Title of Invention

"A PROCESS FOR THE PREPARATION OF A PROSTAGLANDIN COMPOUND OF FORMULA (I)"

Abstract

A process for the preparation of a prostaglandin compound having the formula (I): wherein A is selected from the group consisting of C1-C6 alkyl groups; C7-C16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C1-C6 alkyl groups, alkyl groups, halo and CF3; and (CH2)nOR' wherein n is an integer from 1 to 3 and R' represents a C6-C10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C1-C6 alkyl groups, halo and CF3; B is selected from OR" and NHR" wherein R" is C1-C6 alkyl groups; and represents a double bond or a single bond; the process comprising a step of preparing a compound of formula (VIII): wherein A is selected from the group consisting of C1-C6 alkyl groups; C7-C16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C1-C6 alkyl groups, halo and CF3; and (CH2)n OR' wherein n is an integer from 1 to 3 and R' represents a C6-C10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C1-C6 alkyl groups, halp and CF3; P is a hydroxy protecting group; and represents a double bond or a single bond; said step comprising converting a compound of formula (IX): wherein A, P and are as defined above and X is a leaving group, to a cuprate reagent and performing a 1,4 addition reaction between the cuprate reagent and a compound of formula (X): and wherein P is as defined above.

Full Text

PROSTAGLANPIN SYNTHESIS The present invention relates to a novel process for the synthesis of prostaglandins and prostaglandin analogues. The present invention further relates to novel synthetic intermediates that can be used in the synthesis of prostaglandins and prostaglaaidin analogues. PGFU prostaglandins and prostaglandin analogues comprise a cyclopenryl ring carrying two hydroxyl groups in a cis configuration and two side chains in a trans configuration. The side chains may contain double bonds and a variety of substituents. They have a number of therapeutic uses, e.g. for the treatment of glaucoma and ocular hypertension or to induce and accelerate labour. A variety of methods of synthesising PGFa prostaglandins and prostaglandin analogues arc known and are disclosed in, e.g. Chem. Rev. (1993, vol. 93, pages 1 533- 1564), WO 02/096868, WO 02/090324 and Chinese Journal of Medicinal Chemistry (1998, vol. 36, pages 213-217). The present inventors have sought to provide an alternative method of synthesising PGPa prostaglandins and prostaglandin analogues. Ideally the synthetic route will be generally applicable to a variety of prostaglandin compounds and will provide high yields. Accordingly, the present invention provides a process for the preparation of prostaglandin compounds having the formula (I): (Figure Removed) wherein A is selected from the group consisting of Ci-Q alkyl; C7-C)6 aralky] wherein the aryl group is optionally substituted with one to three substituenls selected from the group consisting of C|-C6 alkyl, halo and CF3; and (CH2),,OR' wherein n is from 1. to 3 and R' represents a C substituents selected from the group consisting of Ci-Cg alkyl, halo and CF^; B is selected from OR" and NHR" wherein R" is Cj-Ce alley]; and =•= represents a double bond or a single bond. Scheme 1 shows the synthesis of prostaglandins of formula (I) starting from an ally! cyclopentenone (X) and a substituted alkene (IX) (P is a hydroxyl protecting group): Scheme (Figure Removed) (a) 1,4 addition of a cuprate reagent formed from compound of formula (IX); (b) stercoselective reduction; (c) protection with a hydroxyl protecting group; (d) dihydro.xylal.ion; (e) reduction; (f) diol cleavage; (g) Wittig reaction: (h) esterifi cation or amidation; (i) duprotection. JP 59-044336 and JP 57-171965 disclose methods of synthesising prostaglandins wherein a compound of Formula (Vila) wherein A is CR1R2OR3, wherein R1 is C}..[0 alkyl, R2 is H or methyl and R3 is H or a hydroxy protecting group, is reacted with a sulphur compound. The methods are not suitable for forming prostaglandins such as Latanoprost, Bimatoprost and Travoprost, wherein the side chains do not contain sulphur. In one aspect the present invention provides a process for the preparation of a compound of Formula (VIII): (Figure Removed) wherein A is (CHi^Ph or CHaOR'", wherein R'" is phenyl, substituted at the meta position with CF3 ; P is a hydroxyl protecting group and =*•=-=- represents a double bond or a single bond; wherein a compound of Formula (IX): (Figure Removed) wherein A, P and ;-"" are as defined above and X is a leaving group, is reacted to form a cuprate reagent which undergoes a 1,4 addition reaction with a compound of Formula (X): (Figure Removed) wherein P is as defined above. Suitably, P is a tetrahydropyranyl (THP) or silyl ether protecting group. Preferably P is a THP protecting group. Suitably X is a halogen, preferably iodine. Techniques for forming suitable cuprate reagents from compounds of Formula (IX) are well known to the person skilled in the art. For example, compounds wherein X is iodine can he reacted with a lithiated alkane, e.g. n-BuLi, in a solvent such as tetrahydrofuran (THF) or tert-butyl methyl ether (TBME) at -7S°C for one hour. Subsequently, copper cyanide and methyl lithium are added to the reaction mixture, and the temperature rises to 0°C over 45 minutes. The cuprate reagent is formed in the reaction mixture. The cyclopentenone of formula (X) can be added to the reaction mixture, preferably at -78°C, and the cuprate reagent will undergo 1,4 addition to compound (X), forming compound (VIII). Compounds of formula (IX), wherein =~*= represents a double bond and X is a halogen, can be made by a process comprising the following steps: a) reaction of an acid chloride of formula (XV) with a bis(trialkylsilylacelylene) to form an acetylene of formula (XIV); b) reaction of the acetylene of formula (XIV) with a mild base to form an acetylene of formula (XIII); c) hydrohalogennlion of the acetylene of formula (XIII) to form a vinyl halide of formula (XII); d) stercoselective reduction of the prochiral ketone in the vinyl halide of formula (XII) to form a vinyl halide of formula (XI); and e) protection of the hydroxy group in the vinyl halide of formula (XI). Preferred rcactants are shown in the following reaction scheme: O O TMS - SES---TMS j| Borax (Figure Removed) CBS catalyst OP OH Catecholborane O (IX) (XI) (XII) Methods of synthesising compounds of formula (JX) wherein single bond are disclosed in WO 02/90324. represents a Cycl open ten ones of formula (X) can be made from readily available starting materials such as allylmagnesium chloride and 2-furaIdehyde: (Figure Removed) The racemic cyclopentenone can be resolved using standard techniques and the alcohol should be protected. Other methods of forming cyclopentenones of formula (X) are disclosed in EP 115680. In a preferred embodiment of the invention, A is double bond, P is THP and X is I: (Figure Removed) In a -Jbriher aspect, the present invention provides compounds of formula (VIII): (Figure Removed) wherein A, P and are as defined above. fn a preferred embodiment the present invention provides a compound of formula (VIII) wherein A is (CH2)2Ph, «= represents a double bond and P is TUP: THPO In a further aspect the invention provides a process for the preparation of a compound of formula (Vila): wherein A is (CH?J2Ph or CHjOR'", wherein R'" is phenyl, substituted at the meta position with CF3; P is a hydroxyl protecting group and -=^ represents a double bond or a single bond; wherein a compound of Formula (VIII): (Figure Removed) wherein A, P and -=•=•" are as defined above, undergoes selective reduction. Suitably, P is a tetrahydropyranyl (TliP) or silyl ether protecting group. Preferably P is a THP protecting