Title of Invention

PROCESS FOR THE PREPARATION OF A 15(S)- PROSTAGLANDIN INTERMEDIATE

Abstract

A process for the preparation of a 15(S)-prostagiandin intermediate selected from the group consisting of compound (iy): where: (1)R3is-HandR4is-H, or (2) R3 is -H and R4 is -0-CH3l or (3) R3 and R4 are taken together to form a five member ring attached to the 3-and 4-positions of the phenyl ring where the second ring from the R3- position to the R4- position is-CH=CH-0-; where ==? is a single or double bond; and where Xu is phenyl or phenyl substituted with one thru three CrC4 alkyl, one thru three CrC4 alkoxy, one phenyl, one thru three -F, -CI, -Br and -I; and

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13] PHARMACIA & UPJOHN COMPANY, a US company, of 301 Henrietta Street, Kalamazoo, Michigan 49001, United States of America, The following specification particularly describes the nature of the invention and the manner in which it is to be performed :- WO 03/008368 FCT/US 02/30188 PROCESS Affri TWTPRMT?nTATFS TO PREPARE LAlANUVKUtfF- / BACKGROUND OF TIIEiNVENTIOft , 1. Field of the Invention The present invention is a process, including intermediates, to produce atanoprost, a pharmaceutical agent useful in treating ophthalmic conditions. 2. Description of the Related Art US Patent 5,422,368 discloses latanoprost (Example 2) and its usefulness as an ophthalmic agent. The patent discloses a process (Example 2) to prepare latanoprost and two closely related compounds. There are very limited numbers of examples of reductions of Ap-unsaturated enones with chlorodiisopinocampheylborane. J. Am. Chem. Soc, 110(5), 1539-46 (1988) describes a single example of reduction of an acyclic aryl enone, 4-phenyl-3- buten-2-one, with chlorodiisopinocampheylborane giving an 81% eantiomeric selectivity, and no examples of simple acyclic non-aryl conjugated enones. Bull. Korean Chem. Soc, 15(12), 1033-4 (1994) addresses the issue of 1,2 versus 1,4 reduction with chlorodiisopinocampheylborane but did not discuss the enantioselectivity or diastereoselectivity of the reductions. Tetrahedron Letters 1067-1070 (1976) discloses a cyclopentane diol-acid where the side-chain did not contain any aromatic functionality. SUMMARY OF INVENTION Disclosed is a compound of the formula (VI) HO OH (VI) where: (l)R3is-HandR4is-H, (2) R3 is -H and R, is -O-CH3 and (3) R3 and R4 are taken together to form a five member ring attached to the 3- and 4- positions of the phenyl ring where the second ring from the R3- position to the Rj- position is -CH-CH-O- and WO 03/008368 -PCT/US02/20188 under reduced pressure (30° maximum temperature) to a volume of about 100 ML. Ethyl acetate (100 mL) is added and the mixture is concentrated under reduced pressure (30° maximum temperature) to a volume of about 80 mL. The resulting slurry is cooled to -20° for one hovr and then filtered, to give the title compound, mp = 105- 107°; NMR (d6-DMSO, 400 MHz) 5 5.37-5.49, 4.61, 4.58, 4.06, 3.94, 3.76, 2.48, 2.35,2.11-2.16, 1.8, ] .27-1.51 and 0.94; CMR (d6-DMSO, ]00.6 MHz) 5 174.48, 136.33, 131.21, 75.65, 71.40, 69.37, 53.79, 44.42, 44.31, 37.80, 31.82, 31.64, 25.16, 22.49 and 14.23. EXAMPLE 12 (3aS,4S,5S,6aR)-Hexahydro-5-hydroxy-4-[(lE,3R)-3-hydroxy- 1 -octenyi]-2H-Cyclopenta[b]furan-2-one (XX) 2-[(lR, 2R, 3R, 5S)-3,5-dihydroxy-2-[(3R)3hydroxy-l- octenyl]cyclopentyl]acetic acid (XIX, EXAMPLE 11, 2.55g) is stirred with MTBE (100 mL) and trichloroacetic acid (0.102 g). The slurry is heated to reflux for more than one hour. Then triethylamine (0.2 mL) is added. The mixture is cooled and washed once with water{(50 mL) of water. The mixture is dried over anhydrous granular sodium sulfate and then concentrated under reduced pressure to give the title compound, NMR (CDC13, 400 MHz) 5 5.58, 5.43, 4.88, 4.03, 3.92, 3.55, 2.8, 2.71, 2.3-2.5,2.22, 1.9, 1.2- 1.6 and 0.89; CMR (CDCI3, 100.6 MHz) 6 176.94, 136.79, 130.20, 82.41, 76.27, 72.78, 56.12, 42.34, 39.61, 37.05, 33.98, 31.60, 25.06, 22.52 and 13.94. WO 03/ 008368 CHART A (X) (XI) (XIV) A process as claimed in claim 6 where the reaction mixture temperature is from -35° C to -45° C. 8. A process as claimed in claim 5 where 3 to 4 equivalents of (-)-chlorodiisopinocampheylborane are used. 9. A process as claimed im claim 8 where at least 3.5 equivalents of (-)-chlorodiisopino-campheyl-borane are used. 10. A process as claimed in, claim 5 where prior to step (2), the reaction mixture of step (1) is contacted with a readily reducible aldehyde or ketone. 11. A process as claimed in claim 10 where the readily reducible aldehyde or ketone is selected from the group consisting of CrC6 aldehydes, (VCe ketones and benzaldehyde. 12. A process as claimed in, claim 11 where the readily reducible aldehyde or ketone is acetone or methylethylketone. 13. A process as claimed in claim 5 where the boron complexing agent is selected from the group consisting of water, CrC6 alcohols, (VCg diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. 14. A process as claimed in claim 13 where the boron complexing agent is selected from the group consisting of water and diethanolamine. 