AN IMPROVED AND SCALABLE PROCESS FOR PREPARATION OF PROSTAGLANDIN DERIVATIVES AND INTERMEDIATES THEREOF

Technical field:

The present invention is related to an improved and scalable process for the preparation of prostaglandin derivatives and intermediates thereof, in high yield and purity.

Background of the invention: Prostaglandins are a family of biologically active compounds that are found in virtually all tissues and organs. These naturally occurring prostaglandins have extremely complex biological functions (e.g. stimulation of smooth muscles, dilation of smaller arteries and bronchi, lowering blood pressure etc.). Structurally, prostaglandins are formed of a ring and two side chains, said ring and chains being replaceable (usually hydroxyl or keto group) and optionally being partly unsaturated.

The compounds Bimatoprost, Travoprost and Latanoprost are analogues of prostaglandin F _2a and used in therapy in the treatment of glaucoma, in particular to reduce high endo- ocular pressure.

The known methods for the synthesis of prostaglandin compounds for example Travoprost as in USPatent 7166730 ('730) is depicted in Scheme 1 and include following steps i.e. (i) oxidation of alcohol to corresponding ketone, (ii) Wittig reaction using aqueous alkali in THF, (iii) reduction using (-)-DIP chloride, (iv) TBDMS protection of hydroxyl group (v)DIBAL-H reduction, (vi) Wittig reaction, (vii) TBDMS deprotection and (viii) derivatization to obtain Travoprost. Scheme 1

US Application 20100010239 ('239) disclosed a process for preparing prostaglandins like Travoprost, using LiCl/TEA for Wittig reaction is depicted in scheme 2, Scheme 2

PCT Application WO2011055377 ('377) disclosed a method for preparation of prostaglandin derivatives like Travoprostcomprising; (i) Wittig reactionusing NaH, (ii) reduction using methyl oxazaborolidine (Me-CBS) and borane Ν,Ν' -diethylaniline complex (DEANB),

(iii) deprotection of p-phenylbenzoyl (PPB), (iv) protection using2-methoxyethoxymethyl (MEM) chloride, (v) DIBAL-H reduction, (vi) Wittig reaction using NaHMDS,

(vii)derivatizationand (viii) deprotection using cerium chloride. The process disclosed in '377 application is schematically represented by the Scheme 3, Scheme 3

Travo ost

PCT Application WO2010104344 ('344) disclosed a method for deprotection of hydroxy protecting groups using PPTS in suitable solvent. The prior art process for preparation of prostaglandin derivatives has following disadvantages and drawbacks:

i) use of hazardous reagents such as n-butyl lithium, lithium chloride, sodium hydride, NaHMDS in the reaction.

ii)low temperatures are required for Wittig reaction using LiCl/TEA.

iii) tedious methods like column chromatography are involved during intermediate preparation, reducing the yields.

iv) thedeprotection reaction using PPTS is a time consuming reaction.

v) Prep HPLC method is required to obtain high purity prostaglandin analogs.

Such conditions are difficult to maintain at plant scale. Hence there remains a need for a simple, cost effective, industrially feasible and scalable process for the synthesis of prostaglandins and prostaglandin analogs that would avoid the aforementioned difficulties.

Summary of the invention:

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

(A)

wherein ^=represents a double bond or a single bond;R4 is alkoxy or alkyl amino group; W is a residue from group consisting of substituted and unsubstituted Ci-C ₆ alkyl, C ₇ - Ciearalkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of Ci-Ceaikyl, halo and CF ₃ , and (CH ₂ ) _n OR _a , wherein n is from 1-3 and R _a represents a Ce-Cio aryl group which is optionally substituted with one to three substituents selected from the group consisting of Ci-C ₆ alkyl, halo and CF ₃ ;

