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【结 构 式】 
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【分子编号】54009 【品名】N~1~-methyl-N~2~-(3-methylbenzyl)-1,2-ethanediamine; N-methyl-N-{2-[(3-methylbenzyl)amino]ethyl}amine 【CA登记号】n/a |
【 分 子 式 】C11H18N2 【 分 子 量 】178.2774 【元素组成】C 74.11% H 10.18% N 15.71% |
合成路线1
该中间体在本合成路线中的序号：(VI)The reductocondensation of ethanolamine (I) with 3-methylbenzaldehyde (II) by means of NaBH4 gives N-(3-methylbenzyl)ethanolamine (III), which is treated with SOCl2 to yield the 2-chloroethyl derivative (IV). The reaction of (IV) with methylamine (V) affords N-methyl-N'-(3-methylbenzyl)ethane-1,2-diamine (VI), which is condensed with the pyrazole-carboxamide derivative (VII) to provide the unstable compound (VIII)?? (IX). The reduction of (IX) with NaBH4 gives the racemic amide (X), which is submitted to optical resolution by preferential crystallization to yield the (R)-isomer (XI) (1,2). The hydrogenation of (XI) with H2 over Pd/C in ethanol affords the debenzylated compound (XII), which is alkylated by reductocondensation with acetaldehyde (XIII) and NaBH4 in methanol to provide the chiral N-(1-ethyl-4'-methylperhydro-1,4-diazepin-6-(R)-yl)-1H-pyrazole-3-carboxamide (XIV). Finally, this compound is treated with refluxing aqueous HCl to give the corresponding 6(R)-amino derivative (XV).
| 【2】 Hirokawa, Y.; et al.; Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives, novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist. Chem Pharm Bull 2002, 50, 7, 941. |
| 【1】 Harada, H.; et al.; Synthesis and resolution of (±)-N-[1-methyl-4-(3-methylbenzyl)hexahydro-1H-1,4-diazepin-6-yl]-1H-indazole-3-carboxamide by preferential crystallization. Tetrahedron Asymmetry 1997, 8, 14, 2367. |
| 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) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (II) | 41077 | 3-methylbenzaldehyde | 620-23-5 | C8H8O | 详情 | 详情 |
| (III) | 58175 | 2-[(3-methylbenzyl)amino]-1-ethanol | C10H15NO | 详情 | 详情 | |
| (IV) | 58176 | 2-chloro-N-(3-methylbenzyl)-1-ethanamine; N-(2-chloroethyl)-N-(3-methylbenzyl)amine | C10H14ClN | 详情 | 详情 | |
| (V) | 11021 | Methanamine; Methylamine | 74-89-5 | CH5N | 详情 | 详情 |
| (VI) | 54009 | N~1~-methyl-N~2~-(3-methylbenzyl)-1,2-ethanediamine; N-methyl-N-{2-[(3-methylbenzyl)amino]ethyl}amine | n/a | C11H18N2 | 详情 | 详情 |
| (VII) | 58177 | ethyl 3-{[(1-formylvinyl)amino]carbonyl}-1H-indazole-1-carboxylate | C14H13N3O4 | 详情 | 详情 | |
| (VIII) | 58178 | ethyl 3-({[1-formyl-2-(methyl{2-[(3-methylbenzyl)amino]ethyl}amino)ethyl]amino}carbonyl)-1H-indazole-1-carboxylate | C25H31N5O4 | 详情 | 详情 | |
| (IX) | 58179 | 6-({[1-(ethoxycarbonyl)-1H-indazol-3-yl]carbonyl}amino)-4-methyl-1-(3-methylbenzyl)-3,4,5,6-tetrahydro-2H-1,4-diazepin-1-ium | C25H30N5O3 | 详情 | 详情 | |
| (X) | 58180 | N-[1-methyl-4-(3-methylbenzyl)-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide | C22H27N5O | 详情 | 详情 | |
| (XI) | 58181 | N-[(6S)-1-methyl-4-(3-methylbenzyl)-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide | C22H27N5O | 详情 | 详情 | |
| (XII) | 58182 | N-[(6S)-1-methyl-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide | C14H19N5O | 详情 | 详情 | |
| (XIII) | 11974 | Acetaldehyde | 75-07-0 | C2H4O | 详情 | 详情 |
| (XIV) | 58183 | N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-1H-indazole-3-carboxamide | C16H23N5O | 详情 | 详情 | |