15. A process as claimed in claim 14 where the boron complexing agent is water. 16. A process as claimed in claim 15 where base is added with the boron complexing agent. 17. A process as claimed in claim 16 where the base is selected from the group consisting of carbonate, bicarbonate, mono-, di- and tri- C-i-C6 alkylamines, pyridine and pyridine substituted with CrC4 alkyl. 18. A process as claimed in claim 17 where the base is bicarbonate or carbonate. 19. A process according to claim 5 where prior to, or after, step (2), the reaction mixture is warmed to 15° C to 25° C. -4S~ JAN 0? 2QQ4 12:03 PH FP ^POTOff -0PEISN FILlMb4l 5082 TO ?EMFPEY & 9P WO l)3/0083(iS PCT/US02/201SS mL) is added and the mixture is allowed to warm to 20-25° and stirred for two hours. MTBE (100 mL) is added and then a solution of sodium bicarbonate (10 g) in water (150 mL) is added. The two phase mixture is stirred for 15 min. The phases are separated and the organic phase is washed with water (100 mL). The organic phase is 5 concentrated under reduced pressure. MTBE (300 mL) is added and the mixture then concentrated. Acetonitrilc (100 mL) is added and the mixture is again concentrated. Acetonitrile (150 mL) and heptane (100 mL) are added. The two-phase mixture is stirred for 5 min and then allowed to settle. The phases are separated. The acetonitrile phase is extracted with heptane (3 x 100 mL). The acetonitrile phase is 10 concentrated. A portion of the concentrate is removed and purified by chromatography (silica gel, 230-400 mesh; heptane/ethyl acetate, 1/1) to give the title compound, mp = 78-81°; NMR (CDCU, 400 MHz) 5 7.77, 7.32, 7.19, 7.04, 6.94, 5.45, 5.37, 5.01, 4.79, 3.88, 2.61-2.23, 2.01 and 1.60; CMR (CDC13, 100.6 MHz) 5 176.5, 166.0, 141.7, 136.0, 133.3, 129.5,128.4, 125.8,83.3,79.2,71.2,53.9,42.6, 15 38.7, 37.5, 34.9 and 31.5. EXAMPLE 3 [3aR-[3aa,4a(lE,3S*),5?,6aa]]-5-(Benzoyloxy)hexahydro-4- (3-hydroxy-5-phenyl-1 -pentyl)^2H-cyclopenta[b]furan-2-one (V) [3aR-[3a a ,4a(lE,3S*),5P,6aa]]-5-(benzoyloxy)hexahydro-4~(3-hydroxy-5- 20 phenyl-l-pentcrtyl)-2H-cyclopenta[b]furan-2-one (IV, EXAMPLE 2) is dissolved in THF (125 mL). Platinum on carbon catalyst (5%, 1 g) and triethylamine (3.4 mL) are added. The mixture is purged with nitrogen and then and the mixture is stirred vigorously under 5 psi hydrogen at 20° ± 5°. When the reaction was complete as measured by HP1 C, the reaction is purged with nitrogen. The mixture is filtered over 25 celite. The filtrate is concentrated under reduced pressure to give the crude product A portion of the product is removed and purified by chromatography (silica gel, 230-400 mesh; heptane/ethyl acetate, 1/1) to give the title compound, mp = 68-70°, NMR (CDCI3, 400 MHz) 5 7.91, 7.47, 7.36, 7.19, 7.10, 5.18, 4.99, 3.56, 2.84-2.57, 2.44-2.26, 1.71-1.16; CMR(CDC13) 100.6 MHz) 5 176.9, 166.0, 141.8, 133.2, 129.6, 30 128.4, 125.9, 84.4, 80.1, 70.8, 52.6, 43.5, 39.0, 37.7, 36.2, 35.1, 32.0 and 29.5; MS calculated m/z~ 408, found m/z = 409 (m 1- 1). EXAMPLE 4 2-[(lR, 2R, 3R, 5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-5- phenylpentyl]cyclopenryl]acetic acid (VI) -8- Q--JHM-2QQ4 23:08 860 441 5062 39". \VO 03/003368 PCT/US02/20188 The mixture is seeded with a small amount of the title compound. The mixture is stirred at about 30° for 10 min, during which time massive crystallization occurred. After the product had crystallized, heptane (30 mL) is added over 15 min. The slurry is cooled to 20-25' and stirred for 1 hour. The product is filtered and dried under 5 nitrogen to give the title compound, mp = 69-7 ] °; NMR (CDClj, 400 MHz) 8 7.35, 7.26, 5.00, 4.065 3.68, 2.89-2.55, 2.34-2.07 and 1.87-1.34; CMR (CDCI3, 100.6 MHz) 6 177.8, 141.9, 128.4, 125.9, 84.0, 71.2, 53.9, 43.1, 41.4, 39.1, 36.0, 35.2, 32.0 and 28.9. EXAMPLE 6 (3aR,4R,5R,6aS)-5-(l-Ethoxyethoxy)-4-[(3R)-3-(l- 10 ethoxyethoxy)-5-phenylpentyl]hexahydro-2H- cyclopenta[b]furan-2-one (X) [3aR-[3aa,4a(R*),5p,6aa]]-Hexahydro-5-hydroxy-4-(3-hydroxy-5-phenylpentyl)-2H-cyclopenla[b]fiiran-2-one (VII, EXAMPLE 5, 1.0 g, 3.3 mmoles) is dissolved in methylene chloride (3 mL) and the mixture is placed in a sealable 15 pressure tube. Add 1.0 mL of a mixture of trichloracetic acid (0.27 g) in methylene chloride (10 mL) followed by ethyl vinyl ether (6.3 mL). The pressure tube is closed and heated to 45° in an oil bath for about S hours. At this time, triethylamine (0.12 mL) is added and the mixture is stirred for 10 minutes. The mixture is then concentrated under reduced pressure. 20 EXAMPLE 7 (3aR,4R,5R,6aS)-5-(J-Ethoxyethoxy)-4-[(3R)-3-()- ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cycIopenta[b]furan-2-ol (XI) (3aR,4R,5R,6aS)-5-(l-Ethoxyethoxy)-4-[(3R>3-(l-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cycIopenta[b]furan-2-one (X, EXAMPLE 6) is 25 dissolved in THF (14 mL) and the mixture cooled to -40°. Using a syringe pump, DIBAL(1.0 M, 3.78 mL in toluene) is added over 15 minutes, maintaining the internal temperature at less than -30°. The mixture is stirred for 15 minutes after the completion of the addition, then ethyl acetate (0.38 mL) is added. The mixture is poured into a solution of potassium sodium tartarate (\0g in 30 mL of water) and 30 warmed to 20-25c. The two phase mixture is heated to 45° for 1 hi and then cooled The phases are separated and the organic phase is concentrated. - 10- .:r-JAM-2004 23:08 860 441 5Q82 9G = WO O3/O083G8 PCT/US02/20188 CHART A STEP(D) HO OH HO OH (VI) (VII - 14 - JAN 0? 