According to another aspect, the present invention provides a process for the preparation of compound of formula A;

wherein = represents a double bond or a single bond;R ₄ is alkoxy or alkyl amino group; W is a residue from group consisting of substituted and unsubstituted Ci-C ₆ alkyl, C7- Ciearalkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of Ci-Cealkyl, halo and CF ₃ , and (CH2) _n OR _a , wherein n is from 1-3 and R _a represents a Ce-Cio aryl group which is optionally substituted with one to three substituents selected from the group consisting of Ci-Cealkyl, halo and CF ₃ ; by deprotection of compound of formula (X),

wherein _^ = represents a double bond or a single bond;R _x and R ₂ are hydroxyl protecting groups; R ₄ is alkoxyor alkyl amino group; W is as defined above. According to another aspect, the present invention provides a process for preparation of compound of formula (III),

(III)

wherein P is p-phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP group and W is as defined above.

According to another aspect, the present invention provides a process for preparation of compound of formula (V),

M

whereinRj is p-nitrobenzoyl (PNB) group; = _t p and W are as defined above.

According to another aspect, the present invention provides a process for isolating compound of formula (V).

According to another aspect, the present invention provides a process for producinghigh purity prostaglandin and prostaglandin derivatives.

Description of the invention:

In one aspect, there is provided an improved process for the preparation of compound of formula A; wherein = represents a double bond or a single bond; R4 is alkoxy or alkyl amino group;W is a residue from group consisting of substituted and unsubstituted Ci-Ce alkyl, C7-Ci ₆ aralkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of Ci-Ce alkyl, halo and CF ₃ , and (CH ₂ )nOR _a , wherein n is from 1-3 and R _a represents a Ce-Cio aryl group which is optionally substituted with one to three substituents selected from the group consisting of Ci-Ce alkyl, halo and CF ₃ ;

comprising:

i) Oxidation of compound of formula (I),

toobtain compound of formula (II) using suitable oxidising agent,

whereinP is p-phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP group; ii)reaction of compound of formula (Il)with 2-oxo-3[(3- trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester in presence of Ζη(¾ and base in organic solvent to obtain compound of formula (III),

(III) wherein P and W are as defined above.

iii)reduction of compound of formula (III) using suitable reducing agent to obtain compound of formula (IV),

wherein P and W are as defined above.

iv)optionally reducing compound of formula (IV)to obtain compound of formula (IV-a),

(IV- a)

wherein P and W are as defined above.

v)protection of compound of formula (IV) or formula (IV-a) using 4-nitrobenzoyl halideunder basic conditions optionally in presence of catalyst and organic solvent to obtain compound (V),

(V)

wherein R ₃ is p-nitrobenzoyl (PNB) group; = ,P and W is as defined above.

vi)deprotection of compound of formula (V)using base and organic solventto obtain compound of formula (VI)

wherein = and W are as defined above.

vii)protection of compound of formula (VI) with suitable hydroxy protecting groupoptionally in presence of catalyst to obtain compound of formula (VII),

wherein Ri, R ₂ are hydro xyl protecting group; =and W is as defined above.

viii)reducing the carbonyl group of compound of formula (VII) using DIBAL-H to obtain compound of formula (VIII),

wherein Ri, R ₂ , == and W are as defined above. ix) reacting the compound of formula (VIII) with (4-carboxybutyl)triphenylphosphonium bromide in the presence of potassium tert-butoxide to obtain compound of formula (IX),

(IX)

wherein Ri, R ₂ ,== and W are as defined above.

x)derivatization of compound of formula (IX) to obtain compound of formula (X),

wherein Ri, R ₂ , R4, =^ and W are as defined above.

xi)deprotecting compound of formula (X) using ZrCl ₄ in organic solvent to obtain compound of formula (A),

whereinR ₄ , =^and W are as defined above.

In one embodiment, the oxidizing agentused in step (i) is selected fromSwern oxidation (DMSO, oxalyl chloride and TEA),Dess-Martin reagent, manganese-, chromium-, or selenium reagents, tertiary amine oxides or via radical oxidation producers using catalytic amount of TEMPO in combination with co-oxidants such as NaOCl; preferably, the oxidizing agent selected from Swern oxidation (DMSO, oxalyl chloride and TEA),Dess- Martin reagent;and more preferablythe oxidizing agent is Dess-Martin reagent.

