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【结 构 式】 
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【药物名称】Prinomide triethanolamine, CGS-10787B 【化学名称】2-(2-Cyano-2-phenylaminocarbonyl)acetyl-1-methylpyrrol triethanolamine salt 【CA登记号】77639-66-8 (free base) 【 分 子 式 】C21H28N4O5 【 分 子 量 】416.48111 |
【开发单位】Novartis (Originator) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Non-Steroidal Antiinflammatory Drugs |
合成路线1
The synthesis of [14C]-labeled prinomide has been described: The carboxylation of 1-methylpyrrole (I) with 14CO2 and butyllithium in THF gives labeled 1-methylpyrrole-2-carboxylic acid (II), which is esterified with diazomethane to the methyl ester (III). The reaction of (III) with acetonitrile by means of NaH in DMF affords 3-(1-methylpyrrol-2-yl)-3-oxopropanenitrile (IV) labeled in the carbonyl group. Finally, this compound is condensed with phenylisocyanate (V) by means of triethylamine in toluene, affording the prinomide labeled in the carbonyl group. The condensation of unlabeled (IV) with (V) labeled in the phenyl ring yields the corresponding prinomide labeled in the aromatic ring.
| 【1】 Chaudhuri, N.K.; Markus, B.; Synthesis of two 14C-labeled forms of prinomide, a potential anti-inflammatory compound and its hydroxy metabolite, labeled with 14C. J Label Compd Radiopharm 1990, 28, 3, 321. |
| 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) | 11285 | 1-Methyl-1H-pyrrole; Methylpyrrole | 96-54-8 | C5H7N | 详情 | 详情 |
| (II) | 11286 | 1-Methyl-1H-pyrrole-2-carboxylic acid; 1-Methyl-2-pyrrolecarboxylic acid | 6973-60-0 | C6H7NO2 | 详情 | 详情 |
| (II) | 45058 | 1-methyl-1H-pyrrole-2-carboxylic acid | C6H7NO2 | 详情 | 详情 | |
| (III) | 11287 | methyl 1-methyl-1H-pyrrole-2-carboxylate | 37619-24-2 | C7H9NO2 | 详情 | 详情 |
| (III) | 45059 | methyl 1-methyl-1H-pyrrole-2-carboxylate | C7H9NO2 | 详情 | 详情 | |
| (IV) | 11288 | 3-(1-Methyl-1H-pyrrol-2-yl)-3-oxopropanenitrile | C8H8N2O | 详情 | 详情 | |
| (IV) | 45060 | 3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanenitrile | C8H8N2O | 详情 | 详情 | |
| (V) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
合成路线2
The esterification of N-methylpyrrol-2-carboxylic acid (I) with NaH and methyl iodide in DMF gives methyl N methylpyrrol 2 carboxylate (II), which is condensed with acetonitrile by means of NaH in DMF yielding 3-(1-methyl-2-pyrrolyl)-3-oxopropionitrile (III). The reaction of (III) with phenylisocyanate (IV) by means of triethylamine in toluene affords 2-cyano-3-(1-methyl-2-pyrrolyl)-3-oxo-N-phenylpropionamide (V), which is finally treated with triethanolamine (VI) in hot ethanol.
| 【1】 Walker, G.N. (Novartis AG); alpha-Carbamoyl-pyrrolpropionitriles, process fortheir preparation and pharmaceutical preparations containing them. EP 0143142 . |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Prinomide Triethanolamine. Drugs Fut 1987, 12, 8, 773. |
| 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) | 11286 | 1-Methyl-1H-pyrrole-2-carboxylic acid; 1-Methyl-2-pyrrolecarboxylic acid | 6973-60-0 | C6H7NO2 | 详情 | 详情 |
| (II) | 11287 | methyl 1-methyl-1H-pyrrole-2-carboxylate | 37619-24-2 | C7H9NO2 | 详情 | 详情 |
| (III) | 11288 | 3-(1-Methyl-1H-pyrrol-2-yl)-3-oxopropanenitrile | C8H8N2O | 详情 | 详情 | |
| (IV) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (V) | 28167 | 2-cyano-3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-N-phenylpropanamide | C15H13N3O2 | 详情 | 详情 | |
| (VI) | 28168 | 2-[bis(2-hydroxyethyl)amino]-1-ethanol | 102-71-6 | C6H15NO3 | 详情 | 详情 |
合成路线3
The reaction of acid (I) with SOCl2 in ethyl ether containing triethylamine gives the corresponding acyl chloride (VII), which is condensed with ethyl cyanacetate (VIII) by means of NaH in glyme yielding ethyl 2-cyano-3-(1-methyl-2-pyrrolyl)-3-oxopropanoate (IX). The reaction of (IX) with aniline (X) in refluxing xylene affords the corresponding anilide (V) already obtained.
| 【1】 Walker, G.N. (Novartis AG); alpha-Carbamoyl-pyrrolpropionitriles, process fortheir preparation and pharmaceutical preparations containing them. EP 0143142 . |
| 【2】 Serradell, M.N.; Castaner, J.; Castaner, R.M.; Prinomide Triethanolamine. Drugs Fut 1987, 12, 8, 773. |
| 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) | 11286 | 1-Methyl-1H-pyrrole-2-carboxylic acid; 1-Methyl-2-pyrrolecarboxylic acid | 6973-60-0 | C6H7NO2 | 详情 | 详情 |
| (V) | 28167 | 2-cyano-3-(1-methyl-1H-pyrrol-2-yl)-3-oxo-N-phenylpropanamide | C15H13N3O2 | 详情 | 详情 | |
| (VI) | 28168 | 2-[bis(2-hydroxyethyl)amino]-1-ethanol | 102-71-6 | C6H15NO3 | 详情 | 详情 |
| (VII) | 28169 | 1-methyl-1H-pyrrole-2-carbonyl chloride | C6H6ClNO | 详情 | 详情 | |
| (VIII) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (IX) | 28170 | ethyl 2-cyano-3-(1-methyl-1H-pyrrol-2-yl)-3-oxopropanoate | C11H12N2O3 | 详情 | 详情 | |
| (X) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |