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【结 构 式】 
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【分子编号】27317 【品名】benzyl (1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate 【CA登记号】 |
【 分 子 式 】C15H16N2O6 【 分 子 量 】320.30192 【元素组成】C 56.25% H 5.03% N 8.75% O 29.97% |
合成路线1
该中间体在本合成路线中的序号：(V)The cyclization of 1-benzyloxycarbonyl-4-oxoproline methyl ester (I) with ethanedithiol (II) by means of p-toluenesulfonic acid in refluxing acetic acid gives methyl 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (III), which is deprotected with 20% HBr to give methyl 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (IV). The condensation of (IV) with N-benzyloxycarbonyl alanine N-hydroxysuccinimide ester (V) affords the corresponding dipeptide methyl ester (VI), which is hydrolyzed with NaOH to the free acid (VII), and deprotected with 20% HBr as before to 7-alanyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (VIII). Finally, this compound is condensed with ethyl 2-oxo-4-phenylbutyrate (IX) by means of sodium cyanoborohydride in methanol.
| 【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 . |
| 【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 27314 | benzyl hydrogen sulfate | C7H8O4S | 详情 | 详情 | |
| (I) | 27312 | 1-benzyl 2-methyl (2R)-4-oxo-1,2-cyclopentanedicarboxylate | C15H16O5 | 详情 | 详情 | |
| (II) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
| (III) | 27315 | 7-benzyl 8-methyl (8R)-1,4-dithiaspiro[4.4]nonane-7,8-dicarboxylate | C17H20O4S2 | 详情 | 详情 | |
| (IV) | 27316 | methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C8H13NO2S2 | 详情 | 详情 | |
| (V) | 27317 | benzyl (1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate | C15H16N2O6 | 详情 | 详情 | |
| (VI) | 27318 | methyl (8S)-7-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C19H24N2O5S2 | 详情 | 详情 | |
| (VII) | 27319 | (8S)-7-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C18H22N2O5S2 | 详情 | 详情 | |
| (VIII) | 27320 | (8S)-7-[(2S)-2-aminopropanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C10H16N2O3S2 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 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 title compound was obtained by solution-phase peptide synthesis. Acylation of L-aspartic acid beta-benzyl ester (II) with the succinimidyl ester of N-Boc-gamma-benzyl-L-glutamic acid (I) led to the protected dipeptide (III). Removal of the Boc protecting group of (III) by means of trifluoroacetic acid afforded amine (IV), which was subsequently condensed with N-Cbz-L-alanine succinimidyl ester (V) to furnish tripeptide (VI). Coupling of (VI) with glycine benzyl ester (VII) using DCC and HOBt gave the fully protected peptide (VIII). The N-Cbz and benzyl ester groups of (VIII) were finally removed by catalytic hydrogenation over Pd/C to provide the target tetrapeptide.
| 【1】 Khavinson, V.K.; Tetrapeptide revealing geroprotective effect, pharmacological substance on its basis, and the method of its application. WO 0068255 . |
| 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) | 58712 | benzyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentanoate | C21H26N2O8 | 详情 | 详情 | |
| (II) | 58713 | (2S)-2-amino-4-(benzyloxy)-4-oxobutanoic acid | C11H13NO4 | 详情 | 详情 | |
| (III) | 58714 | (2S)-4-(benzyloxy)-2-({(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoyl}amino)-4-oxobutanoic acid | C28H34N2O9 | 详情 | 详情 | |
| (IV) | 58715 | (2S)-2-{[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]amino}-4-(benzyloxy)-4-oxobutanoic acid | C23H26N2O7 | 详情 | 详情 | |
| (V) | 27317 | benzyl (1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate | C15H16N2O6 | 详情 | 详情 | |
| (VI) | 58716 | (5S,8S,11S)-11-[2-(benzyloxy)-2-oxoethyl]-8-[3-(benzyloxy)-3-oxopropyl]-5-methyl-3,6,9-trioxo-1-phenyl-2-oxa-4,7,10-triazadodecan-12-oic acid | C34H37N3O10 | 详情 | 详情 | |
| (VII) | 13601 | benzyl 2-aminoacetate; Glycine benzyl ester hydrochloride | 1738-68-7 | C9H11NO2 | 详情 | 详情 |
| (VIII) | 58717 | benzyl (5S,8S,11S)-11-[2-(benzyloxy)-2-oxoethyl]-8-[3-(benzyloxy)-3-oxopropyl]-5-methyl-3,6,9,12-tetraoxo-1-phenyl-2-oxa-4,7,10,13-tetraazapentadecan-15-oate | C43H46N4O11 | 详情 | 详情 |