol (7);
e) deprotecting obtained allylic alcohol (7) to get lactone diol (8);

f) optionally reducing lactone diol (8) in presence of catalyst to get lactone diol (9);


g) treating lactone diol (8) or (9) with a protecting agent to get protected lactone diol (10);


where R is as defined above
h) reducing the protected lactone diol (10) with diisobutylaluminium hydride to get lactol(ll);



i) reacting the lactol (11) with ylide compound to get compound (12);
j) treating the compound (12) with alkylating agent to get compound (13);
wherein R1 - alkyl, preferably, methyl or isopropyl; R = -CH2C6H5 or -OC6H4CF3-m and — is double bond or single bond.
Preferably, Corey lactone aldehyde formed in step a) is not isolated. Preferably, chiral reducing agent used in step c) is (-)-DIP chloride and is employed in 3-5 fold excess with respect to enone (6).
According to another aspect of the present invention, compound (13) is converted to Bimatoprost or Latanoprost or Travoprost.
Brief description of the drawings:
Fig. 1: X-ray powder diffraction pattern of (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-[3-

oxo-5-phenyl-(E)-l-pentenyl]-2-oxabicycIo [3.3.0]octan-3-one obtained according to the
present invention.
Fig. 2: X-ray powder diffraction pattern of (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-
[3(S)-3-hydroxy-5-phenyl-l(E)-pentenyl]-2-oxabicyclo [3.3.0]octan-3-one obtained
according to the present invention.
Fig. 3: X-ray powder diffraction pattern of 7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(lE,3S)-3-
hydroxy-5-phenyl-1 -pentenyl]cyclopentyl-5(Z)-heptenoic acid, N-ethyl amide
(Bimatoprost) obtained according to the present invention.
Fig. 4: X-ray powder diffraction pattern of (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-[3-
oxo-4-{3-(trifluoromethyl)phenoxy}-(E)-l-butenyl]-2-oxabicyclo [3.3.0]octan-3-one
obtained according to the present invention.
Fig. 5: X-ray powder diffraction pattern of (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-
[3(R)-3-hydroxy-4-{3-(trifluoromethyl)phenoxy}-(E)-l-butenyl]-2-oxabicyclo [3.3.0]
octan-3-one obtained according to the present invention.
Fig. 6: X-ray powder diffraction pattern of (lS,5R,6R,7R)-7-hydroxy-6-[3(R)-3-hydroxy-
4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyI]-2-oxabicyclo [3.3.0]octan-3-one obtained
according to the present invention.
Detailed description of the invention:
The present invention provides an improved process for preparation of PGF2α analogues. More particularly, the present invention provides a simple process for preparation of Bimatoprost, Latanoprost and Travoprost.
According to one embodiment of the present invention there is provided a process for preparation of key intermediate, compound (13), useful for preparation of Bimatoprost or Travoprost or Latanoprost.
The process for preparation of compound (13) comprises the following steps,
a) treating phosphonate of compound (2) with base in presence of suitable solvent to generate an anion followed by reaction of obtained anion with R-CH2C02Rx (where R = -OC6H,CF3-m or -CH2C6H5, Rx = methyl, ethyl) to get β-ketophosphonate (3);

(2) (3)
wherein R = -OC6H4CF3-m or -CH2C6H5 and R" = methyl, ethyl
b) oxidizing Corey lactone alcohol (4) in presence of oxidizing agent in suitable solvent to yield Corey lactone aldehyde (5);
c) reacting the obtained Corey lactone aldehyde (5) with p-ketophosphonate (3) produced in step (a) to yield enone (6);

where R = -OC6H4CF3-m or -CH2C6H5 d) reducing enone (6) with a chiral reducing agent in suitable solvent to get allylic alcohol (7) along with unwanted isomer;

e) separating unwanted isomer by chromatography to get pure allylic alcohol (7);
f) deprotecting the obtained allylic alcohol (7) using suitable base in suitable solvent to get lactone diol (8);

g) optionally reducing diol (8) in presence of metal catalyst to get lactone diol (9);

h) treating lactone diol (8) or (9) with a protecting agent in suitable solvent to get

protected lactone diol (10);

wherein PG and R is as defined above i) reducing the protected lactone diol (10) with diisobutylaluminium hydride in presence of suitable solvent to get lactol (11);

j) reacting lactol (11) with ylide compound to get compound (12);

k) treating compound (12) with alkylating agent to get compound (13);

wherein R1= methyl or isopropyl ; R = -CH2C6H5 or -OC6CF3-m and = is double bond or single bond.
The process for preparation of the key intermediate .i.e., Compound (13) is described
below in stepwise manner,
Step I of the process involves preparation of p-keto phosphonate compound (3) which
comprises reaction of dimethyl methyl phosphonate (2) with suitable base preferably n-
butyl lithium to generate an anion followed by reaction of obtained anion with compound
of formula RCH2C02Rx (R = -CH2C6H5 or -OC5H4CF3-m) to get the desired phosphonate
(3). The crude phosphonate (3) obtained may be purified by either column
chromatography or vacuum distillation preferably vacuum distillation.
In preferred embodiment, a solution of dimethyl methyl phosphonate in suitable solvent
preferably, THF is cooled to -60°C and n-butyl lithium is added over a period of 1 hr

