A process for purification of intermediates of prostaglandin f2Αα compounds and its use in the preparation of prostaglandin f2α compounds

Abstract

The present invention relates to a process for purification of intermediates of prostaglandin F2α compounds and its conversion to therapeutically active prostaglandin F2α compounds, for example, racemic cloprostenol. Particularly relates to a process for purification of intermediates of racemic cloprostenol by solvent crystallization and / or derivatization of hydroxyl compounds and recycling process of the unwanted isomers to make the process commercially viable. Further, the present invention relates to an improved process for preparation of prostaglandin F2α compounds and its sodium salt.

Description

[0001] A PROCESS FOR PURIFICATION OF INTERMEDIATES OF PROSTAGLANDIN F2a COMPOUNDS AND ITS USE IN THE PREPARATION OF PROSTAGLANDIN F2a COMPOUNDS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an improved process for preparation of prostaglandin F2a compounds and its sodium salt; particularly relates to an improved process for preparation of racemic (R and S) Cloprostenol sodium.

[0004] The present invention relates to a process for purification of intermediates of prostaglandin F2a compounds. Particularly relates to a process for purification of intermediates of prostaglandin F2a compounds by solvent crystallization or derivatization of hydroxyl groups to selectively purging unwanted isomers. The present invention also relates to a recycling process of the unwanted isomers to required isomers.

[0005] BACKGROUND OF THE INVENTION

[0006] Cloprostenol is a synthetic analogue of prostaglandin F2a. Cloprostenol acts as a luteolytic agent causing functional and morphological regression of the corpus luteum followed by return to oestrus and normal ovulation in cattle. It may also be used for the induction of parturition in pregnant cows, sows and mares. The usual therapeutic doses for cloprostenol are 500 pg in cattle and 175 pg in pigs, the product is administered by intramuscular route.

[0007] Cloprostenol exists as R-isomer and racemic mixture of R and S-isomer and both products approved as veterinary medicinal products. The structures of the R-cloprostenol and the racemic mixture of R and S-isomer of cloprostenol are represented as follows:

[0008]

[0009] In the syntheses of prostaglandin derivatives, typically corey lactone is converted into enone compound in two stages followed by reduction of enone compound. The enone compound exists as (±) enone or (-) enone or (+) enone based on stereochemistry of starting Corey lactone used.

[0010] When (-) Corey lactone of formula IA is used as starting material, (-) enone compound of Formula IVA is formed and then subsequent reduction gives a mixture of two isomers namely (3aR, 4R, 5R, 6aS, 3R) enol of Formula V-l and (3aR, 4R, 5R, 6aS, 3S) enol of Formula V-2. The (3aR, 4R, 5R, 6aS, 3R) enol of Formula V-l is utilized in the preparation of (R)-Cloprostenol at later stages.

[0011] The structures of the (-) Corey lactone of Formula IA, (-) enone of formula IVA, enol compounds of Formula V-l and V-2 are represented as follows:

[0012]

[0013] When (±) Corey lactone of formula I is used as starting material, (±) enone compound of Formula IV is formed and then subsequent reduction gives four isomer mixture of enol compounds of Formula V-l, V-2, V-3 and V-4.

[0014] The structures of (±) Corey lactone of Formula I, (±) enone of Formula IV, enol compounds of Formula V-l, V-2, V-3 and V-4 are represented as follows:

[0015]

[0016] Known literatures such as J. Am. Chem. Soc, 1969, 91, 5675, Chirality 27, 392-396, 2015, CZ229075, US8,901,319, US7, 166,730, W02002 / 096898 and IN2738 / CHE / 2007 discloses reduction of enone compounds and separation of desired isomeric compounds.

[0017] All the known literatures disclosed reduction of (-) enone compound either by non-specific reduction of (-) enone with a common reducing agents such as zinc borohydride or stereospecific reduction of the (-) enone with (-)DIP-Cl and when the (-) enone compound is the starting material the resultant product is a mixture of alpha hydroxy and beta hydroxy enol compounds and from which the alpha hydroxyl enol is separated by chromatographic methods or making selective derivatization at 3 -hydroxyl group with silyl group and subsequent crystallization.

[0018] Whereas when the (±) enone compound is the starting material in the reduction step the resultant enol product having a mixture of four isomers, which are Formula V-l, V-2, V-3 and V-4. Out of which Formula V-l and V-4 are desired isomers which are used in the preparation of racemic cloprostenol and the undesired enol compounds of Formula V-2 and V-3 are needs to be separated from the mixture prior to further processing steps. None of the existing literatures disclose or teaches the existence or formation of these four possible isomers and subsequent separation of desired and undesired isomers of (±) enol compound by any purification methods.

[0019] The most commonly used technique in the prior-art to separate the desired and undesired isomers of enol is by column chromatography or by solvent crystallization. However, the scope of these techniques are limited as it may be easier to use for mixture of two isomers, whereas the same technique may not be effective when separating desired isomers from a mixture of four isomers as it requires different eluent compositions and different test parameters. Further, it requires appropriate column or eluent for each isomer and it requires large volume of solvents; therefore making the process less selective and uneconomical on largescale.

[0020] Therefore there is a need in the art to develop a process that can selectively purging unwanted isomers without compromising the quality and yield of the product. The process of the present invention addresses this need and provides a simple method to purify the racemic mixture of enol compounds of Formula V-l and V-4 from a mixture of isomers of Formula V-l, V-2, V-3 and V-4 by either solvent crystallization and / or by selective derivatization techniques.

[0021] Other known literatures such as GB 1524574, CZ287456 and CN104513186B discloses preparation of sodium salt of prostaglandin f2a compounds by saltification of racemic cloprostenol with sodium base like sodium hydroxide or sodium bicarbonate. The conventional sodium base used for the sodium saltification for racemic cloprostenol is having certain process disadvantages in the product isolation. There is a need in the art to develop an improved process for the preparation of a prostaglandin F2a compounds and its sodium salt.

[0022] SUMMARY OF THE INVENTION

[0023] Accordingly, the present invention provides an improved process for preparation of isomerically pure intermediates of prostaglandin F2a compounds and its conversion to therapeutically active prostaglandin F2a compounds, for example, racemic cloprostenol. The improvements include process for purification of intermediates of prostaglandin F2a compounds by solvent crystallization and / or derivatization of hydroxyl compounds to selectively purging unwanted isomers and recycling process of the unwanted isomers to make the process commercially viable. The present invention also provides an improved process for the preparation of prostaglandin F2a compounds and its sodium salt with high product yield and quality.

[0024] In accordance with one embodiment, the present invention provides a process for purification of mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4, comprising: a) suspending or dissolving a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4 in a suitable solvent,

[0025] (3aR, 4R, 5R, 6aS, 3R) - Formula V-l (3aR, 4R, 5R, 6aS, 3S) - Formula V-2 (3aS, 4S, 5S, 6aR, 3R) - Formula V-3 (3aS, 4S, 5S, 6aR, 3S) - Formula V-4 wherein “P” represents hydroxy protecting group, b) optionally heating the reaction mass to about reflux temperature, c) optionally cooling the solution to room temperature or less, and d) isolating the mixture of enol compound of Formula V-l and Formula V-4.

[0026] In accordance with another embodiment, the present invention provides a process for purification of mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and

[0027] Formula V-4, comprising: a) suspending or dissolving a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4 in a suitable solvent, b) optionally heating the reaction mass to about reflux temperature, c) optionally cooling the solution to room temperature or less, and d) isolating the mixture of enol compound of Formula V-l and Formula V-4; wherein the suitable solvent is selected from the group consisting of alcohols, halogenated hydrocarbons, nitriles, ethers, esters, ketones, water and mixture thereof; and wherein the “P” represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP ), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0028] In accordance with another embodiment, the present invention provides a process for preparation of a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4, comprising: a) reacting (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4, wherein “P” represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP ), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS), b) suspending or dissolving the mixture of isomers of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 in a suitable solvent, c) optionally heating the reaction mass to about reflux temperature, d) optionally cooling the solution to room temperature or less, and e) isolating the mixture of enol compound of Formula V-l and Formula V-4. In accordance with another embodiment, the present invention provides a recycling process of mixture of enol compound of Formula V-2 and Formula V-3, comprising; a) reacting a mixture of enol compound of Formula V-2 and Formula V-3 with a suitable oxidizing agent to obtain (±) enone of Formula IV, and b) converting the (±) enone of Formula IV into mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4.

[0029] In accordance with another embodiment, the present invention provides a recycling process of mixture of enol compound of Formula V-2 and Formula V-3, comprising; a) reacting a mixture of enol compound of Formula V-2 and Formula V-3 with a suitable oxidizing agent to obtain (±) enone of Formula IV, b) reacting the (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4, and c) purifying the mixture of enol compound of Formula V-l, Formula V-2, Formula V- 3 and Formula V-4 with a suitable solvent to obtain enol compound of Formula V- 1 and Formula V-4.

[0030] In accordance with another embodiment, the present invention provides a process for preparation of mixture of enol compound of Formula V-l and Formula V-4, comprising: a) suspending or dissolving mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 in a suitable solvent, wherein “P” represents hydroxy protecting group, b) optionally heating the reaction mass to about reflux temperature, c) optionally cooling the solution to room temperature or less, d) isolating the mixture of enol compound of Formula V-l and Formula V-4 as solid, e) reacting mother liquors containing the mixture of enol compound of Formula V-2 and Formula V-3 with a suitable oxidizing agent to obtain (±) enone of Formula IV, f) reacting the (±) enone of Formula IV with a suitable reducing agent to obtain mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4, and g) purifying the enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable solvent to obtain mixture of enol compound of Formula V-l and Formula V-4.

[0031] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or salt thereof, comprising: preparing mixture of enol compound of Formula V-l and Formula V-4 as processes described as above, and converting the mixture of enol compound of Formula V-l and Formula V-4 into racemic cloprostenol or its salt thereof.

[0032] In accordance with another embodiment, the present invention provides a process for preparation of a mixture of diol compound of Formula VII- 1 and Formula VII-4, comprising:

[0033] (3aR, 4R, 5R, 6aS, 3R) - Formula VII- 1

[0034] (3aS, 4S, 5S, 6aR, 3S) - Formula VII-4 a) reacting a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable hydroxyl protecting agent in a suitable solvent to obtain a mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4, wherein the “P” and “Pi” represents a suitable hydroxyl protecting group; b) purifying the mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 in an organic solvent to obtain a mixture of protected enol compounds of Formula VI- 1 and VI-4; and c) converting the mixture of protected enol compounds of Formula VI-1 and VI-4 into mixture of diol compound of Formula VII-1 and Formula VII-4.

[0035] In accordance with another embodiment, the present invention provides a process for preparation of a mixture of diol compound of Formula VII-1 and Formula VII-4, comprising: a) reacting a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable hydroxyl protecting group in a suitable solvent to obtain a mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4, b) purifying the mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 in an organic solvent to obtain a mixture of protected enol compounds of Formula VI- 1 and VI-4; and c) converting the mixture of protected enol compounds of Formula VI-1 and VI-4 into mixture of diol compound of Formula VII-1 and Formula VII-4; wherein the organic solvent is selected from the group consisting of alcohols, esters, hydrocarbons, halogenated hydrocarbons, nitriles, ketones and mixture thereof; and wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p- nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t- butyldimethyl silyl (TBDMS).

[0036] In accordance with another embodiment, the present invention provides a process for preparation of a mixture of diol compound of Formula VII-1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3, comprising:

[0037] (3aR, 4R, 5R, 6aS, 3R) - Formula VII-1

[0038] (3aR, 4R, 5R, 6aS, 3S) - Formula VII-2

[0039] (3aS, 4S, 5S, 6aR, 3R) - Formula VII-3

[0040] (3aS, 4S, 5S, 6aR, 3S) - Formula VII-4 a) reacting (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4; wherein “P” represents a suitable hydroxy protecting group, b) purifying the mixture of enol compound of Formula V-l, Formula V-2, Formula V-

[0041] 3 and Formula V-4 with a suitable solvent, c) reacting a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable hydroxyl protecting group in a suitable solvent to obtain a mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4,

[0042] (3aR, 4R, 5R, 6aS, 3R) - Formula Vl-1 (3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 (3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 (3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 wherein the “P” and “Pi” represents a suitable hydroxyl protecting group; d) purifying the mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 in an organic solvent to obtain a mixture of protected enol compounds of Formula VI-1 and VI-4 having less than 0.5% by HPLC of a mixture of protected enol compound of Formula VI-2 and Formula VI- 3; and e) deprotecting the mixture of protected enol compounds of Formula VI-1 and VI-4 having less than 0.5% by HPLC of a mixture of protected enol compound of Formula VI-2 and Formula VI-3 to obtain a mixture of diol compound of Formula VII- 1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3; wherein the suitable solvent in step b) is selected from the group consisting of alcohols, halogenated hydrocarbons, nitriles, ethers, esters, ketones, water and mixture thereof; wherein the organic solvent is selected from the group consisting of alcohols, esters, hydrocarbons, halogenated hydrocarbons, nitriles, ketones and mixture thereof; and wherein the “P” and “Pi” independently represents p- phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0043] In accordance with another embodiment, the present invention provides a compound of Formula VI:

[0044] Formula VI wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0045] In accordance with another embodiment, the present invention provides a compound of Formula VI- 1 :

[0046] (3aR, 4R, 5R, 6aS, 3R) - Formula VI- 1 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS). In accordance with another embodiment, the present invention provides a compound of

[0047] Formula VI- 1 :

[0048] (3aR, 4R, 5R, 6aS, 3R) - Formula VI- 1 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0049] In accordance with another embodiment, the present invention provides a compound of

[0050] Formula VI-2:

[0051] (3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0052] In accordance with another embodiment, the present invention provides a compound of

[0053] Formula VI-2:

[0054] (3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB). In accordance with another embodiment, the present invention provides a compound of

[0055] Formula VI-3:

[0056] (3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0057] In accordance with another embodiment, the present invention provides a compound of Formula VI-3:

[0058] (3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0059] In accordance with another embodiment, the present invention provides a compound of Formula VI-4:

[0060] (3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0061] In accordance with another embodiment, the present invention provides a compound of

[0062] Formula VI-4:

[0063] (3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0064] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof, comprising: preparing mixture of diol compound of Formula VII- 1 and VII-4 as process described above, and converting the mixture of diol compound of Formula VII- 1 and VII-4 into racemic cloprostenol or its salt thereof.

[0065] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D, comprising: preparing a mixture of diol compound of Formula VII-1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3 as process described above, and converting the mixture of diol compound of Formula VII- 1 and VII-4 into racemic cloprostenol or its salt thereof. [(8R, 9R, HR, 12S, 15S) + (8S,9S,1 IS, 12R,15R)] - Impurity of Formula D

[0066] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A and / or less than 0.5% by HPLC of TPPO impurity of Formula B, comprising: a) reacting a mixture of protected diol compound of Formula VIII-1 and Formula VIII-

[0067] 4 with a suitable keto reducing agent to obtain a protected lactol compound of wherein “P2” represents ethoxy ethyl, methoxy benzyl, acetyl, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) reacting the mixture of protected lactol compound of Formula IX-1 and Formula IX- 4 with a compound of Formula X in a suitable solvent and a base, to obtain a solvent solution containing mixture of protected cloprostenol of formula XI-1 and Formula mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4, d) adjusting pH to about 7.5 to about 9.5 with an acid, e) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of formula XI- 1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A, f) deprotecting the mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A with an acid in a suitable solvent to obtain a solvent solution containing racemic cloprostenol of Formula XII -1 and Formula XII -4, g) adding water immiscible solvent to the solution of step f), h) adjusting pH to about 9 to about 13 with a base, i) separating the aqueous layer and adding water immiscible solvent, j) adjusting the pH to about 4.5 to about 6.5 with an acid, and k) separating the organic layer and evaporating the solvent to obtain a mixture of racemic cloprostenol of Formula XII -1 and Formula XII -4 having less than 0.5% by HPLC of UV active impurity of Formula A and less than 0.5% by HPLC of TPPO impurity of Formula B.

[0068] In accordance with a preferred embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A and / or less than 0.5% by HPLC of TPPO impurity of Formula B, by the procedure as defined just as above.

[0069] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of a) reacting a mixture of protected lactol compound of Formula IX- 1 and Formula IX-

[0070] 4 with a compound of Formula X in a suitable solvent and a base, to obtain a solvent solution containing mixture of protected cloprostenol of formula XI-1 and Formula

[0071] tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) evaporating the solvent and adding water and water immiscible solvent to the mixture of protected cloprostenol of formula XI- 1 and Formula XI-4, c) adjusting pH to about 7.5 to about 9.5 with an acid, d) separating the organic layer and evaporating the solvent to obtain mixture of protected cloprostenol of formula XI- 1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A, and e) converting the protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A into racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A.

[0072] In accordance with a preferred embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A, by the procedure as defined just as above.