group. Suitable selective reduction reagents are well known to the skilled person. Preferably the ketone is selectively reduced using L-Selectride in tetrahydrofuran (THF) solvent at -78"C. In a preferred embodiment, A is (CH^Ph, ="" represents a double bond and P is THP: (Figure Removed) In a further aspect, the present invention provides compounds of formula (Vila): (Figure Removed) 5 wherein A, P and =-=-=^= are as defined above. OP In a preferred embodiment the present invention provides a compound of formula (Vila) wherein A is (Ct-Ph, "-- represents a double bond and P is THP: TTIPO" Oil-IP 10 In a further aspect the invention provides a process for the preparation of a compound of formula (Vllb): (Figure Removed) wherein A (CH2)2Ph or CrliOR'", wherein R'" is phenyl, substituted at the nieta position with CFj; P is a hydroxyl protecting group and =•=•= represents a double bond or a single bond; wherein a compound of Formula (VITa): wherein A, P and =- are as defined above, is protected with a hydroxyl protecting group. Suitably, P is a tetrahydropyranyl (TUP) or silyl ether protecting group. Preferably P is a TUP protecting group. Methods of protecting hydroxyl groups are well known to the skilled person. If P is THP, the hydroxyl group can be protected by reaction with 2,3-dihydro-4H-pyran (DHP) and pyridinium p-toluenesulfonate (PPTS) at room temperature in a dichloromethane (DCM) solvent. In a preferred embodiment, A is (CHa^Ph, """ represents a double bond and P is THP: DHP, PPTS, DCM TTIPO hi a further aspect, the present invention provides compounds of formula (Vllb): PO (Figure Removed) wherein A, P and ^^ are as defined above. In a preferred embodiment the present invention provides a compound of formula (Vllb) wherein A is (CH/^Ph, =""-~-= represents a double bond and P is THP: (Figure Removed) In a further aspect the invention provides a process for the preparation of a compound of formula (Vile): wherein A is (CHi^Ph or CH^OR'", wherein R"' is phenyl, substituted at the meta position with CF and =-=" represents a double bond or a single bond; wherein a compound of Formula (Vila): (Figure Removed) wherein A, P and -=•==•= are as defined above, is deprotected. Suitably, P is a tetrahydropyranyl (THP) or silyl ether protecting group. Preferably P is a THP protecting group. Methods of deprotecting protected hydroxyl groups are well known to the skilled person. If P is THP, the hydroxyl groups can be removed by reaction by reaction with pyridinium p-toluenesulfonate (PPTS) in a methanol solvent. In a preferred embodiment, A is (CHoPh and "- represents a double bond: (Figure Removed) In a further aspect, the present invention provides compounds of formula (VTIc): HO (Figure Removed) wherein A and ="" are as defined above. In a preferred embodiment the present invention provides a compound of formula (VITc) wherein A is (Cl-lPh and =--^=^ represents a double bond: HO In a further aspect the invention provides a process for the preparation of a compound of formula (Via), (VIb), (Vic), (Va), (Vb) or (Vc): (Figure Removed) wherein A is selected from the group consisting of Cj-C6 alkyj; C-/-C\6 aralkyl wherein the aryl group is optionally substituted with one to three substituents selected from the group consisting of Cj-Cg alky], halo and Cp3.; and (CH2)nOR' wherein n is from 1 to 3 and R1 represents a C6-C10 aryl group which is optionally substituted with one to three substituents selected from the group consisting of Ci-Cg alkyl, halo and CFs; and P is a hydroxyl protecting group; wherein a compound of Formula (Vila), a compound of Formula (Vllb) or a compound of Formula (Vile): (Figure Removed) wherein A and P are as defined above and dihydroxylalion. (Figure Removed) is a double or single bond, undergoes If there is more than one double bond in the compound of formula (Vila), (Vllb) or (VTIc), then it is the terminal double bond that undergoes dihydroxylation. Suitably, P is a tetrahydropyranyl (THP) or silyl ether protecting group. Preferably P is a THP protecting group. Suitable methods of dihydroxylating double bonds are well known to the skilled person. A preferred reagent is N-me&iyi morphohne-N-oxide (NMO) in the presence of catalytic amounts of osmium tetroxide. The solvent is preferably a 4:1 mixture of tetrahydrofuran (THF) and water. The reaction is suitably earned out from -10 to -4°C. In a preferred embodiment, A is (ClL^Ph, P is THP, =*=-• represents a double bond, and (Vila) is reacted to give (Via): (Figure Removed) In a second preferred embodiment, A is double bond, and (Vllb) is reacted to give (Vlb): (Figure Removed) wherein A and P are as defined above. In a preferred embodiment the present invention provides compounds of formula (Via), (VIb), (Va) and (Vb) wherein A is (CH2)2Ph and P is THP, and compounds of formula (Vic) and (Vc) wherein A is (CH2)2Ph: (Figure Removed) In a further aspect the invention provides a process for the preparation of a compound of formula (Va), (Vb) or (Vc): (Figure Removed) wherein A is selected from the group consisting of Ci-Cg alkyl; Cy-Cie aralkyl wherein the aryl group is optionally substituted with one to three substituents selected from the group consisting of CpCf, alkyl, halo and CF3; and (CH2)nOR' wherein n is from 1 to 3 and R' represents a Q,-Cio aryl group which is optionally substituted with one to three substiluents selected from the group consisting of Q-Ce alkyl, halo and CF3; and P is a hyclroxyl protecting group; wherein a compound of Formula (Via), a compound of Formula (VIb) or a compound of Formula (Vic): (Figure Removed) wherein A and P are as defined above, undergoes reduction of the double bond. Suitably, P is a tetrahydropyranyl (THP) or silyl ether protecting group. Preferably P is a TUP protecting group. Suitable methods of reducing double bonds are well known to the skilled person. In a preferred method, the double bond is hydrogenated, e.g. by passing hydrogen gas.at a pressure of 40psi into the reaction mixture which comprises a 5% Pd on carbon catalyst in an ethanol solvent. In a preferred embodiment, A. is (CHa)2Ph, P is TUP and (Via) is reacted to give (Va): (Figure Removed) In a second preferred embodiment, A is (CH2)2Ph, P is THP and (VIb) is reacted to give (Vb): (Figure Removed) In a third preferred embodiment, A is (CH2)2Ph and (Vic) is reacted to give (Vc): (Figure Removed) In a further aspect the invention provides a process for the preparation of a compound of formula (IVa), (IVb) or (IVc): oil (Figure Removed) wherein A is selected from the group consisting of C\~C(, allcyl; Cy-Cig aralkyl wherein the aiyl group is optionally substituted with one to three substituents selected from the group consisting of Cj-C-e allcyl, halo and CF3; and (CH2)nOR' wherein n is from 1 to 3 and R' represents a Qj-Cio aryl group which is optionally substituted with one to three substituents selected from die group consisting of Ci-Q allcyl, halo and CF3; P is a hydroxyl protecting group and ="^" represents a double bond or a single bond; wherein a compound of Formula (Via), (Va), (Vlb), (Vb), (Vic) or (Vc): (Figure Removed) Suitably, P is a tctrahydropyranyJ (THP) or silyl ether protecting group. Preferably P is a THP protecting group. Suitable methods of diol cleavage are well known to the skilled person. A preferred method uses two equivalents of sodium perioclate and silica in a 1:1 ratio. A suitable solvent is a mixture of water and dichloroniethane. In a preferred embodiment, A is (CHa^Ph, P is THP, ===== represents a single bond, and (Va) is reacted to give (IVa): (Figure Removed) In a second preferred embodiment, A is single bond, and (Vb) is reacted to give (IVb): , P is THP, == represents a (Figure Removed) In a third prefen-ed embodiment, A is (CH2)2Ph, -•=•= represents a single bond, and (Vc) is reacted to give (IVc): (Figure Removed) fn a further aspect, fhe present invention provides a compound of formula (IVb) wherein A is (CM?)