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【结 构 式】 
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【药物名称】 【化学名称】4-[2-(4-Fluorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrrol-3-yl]pyridine 【CA登记号】188343-77-3 【 分 子 式 】C21H22FN3 【 分 子 量 】335.42799 |
【开发单位】Merck & Co. (Originator) 【药理作用】ANTIINFECTIVE THERAPY, Treatment of Protozoal Diseases, Protein Kinase Inhibitors |
合成路线1
N-(Benzyloxycarbonyl)isonipecotic acid (I) was activated as the acid chloride (II) employing oxalyl chloride in the presence of a catalytic amount of DMF. Addition of diazomethane to acid chloride (II) produced the intermediate diazo ketone (III) which, upon treatment with an ethereal solution of HCl, led to the chloromethyl ketone (IV).
| 【1】 De Laszlo, S.E.; Mantlo, N.B.; Ponticello, G.S.; Selnick, H.G.; Liverton, N.J. (Merck & Co., Inc.); 2-Substd. aryl pyrroles, compsns. containing such cpds. and methods of use. EP 0863757; JP 1999510510; US 5792778; WO 9705877 . |
| 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) | 56082 | Z-Isonipecotic acid | 10314-98-4 | C14H17NO4 | 详情 | 详情 |
| (II) | 36165 | 4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-amine; 4,7-dimethoxy-6-[2-(1-piperidinyl)ethoxy]-1-benzofuran-5-ylamine | C17H24N2O4 | 详情 | 详情 | |
| (III) | 56083 | benzyl 4-(2-diazoacetyl)-1-piperidinecarboxylate | C15H17N3O3 | 详情 | 详情 | |
| (IV) | 56084 | benzyl 4-(2-chloroacetyl)-1-piperidinecarboxylate | C15H18ClNO3 | 详情 | 详情 |
合成路线2
Acylation of the lithium derivative of 4-picoline (VI) with the Weinreb amide of 4-fluorobenzoic acid (V) yielded ketone (VII). The sodium enolate of (VII) was then alkylated with chloro ketone (IV) to afford diketone (VIII). The Paal-Knorr cyclization of diketone (VIII) in the presence of ammonium acetate in boiling HOAc led to pyrrole (IX). Finally, reduction of the benzyloxycarbonyl group of (IX) by means of LiAlH4 furnished the target N-methyl piperidine.
| 【1】 De Laszlo, S.E.; Mantlo, N.B.; Ponticello, G.S.; Selnick, H.G.; Liverton, N.J. (Merck & Co., Inc.); 2-Substd. aryl pyrroles, compsns. containing such cpds. and methods of use. EP 0863757; JP 1999510510; US 5792778; WO 9705877 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 56084 | benzyl 4-(2-chloroacetyl)-1-piperidinecarboxylate | C15H18ClNO3 | 详情 | 详情 | |
| (V) | 29514 | 4-fluoro-N-methoxy-N-methylbenzamide | C9H10FNO2 | 详情 | 详情 | |
| (VI) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (VIII) | 56085 | benzyl 4-[4-(4-fluorophenyl)-4-oxo-3-(4-pyridinyl)butanoyl]-1-piperidinecarboxylate | C28H27FN2O4 | 详情 | 详情 | |
| (IX) | 56086 | benzyl 4-[5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrrol-2-yl]-1-piperidinecarboxylate | C28H26FN3O2 | 详情 | 详情 |