[0073] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of TPPO impurity of Formula B, comprising:

[0074] a) reacting a mixture of protected lactol compound of Formula IX- 1 and Formula IX- 4 with a compound of Formula X in a suitable solvent and a base, to obtain a mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) deprotecting the mixture of protected cloprostenol of formula XI-1 and Formula XI- 4 with an acid in a suitable solvent to obtain a solvent solution containing racemic cloprostenol of Formula XII -1 and Formula XII -4,

[0075] (8R,9R,11R,12S,15R) - Formula XII-1

[0076] (8 S, 9 S, 11 S, 12R, 15 S) - Formula XII- 4 c) adding water immiscible solvent to the solution of step b), d) adjusting pH to about 9 to about 13 with a base, e) separating the aqueous layer and adding water immiscible solvent, f) adjusting the pH to about 4.5 to about 6.5 with an acid, and g) separating the organic layer and evaporating the solvent to obtain mixture of cloprostenol of Formula XII-1 and Formula XII-4 having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0077] In accordance with a preferred embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of TPPO impurity of Formula B, by the procedure as defined just as above.

[0078] In accordance with another embodiment, the present invention provides a process for separation of UV active impurity of Formula A from the solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI-1 and Formula XI-4 and UV the process comprises: a) providing a solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI-1 and Formula XI-4 and UV active impurity of Formula A, b) adjusting pH of the step a) solution to about 7.5 to about 9.5 with an acid, and c) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A.

[0079] In accordance with another embodiment, the present invention provides a process for separation of TPPO impurity of Formula B from the solution comprising water, water immiscible solvent and racemic cloprostenol of Formula XII -1 and Formula XII - 4 and a) providing a solution comprising water, water immiscible solvent and racemic cloprostenol of Formula XII -1 and Formula XII - 4 and TPPO impurity of Formula B, b) adjusting pH of the step a) solution to about 9 to about 13 with a base, c) separating the aqueous layer and adding water immiscible solvent, d) adjusting the pH to about 4.5 to about 6.5 with an acid, and e) separating the organic layer and evaporating the solvent to obtain mixture of cloprostenol of Formula XII -1 and Formula XII -4 having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0080] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B and / or less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D, comprising: a) reacting (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4; wherein “P” represents a suitable hydroxy protecting group, b) purifying the mixture of enol compound of Formula V-l, Formula V-2, Formula V-

[0081] 3 and Formula V-4 with a suitable solvent, c) reacting the mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable hydroxyl protecting group in a suitable solvent to obtain a mixture of protected enol compound of Formula VI-1, Formula VI-2,

[0082] Formula VI-3 and Formula VI-4, (3aR, 4R, 5R, 6aS, 3R) - Formula Vl-1 (3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 (3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 (3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 d) purifying the mixture of protected enol compound of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 with an organic solvent to obtain a mixture of protected enol compound of Formula VI- 1 and Formula VI-4 having less than 0.5% by HPLC of a mixture of protected enol compound of Formula VL2 and Formula VI-3, deprotecting the mixture of protected enol compounds of Formula VI- 1 and Formula

[0083] VI-4 having less than 0.5% by HPLC of a mixture of protected enol compound of Formula VI-2 and Formula VI-3 to obtain a mixture of diol compound of Formula

[0084] VII- 1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3, II- 1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3 with a suitable hydroxyl protecting group to obtain a protected diol compound of Formula VIII- 1 and Formula VIII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VIII-2 and Formula VIII-3, (3aR, 4R, 5R, 6aS, 3R) - Formula VIII- 1

[0085] (3aR, 4R, 5R, 6aS, 3S) - Formula VIII-2 (3aS, 4S, 5S, 6aR, 3R) - Formula VIII-3 (3aS, 4S, 5S, 6aR, 3S) - Formula VIII-4 wherein “P2” represents ethoxy ethyl, methoxy benzyl, acetyl, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; g) reacting the mixture of protected diol compound of Formula VIII-1 and Formula VIII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VIII-2 and Formula VIII-3 with a suitable keto reducing agent to obtain a protected lactol compound of Formula IX-1 and Formula IX-4 having less than 0.5% by HPLC of a mixture of enol compound of Formula IX-2 and Formula IX-3,

[0086] (3aR, 4R, 5R, 6aS, 3R) - Formula IX-1

[0087] (3aR, 4R, 5R, 6aS, 3S) - Formula IX-2 (3aS, 4S, 5S, 6aR, 3R) - Formula IX-3 (3aS, 4S, 5S, 6aR, 3S) - Formula IX-4 h) reacting the mixture of protected lactol compound of Formula IX-1 and Formula IX- 4 having less than 0.5% by HPLC of a mixture of enol compound of Formula IX-2 and Formula IX-3 with a compound of Formula X in a suitable solvent and a base, to obtain a solvent solution containing mixture of protected cloprostenol of Formula XL1 and Formula XL4 having less than 0.5% by HPLC of protected cloprostenol i) evaporating the solvent and adding water and water immiscible solvent to the mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of protected cloprostenol of Formula XI-2 and Formula XI-3, j) adjusting pH to about 7.5 to about 9.5 with an acid, k) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of formula XI- 1 and Formula XI-4 having less than 0.5% by HPLC of protected cloprostenol of formula XI-2 and Formula XI-3 and less than 0.5% by HPLC of UV active impurity of Formula A, l) deprotecting the protected cloprostenol of formula XL1 and Formula XL4 having less than 0.5% by HPLC of a mixture of protected cloprostenol of Formula XL2 and Formula XL3 and less than 0.5% by HPLC of UV active impurity of Formula A with an acid in a suitable solvent to obtain solvent solution containing racemic cloprostenol of Formula XII-1 and Formula XIL4 having less than 0.5% by racemic cloprostenol of Formula XIL2 and Formula XIL3 and less than 0.5% by HPLC of UV active impurity of Formula A,

[0088] (8R,9R,11R,12S,15R) - Formula XII -1 (8R,9R, 11R, 12S, 15 S) - Formula XII-2 (8 S, 9 S, 11 S, 12R, 15R) - Formula XIL3 (8 S, 9 S, 11 S, 12R, 15 S) - Formula XII -4 m) adding water immiscible solvent to the solution of step 1), n) adjusting pH to about 9 to about 13 with a base, o) separating the aqueous layer and adding water immiscible solvent, p) adjusting the pH to about 4.5 to about 6.5 with an acid, and q) separating the organic layer and evaporating the solvent to obtain mixture of racemic cloprostenol of Formula XII -1 and Formula XII -4 having less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D and less than 0.5% by HPLC of UV active impurity of Formula A and less than 0.5% by HPLC of TPPO impurity of Formula B.

[0089] In accordance with a preferred embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B and / or less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D, by the process described just as above.

[0090] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol sodium, comprising: i) dissolving or suspending racemic cloprostenol of Formula XII in an organic solvent, ii) treating the step i) reaction mixture with a suitable sodium source; iii) optionally adding an anti-solvent to the step ii) reaction mixture or vice-versa, and iv) isolating the racemic cloprostenol sodium salt; wherein the sodium source is selected from the group comprising sodium methoxide, sodium ethoxide or sodium 2-ethyl hexanoate.

[0091] In accordance with another embodiment, the present invention provides a process for preparation of racemic cloprostenol sodium, comprising: i) dissolving or suspending racemic cloprostenol of Formula XII in an organic solvent, ii) treating the step i) reaction mixture with a suitable sodium source, iii) optionally adding an anti-solvent to the step ii) reaction mixture or vice-versa, and iv) isolating the racemic cloprostenol sodium; wherein the organic solvent is selected from the group comprising ketones, ethers and mixtures thereof; wherein the antisolvent is selected from the group comprising ethers, aliphatic hydrocarbons, alicyclic hydrocarbons or mixtures thereof and wherein the suitable sodium source is selected from the group comprising sodium methoxide, sodium ethoxide and sodium 2-ethyl hexanoate. In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of UV active impurity of Formula A.

[0092] UV active impurity of Formula A

[0093] In accordance with preferred embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of UV active impurity of Formula A.

[0094] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0095] TPPO impurity of Formula B

[0096] In accordance with preferred embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of TPPO impurity of Formula B.

[0097] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C.

[0098] 5,6-Trans-[(8R,9R,l 1R,12S,15R) + (8S,9S,11S,12R,15S)] - Impurity of formula C

[0099] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C.

[0100] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0101] [(8R,9R,11R,12S,15S) + (8S,9S,11S,12R,15R)] - Impurity of Formula D

[0102] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0103] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.5% by HPLC of racemic 15- Epi Cloprostenol impurity of Formula D.

[0104] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.2% by HPLC of racemic 15- Epi Cloprostenol impurity of Formula D.

[0105] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of UV active impurity of Formula A.

[0106] In accordance with preferred embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of UV active impurity of Formula A.

[0107] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0108] In accordance with preferred embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of TPPO impurity of Formula B.

[0109] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C.

[0110] In accordance with preferred embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C.

[0111] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0112] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0113] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6- trans racemic cloprestenol impurity of formula C, and / or less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D. In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, less than 0.2% by HPLC of 5,6- trans racemic cloprestenol impurity of formula C, and / or less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0114] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having a total purity of greater than 99% by HPLC.

[0115] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of Impurity at RRT at 0.83.

[0116] In accordance with another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of Impurity at RRT at 2.23.

[0117] In accordance with another embodiment, the present invention provides a pharmaceutical or a veterinary composition comprising racemic cloprostenol or its sodium salt thereof prepared by the processes of the present invention and at least one suitable excipient.

[0118] DETAILED DESCRIPTION OF THE INVENTION

[0119] The present invention provides a process for purification of intermediates of prostaglandin F2a compounds and its conversion to therapeutically active prostaglandin F2a compounds, for example, racemic cloprostenol. Particularly the present invention relates to a process for purification of intermediates of prostaglandin F2a compounds by solvent crystallization and / or derivatization of hydroxyl compounds to selectively purging unwanted isomers and recycling process of the unwanted isomers to make the process commercially viable. The present invention also provides an improved process for the preparation of prostaglandin F2a compounds and its sodium salt with high product yield and quality.

[0120] Reduction of (±) enone compound of Formula IV forms mixture of isomers such as four enol compounds of Formula V-l, V-2, V-3 and V-4, which are as follows:

[0121]

[0122] Out of these four isomers, compounds of Formula V-l and V-4 are considered as desired isomers which are used in the preparation of racemic cloprostenol of Formula XII. Therefore it is necessary to separate out undesired racemic mixture of enol compounds of Formula V-2 and V-3 from the mixture of enol compounds of Formula V-l, V-2, V-3 and

[0123] V-4 otherwise these undesired isomers involve in subsequent reactions and carry forward to final stage and contaminate with the final racemic cloprostenol. Hence, the purification of these isomers to selectively purify to isolate Formula V-l and V-4 is the critical parameter in the preparation of racemic cloprostenol as it maintains the same purity level until the final API. If these impurities fails to control properly at the intermediate stage, subsequent purification steps to remove these impurities at final stage is very difficult.

[0124] Hence, the present invention encompasses a process for purification of isomers of enol compound of Formula V-l, V-2, V-3 and V-4, wherein the purification process involves separation of isomers of enol compounds of Formula V-l and V-4 from the mixture of isomers of Formula V-l, V-2, V-3 and V-4 by simple crystallization method from a suitable solvent. In accordance with one embodiment, the present invention provides a process for purification of mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4, comprising: wherein “P” represents hydroxy protecting group,

[0125] (3aR, 4R, 5R, 6aS, 3R) - Formula V-l (3aR, 4R, 5R, 6aS, 3S) - Formula V-2 (3aS, 4S, 5S, 6aR, 3R) - Formula V-3 (3aS, 4S, 5S, 6aR, 3S) - Formula V-4 a) suspending or dissolving a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4 in a suitable solvent, b) optionally heating the reaction mass to about reflux temperature, c) optionally cooling the solution to room temperature or less, and d) isolating the mixture of enol compound of Formula V-l and Formula V-4.

[0126] Unless otherwise specified the term “hydroxyl protecting group” used herein is selected from but not limited to p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), Trimethyl silyl (TMS), Triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS) and the like.

[0127] The mixture of isomers of Formula V-l, V-2, V-3 and V-4 which are used herein as a starting material is prepared by reduction of (±) enone compound of Formula IV as described below or the mixture of isomers of Formula V-l, V-2, V-3 and V-4 are obtained by any processes known in the art. The (±) enone compound of Formula IV may be prepared as per the process disclosed in IN2738 / CHE / 2007.

[0128] The mixture of isomers of Formula V-l, V-2, V-3 and V-4 in the enol mixture, each isomer comprises any ratio as long as the purification process of the present invention separates out the unwanted isomers from the starting mixture; preferably each isomer in the mixture of isomers of Formula V-l, V-2, V-3 and V-4 is about 15 to about 35% by HPLC; more preferably about 20 to about 30%. The reduction of (±) enone compound of Formula IV is carried out with a suitable reducing agent in a suitable solvent to obtain an enol compound as a mixture of isomers of Formula V-l, V-2, V-3 and V-4. The structure of (±) enone compound of Formula IV is represented as follows:

[0129] The (3aR,4R,5R,6aS) and (3aS,4S,5S,6aR) isomers are represented as follows:

[0130] (3aR, 4R, 5R, 6aS) (3aS,4Ss 5Ss 6aR)

[0131] In a preferred embodiment, the starting (±) enone compound of Formula IV used in the present invention is a compound of Formula IVa (wherein the “P” is para phenyl benzoyl

[0132] (±) enone of Formula IVa Typically, the reduction reaction may be carried out in presence of a suitable reducing agent and in a suitable solvent at a temperature of about -50°C to 0°C; preferably the reaction temperature is about -45°C to about -35°C.

[0133] The reducing agent used herein is selected from hydride reducing agents such as lithium aluminum hydride, lithium trialkoxyaluminum hydride and the like; alkali metal borohydride such as sodium borohydride, potassium borohydride, lithium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, zinc borohydride, copper borohydride, DIBALH and the like and mixtures thereof; preferably sodium borohydride.

[0134] The reduction reaction may alternatively carried out by using a combination of reducing agent and lanthanide salt. The lanthanide salts such as cerium (III) chloride or samarium (III) iodide; preferably a combination of cerium (III) chloride / sodium borohydride used.

[0135] In another embodiment, the combination of cerium (III) chloride / sodium borohydride used in the reduction of (±) enone compound of Formula IV selectively reducing the keto group at side chain and avoids the reduction of unsaturated double bond at side chain.

[0136] The suitable solvent used herein for reduction includes, but is not limited to alcohols, halogenated hydrocarbons, ethers, aromatic hydrocarbons and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, propanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to dichloromethane, dichloroethane, chloroform and the like; aromatic hydrocarbons include, but are not limited to toluene, xylene and the like; ethers include, but are not limited to tetrahydrofuran, methyl tert, butyl ether and the like, and mixtures thereof; preferably the solvent is a mixture of di chloromethane and methanol.

[0137] After completion of the reaction, the resultant isomer mixture of enol compound of Formula V-l, V-2, V-3 and V-4 may be isolated by known techniques such as solvent extractions, solvent distillation and precipitation by adding an another solvent. For example, the resultant product may be isolated by first if required adjust the reaction pH to acidic, preferably less than 5 with a suitable acid and / or water, wherein the suitable acid is selected from the group consisting acetic acid, citric acid, oxalic acid, hydrochloric acid, sulfuric acid and the like; preferably with dilute hydrochloric acid. The resultant reaction solution may be extracted with a suitable water immiscible solvent to separate the aqueous and organic layers. Suitable water immiscible solvent include but are not limited to dichloromethane, toluene, xylene, ethyl acetate and the like and mixtures thereof; preferably dichloromethane. Then the product containing dichloromethane layer may be concentrated to obtain a mixture of enol compound of Formula V-l, V-2, V-3 and V-4.

[0138] The starting enol compounds of Formula V-l, V-2, V-3 and V-4 obtained by the process as described above, contains each isomer is about 15 to about 35%; more preferably about 20 to about 30% by chiral HPLC.

[0139] In a preferred embodiment, the enol compound of Formula V represented specifically as follows:

[0140] Formula V-3 a Formula V-4a

[0141] The step a) of the aforementioned process involves suspension or dissolution of a mixture of isomers of Formula V-l, V-2, V-3 and V-4 in a suitable solvent.

[0142] The reported literature involves the reduction of (-) enone results in formation of mixture of two isomers namely desired alpha hydroxy enol compound and undesired beta hydroxy enol compound and the processes described under known literatures involve separation of desired alpha hydroxy isomer compound by chromatographic methods or making selective derivatization at 3 -hydroxyl group with silyl group and subsequent crystallization. None of the prior-art methods that discloses or teaches the existence or formation of mixture of four isomers and its separation of pair of desired isomers from (±) enol compound by any purification methods as like (-) enol compound. The present invention provides a simple method to separate out the desired racemic mixture of enol compounds of Formula V-l and V-4 from the mixture of isomers of Formula V-l, V-2, V-3 and V-4 by simple solvent crystallization. The purification process of the present invention is more economic and easy to scale up to commercial level.

