Diastereoselective reductive amination process
View Patent ↗This invention describes a reductive amination process whereby perfluorinated ketones or ketals are combined with α-aminoesters under basic conditions to form metal carboxylates. Diastereoselective reductions of the metal carboxylates enable access to two diastereomers, depending on the reducing conditions.
1. A process for preparing a compound of formula IA or IB:
comprising the steps of:
a. Combining a ketone or ketal with an α-aminoester of formula II in the presence of a base and solvent to form an imine metal carboxylate of formula III, and
b. Reducing the imine metal carboxylate of formula III to produce a compound of formula IA or IB;
wherein R 1 is C 1-5 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl;
R 2 is C 1-5 alkyl, C 1-5 haloalkyl, C 3-8 cycloalkyl, arylalkyl, aryl or heteroaryl;
R 3 C 1-5 alkyl, C 1-5 haloalkyl, C 3-8 cycloalkyl, aryl, heteroaryl, CF 3 , CHF 2 , CH 2 F or C 2 F 5 ;
R 4 is C 1-5 alkyl;
M is hydrogen, lithium, sodium, potassium or cesium.
2. The process of claim 1 wherein the base is a metal carbonate or alkoxide, and the solvent is an alcohol, an ether, an ester or an amide.
3. The process of claim 2 wherein the base is potassium carbonate, potassium methoxide or potassium phosphate and the solvent is methanol.
4. The process of claim 1 wherein step a is performed at a temperature of about 15° C. to about 80° C.
5. The process of claim 4 wherein the temperature is about 30° C. to about 60° C.
6. The process of claim 1 wherein the imine metal carboxylate of formula III is not isolated, and the reduction is performed with a metal borohydride prepared in an ether solvent to yield a compound of formula IA.
7. The process of claim 6 wherein the metal borohydride is calcium borohydride, magnesium borohydride, zinc borohydride or zirconium borohydride and the ether solvent is tetrahydrofuran, diethyl ether, diisopropyl ether, dibutyl ether, t-butylmethyl ether, dimethoxyethane, ethyleneglycoldimethyl ether or mixtures thereof.
8. The process of claim 6 wherein a co-solvent is added in a volume of 50–95%.
9. The process of claim 8 wherein the co-solvent is C 1-4 alkyl or aryl nitrile.
10. The process of claim 1 wherein step b is performed at a temperature of about 25 to about −40° C.