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【结 构 式】

【分子编号】68622

【品名】(6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone

【CA登记号】 

【 分 子 式 】C12H17N3O

【 分 子 量 】219.2866

【元素组成】C 65.73% H 7.81% N 19.16% O 7.3%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

Metalation of 2-chloropyridine (I) with BuLi in the presence of N,Ndimethylethanolamine in hexane at –78 °C, followed by condensation with N-methoxy-N,1-dimethylpiperidine-4-carboxamide (II) in hexane provides (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone (III). Condensation of chloropyrimidine derivative (III) with benzophenone imine, Pd2dba3, BINAP and t-BuONa in refluxing toluene yields compound (IV), which by hydrolysis with HCl in THF furnishes (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (V). N-Acylation of amine (V) with 2,4,6-trifluorobenzoyl chloride (VI), optionally in the presence of Et3N in THF or refluxing 1,4-dioxane, generates lasmiditan (VII), which is finally treated with NH4Cl in MeOH or HCl in refluxing i-PrOH .

1 Kohlman, D.T., Mancuso, V., Cohen, M.P. et al. (Eli Lilly and Company). Pyridinoylpiperidines as 5-HT1F agonists. EP 1492786, JP 2005530722, JP 2010159272, US 2005222206, US 7423050, US 8044207, WO 2003084949.
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) 17503 2-chloropyridine 109-09-1 C5H4ClN 详情 详情
(II) 68619 N-methoxy-N,1-dimethylpiperidine-4-carboxamide   C9H18N2O2 详情 详情
(III) 68620 (6-chloropyridin-2-yl)(1-methylpiperidin-4-yl)methanone   C12H15ClN2O 详情 详情
(IV) 68621 (6-((diphenylmethylene)amino)pyridin-2-yl)(1-methylpiperidin-4-yl)methanone   C25H25N3O 详情 详情
(V) 68622 (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone   C12H17N3O 详情 详情
(VI) 68623 2,4,6-trifluorobenzoyl chloride 79538-29-7 C7H2ClF3O 详情 详情
(VII) 68624 2,4,6-trifluoro-N-(6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl)benzamide   C19H18F3N3O2 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

N-Methylation of piperidine-4-carboxylic acid (VIII) by means of HCHO in the presence of H2 over Pd/C in H2O gives 1-methylpiperidine-4-carboxylic acid (IX), which by chlorination with (COCl)2 in the presence of DMF in refluxing CH2Cl2 furnishes 1-methylpiperidine-4-carbonyl chloride hydrochloride (X). Condensation of acid chloride (X) with Me2NH in the presence of Et3N in THF yields N,N,1-trimethylpiperidine-4-carboxamide (XI), which then condenses with 2,6-dibromopyridine (XII) in the presence of BuLi in methyl t-butyl ether (MTBE), affording (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone (XIII). Amination of bromo derivative (XIII) with NH3 in the presence of Cu2O in ethylene glycol at 85 °C produces the desired intermediate (V) .

1 Kohlman, D.T., Mancuso, V., Cohen, M.P. et al. (Eli Lilly and Company). Pyridinoylpiperidines as 5-HT1F agonists. EP 1492786, JP 2005530722, JP 2010159272, US 2005222206, US 7423050, US 8044207, WO 2003084949.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(V) 68622 (6-aminopyridin-2-yl)(1-methylpiperidin-4-yl)methanone   C12H17N3O 详情 详情
(VIII) 17402 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid 498-94-2 C6H11NO2 详情 详情
(IX) 68625 1-methyl-4-Piperidinecarboxylicacid;1-methylpiperidine-4-carboxylic acid;1-methyl-Isonipecoticacid;4-Carboxy-N-methylpiperidine;N-Methylpiperidine-4-carboxylic acid 68947-43-3 C7H13NO2 详情 详情
(X) 68626 1-methylpiperidine-4-carbonyl chloride hydrochloride   C7H12ClNO.HCl 详情 详情
(XI) 68627 N,N,1-trimethylpiperidine-4-carboxamide   C9H18N2O 详情 详情
(XII) 10159 2,6-Dibromopyridine 626-05-1 C5H3Br2N 详情 详情
(XIII) 68628 (6-bromopyridin-2-yl)(1-methylpiperidin-4-yl)methanone   C12H15BrN2O 详情 详情
Extended Information