【药物名称】L-838751
化学结构式(Chemical Structure):
参考文献No.616493
标题:3-(4-Fluoropiperidin-3-yl)-2-phenylindoles as high affinity, selective, and orally bioavailable h5-HT2A receptor antagonists
作者:Rowley, M.; Hallett, D.J.; Goodacre, S.; Moyes, C.R.; Crawforth, J.; Sparey, T.J.; Patel, S.; Marwood, R.; Thomas, S.; Hitzel, L.; O'Connor, D.; Szeto, N.; Castro, J.L.; Hutson, P.H.; MacLeod, A.M.
来源:J Med Chem 2001,44(10),1603
合成路线图解说明:

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.

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