Scalable synthesis of the VEGF-R2 kinase inhibitor JNJ-17029259 using ultrasound-mediated addition of MeLi-CeCl3 to a nitrile.
The preparation of the selective VEGF-R2 kinase inhibitor 10 (JNJ-17029259) is described in which the key precursor, 4-(5-isoxazolyl)benzonitrile, undergoes clean transformation to the corresponding cumylamine derivative with CeCl(3)-MeLi in THF. This high-yielding cerium mediated transformation is robust, reproducible, and readily scalable based on a requirement for the anhydrous CeCl(3) to be milled and subjected to ultrasound treatment prior to addition of methyllithium.
Reuman
Michael
M
Johnson and Johnson Pharmaceutical Research & Development, L.L.C., 1000 Route 202, Raritan, New Jersey 08869, USA. mreuman@prdus.jnj.com
Beish
Sandra
S
Davis
Jeremy
J
Batchelor
Mark J
MJ
Hutchings
Martin C
MC
Moffat
David F C
DF
Connolly
Peter J
PJ
Russell
Ronald K
RK
D001554:Benzene / Q000737:chemistry; D002563:Cerium / Q000737:chemistry*; D002586:Cesium / Q000737:chemistry*; D002712:Chlorides / Q000737:chemistry*; D018020:Lithium Compounds / Q000737:chemistry*; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014465:Ultrasonics
C492802:4-(4-(1-Amino-1-methylethyl)phenyl)-2-(4-(2-morpholin-4-yl-ethyl)phenylamino)pyrimidine-5-carbonitrile; D002712:Chlorides; D018020:Lithium Compounds; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D002586:Cesium; D002563:Cerium; D040262:Receptors, Vascular Endothelial Growth Factor; C028019:cesium chloride; D001554:Benzene; C026690:cerous chloride