[0143] The suitable solvent used herein for purifying mixture of enol compound of Formula V-l, V-2, V-3 and V-4 is selected from the group comprising alcohols, halogenated hydrocarbons, nitriles, ethers, esters, ketones, water and mixture thereof. The alcohols include, but are not limited to methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol and the like; halogenated hydrocarbons include, but are not limited to dichloromethane, dichloroethane, chloroform and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like; ethers include, but not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-di oxane and the like; esters include, but are not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like; ketones include, but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; and mixtures thereof; preferably the suitable solvent is selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, di chloromethane, methyl tert butyl ether and mixtures thereof; more preferably methanol.

[0144] Typically, the mixture of isomers of Formula V-l, V-2, V-3 and V-4 are dissolved in a suitable solvent at a temperature of about ambient temperature to about reflux; preferably at about 45°C to about reflux.

[0145] In another embodiment, the solvent may be utilized for the purification is about any ratio as long as the purification of the present invention that effectively separate out the unwanted isomers from the starting mixture of isomers. Preferably the solvent may be utilized from about 1 volume to about 100 volumes to the weight of the starting material; more preferably about 2 volume to about 50 volume of the solvent.

[0146] The optional step b) of the process involves heating of the reaction mass to reflux temperature to complete dissolution of the starting material into the solvent. If the starting material is dissolved or suspended in the solvent at higher temperatures then the resultant solution may be allowed to cool to room temperature or less to precipitate out the product. The cooling step may be involved at any phase such as either sudden cooling or cooling with specific time interval; preferably the optional step c) of the aforementioned process involves gradual cooling of the reaction mass to below 35 °C temperature to precipitate the product.

[0147] The step d) of the aforementioned process involves isolation of the precipitated racemic mixture of enol compounds of Formula V-l and V-4 by techniques known in the art, for example, filtration, optionally washing or slurry of wet product with same solvent and etc; preferably by filtration.

[0148] The resultant product containing desired isomers of enol compounds of Formula V-l and V-4 may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like; preferably the drying can be carried out at a temperature of below 60°C.

[0149] In another embodiment, the enol compounds of Formula V-l, V-2, V-3 and V-4 obtained by the purification process of the present invention contains about 45% by chiral HPLC of each of Formula V-l and V-4 isomer and about 5% by chiral HPLC of each of Formula V- 2 and V-3 isomer.

[0150] In another embodiment, the present invention provides a process for preparation of racemic cloprostenol or a salt thereof, comprising: preparing isomers of enol compound of Formula V-l and V-4 as process described above, and converting the enol compound of Formula V- 1 and V-4 into racemic cloprostenol or a salt thereof.

[0151] As per the known methods when performing the isomer separation by solvent crystallization the undesired isomers are considered as waste and discarded, which contributes substantial product loss, thereby the processes disclosed under the prior art are uneconomical, particularly in commercial scale operations. It is always beneficial to convert the undesired isomer into desired one to increase the product yield thereby decreasing the manufacturing cost.

[0152] The present inventors have addressed these problems and have tried to recycle undesired isomers which are separated along with the mother liquors produced during the purification process, thereby reducing cost of production and wastage of valuable material. Accordingly, the present invention provides a process of converting undesired enol isomers of Formula V-2 and V-3 into desired enol isomers of Formula V-l and V-4 by oxidation of the mother liquor’s obtained by the purification process described as above or obtained by any similar processes with an oxidizing agent to obtain corresponding (±) enone of Formula IV which can be again reduced to a mixture of isomers of Formula V-l, V-2, V-3 and V-4.

[0153] In another embodiment, the present invention provides a recycling process of mixture of enol compound of Formula V-2 and Formula V-3, comprising; a) reacting a mixture of enol compound of Formula V-2 and Formula V-3 with a suitable oxidizing agent to obtain (±) enone of Formula IV, b) reacting the (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a mixture of enol compound of Formula V-l, Formula V- 2, Formula V-3 and Formula V-4, and c) purifying the mixture of enol compound of Formula V-l, Formula V-2, Formula V- 3 and Formula V-4 with a suitable solvent to obtain mixture of enol compound of Formula V-l and Formula V-4.

[0154] The mother liquors containing mixture of enol compounds of Formula V-2 and V-3 obtained by the purification process as described above may be evaporated to remove the solvent completely under reduced pressure. Then oxidizing the resulting product with a suitable oxidizing agent in a suitable solvent. Suitable oxidizing agent include but are not limited to Dess-Martin periodinane, TEMPO / potassium bromide / sodium hypochlorite, DCC / DMSO and CrO3 / Pyridine; preferably TEMPO / potassium bromide / sodium hypochlorite and the suitable solvent include but are not limited dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, N,N-dimethylformaide, N,N- dimethylacetamide, water or mixtures thereof; preferably di chloromethane.

[0155] The oxidation reaction may be carried out at a temperature ranging from about -20°C to about room temperature; preferably the oxidation reaction at temperature of about 0°C to about -10°C.

[0156] After completion of the oxidation, the resultant (±) enone compound of Formula IV may be isolated by known techniques such as solvent extractions, solvent distillation and precipitation by adding another solvent. For example, the resultant reaction mass may be extracted with a suitable water immiscible solvent followed by concentrating the organic layer. Suitable water immiscible solvents include but are not limited to dichloromethane, toluene, xylene, ethyl acetate and the like and mixtures thereof; preferably dichloromethane. Then the resulting residue may be dissolved in a suitable solvent preferably an alcohol solvent particularly methanol and isolating the (±) enone compound of Formula IV by techniques known in the art, for example, filtration.

[0157] Then the obtained (±) enone compound of Formula IV can be used as starting material for the preparation of enol isomers of Formula V-l, V-2, V-3 and V-4 and then separation of desired enol isomers of Formula V-l and V-4 by the solvent purification methods as described in the above embodiments.

[0158] The mixture of enol compounds of Formula V-l and V-4 obtained using the process of the present invention having a chemical purity of at least 85% by HPLC; preferably at about 90% by HPLC and chiral purity of each about 45% by chiral HPLC.

[0159] In another embodiment, the mixture of enol compounds of Formula V-l and V-4 obtained using the process of the present invention there still possibility to have undesired enol isomers of Formula V-2 and V-3 as impurities with a limit of up to about 10%, which limit still cumbersome for the commercial processes and which needs to be controlled to lower level otherwise the undesired isomers may carry forwarded to final stages.

[0160] Therefore, it is further required to improve chemical purity of desired mixture of enol compounds of Formula V-l and V-4 by minimizing the content of undesired isomers. In order to improve the purity further, the present inventors have proposed derivatization process to selectively purging out the undesired isomers.

[0161] The derivatization process as proposed by the present invention involves first derivatizing the mixture of enol compounds of Formula V-l and V-4 contains specified limits of undesired mixture of enol compounds of Formula V-2 and V-3 as contaminants to make corresponding hydroxyl protected enol compounds of Formula VI- 1 and VI-4 along with hydroxyl protected enol compounds of Formula VI-2 and VI-3 followed by solvent purification to selectively purging out undesired isomers followed by deprotecting the hydroxyl protections to get the pure desired diol isomers of Formula VIL1 and VII-4.

[0162] In another embodiment, the present invention provides a process for preparation of a mixture of diol compound of Formula VIL1 and Formula VII-4, comprising:

[0163] (3aR, 4R, 5R, 6aS, 3R) - Formula VII- 1

[0164] (3aS, 4S, 5S, 6aR, 3S) - Formula VII-4 a) reacting a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable hydroxyl protecting agent in a suitable solvent to obtain a mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4, wherein the “P” and “Pi” represents a suitable hydroxyl protecting group; b) purifying the mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 in an organic solvent to obtain a mixture of protected enol compounds of Formula VI- 1 and VI-4; and c) converting the mixture of protected enol compounds of Formula VI-1 and VI-4 into mixture of diol compound of Formula VII-1 and Formula VII-4.

[0165] The step a) of the aforementioned process involves derivatization of 3 -hydroxyl group of desired isomers of enol compound of Formula V-l and V-4 having undesired isomers of enol compound of Formula V-2 and V-3 as impurities into a mixture of hydroxyl protected enol compounds of Formula VI-1 and VI-4 along with undesired isomers of hydroxyl protected enol compound of Formula VI-2 and VI-3 as impurities. Preferably the enol compound of Formula V-l and V-4 using the process of derivatization is having about up to 10% by HPLC of undesired enol isomers of Formula V-2 and V-3; more preferably about up to 5% by HPLC of undesired enol isomers of Formula V-2 and V-3.

[0166] The derivatization reaction may be carried out with a suitable derivatization agents in presence of a catalyst and a base. The suitable derivatization agents used here to form a suitable hydroxyl protecting groups (Pi) include, but is not limited to p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p- nitrobenzoyl group (PNB), Trimethyl silyl (TMS), Triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS) and the like; preferably p-nitrobenzoyl group (PNB). The p-nitrobenzoyl group may be formed with the use of p-nitrobenzoyl halide as derivatizing agent, specifically p-nitrobenzoyl chloride or bromide.

[0167] Wherein the “P” represents a suitable hydroxyl protecting group, preferably p- phenylbenzoyl (PPB).

[0168] The suitable solvent used herein for derivatization step include, but is not limited to alcohols such as methanol, ethanol, isopropanol and the like; chlorinated solvent such as dichloromethane, di chloroethane, chloroform and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; ethers such as diethyl ether, THF, methyl tertiary butyl ether, diisopropyl ether and the like, hydrocarbons such as hexane, heptane, cyclohexane, toluene and the like; water or mixtures thereof; preferably di chloromethane, methanol, ethyl acetate, acetone, THF, methyl tertiary butyl ether, hexane, toluene or mixtures thereof; more preferably dichloromethane.

[0169] The base used herein for derivatization step include, but is not limited to triethyl amine, diisopropylamine, diisopropyl ethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like and mixtures thereof; preferably triethyl amine and the catalyst used is, such as dimethyl amino pyridine (DMAP) and the like.

[0170] The derivatization reaction may be carried out at a temperature of about -10°C to about reflux temperature of the solvent used; preferably at about 10°C to about 45°C, more preferably at about 25°C to about 35°C. In a preferred embodiment, the desired derivatized mixture of enol compound of Formula VI-1 and VI-4 contains undesired derivatized mixture of enol compound of Formula VI-2 and VI-3 are represented as follows:

[0171] After completion of the derivatization reaction, the mixture of derivatized compounds can be isolated by known techniques, for example, the reaction mass may be mixed with water and then layers were separated. The product containing organic layer may be concentrated and proceed further with or without isolating the product in to subsequent solvent purification step.

[0172] The step b) of the aforementioned process involves purification of derivatized compounds of Formula VI- 1, VI-2, VI-3 and VI-4 in an organic solvent to purging out undesired enol compounds of Formula VI-2 and VI-3. The organic solvent used herein for purification include, but is not limited to alcohols such as methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, tertiary butanol and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate and the like; hydrocarbons selected from the group consisting of aromatic hydrocarbons such as toluene, xylene and the like; cyclic hydrocarbons such as n-hexane, n-heptane, cyclohexane and the like; halogenated hydrocarbons such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; nitriles such as acetonitrile, propionitrile and the like, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like and their mixtures; preferably methanol, ethyl acetate, hexane, acetonitrile or acetone and their mixtures; more preferably acetonitrile, acetone, methanol or mixture thereof; most preferably acetonitrile.

[0173] The step b) of the aforementioned process may optionally be heated to dissolve the derivitized mixture of isomers of Formula VI-1, VI-2, VI-3 and VI-4 in an organic solvent at a temperature of about room temperature to about reflux; preferably at about 40°C to about reflux. The resultant product may be isolated by known techniques, for example, cooled to precipitation if the starting material dissolved completely in the solvent used and then filter the product or solvent evaporation under vacuum or addition of an anti- solvent to precipitation. Preferably the product may be isolated by cooling the reaction solution to room temperature or less. The cooling step may be involved at any phase such as either sudden cooling or cooling with specific time interval to precipitate the product; preferably the reaction mass slowly cooled to room temperature and then further cooled to below 15°C to precipitate the product.

[0174] The protected enol compound of Formula VI- 1 and VI-4 obtained after purification of the step b) process is having a purity of above 98%, preferably above 99.5% and contains less than 0.5% by HPLC of undesired enol isomer compound of Formula VI-2 and VI-3.

[0175] In another embodiment, the purification process described as above for purifying enol compounds of Formula VI-1, VI-2 VI-3 and VI-4 is not only effective to remove undesired enol compounds of Formula VI-2 and VI-3 but also effectively removes the un-reacted raw materials and unwanted by-products formed along with the enol compounds of Formula VI- 1, VI-2 VI-3 and VI-4, for example, para nitro benzoic acid in case of p-nitrobenzoyl chloride or bromide. The step c) of converting the mixture of protected enol compounds of Formula VI-1 and VI-4 into mixture of diol compound of Formula VII-1 and Formula VII-4 by deprotecing the both hydroxyl protecting groups with a suitable deprotecing agents such as a base.

[0176] The deprotection reaction may be carried out by using a base in an organic solvent at a temperature of about 0°C to about 50°C; preferably at about 25°C to about 35°C. The base include, but is not limited to organic bases such as tri ethyl amine, diisopropyl amine, diethyl amine and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; preferably potassium carbonate. The organic solvent include, but is not limited to alcohols such as methanol, ethanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; chlorinated solvents such as dichloromethane, di chloroethane, chloroform and the like; hydrocarbons such as n- hexane, n-heptane, cyclohexane, toluene, xylene and the like and mixtures thereof; preferably methanol.

[0177] The resultant compound of mixture of diol compounds of Formula VII-1 and VII-4 thus formed can be isolated by known techniques, for example, solvent extractions, solvent precipitation and filtration or solvent evaporation; preferably solvent extraction using a water immiscible solvent like dichloromethane, toluene and both followed by concentration of the solvent and then crystallizing the product using a solvent like ethyl acetate, hexane or mixture thereof.

[0178] In another embodiment, the mixture of diol compound of Formula VII-1 and Formula VII- 4 obtained using the process as described above having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3.

[0179] In another embodiment, the present invention provides a mixture of diol compound of Formula VII-1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3.

[0180] The resultant mixture of diol compound of Formula VII-1 and Formula VII-4 represented as follows:

[0181] (3aR, 4R, 5R, 6aS, 3R) - Formula VII- 1

[0182] (3aS, 4S, 5S, 6aR, 3S) - Formula VII-4

[0183] Preferably, the resultant mixture of protected diol compounds of Formula VII-1 and ¥11-4 represented as follows:

[0184] In another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof, comprising: preparing a mixture of diol compound of Formula VILl and VII-4 as process described above, and converting the mixture of diol compound of Formula VILl and VII-4 into racemic cloprostenol or its salt thereof.

[0185] In another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of racemic 15-epi cloprostenol impurity of Formula D, comprising: preparing a mixture of diol compound of Formula VII-1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VIL2 and Formula VII-3 as process described above, and converting the mixture of diol compound of Formula VII-1 and VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3 into racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of racemic 15-epi cloprostenol impurity of Formula D.

[0186] In another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof from a mixture of diol compound of Formula VII-1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3 as process described above and converting said intermediates into a mixture of protected diol compound of Formula VIILl and Formula VIII-4 by protection of hydroxyl groups followed by reduction of keto group from the mixture of protected diol compound of Formula VIILl and Formula VIII-4 to obtain a mixture of lactol compound of Formula IX-1 and Formula IX -4 and then converting the mixture of lactol compound of Formula IX-1 and Formula IX -4 into racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of racemic 15-epi cloprostenol impurity of Formula D.

[0187] In another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof, comprising:

[0188] [(8R,9R,11R,12S,15R) - Formula XII -1 (8 S,9 S, 11 S, 12R, 15 S)] - Formula XII -4 Racemic cloprostenol (XII) a) reacting a mixture of protected diol compound of Formula VIII-1 and Formula VIII-

[0189] 4 with a suitable keto reducing agent to obtain a protected lactol compound of Formula IX-1 and Formula IX-4, wherein “P2” represents ethoxy ethyl, methoxy benzyl, acetyl, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) reacting the mixture of protected lactol compound of Formula IX-1 and Formula IX- 4 with a compound of Formula X in a suitable solvent and a base, to obtain a solvent solution containing mixture of protected cloprostenol of formula XI-1 and Formula mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4, d) adjusting pH to about 7.5 to about 9.5 with an acid, e) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4, f) deprotecting the mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 with an acid in a suitable solvent to obtain a solvent solution containing racemic cloprostenol of Formula XII -1 and Formula XII -4, g) adding water immiscible solvent to the solution of step f), h) adjusting pH to about 9 to about 13 with a base, i) separating the aqueous layer and adding water immiscible solvent, j) adjusting the pH to about 4.5 to about 6.5 with an acid, and k) separating the organic layer and evaporating the solvent to obtain mixture of racemic cloprostenol of Formula XII -1 and Formula XII -4.

