|
【结 构 式】 
|
【分子编号】19352 【品名】4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate 【CA登记号】144222-22-0 |
【 分 子 式 】C11H22N2O2 【 分 子 量 】214.30796 【元素组成】C 61.65% H 10.35% N 13.07% O 14.93% |
合成路线1
该中间体在本合成路线中的序号：(II)4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI) to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).
| 【1】 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 . |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (III) | 29971 | 4-chloro-3-nitropyridine | C5H3ClN2O2 | 详情 | 详情 | |
| (IV) | 59460 | tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H24N4O4 | 详情 | 详情 | |
| (V) | 59461 | tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H26N4O2 | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 59462 | tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate | C18H26N4O2 | 详情 | 详情 | |
| (VIII) | 59463 | 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine | C13H18N4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)4-(Aminomethyl)piperidine (I) was protected as the benzylideneimine (III) by condensation with benzaldehyde (II). Further acylation of (III) at the secondary amino group by treatment with di-tert--butyl dicarbonate gave, after acid hydrolysis of the imine, the N-Boc-piperidine (IV). The benzoic acid derivative (V) was activated as the mixed anhydride by treatment with ethyl chloroformate and triethylamine, and subsequently condensed with amine (IV) to provide the corresponding amide (VI). Then, the N-tert-butoxycarbonyl group was eliminated with HCl to give the piperidine (VII), which was finally alkylated with halide (VIII) in the presence of K2CO3 in DMF to furnish the title compound.
| 【1】 Baker, S.R.; et al.; Synthesis and pharmacological evaluation of benzamides as selective 5-HT4 receptor agonists. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abs P 270. |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 19351 | N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine | C13H18N2 | 详情 | 详情 | |
| (IV) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (V) | 12419 | 4-Amino-5-chloro-2-methoxybenzoic acid | 7206-70-4 | C8H8ClNO3 | 详情 | 详情 |
| (VI) | 19354 | tert-butyl 4-[[(4-amino-5-chloro-2-methoxybenzoyl)amino]methyl]-1-piperidinecarboxylate | C19H28ClN3O4 | 详情 | 详情 | |
| (VII) | 19355 | 4-amino-5-chloro-2-methoxy-N-(4-piperidinylmethyl)benzamide | C14H20ClN3O2 | 详情 | 详情 | |
| (VIII) | 19356 | benzyl 4-chlorobutyl sulfone; benzyl(4-chlorobutyl)dioxo-lambda(6)-sulfane | 14633-43-3 | C11H15ClO2S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)4-(Aminomethyl)piperidine (I) was selectively protected at the piperidine N by means of Boc2O. The resultant 1-Boc-4-(aminomethyl)piperidine (II) was condensed with 4-chloro-3-nitropyridine (III) to afford the amino pyridine compound (IV). Catalytic hydrogenation of the nitro group of (IV) furnished the 3,4-diaminopyridine (V), which was cyclized with ethyl acetimidate hydrochloride (VI), to produce the imidazopyridine (VII). Subsequent acid cleavage of the Boc protecting group of (VII) provided the intermediate piperidine (VIII).
