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【结 构 式】 
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【药物名称】 【化学名称】1-[4-[N-(4-Benzyloxyphenyl)-N-(3-methylbut-2-enyl)amino]piperidin-1-yl]-1-[4-isopropyl-1-(3-methylbutyl)piperazin-2-yl]methanone 【CA登记号】 【 分 子 式 】C36H54N4O2 【 分 子 量 】574.85738 |
【开发单位】Pfizer (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Calcium Channel Blockers |
合成路线1
Reductive condensation of N-Boc-4-piperidone (I) with 4-(benzyloxy)aniline (II) in the presence of NaBH(OAc)3 produced the secondary amine (III), which was further alkylated with 4-bromo-2-methyl-2-butene (IV) to afford the tertiary amine (V). Subsequent acid cleavage of the Boc protecting group of (V) furnished the intermediate piperidine (VI).
| 【1】 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 |
|---|---|---|---|---|---|---|
| (I) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (II) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (III) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IV) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (V) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 | |
| (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 |
合成路线2
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 |