while maintaining the temperature below -60°C. The reaction mixture is stirred for 1.5 hr at the same temperature. A solution of methyl-3-phenyl propionate or ethyl-[3-(trifluoromethyl)phenoxy] acetate in THF is added to the obtained reaction mixture over a period of lhr while maintaining temperature below -60°C and further for 4h. The reaction mixture is acidified to pH 4 using 5% potassium hydrogen sulfate solution. The product is isolated using suitable solvent and purified by distillation under reduced pressure.
Step II of the process involves oxidation of Corey lactone alcohol (4) using suitable oxidizing agent in presence of suitable solvent to get Corey lactone aldehyde (5). Amongst various oxidizing agents, it is observed that Dess-Martin periodinane provides selective formation of aldehyde without over oxidation to its acid. The reaction is preferably carried out in non-polar hydrocarbon solvent preferably methylene dichloride (MDC). The solution containing Corey lactone aldehyde in MDC is used as such in the next step.
In preferred embodiment, Dess-Martin reagent is suspended in suitable solvent preferably MDC. The obtained solution is cooled to 5-10°C with stirring followed by addition of Corey lactone alcohol in MDC maintaining the same temperature. After complete addition the temperature of the reaction mixture is allowed to attain room temperature. The reaction mixture is monitored by TLC. After completion of reaction aqueous solution of sodium thiosulfate pentahydrate and sodium bicarbonate is added to the reaction mixture with stirring for 15 minutes. The separated aqueous layer is extracted with MDC. The MDC layer is immediately used for the next step. Corey lactone aldehyde (5) is highly unstable thus should be immediately used for the next step.
Step III involves reaction of compound (3) with solution of Corey lactone aldehyde (5) in MDC of step II in suitable base in presence of suitable solvent to get enone (6). The oily product is isolated by adjusting pH of the reaction mixture with acetic acid. In preferred embodiment, a solution of dimethyl (2-oxo-4-phenyIbutyl)phosphonate or dimethyl {2-oxo-3-[3-(trifluoromethyl)phenoxy]propyl} phosphonate in MDC is added dropwise at 0°C to a suspension of sodium hydride [60% dispersion in mineral oil] in MDC. The mixture is stirred at 0°C for 1 hr. The solution of aldehyde in MDC prepared in Step II is added dropwise maintaining temperature -5 to 0°C. The reaction mixture is

stirred while monitoring reaction by TLC. After complete disappearance of aldehyde, the reaction mixture is acidified with acetic acid to pH 6 and water is added to the reaction mixture. The separated aqueous layer is extracted with MDC. The organic solvent is concentrated under reduced pressure to get oily residue which is stirred with MTBE for 6 hr to get the crystallized compound (6).
In Step IV, the stereoselective reduction of enone (6) obtained in step III is carried out using chiral reducing agent, preferably (-)-DIP chloride to get a mixture of compound (7) and unwanted isomer. (-)-DIP chloride is usually used 3-5 fold excess than enone (6). The reaction results in formation of around 8-10% unwanted isomer. The crude product is isolated by adding boron complexing agent like methanol and concentrating the reaction mixture. The reaction results in formation of a-pinene as a byproduct. The crude product is adsorbed on alumina and stirred with hexane to get rid of a-pinene byproduct. The product is further purified by column chromatography to remove the unwanted isomer. In preferred embodiment, a solution of (-)- DIP chloride is added to the solution of compound (6) in dry THF and the reaction mixture is stirred at 0-5°C. After completion of reaction, methanol is added to the reaction mixture followed by stirring the reaction mixture for 16 hr. The organic solvent is removed to get residue. The obtained residue is stirred in ethyl acetate and water for lhr. The organic solvent is concentrated to get product which is purified by column chromatography to get desired product (7) containing <0.5% of unwanted isomer.
According to the present invention, it is necessary to take care of the unwanted isomer at this stage itself as it leads to formation of two impurities (as shown in Table below) in the desired end product. For example, in case of Latanoprost, if the unwanted (S)-isomer is not removed, it will lead to formation of two Latanoprost-isomer impurities in the end product viz.,15(S) cis-Latanoprost and 15(S) trans-Latanoprost. 15(R) trans-Latanoprost impurity arises from the desired (R)-isomer of Latanoprost during Wittig reaction (Latanoprost is 15(R) cis isomer).

PGF2aDesired isomer Unwanted isomer
Latanoprostl5(R), cis 15(R),trans ; 15(S),trans ; 15(S),cis
Travoprostl5(R), cis 15(R),trans ; 15(S),trans ; 15(S),cis
Bimatoprostl5(S), cis 15(S),trans ; 15(R),trans ; 15(R),cis
Step V of the process involves deprotection of allylic alcohol (7) with suitable base to remove arylcarbonyl group on cyclopentane ring. The reaction is usually carried out in suitable solvent like methanol to get diol compound (8). The by-product formed, p-phenyl benzoate ester, can be removed by column chromatography to get pure lactone diol (8). In preferred embodiment, the compound (7) in dry methanol is treated with anhydrous potassium carbonate and the mixture is stirred at ambient temperature until TLC shows completion of reaction. After the completion of reaction, the pH of the reaction mixture is adjusted to 6.8-7 using 1M hydrochloric acid. The mixture is then evaporated to dryness to get the residue. The obtained residue is dissolved in suitable solvent and concentrated to get crude product which was further purified by column chromatography to yield pure product (8).
Step VI of the process involves optionally reducing the diol (8) using suitable catalyst such as palladium or platinum supported on carbon to get compound (9).
In Step VII compound (8) or (9) is protected using suitable protecting agent like ethyl vinyl ether, 3,4-dihydro-2(H)-pyran or silyl protecting agent such as tert-butyldimethylsilyl chloride optionally in presence of catalyst to get compound (10). The reduction of unprotected compound (8) or (9) is undesirable because each free hydroxyl group coordinates with DIBAL-H (diisobutylaluminium hydride). This difficulty becomes a serious problem when the synthesis is carried out on a large scale. The protecting agent used is 3,4-dihydro-2(H)-pyran preferably in non-polar aprotic solvent like MDC preferably in presence of acid catalyst such as p-toluenesulfonic acid to form protected diol. The product is isolated by basic work-up followed by column chromatography to obtain pure protected diol (10).
In preferred embodiment, diol compound (8) or (9) and 3,4-dihydro-2H-pyran are dissolved in MDC and p-toluenesulfonic acid monohydrate is added to the obtained