?.!1!}, P is TUP and =•=-=-= is a single bond: (Figure Removed) whereiji A is selected from the group consisting of Ci-Cg alkyl; Cv-Cig aralkyl wherein the aryl group is optionally substituted with one to three substituents selected from the group consisting of Ci-C-s allcyl, halo and CF3; ajid (CH2)nOR' wherein n is fi-om 1 to 3 and R' represents a C(;-C[0 aryl group which is optionally substituted with one to three subslituenis selected from the group consisting of CrC,-, alkyl, halo and CF3; P is a hydroxyl protecting group and =- represents a double bond or a single bond; can be reacted w i t h VVittig reagents to give compounds of formula (II la), (II Ib) and (Tile): (Figure Removed) wherein A, P and ---~ are as defined above. Suitable W i t t i g reagents will be well known to the person skilled in the art. A preferred VVittig reagent is (4-Carboxybutyl)triphenylphosphoniuni bromide and this is reacted with the compound of formula (1 Va), (IVb) or (IVc) and potassium t-butoxide in tetrahydrofuran (Tl IF) solvent at 0°C. For example, a compound of formula (IVa) wherein A is (C'Fr2)2Ph, P is TBP, =---- represents a single bond is reacted to give a compound of formula ( I l i a ) : Wiltig salt KO'liu,Tlfl? O'U-JP THTO In a second example, a compound of formula (IVb) wherein A is (CH^Ph, P is TH P, -'------- represents a single bond is reacted to give a compound of formula (Illb): (Figure Removed) In a third example, a compound of formula (IVc) wherein A is represents a single bond is reacted to give a compound of formula (life): OH OH and Compounds of formula (Ilia), (lllb) or (IIIc): (Figure Removed) wherein A is selected from the group consisting of Ci-Cg alkyl; Cy-C^ aralkyl wherein the aryl group is optionally substituted with one to three substiruents selected from the group consisting of Ci-Cg alkyl, halo and CF3; and (CH2)nOR' wherein n is from 1 to 3 and R' represents a CVCio aryl group which is optionally substituted with one to three substituents selected from the group consisting of Ci-Ce alkyl, halo and CF3; P is a hydroxyl protecting group and =-=•"•= represents a double bond or a single bond; can be esterified or amidated to give compounds of fonnula (Ila), (lib) and (I): 77 MO wherein A, P and =^= are as defined above, and B is selected from OR" and NHR" wherein R" is Ci-Q alkyl. Suitable esterification/ amidation reagents will be well known to the person skilled in the art. A preferred esterification reagent is 2-iodopropane (isopropyl iodide) and the reaction mixture further comprises a base such as l,8~diazabicyclo[5.4.0]undcc-7-ene (DBU). Acetone is a suitable solvent. A preferred amidation reagent is ethylamine (EtNHz) and the reaction mixture suitably farther comprises l-(3-Dimetlrylaminopropyl)~ 3-ethylcarbodiirmde hydrochloride (EDC-HC1). Amidation can also be achieved via a multi-step process wherein the compound of fonnula (Ilia), (lllb) or (IIlc) is initially esterified before exposure to an amidation reagent such as ethylamine. For example, a compound of formula (Ilia) wherein A is (CH^^Ph, P is THP and =--- represents a single bond, is esterified to give a compound of formula (Ha): (Figure Removed) In a second example, a compound of fonnula (Ilia) wherein A is (CH2):>Ph, P is THP and •-==--•= represents a double bond is amidated, to give a compound of formula (Figure Removed) hi a third example, a compound of formula (IIIc) wherein A is (CH^Ph and =-« represents a single bond, is esterified to give a compound of formula (I) which is commonly known as Latanoprost: (Figure Removed) wherein A is selected from the group consisting of C-C6 alkyl; C7-C[6 aralkyl wherein the aryl group is optionally substituted with one to three substituents selected from the group consisting of C-Cg alky], halo and CFj; and (CHnGR1 wherein n is from 1 to 3 and R' represents a Cg-Cio aryl group which is optionally substituted with one to three substituents selected from the group consisting of C-C(, alkyl, halo and CF3; P is a hyclroxyl protecting group, =" represents a double bond or a single bond and B is selected from OR" and NHR" wherein R" is C,-C6 alkyl; can be deprotected to give compounds of formula (I): (Figure Removed) wherein A, B and are as defined above. Suitable deprotection reagents are well known to the person skilled in the art. A preferred reagent is pyridinium p-toluenesulfonate (PPTS) in a methanol solvent. For example, a compound of formula (Ila) wherein A is (CFL^Ph, P is TUP, "-'•=- represents a single bond and B is O'Pr, can be deprotected to give a compound of formula (I) which is commonly known as Latanoprost: no (19) HO (Figure Removed) In a second example, a compound of formula (Ila) wherein A is (CH2)2Ph, P is THP, " represents a double bond and B is NHEt can be deprotected to give a compound of formula (I) which is commonly known as Bimatoprost: (Figure Removed) The present invention further provides methods for synthesising Latanoprost as shown in Scheme 2: (Figure Removed) (;i) 1,4 addition of a cuprate reagent formed from compound of formula (IX); (b) stereoselective reduction; (c) protection with a hydroxyl protecting group; (d) dihydroxylation; (e) reduction; (f) diol cleavage; (g) Wittig reaction: (h) esterification; (i) deprotection. The present invention further provides methods ix>r synthesising Bimatoprost as shown in Scheme 3: (Figure Removed) (a) 1,4 addition of a cuprate reagent formed from compound of formula (IX); (b) stereoselective redaction; (c) protection with a hydroxy[ protecting group; (d) (lihydroxylation; (f) diol cleavage; (g) Wittig reaction: (h) amidation; (i) deprotection. The present invention further provides methods for synthesising Travoprost as shown in Scheme 4: (Figure Removed) (a) 1,4 addition of a cuprate reagent formed from compound of formula (IX); (b) stereosclective reduction; (c) protection with a hydroxyl protecting group; (d) dihydroxylation; (f) diol cleavage; (g) Wittig reaction: (h) esterification; (i) deprotection. 31 The invention will now be described by reference to examples which are not intended to be limiting of the invention: Step (a): A 51, three-necked round bottom flask equipped with a mechanical stirrer, a dropping funnel, a cooling bath and an internal temperature probe was charged with AIC13 (217.48g, 1.63mole, l.leq.) and CH2C12 (11) under N2 atmosphere. The reaction mixture was cooled using ice/saJt/methanol bath while the agitation was initiated. Once the temperature was 250g, 1.48mole, leq.) and bis(trimethylsilyl)acetylene (GFS Chemicals, 278g, 1.63 mole, 1.1 eq.) in CHCU (11) was added slowly via addition funnel keeping the temperature removed and the mixture was allowed to warm to RT with agitation. After ~0.5h, the reaction was monitored by TLC for completion. Upon completion of the reaction (ca. 20 min), the mixture was poured slowly to phosphate buffer (pH ~7, 41) with agitation. The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (500ml). The organic layers were combined, washed with 10% aq. NaCl (2 x 750ml), dried over anhydrous MgSCXj (500g), filtered and the solvent was removed in vacua to produce a dark oil. The oil was further dried under high vacuum at RT for ~18 h. Step (b); A 121, three-necked round bottom flask equipped with a mechanical stirrer and a dropping funnel was charged with the oil produced in step (a) (316g, 1.37mole, leq.) and methanol (31). To this was added 0.01M Na2B4O7.1OH2O (11.44g in 31 of H^O) slowly via addition funnel with agitation. The mixture was stirred at room temperature. The progress of the reaction was monitored by TLC. Upon completion