Amidation process for the preparation of cathepsin K inhibitors
This invention describes an amidation process whereby amino acids of the Formulae IIA or IIB can be activated and treated with an amine in the presence of a base to yield amides of the Formula (I), without loss of optical purity.
1. A process for preparing a compound of formula I:
comprising amidating a salt of formula IIA or an acid of formula IIB
with 1-aminocyclopropane carbonitrile, in the presence of a coupling agent, wherein the coupling agent is a carbodiimide, a phosphonium salt or a uronium salt;
a base, wherein the base is N-methyl morpholine, TEA, N-ethyldiisopropylamine, 2,6-lutidine, 2,4,6 collidine or 1-methylpiperidine;
a solvent, wherein the solvent is DMF, DMAc, NMP, acetonitrile, THF or DMSO;
and an activating agent;
wherein R 1 is C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is SO m (C 1-6 alkyl);
X is a tertiary amine, a secondary amine or a metal salt; and
m is an integer from zero to two.
2. The process of claim 1 wherein the activating agent is N-hydroxy succinimide, 2-hydroxypyridine, N-hydroxyphthalimide, CDI or HOBt.
3. The process of claim 2 wherein the coupling agent is EDC; the activating agent is HOBt; the base is N-methyl morpholine; and the solvent is DMF.
4. The process of claim 1 wherein R 1 is C 1-6 haloalkyl; R 2 is C 1-6 haloalkyl and R 3 is SO 2 (C 1-6 alkyl).
5. The process of claim 4 wherein R 1 is (2-fluoro,2-methyl)propyl; R 2 is trifluoromethyl and R 3 is SO 2 CH 3 .