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【结 构 式】

【分子编号】43411

【品名】1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate

【CA登记号】

【 分 子 式 】C11H18N4O4

【 分 子 量 】270.28848

【元素组成】C 48.88% H 6.71% N 20.73% O 23.68%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(III)

The title compound was constructed from two tripeptide fragments. Preparation of tripeptide (XI) is shown in Scheme 29208701a. Boc-Hydroxyproline methyl ester (I) was converted to the corresponding mesylate (II), which was displaced with NaN3 in DMF to afford azide (III). Subsequent acid deprotection of the Boc group of (III) yielded 4-azidoproline methyl ester (IV). This was coupled with the protected ornithine (V) using EDC and HOBt to furnish dipeptide (VI). Further cleavage of the Boc group of (VI) using HCl in EtOAc provided (VII). After protection of homotyrosine (VIII) as the Fmoc derivative (IX), coupling with dipeptide (VII) yielded the protected tripeptide (X). The Fmoc group of (X) was then removed by treatment with diethylamine in acetonitrile, yielding tripeptide intermediate (XI).

1 Chen, H.-J.; Klein, L.L.; Li, L.; et al.; Total synthesis and antifungal evaluation of cyclic aminohexapeptides. Bioorg Med Chem Lett 2000, 8, 7, 1677.
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) 15780 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate C11H19NO5 详情 详情
(II) 15781 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate C12H21NO7S 详情 详情
(III) 43411 1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate C11H18N4O4 详情 详情
(IV) 43412 methyl (2S,4S)-4-azido-2-pyrrolidinecarboxylate C6H10N4O2 详情 详情
(V) 43413 (2S)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid 2480-93-5 C18H26N2O6 详情 详情
(VI) 43414 methyl (2S,4S)-4-azido-1-[(2S)-5-[[(benzyloxy)carbonyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoyl]-2-pyrrolidinecarboxylate C24H34N6O7 详情 详情
(VII) 43415 methyl (2S,4S)-1-((2S)-2-amino-5-[[(benzyloxy)carbonyl]amino]pentanoyl)-4-azido-2-pyrrolidinecarboxylate C19H26N6O5 详情 详情
(VIII) 43416 (2R)-2-amino-4-(4-hydroxyphenyl)butyric acid C10H13NO3 详情 详情
(IX) 43417 (2R)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-(4-hydroxyphenyl)butyric acid C25H23NO5 详情 详情
(X) 43418 methyl (2S,4S)-4-azido-1-((2S)-5-[[(benzyloxy)carbonyl]amino]-2-[[(2S)-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-(4-hydroxyphenyl)butanoyl]amino]pentanoyl)-2-pyrrolidinecarboxylate C44H47N7O9 详情 详情
(XI) 43419 methyl (2S,4S)-1-((2S)-2-[[(2S)-2-amino-4-(4-hydroxyphenyl)butanoyl]amino]-5-[[(benzyloxy)carbonyl]amino]pentanoyl)-4-azido-2-pyrrolidinecarboxylate C29H37N7O7 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

The esterification of 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid (I) gives the methyl ester (II), which is N-protected to yield 1-Boc-4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester (III). Compound (III) which is mesylated to afford 1-Boc-4(R)-(mesyloxy)pyrrolidine-2(S)-carboxylic acid methyl ester (IV). The reaction of (IV) with sodium azide affords (V), which is reduced with H2 over Pd/C in ethanol to provide 4(S)-amino-1-Boc-pyrrolidine-2(S)-carboxylic acid methyl ester (VI). The reductocondensation of (VI) with 3-methoxybenzaldehyde (VII) by means of NaBH(OAc)3 provides the secondary amine (VIII), which is acylated with 3,3-dimethylbutyryl chloride (IX) and TEA in dichloromethane to give the amide (X). The deprotection of the pyrrolidine NH of (X) by means of TFA yields the pyrrolidine (XI), which is reductocondensed with piperonal (XII) by means of NaBH3CN to afford the N-substituted pyrrolidine (XIII). The hydrolysis of the ester group of (XIII) with LiOH in methanol/water provides the carboxylic acid (XIV), which is condensed with N-Boc-piperazine (XV) by means of TBTU and DIEA in DMF to give the protected intermediate (XVI). Finally, this compound is deprotected by means of TFA in dichloromethane to furnish the target carboxamide.

1 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Rubin, L. (Curis, Inc.); Mediators of hedgehog signaling pathways, compsns. and uses related thereto. WO 0126644 .
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) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 15796 methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate C6H11NO3 详情 详情
(III) 15780 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate C11H19NO5 详情 详情
(IV) 15781 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate C12H21NO7S 详情 详情
(V) 43411 1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate C11H18N4O4 详情 详情
(VI) 55407 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate C11H20N2O4 详情 详情
(VII) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(VIII) 55407 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate C11H20N2O4 详情 详情
(IX) 21738 3,3-dimethylbutanoyl chloride 7065-46-5 C6H11ClO 详情 详情
(X) 55409 1-(tert-butyl) 2-methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-1,2-pyrrolidinedicarboxylate C25H38N2O6 详情 详情
(XI) 55410 methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate C20H30N2O4 详情 详情
(XII) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(XIII) 55411 methyl (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate C28H36N2O6 详情 详情
(XIV) 55412 (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylic acid C27H34N2O6 详情 详情
(XV) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(XVI) 55413 tert-butyl 4-({(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]pyrrolidinyl}carbonyl)-1-piperazinecarboxylate C36H50N4O7 详情 详情
Extended Information