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【结 构 式】 
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【药物名称】Tenidap sodium, CP-66248-2, Enable, Enablex 【化学名称】(Z)-5-Chloro-3-(alpha-hydroxy-2-thenylidene)-2-oxo-1-indolinecarboxamide monosodium salt 【CA登记号】119784-94-0, 120210-48-2 (free acid) 【 分 子 式 】C14H8ClN2NaO3S 【 分 子 量 】342.73826 |
【开发单位】Pfizer (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Cyclooxygenase Inhibitors, Non-Steroidal Antiinflammatory Drugs |
合成路线1
5-Chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (X), a key intermediate in the synthesis of tenidap, has been obtained by several different ways, all of them starting from 5-chloro-2,3-dihydro-1H-indol-2-one (I). 1. The reaction of indolone (I) with cyclohexylcarbonyl isocyanate (II) gives the N-acyl carboxamide (III), which is treated with KOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (IV). Finally, this compound is cyclized to the target carboxamide by treatment with trifluoroacetic anhydride and trifluoroacetic acid. 2. The reaction of indolone (I) with isobutyryl isocyanate (XI) gives the N-acyl carboxamide (V), which is treated with KOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (III). Finally, this compound is cyclized to the target carboxamide as before. 3. The reaction of indolone (I) with trichloroacetyl isocyanate (VI) in hot toluene gives the target carboxamide in one step. 4. The reaction of indolone (I) with chlorosulfonyl isocyanate (VII) gives the N-chlorosulfonyl carboxamide (VIII), which is hydrolyzed to the target carboxamide with aqueous acetic acid. 5. The reaction of indolone (I) with NaOH and then with H2SO4 gives 2-(2-amino-5-chlorophenyl)acetic acid (IX), which is treated with potassium isocyanate and AcOH to yield 2-(5-chloro-2-ureidophenyl)acetic acid (III). Finally, this compound can be cyclized to the target intermediate by means of AcOH and NaOAc.
| 【1】 Sarma, M.R.; Goud, P.S.; Sailaja, M.; Kumar, P.R.; Reddy, G.O.; Raju, S.; Synthesis of tenidap: An improved process for the preparation of 5-chloro-2-oxindole-1-carboxamide. Org Process Res Dev 2001, 5, 1, 61. |
| 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) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (II) | 47903 | cyclohexanecarbonyl isocyanate | C8H11NO2 | 详情 | 详情 | |
| (III) | 47904 | 5-chloro-N-(cyclohexylcarbonyl)-2-oxo-1-indolinecarboxamide | C16H17ClN2O3 | 详情 | 详情 | |
| (IV) | 47905 | 2-[2-[(aminocarbonyl)amino]-5-chlorophenyl]acetic acid | C9H9ClN2O3 | 详情 | 详情 | |
| (V) | 47906 | 5-chloro-N-isobutyryl-2-oxo-1-indolinecarboxamide | C13H13ClN2O3 | 详情 | 详情 | |
| (VI) | 40725 | 2,2,2-trichloroacetyl isocyanate | 3019-71-4 | C3Cl3NO2 | 详情 | 详情 |
| (VII) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (VIII) | 47907 | 5-chloro-1-[[(chlorosulfonyl)amino]carbonyl]-2-oxoindoline | C9H6Cl2N2O4S | 详情 | 详情 | |
| (IX) | 47908 | 2-(2-amino-5-chlorophenyl)acetic acid | C8H8ClNO2 | 详情 | 详情 | |
| (X) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (XI) | 47909 | 2-methylpropanoyl isocyanate | C5H7NO2 | 详情 | 详情 |
合成路线2
A new synthesis of tenidap sodium has been described: The reaction of 4,5-dibromothiophene-2-carboxylic acid (I) with hot SOCl2 gives the corresponding acyl chloride (II), which is condensed with 5-chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (III) by means of 4-(dimethylamino)pyridine (DMAP) in DMF, yielding 5-chloro-3-[(4,5-dibromothien-2-yl)hydroxymethylene]-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (IV). Finally, this compound is debrominated by hydrogenation with H2 over Pd/BaSO4 in methanol.