mixture at 0°C. After completion of the reaction, the obtained mixture is poured into saturated sodium bicarbonate solution. The product is isolated using suitable solvent which is further purified by column chromatography (MDC : ethyl acetate) to yield the title compound (10).
Step VIII of the process comprises reduction of protected lactone diol (10) using diisobutylaluminium hydride to get lactol (11). The reaction is usually carried out in presence of suitable solvent preferably THF at temperature -50 to -80°C. In preferred embodiment, the protected lactone diol (10) dissolved in dry THF is cooled to -60°C and diisobutylaluminium hydride (25% solution in toluene) is added to it maintaining the temperature below -60°C. The reaction mixture is then stirred at this temperature until TLC showed completion of reaction. The compound (11) is isolated using suitable solvent.
In Step IX, the compound (11) is subjected to Wittig reaction with ylide compound at 0
to 70°C. The reaction results in the formation of desired acid (12) along with secondary
products resulting from ylide like triphenylphosphine oxide and 4-
(carboxybutyl)diphenylphosphine. The crude acid (12) is used as such in the next step. The ylide compound is prepared by reacting 4-(carboxybutyl trialkyl/aryl) phosphonium halide of formula H02C(CH2)4P+(R)3X- with suitable base; R= C1-C6 alkyl or phenyl and X= -CI or -Br, preferably R= phenyl and X=-Br.
In preferred embodiment, 4-(carboxybutyl)-triphenylphosphonium bromide is suspended in suitable solvent preferably dry THF followed by potassium tert-butoxide. The mixture is heated to reflux for 1 hr and resulting suspension is allowed to cool to ambient temperature to get ylide compound. Preferably, a mixture of 3-5 equivalents of 4-(carboxybutyl)-triphenylphosphonium bromide in THF and 5-10 equivalents of potassium tert-butoxide is heated at 30-60°C for lhr. More preferably, 3.6 equivalents of phosphonium bromide and 7.2 equivalents of base is used for ylide formation. A solution of lactol compound (11) in THF is then added to the obtained suspension containing ylide compound at ambient temperature. After completion of reaction, the mixture is concentrated and the obtained residue is partitioned between ethyl acetate and water. The pH of the separated aqueous layer is adjusted between 5 and 6 using 5% citric acid and

isolating crude acid (12) which is used in the next step without further purification.
Step X of the process involves esterification of the carboxylic group of acid compound (12) which is carried out with alkylating agents preferably alkyl halide in presence of suitable solvent and suitable base. After usual work-up the product is purified by column chromatography.
In preferred embodiment, l,8-diazabicyclo[5.4.0]undec-7-ene is added dropwise to a stirred suspension of compound (12) in acetone at 0-5°C and the obtained solution is stirred for 1 hr. The temperature of solution is raised to ambient temperature followed by addition of methyl iodide or isopropyl iodide. The resulting reaction mixture is stirred overnight at room temperature. After TLC shows completion of reaction, the mixture is concentrated to get the residue which is partitioned between ethyl acetate and water. The reaction mass is acidified with 5% citric acid and the product is isolated using suitable organic solvent. The obtained crude ester is purified by column chromatography using MDC : ethyl acetate to yield pure compound (13).
The reaction scheme of the present invention is represented in Scheme 2,


According to another embodiment the present invention provides process for preparation of Bimatoprost which comprises deprotecting acid compound (12) using acid catalyst and converting the resulting compound into Bimatoprost (15) using alkylamine.

wherein R1 = Ethyl; R = -CH2C6H5 and = is double bond

wherein R1 = alkyl; R = -CH2C6H5 and = is double bond.

According to another embodiment, the present invention provides process for preparation of Bimatoprost which comprises deprotecting the ester compound (13) using acid catalyst to get triol of compound (14) and treating withalkyl amine to get the compound (15).
wherein R1 = Ethyl ; R = CH2C6H5 and = is double bond
In preferred embodiment, pyridinium p-toluenesulfonate is added to a stirred solution of the compound (13) in ethanol or methanol at room temperature and the mixture is stirred at 45-50°C for 7-8 hr. After completion, the mixture is evaporated to dryness to get compound (14) which may be purified using suitable solvent. A mixture of compound (14) and 70% aqueous ethylamine is stirred at room temperature (TLC monitoring). After completion, the reaction mixture is concentrated, acidified with 5% citric acid and extracted with suitable solvent preferably ethyl acetate. The organic layer is concentrated under reduced pressure to get crude product (15). The crude product may be purified by column chromatography or crystallization with suitable solvent preferably ether to get pure Bimatoprost (15).
Bimatoprost obtained according to the present invention has X-ray powder diffraction as

shown in figure 3 having characteristic peaks expressed in degrees 20 at about 6.9, 10.4, 13.9, 17.4, 18.3, 19.0, 19.5, 19.7, 20.8, 21.1, 22.4, 24.6, 27.9 and 28.5.
In an alternate embodiment, compound (12) can be converted to Bimatoprost.
Another embodiment of the present invention provides process for preparation of Latanoprost (14) which comprises deprotecting the compound (13) to get Latanoprost (14).

wherein Rl = isopropyl; R = -CH2C6H5 and = is single bond. In preferred embodiment of the present invention, pyridinium p-toluenesulfonate is added to a stirred solution of the compound (13) in ethanol or methanol at room temperature. The mixture is stirred at 45-50°C. After completion of reaction, the mixture is evaporated to dryness The obtained residue is dissolved in MDC and the obtained solution is washed with sodium bicarbonate solution and water. The organic layer is concentrated to get the title compound. The crude product is purified by column chromatography to give pure Latanoprost with purity 99.9% (by HPLC).
According to another embodiment the present invention provides process for preparation of Travoprost comprising deprotecting compound (13) to get Travoprost (14).

wherein R, = isopropyl; R = -OC6H4CF3-m and = is double bond. In preferred embodiment of the present invention pyridinium p-toluenesulfonate is added to a stirred solution of the compound (13) in suitable solvent such as methanol or ethanol preferably ethanol at room temperature. The mixture is stirred at 45-50°C while monitoring the reaction by TLC. After completion, the mixture is evaporated to dryness to

get the residue. The obtained residue is dissolved in MDC, dried with sodium sulfate and MDC layer is concentrated to get title compound. The crude product is purified by column chromatography to get pure Travoprost with HPLC purity of 99.5%.
The Phenomenex™ Luna silica gel is used as column packing material. The eluent used is a mixture of solvent selected from halogenated/non-halogenated hydrocarbons, alcohol, acetonitrile, ether or ester. Preferably mixture of hydrocarbons and alcohols is used for separation purpose. If product is solid, it is stirred with ether for crystallization (e.g. Bimatoprost).
The acid catalyst used in the present invention may be selected from sulfonic acids, mineral acids or salts thereof. Sulfonic acid and their salts may be selected from the group consisting of p-toluenesulfonic acid, benzenesulfonic acid, nitrophenylsulfonic acid, halophenylsulfonic acid, methanesulfonic acid, sulfamic acid, benzyl sulfonic acid and pyridine salts thereof. The alkyl lithium used in the present invention may be selected from n-butyl lithium, sec-butyl lithium or tert-butyl lithium. Alkylamine is selected from the group consisting of methylamine or ethylamine preferably ethylamine.
Suitable base used in the present invention may be organic or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, N-ethyl dicyclohexylamine, dimethylaniline, pyridine, piperidine, picoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, diisopropylethylamine or mixture thereof. The inorganic base may be selected from n-butyl lithium, sodium hydride, sodium methoxide, potassium tert-butoxide, alkali metal hydroxide, alkali metal carbonate or mixture thereof. The alkali metal hydroxide may be selected from group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide and cesium hydroxide. The alkali metal carbonate is selected from sodium carbonate or potassium carbonate.
Suitable solvent may be selected from polar aprotic solvent and non-polar aprotic solvent. The polar aprotic solvent used in the present invention may be selected from ketone such as acetone or ethyl methyl ketone; nitrile such as acetonitrile; ether such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran or dioxane; dimethylformamide, dimethylacetamide; dimethylsulfoxide; N,N-dimethylpyrrolidinone; sulfolane or mixture

