Development of a novel Pd-catalyzed N-acyl vinylogous carbamate synthesis for the key intermediate of ICE inhibitor VX-765.
A novel Pd-catalyzed coupling of Cbz-protected proline amide with 4-bromo-5-ethoxyfuran-2(5H)-one was developed for the synthesis of the P1-P2 unit (5) of VX-765. The process afforded quantitative coupling in the presence of water, providing a 1:1 mixture of 5 and its ethoxy epimer epi-5. Compound 5 was isolated as a single diastereomer via fractional crystallization, which was stereoselectively converted to 17 via hydrogenation, and subsequently transformed to VX-765. Nine examples of the Pd coupling are presented with yields ranging from 76-98%.
Tanoury
Gerald J
GJ
Chemical Development, Vertex Pharmaceuticals Inc., 130 Waverly Street, Cambridge, Massachusetts 02139, USA. jerry_tanoury@vrtx.com
Chen
Minzhang
M
Dong
Yong
Y
Forslund
Raymond E
RE
Magdziak
Derek
D
D010129:4-Aminobenzoic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020106:Acrylamide / Q000138:chemical synthesis* / Q000737:chemistry; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry; D061945:Caspase Inhibitors; D002384:Catalysis; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006842:Hydrocarbons, Brominated / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism; D062366:para-Aminobenzoates
D002219:Carbamates; D061945:Caspase Inhibitors; D004151:Dipeptides; D006842:Hydrocarbons, Brominated; D062366:para-Aminobenzoates; C520022:belnacasan; D020106:Acrylamide; D010165:Palladium; D010129:4-Aminobenzoic Acid