Claims for Patent: 6,765,117

Summary for Patent: 6,765,117

Title:	Process for stereoselective synthesis of prostacyclin derivatives
Abstract:	An improved method is described for making 9-deoxy-PGF.sub.1 -type compounds. In contrast to the prior art, the method is stereoselective and requires fewer steps than the known methods for making these compounds. The invention also relates to novel intermediates prepared during the synthesis of the 9-deoxy-PGF.sub.1 -type compounds.
Inventor(s):	Moriarty; Robert M. (Oak Park, IL), Penmasta; Raju (Bolingbrook, IL), Guo; Liang (Chicago, IL), Rao; Munagala S. (Westmont, IL), Staszewski; James P. (Naperville, IL)
Assignee:	United Therapeutic Corporation (Washington, DC)
Application Number:	10/184,907
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 6,765,117
Patent Claims:	1. A stereoselectively produced isomeric compound according to the following formula: ##STR26## that is produced by a process for making 9-deoxy-PGF.sub.1 -type compounds, the process comprising cyclizing a starting compound of the formula: ##STR27## into a compound of the following formula: ##STR28## by intramolecular cyclization of the enyne, wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is H, alkyl, a pharmacologically acceptable cation, THP or TBDMS; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH.dbd.CH--, cis-CH.dbd.CH--, CH.sub.2 (CH.sub.2).sub.m -, or --C.ident.C--; m is 1,2, or 3; wherein R.sub.1 is an alcohol protecting group; wherein R.sub.7 is (1) --C.sub.2 H.sub.2p --CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH.dbd.CH--CH.sub.2 --CH.sub.3, (5) --(CH.sub.2).sub.2 --CH(OH)--CH.sub.3, or (6) --(CH.sub.2).sub.3 --CH.dbd.C(CH.sub.3).sub.2 ; wherein --C(L.sub.1)--R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH or .alpha.-OR.sub.1 :.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OR.sub.1, wherein R.sub.5 is hydrogen or methyl and R.sub.1 is an alcohol protecting group; and wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro. 2. The stereoselectively produced isomeric compound of claim 1, wherein Z is O, n is 1, X is COOH, Y.sub.1 is -CH.sub.2 CH.sub.2 - M.sub.1 is .alpha.-OH:.beta.-R.sub.5, wherein R.sub.5 is hydrogen, L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, wherein R.sub.3 and R.sub.4 are hydrogen and R.sub.7 is butyl. 3. A steroselectively produced isomeric compound according to the following formula: ##STR29## that is produced by a process for making 9-deoxy-PFG.sub.1 -type compounds, the process comprising cyclizing a starting compound of the formula: ##STR30## into a compound of the following formula: ##STR31## by intramolecular cyclization of the enyne, wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is H; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH=CH-, cis-CH=CH-, -CH.sub.2 (CH.sub.2).sub.m -, or -C=C-; m is 1,2, or 3; wherein R.sub.1 is an alcohol protecting group; wherein R.sub.7 is (5) -C.sub.p H.sub.2p -CH.sub.3, wherein p is an integer from one to 5, inclusive, (6) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are lydrogen or methyl, being the same or different, (7) phenyl, bnezyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoyx, with the proviso that not more than two substituents are other than alkyl, (8) cis-CH=CH-CH.sub.2 -CH.sub.3, (9) -(CH.sub.2).sub.2 -CH(OH)-CH.sub.3, or (10) -(CH.sub.2).sub.3 -CH=C(CH.sub.3).sub.2 ; wherein -C(L.sub.1)-R.sub.7 taken together is (11) (C.sub.6 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl; (12) 2-(2-furyl)ethyl, (13) 2-(3-thienyl)ethoxy, or (14) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OH or .alpha.-OR.sub.1 :.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OR.sub.1, wherein R.sub.5 is hydrogen or methyl and R.sub.1 is an alcohol protecting group; and wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro. 4. A steroselectively produced isomeric compound in pharmacologically acceptable salt form according to the following formula: ##STR32## that is produced by process for making 9-deoxy-PGF.sub.1 -type compounds, the process comprising cyclizing a starting compound of the formula: ##STR33## into a compound of the following formula: ##STR34## by intramolecular cyclization of the enyne, wherein Z is O, S, CH.sub.2, or NR.sub.8 in which R.sub.8 is H, alkyl or aryl; X is H, CN, OR.sub.9, or COOR.sub.9 in which R.sub.9 is a pharmacologically acceptable cation; wherein n is 0, 1, 2, or 3; wherein Y.sub.1 is trans-CH=CH-, cis-CH=CH-, -CH.sub.2 (CH.sub.2).sub.m -, or -C=C-; m is 1,2, or 3; wherein R.sub.1 is an alcohol protecting group; wherein R.sub.7 is (1) -C.sub.p H.sub.2p -CH.sub.3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R.sub.7 is phenoxy or substituted phenoxy, only when R.sub.3 and R.sub.4 are hydrogen or methyl, being the same or different, (3) phenyl ,benzyl, phenylethyl, or phenylpropyl optionally substituted on the aromatic ring by one, tow or three chloro, fluoro, tribluoromethyl, (C.sub.1 -C.sub.3)alkyl, or (C.sub.1 -C.sub.3)alkoyx, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH=CH-CH.sub.2 -CH.sub.3, (5) -(CH.sub.2).sub.2 -CH(OH)-CH.sub.3, or (6) -(CH.sub.2).sub.3 -CH=C(CH.sub.3).sub.2 ; wherein -C(L.sub.1)-R.sub.7 taken together is (1) (C.sub.4 -C.sub.7)cycloalkyl optionally substituted by one to 3 (C.sub.1 -C.sub.5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M.sub.1 is .alpha.-OH:.beta.-R.sub.4 or .alpha.-R.sub.5 :.beta.-OH or .alpha.-OR.sub.1 :.beta.-R.sub.5 or .alpha.-R.sub.5 :.beta.-OR.sub.1, wherein R.sub.5 is hydrogen or methyl and R.sub.1 is an alcohol protecting group; and wherein L.sub.1 is .alpha.-R.sub.3 :.beta.-R.sub.4, .alpha.-R.sub.4 :.beta.-R.sub.3, or a mixture of .alpha.-R.sub.3 :.beta.-R.sub.4 and .alpha.-R.sub.4 :.beta.-R.sub.3, wherein R.sub.3 and R.sub.4 are kydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R.sub.3 and R.sub.4 is fluoro only when the other is hydrogen or fluoro.