L-838751

Chemical Name: 6-Fluoro-3-[4(R)-fluoropiperidin-3(R)-yl]-2-phenyl-1H-indole
CAS No. 244086-93-9 (undefined isomer)
项目整合开发状态: Preclinical
项目研究机构: Merck Sharp & Dohme (Originator)
合成路线:Condensation between 2-iodo-5-fluoroaniline (I) and phenylacetylene (II) under catalysis with Pd(PPh3)4,CuI and diethylamine,followed by cyclization catalyzed by CuI and CaCO3 in DMF,affords phenylindole (III),which is then coupled with 4-piperidone (IV) in H3PO4/HOAc to provide tetrahydropyridine derivative (V).Protection of (V) as its benzyloxycarbonyl derivative (VII) by reaction with acid chloride (VI),followed by hydroboration with bis-isopinocampheylborane ((-)-Ipc2BH) and H2O2 in NaOH,provides the secondary alcohol (VIII).Isolation of enantiomer (IX) is then performed by reaction of (VIII) with the acid chloride derived from (1R)-(+)-camphanic acid,separation of diastereoisomers by chromatography and hydrolysis with K2CO3 in MeOH.Treatment of (IX) with diethylaminosulfur trifluoride (DAST) in EtOAc induces a regiospecific and enantioselective rearrangement affording 3-(3-indolyl)-4-fluoropiperidine (X),which is finally converted into the desired compound by deprotection with formic acid and Pd/C.