2QG4 12:04 PM FP -iPOTON POPEIGN FlLIr^Ji 5082 TO PE'-'FPEY a 3~ WO 03/008368 PCT/LIS02/201S8 13. A process according to claim 5 where the boron complexing agent is selected from the group consisting of water, Cj-Q alcohols and diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. 5 14. A process according to claim 13 where the boron complexing agent is selected from the group consisting of water and diethanolamine. 15. A process according to claim 14 where the boron compJexing agent is wacer. 10 16. A process according to claim 15 where base is added with the boron complexing agent. 17. A process according to claim 16 where the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tri- Ci-Ca alkylamines, pyridine and pyridine substituted with G-C4 alkyl. 15 18. A process according to claim 17 where the base is bicarbonate or carbonate. 19. A process according to claim 5 where prior to, or after, step (2), the reaction mixture is warmed to about 15 to about 25*. 20 20. A process according to claim 19 where the where the reaction mixture is warmed from about 1 to about 3 hr. 21. A process according to claim 5 where Xii is phenyl. 25 22. A process according to claim 5 where the 15(S)-prostaglandin intermediate is compound (IV) O o- -20- 0--JHN-20QJ 23:39 8bQ 441 5082 2S04 1 2 : CZ ="■] ~P -~POTO\ -OPE I '3M F I L. : '■ 3-; : 5QB, WO U3/00S36S PCT/DSO2/20JSS where is a single or double bond and pharmaceutical!)7 acceprable salts thereof. Also disclosed is a process for the preparation of a I5(S)-prostaglandin intermediate selected from the group consisting of compound 'IV'i O O' where R3, FU and 1 .^. are as defined above and where X, - is phenyl or phenyl substituted with one thru three d-C* alkyl, one thru three CrC- alkoxy, one phenyl one thru three-F. -CI,-Br and-I and compound (XVIII) 10 X n CO where Xi: i^> defined above which comprises: (]) contacting a compound selected from the group consisting of compoun; 15 (III) O O' where R3, P^ X: ■ and are as defined above or compound (XVII). respective! 22CJ. 12:C2 ?r-' rp iBPO"1".:-; FOREIGN FILi'^^i 5992 ~; ~2''-?EY *■ I- ': WO ()3/()()S3f.8 PCT/US02/7MXK the enone (III). Suitable solvents include THF, methylene chloride and DME and mixtures thereof. MTBE and toluene alone are not operable. The use of a cosolver.;, such as hexane, heptane, isooctane or similar hydrocarbons is not necessary but is preferred. This is important since (-)-chlorodiisopinPcampheylborane is available 5 commercially as a solution in these solvents. MTBE and toluene can be used as the cosolveni. The narure of the solvent has virtually no effect with regard to the 15(Sl/15(R) ratio in the product It is preferred that from about 3 to about 4 equivalents of (-)-chlorodjisopinocampheylborane be used; it is more preferred tha: ai least 3.5 equivalents of (-)-chlorodiisopinoc3rnphcyIrporane be used. With fewer 10 equivalents the reaction is incomplete; there is no improvement in rate or selectivity with more equivalents. When the (-)-chlarodiisopinoPamphcy]borane is contacted with the cc.p-unsaturated enone (111), the temperature should be maintained less than 0°. It :s preferred that the temperature be maintained at less than -20c; it is more preferred that the temperature be maintained in the range of from about-35 to about is _45c. Above -35° the selectivity decreases and below about -45° the rate becomes ioc slow to be practical. When the reaction is complete, the excess (-Vchlorodiisopinocampheylboranc must be destroyed by use of a boron complexing agent which is selected from thi; group consisting of water, C-Cfi alcohols and diols, ethanolaminc, diethanolammc, 20 triethanolamine and mixtures thereof. It is preferred that the boron complexing agent be group be water and diethanolamme; it is more preferred that the complexing agent be water. It is preferred that pnor to step (2), the reaction mixture of s:cp(l)is contac.'ed with a readily reducible aldehyde or ketone. It is preferred tha; the readily reducible 25 aldehyde or ketone is selected from the group consisting of CpQ aldehydes and ketones and benzaldebyde; it is more preferred that the readily reducible aldehyde or ketone is acetone or methylethylketone. When adding ™e boron complexing agent it is preferred that a base also be added. It is preferred tfiat the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tri- C|-Q, alkylamines, 30 pyridine and pyridine substituted with d-C* alkyl; it is more preferred that the base be bicarbonate or carbonate, h is even more preferred that the base be bicarbonate. . A . 2004 \2-Z2 ?