thereof. Non-polar aprotic solvents may be selected from aliphatic hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon or mixture thereof. Aliphatic hydrocarbon may be selected from pentane, hexane or heptane preferably hexane. Aromatic hydrocarbon may be selected from toluene, xylene or the like. Halogenated hydrocarbon may be selected from chloroform, dichloromethane, dichloroethane, chlorobenzene, o-dichlorobenzene or mixture thereof.
PGF2a according to the invention may be combined with a pharmaceutically acceptable carrier to form suitable pharmaceutical compositions, used in therapy such as in a method of treating elevated intraocular pressure in patients with ocular hypertension or open angle glaucoma.
The process of the present invention is described herein below with reference to the following examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
Example 1: Process for preparation of Bimatoprost (15) Step A: Dimethyl-2-oxo-4-phenybutyl phosphonate
619 gm of dimethyl methyl phosphonate (4.99 mol) was dissolved in THF (5 lit) and the resulting solution was cooled to -60°C. 3.03 lit of n-butyl lithium (1.6M hexane solution, 4.84 mol) was added to the cooled solution over a period of 1 hr maintaining the temperature below -60°C. The mixture was stirred for 1.5 hr at the same temperature. A solution of methyl-3-phenyl propionate (500 gm, 3.05 mol) in THF (2.5 lit) was added over a period of lhr while maintaining temperature below -60°C. The reaction mixture was maintained at the same temperature for 4h and further at room temperature for 6 hr. The reaction mixture was acidified to pH 4 using 5% potassium hydrogen sulfate solution. The separated aqueous layer was extracted with ethyl acetate (2.5 lit). The combined organic layer was washed with brine solution, dried over sodium sulfate, filtered and concentrated to get the product. The obtained product was purified by distillation under reduced pressure to give 375 gm (48%) colourless oil.

Step B: (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-formyl-2-oxabicyclo[3.3.0]octan-3-one (Corey lactone aldehyde)
Dess-Martin reagent (416gm, 0.98 mol) was suspended in methylenedichloride (MDC) (1.5 lit) and cooled to 5-10°C. To this stirred suspension solution of 150 gm of Corey lactone alcohol ( 0.43 mol) in MDC (750 ml) was added maintaining the temperature in the range of 5-10°C. After the complete addition, the temperature of the reaction mixture was raised to room temperature and the reaction was monitored by TLC. After the completion of reaction, aqueous solution of sodium thiosulfate pentahydrate and sodium bicarbonate were added to the reaction mixture followed by stirring for 15 minutes. The organic layer was separated and aqueous layer was extracted with MDC (750 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and immediately introduced into next step. The compound (5) was used for next step without isolation.
Step C: (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-[3-oxo-5-phenyl-(E)-l-pentenyl]-2-oxabicyclo [3.3.0]octan-3-one
A solution of dimethyl (2-oxo-4-pbenylbutyl)phospbonate (185 gm, 0.72 mol) in MDC (750 ml) was added dropwise at 0°C to a suspension of 26.4 gm of sodium hydride (60% dispersion in mineral oil, 0.66 mol) in MDC (1.5 lit) and the reaction mixture was stirred at 0°C for 1 hr. The solution of Corey lactone aldehyde in MDC prepared in previous step (Step B) was added dropwise to the stirred mixture maintaining temperature between -5 to 0°C. The reaction mixture was stirred while monitoring reaction by TLC. After complete disappearance of aldehyde on TLC, the reaction mixture was acidified with acetic acid to pH 6 followed by addition of water and stirring for 10 min. The obtained mixture was filtered through celite. The separated aqueous layer was extracted with MDC (750ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to get the oily residue. The obtained residue was stirred with MTBE (900 ml) for 6 hr to get the material which was filtered to obtain 135 gm of pure title compound (66%).
The X-ray powder diffraction has characteristic peaks expressed in degrees 20 at approximately 8.9, 13.4, 13.6, 17.1, 18.6, 18.8, 19.6, 20.3, 20.9, 22.4, 22.9, 23.3, 23.8, 24.4, 26.0, 27.4, 28.0 and 30.6 (Fig. 1).

