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【结 构 式】 
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【药物名称】Morniflumate, UP-164, Niflam, Morniflu 【化学名称】2-[3-(Trifluoromethyl)phenylamino]pyridine-3-carboxylic acid 2-morpholinoethyl ester 【CA登记号】65847-85-0 【 分 子 式 】C19H20F3N3O3 【 分 子 量 】395.38475 |
【开发单位】Chiesi (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Non-Steroidal Antiinflammatory Drugs |
合成路线1
The title morpholinoethyl ester was prepared by reaction of niflumic acid (I) with N-(2-chloroethyl)morpholine (II) in refluxing isopropanol.
| 【1】 Hoffmann, C. (Hexachimie SA); 2-Anilino-nicotinic acid esters. US 3708481 . |
合成路线2
In a different procedure, 2-chloronicotinic acid (III) was chlorinated to (IV) by means of boiling thionyl chloride. Condensation of acid chloride (IV) with 2-morpholinoethanol (V) gave rise to the morpholinoethyl chloronicotinate (VI). Finally, displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) in the presence of zinc oxide and iodine furnished the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VI) | 56318 | 2-(4-morpholinyl)ethyl 2-chloronicotinate | C12H15ClN2O3 | 详情 | 详情 | |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
合成路线3
Alternatively, acid chloride (IV), prepared from 2-chloronicotinic acid (III), was treated with methanol and triethylamine to afford the methyl ester (VIII). Displacement of the 2-chloro with m-(trifluoromethyl)aniline (VII) yielded methyl niflumate (IX). Finally, transesterification of methyl ester (IX) with 2-morpholinoethanol (V) in the presence of sodium metal gave rise to the title compound.
| 【1】 Chiesi, P.; Servadio, V.; Pighi, R. (Chiesi Farmaceutici SpA); Processes for the preparation of morniflumate and analogous cpds.. EP 0349902 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 28824 | 2-Chloropyridine-3-carboxylic acid; 2-Chloronicotinic acid | 2942-59-8 | C6H4ClNO2 | 详情 | 详情 |
| (IV) | 15224 | 2-chloronicotinoyl chloride | 49609-84-9 | C6H3Cl2NO | 详情 | 详情 |
| (V) | 12856 | 4-(2-Hydroxyethyl)morpholine; 2-(4-Morpholinyl)-1-ethanol; N-(2-Hydroxyethyl)morpholine | 622-40-2 | C6H13NO2 | 详情 | 详情 |
| (VII) | 26347 | 3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride | 98-16-8 | C7H6F3N | 详情 | 详情 |
| (VIII) | 56319 | methyl 2-chloronicotinate | C7H6ClNO2 | 详情 | 详情 | |
| (IX) | 56320 | methyl 2-[3-(trifluoromethyl)anilino]nicotinate | C14H11F3N2O2 | 详情 | 详情 |