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【结 构 式】 
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【药物名称】Lasmiditan;COL-144 LY-573144;LY-573144 【化学名称】2,4,6-Trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)pyridin-2-yl]benzamide hydrochloride 【CA登记号】613677-28-4；439239-90-4 (free base) 【 分 子 式 】C19H18F3N3O2.HCl 【 分 子 量 】413.821 |
【开发单位】CoLucid Pharmaceuticals, Inc. (US); licensed from Eli Lilly Co., Inc. (US) 【药理作用】5-HT1F Receptor Agonist;Antimigraine Drug |
合成路线1
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
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 |