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-PGF1-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-PGF1-type compounds.
Inventor(s):	Robert M. Moriarty, Raju Penmasta, Liang Guo, Munagala S. Rao, James P. Staszewski
Assignee:	United Therapeutics Corp
Application Number:	US10/184,907
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: that is produced by a process for making 9-deoxy-PGF1-type compounds, the process comprising cyclizing a starting compound of the formula: into a compound of the following formula: by intramolecular cyclization of the enyne, wherein Z is O, S, CH2, or NR8 in which R8 is H, alkyl or aryl; X is H, CN, OR9, or COOR9 in which R9 is H, alkyl, a pharmacologically acceptable cation, THP or TBDMS; wherein n is 0, 1, 2, or 3; wherein Y1 is trans-CH═CH—, cis-CH═CH—, CH2(CH2)m-, or —C≡C—; m is 1,2, or 3; wherein R1 is an alcohol protecting group; wherein R7 is (1) —C2H2p—CH3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 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, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH═CH—CH2—CH3, (5) —(CH2)2—CH(OH)—CH3, or (6) —(CH2)3—CH═C(CH3)2; wherein —C(L1)—R7 taken together is (1) (C4-C7)cycloalkyl optionally substituted by one to 3 (C1-C5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M1 is α-OH:β-R5 or α-R5:β-OH or α-OR1:β-R5 or α-R5:β-OR1, wherein R5 is hydrogen or methyl and R1 is an alcohol protecting group; and wherein L1 is α-R3:β-R4, α-R4:β-R3, or a mixture of α-R3:β-R4 and α-R4:β-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 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, Y1 is -CH2CH2- M1 is α-OH:β-R5, wherein R5 is hydrogen, L1 is α-R3:β-R4, wherein R3 and R4 are hydrogen and R7 is butyl. 3. A steroselectively produced isomeric compound according to the following formula: that is produced by a process for making 9-deoxy-PFG1-type compounds, the process comprising cyclizing a starting compound of the formula: into a compound of the following formula: by intramolecular cyclization of the enyne, wherein Z is O, S, CH2, or NR8 in which R8 is H, alkyl or aryl; X is H, CN, OR9, or COOR9 in which R9 is H; wherein n is 0, 1, 2, or 3; wherein Y1 is trans-CH=CH-, cis-CH=CH-, -CH2(CH2)m-, or -C=C-; m is 1,2, or 3; wherein R1 is an alcohol protecting group; wherein R7 is (5) -CpH2p-CH3, wherein p is an integer from one to 5, inclusive, (6) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 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, (C1-C3)alkyl, or (C1-C3)alkoyx, with the proviso that not more than two substituents are other than alkyl, (8) cis-CH=CH-CH2-CH3, (9) -(CH2)2-CH(OH)-CH3, or (10) -(CH2)3-CH=C(CH3)2; wherein -C(L1)-R7 taken together is (11) (C6-C7)cycloalkyl optionally substituted by one to 3 (C1-C5) alkyl; (12) 2-(2-furyl)ethyl, (13) 2-(3-thienyl)ethoxy, or (14) 3-thienyloxymethyl; wherein M1 is α-OH:β-R5 or α-R5:β-OH or α-OR1:β-R5 or α-R5:β-OR1, wherein R5 is hydrogen or methyl and R1 is an alcohol protecting group; and wherein L1 is α-R3:β-R4, α-R4:β-R3, or a mixture of α-R3:β-R4 and α-R4:β-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 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: that is produced by process for making 9-deoxy-PGF1-type compounds, the process comprising cyclizing a starting compound of the formula: into a compound of the following formula: by intramolecular cyclization of the enyne, wherein Z is O, S, CH2, or NR8 in which R8 is H, alkyl or aryl; X is H, CN, OR9, or COOR9 in which R9 is a pharmacologically acceptable cation; wherein n is 0, 1, 2, or 3; wherein Y1 is trans-CH=CH-, cis-CH=CH-, -CH2(CH2)m-, or -C=C-; m is 1,2, or 3; wherein R1 is an alcohol protecting group; wherein R7 is (1) -CpH2p-CH3, wherein p is an integer from one to 5, inclusive, (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are other than alkyl, with the proviso that R7 is phenoxy or substituted phenoxy, only when R3 and R4 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, (C1-C3)alkyl, or (C1-C3)alkoyx, with the proviso that not more than two substituents are other than alkyl, (4) cis-CH=CH-CH2-CH3, (5) -(CH2)2-CH(OH)-CH3, or (6) -(CH2)3-CH=C(CH3)2; wherein -C(L1)-R7 taken together is (1) (C4-C7)cycloalkyl optionally substituted by one to 3 (C1-C5) alkyl; (2) 2-(2-furyl)ethyl, (3) 2-(3-thienyl)ethoxy, or (4) 3-thienyloxymethyl; wherein M1 is α-OH:β-R4 or α-R5:β-OH or α-OR1:β-R5 or α-R5:β-OR1, wherein R5 is hydrogen or methyl and R1 is an alcohol protecting group; and wherein L1 is α-R3:β-R4, α-R4:β-R3, or a mixture of α-R3:β-R4 and α-R4:β-R3, wherein R3 and R4 are kydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or fluoro.