| 【1】 Carceller, E.; Jimenez, P.J.; Salas, J.; Almansa, C.; Bartroli, J.; Merlos, M.; Giral, M.; Balsa, D.; Ferrando, R.; Garcia-Rafanell, J.; Forn, J. (J. Uriach & Cía., SA); Azo derivs. of 5-aminosalicylic acid for treatment of inflammatory bowel disease. EP 0790998; ES 2104513; ES 2106682; JP 1999501939; US 5747477; WO 9709329 . |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (III) | 29971 | 4-chloro-3-nitropyridine | C5H3ClN2O2 | 详情 | 详情 | |
| (IV) | 59460 | tert-butyl 4-{[(3-nitro-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H24N4O4 | 详情 | 详情 | |
| (V) | 59461 | tert-butyl 4-{[(3-amino-4-pyridinyl)amino]methyl}-1-piperidinecarboxylate | C16H26N4O2 | 详情 | 详情 | |
| (VI) | 12831 | ethyl ethanimidoate | 1000-84-6 | C4H9NO | 详情 | 详情 |
| (VII) | 59462 | tert-butyl 4-[(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)methyl]-1-piperidinecarboxylate | C18H26N4O2 | 详情 | 详情 | |
| (VIII) | 59463 | 2-methyl-1-(4-piperidinylmethyl)-1H-imidazo[4,5-c]pyridine | C13H18N4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Selective protection of the secondary amino group of 4-(aminomethyl)piperidine (I) was achieved via conversion to imine (III) upon condensation with benzaldehyde (II), followed by treatment with di-tert-butyl dicarbonate to afford carbamate (IV). Subsequent acid hydrolysis of the imine function of (IV) furnished the mono-protected diamine (V). Coupling of amine (V) with 3-methoxy-4-(3-o-tolylureido)phenylacetic acid (VI) using HATU furnished amide (VII). Acidic cleavage of the N-Boc protecting group of (VII) gave piperidine (VIII). Aziridine (X) was prepared from ethyl 2,3-dibromopropionate (IX) by treatment with ammonia in acetonitrile. Condensation of (X) with N-(benzyloxycarbonyloxy)succinimide produced the benzyl carbamate (XI). Regioselective ring opening of the aziridine (XI) with piperidine (VIII) yielded adduct (XII). The ethyl ester group of (XII) was finally hydrolyzed to the target carboxylic acid under basic conditions.
| 【1】 Astles, P.C.; et al.; Diamine containing VLA-4 antagonists. Bioorg Med Chem 2001, 9, 8, 2195. |
| 【2】 McCarthy, C.; Morley, A.D.; Harris, N.V. (Rhone-Poulenc Rorer Ltd.); Substd. diamines and their use as cell adhesion inhibitors. WO 9954321 . |
| 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) | 19349 | 4-piperidinylmethylamine; 4-piperidinylmethanamine; 4-(Aminomethyl)piperidine | 7144-05-0 | C6H14N2 | 详情 | 详情 |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 19351 | N-[(E)-benzylidene]-N-(4-piperidinylmethyl)amine; N-[(E)-benzylidene](4-piperidinyl)methanamine | C13H18N2 | 详情 | 详情 | |
| (IV) | 49958 | tert-butyl 4-([[(E)-benzylidene]amino]methyl)-1-piperidinecarboxylate | C18H26N2O2 | 详情 | 详情 | |
| (V) | 19352 | 4-Aminomethyl-1-N-Boc-piperidine; tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate | 144222-22-0 | C11H22N2O2 | 详情 | 详情 |
| (VI) | 39718 | 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetic acid | C17H18N2O4 | 详情 | 详情 | |
| (VII) | 49959 | tert-butyl 4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinecarboxylate | C28H38N4O5 | 详情 | 详情 | |
| (VIII) | 49960 | 2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]-N-(4-piperidinylmethyl)acetamide | C23H30N4O3 | 详情 | 详情 | |
| (IX) | 18341 | ethyl 2,3-dibromopropanoate | 3674-13-3 | C5H8Br2O2 | 详情 | 详情 |
| (X) | 49961 | ethyl 2-aziridinecarboxylate | C5H9NO2 | 详情 | 详情 | |
| (XI) | 49962 | 1-benzyl 2-ethyl 1,2-aziridinedicarboxylate | C13H15NO4 | 详情 | 详情 | |
| (XII) | 49963 | ethyl 2-[[(benzyloxy)carbonyl]amino]-3-(4-[[(2-[3-methoxy-4-[(2-toluidinocarbonyl)amino]phenyl]acetyl)amino]methyl]-1-piperidinyl)propanoate | C36H45N5O7 | 详情 | 详情 |