The reaction of step (i) is carried out in solvent or mixture of solvents selected from DCM, acetone, THF or mixtures thereof; and more preferably the reaction solvent isDCM.

The reaction of step (i) is carried out at a temperature of-20° C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 8 hours, and preferably at a temperature of about 10°C to about 50°C for about 1 hour to about 6 hours.

In another embodiment, the base usedin reaction step (ii) isorganic or inorganic base. Specific organic bases are triethylamine, trimethylamine, dimethyl amine and tert- butyl amine.

In another embodiment, the base is an inorganic base. Exemplary inorganic bases include, but are not limited to, hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals; and ammonia. Specific inorganic bases are ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and preferably sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, sodium carbonate and potassium carbonate.

The organicsolvent used in step (ii)selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and mixtures thereof; preferably, the organic solvent is selected from the group consisting of water, methylene chloride tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether; and/or water and mixtures thereof; and more preferably, the organic solvent is tetrahydrofuran.

The reaction of step (ii) is carried out at a temperature of-20°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 48 hours, and preferably at a temperature of about 10°C to about 50°C for about 1 hour to about 24 hours.

In another embodiment, the compound of formula (II) optionally isolating from mother liquor.

In another embodiment, the reducing agent usedin reaction step(iii) is selected fromborane-dimethylsulfide complex, (-)-DIP chloride, lithium l,l'-binaphthyl-2,2'- dioxyaluminium hydride; and more preferably the reducing agent is (-)-DIP chloride. The solvent used in step (iii)selected fromthe group consisting of methanol, ethanol, n- propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene,and/or water and mixtures thereof; preferably, the solvent is selected from the group consisting of dichloromethane,tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,and/or water and mixtures thereof; and more preferably,a mixture of tetrahydrofuran and dichloromethane.

The reaction of step (iii) is carried out at a temperature of-80° C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about -50°C to about 60°C for about 30 minutes to about 15 hours, and preferably at a temperature of about -30°C to about 5°C for about 1 hour to about 8 hours.

In another embodiment, the optional reduction of step (iv) comprising catalytic hydrogenation.

In another embodiment, the 4-nitrobenzoyl halide used in step (v) is selected from 4- nitrobenzoyl chloride, 4-nitrobenzoyl bromide and the like;more preferably,4- nitrobenzoyl chloride.

The catalyst used in step (v) is DMAP and the like; and the base used in step (v) is organic or inorganic base, selected from triethylamine, trimethylamine, dimethyl amine and tert-butyl amine; ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and more preferably, the base istriethylamine.

The organicsolvent used in step (v)selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene,and/or water and mixtures thereof; preferably, the organic solvent is selected from the group consisting of methylene chloride,tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, and/or water and mixtures thereof; and more preferably, the organic solvent is methylene chloride.

The reaction of step (v) is carried out at a temperature of -5°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 10 hours, and preferably at a temperature of about 5°C to about 30° C for about 1 hour to about 6 hours. In another embodiment, the base used in step (vi) is organic or inorganic base, selected from triethylamine, trimethylamine, dimethyl amine and tert-butyl amine; ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and more preferably, the base is potassium carbonate.

The organicsolvent used in step (vi)selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or waterand mixtures thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol,methylene chloride,tetrahydrofuran, and/or water and mixtures thereof; and more preferably,the organic solvent is methanol.

The reaction of step (vi) is carried out at a temperature of -5°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 10 hours, and preferably at a temperature of about 5°C to about 30°C for about 1 hour to about 6 hours.

In another embodiment, the suitable hydroxy protecting groupof step (vii) selected fromtrimethylsilylhalide,tetrabutyl dimethyl silyl halide, 2-methoxyethoxymethyl halide, 3,4-dihydro-2H-pyran and the like; more preferably, the hydroxy protecting groupis 3,4- dihydro-2H-pyran.

