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【结 构 式】 
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【药物名称】Ketorolac, RS-37619 【化学名称】(±)-5-Benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid 【CA登记号】74103-06-3, 74103-07-4 (tromethamine salt) 【 分 子 式 】C15H13NO3 【 分 子 量 】255.27576 |
【开发单位】Roche (Originator), Allergan (Licensee), Recordati (Licensee) 【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Non-Opioid Analgesics, Non-Steroidal Antiinflammatory Drugs |
合成路线1
The benzoylation of 2-methylthiopyrrole (I) with N,N-dimethylbenzamide (II) by means of POCl3 in refluxing CH2Cl2 gives 5-benzoyl-2-methylthiopyrrole (III), which is condensed with spiro[2.5]-5,7-dioxa-6,6-dimethyloctane-4,8-dione (IV) by means of NaH in DMF yielding compound (V). The oxidation of (V) with m-chloroperbenzoic acid in CH2Cl2 affords the sulfone (VI), which is submitted to methanolysis with methanol and HCl giving 1-(3,3-dimethoxycarbonylpropyl)-2-methanesulfonyl-5-benzoylpyrrole (VII). The cyclization of (VII) with NaH in DMF yields dimethyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,1-dicarboxylate (VIII), which is finally hydrolyzed and decarboxylated with KOH in refluxing methanol. Compound (III) can be oxidized with m-chloroperbenzoic acid as before giving 2-methanesulfonyl-5-benzoylpyrrole (IX), which is then condensed with spiro compound (IV) as before to afford compound (VI), already obtained.
| 【1】 Muchowski, J.M.; Franco, F.; Greenhouse, R.; Novel syntheses of 5-aryl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids. J Org Chem 1982, 47, 9, 1682-88. |
| 【2】 Arrigoni-Martelli, E.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RS-37,619. Drugs Fut 1983, 8, 10, 871. |
| 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) | 24831 | 2-(methylsulfanyl)-1H-pyrrole | C5H7NS | 详情 | 详情 | |
| (II) | 30757 | N,N-dimethylbenzamide | 611-74-5 | C9H11NO | 详情 | 详情 |
| (III) | 30758 | [5-(methylsulfanyl)-1H-pyrrol-2-yl](phenyl)methanone | C12H11NOS | 详情 | 详情 | |
| (IV) | 11639 | 6,6-Dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione | 5617-70-9 | C8H10O4 | 详情 | 详情 |
| (V) | 30759 | 5-[2-[2-benzoyl-5-(methylsulfanyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C20H21NO5S | 详情 | 详情 | |
| (VI) | 30760 | 5-[2-[2-benzoyl-5-(methylsulfonyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4,6-dione | C20H21NO7S | 详情 | 详情 | |
| (VII) | 30761 | dimethyl 2-[2-[2-benzoyl-5-(methylsulfonyl)-1H-pyrrol-1-yl]ethyl]malonate | C19H21NO7S | 详情 | 详情 | |
| (VIII) | 30762 | dimethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate | C18H17NO5 | 详情 | 详情 | |
| (IX) | 30763 | [5-(methylsulfonyl)-1H-pyrrol-2-yl](phenyl)methanone | C12H11NO3S | 详情 | 详情 |
合成路线2
The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol - water.
| 【1】 Blancafort, P.; Serradell, M.N.; Hillier, K.; Castaner, J.; BPPC. Drugs Fut 1981, 6, 11, 669. |
| 【2】 Muchowski, J.M.; Kluge, A.F. (Roche Bioscience); 1,2-Dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acids derivatives and process for the production thereof. DE 2731678; ES 460706; ES 470214; FR 2358406; FR 2375234; GB 1554075 . |
| 【3】 Arrigoni-Martelli, E.; Castaner, J.; Blancafort, P.; Serradell, M.N.; RS-37,619. Drugs Fut 1983, 8, 10, 871. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 22692 | dimethyl 3-oxopentanedioate | 1830-54-2 | C7H10O5 | 详情 | 详情 |
| (XI) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XII) | 30764 | dimethyl (E)-3-[(2-hydroxyethyl)amino]-2-pentenedioate | C9H15NO5 | 详情 | 详情 | |
| (XIII) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (XIV) | 30765 | methyl 1-(2-hydroxyethyl)-2-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate | C11H15NO5 | 详情 | 详情 | |
| (XVI) | 30766 | methyl 2-(2-methoxy-2-oxoethyl)-1-(2-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]ethyl)-1H-pyrrole-3-carboxylate | C14H21NO5S | 详情 | 详情 | |
| (XVII) | 30767 | methyl 1-(2-iodoethyl)-2-(2-methoxy-2-oxoethyl)-1H-pyrrole-3-carboxylate | C11H14INO4 | 详情 | 详情 | |
| (XVIII) | 30768 | dimethyl 2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylate | C11H13NO4 | 详情 | 详情 | |
| (XIX) | 30769 | 2,3-dihydro-1H-pyrrolizine-1,7-dicarboxylic acid | C9H9NO4 | 详情 | 详情 | |
| (XX) | 30770 | 1-(isopropoxycarbonyl)-2,3-dihydro-1H-pyrrolizine-7-carboxylic acid | C12H15NO4 | 详情 | 详情 | |
| (XXI) | 30771 | isopropyl 2,3-dihydro-1H-pyrrolizine-1-carboxylate | C11H15NO2 | 详情 | 详情 | |
| (XXII) | 30757 | N,N-dimethylbenzamide | 611-74-5 | C9H11NO | 详情 | 详情 |
| (XXIII) | 30772 | isopropyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate | C18H19NO3 | 详情 | 详情 |