of the reaction (ca. 30 min), the pH of the reaction mixture was adjusted to ~3 (pH paper) using IN HC1 (82.6ml). The solvent was removed in vacuo and the aqueous layer was extracted with Cll?C\2 (SxSOOml). The organic layers were combined, washed with brine solution (500ml), dried over anhydrous MgSCvj, filtered and the solvent was removed in vac.uo to give a dark viscous oil. The oil was passed through a plug of silica gel (550g) using 2.5% EtOAc/Hcptane (v/v, 5 L) as an eluent. Step (c): A 51 three-necked round bottom flask equipped with a mechanical stirrer, a dropping, funnel and an internal temperature probe was charged with the oil produced in step (b) (121.36g, 0.77mole, leq.), Nal (117.42g, 0.78 mole, 1.02 mole), n- BujNI (28.4g, 0.077mole, 10rnole%) and MTBE (1213ml). The agitation was initiated. To this was slowly added 4M HoSC^j (348g) via addition funnel with agitation. After ~0.5h, additional amount of 4M H2SO4 (174g) was added. The completion of the reaction was monitored by TLC. Upon completion of the reaction (ca 4.5 h), the reaction mixture was transferred to a 41 separator/ funnel. The organic layer was separated and the aqueous layer was extracted with MTBE (500ml). The organic layers were combined and washed with 5%aq. NaHCO3 (2 x 750ml), saturated brine (750ml), dried over MgSCX, (300g), filtered and the solvent was removed in vacuo to produce a brown red viscous oil. The oil was passed through a pad of silica gel (600g) using 2.5% EtOAc / Heptane (v/v, 6L) to give a viscous oil, which was further dried under high vacuum for -18 h at RT. Step (d): A 11 three-necked round bottom flask equipped with a cooling bath, a magnetic stirrer, a NT inlet and an internal temperature probe was charged with the oil produced in step (c) (35g, 0.12mole, leq.), dry toluene (350ml) and 7?-2-methyl-CBSoxazoborolidine (Gallery Chemicals, 24.47ml, 20 mole%, 1M solution in toluene). The mixture was cooled in an acetone-dry ice bath to -78 °C (internal temperature) with stirring, and a solution of catecholborane (Gallery Chemicals, 29.34g, 0.25 mole, 2eq.) in dry toluene (260ml) was added over a period of 8 to 9 hours via a syringe pump. Upon completion of the addition, the reaction flask was kept in the bath, and the reaction mixture was allowed to warm slowly to RT overnight. TLC analysis showed that the reaction was complete. The mixture was cooled to (150ml) was added slowly. The mixture was allowed to warm to room temperature (~20°C) and 4N NaOH solution (] 65ml) was added. The biphasic solution was allowed to stir at room temperature for -45 minutes and then transferred to a separator/ funnel. The organic layer was separated and the aqueous layer was back washed with toluene (100ml). The organic layers were combined and washed with 4 N HCI (2 x 150ml), saturated brine solution (250ml), dried over MgSO4 (lOOg), filtered and the solvent was removed 777 vacuo to give a viscous oil which solidified upon standing at RT. The crude product was purified by silica gel chromatography (250 g) using 5% EtOAc-heptane (v/v). The product was obtained as a solid (30g), which was further triturated with heptane (60 mL) at room temperature to give an off-white solid. The solid was suction filtered and dried under high vacuum at room temperature for ~16h. Step (e): The hydroxy group of the product of step (d) was protected using 3,4- dihydro-2//-pyran and standard techniques. Synthesis of cyclopentenpne (2) HO Step (a): A 221 3-necked round bottom flask equipped with an overhead mechanical stirrer, a temperature probe, and an addition funnel was purged with nitrogen and charged with a 2M solution of allylmagnesium chloride in THF (81, 16mol). The flask was cooled in an ice bath to bring the internal temperature to 5°C. A solution of 2- furaldehydc (1.2kg, 12.5mol) in anhydrous THF (21) was added to the Grignard solution slowly over 4.751: maintaining the internal temperature below 12°C. TLC analysis after ]5min indicated that the reaction was complete. The reaction was quenched by the sequential addition of saturated NH4C1 (41), water (21), and concentrated HCI (1.41). The layers were separated, and the aqueous layer was extracted with ethyl acetate (31). The combined organic layers were washed with brine (SOOg of NaCl dissolved in 31 of water), and concentrated on a rotary evaporator to give the addition product as a dark coloured oil (2.1 leg), which was used without further purification. 'H NMR spectrum conformed to structure. Step (b): A 221 3-necked round bottom flask equipped with an overhead mechanical stirrer, a temperature probe, and a heating mantle was charged with a buffered solution with a pi I of 4.80. A solution of the product of step (a) (SOOg, 2.9mol) in 1,4- dioxaive (1.51) was added in one portion, and the mixture was heated to around 95°C over a 5.5h period. The reaction mixture was stirred at this temperature for ca. 60h, at which time TLC analysis indicated near complete consumption of the step (a) product. The reaction mixture was allowed to cool to 5()°C, and solid NaCl (6kg) was added with stirring. The resulting solution was extracted with ethyl acetate (1 x 31 and 1 x 21), and the combined organic phases were dried over MgSO4. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was coevaporated with toluene (250ml) and dried under high vacuum to give a reddish brown viscous oil (456g). Step (c): A 51 3-necked round bottom flask equipped with an overhead mechanical stirrer, and a nitrogen inlet was charged with the above enone mixture (456g), toluene (3.51), triethylamine (367.3 g, 3.6mol), and anhydrous tribromoacetaldehyde (92.65g, 0.33mol). The resulting mixture was allowed to stir at room temperature for 21h, and diluted with water (31). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 0.751). The combined organic layers were washed with 25% wt/v brine solution (21) and dried over MgSO4. The drying agent was filtered off and the filtrate was concentrated under reduced pressure to give a dark viscous oil (415g). The oil was chromatographed on silica gel (1kg) during with 15:85 ethyl acetate-heptane (71), 30:70 ethyl acetate-heptane (21), and 50:50 ethyl acetate-heptane (51) to give an enone as an oil (199g, 50% yield). Step (d): The enone prepared in step (c) was resolved by Simulated Moving Bed chiral chromatography (8MB). The desired .R-enantiomer was obtained in >99% optical purity. To form the cyclopentenone (2), the alcohol of the #-enantiomer formed in step (d) was protected using 3,4-dihydro-2//-pyran and standard techniques. Example J; 1,4 addition of a cuprate reagent formed from a compound. of foimula (IX) 1) n-BuLi, TBME 2) CuCN, TBME, MeLi THPO" A dry 250ml 3-necked round bottom flask equipped with a magnetic stirring bar, a temperature probe, and rubber septa, was purged with nitrogen. The flask was charged with a solution of vinyl iodide (1) (8.43g, 22.65mmol) in tot-butyl methyl ether (TBME, 40ml) and cooled in an acetone-dry ice bath. A solution of 77-butyllithium in hexanes (2.517M, 9.5ml, 23.8mmol) was added, and the mixture was stirred at -78°C for 2h. A diy 11 3-necked round bottom flask equipped with a magnetic stirring bar, a temperature probe, and rubber septa, was purged with nitrogen and charged with solid cuprous cyanide (2.12g, 23.7Smmol). Anhydrous TBME (60ml) was added and the flask was cooled to -78°C in an acetone-dry ice bath. A solution of methyllilhium in THFcumene (1M, 23.78ml, 23,78mmol) was slowly added to the stirring suspension. After the addition was complete, the flask was placed in an ice bath and the contents stirred for 30min giving a clear solution. The cuprate solution was cooled again to -78°C, and the vinyl lithium solution was added from the 250ml flask via cannula. The resulting