The catalyst used in step (vii) is PPTS and the like;

The organicsolvent used in step (vii)selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene ;and/or waterand mixtures thereof; preferably, the organic solvent is selected from the group consisting of dichloromethane, dichloroethane, chloroform, carbon tetrachloride,tetrahydrofuran,and/or water and mixtures thereof; and more preferably,the organic solvent is dichloromethane.

The reaction of step (vii) is carried out at a temperature of -5°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 10 hours, and preferably at a temperature of about 5°C to about 30°C for about 1 hour to about 8 hours.

In another embodiment, the derivatization reaction step (X) is carried out using alkyl halide or alkyl amine. Exemplary alkyl halide includes, but not limited to, ethyl halide, methyl halide or isopropyl halide. Exemplaryalkyl amine includes, but not limited to, ethyl amine, methyl amine or isopropyl amine.

In another embodiment, the reaction solvent used in step (viii), (ix), (x) and (xi) selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or waterand mixtures thereof; preferably, the solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanolacetone, dichloromethane, dichloroethane, chloroform, carbon tetrachloride,tetrahydrofuran, and/or water and mixtures thereof; and more preferably, dichloromethane, tetrahydrofuran, acetone,isopropanoland mixtures thereof.

In another embodiment, the reaction of step (viii), (ix), (x) and (xi) is carried out at a temperature of -75°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about -65°C to about 45°C for about 30 minutes to about 10 hours, and preferably at a temperature of about -65°C to about 35°C for about 1 hour to about 8 hours. According to another aspect, there is provided an improved process for the preparation of compound of formula A;

wherein _^ =represents a double bond or a single bond;R4 is alkoxy or alkyl amino group; W is a residue from group consisting of substituted and unsubstituted Ci-C ₆ alkyl, C7- Ciearalkyl wherein the aralkyl group is optionally substituted with one to three substituents selected from the group consisting of Ci-Cealkyl, halo and CF ₃ , and (CH ₂ ) _n OR _a , wherein n is from 1-3 and R _a represents a Ce-Cio aryl group which is optionally substituted with one to three substituents selected from the group consisting of Ci-Cealkyl, halo and CF ₃ ; by deprotection of compound of formula (X),

wherein Ri, R ₂ ,R ₄ and W are as defined above; in the presence of ZrCl ₄ and organic solvent.

In one embodiment, the organicsolvent used in deprotection of formula (X) selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene, and/or waterand mixtures thereof; preferably, the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane, dichloroethane, chloroform, carbon tetrachloride,tetrahydrofuran,and/or water and mixtures thereof; and more preferably, water, methanol, ethanol, n-propanol, isopropanol and mixtures thereof. Thedeprotection of formula (X)is carried out at a temperature of -5°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 65°C for about 30 minutes to about 10 hours, and preferably at a temperature of about 35°C to about 45°C for about 1 hour to about 8 hours.

According to another aspect, there is provided an improved process for the preparation of compound of formula (III),

(I II)

wherein P is p-phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP group and W are as defined above ;comprisingreaction of compound of formula (II),

(Π)

with 2-oxo-3[(3-trifluoromethyl)phenoxy]propylphosphonic acid dimethyl ester in presence Ζη(¾ and base in organic solvent, and/or water;wherein P is as defined above. In one embodiment, the base usedin process for the preparation of compound of formula (III) is organic or inorganic base selected fromtriethylamine, trimethylamine, dimethyl amine and tert-butyl amine, ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and preferably sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, sodium carbonate and potassium carbonate.

The organicsolvent used in preparation of compound of formula (III) selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n- hexane, n- heptane, cyclohexane, toluene, xylene, and/or waterand mixtures thereof; preferably, the organic solvent is selected from the group consisting of methylene chloride tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, and/or water and mixtures thereof; and more preferably, the organic solvent is tetrahydrofuran.

