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【结 构 式】 
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【药物名称】Tenoxicam, Ro-120068, Liman, Tilcotil 【化学名称】4-Hydroxy-2-methyl-N-(2-pyridyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide 1,1-dioxide 【CA登记号】59804-37-4 【 分 子 式 】C13H11N3O4S2 【 分 子 量 】337.37832 |
【开发单位】Kali-Chemie (Originator), Roche (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Non-Steroidal Antiinflammatory Drugs |
合成路线1
The reaction of methyl 3-hydroxythiophene-2-carboxylate (I) with PCl5 in refluxing CCl4 gives 3-chlorothiophene-2-carboxylic acid (II), which by treatment with NaHSO3 and Cu in basic water at 143 C in a pressure vessel is converted into 3-sulfothiophene-2-carboxylic acid (III). The esterification of (III) with refluxing methanol affords methyl 3-sulfothiophene-2-carboxylate (IV), which by reaction with refluxing SOCl2 yields methyl-3-chlorosulfonylthiophene-2-carboxylate (V). The condensation of (V) with sarcosine ethyl ester (VI) in hot CHCl3 gives methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate (VII), which is cyclized by treatment with sodium methoxide in refluxing methanol affording 3-ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide (VIII). Finally, this compound is condensed with 2-aminopyridine (IX) in refluxing toluene.
| 【1】 Horomatka, O.; Binder, D.; Pfister, R.; Zeller, P. (F. Hoffmann-La Roche AG); Thienothaiazine derivatives. DE 2537070; FR 2303803; JP 51048694; NL 7510057 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Tenoxicam. Drugs Fut 1982, 7, 7, 493. |
| 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) | 32134 | Methyl 3-hydroxy-2-thiophenecarboxylate | C6H6O3S | 详情 | 详情 | |
| (II) | 32135 | 3-Chloro-2-thiophenecarboxylic acid | 59337-89-2 | C5H3ClO2S | 详情 | 详情 |
| (III) | 32136 | 3-Sulfothiophene-2-carboxylic acid; 3-Sulfo-2-thiophenecarboxylic acid | C5H4O5S2 | 详情 | 详情 | |
| (IV) | 32137 | Methyl 3-sulfothiophene-2-carboxylate; 2-(Methoxycarbonyl)-3-thiophenesulfonic acid | C6H6O5S2 | 详情 | 详情 | |
| (V) | 17836 | Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate | C6H5ClO4S2 | 详情 | 详情 | |
| (VI) | 32138 | Sarcosine ethyl ester; Ethyl 2-(methylamino)acetate | 52605-49-9 | C5H11NO2 | 详情 | 详情 |
| (VII) | 32139 | Methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate; Methyl 3-[[(2-ethoxy-2-oxoethyl)(methyl)amino]sulfonyl]-2-thiophenecarboxylate | C11H15NO6S2 | 详情 | 详情 | |
| (VIII) | 32140 | Ethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-thieno[2,3-e][1,2]thiazine-3-carboxylate; 3-Ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide | C10H11NO5S2 | 详情 | 详情 | |
| (IX) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |