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【结 构 式】 
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【药物名称】 【化学名称】2(R)-[4-(2,3-Dimethyl[1]benzothieno[3,2-f]benzofuran-4-yl)-2,6-diiodophenoxy]-3-phenylpropionic acid 【CA登记号】 【 分 子 式 】C31H22I2O4S 【 分 子 量 】744.39139 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Protein Tyrosine Phosphatase PTP-1B Inhibitors |
合成路线1
Oxidation of 2,3-dimethylfuran (I) under Vilsmeier conditions with POCl3 in DMF affords aldehyde (II), which is then condensed with benzothiophene (III) by means of n-BuLi in THF to provide secondary alcohol (IV). Reduction of (IV) under Nutaitis conditions with NaBH4 and TFA in THF yields methylene congener (V), which is then treated with p-anisoyl chloride (VI) under Friedel-Crafts conditions with SnCl4 in CS2 to give 1-oxa-9-thiacyclopenta[b]fluorene heterocycle (VII). Demethylation of methyl ether (VII) with BBr3 in CH2Cl2 affords phenol (VIII), which is then bis-iodinated with molecular iodine and NaOH in MeOH to yield di-iodo phenol (IX). Compound (IX) is then condensed with (S)-2-hydroxy-3-phenylpropionic acid (X) under Mitsunobu conditions with DEAD and PPh3 in benzene to furnish (R)-2-benzyl-acetic acid derivative (XI), which is finally hydrolyzed by treatment with KOH in H2O/dioxane to provide the desired product.
| 【1】 Sredy, j.; Seesteller, L.; Li, Z.; Sawicki, D.R.; Wrobel, J.; Sullivan, D.; Synthesis and PTP1B inhibition of novel 4-aryl-1-oxa-9-thiacyclopenta[b]fluorenes. Bioorg Med Chem Lett 2000, 10, 14, 1535. |
| 【2】 Li, Z.; Wrobel, J.E. (American Home Products Corp.); 4-Aryl-1-oxa-9-thia-cyclopenta[b]fluorenes. US 6057316 . |
| 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) | 48451 | 2,3-Dimethylfuran | 14920-89-9 | C6H8O | 详情 | 详情 |
| (II) | 48452 | 4,5-Dimethyl-2-furaldehyde; 4,5-Dimethylfurfural | C7H8O2 | 详情 | 详情 | |
| (III) | 25578 | 1-benzothiophene | 95-15-8 | C8H6S | 详情 | 详情 |
| (IV) | 48453 | 1-benzothiophen-2-yl(4,5-dimethyl-2-furyl)methanol | C15H14O2S | 详情 | 详情 | |
| (V) | 48454 | 5-(1-benzothiophen-2-ylmethyl)-2,3-dimethylfuran | C15H14OS | 详情 | 详情 | |
| (VI) | 22671 | 4-Methoxybenzoyl chloride; p-Methoxybenzoyl chloride; 4-Anisoyl chloride | 100-07-2 | C8H7ClO2 | 详情 | 详情 |
| (VII) | 48455 | 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)phenyl methyl ether; 4-(4-methoxyphenyl)-2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran | C23H18O2S | 详情 | 详情 | |
| (VIII) | 48456 | 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)phenol | C22H16O2S | 详情 | 详情 | |
| (IX) | 48457 | 4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)-2,6-diiodophenol | C22H14I2O2S | 详情 | 详情 | |
| (X) | 39252 | methyl (2S)-2-hydroxy-3-phenylpropanoate | C10H12O3 | 详情 | 详情 | |
| (XI) | 48458 | methyl (2R)-2-[4-(2,3-dimethyl[1]benzothieno[3,2-f][1]benzofuran-4-yl)-2,6-diiodophenoxy]-3-phenylpropanoate | C32H24I2O4S | 详情 | 详情 |