The process for the preparation of compound of formula (III) is carried out at a temperature of-20°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 48 hours, and preferably at a temperature of about 10°C to about 50°C for about 1 hour to about 24 hours. According to another aspect, there is provided an improved process for the preparation of compound of formula (V),

(V)

comprising reaction of compound of formula (IV)

withp-nitrobenzoyl halide under basic conditions optionally in presence of catalyst in organic solvent;wherein represents a double bond or a single bond; P is p- phenylbenzoyl (PPB), p-methoxy benzyl (PMB) or THP group and R ₃ is p-nitrobenzoyl (PNB) group.

In one embodiment, the 4-nitrobenzoyl halide used in the preparation of compound of formula (V) is selected from 4-nitrobenzoyl chloride, 4-nitrobenzoyl bromide and the like;more preferably,4-nitrobenzoyl chloride.

The catalyst used in the preparation of compound of formula (V) is DMAP and the like; and the base used in process for the preparation of compound of formula (V) is organic or inorganic base, selected from triethylamine, trimethylamine, dimethyl amine and tert- butyl amine; ammonia solution, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert- butoxide, sodium isopropoxide and potassium tert-butoxide; and more preferably, the base is triethylamine.

The organicsolvent used in the preparation of compound of formula (V) selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n- hexane, n- heptane, cyclohexane, toluene, xylene, and/or waterand mixtures thereof; preferably, the organic solvent is selected from the group consisting of methylene chloride,tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, and/or water and mixtures thereof; and more preferably, the organic solvent is methylene chloride.

The process for the preparation of compound of formula (V) is carried out at a temperature of -5°C to the reflux temperature of the solvent used for at least 15 minutes, specifically at a temperature of about 0°C to about 60°C for about 30 minutes to about 10 hours, and preferably at a temperature of about 5°C to about 30°C for about 1 hour to about 6 hours.

In another aspect, there is provided a process for isolation of compound of formula (V);

(V)

comprising:

i) dissolving or slurring the compound of formula (V) in organic solvent, ii) heating the resultant reaction mass at ambient temperature,

iii) cooling to precipitate and filter the obtained product.

In one embodiment, the organicsolvent used in step (i) selected fromthe group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, n-pentane, n-hexane, n- heptane, cyclohexane, toluene, xylene,and/or water and mixtures thereof; preferably, the organic solvent is selected from the group consisting of acetone, methanol, ethanol, n- propanol, isopropanol, n-butanol, methylene chloride, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether and mixtures thereof; and more preferably, water,acetone, methanol, ethanol, n-propanol, isopropanol, methylene chloride,tetrahydrofuran, and/or water and mixtures thereof.

In another aspect, there is provided purification of prostaglandins and prostaglandin analogs by suitable methods such as prep HPLC, crystallization, gravity column chromatography using suitable organic solvents. Most preferably gravity column chromatography is used. Organic solvents includeethers such as ethyl acetate, methyl acetate and the like; cyclic hydrocarbons such as n-hexane, n- heptan, cyclohexane and the like; ketones such as acetone, ethyl methyl ketone, and the like; and their mixtures thereof. Most preferably 30% cyclohexane and acetone is used.

The highly pure prostaglandins and prostaglandin analogsobtained by the above process may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.

In one embodiment, the drying is carried out at atmospheric pressure or a reduced pressure, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 70°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like. Drying equipment selection is well within the ordinary skill in the art.

Definitions and conventions

The definitions and conventions below are for the terms as used throughout this entire document including both the specification and the claims.

All temperatures are in degrees Celsius.

