Practical asymmetric synthesis of a non-peptidic alphavbeta3 antagonist.
The development of a practical and highly convergent synthesis of an alpha(v)beta3 antagonist is described. The two key fragments present in this compound, a tetrahydropyrido[2,3-b]azepine ring system and a chiral 3-aryl-5-oxopentanoic acid, were constructed independently and then coupled at a late stage using a Wittig reaction. The pyridoazepine moiety was prepared from N-Boc 6-chloro-2-aminopyridine via directed ortho-metalation/alkylation followed by in situ cyclization. A Suzuki reaction was then used to attach the propionaldehyde side-chain required for Wittig coupling. The coupling partner was prepared from asymmetric methanolysis of a 3-substituted glutaric anhydride followed by elaboration of the acid moiety to the requisite beta-keto phosphorane. Using this route, kilogram quantities of the desired drug candidate were prepared.
Keen
Stephen P
SP
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, United Kingdom. stephen_keen@merck.com
Cowden
Cameron J
CJ
Bishop
Brian C
BC
Brands
Karel M J
KM
Davies
Antony J
AJ
Dolling
Ulf H
UH
Lieberman
David R
DR
Stewart
Gavin W
GW
D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001381:Azepines; D039302:Integrin alphaVbeta3; D010421:Pentanoic Acids