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【结 构 式】

【分子编号】34738

【品名】methyl (2S)-2-([2-[[(2S,3S)-2-amino-3-methylpentyl](1-naphthylmethyl)amino]acetyl]amino)-4-(methylsulfanyl)butanoate

【CA登记号】

【 分 子 式 】C25H37N3O3S

【 分 子 量 】459.6532

【元素组成】C 65.33% H 8.11% N 9.14% O 10.44% S 6.98%
与该中间体有关的原料药合成路线共 4 条
合成路线1合成路线2合成路线3合成路线4

合成路线1

该中间体在本合成路线中的序号：(IX)

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
合成目标
【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

该中间体在本合成路线中的序号：(IX)

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
合成目标
【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

合成路线3

该中间体在本合成路线中的序号：(IX)

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 (VIII) with HCl in cold EtOAc furnished the required intermediate (IX).

参考文献 中间体
合成目标
【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4

该中间体在本合成路线中的序号：(IX)

Protection of 4-imidazoleacetic acid methyl ester (X) with triphenylmethyl bromide provided the N1-trityl derivative (XI). Subsequent alkylation 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). This was finally coupled with the intermediate amine (IX) using EDC and 3-hydroxy-1,2,3-benzotriazin-4-one (HOOBT) to provide the title compound.

参考文献 中间体
合成目标
【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
Extended Information