L-739943

Chemical Name: 2-Amino-2-methyl-N-[1-[2'-(3-methylureidomethyl)biphenyl-4-ylmethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3(R)-yl]propionamide
CAS No. 197650-99-0
项目整合开发状态: Preclinical
项目研究机构: Merck & Co. (Originator)
合成路线:4-Bromobenzyl alcohol (I) was protected as the silyl ether (II) by treatment with tert-butylchlorodiphenylsilane (TBDPSCl) and Et3N in DMF.Treatment of (II) with BuLi in THF at -78 C,followed by reaction with triisopropyl borate and acid hydrolysis afforded boronic acid (III).Palladium catalyzed coupling of (III) with N-Boc-2-bromobenzylamine (V) (obtained by reaction of 2-bromobenzylamine (IV) with di-tert-butyl dicarbonate),provided biphenyl (VI).This was desilylated by treatment with tetrabutyl ammonium fluoride in THF,and the resulting benzyl alcohol (VII) was converted to mesylate (VIII) with methanesulfonyl chloride and Et3N in CH2Cl2 at 0 C.Coupling of (R)-3-aminobenzazepinone (IX) with N-benzyloxycarbonyl-2-methylalanine (X) using benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) gave amide (XI).Then,regioselective alkylation of (XI) with mesylate (VIII) in the presence of NaH in DMF at low temperature afforded (XII).Subsequent removal of the tert-butoxycarbonyl protecting group with HCl at r.t.yielded amine hydrochloride (XIII),which was condensed with methyl isocyanate to afford urea (XIV).Finally,the N-benzyloxycarbonyl group was removed by hydrogenolysis in the presence of Pd(OH)2 to furnish the title compound.