-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[2(S)-[2-[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetamido]-3(S)-methylpentyl]-N-(1-naphthylmethyl)glycyl-L-methionine

【CA登记号】179025-19-5, 179025-20-8 (trifluoroacetate)

【分子式】C₃₇H₄₄N₆O₄S

【分子量】668.86503

【开发单位】

【药理作用】　

合成路线1 合成路线2

合成路线1

The reductive condensation of N-Boc-L-isoleucinal (I) with glycine methyl ester (II) using sodium triacetoxyborohydride afforded secondary amine (III), which was further reductively condensed with 1-naphthaldehyde (IV), yielding tertiary amine (V). After basic hydrolysis of the methyl ester group of (V), the resulting carboxylic acid (VI) was coupled with L-methionine methyl ester (VII) by means of EDC and HOBt to give peptide (VIII). Subsequent deprotection of the Boc group of (VII) with HCl in cold EtOAc furnished the required intermediate (IX).

参考文献中间体

【1】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 .

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)	34733	tert-butyl (1S,2S)-1-formyl-2-methylbutylcarbamate		C₁₁H₂₁NO₃	详情	详情
(II)	17568	methyl 2-aminoacetate		C₃H₇NO₂	详情	详情
(III)	34734	methyl 2-([(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl]amino)acetate		C₁₄H₂₈N₂O₄	详情	详情
(IV)	12314	1-Naphthaldehyde	66-77-3	C₁₁H₈O	详情	详情
(V)	34735	methyl 2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetate		C₂₅H₃₆N₂O₄	详情	详情
(VI)	34736	2-[[(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentyl](1-naphthylmethyl)amino]acetic acid		C₂₄H₃₄N₂O₄	详情	详情
(VII)	17950	D-Methionine methyl ester; methyl (2S)-2-amino-4-(methylsulfanyl)butanoate hydrochloride	21691-49-6	C₆H₁₃NO₂S	详情	详情
(VIII)	34737	methyl (6S,12S)-2,2-dimethyl-6-[(1S)-1-methylpropyl]-12-[2-(methylsulfanyl)ethyl]-8-(1-naphthylmethyl)-4,10-dioxo-3-oxa-5,8,11-triazatridecan-13-oate		C₃₀H₄₅N₃O₅S	详情	详情
(IX)	34738	methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate		C₂₅H₃₇N₃O₃S	详情	详情

合成路线2

Protection of 4-imidazoleacetic acid methyl ester (X) with triphenylmethyl bromide provided the N1-trityl derivative (XI). Subsequent alkylation of (XI) with 4-cyanobenzyl bromide (XII) resulted in the formation of the imidazolium salt (XIII). Deprotection of the trityl group of (XIII) was achieved upon refluxingin MeOH to give (XIV). Hydrolysis of the methyl ester group of (XIV) under either acidic or basic conditions yielded imidazoleacetic acid (XV), which was subsequently coupled with the intermediate amine (IX) using EDC and 3-hydroxy-1,2,3-benzotriazin-4-one (HOOBT) to provide amide (XVI). Finally, saponification of the methyl ester group of (XVI) furnished the title compound.

参考文献中间体

【1】 Gomez, R.P.; Schaber, M.D.; Anthony, N.J.; et al.; Design and in vivo analysis of potent non-thiol inhibitors of farnesyl protein transferase. J Med Chem 1999, 42, 17, 3356.
【2】 Anthony, N.J.; Desolms, S.J.; Gomez, R.P.; Graham, S.L.; Hutchinson, J.H.; Stokker, G.E. (Merck & Co., Inc.); Thio-free inhibitors of farnesyl-protein transferase. JP 1998508005; US 5652257; WO 9610034 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	34738	methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate		C₂₅H₃₇N₃O₃S	详情	详情
(X)	34739	methyl 2-(1H-imidazol-4-yl)acetate		C₆H₈N₂O₂	详情	详情
(XI)	34740	methyl 2-(1-trityl-1H-imidazol-4-yl)acetate		C₂₅H₂₂N₂O₂	详情	详情
(XII)	14200	4-(Bromomethyl)benzonitrile; alpha-Bromo-p-tolunitrile	17201-43-3	C₈H₆BrN	详情	详情
(XIII)	34741	3-(4-cyanobenzyl)-4-(2-methoxy-2-oxoethyl)-1-trityl-1H-imidazol-3-ium bromide		C₃₃H₂₈BrN₃O₂	详情	详情
(XIV)	34742	methyl 2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetate		C₁₄H₁₃N₃O₂	详情	详情
(XV)	34743	2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetic acid		C₁₃H₁₁N₃O₂	详情	详情
(XVI)	34805	methyl (2S)-2-([2-[[(2S,3S)-2-([2-[1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetyl]amino)-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate		C₃₈H₄₆N₆O₄S	详情	详情

Extended Information