yellow solution was quickly warmed to -40°C, stirred for 20min, and recooled to -78°C. A solution of cyclopentenone (2) (2.52g, 11.34mmoi) in anhydrous TBME (30ml) was added by cannula, and the mixture was stirred at -78 °C for 30 min. The reaction flask was removed from Ibe cooling bath, and the reaction was quench.ec! by the careful addition of saturated NH4Cl (15ml). The layers were separated and the organic layer was washed with 1:9 NH/tOH-NPLiCl (2 x 200ml). The combined aqueous washes were back extracted with TBME (100ml). The combined organic layers were washed with saturated brine (100ml), dried (NajSC^), filtered and concentrated to give a pale yellow oil (22.80g). The oil was chromatographed on silica gel (200g) eluting with 1:9 ethyl acetate-heptane (11) and 1.5:8.5 ethyl acetate-heptane (31) to give the pure product (3) (4.15g, 78.6% yield). ' H NMR conformed to structure. Example 2: Stereo selective Reduction (3) HO L-Selectride, THF Ph TUPO" A-rnr, THPCJ A dry 250ml 3-necked round bottom flask equipped with a magnetic stirring bar, a temperature probe, and an addition funnel, was purged with nitrogen. The flask was charged with a solution of L-Selectride in THF (IM, 16.25ml, 16.25mmol) and cooled to -78°O in an acetone-dry ice bath. A solution of (3) (3,80 g, 8.13 mmol) in anhydrous THF (60ml) was added slowly from the addition funnel over 35min, and the mixture was stirred at -78°C for 4.5h. TLC analysis indicated that the reaction was complete. The cooling bath was removed, and the mixture was quenched by the addition of 30% hydrogen peroxide (2.2ml, 19.4mmol) followed by saturated NH4CI (50ml). Ethyl acetate (20()ml) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (200ml)- The combined organic layers were washed with 10% sodium bisulfite (50ml), dried (NajSC^), filtered and concentrated to give the crude product (5.05g). This material was chromatographed on silica gel (75g) eluting with 1:9 ethyl acetate-heptane and 3:7 ethyl acetate-heptane to give the pure product (4) (3.25g, 85.1% yield). (H NMR conformed to structure. Example 3a: Selective Pjjrydroxylatipn (Figure Removed) A solution of alkene (4) (2.5g, 5.3mmol) in THF (20ml) was cooled to -9°C and a solution of A/-methyknorprioline oxide monohydrate (NMO, 1.6g, 11.7mrnol) in water (4ml) was added. A solution of osmium tetroxide (60mg, 0.236mmol) in water (1.5ml) was added slowly while keeping the reaction temperature below -7°C. After the addition was complete, the reaction mixture was stured at -7 to -5°C for 4h. The reaction was quenched by the addition of solid sodium bisulfite (1.5g), the mixture stirred for 5mm, and filtered through a bed of celite. The filter cake was washed with ethyl acetate, and the combined filtrate was washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried (NaiSO^, filtered and concentrated to give the crude product. as a dark brown oil. This oil was chroinatographed on silica gel (50g) eluting with 1:99 methanol-dichloromethane and 5:95 methanol-dichloroinethane to give the pure triol (7) as a yellow oil (2.3g, 86.8% yield). ]H NMR conformed to structure. Example 3b: Selective Dihydroxvlation (Figure Removed) A solution of alkene (5) (11.37g, 20.17mmol) in THF (100ml) was cooled to -9°C and a solution of 7V-mefhyhnorpholine oxide monohydrate (NMO, 6.84g, 50.42mmol) in water (20ml) was added. A solution of osmium tetroxide (256mg, l.OlOmmol) in water (6.42ml) was added slowly while keeping the reaction temperature below -6.5°C. After the addition was complete, the reaction mixture was stirred at -10 to -7.S°C for 4b. The reaction was quenched by the addition of solid sodium bisulfite (6.84g), the mixture stirred for 5min, and filtered through a bed of celite. The filter cake was washed with ethyl acetate (200ml), and the combined filtrates were washed with saturated aqueous sodium bicarbonate and water. The organic layer was dried (Na2SCXi), filtered and concentrated to give the crude product as a dark brown oil. Tin's oil was chromatographed on siJica gel (J40g) eluting with 70:30 ethyl acetate-heptane, ethyl acetate, and 2:98 methanol-ethyl acetate to give the pure diol (8) (8.70g, 72.1% yield). 'H NMR spectrum conformed to structure. (Figure Removed) A solution of alkene (7) (2.3g, 4.6mmol) in ethanol (200ml) and 5% palladium on activated carbon (contains 50-60wt% water, 300mg) was stirred under 40psi of hydrogen for 4h. A fresh charge of catalyst (200mg) was added and the hydrogenation continued for 8h. 'H NMR analysis indicated complete reduction of the double bond. The reaction mixture was filtered through a bed of celite and the filtrate was concentrated to give triol (10) as an oil (2.1 g, 91.3% yield). (Figure Removed) A solution of alkene (8) (9.32g, 15.59inmol) in ethyl acetate (200ml) arid 5% palladium on activated carbon (contains 50-60wt% water, l.Og) was stirred under 45psi of hydrogen for 1 8h. A fi-esh charge of catalyst (0.5g) was added and the hydrogenation continued for 2 days. A second charge of fresh catalyst (0.5g) was added and the hydrogenation continued for 1 day. 1H NMR analysis indicated that the double bond was not completely reduced. The reaction mixture was filtered, concentrated to dryness, the residue dissolved in ethanol (200ml), and hydrogenated over 5% palladium on activated carbon (0.5 g, 40psi of hydrogen) for 24h. The reaction mixture was filtered through a bed of celite and Hie filtrate was concentrated to give diol (11) as a colourless oil (8.40g, 89.8% yield). Example 5a: Diol Cleavage (Figure Removed) A mixture of sodium periodate (1.90g, 8.14mmol), silica gel (2.00g) and water (2ml) were stirred until a free flowing powder was obtained. This powder was added in one portion to a solution of triol (10) (2.10g, 4.14mmol) in dichloromethane (25ml) and the mixture was stirred at room temperature for 2h. The solids were removed by filtration through a short pad of Na2SO4 (5g), and the filtrate was concentrated to dryness. The crude product was chromatographed on silica gel (30g) eluting with 20:80 ethyl acetateheptane to give the product (13) as an oil which solidified slowly on storage (1.65g, 83.8% yield). ' H NMR conformed to structure. Example 5b: Diol Cleavage (Figure Removed) A mixture of sodium pcriodate (5.00g, 23.38mmol), silica gel (S.OOg) and water (5ml) were stirred until a free flowing powder was obtained. This powder was added in one portion to a solution of diol (11) (7.00g, 11.69mmol) in dichloromethane (50ml) and the mixture was stirred at room temperature for 3h. The solids were removed by filtration through a short pad of Na2SO4 (lOg), and the filtrate was concentrated to dryness. The crude product was chromatographed on silica gel (55g) eluting with 15:85 ethyl acetateheptane to give aldehyde (2.25g, 33.9% yield). 