[0190] As per the literature, racemic cloprostenol obtained by the known methods contaminate with

[0191] Formation of these bi-products may be possible in the witting reaction with the use of 4- carboxybutyltriphenyl phosphonium bromide (compound of Formula X). These bi-products once formed in the reaction may carry forward to final stage of the process and at the final stage removal of these bi-products is very difficult under normal process purifications and moreover repeated purifications at last stage of the process always burden in yield point of view.

[0192] The inventors of the present invention have surprisingly found that removal of these biproducts from the reaction mass by specific solvent extractions at specific pH conditions, thereby making the process free from tedious column purifications. The process of the present invention is more suitable for commercial applications with higher purity. In another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of a) reacting a mixture of protected lactol compound of Formula IX- 1 and Formula IX- 4 with a compound of Formula X in a suitable solvent and a base, to obtain a solvent solution containing mixture of protected cloprostenol of formula XI-1 and Formula wherein “P2” independently represents ethoxy ethyl, methoxy benzyl, acetyl, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) evaporating the solvent and adding water and water immiscible solvent to the mixture of protected cloprostenol of formula XI- 1 and Formula XI-4, c) adjusting pH to about 7.5 to about 9.5 with an acid, d) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of formula XI- 1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A, and e) converting the protected cloprostenol of Formula XI- 1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A into racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A.

[0193] The mixture of protected lactol compound of Formula IX-1 and Formula IX-4 can be prepared from a mixture of diol compound of Formula VIL1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VIL2 and Formula VIL3 as process described as above and converting said intermediates into a mixture of protected diol compound of Formula VIIL1 and Formula VIII-4 by protection of hydroxyl groups followed by reduction of keto group from the mixture of protected diol compound of Formula VIII-1 and Formula VIII-4 to obtain a mixture of lactol compound of Formula IX- 1 and Formula IX -4.

[0194] In an another embodiment, the protection of two hydroxyl groups of mixture of diol compounds of Formula VIL1 and Formula VII-4 may be carried out with a suitable protecting groups such as ethoxy ethyl, methoxy benzyl, acetyl, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl in presence of a suitable catalyst such as Pyridinium p-Toluenesulfonate and a suitable solvent such as di chloromethane at a temperature of about ambient to reflux temperature.

[0195] The resultant mixture of protected diol compounds of Formula VIII- 1 and VIII-4 represented as follows:

[0196] (3aR, 4R, 5R, 6aS, 3R) - Formula VIII- 1 (3aS, 4S, 5S, 6aR, 3S) - Formula VIII-4 Preferably, the resultant mixture of protected diol compounds of Formula VIII- 1 and VIII-

[0197] In an another embodiment, the reduction of mixture of protected diol compounds of Formula VIII-1 and VIII-4 may be carried out in presence of DIBAL-H in an organic solvent at a temperature of about -80°C to about -10°C. The organic solvent include, but are not limited to toluene, THF, diethyl ether, methyl tertiary butyl ether, dichloromethane and the like and mixtures thereof; preferably dichloromethane, THF and mixtures thereof; and the temperature is at about -85°C to -75°C.

[0198] The resultant mixture of protected lactol compounds of Formula IX- 1 and IX-4 represented as follows:

[0199] (3aR, 4R, 5R, 6aS, 3R) - Formula IX- 1

[0200] (3aS, 4S, 5S, 6aR, 3S) - Formula IX-4

[0201] Preferably, the resultant mixture of protected lactol compounds of Formula IX-1 and IX-4

[0202] The reaction of a mixture of protected 1 actol compound of Formula IX- 1 and Formula IX-4 with a compound of Formula X is carried out in a suitable solvent and a base. The base used in the process is alkali metal tertiary butoxide, which include, but is not limited to potassium tertiary butoxide, magnesium tertiary butoxide, lithium tertiary butoxide and the like, preferably potassium tertiary butoxide and the solvent is selected from toluene, THF, diethyl ether, methyl tertiary butyl ether, dichloromethane and the like and mixtures thereof; preferably THF and the temperature is at about -15°C to about -5°C. The isolation of mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4 from the resultant solvent solution may be carried out under the following work-up procedure of the present invention to effective removal of UV active impurity of Formula A.

[0203] In an another embodiment, the present invention provides a process for separation of UV active impurity of Formula A from the solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI- 1 and Formula XI-4 and UV active impurity of the process comprises: a) providing a solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI-1 and Formula XI-4 and UV active impurity of Formula A, b) adjusting pH of the step a) solution to about 7.5 to about 9.5 with an acid, and c) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A.

[0204] Step a) of providing a solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI-1 and Formula XI-4 and UV active impurity of Formula A can be obtained by the process described as above from the wittig reaction by evaporating the solvent from the reaction mass and followed by adding water and water immiscible solvent to the residue containing mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4 to form a reaction solution.

[0205] The water immiscible solvent used herein but are not limited to dichloromethane, toluene, ethyl acetate, methyl tert butyl ether and the like and mixtures thereof; preferably ethyl acetate.

[0206] The suitable acid used herein for step b) to adjusting and / or maintaining pH of the solution is any acid that capable of achieve the result. The suitable acid includes but is not limited to hydrochloric acid, hydrobromic acid, ortho phosphric acid, sulfuric acid and the like; preferably ortho phosphric acid. After achieving the pH of the resultant solution from about 7.5 to about 9.5 preferably at about 7.5 to about 8.5; more preferably at about 7.8 to about 8.2; the resultant aqueous and organic layers may be separated and the aqueous layer containing UV active impurity of Formula A is discarded and the product containing organic layer may be washed with aqueous base solution such as aqueous sodium bicarbonate solution and then product containing organic layer may be evaporated under vacuum to obtain a mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A. The step b) procedure may be repeated until the UV active impurity of Formula A is reached below the limit of 0.5% by HPLC, preferably less than 0.2%.

[0207] The resultant mixture of protected compounds of Formula XI- 1 and XI-4 represented as follows:

[0208] (8R,9R,11R,12S,15R) - Formula XI-1 (8S,9S,11S,12R,15S) - Formula XI-4

[0209] Preferably, the resultant mixture of protected compounds of Formula XI- 1 and XI-4 In another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of UV active impurity of Formula A.

[0210] UV active impurity of Formula A

[0211] In a preferred embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of UV active impurity of Formula A. In an another embodiment, the present invention provides a process for preparation of racemic cloprostenol or its salt thereof having less than 0.5% by HPLC of TPPO impurity a) reacting a mixture of protected lactol compound of Formula IX- 1 and Formula IX- 4 with a compound of Formula X in a suitable solvent and a base, to obtain mixture of protected cloprostenol of formula XI- 1 and Formula XL4,

[0212] tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) deprotecting the mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 with an acid in a suitable solvent to obtain a solvent solution containing racemic cloprostenol of Formula XII -1 and Formula XII -4,

[0213] (8R,9R,11R,12S,15R) - Formula XII-1

[0214] (8 S, 9 S, 11 S, 12R, 15 S) - Formula XII- 4 c) adding water immiscible solvent to the solution of step b), d) adjusting pH to about 9 to about 13 with a base, e) separating the aqueous layer and adding water immiscible solvent, f) adjusting the pH to about 4.5 to about 6.5 with an acid, and g) separating the organic layer and evaporating the solvent to obtain a mixture of cloprostenol of Formula XII -1 and Formula XII -4 having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0215] The step a) of reacting a mixture of protected lactol compound of Formula IX- 1 and Formula IX-4 with a compound of Formula X in a suitable solvent and a base is carried out as per the procedure described as in above embodiments. The mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 can be taken either after removal of UV active impurity by the pH adjustment process as described above or obtained directly without removal of UV active impurity; preferably the mixture of protected cloprostenol of Formula XI- 1 and Formula XI-4 can be taken after removal UV active impurity by the pH adjustment process as described above embodiments.

[0216] Step b) of deprotection of the mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 with an acid is carried out in a suitable solvent. The acid used herein is selected from hydrochloric acid, ortho phosphoric acid, sulfuric acid and the like; preferably ortho phosphoric acid. The suitable solvent used herein may be selected from ethers such as THF, 1,4-di oxane, methyl tert butyl ether and the like; water and mixture thereof; preferably a mixture of THF and water. The reaction may be carried out at a temperature of about room temperature to about reflux; preferably about 25°C to 35°C.

[0217] After completion of the step b) deprotection reaction, to the reaction mass a water immiscible solvent may be added and adjust the reaction pH to about 9 to about 13 with a base. The water immiscible solvent used herein for step c) may be selected from esters such as methyl acetate, ethyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; preferably ethyl acetate or toluene; more preferably ethyl acetate.

[0218] The base used herein for step d) to adjust pH of the solution to about 9 to about 13 may be selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide; preferably sodium hydroxide.

[0219] The reaction pH may be adjusted to about 9 to about 13; preferably about 10 to about 12.5; more preferably about 11 to 12. After achieving the required pH the layers may be separated and product containing aqueous layer may be treated further to isolate the product and the TPPO containing organic layer is discarded.

[0220] The product containing aqueous layer is taken back and may be added with water immiscible solvent. The water immiscible solvent used herein for step e) may be selected from ethyl acetate, toluene, dichloromethane or mixtures thereof; preferably ethyl acetate and adjust the pH to about 4.5 to about 6.5; preferably about 5 to 6 with an acid such as hydrochloric acid, ortho phosphoric acid and the like; preferably ortho phosphoric acid. Then the product containing organic layer is separated and isolated by the known techniques, for example, solvent evaporation, precipitation by adding an anti-solvent and filtration; preferably solvent evaporation under vacuum.

[0221] The racemic cloprostenol obtained from the above embodiment is having less than 0.5% by HPLC of UV active impurity of Formula A and less than 0.5% by HPLC of TPPO impurity of Formula B; preferably having less than 0.2% by HPLC of UV active impurity of Formula A and less than 0.2% by HPLC of TPPO impurity of Formula B.

[0222] In another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0223] TPPO impurity of Formula B

[0224] In a preferred embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of TPPO impurity of Formula B.

[0225] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C.

[0226] 5,6-Trans-[(8R,9R,l 1R,12S,15R) + (8S,9S,11S,12R,15S)] - Impurity of formula C

[0227] In accordance with preferred embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C. In an embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0228] [(8R,9R,11R,12S,15S) + (8S,9S,11S,12R,15R)] - Impurity of Formula D

[0229] In an embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0230] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.5% by HPLC of racemic 15- Epi Cloprostenol impurity of Formula D.

[0231] In accordance with another embodiment, the present invention provides racemic cloprostenol having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.2% by HPLC of racemic 15- Epi Cloprostenol impurity of Formula D.

[0232] In another embodiment, the present invention provides a compound of Formula VI:

[0233] Formula VI wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB). In accordance with another embodiment, the present invention provides a compound of

[0234] Formula VI- 1 :

[0235] (3aR, 4R, 5R, 6aS, 3R) - Formula VI- 1 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0236] In accordance with another embodiment, the present invention provides a compound of

[0237] Formula VI- la:

[0238] (3aR, 4R, 5R, 6aS, 3R) - Formula VI- 1 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0239] In accordance with another embodiment, the present invention provides a compound of

[0240] Formula VI-2:

[0241] (3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0242] In accordance with another embodiment, the present invention provides a compound of Formula VI-2a:

[0243] (3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0244] In accordance with another embodiment, the present invention provides a compound of

[0245] Formula VI-3:

[0246] (3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0247] In accordance with another embodiment, the present invention provides a compound of Formula VI-3a:

[0248] (3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).

[0249] In accordance with another embodiment, the present invention provides a compound of Formula VI-4:

[0250] (3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).

[0251] In accordance with another embodiment, the present invention provides a compound of Formula VI-4a:

[0252] (3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB). In another embodiment, the present invention provides a process for preparation of racemic cloprostenol sodium, comprising: i) dissolving or suspending racemic cloprostenol in an organic solvent, ii) treating the step i) reaction mixture with a suitable sodium source, iii) optionally adding an anti-solvent to the step ii) reaction mixture or vice-versa, and iv) isolating the racemic cloprostenol sodium; wherein the organic solvent is selected from the group comprising ketones, ethers and mixtures thereof; wherein the antisolvent is selected from the group comprising ethers, aliphatic hydrocarbons, alicyclic hydrocarbons or mixtures thereof and wherein the suitable sodium source is selected from the group comprising sodium methoxide, sodium ethoxide and sodium 2-ethyl hexanoate.

[0253] The racemic cloprostenol used in the above embodiment can be prepared as per the procedure described as above embodiments or prepared as per the known literatures.

[0254] The step i) of the aforementioned process include dissolving racemic cloprostenol obtained by the processes described as above embodiments in an organic solvent at a suitable temperature followed by addition of sodium source at the same temperature. Examples of organic solvents of step i) includes but are not limited to ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; ethers such as tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-di oxane and mixtures thereof; preferably acetone or tetrahydrofuran.

[0255] The suitable temperature for step i) reaction is about 20°C to about reflux temperature of the solvent used. Any other temperatures may also be acceptable, provided a clear solution of the concerned materials is obtained in the solvents chosen; preferably the step i) reaction carried out at temperature of about 25°C to about 35°C.

[0256] The suitable sodium source is selected from the group consisting of sodium methoxide, sodium ethoxide and sodium 2-ethyl hexanoate; preferably sodium methoxide or sodium 2- ethyl hexanoate.

[0257] The suitable sodium source can be added either as a solution in one or more solvents or it may be added as a solid to the solution of racemic cloprostenol in one or more solvents or the solution of racemic cloprostenol in one or more solvents may be added to a solution of sodium source. The way of addition of the sodium source is not particularly critical.

[0258] The addition of sodium source is carried out at a temperature of about 25°C to about 60°C; preferably at about 25°C to about 35°C.

[0259] The step iv) of isolation of racemic cloprostenol sodium salt may be carried out either by removal of solvent or cooling the solution to precipitation of step ii) reaction mass or by addition of anti-solvent to step ii) reaction mass to precipitation followed by filtration; preferably the isolation of the resultant racemic cloprostenol sodium product is accomplished by removal of solvent from the solution or by addition of anti-solvent to step ii) reaction mass to precipitation followed by filtration.

[0260] The removal of solvent includes evaporation, distillation or distillation under vacuum. Evaporation can be achieved at sub-zero temperatures by the lyophilisation or freeze-drying technique, a rotational drying (such as with the Buchi Rotavapor), spray drying, fluid bed drying, flash drying, spin flash drying and thin-film drying; more preferably, the solvent may be removed completely by distillation under vacuum at a temperature of about 25°C to about 70°C to obtain racemic cloprostenol sodium.

[0261] Alternatively, racemic cloprostenol sodium may also be prepared by precipitation of racemic cloprostenol sodium by either addition of suitable antisolvent to the step ii) solution or addition of step ii) solution into a suitable antisolvent.

[0262] The suitable anti-solvent includes, but is not limited to ethers, aliphatic hydrocarbons, alicyclic hydrocarbons and the like and mixtures thereof. The ethers include, but are not limited to dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4- dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane and the like; alicyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; water and mixture thereof; preferably diisopropyl ether, methyl tertiary butyl ether and hexane; more preferably diisopropyl ether.

[0263] Then, the resulting reaction mass may be stirred at a temperature of about 25°C to about 35°C or cooled to lower temperature to precipitate out the product. Preferably, the resulting reaction mass may be stirred at about 25°C to about 35°C for about 60 min to about 3 hrs to precipitate out the product. The isolation of pure racemic cloprostenol sodium can be carried out by conventional techniques, for example filtration. The resultant pure racemic cloprostenol sodium may optionally be further dried at a temperature ranging from about 40°C to about 80°C; preferably dried at a temperature ranging from about 50°C to about 60°C for about 10-20 hrs.

[0264] Prior-art methods involves saltification of racemic cloprostenol with conventional sodium bases in an aqueous medium or anhydrous solvent medium. The conventional sodium source used in the art is having operational disadvantages as the sodium source in aqueous medium results the product formation but the obtained sodium salt is highly soluble in water and in order to isolate the product from water medium there is a need to follow water distillation and followed by product isolation from another solvent and even after these lengthy process steps the obtained final product is not in freely powdered nature. Whereas the same process in non-aqueous solvent medium the salt product is in gummy in nature and difficult to handle for further processing steps.

[0265] To overcome the difficulties associated with the known processes, the present inventors incorporating use of suitable sodium source in non-aqueous medium for the saltification of racemic cloprostenol which allows the final product as free flowing crystalline powder and can easily filterable to isolate the product which is useful for scale-up production, especially in terms of operational efficiency.

