tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-1-hydrazinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】28443

【品名】tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-1-hydrazinecarboxylate

【CA登记号】

【分子式】C₃₃H₄₃N₃O₅

【分子量】561.72164

【元素组成】C 70.56% H 7.72% N 7.48% O 14.24%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【1】 Fassler, A.; Bold, G.; Capraro, H.-G.; Lang, M. (Novartis AG); Azahexane derivs. as substrate isosters of retroviral asparate proteases. EP 0876336; JP 1999514996; WO 9719055 .
【2】 Fassler, A.; Steiner, H.; Bold, G.; Capraro, H.-G. (Novartis AG); Process for the preparation of hydrazine derivs. useful as intermediates for the preparation of peptide analogues. WO 9746514 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	23452	tert-butyl (1S)-1-benzyl-2-oxoethylcarbamate		C₁₄H₁₉NO₃	详情	详情
(II)	28439	[1,1'-biphenyl]-4-carbonyl chloride	14002-51-8	C₁₃H₉ClO	详情	详情
(III)	28440	(2S)-2-[(tert-butoxycarbonyl)amino]-1-cyano-3-phenylpropyl [1,1'-biphenyl]-4-carboxylate		C₂₈H₂₈N₂O₄	详情	详情
(IV)	28441	(1R,2S)-2-[(tert-butoxycarbonyl)amino]-1-[[(E)-2-(tert-butoxycarbonyl)hydrazono]methyl]-3-phenylpropyl [1,1'-biphenyl]-4-carboxylate		C₃₃H₃₉N₃O₆	详情	详情
(V)	28442	tert-butyl 2-([1,1'-biphenyl]-4-ylcarbonyl)-2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-1-hydrazinecarboxylate		C₃₃H₄₁N₃O₆	详情	详情
(VI)	28443	tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-1-hydrazinecarboxylate		C₃₃H₄₃N₃O₅	详情	详情
(VII)	28444	(2S,3S)-3-amino-1-[1-([1,1'-biphenyl]-4-ylmethyl)hydrazino]-4-phenyl-2-butanol		C₂₃H₂₇N₃O	详情	详情
(VIII)	28445	(2S)-2-amino-3,3-dimethylbutyric acid		C₆H₁₃NO₂	详情	详情
(IX)	23447	(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid		C₈H₁₅NO₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

In an alternative procedure, condensation of 4-biphenylcarbaldehyde (X) with tert-butyl carbazate afforded hydrazone (XI), which was reduced to the benzylhydrazine (XII) by hydrogenation over Pd/C. Opening of the Boc-protected epoxide (XIII) with hydrazine (XII) gave hydrazinoalcohol (VI). This was deprotected with HCl and then coupled as above with N-methoxycarbonyl-L-tert-leucine (X) by means of TPTU.

参考文献中间体

合成目标

【1】 New aza-dipeptide analogues as potent and orally a. J Med Chem 1998, 41, 18, 3387.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	28443	tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-2-[(2S,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-4-phenylbutyl]-1-hydrazinecarboxylate		C₃₃H₄₃N₃O₅	详情	详情
(IX)	23447	(2S)-2-[(methoxycarbonyl)amino]-3,3-dimethylbutyric acid		C₈H₁₅NO₄	详情	详情
(X)	28446	[1,1'-biphenyl]-4-carbaldehyde	3218-36-8	C₁₃H₁₀O	详情	详情
(XI)	28447	tert-butyl (Z)-2-([1,1'-biphenyl]-4-ylmethyl)-1-diazenecarboxylate		C₁₈H₂₀N₂O₂	详情	详情
(XII)	28448	tert-butyl 2-([1,1'-biphenyl]-4-ylmethyl)-1-hydrazinecarboxylate		C₁₈H₂₂N₂O₂	详情	详情
(XIII)	23444	tert-butyl (1S)-1-[(2R)oxiranyl]-2-phenylethylcarbamate		C₁₅H₂₁NO₃	详情	详情

Extended Information