Step D: (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-I3(S)-3-hydroxy-5-phenyl-l(E)-pentenyl]-2-oxabicyclo [3.3.0]octan-3-one
674 ml of (-)- DIP chloride (60% solution in hexane, 1.13 mol) was added to solution of 135 gm of compound obtained in step C (0.28 mol) in dry THF (2.7 lit) followed by stirring at 0-5°C. After the completion of reaction, methanol (135 ml) was added to the reaction mixture and stirred for 16 hrs. The reaction mixture was concentrated to get the residue. 1.35 lit of ethyl acetate and 1.35 lit of water was added to the obtained residue followed by stirring for lhr. To the separated ethyl acetate layer alumina ( 1.2 Kg) was added and the reaction mixture was concentrated followed by stirring the product adsorbed on alumina with hexane (12 lit) for 3hr and filtered. The product was then desorbed by stirring alumina with ethyl acetate (2 X 12). The ethyl acetate layer was concentrated to get thick oily crude product. It was further purified by column chromatography to get desired product containing <0.5% of unwanted isomer (80 gm, 59%).
The X-ray powder diffraction has characteristic peaks expressed in degrees 26 at approximately 6.3, 11.1, 11.5, 12.7, 13.7, 16.4, 16.7, 17.0, 17.6, 17.8, 18.7, 19.3, 19.6, 19.9, 20.1, 20.7, 20.9, 22.5, 22.9, 23.7, 24.4, 24.6, 25.1, 25.7, 25.9, 26.9 and 27.5 (Fig. 2)
Step E: (lS,5R,6R,7R)-7-hydroxy-6-[3(S)-3-hydroxy-5-phenyl-l(E)-pentenyl]-2-oxabicyclo [3.3.0]octan-3-one
To the solution of compound obtained in step D (80 gm, 0.17) in dry methanol ( 1.2 lit) was added anhydrous potassium carbonate (14.9.gm, 0.11). The reaction mixture was stirred at ambient temperature until TLC shows completion of reaction. IM hydrochloric acid was added to adjust the pH of the reaction mixture to 6.8-7 and the mixture was then evaporated to dryness. The residue was dissolved in ethyl acetate (800 ml) and the obtained solution was washed with water. The organic layer was concentrated to obtain crude product which was further purified by column chromatography to yield 46 gm of pure product (91%).
Step F: (lS,5R,6R,7R)-6-[3(S)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)-(lE)-pentenyl}-7-(tetrahydro-2H-pyran-2-yloxy)]-2-oxabicyclo [3.3.0]octan-3-one
The compound obtained in step E (46 gm, 0.15 mol) and 3,4-dihydro-2H-pyran (47.2 gm,

0.6 mol) were dissolved in MDC (690 ml) and p-toluenesulfonic acid monohydrate (460 mg) was added at 0°C. After completion of the reaction, the obtained solution was poured into saturated sodium bicarbonate solution. The separated aqueous layer was extracted with MDC (230 ml). The combined organic layers were dried with sodium sulfate and concentrated to get the titled compound which was further purified by column chromatography (MDC : ethyl acetate) to yield 58 gm (81%) of the title compound.
Step G: (lS,5R,6R,7R)-6-[3(S)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)-(lE)-pentenyl}-7-(tetrahydro-2H-pyran-2-yloxy)-2-oxabicyclo [3.3.0]octan-3-ol
58 gm of compound obtained in step F (0.12 mol) was dissolved in dry THF (870 ml) and cooled to -60°C. Diisobutylaluminium hydride (25% solution in toluene, 165 ml, 0.25 mol) was added to the reaction mixture while maintaining the temperature below -60°C. The reaction mixture was then stirred at this temperature until TLC showed completion of reaction. Methanol (58 ml) was then added to the reaction mixture and stirred for 30 min. The temperature of the reaction mixture was then raised to -10°C and water (580 ml) and ethyl acetate (870 ml) were added to the reaction mixture followed by stirring the reaction mixture for further 30 min to get gelatinous white precipitate which was filtered through celite and washed with ethyl acetate. The separated organic layer was dried over sodium sulfate and concentrated to yield pale yellow oily compound (58 gm, 100%).
Step H: 7-[(lR,2R,3R,5S)-5-Hydroxy-2-{3(S)-{5-phenyl-3-(tetrahydro-2H-pyran-2-
yloxy)-(lE)-pentenyI}-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl-5(Z)-heptenoic
acid
4-(carboxybutyl)-triphenylphosphonium bromide (196.4 gm, 0.44 mol) was suspended in dry THF (870 mol) and potassium tert-butoxide (98.7 gm, 0.88 mol) was added to the obtained suspension. The mixture was heated to reflux for 1 hr and resulting orange coloured suspension was allowed to cool to ambient temperature. A solution of compound obtained in step G (58 gm, 0.12 mol) in THF (290 ml) was then added to the reaction mixture at ambient temperature. After TLC showed completion of reaction, the reaction mixture was concentrated to get the residue. The obtained residue was partitioned between ethyl acetate and water. The pH of the separated aqueous layer was adjusted between 5 to 6 using 5% citric acid followed by extraction with ethyl acetate (2 x 580 ml). The organic

layer was concentrated to get crude acid which was used in the next step directly without further purification.
Step I: 7-[(lR,2R,3R,5S)-5-Hydroxy-2-{3(S)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)-(lE)-pentenyl}-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl-5(Z)-heptenoic acid, methyl ester
l,8-Diazabicyclo[5.4.0]undec-7-ene (133.2 gm, 0.88 mol) was added dropwise to a stirred suspension of compound obtained in step H (81 gm) in acetone (1.2 lit) at 0-5°C. The resulting solution was stirred at this temperature for 1 hr and then raised to ambient temperature followed by addition of methyl iodide (83 gm, 0.58 mol). The resulting mixture was stirred overnight at room temperature. After TLC shows completion of reaction, the reaction mixture was concentrated to get the residue which was partitioned between ethyl acetate and water. The obtained reaction mixture was acidified with 5% citric acid. The separated aqueous layer was extracted with ethyl acetate (800 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude ester obtained was purified by column chromatography using MDC : ethyl acetate to yield 27 gm (39% over two Steps H and I) of titled product.
Step J: 7-[(lR,2R,3R,5S)-3,5-diydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl-5(Z)-heptenoic acid, methyl ester
Pyridinium p-toluenesulfonate (202 mg) was added to a stirred solution of the compound from step I (27 gm, 0.05 mol) in ethanol (405 ml) at room temperature. The mixture was stirred at 45-50°C for 7-8 hr while monitoring the reaction by TLC. After completion, the mixture was evaporated to dryness to get the residue. The obtained residue was dissolved in MDC and washed with sodium bicarbonate solution and water. The MDC layer was dried over sodium sulfate and concentrated to get the title compound (18 gm ) (89%).
StepK:7-[(lR,2R,3R,5S)-3,5-diydroxy-2-[(lE,3S)-3-hydroxy-5-phenyl-l-pentenyl]cyclopentyl-5(Z)-heptenoic acid, N-ethyl amide (15)
A mixture of compound obtained in step J (18 gm) and 70% aqueous ethylamine (378 ml) were stirred at room temperature (TLC monitoring). After completion, the reaction mixture was concentrated and acidified with 5% citric acid followed by extraction with ethyl acetate (180 ml). The separated organic layer was washed with brine, dried over

