Synthesis Of Sitaxsentan And Its Intermediates

Sitaxsentan is a novel drug developed by Encysive Corporation for the treatment of Pulmonary Hypertension (PAH), which is one of the most efficient and selective endothelin A (ET_A) receptor antagonists.According to the literature, a total synthesis route was proposed . Firstly, acetonitrile was demonized to give 3-amino-2-butenenitrile. The butenenitrile above reacted with hydroxylamine hydrochloride to give 5- amino -3- methyl-5-isoxazole which chloridized with N-chlorosuccinimide to give 5- amino 4-chloro-3-methyl -5-isoxazole. 5- amino-4-chloro-3-methyl-5-isoxazole reacted with 2-(methoxycarbo nyl)-thiopene-3-sulfonyl chloride to give 3-[[(4-chloro-3-methyl-5- isoxazolyl) amino]sulfonyl]-2-Thiophenecarboxylic acid . 4-methyl-catechol another material reacted with CH₂Cl₂ to give 3,4-(Methylenedioxy)-toluene which was chloromethylated to give 3,4-(Methylenedioxy)-6-methylbenzyl chloride. A Weinreb ketone synthesis reaction was carried out with the acid and benzyl chloride above to get Sitaxsentan which treated with saturated NaHC03 solution to give Sitaxsentan sodium.The effects of various factors were investigated. We have got the optimum conditions of the reactions. Dimerization of acetonitrile: the reaction temperature, below 10℃; the hydrolyzation temperature 80℃; reaction time 4 h ; molar ratio of acetonitrile and sodium, 1.6:1; the yield was 89%. The cyclization: the reaction temperature was 10℃; 1.1 fold hydroxylamine hydrochloride, a small amount of phase transfer catalyst and 4 h are needed; enrichment and crystallization gave the product with the yield of 88.4%.The chloridization: 5- amino -3- methyl-5-isoxazole reacted with 1.05 fold NCS in dichloromethane for 4h, then wash with half-saturated NaHO₃ aqueous solution to remove succinimide;. Crystallization gave 5- amino 4-chloro-3-methyl-5-isoxazole and the yield was 93.0%. The product got abovereacted with 1 fold 2-(methoxycarbonyl)-thiopene-3-sulfonyl chloride for 4h with the catalyst (NaH) in anhydrous THF at 0°C, then the hydrolyzation and acidification would execute to get 3-[[(4-chloro-3-methyl-5- isoxazolyl)amino]sulfonyl] -2-Thiophenecarboxylic acid; the yield was 74.5 %4-methyl-catechol reacted with excessive dichloromethane in the NaOH aqueous solution (remove hydrogen before use) in pressure pan. The reaction was lasted for 6h at temperature 100 °C. Wet distillation gave the intermediate (>96% except solvent), and then reacted with HC1 and formaldehyde. The HC1 would be supplied successive in 8h at 0-5 °C. Another 4h was needed after the HC1 supply stopped at room temperature. A few transfer catalyst (tetrabutyl ammonium chloride) was needed in the process and the yield is 68.8%.The acid got above reacted with l,l'-carbonyldiimidazole for 0.5h, then triethyl-amine and 2 fold N,O-dimethyl-hydroamine were added. 4.5h was needed before the actraction and concentraction to give the Weinreb amide which could fullfill the next reaction demand. The Grignard reaction was initiated by dibromethane, then the Weinreb amide and benzyl chloride added at the same time for 1.5h at <5°C. Another 1.5h was neeeded when the actraction and concentraction were executed to give Sitaxsentan, then treacted with saturated NaHCO3 solution to give Sitaxsentan sodium.The yield was 52.6%. The composition and structure of product were ananlysed by NMR, which helped to confirm the corresponding character.The improved technology is moer efficient, less pollution, better yield and easy to bring into commercial process.