[0266] In another embodiment, racemic cloprostenol sodium obtained by the process of the present invention having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.5% by HPLC of racemic 15- Epi cloprostenol impurity of Formula D.

[0267] In another embodiment, racemic cloprostenol sodium obtained by the process of the present invention having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.2% by HPLC of racemic 15- Epi cloprostenol impurity of Formula D. In another embodiment, racemic cloprostenol sodium obtained by the process of the present invention having less than 0.2% by HPLC of Impurity of RRT at 0.83.

[0268] In another embodiment, racemic cloprostenol sodium obtained by the process of the present invention having less than 0.2% by HPLC of Impurity of RRT at 2.23.

[0269] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of UV active impurity of Formula A.

[0270] In a preferred embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of UV active impurity of Formula A.

[0271] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of TPPO impurity of Formula B.

[0272] In a preferred embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of TPPO impurity of Formula B.

[0273] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0274] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0275] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0276] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, less than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C, and / or less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.

[0277] In another embodiment, the present invention provides racemic cloprostenol sodium having a total purity of greater than 99% by HPLC. In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of Impurity of RRT at 0.83.

[0278] In another embodiment, the present invention provides racemic cloprostenol sodium having less than 0.2% by HPLC of Impurity of RRT at 2.23.

[0279] In another embodiment, the present invention provides a pharmaceutical composition comprising racemic cloprostenol or its sodium salt thereof prepared by the processes of the present invention and / or at least one suitable excipient.

[0280] In another embodiment, the present invention provides a veterinary composition comprising racemic cloprostenol or its sodium salt thereof prepared by the processes of the present invention and / or at least one suitable excipient.

[0281] In another embodiment, the desired racemic mixture of Formula V-l & Formula V-4 and the undesired isomer mixture of Formula V-2 & Formula V-3 obtained by the above processes, were analysed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:

[0282] Table-1:

[0283] In another embodiment, the isomeric compounds of Formula V-l, Formula V-2, Formula V-3 & Formula V-4 obtained by the above process, were analysed using chiral high performance liquid chromatography (“chiral HPLC”) with the conditions are tabulated below:

[0284] Table-2:

[0285] In another embodiment, the desired racemic mixture of Formula VI-1 & Formula VI-4 obtained by the above processes, were analysed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:

[0286] Table-3: In another embodiment, the racemic cloprostenol of Formula XII -1 and Formula XII -4 (racemic cloprostenol of Formula XII) obtained by the above processes, were analysed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:

[0287] Table-4:

[0288] EXAMPLES

[0289] The following non-limiting examples illustrate specific embodiments of the present invention. They are not intended to be limiting the scope of the present invention in any way.

[0290] EXAMPLE-1:

[0291] Preparation of racemic mixture of Formula V-la and V-4a.

[0292] (±) enone of Formula IVa (200 gms), dichloromethane (1000 ml) and methanol (1000 ml) were added to a round bottom flask. The contents were cooled to -37 to -43°C and Sodium borohydride (8.78 gms) was added in 4 equal lots over 45 min at -37 to -43°C. The reaction mass was stirred at the same temperature for 1-1.5 hrs. The reaction mass temperature was raised to -5 to -15°C and pH was adjusted to 3.5-4.5 with citric acid solution (prepared by dissolving 10 gms citric acid in 90 ml of water) at <5°C. Temperature was raised to 27- 33°C and the solvent was distilled under vacuum at below 45°C up to -150 ml of reaction mass remains. The resulting reaction mass was cooled to 27-33°C and dichloromethane (2000 ml) and water (2000 ml) were added. Stirred the reaction mass for 15-20 min and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with di chloromethane (2 X 1000 ml), combined all organic layers and washed with water (1000 ml). The resulting organic layer was distilled completely under vacuum at <45°C to get residue mass. Yield=200 gms.

[0293] Crystallization: Methanol (6000 ml) was added to the above residue at 25-35°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30mins. The reaction mass was allowed to cool to 25-35°C gradually and stirred for about 4 hrs. The resulting solids were filtered, washed with methanol (400 ml) and suck dried for 15- 30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford the title compound. Yield=86 gms.

[0294] EXAMPLE-2:

[0295] Preparation of racemic mixture of Formula V-la and V-4a.

[0296] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (25 gms) and methanol (250 mL) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30mins. The reaction mass was cooled to 25-35°C gradually and stirred for about 30 mins. The resulting solids were filtered. Methanol (250 mL) was added to the resulting solid and stirred under reflux for 30mins. The reaction mass was cooled to 25-35°C gradually and stirred for about 30mins. The resulting solids were filtered, washed with methanol (25 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 50- 56°C for about 4 hr under vacuum to afford title compound. Yield=10 gms.

[0297] EXAMPLE-3:

[0298] Preparation of racemic mixture of Formula V-la and V-4a.

[0299] (±) enone of Formula IVa (100 gms) and Sodium borohydride (2.93 gms) were added to a round bottom flask at 25-35°C. Dichloromethane (500 mL) was added to the above reaction and contents were cooled to -37 to -43°C and then methanol (100 ml) was added at -37 to - 43°C. The reaction mass was stirred at the same temperature for 1-1.5 hrs. The reaction mass temperature was raised to -5 to -15°C and pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 15 mL hydrochloric acid in 15 ml of water) at <5°C. The temperature of the reaction mass was raised to 27-33°C. Water (300 mL) was added to the reaction mass, stirred for 15-30 mins and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with di chloromethane (2 X 300 ml), combined all organic layers and washed with water (500 ml). The resulting organic layer was distilled completely under vacuum at <45°C to get residue mass. The resulting residue was stripped off with methanol (200 mL) to obtain crude product. Yield=100 gms.

[0300] Crystallization: Methanol (3000 ml) was added to the above residue (100 gms from Ex-5) at 35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30-60 mins. The reaction mass was allowed to cool to 25-35°C gradually and stirred for about 6hrs. The resulting solids were filtered, washed with methanol (100 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=40 gms.

[0301] EXAMPLE-4:

[0302] Preparation of racemic mixture of Formula V-la and V-4a.

[0303] (±) enone of Formula IVa (100 gms) and dichloromethane (1000 mL) were added to a round bottom flask at 25-35°C. Cerium (III) chloride heptahydrate solution (prepared by dissolving 21.62 gms of Cerium (III) chloride heptahydrate in 500 mL of methanol) was added to the above reaction mass at 25-35°C. The contents were cooled to -37 to -43°C and Sodium borohydride (3.66 gms) was added in 4 equal lots over 45 min at -37 to -43 °C. The reaction mass was stirred at the same temperature for 1-1.5 hrs. The reaction mass temperature was raised to -5 to -15°C and pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 10 gms hydrochloric acid in 10 ml of water) at <5°C. Temperature was raised to 20-30°C and water 300 (mL) was added. Stirred the reaction mass for 15-30 min and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with di chloromethane (2 X 300 mL), combined all organic layers and washed with water (500 ml). The resulting organic layer was distilled completely under vacuum at <45°C to get residue mass. Yield=100 gms.

[0304] Crystallization: Methanol (3000 ml) was added to the above residue (100 gms from Ex-6) at 35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30-60 mins. The reaction mass was allowed to cool to 25-35°C gradually and stirred for about 6hrs. The resulting solids were filtered, washed with methanol (100 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=40 gms.

[0305] EXAMPLE-5

[0306] Preparation of racemic mixture of Formula V-la and V-4a.

[0307] Isomeric mixture of compounds of Formula V-l, V-2, V-3 and V-4 (30 gms) and methanol 150 (mL) were added to a round bottom flask at 25-35°C and stirred for 1 hrs at the same temperature. The resulting solids were filtered. Methanol (150 mL) was added to the resulting solid and stirred under reflux for 1 hr. The reaction mass was cooled to 25-35°C gradually and stirred for about Ihr. The resulting solids were filtered, washed with methanol (30 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 1 hr under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=11.5 gms.

[0308] EXAMPLE-6:

[0309] Recycling of undesired racemic mixture of Formula V-2a and V-3a into (±) enone of Formula IVa. The mother liquor obtained from example 1 crystallization process was distilled out and co-distilled the resulting reaction mass with dichloromethane (200 mL). Dichloromethane (2600 mL) was added to the resulting residue (130 gms) at 25-35°C, stirred for 15-30 mins. To this reaction mass pre-prepared solution of potassium bromide (4.2 gms), sodium bicarbonate (19.8 gms) and water (350 mL) was added at 25-35°C. The temperature of the reaction mass cooled to -6°C to 0°C and TEMPO (0.40 gms) was added. To this reaction mass pre-prepared solution of sodium bicarbonate (6.7 gms) and Sodium hypochlorite (223.7 gms) was added, stirred for 20-30mins at -6°C to 0°C. Sodium thiosulphate solution (104 g of sodium thiosulphate was dissolved in 130 ml of water) was added to the resulting reaction mass at below 10°C. pH of the reaction mass was adjusted to 4.0 to 5.0 with hydrochloric acid. The temperature of the reaction mass was raised to 20-30°C, stirred for 15-30 mins and layers were separated. The aq layer was extracted with dichloromethane (2 X 650 ml), combined all organic layers and washed with water (650 ml). The resulting organic layer was distilled completely under vacuum at <45°C and stripped off with methanol (100 mL). Methanol (650 ml) was added to the above residue and stirred under reflux for 30mins. The reaction mass was cooled to 25-35°C gradually and stirred for about 2hrs. The resulting solids were filtered, washed with methanol (130 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=100 gms.

[0310] EXAMPLE-7:

[0311] Preparation of racemic mixture of Formula VLla and VI-4a.

[0312] Isomeric mixture of compounds of Formula V-la and V-4a having about 5-8% of undesired V-2a and V-3a (100 gms) and di chloromethane (2000 mL) were added to a round bottom flask at 25-35°C. p-Nitro benzoyl chloride (53.63 gms) and 4-Dimethyl amino pyridine (4.71 gms) were added to the above reaction mass and contents were cooled to 0-10°C and then trimethylamine (35.1 gms) was added. The temperature of the reaction mass was raised to 22-28°C and stirred for 3hrs at the same temperature. Water (300 mL) was added to the reaction mass, stirred for 15-30mins and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with di chloromethane (300 ml), combined all organic layers and the resulting organic layer was distilled completely under vacuum at <45 °C. Crystallization: Acetonitrile (700 ml) was added to the above residue at 35-45°C. The temperature of the reaction mass was raised to 70-76°C and stirred for 30-60 mins at the same temperature. The reaction mass was cooled to 25-35°C, then further cooled to 10- 16°C and stirred for about 2hrs. The resulting solids were filtered, washed with

[0313] Acetonitrile (50 ml) and suck dried for 15-30 mins to afford title compound. Yield=130 gms.

[0314] In addition to Acetonitrile purification, the following table illustrates the effect of other solvents on the effect of removal of undesired racemic mixture of Formula VI-2a and VI- 3a:

[0315] EXAMPLE-8: Preparation of racemic mixture of Formula VII- 1 and VII-4.

[0316] Isomeric mixture of compounds of Formula Vl-la and VI-4a (130 gms), methanol (1000 mL), potassium carbonate (30.9 gms) were added to a round bottom flask at 25-35°C and stirred for 5-6hrs. Reaction mass pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 30 mL hydrochloric acid in 270 ml of water) at 25-35°C, stirred for 15-30 mins, filtered and washed with methanol (50 mL). The solvent was distilled out completely from the resulting filtrate under vacuum at below 50°C. The residue obtained was cooled to 25-35°C and Dichloromethane (900 mL), isopropyl alcohol (100 mL) and Water (1000 ml) were added. The reaction mass was stirred for 15-30 mins and layers were separated. The aqueous layer was extracted with dichloromethane (2 X 400 ml), combined all organic layers. The resulting organic layer was distilled completely under vacuum at <45 °C to get residue. Toluene (400 mL) was added to the above residue at35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux forl-2hrs. The reaction mass was cooled to below 60°C and distilled out solvent completely. The obtained residue was cooled to 25-35°C and Dichloromethane (500 mL) wad added and stirred for 15-30 mins. Sodium bicarbonate solution (prepared by dissolving 18 gms of sodium bicarbonate in 300 mL of water) was added to above reaction mass, stirred for 15-30mins and layers were separated. The organic layer again treated with same sodium bicarbonate solution stirred for 15-30mins and layers were separated. The resulting organic layer was distilled completely under vacuum at <45°C. Ethyl acetate (400 mL) was added to the resulting solid at 35-45°C, stirred for 15-30mins and then cooled to 25-35°C. N-hexane (800 ml) was added to the above reaction mass at same temperature, maintained for 2 hrs, filtered, washed with n-hexane (100 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=50 gms.

[0317] Combined chemical purity of compounds of Formula VII-I and VIL4: 99.11% Combined chemical purity of compounds of Formula VII-2 and VIL3: 0.30%

[0318] EXAMPLE-9:

[0319] Preparation of racemic mixture of protected diol of Formula VIII- la and VIII-4a.

[0320] Racemic mixture of compounds of Formula VIL1 and VIL4 (100 gms) and dichloromethane (1000 mL) were added to a round bottom flask at 25-35°C and stirred for 10-20 mins. Pyridinium p-toluene sulfonate (3.70 gms) and Ethyl vinyl ether (85.2 gms) were added to above reaction mass at same temperature and stirred for 5-6hrs. Sodium bicarbonate solution (prepared by dissolving 35 gms of sodium bicarbonate in 500 mL of water) was added to above reaction mass, stirred for 15-30mins and layers were separated. The aqueous layer was extracted with di chloromethane (2 X 300 ml) and combined all organic layers. The resulting organic layer was distilled completely under vacuum at <45°C. The resulting residue was stripped off with tetrahydrofuran (100 ml) to afford title compound.

[0321] EXAMPLE-10:

[0322] Preparation of racemic mixture of protected lactol of Formula IX- la and IX-4a.

[0323] Tetrahydrofuran (1000 mL) was added to the racemic mixture of protected diol of formula Vlll-la and VIII-4a obtained from example 9 at 25-35°C and stirred for 10-20 mins. The temperature of the reaction mass was cooled to -81 °C to -75 °C, DIBAL-H (443 mL) in toluene was added and stirred for 2hrs. Methanol (40 mL) was added to the reaction mass and stirred for 10-20mins at the same temperature. The temperature of the reaction mass was raised to -15°C to -5°C. Sodium potassium tartrate solution (prepared by dissolving 200 gms of Sodium potassium tartrate in 1000 mL of water) was added to the reaction mass at 10°C and then temperature of reaction mass raised to 25-35°C. Ethyl acetate (1000 mL) was added to the reaction mass, at 25-35°C, then temperature was raised to 35-45°C, stirred for 15-30mins and layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 500 ml) and combined all organic layers, washed with water (500 mL) and layers were separated. The resulting organic layer was distilled completely under vacuum at <45°C to afford title compound.

[0324] EXAMPLE-11:

[0325] Preparation of racemic protected cloprostenol of Formula Xia

[0326] 4-Carboxybutyltriphenylphosphnium bromide (365.6 gms) and Tetrahydrofuran (1000 mL) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was cooled to -15°C to -5°C and Potassium tert butoxide solution (2474.2 mL) was added reaction mass, stirred for 15-30 mins. The temperature of reaction mass was raised to -3°C o 3°C, stirred for 30-60 mins and then cooled to -15°C to -5°C.

[0327] A solution of racemic mixture of protected lactol of Formula IX- la and IX-4a (prepared by dissolving example 10 residue mass of racemic mixture of protected lactol of Formula IX- la and IX-4a in 500 mL of tetrhydrofuran) was added to above reagent at -15°C to -5°C. The temperature of reaction mass raised to -3° to 6°C and stirred for 2 hrs. Water (100 mL) was added to the reaction mass, stirred for 15-30 mins and distilled out the solvent at below 30°C. Water (1000 mLO and ethyl acetate (1000 mL) were added to the resulting residue at 25-35°C and stirred fori 0-20 mins. HPLC analysis revealed the content of UV active impurity of Formula A is 40.5%. Reaction mass pH was adjusted to 7.8-8.2 with orthophosphoric acid solution (100 mL, prepared by dissolving 15 mL orthophosphoric acid in 15 ml of water) at 25-35°C, stirred for 15-30 mins, and layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 500 ml) and combined all organic layers. The combined organic layer was treated with sodium bicarbonate solution (prepared by dissolving 35 gms of sodium bicarbonate in 500 mL of water) at 25-35°C, stirred for 15- 30mins and layers were separated. The resulting organic layer was distilled completely under vacuum at <40°C to afford title compound. The content of UV active impurity Formula A: 0.17% by HPLC.