| (XV) | 17802 | (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine | C8H19N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reaction of N-methyl-N'-(3-methylbenzyl)ethylene-1,2-diamine (VIII) with (Boc)2O in chloroform gives N-(tert-butoxycarbonyl)-N-methyl-N'-(3-methylbenzyl)ethylene-1,2-diamine (IX), which is condensed with the chiral aziridine (X) by heating at 80 C to yield the diaminobutyric ester (XI). Selective elimination of the Boc protecting group of (XI) with HCl in methanol affords the methylamino intermediate (XII), which is treated with NaOH in ethanol/water to provide the carboxylic acid (XIII). The cyclization of (XIII) by means of DEC gives the perhydro-1,4-diazepin-5-one derivative (XIV), which is debenzylated by means of 1-chloroethyl chloroformate to yield the 6(S)-(benzyloxycarbonylamino)-4-methylperhydro-1,4-diazepin-5-one (XV). The reductive alkylation of (XV) with acetaldehyde, NaBH4 and TEA in methanol affords the 1-ethyl derivative (XVI), which is deprotected by means of conc. HBr to provide 6(S)-amino-1-ethyl-4-methylperhydro-1,4-diazepin-5-one (XVII). The reduction of (XVII) with BH3/THF gives 1-ethyl-4-methylperhydro-1,4-diazepin-6(R)-amine (XVIII), which is condensed with 5-bromo-2-methoxy-6-(methylamino)pyridine-3-carboxylic acid (VII) by means of ethyl chloroformate and TEA to yield the target amide (XIX). Finally, this compound is treated with fumaric acid (XX) in ethanol to afford the desired fumarate salt.
| 【1】 Kato, S.; Hirokawa, Y.; Morie, T.; Harada, H.; Yoshida, N. (Dainippon Pharmaceutical Co., Ltd.); (R)-5-Bromo-N-(1-ethyl-4-methylhexahydro-1H-1, 4-diazepin-6-yl)-2-methoxy-6-methylamino-3-pyridine-carboxamide, process for producing the same and medicinal compsn. containing the same. EP 0855397; JP 1997100276; JP 1997118669; US 5945415; WO 9705129 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 17801 | 5-bromo-2-methoxy-6-(methylamino)nicotinic acid | C8H9BrN2O3 | 详情 | 详情 | |
| (VIII) | 54009 | N~1~-methyl-N~2~-(3-methylbenzyl)-1,2-ethanediamine; N-methyl-N-{2-[(3-methylbenzyl)amino]ethyl}amine | n/a | C11H18N2 | 详情 | 详情 |
| (IX) | 54010 | tert-butyl methyl{2-[(3-methylbenzyl)amino]ethyl}carbamate | n/a | C16H26N2O2 | 详情 | 详情 |
| (X) | 54011 | 1-benzyl 2-methyl (2S)-1,2-aziridinedicarboxylate | n/a | C12H13NO4 | 详情 | 详情 |
| (XI) | 54012 | methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(3-methylbenzyl)amino]butanoate | n/a | C29H41N3O6 | 详情 | 详情 |
| (XII) | 54013 | methyl (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[[2-(methylamino)ethyl](3-methylbenzyl)amino]butanoate | n/a | C24H33N3O4 | 详情 | 详情 |
| (XIII) | 54014 | (2S)-2-{[(benzyloxy)carbonyl]amino}-4-[[2-(methylamino)ethyl](3-methylbenzyl)amino]butanoic acid | n/a | C23H31N3O4 | 详情 | 详情 |
| (XIV) | 54015 | benzyl (6S)-4-methyl-1-(3-methylbenzyl)-5-oxo-1,4-diazepan-6-ylcarbamate | n/a | C22H27N3O3 | 详情 | 详情 |
| (XV) | 54016 | benzyl (6S)-1-methyl-7-oxo-1,4-diazepan-6-ylcarbamate | n/a | C14H19N3O3 | 详情 | 详情 |
| (XVI) | 54017 | benzyl (6S)-1-ethyl-4-methyl-5-oxo-1,4-diazepan-6-ylcarbamate | n/a | C16H23N3O3 | 详情 | 详情 |
| (XVII) | 54018 | (6S)-6-amino-1-ethyl-4-methyl-1,4-diazepan-5-one | n/a | C8H17N3O | 详情 | 详情 |
| (XVIII) | 17802 | (6S)-1-ethyl-4-methyl-1,4-diazepan-6-ylamine; (6S)-1-ethyl-4-methyl-1,4-diazepan-6-amine | C8H19N3 | 详情 | 详情 | |
| (XIX) | 53998 | 5-bromo-N-[(6S)-1-ethyl-4-methyl-1,4-diazepan-6-yl]-2-methoxy-6-(methylamino)nicotinamide | n/a | C16H26BrN5O2 | 详情 | 详情 |
| (XX) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |