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US 7,468,459 B2Granted
Process for the preparation of chiral beta amino acid derivatives by asymmetric hydrogenation
AssigneeMerck & Co., Inc.
InventorsYi Xiao, Joseph D. Armstrong, III, Shane W. Krska, Eugenia Njolito, Nelo R. Rivera, Yongkui Sun, Thorsten Rosner
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Abstract
The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives which are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral beta amino acrylic acid derivative substrate in the presence of a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.
Claims22
A process for preparing a compound of structural formula I:
- having the (R)- or (S)-configuration at the stereogenic center marked with an *;
- in an enantiomeric excess of at least 70% over the opposite enantiomer, wherein
- Z is OR2, SR2, or NR2R3;
- R1 is C1-8 alkyl, aryl, heteroaryl, aryl-C1-2 alkyl, or heteroaryl-C1-2 alkyl;
- R2 and R3 are each independently hydrogen, C1-8 alkyl, aryl, or aryl-C1-2 alkyl;
- or R2 and R3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring system optionally containing an additional heteroatom selected from O, S, NH, and NC1-4 alkyl, said heterocyclic ring being unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, C1-4 alkoxy, and C1-4 alkyl wherein alkyl and alkoxy are unsubstituted or substituted with one to five fluorines;
- and said heterocyclic ring system being optionally fused with a 5- to 6-membered saturated or aromatic carbocyclic ring system or a 5- to 6-membered saturated or aromatic heterocyclic ring system containing one to two heteroatoms selected from O, S, and NC0-4 alkyl, said fused ring system being unsubstituted or substituted with one to two substituents selected from hydroxy, amino, fluorine, C1-4 alkyl, C1-4 alkoxy, and trifluoromethyl;
- comprising the step of hydrogenating a prochiral enamine of structural formula II:
- in a suitable organic solvent in the presence of a transition metal precursor complexed to a chiral ferrocenyl diphosphine ligand of structural formula III:
- wherein R4 is C1-4 alkyl or aryl;
- R5 and R6 are each independently C1-6 alkyl, C5-12 cycloalkyl, or aryl;
- and
- R7 is C1-4 alkyl or unsubstituted phenyl.
10 more elements
A process for preparing a compound of structural formula 1:
- having the (R)-configuration at the stereogenic center marked with an ***;
- in an enantiomeric excess of at least 70% over the enantiomer having the opposite (S)-configuration;
- wherein
- Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of fluorine, trifluoromethyl, and trifluoromethoxy;
- and
- R8 is hydrogen or C1-4 alkyl unsubstituted or substituted with one to five fluorines;
- comprising the step of:
- hydrogenating a compound of structural formula 2:
- in a suitable organic solvent in the presence of a rhodium metal precursor and a chiral ferrocenyl disphosphine of structural formula IV:
- wherein R4 is C1-4 alkyl or aryl;
- R5 and R6 are each independently C1-6 alkyl, C5-12 cycloalkyl, or aryl;
- and
- R7 is C1-4 alkyl or unsubstituted phenyl.
10 more elements
A process for preparing a compound of structural formula 1:
- having the (R)-configuration at the stereogenic center marked with an ***;
- in an enantiomeric excess of at least 70% over the enantiomer having the opposite (S)-configuration;
- wherein
- Ar is phenyl which is unsubstituted or substituted with one to five substituents independently selected from the group consisting of fluorine, trifluoromethyl, and trifluoromethoxy;
- and
- R8 is hydrogen or C1-4 alkyl unsubstituted or substituted with one to five fluorines;
- comprising the steps of:
- (a) producing a compound of structural formula 2:
- by treating a compound of structural formula 3:
- with a source of ammonia in a suitable organic solvent;
- and
- (b) hydrogenating a compound of structural formula 2:
- in a suitable organic solvent in the presence of a rhodium metal precursor and a chiral ferrocenyl disphosphine of structural formula IV:
- wherein R4 is C1-4 alkyl or aryl;
- R5 and R6 are each independently C1-6 alkyl, C5-12 cycloalkyl, or aryl;
- and
- R7 is C1-4 alkyl or unsubstituted phenyl.
14 more elements
Dependencies are inferred from the claim text.