[0328] EXAMPLE-12:

[0329] Preparation of racemic cloprostenol of Formula XII

[0330] Tetrahydrofuran (500 mL), water (500 mL) and Orthophosphoric acid were added to the racemic protected cloprostenol of Formula Xia obtained from example 11 at 25-35°C and stirred for 6-8 hrs. HPLC analysis revealed the content of TPPO impurity of Formula B is 47.55%. Ethyl acetate (500 mL) was added to the reaction mass and pH of the reaction mass was adjusted to 11-12 with sodium hydroxide solution (prepared by dissolving 40 gms of sodium hydroxide in 160 ml of water) at 25-35°C, stirred for 15-30 mins and layers were separated. The product containing aqueous layer was extracted with ethyl acetate (3 X 300 ml), ethyl acetate (500 mL) was added to the aqueous layer and the pH of the aqueous layer was adjusted to 5-6 with orthophosphoric acid solution (prepared by dissolving 30 mL orthophosphoric acid in 30 ml of water) at 25-35°C, stirred for 15-30 mins and layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 300 ml) and combined all organic layers. The combined organic layer was treated with water, stirred for 15-30mins and layers were separated. The resulting organic layer was distilled completely under vacuum at below 35°C to afford title compound. The content of TPPO impurity of Formula B: 0.18% by HPLC.

[0331] EXAMPLE-13:

[0332] Preparation of racemic cloprostenol sodium (sodium 2-ethyl hexanoate). Tetrahydrofuran (1080 mL) was added to the racemic cloprostenol of Formula XII obtained from example 12 at 25-35°C and stirred for 15-30 mins. Activated carbon (6 gms) was added to the resulting solution and filtered. Sodium 2-ethyl hexanoate (44.6 gms) was added to the resulting filtrate and stirred for 30 mins. Diisopropyl ether (600 mL) was added to the resulting solution and stirred for about 2 hrs. The precipitated solid was filtered, washed with diisopropyl ether (240 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=80 gms. HPLC analysis: Purity: 99.16%; 15-epimer impurity content: 0.09% and 5,6-trans impurity content: 0.61%.

[0333] EXAMPLE-14:

[0334] Preparation of racemic cloprostenol sodium (sodium methoxide base)

[0335] The procedure described in example 13 was performed by using sodium methoxide instead sodium 2-ethyl hexanoate to yield 80 gms of the title compound.

[0336] EXAMPLE-15:

[0337] Preparation of racemic cloprostenol sodium (Sodium 2-ethyl hexanoate base).

[0338] Racemic cloprostenol of Formula XII (1 gm) and Tetrahydrofuran (10 mL) were added to a round bottom flask at 25-35°C. Sodium 2-ethyl hexanoate (0.37 gms) was added to the resulting solution at the same temperature and stirred for 1 hr. Methyl tert butyl ether (20 mL) was added to the resulting reaction mass and stirred for about 2 hrs. The precipitated solid was filtered, washed with methyl tert butyl ether (8 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=0.6 gms.

[0339] EXAMPLE-16:

[0340] Preparation of racemic cloprostenol sodium (Sodium 2-ethyl hexanoate base).

[0341] Racemic cloprostenol of Formula XII (1 gm) and Tetrahydrofuran (20 mL) were added to a round bottom flask at 25-35°C. Sodium 2-ethyl hexanoate (0.37 gms) was added to the resulting solution at the same temperature and stirred for 4 hrs. The precipitated solid was filtered, washed with Tetrahydrofuran (8 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33 °C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=0.45 gms.

[0342] EXAMPLE-17:

[0343] Preparation of racemic cloprostenol sodium.

[0344] Racemic cloprostenol of Formula XII (1 gm) and acetone (15 mL) were added to a round bottom flask at 25-35°C. Sodium methoxide (0.37 gms) was added to the resulting solution at the same temperature and stirred for 4 hrs. The precipitated solid was filtered, washed with acetone (6 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=0.7 gms.

[0345] EXAMPLE-18:

[0346] Preparation of racemic cloprostenol sodium.

[0347] Racemic cloprostenol of Formula XII (1 gm) and acetone (15 mL) were added to a round bottom flask at 25-35°C. Sodium methoxide (0.37 gms) was added to the resulting solution at the same temperature and stirred for 1 hr. Diisopropyl ether (30 mL) was added to the resulting reaction mass and stirred for about 2 hrs. The precipitated solid was filtered, washed with Diisopropyl ether (12 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=0.65 gms.

[0348] EXAMPLE-19:

[0349] Preparation of racemic cloprostenol sodium.

[0350] The procedure described in example 18 was performed by using n-hexane solvent instead Diisopropyl ether yields 0.78 gms of the title compound.

[0351] EXAMPLE-20:

[0352] Preparation of racemic cloprostenol sodium. Racemic cloprostenol of Formula XII (1 gm) and acetone (10 mL) were added to a round bottom flask at 25-35°C. Sodium 2-ethyl hexanoate (0.37 gms) was added to the resulting solution at the same temperature and stirred for 1 hr. n-hexane (16 mL) was added to the resulting reaction mass and stirred for about 2 hrs. The precipitated solid was filtered, washed with n-hexane (6 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=0.75 gms.

[0353] EXAMPLE-21:

[0354] Purification of racemic cloprostenol sodium.

[0355] Racemic cloprostenol sodium (100 gms) obtained from Ex- 13, acetone (1800 mL) and methanol (200 ml) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to 42-48°C, stirred for 30-60 mins and allowed to cool to 25- 35°C. The precipitated solid was filtered, washed with a mixture of acetone (200 mL) and methanol (180 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=80 gms. HPLC analysis: HPLC Purity: 99.72%; 15-epimer impurity content: 0.01% and 5,6-trans impurity content: 0.19%.

[0356] EXAMPLE-22:

[0357] Preparation of racemic cloprostenol sodium (sodium tert-butoxide base).

[0358] The procedure described in example 16 was performed by using sodium tert-butoxide base instead of sodium 2-ethyl hexanoate resulted no solid material was formed.

[0359] EXAMPLE-23:

[0360] Preparation of racemic cloprostenol sodium (sodium bicarbonate base).

[0361] The procedure described in example 16 was performed by using sodium bicarbonate base instead of sodium 2-ethyl hexanoate resulted no solid material was formed.

[0362] EXAMPLE-24:

[0363] Preparation of racemic cloprostenol sodium (sodium hydroxide base) The procedure described in example 16 was performed by using sodium hydroxide base and ethanol solvent instead of sodium 2-ethyl hexanoate base and tetrahydrofuran solvent resulted no solid material was formed.

[0364] EXAMPLE-25:

[0365] Preparation of racemic mixture of Formula V-la and V-4a.

[0366] (±) enone of Formula IVa (90 gms) and Sodium borohydride (2.637 gms) were added to a round bottom flask at 25-35°C. Dichloromethane (450 mL) was added to the above reaction and contents were cooled to -37 to -43 °C and then methanol (90 ml) was added at -37 to - 43°C. The reaction mass was stirred at the same temperature for 1 hr-1 hr 15 mins. The reaction mass temperature was raised to -7 to -13°C and pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 5 mL hydrochloric acid in 5 mL of water) at <5°C. The temperature of the reaction mass was raised to 20-30°C. Water (270 mL) was added to the reaction mass, stirred for 15-30 mins and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane (2 X 270 ml), combined all organic layers and washed with water (450 ml). The resulting organic layer was distilled completely under vacuum at <45°C to get residue mass. The resulting residue was stripped off with methanol (180 mL) to obtain crude product. Yield=90 gms.

[0367] Crystallization: Methanol (2700 ml) was added to the above residue (90 gms) at 35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30- 60 mins. The reaction mass was allowed to cool to 25-35°C gradually and stirred for about 6hrs. The resulting solids were filtered, washed with methanol (90 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=32 gms.

[0368] EXAMPLE-26:

[0369] Preparation of racemic mixture of Formula Vl-la and VI-4a.

[0370] Isomeric mixture of compounds of Formula V-la and V-4a having about 5.08% of undesired V-2a and V-3a obtained from example 25 (30 gms ) and dichloromethane (600 mL) were added to a round bottom flask at 25-35°C. p-Nitro benzoyl chloride (16.08 gms) and 4-Dimethyl amino pyridine (1.41 gms) were added to the above reaction mass and contents were cooled to 0-10°C and then trimethylamine (10.53 gms) was added. The temperature of the reaction mass was raised to 22-28°C and stirred for 3hrs at the same temperature. Water (90 mL) was added to the reaction mass, stirred for 15-30mins and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane (90 ml), combined all organic layers and the resulting organic layer was distilled completely under vacuum at <45°C.

[0371] Crystallization: Acetonitrile (210 ml) was added to the above residue at 35-45°C. The temperature of the reaction mass was raised to 70-76°C and stirred for 30-60 mins at the same temperature. The reaction mass was cooled to 25-35°C, then further cooled to 10- 16°C and stirred for about 2hrs. The resulting solids were filtered, washed with chilled acetonitrile (15 ml) and suck dried for 15-30 mins to afford title compound. Yield=37.8 gms. EXAMPLE-27:

[0372] Preparation of racemic mixture of Formula VII- 1 and VII-4.

[0373] Isomeric mixture of compounds of Formula VI-1 a and VI-4a obtained from example 26 (37 gms), methanol (300 mL), potassium carbonate (9.3 gms) were added to a round bottom flask at 25-35°C and stirred for 5-6hrs. Reaction mass pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 9 mL hydrochloric acid in 81 ml of water) at 25-35°C, stirred for 15-30 mins, filtered and washed with methanol (15 mL). The solvent was distilled out completely from the resulting filtrate under vacuum at below 40°C. The residue obtained was cooled to 25-35°C and Dichloromethane (152 mL), isopropyl alcohol (38 mL) and Water (300 ml) were added. The reaction mass was stirred for 15-30 mins and layers were separated. The aqueous layer was extracted with dichloromethane (2 X 120 ml), combined all organic layers. The resulting organic layer was distilled completely under vacuum at <50°C to get residue. Toluene (120 mL) was added to the above residue at35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux forl-2hrs. The reaction mass was cooled to below 60°C and distilled out solvent completely. The obtained residue was cooled to 20-30°C and Dichloromethane (120 mL) and isopropyl alcohol (30 mL) were added and stirred for 15- 30 mins. Sodium bicarbonate solution (prepared by dissolving 5.4 gms of sodium bicarbonate in 90 mL of water) was added to above reaction mass, stirred for 15-30mins and layers were separated. The organic layer again treated with same sodium bicarbonate solution stirred for 15-30mins and layers were separated. The resulting organic layer was distilled completely under vacuum at <45°C. Ethyl acetate 120 mL) was added to the resulting solid at 35-45°C, stirred for 15-30mins and then cooled to 25-35°C. n-hexane (240 ml) was added to the above reaction mass at same temperature, maintained for 4 hrs, filtered, washed with n-hexane (30 mL) and suck dried for 15-30 mins. The wet material was dried at 25-35°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=16.4 gms.

[0374] Combined chemical purity of compounds of Formula VII-I and VII-4: 96.72% Combined chemical purity of compounds of Formula VII-2 and VII-3: 0.34%

[0375] EXAMPLE-28:

[0376] Preparation of racemic mixture of protected diol of Formula VIII- la and VIII-4a. Racemic mixture of compounds of Formula VII-1 and VII-4 (16 gms) obtained from example 27 and dichloromethane (160 mL) were added to a round bottom flask at 25-35°C and stirred for 10-20 mins. Pyridinium p-toluene sulfonate (0.592 gms) and Ethyl vinyl ether (13.63 gms) were added to above reaction mass at same temperature and stirred for 5-6hrs. Sodium bicarbonate solution (prepared by dissolving 5.6 gms of sodium bicarbonate in 80 mL of water) was added to above reaction mass, stirred for 15-30mins and layers were separated. The aqueous layer was extracted with di chloromethane (2 X48 ml) and combined all organic layers. The resulting organic layer was distilled completely under vacuum at <40°C. The resulting residue was stripped off with tetrahydrofuran (16 ml) to afford title compound.

[0377] EXAMPLE-29:

[0378] Preparation of racemic mixture of protected lactol of Formula IX- la and IX-4a.

[0379] Tetrahydrofuran (160 mL) was added to the racemic mixture of protected diol of formula Vlll-la and VIII-4a obtained from example 28 at 25-35°C and stirred for 10-20 mins. The temperature of the reaction mass was cooled to -81°C to -75°C, DIBAL-H (70.88 mL) in toluene was added and stirred for 2hrs. Methanol (6.4 mL) was added to the reaction mass and stirred for 10-20mins at the same temperature. The temperature of the reaction mass was raised to -15°C to -5°C. Sodium potassium tartrate solution (prepared by dissolving 32 gms of Sodium potassium tartrate in 160 mL of water) was added to the reaction mass at 10°C and then temperature of reaction mass raised to 25-35°C. Ethyl acetate (160 mL) was added to the reaction mass, at 25-35°C, then temperature was raised to 35-45°C, stirred for 15-30mins and layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 80 ml) and combined all organic layers, washed with water (80 mL) and layers were separated. The resulting organic layer was distilled completely under vacuum at <45°C to afford title compound.

[0380] EXAMPLE-30:

[0381] Preparation of racemic protected cloprostenol of Formula XI- la and XI-4a.

[0382] 4-Carboxybutyltriphenylphosphnium bromide (58.5 gms) and Tetrahydrofuran (160 mL) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was cooled to -15°C to -5°C and Potassium tert butoxide solution (395.87 mL) was added reaction mass, stirred for 15-30 mins. The temperature of reaction mass was raised to -3°C to 3°C, stirred for 30-60 mins and then cooled to -15°C to -5°C.

[0383] A solution of racemic mixture of protected lactol of Formula IX- la and IX-4a (prepared by dissolving example-29 residue mass of racemic mixture of protected lactol of Formula IX- la and IX-4a in 80 mL of tetrhydrofuran) was added to above reaction mass at -15°C to - 5°C. The temperature of reaction mass raised to -3° to 3°C and stirred for 2 hrs. Water (16 mL) was added to the reaction mass, stirred for 15-30 mins and distilled out the solvent at below 30°C. Water (160 mL) and ethyl acetate (160 mL) were added to the resulting residue at 25-35°C and stirred forl0-20 mins. HPLC analysis revealed the content of UV active impurity of Formula A is 40.5%. Reaction mass pH was adjusted to 7.8-8.2 with orthophosphoric acid solution (4.8 mL, prepared by dissolving 2.4 mL orthophosphoric acid in 2.4 ml of water) at 25-35°C, stirred for 15-30 mins, and layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 80 ml) and combined all organic layers. The combined organic layer was treated with sodium bicarbonate solution (prepared by dissolving 5.6 gms of sodium bicarbonate in 80 mL of water) at 25-35°C, stirred for 15- 30mins and layers were separated. The resulting organic layer was distilled completely under vacuum at <40°C to afford title compound. The content of UV active impurity Formula A: 0.17% by HPLC.

[0384] EXAMPLE-31:

[0385] Preparation of racemic cloprostenol of Formula XII

[0386] Tetrahydrofuran (80 mL), water (80 mL) and Orthophosphoric acid (19 gms) were added to the racemic protected cloprostenol of Formula XLla and XI-4a obtained from example 30 at 25-35°C and stirred for 6-8hrs. HPLC analysis revealed the content of TPPO impurity of Formula B is 47.55%. Ethyl acetate (80 mL) was added to the reaction mass and pH of the reaction mass was adjusted to 11-12 with sodium hydroxide solution (prepared by dissolving 6.4 gms of sodium hydroxide in 26 ml of water) at 25-35°C, stirred for 15-30 mins and layers were separated. The product containing aqueous layer was extracted with ethyl acetate (4 X 48 ml), ethyl acetate (80 mL) was added to the aqueous layer and the pH of the aqueous layer was adjusted to 5-6 with orthophosphoric acid solution (prepared by dissolving 4.8 mL orthophosphoric acid in 4.8 ml of water) at 25-35°C, stirred for 15-30 mins and layers were separated. The aqueous layer was extracted with ethyl acetate (2 X 48 ml) and combined all organic layers. The combined organic layer was treated with water, stirred for 15-30mins and layers were separated. The resulting organic layer was distilled completely under vacuum at below 35°C to afford title compound. HPLC Analysis: Purity: 97.98%, 15-epimer impurity content: 0.25%; 5,6-trans impurity content: 1.12%; TPPO impurity of Formula B: 0.19%; UV active impurity Formula A: Not detected; Impurity at 0.83 RRT content: 0.15% and Impurity at 2.23 RRT content: 0.11%.

[0387] EXAMPLE-32:

[0388] Preparation of racemic cloprostenol sodium (sodium 2-ethyl hexanoate).