THF refers to tetrahydrofuran

DCM refers to dichloromethane

DMSO refers to N,N-dimethylsulfoxide

DMF refers to N,N-dimethylformamide

IPA refers to isopropyl alcohol DIBAL-H refers to diisobutylaluminium hydride

DMAP refers to 4-dimethylaminopyridine

DBU refers to l ,8-diazabicyclo[5.4.0]undec-7-ene

(-)-DIP chloride refers to (-)-B-chlorodiisopinocamphenylborane

PPTS refers to pyridinium p-toluene sulfonate

THP refers to tetrahydropyran

ZnCl ₂ refers to zinc chloride

ZrCLi refers to zirconium chloride

NH ₄ C1 refers to ammonium chloride

NaCl refers to sodium chloride

K ₂ CO ₃ refers to potassium carbonate

NaHMDS refers to sodium hexamethyldisilazide

NaHCC>3 refers to sodium hydrogen carbonate

NaOCl refers to sodium hypochlorite

KO'Bu refers to potassium tertbutoxide

TEMPO refers to 2,2,6,6-Tetramethylpiperidinyloxy

DM water refers to demineralised water

gm refers to gram

eq refers to equivalents

hr/ hrs refers to hours

RT refers to room temperature

The process for preparing prostaglandins or prostaglandin analogslike Travoprostaccording to present invention is depicted in Scheme 4, Scheme 4

Examples:

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

Example 1:

(3aR,4R,5R,6aS)-2-oxo-4-((E)-3-oxo-4-(3-(trifluoromethyl)phe noxy)but-l-en-l- yl)hexahydro-2H-cyclopenta[b]furan-5-yl [l,l'-biphenyl]-4-carboxylate(III) a) Dess martin (132.36 g, 1.1 eq) was added to a solution of Corey's lactone (100 g, 1 eq) in DCM (1500 ml) at 5-10°C. The mixture was stirred for 1-2 hrs at 15-20°C. The solution was filtered and washed with DCM. DCM layer was washed with solution of sodium thiosulfate and sodium bicarbonate in DM water followed by washing with 10% NaCl solution. b) KO'Bu (39.7 g, 1.25 eq) was added to a solution of THF (500 ml) and 2-oxo-3-[(3- trifluoromethyl)phenoxy] propylphosphonic aciddimethyl ester( 115.8 g, 1.25 eq) at 0°C to 5°C. The mixture was stirred for 20-30 min. ZnCl ₂ (27 g, 0.7eq) was added into the reaction mass maintaining temperature at 15°C to 20°C for 1 hr. Aldehyde solution obtained in step (a) was added into above reaction mass at 5°C to 10°C for 20-30 min. Reaction mixture was stirred for 22-24 hrs.

After completion of reaction, reaction mixture was neutralized using acetic acid (30 ml) and washed with water several times. Organic layer was separated and concentrated under vacuum. Methanol (400 ml) was added to the reaction mass and the mixture was stirred for 1-2 hrs. Solid obtained was filtered and washed with methanol, dried under vacuum at 55°C to 60°C for 20-24 hrs to afford compound (III).

Yield: 110 gm, 70%

HPLC purity: 95% Example 2

(3aR,4R,5R,6aS)-4-(( ,E)-3-hydroxy-4-(3-(trifluoromethyl)phenoxy)but-l-en-l-yl)- 2-oxohexahydro-2H-cyclopenta[b]furan-5-yl [l,l'-biphenyl]-4-carboxylate(IV)

A solution of THF (800 ml) and compound (III) (100 gm, 1 eq) was stirred at -25°C to - 30°C for 10-15 mins. (-) DIP chloride (320 ml, 2.75 eq) was added to the solution maintaining temperature at -20°C to -25°C for lhr. Reaction mass was raised to temperature at -5°C to 0°C and stirred for 4-5 hrs. After completion of the reaction methanol was added and stirred for 10-15 min. Solvent was removed under vacuum.

Reaction mass was extracted using DCM-water, washed with 20% NH ₄ C1 solution. Combined organic layers were concentrated under vacuum. The solid obtained was stirred into the solution containing IPA (200 ml)and cyclohexane (800 ml) for 1-2 hrs. Solid was filtered and dried under vacuum to afford compound (IV).

