Practical synthesis of a vanilloid receptor-1 antagonist.
Small molecule TRPV1 antagonists have been a recent focus in the search for pain treatment agents. We herein describe a practical and scalable synthesis of AMG 628 (1), a bis-substituted pyrimidine derivative that was identified as a highly efficacious agent, suitable for clinical development. Highlights of our approach include a practical route to a substituted benzothiazole, a scalable synthesis of an enantiopure piperazine fragment, and identification of conditions for selective coupling reactions on 2,6-dichloropyrimidine, to access the active pharmaceutical ingredient in high purity and overall yield.
Thiel
Oliver R
OR
Chemical Process Research and Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, USA. othiel@amgen.com
Bernard
Charles
C
King
Tony
T
Dilmeghani-Seran
Mina
M
Bostick
Tracy
T
Larsen
Robert D
RD
Faul
Margaret M
MM
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D008670:Metals / Q000737:chemistry; D015394:Molecular Structure; D000077489:Piperazine; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry
D000081:Acetamides; D052160:Benzothiazoles; D008670:Metals; C523410:N-(4-(6-(4-(1-(4-fluorophenyl)ethyl)piperazin-1-yl)pyrimidin-4-yloxy)benzo(d)thiazol-2-yl)acetamide; D010879:Piperazines; D011743:Pyrimidines; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D013830:Thiadiazoles; D000077489:Piperazine; C015700:benzo-1,2,3-thiadiazole; C030686:acetamide