[0389] Tetrahydrofuran (180 mL) was added to the racemic cloprostenol of formula XII obtained from example 31 at 25-35°C and stirred for 15-30 mins. Activated carbon (1 gms) was added to the resulting solution and stirred for 30-60 mins. The resulting solution filtered through hyflo bed (1 gm), washed with tetrahydrofuran (20 ml) and filtered. Sodium 2-ethyl hexanoate (7.43 gms) was added to the resulting filtrate and stirred for 30 mins. Diisopropyl ether (100 mL) was added to the resulting solution and stirred for about 2 hrs at 25-35°. The precipitated solid was filtered, washed with diisopropyl ether (40 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=l 1.6 gms. HPLC analysis: Purity: 99.16%, 15-epimer impurity content: 0.09%; 5,6-trans impurity content: 0.61%; TPPO impurity of Formula B: 0.03%; UV active impurity Formula A: 0.007%; Impurity at 0.83 RRT content: 0.06% and Impurity at 2.23 RRT content: 0.08%.

[0390] EXAMPLE-33:

[0391] Purification of racemic cloprostenol sodium.

[0392] Racemic cloprostenol sodium obtained from example 32 (5.5 gms), acetone (100 mL) and methanol (10 ml) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to 42-48°C, stirred for 30-60 mins and allowed to cool to 25- 35°C and maintained for 4 hrs. The precipitated solid was filtered, washed with a mixture of acetone (8 mL) and methanol (2 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 12 hrs under vacuum to afford title compound. Yield=3.7 gms. HPLC analysis: Purity: 99.77%; 15-epimer impurity content: 0.02%; 5,6-trans impurity content: 0.22%; TPPO impurity of Formula B: Not detected; UV active impurity Formula A: Not detected; Impurity at 0.83 RRT content: 0.03% and Impurity at 2.23 RRT content: Not detected.

[0393] Example 34:

[0394] Preparation of racemic mixture of Formula V-la and V-4a.

[0395] (±) enone of Formula IVa (150 gms) and Sodium borohydride (4.38 gms) were added to a round bottom flask at 25-35°C. Dichloromethane (500 mL) was added to the above reaction and contents were cooled to -37 to -43°C and then methanol (150 ml) was added at -37 to - 43°C. The reaction mass was stirred at the same temperature for 1 hr-1 hr 15mins. The reaction mass temperature was raised to -5 to -15°C and pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 17 mL hydrochloric acid in 17 ml of water) at <5°C. The temperature of the reaction mass was raised to 27-33°C. Water (300 mL) was added to the reaction mass, stirred for 15-30 mins and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane (2 X 450 ml), combined all organic layers and washed with water (750 ml). The resulting organic layer was distilled completely under vacuum at <45°C to get residue mass. The resulting residue was stripped off with methanol (200 mL) to obtain crude product. Yield= 165 gms

[0396] Crystallization: Methanol (4500 ml) was added to the above residue (165 gms) at 35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30-60 mins. The reaction mass was allowed to cool to 25-35°C gradually and stirred for about 6hrs. The resulting solids were filtered, washed with methanol (150 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=59.2 gms.

[0397] Example 35: Recycling of undesired racemic mixture of Formula V-2a and V-3a into (±) enone of Formula IVa.

[0398] The mother liquor obtained from example 34 crystallization process was distilled out and co-distilled the resulting reaction mass with dichloromethane (2x300 mL) to obtain a residue (100 gms).

[0399] The resulting residue (100 gms) contained the following isomers (content by HPLC):

[0400] Dichloromethane (2000 mL) was added to the above resulting residue (100 gms) at 25- 35°C, stirred for 15-30 mins. To this reaction mass pre-prepared solution of potassium bromide (3.2 gms), sodium bicarbonate (15.2 gms) and water (270 mL) was added at 25- 35°C. The temperature of the reaction mass cooled to -6°C to 0°C and TEMPO (0.30 gms) was added. To this reaction mass pre-prepared solution of sodium bicarbonate (5.18 gms) and Sodium hypochlorite (172.11 gms) was added, stirred for 20-30mins at -6°C to 0°C. Sodium thiosulphate solution (80 g of sodium thiosulphate was dissolved in 100 ml of water) was added to the resulting reaction mass at below 10°C. pH of the reaction mass was adjusted to 3.5 to 4.5 with hydrochloric acid. The temperature of the reaction mass was raised to 25-35°C, stirred for 15-30 mins and layers were separated. The aq layer was extracted with dichloromethane (2 X 500 ml), combined all organic layers and washed with water (500 ml). The resulting organic layer was distilled completely under vacuum at <45°C and stripped off with methanol (100 mL). Methanol (500 ml) was added to the above residue and stirred under reflux for 30mins. The reaction mass was cooled to 25- 35°C gradually and stirred for about 2hrs. The resulting solids were filtered, washed with methanol (200 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield= 85 gms

[0401] Example 36: (±) enone of Formula IVa obtained from example 35 (85 gms) and Sodium borohydride (2.48 gms) were added to a round bottom flask at 25-35°C. Dichloromethane (425 mL) was added to the above reaction and contents were cooled to -37 to -43°C and then methanol (85 ml) was added at -37 to -43 °C. The reaction mass was stirred at the same temperature for 1 hr-1 hr 15 mins. The reaction mass temperature was raised to -5 to -15°C and pH was adjusted to 3.5-4.5 with hydrochloric acid solution (prepared by dissolving 15 mL hydrochloric acid in 15 ml of water) at <5°C. The temperature of the reaction mass was raised to 27-33°C. Water (255 mL) was added to the reaction mass, stirred for 15-30 mins and the resulting organic and aqueous layers were separated. The aqueous layer was extracted with di chloromethane (2 X 255 ml), combined all organic layers and washed with water (425 ml). The resulting organic layer was distilled completely under vacuum at <45°C to get residue mass. The resulting residue was stripped off with methanol (170 mL) to obtain crude product. Yield=90 gms

[0402] Crystallization: Methanol (2550 ml) was added to the above residue (90 gms) at 35-45°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30-60 mins. The reaction mass was allowed to cool to 25-35°C gradually and stirred for about 6hrs. The resulting solids were filtered, washed with methanol (85 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=40 gms. Example 37:

[0403] Preparation of racemic mixture of Formula V-la and V-4a.

[0404] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms) and methanol (100 mL) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 30mins. The reaction mass was cooled to 25-35°C gradually and stirred for about 30 mins. The resulting solids were filtered, washed with methanol (10 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30 mins under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=2 gms. HPLC Purity: 93.97%.

[0405] Example 38:

[0406] Preparation of racemic mixture of Formula V-la and V-4a.

[0407] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms) and methanol (200 mL) were added to a round bottom flask at 25-35°C. The temperature of the reaction mass was raised to reflux and stirred under reflux for 15mins. The reaction mass was cooled to 25-35°C gradually and stirred for about 4hrs. The resulting solids were filtered, washed with methanol (10 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30mins under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=1.8 gms. HPLC Purity: 95%.

[0408] Example 39:

[0409] Preparation of racemic mixture of Formula V-la and V-4a.

[0410] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms), methanol (40 mL) and acetonitrile (10 mL) were added to a round bottom flask at 25-35°C and stirred for 30 min at the same temperature. The resulting solids were filtered. Methanol (40 mL) and acetonitrile (10 mL) were added to the resulting solid and stirred under reflux for 30mins. The reaction mass was cooled to 25-35°C gradually and stirred for about 4hrs. The resulting solids were filtered, washed with methanol (5 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=2.0 gms. HPLC Purity: 94%.

[0411] EXAMPLE-40: Preparation of racemic mixture of Formula V-la and V-4a.

[0412] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms) and methanol 35 (mL) and dichloromethane (15 mL) were added to a round bottom flask at 25-35°C and stirred for 30 min at the same temperature. The resulting solids were filtered, washed with methanol (10 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30 mins under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=1.6 gms. HPLC Purity: 92.39%.

[0413] EXAMPLE-41:

[0414] Preparation of racemic mixture of Formula V-la and V-4a.

[0415] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms) and ethyl acetate 50 (mL) were added to a round bottom flask at 25-35°C and stirred for 30 min at the same temperature. The resulting solids were filtered, washed with ethyl acetate (5 mL) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30 mins under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=1.7 gms. HPLC Purity: 91.93%.

[0416] EXAMPLE-42:

[0417] Preparation of racemic mixture of Formula V-la and V-4a.

[0418] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms) and acetonitrile 50 (mL) were added to a round bottom flask at 25-35°C and stirred for 30 min at the same temperature. The resulting solids were filtered, washed with acetonitrile (5 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30 mins under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=1.9 gms. HPLC Purity: 92.89%.

[0419] EXAMPLE-43:

[0420] Preparation of racemic mixture of Formula Va-1 and Va-4.

[0421] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms) and acetone 50 (mL) were added to a round bottom flask at 25-35°C and stirred for 30 min at the same temperature. The resulting solids were filtered, washed with acetone (5 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30 mins under vacuum and then at 50-56°C for about 4 hr under vacuum to afford title compound. Yield=1.3 gms. HPLC Purity: 93.04%.

[0422] EXAMPLE-44:

[0423] Preparation of racemic mixture of Formula V-la and V-4a.

[0424] Isomeric mixture of compounds of Formula V-la, V-2a, V-3a and V-4a (5 gms), dichloromethane (20 mL) and methyl tert-butyl ether (40 mL) were added to a round bottom flask at 25-35°C and stirred for 4 hrs at the same temperature. The resulting solids were filtered. Dichloromethane (10 mL) and methyl tert-butyl ether (20 mL) were added to the resulting solid and stirred for 30 mins at 37-43°C. The reaction mass was cooled to 25-35°C gradually and stirred for about 30 mins. The resulting solids were filtered, washed with methyl tert-butyl ether (5 ml) and suck dried for 15-30 mins. The wet material was dried at 27-33°C for 30-60 mins under vacuum and then at 52-58°C for about 4 hr under vacuum to afford title compound. Yield=1.70 gms. Chemical HPLC Purity: 98.99%.

[0425] It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be constructed as limiting, but merely as exemplifications of preferred embodiments. For example, the functions described above and implemented as the best mode for operating the present invention are for illustration purposes only. Other arrangements and methods may be implemented by those skilled in the art without departing from the scope and spirit of this invention. Moreover, those skilled in the art will envision other modifications within the scope and spirit of the specification appended hereto.