| 【1】 Schulte, G.R.; Ehrgott, F.J. (Pfizer Inc.); 3-Aroyl-2-oxindole-1-carboxamides. EP 0421749; JP 1991151380; US 5059693 . |
| 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) | 14094 | 4,5-Dibromo-2-thiophenecarboxylic acid; 4,5-Dibromothiophene-2-carboxylic acid | 7311-68-4 | C5H2Br2O2S | 详情 | 详情 |
| (II) | 14095 | 4,5-Dibromo-2-thiophenecarbonyl chloride | C5HBr2ClOS | 详情 | 详情 | |
| (III) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (IV) | 14097 | 5-Chloro-3-[(Z)-(4,5-dibromo-2-thienyl)(hydroxy)methylidene]-2-oxo-1H-indole-1(2H)-carboxamide | C14H7Br2ClN2O3S | 详情 | 详情 |
合成路线3
The synthesis of [14C]-labeled tenidap sodium has been reported: The chlorination of [14C]-2,3-dihydro-1H-indole-2,3-dione (I) with sulfuryl chloride and triethylamine in hot acetonitrile gives the 5-chloro derivative (II), which is partially reduced by treatment with hydrazine hydrate in refluxing ethanol, followed by a treatment with KOH in the same refluxing solvent, to yield 5-chloro-2,3-dihydro-1H-indol-2-one (III). The reaction of (III) with chlorosulfonyl isocyanate (IV) in refluxing dichloromethane affords 5-chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (V), which is condensed with 2-thienylcarbonyl chloride (VI) by means of dimethylaminopyridine (DMAP) and triethylamine (TEA) in DMF, giving tenidap (VII). Finally, this compound is treated with NaHCO3 in hot acetone.
| 【1】 Hale, K.J.; Lennon, J.A.; Hobbs, C.J.; Javaid, M.H.; Manaviazar, S.; Asymmetric synthesis of the C17-C27 segment of the antineoplasticmacrolide bryostatin 1. J Label Compd Radiopharm 1995, 36, 8, 1359. |
| 【2】 Johnson, D.L.; Melvin, L.S.; Falkner, F.C.; Rusek, F.W.; Robinson, R.P.; Synthesis of C-14 isotopic isomers of tenidap - A novel antiinflammatory agent. J Label Compd Radiopharm 1996, 38, 3, 207. |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (I) | 45196 | C8H5NO2 | 详情 | 详情 | ||
| (II) | 14099 | 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin | 17630-76-1 | C8H4ClNO2 | 详情 | 详情 |
| (II) | 45197 | C8H4ClNO2 | 详情 | 详情 | ||
| (III) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (III) | 45198 | C8H6ClNO | 详情 | 详情 | ||
| (IV) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (V) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (V) | 45199 | C9H7ClN2O2 | 详情 | 详情 | ||
| (VI) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (VII) | 14104 | 5-Chloro-3-[(Z)-hydroxy(2-thienyl)methylidene]-2-oxo-1H-indole-1(2H)-carboxamide | C14H9ClN2O3S | 详情 | 详情 | |
| (VII) | 45200 | C14H9ClN2O3S | 详情 | 详情 |
合成路线4
A new synthesis of tenidap has been developed: The reaction of 5-chloroindolin-2-one (I) with phenyl chloroformate and Et3N in THF gives 5-chloro-2-(phenoxycarbonyloxy)indole-1-carboxylic acid phenyl ester (II), which is treated with ammonium carbonate in DMF at 5 C yielding 5-chloro-2-oxoindoline-1-carboxylic acid phenyl ester (III). Compound (III) is acylated with 2-thienylcarbonyl chloride (IV) and DMAP in DMF and then acidified with conc. HCl affording 5-chloro-3-[1-hydroxy-1-(2-thienyl)methylene]-2-oxoindoline-1-carboxylic acid phenyl ester (V), which is finally treated with ammonium carbonate in DMF at 75-80 C for 5 h and acidified with conc. HCl.
| 【1】 Siming, G.; Porcs-Makkay, M.; New practical synthesis of tenidap. Org Process Res Dev 2000, 4, 1, 10. |
| 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) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (II) | 40474 | phenyl 5-chloro-2-[(phenoxycarbonyl)oxy]-1H-indole-1-carboxylate | C22H14ClNO5 | 详情 | 详情 | |
| (III) | 40475 | phenyl 5-chloro-2-oxo-1-indolinecarboxylate | C15H10ClNO3 | 详情 | 详情 | |
| (IV) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (V) | 40476 | phenyl 5-chloro-3-[(Z)-hydroxy(2-thienyl)methylidene]-2-oxo-1H-indole-1(2H)-carboxylate | C20H12ClNO4S | 详情 | 详情 |