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【结 构 式】 
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【分子编号】15781 【品名】1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate 【CA登记号】 |
【 分 子 式 】C12H21NO7S 【 分 子 量 】323.36728 【元素组成】C 44.57% H 6.55% N 4.33% O 34.63% S 9.92% |
合成路线1
该中间体在本合成路线中的序号：(II)1) The mesylation of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (I) with mesyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (II), which is treated with sodium benzoate in DMSO yielding the (2S,4S)-benzoate (III). The hydrolysis of (III) with K2CO3 in methanol affords (2S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (IV), which is mesylated with mesyl chloride and triethylamine as before giving the mesylate (V). The reaction of (V) with sodium azide in DMSO yields the corresponding (2S,4R)-azide (VI), which is reduced with H2 over Pd/C in methanol affording (2S,4R)-4-amino-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid methyl ester (VII). The acylation of (VII) with 4-chlorobenzenesulfonyl chloride (VIII) and triethylamine in dichloromethane gives the corresponding amide (IX), which is reduced with diisobutylaluminum hydride (DIBAL) in toluene/THF yielding the aldehyde (X). The Wittig condensation of aldehyde (X) with (4-carboxybutyl)triphenylphosphonium bromide (XI) by means of lithium bis(trimethylsilyl)amide (LBSA) in HMPT affords 6-[1-(tert-butoxycarbonyl)-4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid (XII), which is esterified and deprotected with methanol/HCl to give 6-[4(R)-(4-chlorophenylsulfonamido)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XIII). The condensation of (XIII) with 3-(chloromethyl)pyridine (XIV) and triethylamine in refluxing THF yields 6-[4(R)-(4-chlorophenylsulfonamido)-1-(3-pyridylmethyl)pyrrolidin-2(S)-yl]-5(Z)-hexenoic acid methyl ester (XV), which is finally hydrolyzed with NaOH in methanol/water.
| 【1】 Graul, A.; Castaner, J.; KDI-792. Drugs Fut 1996, 21, 12, 1224. |
| 【2】 Setoi, H.; Sawada, A.; Tanaka, H.; Hashimoto, M. (Fujisawa Pharmaceutical Co., Ltd.); Pyrrolidine derivs. AU 8943753; EP 0367130; JP 1990152960; US 5130323; US 5264453; US 5514701 . |
| 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) | 15782 | 1-(tert-butyl) 2-methyl (2S,4S)-4-(benzoyloxy)tetrahydro-1H-pyrrole-1,2-dicarboxylate | C18H23NO6 | 详情 | 详情 | |
| (IV) | 15783 | 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H19NO5 | 详情 | 详情 | |
| (V) | 15784 | 1-(tert-butyl) 2-methyl (2S,4S)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C12H21NO7S | 详情 | 详情 | |
| (VI) | 15785 | 1-(tert-butyl) 2-methyl (2S,4R)-4-azidotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H18N4O4 | 详情 | 详情 | |
| (VII) | 15786 | 1-(tert-butyl) 2-methyl (2S,4R)-4-aminotetrahydro-1H-pyrrole-1,2-dicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (VIII) | 15787 | 4-chlorobenzenesulfonyl chloride;4-chlorobenzene-1-sulfonyl chloride | 98-60-2 | C6H4Cl2O2S | 详情 | 详情 |
| (IX) | 15788 | 1-(tert-butyl) 2-methyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrole-1,2-dicarboxylate | C17H23ClN2O6S | 详情 | 详情 | |
| (X) | 15789 | tert-butyl (2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-2-formyltetrahydro-1H-pyrrole-1-carboxylate | C16H21ClN2O5S | 详情 | 详情 | |
| (XI) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XII) | 15791 | (Z)-6-((2S,4R)-1-(tert-butoxycarbonyl)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoic acid | C21H29ClN2O6S | 详情 | 详情 | |
| (XIII) | 15792 | methyl (Z)-6-((2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]tetrahydro-1H-pyrrol-2-yl)-5-hexenoate | C17H23ClN2O4S | 详情 | 详情 | |
| (XIV) | 15793 | 3-(Chloromethyl)pyridine | 3099-31-8 | C6H6ClN | 详情 | 详情 |
| (XV) | 15794 | methyl (Z)-6-[(2S,4R)-4-[[(4-chlorophenyl)sulfonyl]amino]-1-(3-pyridinylmethyl)tetrahydro-1H-pyrrol-2-yl]-5-hexenoate | C23H28ClN3O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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3
该中间体在本合成路线中的序号：(IV)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 |