- r=? l^r--;y, r0pE[r-N -i^;.,,;^ 5QS2 -: = E,._ = EV . -_ WO03/00S36S PCT/US02/2018K that the appropriate fractions are pooled and concentrated to give the desired compound(s). CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (5) down field from IMS. 5 NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported m ppm (5) downfield from tctramethylsilane, TMS refers to trimethylsilyl. -d> refers to phenyl (CcH>). MS refers to mass spectrometry expressed as rn/e, m/z or mass/charge unit. 10 [M + H]* refers to the positive ion of aparent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment. HRMS refers to high resolution mass spectrometry. Pharmaceutically acceptable refers to those properties and/or substances whicl 15 are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability, psi refers to pounds per square inch. When solvent pairs are used, the ratios of solvents used are volume/volume 20 (v/vj. When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight-Volume (wt/v). DIBAL refers to diisobutyl aluminum hydride. THAM refers to rris(hydroxymcthyl)aminomethane. 25 EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely 30 illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. PREPARATION 1 Potassium 5-(rriphenylphosphoranylidene)pentaonate -G- WO 03/()OS3C,R PCT/i:S02/20lSS* mL) is added and the mixture is allowed to warm to 20-25° and stirred for two hours. MTBE (100 mL; is added and then a solution of sodium bicarbonate {10 g) in water (150 mL) is added. The two phase mixture is stirred for 15 min. The phases are separated and the organic phase is washed with water ("100 mL). The organic phase :s 5 concentrated under reduced pressure. MTBE (300 mL) is added and the mixture men concentrated. Acetonitrile (100 mL) is added and the mixture is again concentrated. Acetonitrile (150 mL) and heptane (100 mL) are added. The two-phase mixture is stirred for 5 min and then allowed to settle. The phases are separated. The acefonitriJe phase is extracted with heptane (3 x 100 mL). The acetonitrile phase is 10 concentrated. A portion of the concentrate is removed and purified by chromatography (silica gel, 230-400 mesh; heptane/ethyl acetate; l/l) to give the title compound, mp = 7S-8]0; NMR (CDCU, 400 MHz) 5 7.77, 7.32, 7.19, 7.04, 6.94, 5.45,5.37,5.01,4,79, 3.SS, 2.61-2.23, 2.01 and 1.60; CMR (CDCh, 100.6 MHz) d 176.5, 166.0, 141.7, 136.0, 133.3, 129.5, 12S.4, 125.8,83.3,79.2,71.2,53.9,42.6, 15 38.7,37.5, 34.9 aj.d 31.5. EXAMPLE 3 paR-[3aa,4a(lE,3S*),53,6aa]]-5-(Benzo}'loxy)hexahydro-4- (3-hydroxy-5-phenyl-l-pcnryI)-2H-cyclopenta[b)furan-2-one (V) [3aR-[3a a ,4a(lE,3S*),5|3,6aa]j-5-(benzoyloxy)hexahydro-^-(3-hydioxvo- 20 phenyl-l-pentcnyI)-2H-cyclopenta[b]furan-2-one (IV, EXAMPLE 2) is dissolved in THE (125 mL). Platinum on carbon catalyst (5%, 1 g) and triethylaminc (3.4 mL) are added. The mixture is purged with nitrogen and then and the mixture is stirred vigorously under 5 psi hydrogen at 20c ± 5°. V.'ben the reaction was complete as measured by HPLC, the reaction is purged with nitrogen. The mixture is filtered over 25 celite. The filtrate is concentrated under reduced pressure to give the crude product A portion of the product is removed and purified by chromatograDhy (silica gel, 230- 400 mesh; heptane/ethyl acetate, 1/1) to give the title compound, mp = 68-70°; NMR (CDCh, 400 MHz) 0 7.91, 7.47, 7.36, 7.19, 7.10, 5.IS, 4.99, 3.56, 2.§4-2.57,2.44- 2.26, 1.71-1.16: CMR(CDC1}, 100.6 MHz) 5 176.9, 166.0, 141.8, 133.2, 129.6, 30 128.4, 125.9, 84.4, 80.1, 70.8, 52.6,43.5,39.0, 37.7, 36.2, 35.1, 32.0 and 29.5; MS calculated m / z = 408 , found m ' z = 409 (m - }\. EXAMPLE 4 2-f(lR, 2R, 3R: 5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-5- phenylpentyi]cyclopenry]]acetic acid (VI) -8- 23C-4 !2:C3 ?!-' -P ^OT,-, -0-E!GN -!_:N-3U; 503d "C "EM-PE'i 4- 3- WO ()3/lKJS5('»8 PCT/US02/2IHSR The mixture is seeded with a small amount of the title compound. The mixture is stirred at about 30° for 10 min, dunng which time massive crystallization occurred. After the product had crystallized, heptane (30 mL) is added over 15 min. The slurry is cooled to 20-251' and stirred for 1 hour. The product is filtered and dried under 5 nitrogen to give the title compound, mp = 69-^1°; NMR (CDCh, 400 MHz) 8 7.35- 7.26, 5_00f 4.06, 3.68, 2.89-2.55, 2.34-2.07 and 1.87-1.34; CMR (CDC13, 100.6 MHz; 5 177.8, 141.9, 123.4, 125.9, 84.0, 71.23 53.9, 43.1, 41.4, 39.1, 36.0, 35.2, 32.0 and 2S..9. EXAMPLE 6 (3aR,4R.5R,6aS)-5-(l-Ethoxyethoxy)-4-[(3RV3-(l- 10 ethoxyethoxy)-5-pbenyfpentyI]hexahydro-2H- cyc1openta[b]furan-2-onc (X) [3aR-[3aa,4a(R*),5p,6aa]]-Hexahydro-5-hydroxy-4-(3-hydroxy-5- phenylpentyl)-2H-cyclopenta[b]furan-2-onc (VII, EXAMPLE 5, 1.0 g. 3.3 mmolesj is dissolved in methylene chloride (3 mL) and the mixture is placed in a sealable 15 pressure rube. Add 1.0 mL of a mixture of trichloracetic acid (0.27 q) in methylene chloride (10 mL) followed by ethyl vinyl ether (63 mL). The pressure tube is closed and heated to 45° in an oil bath for about S hours. At this time, rriethyiarmne (0.1 2 mL) is added and the mixture is stirred for 10 minutes. The mixture is then concentrated under reduced pressure. 