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【结 构 式】 
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【药物名称】Indanone, Indacrinic acid, Indacrinone, MK-196 【化学名称】6,7-Dichloro-2-methyl-2-phenyl-1-oxo-5-(indanyloxy)acetic acid 【CA登记号】57296-63-6 【 分 子 式 】C18H14Cl2O4 【 分 子 量 】365.21588 |
【开发单位】Merck Sharp & Dohme (Originator) 【药理作用】Diuretics, METABOLIC DRUGS, RENAL-UROLOGIC DRUGS, Treatment of Disorders of Purine and Pyrimidine Metabolism, Treatment of Gout, Uricosurics |
合成路线1
The condensation of 2,3-dichloroanisole (I) with phenylacetyl chloride (A) by means of AlCl3 in CS2 gives 2,3-dichloro-4-phenylacetylanisole (II), which by reaction with bis(dimethylamino)methane (B) in acetic anhydride is converted into 2,3-dichloro-4-(2-phenylacryloyl)anisole (III). The cyclization of (III) by means of H2SO4 yields 6,7-dichloro-2-phenyl-5-methoxy-1-indanone (IV), which by demethylation with pyridine hydrochloride at 190 C yields 6,7-dichloro-2-phenyl-5-hydroxy-1-indadone (V). The treatment of the phenol (V) with iodoacetic acid (C) and K2CO3 in acetone affords 6,7-dichloro-2-phenyl-1-oxo-5-indanyloxyacetic acid (VI), which is finally methylated with methyl iodide and NaH in DMF.
| 【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 14349 | N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine | 51-80-9 | C5H14N2 | 详情 | 详情 |
| (A) | 25890 | 2-phenylacetyl chloride；Phenylacetyl chloride;Phenacetyl chloride;Benzeneacetyl chloride | 103-80-0 | C8H7ClO | 详情 | 详情 |
| (I) | 40081 | 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether | 1984-59-4 | C7H6Cl2O | 详情 | 详情 |
| (II) | 40082 | 1-(2,3-dichloro-4-methoxyphenyl)-2-phenyl-1-ethanone | C15H12Cl2O2 | 详情 | 详情 | |
| (III) | 40083 | 1-(2,3-dichloro-4-methoxyphenyl)-2-phenyl-2-propen-1-one | C16H12Cl2O2 | 详情 | 详情 | |
| (IV) | 40084 | 6,7-dichloro-5-methoxy-2-phenyl-1-indanone | C16H12Cl2O2 | 详情 | 详情 | |
| (V) | 40085 | 6,7-dichloro-5-hydroxy-2-phenyl-1-indanone | C15H10Cl2O2 | 详情 | 详情 | |
| (VI) | 40087 | 2-[(6,7-dichloro-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetic acid | C17H12Cl2O4 | 详情 | 详情 | |
| (C) | 40086 | 2-iodoacetic acid | 64-69-7 | C2H3IO2 | 详情 | 详情 |
合成路线2
The condensation of 2,3-dichloroanisole (I) with isobutyryl chloride (D) by means of AlCl3 in CH2Cl2 gives 2',3'-dichloro-4'-methoxyisobutyrophenone (VII), which is brominated with Br2 in acetic acid yielding 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (VIII). The dehydrobromination of (VIII) with LiBr in DMF affords (IX), which is cyclized with H2SO4 giving 6,7-dichloro-2-methyl-5-methoxy-1-indanone (X). The phenylation of (X) with diphenyliodonium chloride (E) and potassium tert-butoxide in tert-butanol gives 6,7-dichloro-2-methyl-2-phenyl-5-methoxy-1-indanone (XI), which is demethylated with pyridine hydrochloride at 190 C yielding 6,7-dichloro-2-methyl-2-phenyl-5-hydroxy-1-indanone (XII). Finally, (XII) is treated first with ethyl bromoacetate (G) and K2CO3 in DMF, and then with KOH in hot water-methanol. The phenol (XII) can also be treated with chloroacetonitrile (H) and K2CO3 in acetone to give 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxyacetonitrile (XIII), which is finally hydrolyzed with H2SO4 in acetic acid. The phenol (XII) can also be condensed with diethyl bromomalonate (F) by means of NaH in dimethoxyethane giving diethyl 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonate (XIV), which is hydrolyzed with Na2CO3 in refluxing ethanol yielding 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonic acid (XV). Finally, this acid is decarboxylated by heating at 150 C.
| 【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (H) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (D) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (G) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (F) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (E) | 40097 | diphenyliodonium chloride | 1483-72-3 | C12H10ClI | 详情 | 详情 |
| (I) | 40081 | 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether | 1984-59-4 | C7H6Cl2O | 详情 | 详情 |
| (VII) | 40088 | 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone | C11H12Cl2O2 | 详情 | 详情 | |
| (VIII) | 40089 | 2-bromo-1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone | C11H11BrCl2O2 | 详情 | 详情 | |
| (IX) | 40090 | 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-2-propen-1-one | C11H10Cl2O2 | 详情 | 详情 | |
| (X) | 40091 | 6,7-dichloro-5-methoxy-2-methyl-1-indanone | C11H10Cl2O2 | 详情 | 详情 | |
| (XI) | 40092 | 6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone | C17H14Cl2O2 | 详情 | 详情 | |
| (XII) | 40093 | 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone | C16H12Cl2O2 | 详情 | 详情 | |
| (XIII) | 40094 | 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetonitrile | C18H13Cl2NO2 | 详情 | 详情 | |
| (XIV) | 40095 | diethyl 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonate | C23H22Cl2O6 | 详情 | 详情 | |
| (XV) | 40096 | 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonic acid | C19H14Cl2O6 | 详情 | 详情 |