sodium sulfate and concentrated under reduced pressure to give crude product (18 gm). The crude product was purified by column chromatography and crystallized from ether to give 9 gm of pure Bimatoprost as a white solid (yield=49%, HPLC Purity 99.97 %). The X-ray powder diffraction has characteristic peaks expressed in degrees 28 at approximately 6.9, 10.4, 13.9, 17.4, 18.3, 19.0, 19.5, 19.7, 20.8, 21.1, 22.4, 24.6, 27.9 and 28.5 (Fig. 3).
Example 2: Process for preparation of Latanoprost (14)
Step A: (lS,5R,6R,7R)-7-hydroxy-6-[3(R)-(3-hydroxy-5-phenyl)pentyl]-2-oxabicyclo
[3.3.0]octan-3-one
A mixture of (lS,5R,6R,7R)-7-hydroxy-6-[3(S)-3-hydroxy-5-phenyl-l(E)-pentenyl]-2-oxabicyclo [3.3.0]octan-3-one (46 gm, 0.15 mol) and 5% Pd/C in ethanol (460ml) was hydrogenated at 70 psi for 2 fir. After TLC showed completion of reaction, the mixture was filtered through celite and concentrated to yield 46 gm (100 %) pale yellow oil of the product.
Step B: (lS,5R,6R,7R)-6-[3(R)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl}-7-(tetrahydro-2H-pyran-2-yloxy)-2-oxabicyclo [3.3.0]octan-3-one
(lS,5R,6R,7R)-7-hydroxy-6-[3(R)-(3-hydroxy-5-phenyl)pentyl]-2-oxabicyclo [3.3.0]octan-3-one (46 gm, 0.15 mol) formed in step A and 3,4-dihydro-2H-pyran (47.2 gm, 0.6 mol) were dissolved in MDC (460 ml) and p-toluenesulfonic acid monohydrate (460 mg) was added at 0°C. After completion of the reaction, solution was poured into saturated sodium bicarbonate solution. The aqueous layer was extracted with MDC (230 ml). The combined organic layers were dried over sodium sulfate and concentrated to get the titled product. It was further purified by column chromatography to yield pure titled compound (58 gm, 81%).
Step C: (lS,5R,6R,7R)-6-[3(R)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl}-7-(tetrahydro-2H-pyran-2-yloxy)-2-oxabicyclo [3.3.0]octan-3-ol
The compound obtained in step B (58 gm, 0.12 mol) was dissolved in dry THF and cooled to -60°C. Diisobutylaluminium hydride (25% solution in toluene, 0.25 mol) was added to the reaction mixture while maintaining the temperature below -60°C. The reaction mixture

was then stirred at this temperature until TLC showed completion of reaction. Methanol (58 ml) was then added and stirred for 30 min. The temperature of the reaction mixture was then raised to -10°C. 580 ml of water and 870ml of ethyl acetate were added and the reaction mixture was stirred for further 30 min. The gelatinous white precipitate was filtered through celite and washed with ethyl acetate. The separated organic layer was dried over sodium sulfate and concentrated to yield pale yellow oily compound (58 gm, 100%).
Step D: 7-[(lR,2R,3R,5S)-5-Hydroxy-2-{3(R)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pentyl}-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl-5(Z)-heptenoicacid
(4-Carboxybutyl)-triphenylphosphonium bromide (196.4 gm, 0.44 mol) was suspended in dry THF (870 mol) followed by addition of potassium tert-butoxide (98.7 gm, 0.88 mol). The mixture was heated to reflux for 1 hr and resulting orange colour suspension was allowed to cool to ambient temperature. A solution of the compound obtained in step E (58 gm, 0.12 mol) in THF (290 ml) was then added to the reaction mixture at ambient temperature. After TLC showed completion of reaction concentrated the reaction mixture to get residue. The obtained residue was partitioned between ethyl acetate and water. The aqueous layer was separated and adjusted pH of the aqueous layer with 5% citric acid between 5 to 6 followed by extraction of aqueous layer with ethyl acetate (2 x 580 ml). The organic layer was concentrated to get the crude acid which was used in the next step without further purification.
Step E: 7-[(lR,2R,3R,5S)-5-Hydroxy-2-{3(R)-{5-phenyl-3-(tetrahydro-2H-pyran-2-
yloxy)pentyl}-3-(tetrahydro-2H-pyran-2-yIoxy)cyclopentyl-5(Z)-heptenoic acid,
isopropyl ester
l,8-diazabicyclo[5.4.0]undec-7-ene (133.2 gm, 0.88 mol) was added dropwise to a stirred suspension of compound obtained in step E (81 gm) in acetone (1.2 lit) at 0-5°C. The resulting solution was stirred at this temperature for 1 hr and then raised to ambient temperature. Isopropyl iodide (99 gm, 0.58 mol) was added dropwise to it. The resulting mixture was stirred overnight at room temperature. After TLC showed completion of reaction, the reaction mixture was concentrated to get the residue. The resulting residue was partitioned between ethyl acetate and water. The mixture was acidified with 5% citric

acid. The organic layer was separated and aqueous layer was extracted with ethyl acetate (800 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to get the crude ester which was purified by column chromatography using MDC : ethyl acetate to yield 29 gm (39 %) pure product.
Step F: 7-[(lR,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-(3-hydroxy-5-phenyl) pentyl]cyclo pentyl -5(Z)-heptenoic acid, isopropyl ester
Pyridinium p-toluenesulfonate (202 mg) was added to a stirred solution of the compound from step E (29 gm, 0.05 mol) in ethanol (405 ml) at room temperature. The mixture was stirred at 45-50°C for 7-8 hr while monitoring the reaction by TLC. After completion, the mixture was evaporated to dryness The residue was dissolved in MDC and washed with sodium bicarbonate solution and water. The MDC layer was dried over sodium sulfate and concentrated to give 19 gm of the titled compound. The crude product was purified by column chromatography to give 10.2 gm of pure Latanoprost (yield : 48%, HPLC purity: 99.9%).
Example 3: Process for preparation of Travoprost (14) Step A: Ethyl [3-(trifluoromethyl)phenoxy]acetate
A mixture of 3-trifluoromethyl phenol (400 gm, 2.47 mol), ethyl-2-chloroacetate (438 gm, 3.58 mol) and anhydrous potassium carbonate (681gm, 4.94 mol) were refluxed for 16 hr (TLC monitoring). After completion of reaction, the reaction mixture was filtered and concentrated to get oil. The obtained oil was dissolved in ethyl acetate (4 lit). The obtained solution was washed with water, dried over sodium sulfate and concentrated to get pale yellow oily compound (620 gm). It was used without further purification in the next step. Ethyl 2-bromoacetate can be used in place of ethyl-2-chloroacetate.
Step B: Dimethyl{2-oxo-3-[3-(trifluoromethyl)phenoxy)propyl}phosphonate
Dimethyl methyl phosphonate (508 gm, 4.1 mol) was dissolved in THF (6.2 lit) and the resulting solution was cooled to -60°C. n-Butyl lithium (2.48 lit, 1.6M hexane solution) was added over a period of 1 hr while maintaining the temperature below -60°C. The mixture was stirred for 1.5 hr at the same temperature. A solution of compound obtained in step A (620 gm, 2.5 mol) in THF (3.1 lit) was added over a period of lhr while