Yield: 87 gm, 87%

HPLC: 89%, R-isomer: 11%

Example 3

(3aR,4R,5R,6aS)-4-((R,E)-3-((4-nitrobenzoyl)oxy)-4-(3- (trifluoromethyl)phenoxy)but-l-en-l-yl)-2-oxohexahydro-2H-cy clopenta[b]furan-5- yl [l,l'-biphenyl]-4-carboxylate (V)

4-nitro benzoyl chloride (46.31 gm, 1.5 eq) and DMAP (4.42 gm, 0.2 eq)was added to a solution of DCM (1 Lit) and compound (IV) (lOOgm, 1 eq) at 5°C to 10°C. Tri ethylamine (27.48gm, 1.8 eq) was added to the reaction mixture and the mixture was stirred for 2-3 hrs at RT. After completion of the reaction, 10% citric acid solution was added to the mixture and reaction mass was extracted with DCM. Solvent was removed under vacuum. Methanol was added to the reaction mass and stirred for 1-2 hrs. Solid was filtered and washed with methanol.

The solid was purified by heating it into acetone at 40°C to 45°C for 10-15 mins. Solid was filtered, washed with methanol and dried under vacuum to affordcompound (V). Yield: 100 gm, 80%

HPLC: 99.8%, R-isomer: 0.04%

Example 4

(3aR,4R,5R,6aS)-5-hydroxy-4-((R,E)-3-hydroxy-4-(3-(trifluoro methyl)phenoxy)but- l-en-l-yl)hexahydro-2H-cyclopenta[b]furan-2-one (VI) K ₂ CO ₃ (15.7 gm, 0.8 eq) was added to a solution of methanol (1 lit) and compound (V) (lOOg, 1 eq) and the reaction mixture was stirred for 4-5 hrs. After completion of the reaction, 10% methanolicHCl (300 ml) was added and reaction mixture was stirred for 30-45 min. Solid was filtered and washed with methanol. Filtrate was concentratedunder vacuum. The obtained mass was extracted with ethyl acetate and DM water, washed with 10% NaCl solution. Organic layerwas distilled off under vacuum. The crude mass was stirred in a solution containing 250 ml of diisopropyl ether and 250 ml of cyclohexane. Solid obtained was filtered and washed with cyclohexane. The crude solid was purified using IPA and cyclohexane to afford compound (VI) after drying under vacuum at 45°C to 50°C.

Yield: 42.4 gm, 80%

HPLC: 99.8%, R-isomer: 0.04% Example 5

(3aR,4R,5R,6aS)-5-((tetrahydro-2H-pyran-2-yl)oxy)-4-((3R,E)- 3-((tetrahydro-2H- pyran-2-yl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-l-en-l-yl) hexahydro-2H- cyclopenta[b]furan-2-one (VII)

3,4-dihydropyran (113 gm, 5 eq) was added to a solution of DCM (1500ml) and compound (VI) (100 gm, 1 eq) at 15-20°C. PPTS (6.75 gm, 0.1 eq) was added and reaction mixture was stirred for 4-6 hrs at 20°C to 30°C. After completion of the reaction, 5%NaHCC>3 solution (1 lit) was added to the reaction mass and stirred for 10-15 min. Organic layer was washed with DM water and 10% NaCl solution (500ml). Organic layer was distilled off under vacuum to afford compound (VII) as colourless oil.

Yield: 137 gm, 95%

HPLC: D 94%

Example 6

(3aR,4R,5R,6aS)-5-((tetrahydro-2H-pyran-2-yl)oxy)-4-((3R,E)- 3-((tetrahydro-2H- pyran-2-yl)oxy)-4-(3-(trifluoromethyl)phenoxy)but-l-en-l-yl) hexahydro-2H- cyclopenta[b]furan-2-ol (VIII)

DIBAL-H (259 ml, 1.4 eq) was added drop wise to a solution of DCM (1 Lit) and compound (VII) (100 gm, 1 eq) at -60°C to -65°C for 20 min. Reaction mass was stirred at this temperature for 1-2 hrs. After completion of reaction 110 ml of methanol was added at -60°C to -65°C and reaction mass was stirred for 10-15 min. Reaction mass was raised to 0°C to 5°C and sodium/potassium tartarate (289 gm) solution was added for 15- 20 min. Reaction was stirred at 25°C to 30°C for 1-2 hrs. The organic layer was washed with 20% NaCl solution and solvent was distilled off under vacuum to afford compound (VIII) as colourless oil. Yield: 90 gm