1H N.MR speclaim conformed to structure. Example 5c: Diol Cleavage (Figure Removed) A mixture of sodium periodate (155.0g, 724.6mmol), silica gel (275g) and water (175ml) was stirred until a free flowing powder was obtained. This powder was added in portions to a solution of crude triol (7) (230g, 369mmol) in dichloromethane (1.51) and the mixture was stirred at room temperature for 4h. Solid anhydrous sodium sulfate (500g) was added and the mixture was stirred for lOmin. The solids were collected by vacuum filtration, and the filtrate was passed through a plug of silica gel (750g). The plug was washed successively with dichloromethane (21) and ethyl acetate (2.51), and the combined filtrates were concentrated to dryness. The residue was dissolved in toluene (0.51) and concentrated to dryness to give crude lactol (23) (180g). JH NMR conformed to structure. (Figure Removed) A dry 250ml 3-necked round bottom flask equipped with a magnetic stirring bar, a temperature probe, and rubber septa, was purged with nitrogen. The flask was charged with solid 4-carboxybutylphosphonium bromide (3.67g, 8.27mmol) and anhydrous THF (20ml), and cooled to -12?C in an ice-methanol bath. A solution of potassium tertbutoxide (1.86g, 16.54mmol) in anhydrous THF (20ml) was added by syringe keeping the internal temperature below -9°C. The resulting orange-red suspension was stirred for Ih between -9°C and -12°C. A solution of the lactol (13) (l.60g, 3.39nimo.l) in anhydrous THF (20ml) was added by syringe keeping the temperature below -6°C, The resulting suspension was stirred in the cold for 2h, and quenched by the addition of water (50ml). The THF was removed under reduced pressure and TBME (100ml) was added to the residue. The layers were separated, and the organic layer was washed with 6% aqueous sodium chloride (60ml). The combined aqueous layers were acidified to pH 4.0 with 5% aqueous citric acid, and extracted with ethyl acetate (2 x 100ml). The combined ethyl acetate extracts were washed with water (100ml), dried (Na2SO4), filtered and concentrated to a colorless syrup (1.90g) which was carried forward without further purification. 'H NMR showed that this syrup is a mixture of acid (16) and unreacted Wittig salt. (Figure Removed) A dry 250ml 3-necked round bottom flask equipped with a magnetic stilling bar, a temperature probe, and rubber septa, was purged with nitrogen. The flask was charged with solid 4-carboxybutylphosphonium bromide (3.5Ig, 7.93mmol) and anhydrous THF (100ml), and cooled to -10°C in an ice-methanol bath. A solution of potassium tertbutoxide (J.78g, 15.85mmol) in anhydrous THF (10ml) was added by syringe. The resulting orange-red suspension was stirred for Ih at 0°C, cooled to -10°C, and a solution of aldehyde (14) (2.25g, 3.96mmol) in anhydrous THF (15ml) was added by syringe. The resulting suspension was stirred in the cold for 2h, and quenched by the addition of water (50ml). The THF was removed wider reduced pressure and the mixture was washed with TBME (2 x 70ml). The combined organic layers were extracted with water (50ml). The combined aqueous layers -were acidified to pH 3.0 with 5% aqueous citric acid, and extracted with ethyl acetate (2 x 100ml). The combined ethyl acetate extracts were dried (Na2SO4), filtered and concentrated to crude acid (17) (3.30g) which was carried forward without further purification. (Figure Removed) A dry 51 3-necked round bottom flask equipped with an overhead stirrer, a temperature probe, and rubber septa, was purged with nitrogen. The flask was charged with solid 4-carboxybutylphosphonium bromide (360.8g, 814.4mmol) and anhydrous THF (1.21), and cooled to -10°C in an ice-salt bath. A solution of potassium tert-bnloxide (182.4g, I62S.5mmol) in anhydrous THF (0.51) was added by cannula keeping the internal temperature below 0°C. The resulting orange-red suspension was stirred for 2h below 0 °C. A solution of the lactol (23) (ISOg, 369mmol) in anhydrous THF (0.4ml) was added by cannula keeping the temperature below 0 °C. The resulting suspension was stirred in the cold for Ih, and quenched by the careful addition of water (0.61). The solvent was removed under reduced pressure and water (1.41) was added to the residue. The pH of the aqueous mixture was adjusted to between 4 and 4.5 by the addition of 40% aqueous citric acid (300ml), and extracted with ethyl acetate (1 x 1.51 and 1 x 0.61). The combined ethyl acetate extracts were washed with saturated brine (0.51), dried (Na2SC4), filtered, and the filtrate concentrated to dryness. The residue was triturated with acetone (1.01), filtered, and the filter cake was washed with acetone (2 x 0.61). The filtrates contained the crude acid (26), which was carried forward without further purification. Example 7a: Esterificatioij (Figure Removed) The crude olefmation product from example 6a (1.84g) was dissolved in acetone (20ml), and the solution was cooled in an ice bath. The solution was treated with 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 2.02g, 19.S6mmol), and 2-iodopropane (3.38g, 13.24mrnol), and allowed to stir at room temperature under an atmosphere of nitrogen for 16h. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (100ml) and 5% aqueous citric acid (50ml). The layers were separated, the organic layer was washed with saturated aqueous sodium bicarbonate (20ml), and dried (Na2SO4). The drying agent was filtered off and the filtrate was concentrated to dryness. The residue was chroraatographed on silica gel (30g) eluting with 15:85 ethyl acetateheptane to give pure ester (19) (1.41 g, 69.2% yield from lactol (13)). ^-I NMR conformed to structure. (Figure Removed) The crude olcfination product from example 6b (3.30g) was dissolved in acetone (30ml), and the solution was cooled in an ice bath. The solution was treated with 1,8- dia7.abicyclo[5.4.0]undec-7-ene (DBU, 2.85g, 18.72mmol), and 2-iodopropane (4.77g, 28.06mmol), and allowed to stir at room temperature under an atmosphere of nitrogen for 64h. A voluminous precipitate formed. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate (170ml) and 5% aqueous citric acid (75ml). The layers were separated, the organic layer was washed with water (75ml), saturated aqueous sodium bicarbonate (75ml), and dried (NaaSO/t). The drying agent was filtered off and the filtrate was concentrated to dryness. The residue was chvomatographed on silica gel (30 g) eluting with 15:85 ethyl acetate-heptane to give pure ester (20) (2.1Sg, 80.7% yield from aldehyde (14)). H NMR spectrum confomied to structure. Example 7c: Esterjfication no (26) HQ lodomethanc DBU, Acetone THPO THPC5 The combined filtrates containing acid (26) from example 6c were transferred into a dry 51 3 -necked round bottom flask equipped with an overhead stirrer, a temperature probe, and addition funnel. 'Hie contents of the flask were cooled to 5°C in an ice bath, and combined with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 225. Og, 1480.6mmol), keeping the temperature below 10°C. lodomethane (315.1g, 2221.2mmol) was slowly added at less than 15°C, and the mixture was stirred overnight at room temperature under an atmosphere of nitrogen. A second portion of iodomethane (105.0g, 740.4mmol) was added and the mixture stirred for 5h. The precipitated salts were filtered off, and the filtrate was concentrated to dryness. The residue was partitioned between ethyl acetate (2.51) and 10% aqueous citric acid (0.61). The layers were separated, and the aqueous layer was extracted with ethyl acetate (0.61). The combined organic layers were washed with 20% brine (0.61), saturated aqueous sodium bicarbonate (0.51), and dried (Na2SO4). The drying agent was filtered off and the filtrate was concentrated to dryness. The residue was chromatographed on silica gel (2kg) eluting with 15:85 ethyl acetate-heptane followed by 25:75 ethyl acetate-heptane to give pure ester (48) (86.8g) and a slightly contaminated product fraction (58.5g, 69.3% total yield from lactol (23)). 'H NM.R conformed to structure. Example 8a: Deprotection (Figure Removed) To a solution of ester (19) (1.41g, 2.35mmol) in methanol (20ml) was added pyridinium p-toluenesulfonate (PPTS, 30mg, 0.12minol), and the mixture was heated in an oil bath that was maintained at 52°C for 4h. TLC indicated that all the starting material was consumed. Solid sodium bicarbonate (50mg) was added to the reaction mixture and the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (30g) eluting with 30:70 ethyl acetate-heptane (11), 50:50 ethyl acetate-heptane (11), and 65:35 ethyl acetate-heptane (1.51) to give Latanoprost (21) as a colorless oil (910mg, 90.0% yield). 