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US 6,809,223 B2Granted
Process for stereoselective synthesis of prostacyclin derivatives
AssigneeUnited Therapeutics Corporation
InventorsRobert M. Moriarty, Hitesh Bhatra
Life of this patent
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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. “Also described are novel intermediate compounds used in the process described for making 9-deoxy-PGF1-type compounds.”
Claims4
A compound of the formula:
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
- m is 1, 2, or 3;
- wherein R7 is
- (1) —CpH2p—CH3, wherein p is an integer from 1 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 1 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;
- 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.
13 more elements
A compound of the formula:
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C ═C—;
- m is 1, 2, or 3;
- wherein R7 is
- (1) —CpH2p—CH3, wherein p is an integer from 1 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, tho 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 1 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;
- 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.
13 more elements
A compound of the formula
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
- m is 1,2, or 3;
- wherein R7 is
- (1) —CpH2p—CH3, wherein p is an integer from 1 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 1 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;
- 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.
13 more elements
A compound of the formula
- wherein R1 is an alcohol protecting group;
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
- m is 1, 2, or 3;
- wherein R7 is
- (1) —CpH2p—CH3, wherein p is an integer from 1 to 5, inclusive,
- (2) phenoxy optionally substituted by one, two or three chloro, fluoro, trifluoromethyl, (C1-C3)alkyl, or (C1-3)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 1 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;
- 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.
14 more elements
Dependencies are inferred from the claim text.