20 EXAMPLE 7 (3aR,4R,5R,6aS)-5-(l-Ethoxyethoxy)-4-[(3R)o-(> etboxyethoxy)-5-pheny]penty]]bexahydro-2B- cyclopenta[b]furan-2-ol (XI) (3aRJ4R,5R,6aS>5-(l-Ethoxyethoxy)-4-[(3R)-3-(l-ethoxyethoxy)-5- phenylpemyI]hexahydro-2H-cyclopenta[b]furan-2-one (X, EXAMPLE 6) is 25 dissolved in THF (14 mL) and the mixture cooled to -40°. Using a syringe pump, DIBAL (1.0 M, 3.78 mL in toluene) is added over 15 minutes, maintaining the internal temperature at less than -30°. The mixture is stirred for 15 minutes after the completion of the addition, then ethyl acetate (0.38 mL) is added. The mixture is poured into a solution of potassium sodium tartarate (lOg in 30 mL of water) and 30 warmed to 20-25". The two phase mixture is heated to 45° for 1 hr and then cooled The phases are separated and the organic phase is concentrated. - to- \VO03;n0S3f»8 PCT/US02,'201SN Latanoprost acid (XV, EXAMPLE 9) is dissolved in DMF (10 mL) and added to a slurry of cesium carbonate (1.6 g) in DMF (10 mL). 2-Iodoprcpane (0.49 mL) is added and the slurry is heated to 45° for about 6 hours. When the reaction is complete. "MTBE (40 mL) and water (50 mL) arc added and the mixture is stirred for 15 5 minutes. The phases are separated and the aqueous phase is washed with MTBE (20 mL). The organic phases are combined and concentrated. The concentrate is cbromatographed (silica, 150 g, 230-400 mesh) elutingwith MTBE. The appropriate fractions are pooled and concentrated to give the title compound. EXAMPLE 11 2-[(lR, 2R, 3R, 5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-I- 10 octenyl]cyc!opentyl]acetic acid (XIX) (-) Chlorodiisopinocampheyiborane (27.0 g) is dissolved in THF (90 mL) and cooled to-35°. A mixture of [3aR-[3aa,4a(E),53,6aa]]-5-(benzoy]oxy)hexahvdro-4- (3-oxo-l-octenyI)-2H-cyclopenta[b]furan-2-one (XVj^ j\ Am. Chem. Soc, 96(\S). 5865-76 (1974), 7.4 g) in THF (30 mL) is added maintaining the internal temperature 15 of the mixture at (12.3 mL) is added and the solution stirred at 20-25° for 2 hours. MTBE (50 mLi and saturated aqueous sodium bicarbonate solution (50 mL) are added and the two-phase mixture is stirred lor 5 min. The organic phase is separated and washed once with water (50 mL), then concentrated under reduced pressure. The mixture is stirred a: 20 reflux with methanol (75 mL], water ( 7.5 mL) and potassium hydroxide (4.76 e;) for 2 hours. The mixture is concentrated under reduced pressure. The concentrate is partitioned between water (75 mL) and MTBE (75 mL). The aqueous phase is separated and extracted with MTBE (2 x 50 mL). ThepH of the aaueous phase is adjusted to about 1.2 with hydrochloric acid (3 M) and stirred for 2,5 hours. The 25 mixrure is saturated with sodium chloride and then extracted with MTBE (4 x 75 mL). The MTBE mixtures are combined and washed with Sodium carbonate solution (1 M, 2 x 50 mL). The sodium carbonate solutions are back extraered with MTBE (2 x 50 mL). The combined MTBE extracts are concentrated to a volume of about 100 mL, then stirred for one hour with a solution of potassium hydroxide (3.29 g) in water (30 30 mL). The aqueous phase is separated and added to a slurry of anhydrous citric acjd (9.68 g) in ethyl acetate (100 mL). The phases are separated and the aqueous phase is extracted with ethyl acetate (4 x 50 mL). The combined ethyl ace:ate extracts arc filtered through anhydrous sodium sulfate (about lOg). The filtrate is concentrated - 12- 062 .[JL'M I wo i)5/i)s:vf>s PCT/US02/2018S 10 where: fl) R3is-HandR,:s-H, (2) R3 is -H and R^ is -0-CH3 and (3) R3 and R_-. arc taken together TO form a five member nng attached to the 3- and 4- positions of the phenyl ring where the second ring from the R3- position to the R*- position is -CH-CH-0-; where ^^ is a single or double bond and were X;; is phenyl or phenyl substituted with one thru &JCS CrC, alky), one thru three C;-C; nlkoxy, one phenyl, one th.ru three — F, -CI, -Br and -1 and compound (XVJ11) x.r 15 where Xn is defined above which comprises: (2) contacting a compound selected from the group consisting of compound (III) O x,ro o- ?• - ~: ■ -^=-'-k; .-:_;-.■3^: 5032 ~; ~E'- = ^E. i E- woo^/ooiij6y PCT/L'S02WIX$ 13. A process according to claim 5 where the boron complexing agent is selected from the group consisting of water, Ci-Cg alcohols and diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. 5 14. A process according to claim 13 where the boron complexing ager:! is selected from the group consisting of water and diethanolamine. 15. A process according to claim 14 where the boron complexing agent is water. 10 16. A process according to claim 15 where base is added with the boron complexing agent. 17. A process according to claim 16 where the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tri- Ci-C6 alkyiamines, pyridine and pyridine substituted with Ci-Cn alkyl. 15 1S. A process according to claim 17 where the base is bicarbonate or carbonate. 19. A process according to claim 5 where prior to, or after, step (2). the reaction mixture is warmed to about 15 to about 25c'. 20 20. A process according to claim 19 where the where the reaction mixture is warmed from about 1 to about 3 hr. 25 21. A process according to claim 5 where Xii is phenyl. 