合成路线1

The reduction of N-Boc-L-phenylalanine (XIII) with B2H6 in THF gives the expected alcohol (XIV), which is oxidized with SO3/pyridine to yield the corresponding aldehyde (XV). The cyclization of (XV) with 2-sulfanylethylamine (XVI) affords the thiazolidine (XVII), which is dehydrogenated by means of MnO2 to afford the thiazole derivative (XVIII). Finally, the amino group of (XVIII) is deprotected with HCl to afford the desired intermediate, 2-phenyl-1(S)-(2-thiazolyl)ethylamine (XIX).

合成路线2

The reduction of N-Boc-L-phenylalanine (XVI) with diborane in THF gives N-Boc-L-phenylalaninol (XVII), which is oxidized with SO3/pyridine in DMSO to yield N-Boc-L-phenylalaninal (XVIII). The cyclization of (XVIII) with 2-sulfanylethylamine (XIX) affords the thiazolidine (XX), which is dehydrogenated by means of MnO2 to provide the thiazole derivative (XXI). Finally, compound (XXI) is N-deprotected by a treatment with TFA to provide the 2-phenyl-1(S)-(2-thiazolyl)ethylamine intermediate (XXII).

合成路线3

Condensation of N-Boc-L-phenylalaninal (I) with 4-biphenylcarbonyl chloride (II) and KCN in the presence of N-benzylcinchoninium chloride (NBC) afforded alpha-acyloxynitrile (III) as a 4:1 mixture of (2R,3S) and (2S,3S) isomers. Hydrogenation of (III) in the presence of Raney Nickel and tert-butyl carbazate, followed by crystallization of the major isomer from acetonitrile provided hydrazone (IV). Subsequent reduction of (IV) to hydrazine using NaBH3CN and p-toluenesulfonic acid, with concomitant rearrangement of the biphenylcarbonyl group furnished hydrazide (V), which was reduced to the benzyl hydrazine (VI) by means of either BH3 or DIBAL-H. Deprotection of both Boc groups of (VI) with HCl gave diamino compound (VII). Finally, coupling of N-methoxycarbonyl-L-tert-leucine (IX), (prepared by reaction of tert-leucine (VIII) with methyl chloroformate), with diamine (VII) employing O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethyluronium tetra-fluoroborate (TPTU) provided the target bisamide.

合成路线4