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US 2002/0173672 A1Published application
Process for stereoselective synthesis of prostacyclin derivatives
AssigneeUnited Therapeutics Corporation
InventorsRobert M. Moriarty, Raju Penmasta, Liang Guo, Munagala S. Rao, James P. Staszewski
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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.
Claims14
A process for making 9-deoxy-PGF1-type compounds comprising cyclizing a starting compound of the formula:
- 24
- into a compound of the following formula:
- 25
- 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 alkyl, 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) —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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
22 more elements
A stereoselective process of making a 9-deoxy-PGF1-type compound, comprising the following reaction:
- 26
- wherein R1 is an alcohol protecting group;
- 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 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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
18 more elements
A compound of the formula:
- 29
- 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 alkyl, THP or TBDMS;
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
- m is 1,2, or 3;
- wherein n is 0, 1, 2, or 3;
- 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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
19 more elements
A compound of the formula:
- 30
- 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 alkyl, THP or TBDMS;
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
- m is 1,2, or 3;
- wherein n is 0, 1, 2, or 3;
- 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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
19 more elements
A compound of the formula
- 31
- 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 alkyl, THP or TBDMS;
- wherein Y1 is trans-CH═CH—, cis-CH═CH—, —CH2(CH2)m—, or —C≡C—;
- m is 1,2, or 3;
- wherein n is 0, 1, 2, or 3;
- 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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
19 more elements
A compound of the formula
- 32
- 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 alkyl, THP or TBDMS;
- wherein R1 is an alcohol protecting group;
- 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 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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
20 more elements
A compound of the formula
- 33
- 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 alkyl, THP or TBDMS;
- wherein R1 is an alcohol protecting group;
- 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 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, two or three chloro, fluoro, trifluoromethyl, (C1-C3q)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, wherein R5 is hydrogen or methyl;
- 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.
20 more elements
Dependencies are inferred from the claim text.