22. A process according to claim 5 where the 15(S}-prostaglandin intermediate is compound (TV) -OLM 1 2 : U^ PNi FP '3POTO'; =0*E I '3N F 1 _ : \ 34 1 5032 " C =E'1-PE' WO O3/00S56S PCT/[iS02/20JS8 where ^^ is a single or double bond and pharmaceutically acceptable salts thereof. Also disclosed is a process for the preparation of a 15(S)-prost2glandin intermediate selected from the group consisting of compound (TV"i O o- where R3) JU and ^_. are as defined above and where Xn is phenyl or phenyl substituted with one thru three C1-C4 alkyl, one thru three Ci-C- alkoxy, one pheny one thru three -F. -Cl> -Br and -I and compound (XVIII) 10 *n~ co where Xn is defined above which comprises: (1) contacting a compound selected from the group consisting of compound (HI) O o- where R3, FU_ X>; and are as defined above or compound (XVII), respectively i^UJ I^:C2 PM -P ■BFOT>- rOPrl'BN rlL!';^: 5C32 ~ : = F_ "■: ~ P E ; i l- \V0 U3/(lOS3f.S PCT/US02/2O1XS the enone (111). Suitable solvents include THF, methylene chloride and DME and mixtures thereof. N4TBE and toluene alone are not operable. The use of a cosolver.:, such as hexane, heptane, isooctane or similar hydrocarbons is not necessary but is preferred. This is important since C-)-chlorodiisopinocamphey]borane is available 5 commercially as a solution in these solvents. MTBE and toluene can be used as the cosolvent. The narure of the solvent has virtually no effect with regard to the 15(S)/15(R) ratio in the product. It is preferred that from about 3 to about 4 equivalents of (-)-chlorodiisopinocampheylborans be used, it is more preferred that at least 3.5 equivalents of (-)-chIorodiisopinocamphcyIborane be used. With fewer \0 equivalents the reaction is incomplete; there is no improvement in rate or selectivity with more equivalents. "When the (-)-chlorodiisopinocamphcylborane is contacted with the a,p-unsamrated enone (III), the temperature should be maintained less than 0°. It is preferred that the temperature be maintained at less than -20°; it is more preferred that the temperature be maintained in the range of from about-35 to about !5 -45°. Above -35° the selectivity decreases and below about —45° the rate becomes too slow to be practical. When the reaction is complete, the excess (-)-chiorodiisopinocampheylborarrc must be destroyed by use of a boron completing agent which is selected "from the group consisting of watzr, C 20 rriethanolamine and mixtures thereof. It is preferred that the boron complexing agent be group be water and diethanolarmne; it is more preferred that the complexing agent be water. It is preferred that prior to step (2), the reaction mixture of step (I) is contacted with a readily reducible aldehyde or ketone. It is preferred that the readily reducible 25 aldehyde or ketone is selected from the group consisting of CpCc aldehydes and ketones and bcnzaldebyde; it is more preferred that the readily reducible aldehyde or ketone is acetone or methylethylketone. When adding the boron complexing agent it is preferred that a base also be added. It is preferred that the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tn- C]-C& alkylamines. 3G pyridine and pyridine substituted with CrC* alkyl; it is more preferred that the base be bicarbonate or carbonate. It is even more preferred that the base be bicarbonate. -A . WO03/00S36S PCT/US02/2018S that the appropriate fractions are pooled and concentrated to give the desired compound(s). CMR refers to C-l 3 magnetic resonance spectroscopy, chemical shifts are reported in ppm (o) down field from TMS. 5 NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemica,' shifts are reported in ppm (8) downfield from tctramethylsilane. TMS refers to trimethylsilyl. - refers to phenyl (CgHs). MS refers ro mass spectrometry expressed as m/e, m/z or mass^charge unit. 10 [M + H]+ refers to the positive ion of a parent plus a hydrogen atom. El refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment. HRMS refers to high resolution mass spectrometry. Pharmaceutically acceptable refers to those properties and/or substances which 15 are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability', patient acceptance and bioavailability psi refers to pounds per square inch. When so/venf pairs are used, the ratios of solvents used are volume/Volume 20 (v/v). When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weijrht'volume (wt/v), DIBAL refers to diisobutyl aluminum hydride. THAM refers to tris(hydroxymcthy])aminomethane. 25 EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely 30 illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques. PREPARATION 1 Fotzssium 5-(rriph£ny]phosphoranylidene}penraonate -6- _'b^ l^:D3 ?'" -„ .:?C. 0^. -OPETGh' F!.;';^: 5062 ~: = E'-'-?E^, -: E-; WO03/00{f3CS PCT.'i:SU2/20lSS' mL) is added and the mixture is allowed to warm ro 20-25° and stirred for two hours. MTBE (100 mLj is added and then a solution of sodium bicarbonate MO g) in water (150 mL) is added. The two phase mixture is stirred for 15 min. The phases are separated and the organic phase is washed with water ("100 mLj. The organic phase .