HPLC: D94%

Example 7

(Z)-7-((l ,2R,3R,5S)-5-hydroxy-3-((tetrahydro-2H-pyran-2-yl)oxy)-2-((E )-3- ((tetrahydro-2H-pyran-2-yl)oxy)-4-(3-(trifluoromethyl)phenox y)but-l-en-l- yl)cyclopentyl)hept-5-enoic acid (IX)

KO'Bu (118 gm, 5.7 eq)was added to a solution of THF (1000 ml) and (4-carboxybutyl) triphenylphosphonium bromide (130 gm, 3 eq) at 0°C to 5°C. Reaction mixture was stirred for 1 hr at 15°C to 20°C.

A solution of compound (VIII) (90 gm,l eq) in THF (500 ml) was added drop wise to above at -25°C to -30°C and the mixture was stirred for 1 hr. Temperature was raised at 0°C to 5°C and stirred for 2-3 hrs. Toluene (1 lit) was charged in to the reaction mass and stirred for 10-15 min. 1 lit of ethyl acetate was charged into the aqueous layer and the pH was adjusted to 4.2-4.7 with citric acid. Organic layer was separated and aqueous layer was extracted with ethyl acetate (500 ml). Combined organic layers were washed with 10% NaCl solution, and organic layer was distilled under vacuum. Ethyl acetate was added to reaction mass and stirred for 1 hr at ambient temperature. Solid was filtered and washed with ethyl acetate to afford title compound. Compound (IX) was used for next step as such.

Example 8

(Z)-isopropyl 7-((lR,2R,3R,5S)-5-hydroxy-3-((tetrahydro-2H-pyran-2-yl)oxy) -2- ((E)-3-((tetrahydro-2H-pyran-2-yl)oxy)-4-(3-(trifluoromethyl )phenoxy)but-l-en-l- yl)cyclopentyl)hept-5-enoate (X) Isopropyl iodide (189 gm, 6 eq) andDBU (84.4 gm, 3 eq) was added to astirred solution of compound (IX) (1 eq) in acetone (1 lit) under nitrogen atmosphere at 0°C to 5°C. The mass was stirred at that temperature for 20-30 min. Reaction mixture was stirred for 8-10 hrs at 25°C to 30°C followed by heating at 42°C to 47°C for 6-8 hrs. After the reaction completion the mass was concentrated under reduced pressure to remove acetone. DCM and water was added and mass was stirred for 10-15 min. Organic layer was separated and concentrated to afford compound (X) as brown coloured oil.

The oily mass was purified by column chromatograph using7% acetone: cyclohexane as eluting solvent system to afford pure colourless oil.

Yield: 86 gm, 70%

HPLC: D 95%

Example 9

(Z)-isopropyl 7-((lR,2R,3R,5S)-3,5-dihydroxy-2-((E)-3-hydroxy-4-(3- (trifluoromethyl)phenoxy)but-l-en-l-yl)cyclopentyl)hept-5-en oate (A)

ZrCLi (13.9 gm, 0.4 eq) was added to a solution of compound (X) (100 gm, 1 eq) in IPA (1 lit) and contents were heated at 40°C to 45°C for 1-2 hr. After the reaction completion reaction mixture was cooled to 25°C to 30°C. DCM and 5% NaHCC were added and mixture was stirred for 10-15 min. Organic layer was separated and aqueous layer was extracted with DCM. Combined organic layers were washed with DM water and 10% NaClsolution. Organic layer was concentrated under vacuum. The crude compound was purified by column chromatography using 30% acetone: cyclohexane as eluting solvent system to afford compound (A) as colourless oil.

Yield: 44.4 gm, 60%

HPLC: 98.5%, 5,6 trans isomer.