Claims

WE CLAIM:Claim 1 : A process for purification of a mixture of enol compound of Formula V-l,Formula V-2, Formula V-3 and Formula V-4, comprising:wherein “P” represents hydroxy protecting group, (3aR, 4R, 5R, 6aS, 3R) - Formula V-l (3aR, 4R, 5R, 6aS, 3S) - Formula V-2 (3aS, 4S, 5S, 6aR, 3R) - Formula V-3 (3aS, 4S, 5S, 6aR, 3S) - Formula V-4 a) suspending or dissolving a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 in a suitable solvent, b) optionally heating the reaction mass to about reflux temperature, c) optionally cooling the solution to room temperature or less, and d) isolating the mixture of enol compound of Formula V-l and Formula V-4.Claim 2: The process as claimed in claim 1, wherein the hydroxy protecting group represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).Claim 3: The process as claimed in claim 2, wherein the hydroxy protecting group is para phenyl benzoyl group.Claim 4: The process as claimed in claim 1, wherein the each enol compound ofFormula V-l, Formula V-2, Formula V-3 and Formula V-4 in the mixture in step a) is about 15 to about 35% by chiral HPLC.Claim 5: The process as claimed in claim 4, wherein the each of the enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 is about 20 to about 30% by chiral HPLC.Claim 6: The process as claimed in claim 1, wherein the mixture of enol compound ofFormula V-l, Formula V-2, Formula V-3 and Formula V-4 of step a) is prepared by reacting (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent.racemic or (±) enone of Formula IVClaim 7: The process as claimed in claim 6, wherein the suitable reducing agent is cerium (III) chloride and sodium borohydride and wherein the suitable solvent is methanol, dichloromethane or mixture thereof.Claim 8: The process as claimed in claim 1, wherein the suitable solvent is selected from the group consisting of alcohols, halogenated hydrocarbons, nitriles, ethers, esters, ketones, water and mixture thereof.Claim 9: The process as claimed in claim 8, wherein the suitable solvent is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, dichloromethane, di chloroethane, chloroform, acetonitrile, propionitrile, tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-di oxane, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof.Claim 10: The process as claimed in claim 9, wherein the suitable solvent is methanol, ethanol, acetone, ethyl acetate, acetonitrile, dichloromethane, methyl tert butyl ether and mixtures thereof.Claim 11 : The process as claimed in claim 1, wherein the step a) is carried out at a temperature of about 45 °C to about reflux.Claim 12: The process as claimed in claim 1, wherein the step c) is carried out at below 35°C.Claim 13 : The process as claimed in claim 1, wherein the mixture of enol compound of Formula V-l and Formula V-4 of step d) is isolated by filtration and wherein the mixture of enol compound of Formula V-2 and Formula V-3 are purged into mother liquors.Claim 14: The process as claimed in claim 1, wherein the each of the enol compound of Formula V-l and Formula V-4 in step d) mixture is about 45% by chiral HPLC and each of Formula V-2 and V-3 isomer is about 5% by chiral HPLC.Claim 15: A process for recycling of a mixture of undesired enol compound of FormulaV-2 and Formula V-3, comprising;wherein “P” represents hydroxy protecting group, (3aR, 4R, 5R, 6aS, 3S) - Formula V-2 (3aS, 4S, 5S, 6aR, 3R) - Formula V-3 a) reacting a mixture of enol compound of Formula V-2 and Formula V-3 with a suitable oxidizing agent in a suitable solvent to obtain (±) enone of Formula IV,racemic or (±) enone of Formula IV b) reacting the (±) enone compound of Formula IV with a suitable reducing agent in a suitable solvent to obtain a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4, andwherein “P” represents hydroxy protecting group,(3aR, 4R, 5R, 6aS, 3R) - Formula V-l(3aR, 4R, 5R, 6aS, 3S) - Formula V-2(3aS, 4S, 5S, 6aR, 3R) - Formula V-3(3aS, 4S, 5S, 6aR, 3S) - Formula V-4 c) purifying the mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable solvent to obtain a mixture of enol compound of Formula V-l and Formula V-4.Claim 16: The process as claimed in claim 15, wherein the undesired mixture of enol compound of Formula V-2 and Formula V-3 of step a) is obtained by the process in accordance with claim 1 to 14.Claim 17: The process as claimed in claim 15, wherein the hydroxy protecting group represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).Claim 18: The process as claimed in claim 15, wherein the oxidizing agent is selected from Dess-Martin periodinane, TEMPO / potassium bromide / sodium hypochlorite, DCC / DMSO or CrO3 / Pyridine.Claim 19: The process as claimed in claim 15, wherein the suitable solvent of step a) is selected from dichloromethane, tetrahydrofuran, toluene, dimethyl sulfoxide, N,N-dimethylformaide, N,N-dimethylacetamide water and mixtures thereof.Claim 20: The process as claimed in claim 15, wherein the step a) the oxidizing agent is TEMPO / potassium bromide / sodium hypochlorite and the suitable solvent is di chi or om ethane .Claim 21 : The process as claimed in claim 15, wherein the step b) the suitable reducing agent is cerium (III) chloride and sodium borohydride and wherein the suitable solvent is methanol, dichloromethane or mixture thereof.Claim 22: The process as claimed in claim 15, wherein the step c) the suitable solvent is selected from the group consisting of alcohols, halogenated hydrocarbons, nitriles, ethers, esters, ketones, water and mixture thereof; wherein the alcohols selected from methanol, ethanol, isopropanol, n-propanol, n- butanol, and isobutanol; halogenated hydrocarbons selected from dichloromethane, di chloroethane and chloroform; nitriles selected from acetonitrile and propionitrile; ethers selected from tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether and 1,4-di oxane; esters selected from ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and mixtures thereof.Claim 23 : The process as claimed in claim 22, wherein the suitable solvent is methanol, ethanol, acetone, ethyl acetate, acetonitrile, dichloromethane, methyl tert, butyl ether and mixtures thereof.Claim 24: A process for preparation of a mixture of diol compound of Formula VII-1 and Formula VII-4, comprising:(3aR, 4R, 5R, 6aS, 3R) - Formula VII- 1(3aS, 4S, 5S, 6aR, 3S) - Formula VII-4 a) reacting a mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 with a suitable hydroxyl protecting agent in a suitable solvent to obtain a mixture of protected enol compounds of Formula VI- 1, Formula VI-2, Formula VI-3 and Formula VI-4,wherein the “P” and “Pi” represents a suitable hydroxyl protecting group; b) purifying the mixture of protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 in an organic solvent to obtain a mixture of protected enol compounds of Formula VI- 1 and VI-4; and c) converting the mixture of protected enol compounds of Formula VI- 1 and VI-4 into mixture of diol compound of Formula VII- 1 and Formula VII-4; wherein the organic solvent of step b) is selected from the group comprising alcohols, esters, hydrocarbons, nitriles, ketones and mixture thereof.Claim 25 : The process as claimed in claim 24, wherein the suitable hydroxyl protecting group (“P” and “Pi”) represents p-phenylbenzoyl (PPB), acetyl (Ac), p- methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p- nitrobenzoyl group (PNB), Trimethyl silyl (TMS), Triethyl silyl (TES) or t- butyldimethyl silyl (TBDMS) and the like; preferably p-nitrobenzoyl group (PNB).Claim 26: The process as claimed in claim 25, wherein the “P” represents p- phenylbenzoyl (PPB) and the “Pi” represents p-nitrobenzoyl group (PNB).Claim 27: The process as claimed in claim 24, wherein the step a) is carried out in presence of a catalyst and a base.Claim 28: The process as claimed in claim 27, wherein the base is selected from the group consisting of triethyl amine, diisopropylamine, diisopropyl ethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate and mixtures thereof and the catalyst is dimethyl amino pyridine.Claim 29: The process as claimed in claim 28, wherein the base is triethyl amine and the catalyst is dimethyl amino pyridine.Claim 30: The process as claimed in claim 24, wherein the solvent of step a) is selected from the group comprising alcohols selected from methanol, ethanol and isopropanol; chlorinated solvent selected from dichloromethane, di chloroethane and chloroform; esters selected from ethyl acetate and isopropyl acetate; ketones selected from acetone, methyl isobutyl ketone and methyl ethyl ketone; ethers selected from diethyl ether, THF, methyl tertiary butyl ether and diisopropyl ether; hydrocarbons selected from hexane, heptane, cyclohexane, and toluene; water and mixtures thereof.Claim 31 : The process as claimed in claim 30, wherein the solvent is selected from the group consisting of dichloromethane, methanol, ethyl acetate, acetone, THF, methyl tertiary butyl ether, hexane, toluene and mixtures thereof.Claim 32: The process as claimed in claim 30, wherein the base is triethyl amine, the catalyst is dimethyl amino pyridine and the suitable solvent is di chi orom ethane .Claim 33: The process as claimed in claim 24, wherein the step b) comprises; i) dissolving the protected enol compounds of Formula VI-1, Formula VI-2, Formula VI-3 and Formula VI-4 in an organic solvent at a temperature of about 40°C to about reflux, ii) cooling the step i) solution to room temperature or less, iii) Filtering the mixture of protected enol compounds of Formula VI-1 and VI-4.Claim 34: The process as claimed in claim 33, wherein the organic solvent is selected from the group consisting of alcohols selected from methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol and tertiary butanol; esters selected from methyl acetate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate and n-butyl acetate; aromatic hydrocarbons selectedfrom toluene and xylene; cyclic hydrocarbons selected from n-hexane, n- heptane and cyclohexane; halogenated hydrocarbons selected from dichloromethane, di chloroethane, chloroform and carbon tetrachloride; nitriles selected from acetonitrile and propionitrile;, ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone and their mixtures.Claim 35: The process as claimed in claim 34, wherein the organic solvent is methanol, ethyl acetate, hexane, acetonitrile, acetone and their mixtures.Claim 36: The process as claimed in claim 35, wherein the organic solvent is acetonitrile.Claim 37: The process as claimed in claim 24, wherein the step c) comprises deprotecing the protected enol compounds of Formula VI- 1 and VI-4 with a suitable deprotecing agents in an organic solvent.Claim 38: The process as claimed in claim 37, wherein the suitable deprotecing agent is selected from the group comprising organic bases selected from triethyl amine, diisopropyl amine, diethyl amine; inorganic bases selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate; and mixtures thereof.Claim 39: The process as claimed in claim 37, wherein the organic solvent is selected from the group comprising alcohols selected from methanol, ethanol and isopropanol; esters selected from ethyl acetate and isopropyl acetate; chlorinated solvents selected from dichloromethane, di chloroethane and chloroform; hydrocarbons selected from n-hexane, n-heptane, cyclohexane, toluene and xylene and mixtures thereof.Claim 40: The process as claimed in claim 37, wherein the suitable deprotecing agent is potassium carbonate and the organic solvent is methanol.Claim 41 : The process as claimed in claim 24, wherein the mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 of step a) comprises an enol compound of Formula V-l and Formula V-4 each havinga purity of about 45% by chiral HPLC and each of undesired enol compound of Formula V-2 and V-3 isomer is about 5% by chiral HPLC.Claim 42: The process as claimed in claim 24, wherein the mixture of enol compound of Formula V-l, Formula V-2, Formula V-3 and Formula V-4 of step a) is obtained by the process in accordance with claims 1 to 14.Claim 43 : The process as claimed in claim 24, wherein the mixture of diol compound of Formula VII-1 and Formula VII-4 of step c) having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3.Claim 44: A process for preparation of racemic cloprostenol or its salt thereof having less than 0.2% by HPLC of racemic 15-epi cloprostenol impurity of Formula D, comprising: preparing a mixture of diol compound of Formula VII- 1 and Formula VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3 according to claims 1 - 43, and converting the mixture of diol compound of Formula VILl and VII-4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VII-2 and Formula VII-3 into racemic cloprostenol or its salt thereof having less than 0.2% by HPLC of racemic 15-epi cloprostenol impurity of Formula D.[(8R, 9R,11R,12S,15S) + (8S,9S,1 IS, 12R,15R)] - Impurity of Formula DClaim 45: A process for preparation of racemic cloprostenol of (Formula XII-1 and Formula XII-4) or its salt thereof having less than 0.5% by HPLC of UV active impurity of Formula A and / or less than 0.5% by HPLC of TPPO impurity of Formula B, comprising:[(8R,9R,11R,12S,15R) - Formula XII -1 (8 S,9 S, 11 S, 12R, 15 S)] - Formula XII -4 Racemic cloprostenol (XII)a) reacting a mixture of protected diol compound of Formula VIII-1 and Formula VIII-4 with a suitable keto reducing agent to obtain a protected lactol compound of Formula IX-1 and Formula IX-4,wherein “P2” represents ethoxy ethyl, methoxy benzyl, acetyl, tetrahydropyran, trimethyl silyl, triethyl silyl or t-butyldimethyl silyl; b) reacting the mixture of protected lactol compound of Formula IX-1 and Formula IX-4 with a compound of Formula X in a suitable solvent and a base, to obtain a solventsolution containing mixture of protected cloprostenol of formula XI-1 and Formulamixture of protected cloprostenol of Formula XI- 1 and Formula XI-4, d) adjusting pH to about 7.5 to about 9.5 with an acid, e) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of formula XI- 1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A, f) deprotecting the mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A with an acid in a suitable solvent to obtain a solvent solution containing racemic cloprostenol of Formula XII -1 and Formula XII -4, g) adding water immiscible solvent to the solution of step f), h) adjusting pH to about 9 to about 13 with a base, i) separating the aqueous layer and adding water immiscible solvent, j) adjusting the pH to about 4.5 to about 6.5 with an acid, and k) separating the organic layer and evaporating the solvent to obtain a mixture of racemic cloprostenol of Formula XII -1 and Formula XII -4 having less than 0.5% by HPLC of UV active impurity of Formula A and less than 0.5% by HPLC of TPPO impurity of Formula B.Claim 46: The process as claimed in claim 45, wherein the mixture of protected diol compound of Formula VIII-1 and Formula VIII-4 is prepared by protecting the mixture of diol compound of Formula VIL1 and Formula VIL4 having less than 0.5% by HPLC of a mixture of diol compound of Formula VIL2 and Formula VII-3.Claim 47: The process as claimed in claim 45, wherein the “P2” represents ethoxy ethyl group.Claim 48: The process as claimed in claim 45, wherein the step a) is carried out in presence of DIBAL-H in an organic solvent at a temperature of about -80°C to about -10°C; wherein the organic solvent is selected from the group consisting of toluene, THF, diethyl ether, methyl tertiary butyl ether, dichloromethane and mixtures thereof.Claim 49: The process as claimed in claim 48, wherein the organic solvent is dichloromethane, THF and mixtures thereof.Claim 50: The process as claimed in claim 45, wherein the base used in step b) is selected from potassium tertiary butoxide, magnesium tertiary butoxide and lithium tertiary butoxide.Claim 51 : The process as claimed in claim 45, wherein the solvent used in step b) is selected from toluene, THF, diethyl ether, methyl tertiary butyl ether, dichloromethane and mixtures thereof.Claim 52: The process as claimed in claim 45, wherein the water immiscible solvent used in the step c) is selected from the group comprising di chloromethane, toluene, ethyl acetate, methyl tert butyl ether and mixtures thereof.Claim 53 : The process as claimed in claim 52, wherein the water immiscible solvent is ethyl acetate.Claim 54: The process as claimed in claim 45, where in the pH in step d) is about 7.8 to about 8.2.Claim 55: The process as claimed in claim 45, wherein the suitable acid used in step d) is selected from the group comprising hydrochloric acid, hydrobromic acid, ortho phosphric acid and sulfuric acid.Claim 56: The process as claimed in claim 55, wherein the suitable acid is ortho phosphric acid.Claim 57: The process as claimed in claim 45, wherein the acid and suitable solvent of step f) is selected from the group comprising hydrochloric acid, orthophosphoric acid and sulfuric acid; and wherein the suitable solvent is selected from THF, 1,4-di oxane and methyl tert butyl ether; water and mixture thereof.Claim 58: The process as claimed in claim 57, wherein the acid is ortho phosphoric acid and the solvent is mixture of THF and water.Claim 59: The process as claimed in claim 45, wherein the water immiscible solvents of step g) is selected from the group comprising methyl acetate, ethyl acetate, toluene and xylene.Claim 60: The process as claimed in claim 59, wherein the water immiscible solvents is ethyl acetate.Claim 61 : The process as claimed in claim 45, wherein the base used in step h) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.Claim 62: The process as claimed in claim 61, wherein the base sodium hydroxide.Claim 63 : The process as claimed in claim 45, where in the pH in step h) is about 11 to about 12.Claim 64: The process as claimed in claim 45, wherein the pH in step j) is about 5 to 6.Claim 65: The process as claimed in claim 45, wherein the acid used in step j) is hydrochloric acid or ortho phosphoric acid.Claim 66: The process as claimed in claim 65, wherein the acid is ortho phosphoric acid.Claim 67: A process for separation of UV active impurity of Formula A from the solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI-1 and Formula XI-4 and UV active impurity of Formula A,a) providing a solution comprising water, water immiscible solvent and protected cloprostenol of Formula XI-1 and Formula XI-4 and UV active impurity of Formula A, b) adjusting pH of the step a) solution to about 7.5 to about 9.5 with an acid, and c) separating the organic layer and evaporating the solvent to obtain a mixture of protected cloprostenol of Formula XI-1 and Formula XI-4 having less than 0.5% by HPLC of UV active impurity of Formula A. Claim 68: The process as claimed in claim 67, wherein the water immiscible solvent used in step a) is selected from the group comprising dichloromethane, toluene, ethyl acetate, methyl tert butyl ether and mixtures thereof.Claim 69: The process as claimed in claim 67, wherein the pH in step a) is about 7.8 to about 8.

2. Claim 70: The process as claimed in claim 67, wherein the step c) comprises the UV active impurity of Formula A is purged along with the aqueous layer.Claim 71 : A process for separation of TPPO impurity of Formula B from the solution comprising water, water immiscible solvent and racemic cloprostenol of Formula XII -1 and Formula XII - 4 and TPPO impurity of Formula Ba) providing a solution comprising water, water immiscible solvent and racemic cloprostenol of Formula XII -1 and Formula XII - 4 and TPPO impurity of Formula B, b) adjusting pH of the step a) solution to about 9 to about 13 with a base, c) separating the aqueous layer and adding water immiscible solvent, d) adjusting the pH to about 4.5 to about 6.5 with an acid, and e) separating the organic layer and evaporating the solvent to obtain mixture of cloprostenol of Formula XII -1 and Formula XII -4 having less than 0.5% by HPLC of TPPO impurity of Formula B.Claim 72: The process as claimed in claim 71, wherein the water immiscible solvents of step a) is selected from the group comprising methyl acetate, ethyl acetate, toluene and xylene.Claim 73: The process as claimed in claim 72, wherein the water immiscible solvents is ethyl acetate.Claim 74: The process as claimed in claim 71, wherein the base used in step b) is selected from sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.Claim 75: The process as claimed in claim 74, wherein the base sodium hydroxide.Claim 76: The process as claimed in claim 71, where in the pH in step b) is about 11 to about 12.Claim 77: The process as claimed in claim 71, wherein the pH in step d) is about 5 to 6.Claim 78: The process as claimed in claim 71, wherein the acid used in step d) is hydrochloric acid or ortho phosphoric acid.Claim 79: The process as claimed in claim 78, wherein the acid is ortho phosphoric acid.Claim 80: The process as claimed in claim 71, wherein the step c) comprises the TPPO impurity of Formula B is purged along with the organic layer.Claim 81 : A process for preparation of racemic cloprostenol sodium, comprising: i) dissolving or suspending racemic cloprostenol of Formula XII in an organic solvent, ii) treating the step i) reaction mixture with a suitable sodium source, iii) optionally adding an anti-solvent to the step ii) reaction mixture or vice- versa, and iv) isolating the racemic cloprostenol sodium; wherein the organic solvent is selected from the group comprising ketones, ethers and mixtures thereof; wherein the antisolvent is selected from the group comprising ethers, aliphatic hydrocarbons, alicyclic hydrocarbons or mixtures thereof and wherein the suitable sodium source is selected from the group comprising sodium methoxide, sodium ethoxide and sodium 2-ethyl hexanoate.Claim 82: The process as claimed in claim 81, wherein the racemic cloprostenol of Formula XII is prepared by the process in accordance with claim 1 to 80.Claim 83: The process as claimed in claim 81, wherein the organic solvent is selected from the group comprising ketones selected from acetone, methyl isobutyl ketone, and methyl ethyl ketone; ethers selected from tetrahydrofuran, dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,4-di oxane and mixtures thereof.Claim 84: The process as claimed in claim 83, wherein the organic solvent is acetone or tetrahydrofuran.Claim 85: The process as claimed in claim 81, wherein the step i) carried out at a temperature of about 20°C to about reflux temperature.Claim 86: The process as claimed in claim 81, wherein the sodium source is sodium methoxide or sodium 2-ethyl hexanoate.Claim 87: The process as claimed in claim 81, wherein the step ii) carried out at a temperature of about 25 °C to about 60°C.Claim 88: The process as claimed in claim 81, wherein the antisolvent is selected from the group comprising diisopropyl ether, methyl tertiary butyl ether and hexane.Claim 89: A compound of Formula VI:Formula VI wherein the “P” represents p-phenylbenzoyl (PPB) and “Pi” represents p- nitrobenzoyl group (PNB).Claim 90: A compound of Formula VI-1 :(3aR, 4R, 5R, 6aS, 3R) - Formula VI- 1 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).Claim 91 : The compound as claimed in claim 90, wherein the “P” represents p- phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).Claim 92: A compound of Formula VI-2:(3aR, 4R, 5R, 6aS, 3S) - Formula VI-2 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).Claim 93 : The compound as claimed in claim 92 wherein the “P” represents p- phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).Claim 94: A compound of Formula VI-3 :(3aS, 4S, 5S, 6aR, 3R) - Formula VI-3 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).Claim 95: The compound as claimed in claim 94 wherein the “P” represents p- phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB).Claim 96: A compound of Formula VI-4:(3aS, 4S, 5S, 6aR, 3S) - Formula VI-4 wherein the “P” and “Pi” independently represents p-phenylbenzoyl (PPB), acetyl (Ac), p-methoxy benzyl (PMB), tetrahydropyran (THP), benzoyl (Bz), p-nitrobenzoyl group (PNB), trimethyl silyl (TMS), triethyl silyl (TES) or t-butyldimethyl silyl (TBDMS).Claim 97: The compound as claimed in claim 96 wherein the “P” represents p- phenylbenzoyl (PPB) and “Pi” represents p-nitrobenzoyl group (PNB). Claim 98: Racemic cloprostenol having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C and / or less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.Claim 99: The compound as claimed in claim 98, wherein the racemic cloprostenol having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C and / or less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.Claim 100: Racemic cloprostenol sodium having less than 0.5% by HPLC of UV active impurity of Formula A, less than 0.5% by HPLC of TPPO impurity of Formula B, less than 0.5% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C and / or less than 0.5% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.Claim 101 : The compound as claimed in claim 100, wherein the racemic cloprostenol sodium having less than 0.2% by HPLC of UV active impurity of Formula A, less than 0.2% by HPLC of TPPO impurity of Formula B, than 0.2% by HPLC of 5,6-trans racemic cloprestenol impurity of formula C and / or less than 0.2% by HPLC of racemic 15-Epi Cloprostenol impurity of Formula D.Claim 102: Racemic cloprostenol sodium having a total purity of greater than 99% by HPLC.Claim 103: A pharmaceutical or a veterinary composition comprising racemic cloprostenol or its sodium salt thereof obtained by the processes according to claims 1 - 102 and / or at least one suitable excipient.

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