$ 5 concentrated under reduced pressure. MTBE (300 mL) is added and the mixture then concentrated. Aceionitrilc (100 mL) is added and the mixture is again concentrated. Acetonitrile (150 mL) and heptane (100 mL) are added. The rwo-phase mixture is stirred for 5 min and then allowed to settle. The phases are separated. The acetonitrile phase is extracted with heptane (3 x 100 mL). The acetonitrile phase is )0 concentrated, A portion of the concentrate is removed and purified by chromatography (silica gel, 230-400 mesh; heptane/ethyl acetate, 1/1) to give the title compound, mp = 78-81°; NMR (CDC13> 400 MHz) 5 7.77, 732, 7.19, 7.04, 6.94, 5.45., 5.37, 5.01, 4.79, 3.88, 2.61-2.23, 2.01 and 1.60; CMR (CDCh, 100.6 MHn) b 176.5, 166.0, 141.7, 136.0, 133.3, 129.5, 12S.4, 125.8,53.3,79.2,71.2,53.9,42.6, 15 38.7. 37.5, 34.9 and 31.5. EXAMPLE 3 [3aR-[3aa,4aClE,3S*),53,6aa]]-5-(Benzoyloxy)hexahydrn-4- (3-hydroxy-5-phenyI-l-pcntyl)-2H-cyclopenta[b]furan-2-one (V) [3aR-[3a a ,4a(]E,3S;*),5p,6aa]]-5-(benzoyloxy)hexahydro-4-(3-hydroxy-5- 23 phenyl-l-pentenyi)-2H-cyclopenta[b]furan-2"One (JV, EXAMPLE 2) is dissolved m THF (125 mL). Platinum on carbon catalyst (5%, 1 g) and tri ethyl amine (3.4 mL) ar^ added. The mixture is purged with nitrogen and then and the mixture is stirred vigorously under 5 psi hydrogen at 20° ± 5C. When the reaction was complete as measured by HPJ..C, the reaction is purged with nitrogen. The mixture is filtered over 25 celite. The filtrate is concentrated under reduced pressure ro give the crude product A portion of the product is removed and purified by chromatography (silica gel, 230- 400 mesh; heptane/ethyl acetate, 1/1) to give the title compound, mp = 6S-70°; NMR (CDCh, 400 MHz) 6 7.91, 7.47, 7.36, 7.19, 7.10, 5.18, 4.99, 3.56, 2.S4-2.57, 2 44- 2.26, 1.7I-1.16; CMR (CDCI3) 100.6 MHz) o 176.9, 166.0, 141.8, 133.2, 129.6, 30 12S.4, 125.9, 84.-I, 80.1, 70.8, 52.6,43.5,39.0. 37.7, 36.2. 35.1. 32.0 and 29.5; MS calculated m ,'z ^ 408 , found «? ■ EXAMPLE 4 2-[(lR, 2R, 3R, 5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxyo- phenylpentyj]cyclopenryl]acetic acid (VI) -8- WO 1)3/003368 PCT/US(l2/:(nSR The mixture is seeded with a small amount of the title compound. The mixture is stirred at about 30° for 10 min, during which time massive crystallization occurred. After the product had crystallized, heptane (30 mL) is added over 15 min. The slurry is cooled to 20-25^' and stirred for 1 hour. The product is filtered and dried under 5 nitrogen to give the title compound, mp = 69-71°; NMR (CDCL, 400 MHz; 8 7.35. 7.26, 5.00, 4.06, 3.68, 2.89-2.55, 2.34-2.07 and 1.87-] .34; CMR (CDC13, 100.6 MHz; 5 177.8, 141.9, 128.4, 125.9, 84.0, 71.2, 53.9, 43.1, 41.4, 39.1, 36.0, 35.2, 32.0 and 28.9. EXAMPLE 6 (3aR,4R.5R,6aS)-5-(l-E:hoxyethoxy)-4-[(3R)-3-(l- 10 ethoxyethoxy)-5-phenvlpentyl]hexahydro-2H- cyclopenta[b]furan-2-onc (X) [3aR-[3aa,4a(R*),5p,6aaj]-Hexahydro-5-hydroxy-4-(3-hyGroxy-5- phenylpentyl)-2H-cyclopenta[b]furan-2-onc (VJ1, EXAMPLE 5. 1.0 c, 3.3 mmolesj is dissolved in methylene chloride (3 mL) and the mixture is placed in a sealable 35 pressure rube. Add 1.0 mLofa mixture of trichloracetic acid (0.27 jf) in methylene chloride (10 mL) followed by ethyl vinyl ether (6.3 mL) The pressure rube is closed and heated to 45° in an oil bath for about 8 hours. At this time, triethylamine (0.1 2 mL) is added and the mixture is stirred for 10 minutes. The mixture is then concentrated under reduced pressure. 20 EXAMPLE 7 (3aR,4RI5R,6aS)~5-(!-Ethoxyethoxy)-4-[(3R)-3-(l- ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol (XI) (3aR)4R,5R,6aS)-5-(l-Ethoxyethoxy)-^-[(3R)-3-(l-ethoxyethoxy)-5-phenyIpentyI]hexahydro-2H-cyclopentafb]furan-2-one (X, EXAMPLE 6) is 25 dissolved in THF (14 mL) and the mixture cooled to —40°. Using a syringe pump, D1BAL (1.0 M, 378 mL in toluene) is added over 15 minutes, maintaining the interna! temperature at less than -30°. The mixture is stirred for 15 minutes after the completion of the addition, then ethyl acetate (0.38 mL) is added. The mixture is poured into a solution of potassium sodium tartarate (lOg in 30 mL of water) and 30 warmed to 20-257 The two phase mixture is heated to 45° for 1 hr and then coofed The phases are separated and the organic phase is concentrated. 20Q4 k:jM Pr-' r ^ : *c T'V, - 0 f? E : G h" F : _ ; ■ ■ 34 : 53S2 "" : = E'-i"PE' & 3 - = WO-03/0DS368 PCT/U502/2O1SN Latanoprost acid (XV. EXAMPLE 9) is dissolved in DMF f10 mL) and added to a slurry of cesium carbonate (1.6 g) in DMF (10 mL). 2-Iodoprepane (0.49 mL) is added and the slurry is heated to 45° for about 6 hours. When the reaction is complete, MTBE (40 mL) and wale: (50 mL) arc added and the mixture is stirred for 15 S minutes. The phases are separated and the aqueous phase is washed with MTBE '20 mL). The organic phases are combined and concentrated. The concentrate is chxomatographed (silica, 150 g, 230-400 mesh) eluting with MTBE. The appropriate fractions are pooled and concentrated to give the title compound. EXAMPLE 11 2-[(lR, 2R} 3R, 5S)-3,5-Dihydroxy-2-[(3R)-3-hydroxy-l- 10 octenyl]cyclopentyl]acetic acid (XIX) (-) Chlorodiisopinocampheylboranc (21.0 g) is dissolved in THF (90 mL) and cooled to-35°. A mixture of [3aR-[3aa,4a(E);53,6aa]]-5-(benzoyloxy)hexahydio-4- (3-oxo-l-octenyl)-2H-cyclopenta[b]furan-2-one (XVII, J. Am. Chem. Soc, 96(18). 