maintaining temperature below -60°C. The reaction was maintained at the same temperature for 4h and then at RT for 6 hr. The reaction mixture was acidified to pH 4 using 5% potassium hydrogen sulfate solution. The separated aqueous layer was extracted with ethyl acetate (3.1 lit). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated. The product was purified by column chromatography (MDC : ethanol) to give 372 gm of colourless oil (46 % yield ).
Step C: (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-[3-oxo-4-{3-(trinuoromethyl) phenoxy}-(E)-l-butenyl]-2-oxabicyclo [3.3.0]octan-3-one
A solution of dimethyl{2-oxo-3-[3-(trifluoromethyl)phenoxy]propyl}phosphonate (236 gm, 0.72 mol) in MDC (1.5 lit) was added dropwise at 0°C to a suspension of sodium hydride (26.4 gm 60% dispersion in mineral oil, 0.66 mol) in MDC (1.5 lit). The mixture was stirred at 0°C for 1 hr and the solution of Corey lactone aldehyde (Example 1, Step B) was added dropwise maintaining the temperature between -5 to 0°C. The reaction mixture was stirred while monitoring reaction by TLC. After complete disappearance of aldehyde, 1.5 lit of water was added to the reaction mixture, stirred for 10 min and filtered through celite. The separated aqueous layer was extracted with MDC (900 ml).The MDC layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to get oily residue. The obtained residue was stirred with MTBE (900 ml) for 6 hr to crystallize out the material. The obtained solid was filtered to yield 90 gm of pure title compound (38%).
X-ray powder diffraction has characteristic peaks expressed in degrees 28 at approximately S.6, 14.5, 15.6, 16.2, 17.4, 18.3, 18.7, 19.6, 19.9, 20.9, 22.4, 22.9, 23.8, 24.0, 24.3, 25.1, 26.5, 27.0, 29.3 and 30.6 (Fig. 4).
StepD: (lS,5R,6R,7R)-7-(4-phenylbenzoyloxy)-6-[3(R)-3-hydroxy-4-{3-(trifluoromethyl)phenoxy}-(E)-l-butenyl]-2-oxabicyclo [3.3.0]octan-3-one
To the solution of compound obtained in step C (90 gm, 0.16 mol) in dry THF (1.8 lit) was added a solution of (-)- DIP chloride (380 ml 60% solution in hexane, 0.64 mol). The mixture was stirred at this temperature and after completion of reaction 90 ml methanol added was added to it and the reaction mixture was stirred for 16 hr. The reaction mixture was concentrated to get the residue and to the obtained residue, ethyl acetate (900 ml) and

water (900ml) were added followed by stirring for lh. 1 kg alumina was added to the separated ethyl acetate layer and the mixture was concentrated to obtain the product. The product adsorbed on alumina was stirred with hexane (10 lit) for 3 hr and filtered. The product was desorbed by stirring alumina with ethyl acetate (2X10 lit). The ethyl acetate layer was concentrated to get thick oily crude product. It was further purified by column chromatography to get desired product (45 gm, 50%) containing less than 0.5% of unwanted isomer.
X-ray powder diffraction has characteristic peaks expressed in degrees 20 at approximately 12.4, 12.9, 16.0, 16.4, 16.7, 17.0, 18.1, 18.4, 18.6, 20.5, 21.5, 22.6, 23.1, 24.1, 24.6, 24.7, 25.0 and 26.1 (Fig. 5)
Step E: (lS,5R,6R,7R)-7-hydroxy-6-[3(R)-3-hydroxy-4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyl]-2-oxabicyclo [3.3.0]octan-3-one
To the product from step D (45 gm, 0.08 mol) in dry methanol (675 ml) was added anhydrous potassium carbonate (7.3 gm, 0.05 mol). The mixture was stirred at ambient temperature until TLC shows completion of reaction. 1M hydrochloric acid was added to the mixture to adjust the pH of the reaction mixture to 6.8-7 and the mixture was evaporated to dryness. The obtained residue was dissolved in ethyl acetate (450 ml) and washed with water. The ethyl acetate layer was concentrated to obtain crude product. The crude product was further purified by column chromatography to yield 25 gm (83%) of pure product.
X-ray powder diffraction has characteristic peaks expressed in degrees 26 at approximately 11.9, 14.9, 17.9, 18.9, 20.1, 20.7, 21.2, 21.6, 22.9, 24.0, 25.3, 25.5 and 30.1 (Fig. 6).
StepF:(lS,5R,6R,7R)-6-[3(R)-{3-(tetrahydro-2H-pyran-2-yloxy)-4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyl}-7-(tetrahydro-2H-pyran-2-yloxy)]-2-oxabicyclo [3.3.0]octan-3-one
(lS,5R,6R,7R)-7-hydroxy-6-[3(R)-3-hydroxy-4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyl]-2-oxabicyclo[3.3.0]octan-3-one (25 gm, 0.07 mol) and 3,4-dihydro-2H-pyran were dissolved in MDC (375 ml) and p-toluenesulfonic acid monohydrate (250 mg) was added at 0°C. After completion of the reaction, the solution was poured into saturated

