|
【结 构 式】 
|
【药物名称】Exisulind, Aposulind, Sulindac sulfone, FGN-1, Aptosyn, FGN-1, Prevatac(former Brand Name) 【化学名称】(Z)-5-Fluoro-2-methyl-1-[4-(methylsulfonyl)benzylidene]-1H-indene-3-acetic acid 【CA登记号】59973-80-7 【 分 子 式 】C20H17FO4S 【 分 子 量 】372.41849 |
【开发单位】OSI (Originator), Innovex (Licensee), Paladin (Licensee) 【药理作用】Adenomatous Polyposis Therapy, Breast Cancer Therapy, Chemopreventive Agents, Colorectal Cancer Therapy, Esophageal Diseases, Treatment of, GASTROINTESTINAL DRUGS, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Prostate Cancer Therapy, Apoptosis Inducers, Phosphodiesterase Inhibitors |
合成路线1
Condensation of p-fluorobenzaldehyde (I) with propionic anhydride (II) by means of sodium propionate at 140 C affords p-fluoro-alpha-methylcinnamic acid (III), which is then hydrogenated over Pd/C in EtOH to provide p-fluoro-alpha-methylhydrocinnamic acid (IV). Derivative (IV) is subjected to cyclization by treatment with polyphosphoric acid (PPA) to give 6-fluoro-2-methylindanone (V), which is converted into 5-fluoro-2-methylindenyl-3-acetic acid (VII) by first condensation with cyanoacetic acid (VI) by means of acetic acid and ammonium acetate in refluxing toluene, followed by hydrolysis with KOH in hot ethanol. Condensation of derivative (VII) with p-methylthiobenzaldehyde (VIII) by means of sodium methoxide in hot MeOH affords 5-fluoro-2-methyl-1-[p-(methylsulfanyl)benzylidene]-3-indenyl acetic acid (IX), which is then oxidized in MeOH/acetone by means of an aqueous solution of sodium periodate to yield methylsulfinylbenzylidene derivative (X). Finally, the target product is obtained by further oxidation of (X) with H2O2 in the presence of sodium methoxide and sodium bicarbonate in MeOH/acetonitrile at -10 C.
| 【1】 Mayle, M.J.; Menander, K.B. (Cell Pathways, Inc.); A method for treating patients with acne by administering a cyclic GMP PDE inhibitor. WO 0044372 . |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (III) | 48870 | (Z)-3-(4-fluorophenyl)-2-methyl-2-propenoic acid | C10H9FO2 | 详情 | 详情 | |
| (IV) | 48871 | 3-(4-fluorophenyl)-2-methylpropionic acid | C10H11FO2 | 详情 | 详情 | |
| (V) | 48872 | 6-Fluoro-2-methylindanone | C10H9FO | 详情 | 详情 | |
| (VI) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (VII) | 48874 | 2-(5-fluoro-2-methyl-1H-inden-3-yl)acetic acid | C12H11FO2 | 详情 | 详情 | |
| (VIII) | 18815 | 4-(methylsulfanyl)benzaldehyde; 4-(methylmercapto)benzaldehyde | 3446-89-7 | C8H8OS | 详情 | 详情 |
| (IX) | 51940 | 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfanyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid | C20H17FO2S | 详情 | 详情 | |
| (X) | 51941 | 2-(5-fluoro-2-methyl-1-[(E)-[4-(methylsulfinyl)phenyl]methylidene]-1H-inden-3-yl)acetic acid | C20H17FO3S | 详情 | 详情 |