5S65-76 (1974), 7.4 g) in THF (30 mL) is added maintaining the internal temperature 15 of the mixture at 20 reflux with methanol (75 mL). water ( 7.5 mL) and potassium hydroxide (4.76 g) for 2 hours. The mixture is concentrated under reduced pressure. The concentrate is partitioned between water (75 mL) and MTBE (75 mL). The aqueous phase is separated and extracted with MTBE (2 x 50 mL). The pH of the aqueous phase is adjusted to about 1.2 with hydrochloric acid (3 M) and stirred for 2.5 hours. The 25 mixture is saturated with sodium chioridc and then extracted with MTBE (4 x 75 mL). The MTBE mixtures are combined and washed with sodium carbonate solution (1 M, 2x50 mL). The sodium carbonate solutions are back extracted with MTBE (2 x 50 mL). The combined MTBE extracts are concentrated to a volume of about 100 ml, then stirred for one hour with a solution of potassium hydroxide (3.29 g) in water (30 30 mL). The aqueous phase is separated and added to a slurry of anhydrous citric acid (9.68 g) in ethyl acetate (100 mL). The phases are separated and the aqueous phase :s extracted with ethyi acetate (4 x 50 mL). The combined ethyl acetate extracts arc filtered through anhydrous sodium sulfate (about 10g). The filtrate is concentrated - 12- WE CLAIM:- 1. A process for the preparation of a 15(S)-prostagiandin intermediate selected from the group consisting of compound (iy): (IV) where: (1)R3is-HandR4is-H, or (2) R3 is -H and R4 is -0-CH3l or (3) R3 and R4 are taken together to form a five member ring attached to the 3-and 4-positions of the phenyl ring where the second ring from the R3- position to the R4- position is-CH=CH-0-; where ==? is a single or double bond; and where Xu is phenyl or phenyl substituted with one thru three CrC4 alkyl, one thru three CrC4 alkoxy, one phenyl, one thru three -F, -CI, -Br and -I; and -16- compound (XVIII): (XVIII) where Xn is defined above, which comprises: (1) contacting a compound selected from the group consisting of compound (III): where R3, R4| Xn and = = are as defined above, or compound (XVII): o o CXVD) where Xn is defined above, with (-)-chJorodiisopinocampheyiborane while maintaining the reaction mixture temperature in the range of from -50° C to 0° C; and (2) contacting the reaction mixture of step (1) with a boron complexing agent. 2. A process as claimed in claim 1 where the reaction mixture temperature is less than -20° C. -4S---/- 3- A process as claimed in1 claim 2. where the reaction mixture temperature is from -35° C to -45° C. i\. A process as claimed in claim l where 3 to 4 equivalents of (-)-chlorodiisopinocampheyiborane are used. 5. A process as claimed inj claim 4 where at least 3.5 equivalents of (-)-chlorodiisopino-campheyi-borane are used. 6. A process as claimed in, claim 2 where prior to step (2), the reaction mixture of step (1) is contacted with a readily reducible aldehyde or ketone. ^, A process as claimed in, claim 6 where the readily reducible aldehyde or ketone is selected from the group consisting of Ci-C6 aldehydes, Ci-Cs ketones and benzaldehyde. gF A process as claimed in, claim ^ where the readily reducible aldehyde or ketone is acetone or methylethylketone. cj. A process as claimed in claim 1 where the boron compiexing agent is selected from the group consisting of water, CrC6 alcohols, C,-C6 diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. 10. A process as claimed in .claim 9 where the boron compiexing agent is selected from the group consisting of water and diethanolamine. 11. A process as claimed in claim 1o where the boron compiexing agent is water. 12- A process as claimed in claim 11 where base is added with the boron compiexing agent. 13, A process as claimed in claim lz where the base is selected from the group consisting of carbonate, bicarbonate, mono-, di- and tri- CrCs alkylamines, pyridine and pyridine substituted with CrC4 alkyl. Ify. A process as claimed in claim 23 where the base is bicarbonate or carbonate. 15. A process according to claim 1 where prior to, or after, step (2), the reaction mixture is warmed to 15° C to 25° C. -43*- 16 A process as claimed IN claim 15 where the reaction mixture is warmed front 1 HR to 3 hr. T}. A process as claimed in claim 1 where X is phenyl. 18. A process as claimed in claim 1 where the 15(S)-prostagIandin intermediate is compound (IV): o known as [3aR-t3aal4a(1E,3S*),56I6aa]]-5-(benzoylcJxy)hexahydro-4-(3-hydroxy-5-phenyl-1-pentenyl)-2H-cyclopenta[b]furan-2-one. l^f, A process as claimed in claim 1 where the 15(S)-prostag!andin intermediate is compound (XVIII): (xvmi known as [3aR~[3aar4a(E),5 !$,6aa]]-5-(benzoyloxy)hexah/dro-4- (3-hydroxy-1-octenyl)-2H-cyclo- penta[b]furan-2-one. Dated this 6lt1 day of January, 2004. [SANJAYKWMAR] OF REMFR^&SAGAR ATTORNEY FOR THEAPPLICANTS

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