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【结 构 式】 
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【分子编号】38232 【品名】N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-N-(4-piperidinyl)amine; N-[4-(benzyloxy)phenyl]-N-(3-methyl-2-butenyl)-4-piperidinamine 【CA登记号】 |
【 分 子 式 】C23H30N2O 【 分 子 量 】350.50408 【元素组成】C 78.82% H 8.63% N 7.99% O 4.56% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reductocondensation of 4-benzyloxyaniline (I) with 1-(tert-butoxycarbonyl)piperidin-4-one (II) by means of NaBH(OAc)2 in dichloromethane gives N-(4-benzyloxyphenyl)-N-[1-(tert-butoxycarbonyl)piperidin-4-yl]amine (III), which is alkylated with 3-methyl-2-butenyl bromide (IV) by means of DIEA in THF yielding the tertiary amine (V). The deprotection of (V) with TFA in dichloromethane affords the piperidine (VI), which is condensed with N-(tert-butoxycarbonyl)-L-leucine (VII) by means of HBTU and DIEA in DMF to provide the intermediate (VIII). Finally, (VIII) is deprotected with TFA in dichloromethane.
| 【1】 Ryder, T.R.; Hu, L.-Y.; Rafferty, M.F.; et al.; Synthesis of a series of 4-benzyloxyaniline analogues as neuronal N-type calcium channel blockers with improved anticonvulsant and analgesic properties. J Med Chem 1999, 42, 20, 4239. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (II) | 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 |
| (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 | |
| (VII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (VIII) | 38233 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]carbonyl)-3-methylbutylcarbamate | C34H49N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reaction of N-(tert-butoxycarbonyl)-L-leucine (I) with N,O-dimethylhydroxylamine and HBTU in DMF gives the corresponding methoxyamide (II), which is reduced with LiAlH4 in ethyl ether yielding the aldehyde (III). The reductocondensation of (III) with the piperidine (IV) by means of sodium triacetoxyborohydride in dichloromethane affords the protected adduct (V), which is finally deprotected with TFA in dichloromethane. The intermediate piperidine (IV) has been obtained as follows: The reductocondensation of the piperidinone (VI) with 4-(benzyloxy)aniline (VII) by means of sodium triacetoxyborohydride in dichloromethane gives the secondary amine (VIII), which is alkylated with 3-methyl-2-butenyl bromide (IX) and DIPEA in THF yielding the protected piperidine (IX). Finally, this compound is deprotected with TFA in dichloromethane to afford the target intermediate (IV).
| 【1】 Siebers, K.M.; Hu, L.-Y.; Rafferty, M.F.; et al.; Neuronal N-type calcium channel blocker: Structure-activity relationship of a series of (S)-2-amino-1(4-[(4-benzyloxy-phenyl)-(3-methyl-but-2-enyl)-amino]-piperidin-1-yl)-4-methyl-pentan-1-one analogs. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 259. |
| 【2】 Rafferty, M.F.; Ryder, T.R.; Hu, L.-Y. (Pfizer Inc.); Aniline derivs. as calcium channel blockers. WO 9907689 . |
| 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) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (II) | 40395 | tert-butyl (1S)-1-[[methoxy(methyl)amino]carbonyl]-3-methylbutylcarbamate | C13H26N2O4 | 详情 | 详情 | |
| (III) | 27058 | tert-butyl (1S)-1-formyl-3-methylbutylcarbamate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 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 | |
| (V) | 40394 | tert-butyl (1S)-1-([4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinyl]methyl)-3-methylbutylcarbamate | C34H51N3O3 | 详情 | 详情 | |
| (VI) | 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 |
| (VII) | 22460 | 4-(benzyloxy)aniline; 4-(benzyloxy)phenylamine | C13H13NO | 详情 | 详情 | |
| (VIII) | 38230 | tert-butyl 4-[4-(benzyloxy)anilino]-1-piperidinecarboxylate | C23H30N2O3 | 详情 | 详情 | |
| (IX) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (X) | 38231 | tert-butyl 4-[4-(benzyloxy)(3-methyl-2-butenyl)anilino]-1-piperidinecarboxylate | C28H38N2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)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4
该中间体在本合成路线中的序号：(VI)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 |