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【结 构 式】 
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【分子编号】25934 【品名】4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C10H18N2O4 【 分 子 量 】230.264 【元素组成】C 52.16% H 7.88% N 12.17% O 27.79% |
合成路线1
该中间体在本合成路线中的序号：(II)The selective protection of piperazine-2-carboxylic acid (I) with tert-butoxycarbonyl anhydride gives the carbamate (II), which is sulfonated with 4-methoxybenzenesulfonyl chloride (II) and triethylamine yielding the sulfonamide (IV). The esterification and simultaneous deprotection of (IV) with SOCl2 and methanol affords the methyl ester (V), which is treated with benzyl chloroformate (VI) and triethylamine to afford the benzyloxycarbonyl derivative (VII). Finally, this compound is treated with KOH and hydroxylamine in methanol to provide the target hydroxamic acid.
| 【1】 Pikul, S.; Natchus, M.G.; Cheng, M.; et al.; Design and synthesis of piperazine-based MMP inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 044. |
| 【2】 De, B.; Natchus, M.G.; Pikul, S.; Almstead, N.G.; Matthews, R.S.; Taiwo, Y.O.; Cheng, M. (The Procter & Gamble Co.); 1,4-Heterocyclic metalloprotease inhibitors. EP 0923563; EP 0925287; WO 9808825; WO 9808827 . |
| 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) | 25933 | 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
| (II) | 25934 | 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | C10H18N2O4 | 详情 | 详情 | |
| (III) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IV) | 25935 | 4-(tert-butoxycarbonyl)-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylic acid | C17H24N2O7S | 详情 | 详情 | |
| (V) | 25936 | methyl 1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VI) | 10101 | Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene | 501-53-1 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 25938 | 1-benzyl 3-methyl 4-[(4-methoxyphenyl)sulfonyl]-1,3-piperazinedicarboxylate | C21H24N2O7S | 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 selective protection of piperazine-2-carboxylic acid (I) with tert-butoxycarbonyl anhydride gives the carbamate (II), which is sulfonated with 4-methoxybenzenesulfonyl chloride (II) and triethylamine yielding the sulfonamide (IV). The esterification and simultaneous deprotection of (IV) with SOCl2 and methanol affords the methyl ester (V), which is treated with phosgene and N-benzyl-N-methylamine (VI) to afford the cyclic urea derivative (VII). Finally, this compound is treated with KOH and hydroxylamine in methanol to provide the target hydroxamic acid.
| 【1】 De, B.; Natchus, M.G.; Pikul, S.; Almstead, N.G.; Matthews, R.S.; Taiwo, Y.O.; Cheng, M. (The Procter & Gamble Co.); 1,4-Heterocyclic metalloprotease inhibitors. EP 0923563; EP 0925287; WO 9808825; WO 9808827 . |
| 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) | 25933 | 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
| (II) | 25934 | 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | C10H18N2O4 | 详情 | 详情 | |
| (III) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IV) | 25935 | 4-(tert-butoxycarbonyl)-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylic acid | C17H24N2O7S | 详情 | 详情 | |
| (V) | 25936 | methyl 1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C13H18N2O5S | 详情 | 详情 | |
| (VI) | 11969 | N-Methyl(phenyl)methanamine; N-Benzyl-N-methylamine; N-Methylbenzylamine | 103-67-3 | C8H11N | 详情 | 详情 |
| (VII) | 25937 | methyl 4-[[benzyl(methyl)amino]carbonyl]-1-[(4-methoxyphenyl)sulfonyl]-2-piperazinecarboxylate | C22H27N3O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)Piperazine-2-carboxylic acid (VIII) was prepared by catalytic hydrogenation of pyrazine (VII). Sequential protection of the N-4 of (VIII) with 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile and the N-1 with benzyl chloroformate provided the diprotected piperazinecarboxylic acid (X), which was subsequently esterified with diazomethane to give the methyl ester (XI). The N-benzyloxycarbonyl group of (XI) was selectively deprotected by hydrogenation in the presence of Pd/C to yield the N-Boc-piperazine (XII). Reductive alkylation of (XII) with isovaleraldehyde (XIII) afforded the corresponding N-isoamyl piperazine (XIV). After acid removal of the N-Boc group of (XIV) to yield (XV), a second reductive alkylation with acetone (XVI) produced the dialkyl piperazine (XVII). Hydrolysis of the methyl ester group of (XVII) under acidic conditions gave acid (XVIII). This was finally coupled with the intermediate piperidine (VI) in the presence of HBTU to provide the title compound.
| 【1】 Rafferty, M.F.; Hu, L.-Y.; Ryder, T.R.; et al.; Synthesis and biological activity of 4-aminopiperidine derivatives as N-type calcium channel antagonists. Med Chem Res 2000, 10, 1, 11. |
| 【2】 Ryder, T.R.; Rafferty, M.F.; Hu, L.-Y. (Pfizer Inc.); Heterocyclic substd. aniline calcium channel blockers. US 6251919; WO 9943658 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 38232 | N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine | C23H30N2O | 详情 | 详情 | |
| (VII) | 37256 | 2-pyrazinecarboxylic acid; Pyrazinoic acid | 98-97-5 | C5H4N2O2 | 详情 | 详情 |
| (VIII) | 25933 | 2-piperazinecarboxylic acid; Piperazine-2-carboxylic acid | C5H10N2O2 | 详情 | 详情 | |
| (IX) | 25934 | 4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | C10H18N2O4 | 详情 | 详情 | |
| (X) | 48403 | N-4-Boc-N-1-CBz-2-piperazinecarboxylic acid; 1-[(benzyloxy)carbonyl]-4-(tert-butoxycarbonyl)-2-piperazinecarboxylic acid | 129365-23-7 | C18H24N2O6 | 详情 | 详情 |
| (XI) | 48404 | 1-benzyl 4-(tert-butyl) 2-methyl 1,2,4-piperazinetricarboxylate | C19H26N2O6 | 详情 | 详情 | |
| (XII) | 48405 | 1-(tert-butyl) 3-methyl 1,3-piperazinedicarboxylate | C11H20N2O4 | 详情 | 详情 | |
| (XIII) | 26052 | 3-methylbutanal | 590-86-3 | C5H10O | 详情 | 详情 |
| (XIV) | 48406 | 1-(tert-butyl) 3-methyl 4-isopentyl-1,3-piperazinedicarboxylate | C16H30N2O4 | 详情 | 详情 | |
| (XV) | 48407 | methyl 1-isopentyl-2-piperazinecarboxylate | C11H22N2O2 | 详情 | 详情 | |
| (XVI) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (XVII) | 48408 | methyl 1-isopentyl-4-isopropyl-2-piperazinecarboxylate | C14H28N2O2 | 详情 | 详情 | |
| (XVIII) | 48409 | 1-isopentyl-4-isopropyl-2-piperazinecarboxylic acid | C13H26N2O2 | 详情 | 详情 |