sodium bicarbonate solution. The aqueous layer was extracted with MDC (125 ml). The combined organic layers were dried over sodium sulfate and concentrated to get the product. It was further purified by column chromatography (MDC:ethyl acetate) to yield 31 gm (86%) of the title compound.
StepG:(lS,5R,6R,7R)-6-[3(R)-{3-(tetrahydro-2H-pyran-2-yloxy)-4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyl}-7-(tetrahydro-2H-pyran-2-yIoxy)]-2-oxabicyclo [3.3.0]octan-3-ol
The compound obtained in step F was dissolved in dry THF and cooled to -60°C. Diisobutylaluminium hydride (25% solution in toluene, 77 ml) was added to the reaction mixture while maintaining the temperature below -60°C. The reaction mixture was then stirred at this temperature until TLC showed completion of reaction. Methanol (31 ml) was then added to the mixture and stirred for 30 min. The temperature of the reaction mixture was then raised to -10°C followed by addition of water (310 ml) and ethyl acetate (465 ml) and the reaction mixture was stirred for 30 min. The gelatinous white precipitate was filtered through celite and washed with ethyl acetate. The separated organic layer after drying over sodium sulfate was concentrated to yield 31 gm of pale yellow coloured oily compound (100%).
StepH:7-[(lR,2R,3R,5S)-5-Hydroxy-2-{3(R)-{3-(tetrahydro-2H-pyran-2-yloxy)-4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyI}-3-(tetrahydro-2H-pyran-2-yloxy) cyclopentyl-5(Z)-heptenoic acid
(4-Carboxybutyl)-triphenylphosphonium bromide (91 gm, 0.21 mol) was suspended in dry THF (465 ml) followed by addition of potassium tert-butoxide (45.9 gm). The mixture was heated to reflux for 1 hr and resulting orange coloured suspension was allowed to cool to ambient temperature. A solution of compound obtained in step G (31 gm, 0.06 mol) in THF (155 ml) was then added to the reaction mixture at ambient temperature. After TLC showed completion of reaction the reaction mixture was concentrated and the residue obtained was partitioned between ethyl acetate and water. The aqueous layer was separated and pH of the aqueous layer was adjusted between 5 to 6 using 5% citric acid followed by extraction of aqueous layer with ethyl acetate ( 2 X 310 ml). The organic layer was concentrated to get the crude titled compound which was used in the next step

without further purification.
Step I: 7-[(lR,2R,3R,5S)-5-Hydroxy-2-{3(R)-{5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)-(lE)-pentenyI}-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyI-5(Z)-heptenoic acid, isopropyl ester
l,8-Diazabicyclo[5.4.0]undec-7-ene (135.5 gm, 0.89 mol) was added dropwise to a stirred suspension of compound obtained in step H (93 gm) in acetone (1395 ml) at 0-5°C. The resulting solution was stirred at this temperature for 1 hr and then raised to ambient temperature. Isopropyl iodide (101 gm) was added dropwise to it. The resulting mixture was stirred overnight at room temperature. After TLC shows completion of reaction, the reaction mixture was concentrated to get the residue. The resulting residue was partitioned between ethyl acetate and water. The mixture was acidified with 5% citric acid and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (930 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude ester was purified by column chromatography using MDC : ethyl acetate to yield 23 gm pure ester (61%).
Step J: 7-[(lR,2R,3R,5S)-3,5-diydroxy-2-[(lE,3R)-3-hydroxy-4-{3-(trifluoromethyl)phenoxy-(E)-l-butenyl]cyclopentyl-5(Z)-heptenoic acid, isopropyl ester
Pyridinium p-toluene sulfonate (147 mg) was added to a stirred solution of the compound from step I, in ethanol (345 ml) at room temperature. The mixture was stirred at 45-50°C for 7-8 hr while monitoring the reaction by TLC. After completion, the mixture was evaporated to dryness to get the residue. The obtained residue was dissolved in MDC and the obtained solution was washed sodium bicarbonate solution and water. The MDC layer was dried with sodium sulfate and concentrated to give 17 gm of the title compound. The crude product was purified by column chromatography to give 8 gm of pure Travoprost (yield: 46%, HPLC purity : 99.5%).

We claim,
1. A process for preparation of compound 13, a key intermediate in the preparation of prostaglandins comprising the steps of,

where R1 = alkyl, preferably methyl or isopropyl; R = -CH2C6H5 or -OC6H4CF3-m and — is double bond or single bond.
a) oxidizing Corey lactone alcohol (4) in presence of oxidizing agent to yield Corey lactone aldehyde (5);
b) reacting said Corey lactone aldehyde (5) with a p-ketophosphonate compound to yield enone(6);

where R = -OC6H4CF3-m or -CH2C6H5 c) reducing enone (6) with a chiral reducing agent to get allylic alcohol (7) along with unwanted isomer;

d) separating unwanted isomer by chromatography to get pure allylic alcohol (7);
e) deprotecting said pure allylic alcohol (7) to get lactone diol (8);

f) optionally reducing said lactone diol (8) in presence of catalyst to get

lactone diol (9);

g) treating said lactone diol (8) or (9) with a protecting agent to get protected lactone diol (10);


where R is as defined above

i) reacting said lactol (11) with ylide compound to get compound (12);

h) reducing said protected lactone diol (10) with diisobutylaluminium hydride to get lactol(ll);

j) treating said compound (12) with alkylating agent in presence of suitable base to get compound (13).
2. The process as claimed in claim 1 wherein said β-ketophosphonate compound is selected from dimethyl-2-oxo-4-phenylbutyl phosphonate or dimethyl {2-oxo-3-[3 -(trifluoromethy l)phenoxy] propyl} phosphonate.
3. The process as claimed in claim 1 wherein said compound (13) is further converted to Bimatoprost or Latanoprost or Travoprost.

4. The process as claimed in claim 1 wherein said Corey lactone aldehyde formed in step a) is not isolated.
5. The process as claimed in claim 1 wherein said pure allylic alcohol (7) obtained in step d) contains less than about 0.5% of unwanted isomer.
6. The process as claimed in claim 1 wherein said chiral reducing agent in step c) is (-)-DIP chloride and is used in 3-5 fold excess with respect to enone (6).
7. The process as claimed in claim 1 wherein said ylide compound is (4-carboxy-butyl)-triphenylphosphonium halide.
8. The process as claimed in claim 1 wherein said alkylating agent is alkyl halide.
9. Bimatoprost, Latanoprost or Travoprost and process for preparation thereof substantially as herein described with reference to the foregoing examples.