'H NMR conformed to structure. Example 8b: Deprotection (Figure Removed) To a solution of ester (20) (2.15g, 3.15mmol) in methano] (40mL) was added pyridinium j9-toluenesulfonate (PPTS, lOmg, 0.04mmol), and the mixture was heated in an oil bath that was maintained at 45°C for 6h. TLC indicated that all the stalling material was consumed. Solid sodium bicarbonate (200mg) was added to the reaction mixture and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (150ml) and water. The layers were separated and the organic phase was washed with saturated sodium bicarbonate (25ml), and water (25ml). The solvent was removed and the residxie was chromatographed on silica gel (40g) eluting with 35:65 ethyl acetate-heptane (11), and 50:50 ethyl acetate-heptane (11) to give Latanoprost (21) as a colorless oil (1.14g, 83.7% yield). JH NMR spectrum conformed to structure. ,OMc THPG 0'IHP .OMe OH To a solution of ester (48) (86.7g, 152.6mmol) in methanol (600ml) was added pyridinium p-toluenesulfonate (PPTS, l.Og, 4.0mmol), and the mixture was stirred at room temperature overnight, men at 40°C for 4h. TLC indicated that all the starting material was consumed. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate (1.01) and saturated aqueous sodium bicarbonate (300 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (0.21). The combined organic layers were concentrated to dryness, the residue dissolved in methanol and concentrated to dryness giving crude ester (49) (62.4g) as an oil. fH NMR conformed to structure. Example 9: Amidation (Figure Removed) A 21 thick-walled glass vessel equipped with a magnetic stirring bar was charged with a solution of ester (49) (85.2g, 212.7mmol) in methanol (0.41) and 70% aqueous solution of ethylamine (0.41). The vessel was sealed, heated and stirred in an oil bath maintained at 90"C for 45h. TLC analysis showed consumption of ester (49). The volatile.? were removed under reduced pressure, and the residue was partitioned between ethyl acetate (1.51) and saturated brine (0.71). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 0.51). The combined organic layers were dried (NaiSCXt), filtered, and concentrated to dryness. The residue was chromatographed on silica gel (1kg) eluting successively with 80:20 ethyl acetate-heptane (41), ethyl acetate (121), 1:99 methanol-ethyl acetate (161), and 2:99 methanol-ethyl acetate (161). The resulting product (55.6g) was triturated with /-/-butyl methyl ether to give Bimatoprost (22) as a white solid (47.2g). JH and BC NMR conformed to structure. WE CLAIM: 1. A process for the preparation of a prostaglandin compound having the formula (I): (Formula Removed) wherein A is selected from the group consisting of C1-C6 alkyl groups; C7-C16 aralkyl groups wherein an aryl portion thereof is unsubstituted or substituted with one to three substituents selected from the group consisting of C1-C6 alkyl groups, halo and CF3; and (CH2)nOR' wherein n is an integer from 1 to 3 and R' represents a C6-C10 aryl group which is unsubstituted or substituted with one to three substituents selected from the group consisting of C1-C6 alkyl groups, halo and CF3; B is selected from OR" and NHR" wherein R" is C1-C6 alkyl groups; and represents a double bond or a single bond; (a) the process comprising a step of preparing a compound of formula (VIII): (Formula Removed) wherein A is as defined above; and represents a double bond or a single bond; said step comprising converting a compound of formula (IX): (Formula Removed) wherein A, P and are as defined above and X is a leaving group, to a cuprate reagent and performing a 1,4 addition reaction between the cuprate reagent and a compound of formula (X): (Formula Removed) wherein P is as defined above; (b) the process comprising a step of preparing a compound of formula (VIIa): (Formula Removed) wherein A is as defined above; and represents a double bond or a single bond; said step comprising selectively reducing a compound of formula (VIII): (Formula Removed) wherein A, P and are as defined above; (c) the process comprising a step of preparing a compound of formula (VIIb): (Formula Removed) wherein A is as defined above; and represents a double bond or a single bond; said step comprising protecting a compound of formula (VIIa): (Formula Removed) wherein A, P and are as defined above, with a hydroxyl protecting group; (d) the process comprising a step of preparing a compound of formula (VIb) or (Vb): (Formula Removed) wherein A is as defined above; said step comprising dihydroxylating a compound of formula (VIIb): (Formula Removed) wherein A and P are as defined above and is a double or single bond; (e) the process comprising a step of preparing a compound of formula (Vb): (Formula Removed) wherein A is defined as above; said step comprising reducing a double bond of a compound of formula (VIb): (Formula Removed) wherein A and P are as defined above; (f) the process comprising a step of preparing a compound of formula (IVb): (Formula Removed) wherein A is as defined above; and represents a double bond or a single bond; said step comprising performing a diol cleavage reaction on a compound of formula (VIb) or (Vb): (Formula Removed) wherein A and P are as defined above; (g) the process comprising a step of preparing a compound of formula (IIIb): (Formula Removed) wherein A is as defined above and represents a double bond or a single bond; said step comprising performing Wittig reaction on a compound for formula (IVb): (Formula Removed) wherein A and P are as defined above; (h) the process comprising a step of preparing a compound of formula (IIb): (Formula Removed) wherein A is as defined above and represents a double bond of a single bond; said step comprising performing esterification or amidation on a compound of formula (IIIb); (Formula Removed) wherein A and P are as defined above; (i) the process of comprising a step of preparing a compound of formula (I): (Formula Removed) wherein A is as defined above and represents a double bond or a single bond; said step comprising deprotection of a compound of formula (IIb): (Formula Removed) wherein A and P are as defined above. 2. The process as claimed in claim 1, wherein P is a tetrahydropyranyl (THP) protecting group. 3. The process as claimed in claim 1 or claim 2, wherein X is iodine. 4. The process as claimed in claim 1, wherein A is (CH2)2Ph, represents a double bond and P is THP and X is I. 5. The process as claimed in claim 1, wherein A is (CH2)2Ph, represents a double bond and P is THP. 6. The process as claimed in claim 1, wherein A is (CH2)2Ph, P is THP, represents a double bond, and compound (VIIb) reacts to give compound (VI b). 7. The process as claimed in claim 1, wherein A is (CH2)2Ph, P is THP and compound (VIb) reacts to give compound (Vb). 8. The process as claimed in claim 1, wherein A is (CH2)2Ph, P is THP, represents a single bond, and compound (Vb) reacts to give compound (IVb). 9. The process as claimed in claim 1, wherein the compound having the formula (I) is Travoprost. 10. The process as claimed in claim 1, wherein A is CH2CH2-Ph, represents a double bond and P is THP, the process further comprising selectively reducing the compound of formula (VIII) to provide a compound of formula (4): (Formula Removed) protecting the compound of formula (4) to provide a compound of formula (5); (Formula Removed) dihydroxylating the compound of formula (5) to provide a compound of formula (8); (Formula Removed) performing a diol cleavage reaction on the compound of formula (8) to provide a compound of formula (24): (Formula Removed) performing a Wittig reaction on the compound of formula (24) to provide a compound of formula (27): (Formula Removed) amidating the compound of formula (27) to provide a compound of formula (30): (Formula Removed) deprotecting the compound of formula (30) to provide Bimatoprost.

Documents:

3143-DELNP-2006-Abstract-(05-09-2011).pdf

3143-delnp-2006-abstract.pdf

3143-DELNP-2006-Claims-(05-09-2011).pdf

3143-DELNP-2006-Claims-(26-06-2012).pdf

3143-DELNP-2006-Claims-(28-02-2012).pdf

3143-delnp-2006-claims.pdf

3143-DELNP-2006-Correspondence Others-(05-09-2011).pdf

3143-DELNP-2006-Correspondence Others-(26-06-2012).pdf

3143-DELNP-2006-Correspondence Others-(28-02-2012).pdf

3143-delnp-2006-correspondence-others-1.pdf

3143-delnp-2006-correspondence-others.pdf

3143-delnp-2006-description (complete).pdf

3143-DELNP-2006-Form-1-(05-09-2011).pdf

3143-delnp-2006-form-1.pdf

3143-delnp-2006-form-18.pdf

3143-DELNP-2006-Form-2-(05-09-2011).pdf

3143-delnp-2006-form-2.pdf

3143-delnp-2006-form-3.pdf

3143-delnp-2006-form-5.pdf

3143-DELNP-2006-GPA-(05-09-2011).pdf

3143-delnp-2006-gpa.pdf

3143-delnp-2006-pct-237.pdf

3143-delnp-2006-pct-306.pdf

3143-delnp-2006-pct-326.pdf

3143-delnp-2006-pct-373.pdf

3143-DELNP-2006-Petition-137-(05-09-2011).pdf