合成路线:Reaction of 4-cyano-pyridine (I) with Na in methanol followed by treatment with ammonium chloride provides 4-amidino-pyridine hydrochloride (II),which is then converted into 5-(2-methoxyphenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (IV) by condensation with diethyl malonate derivative (III) by means of Na in MeOH.By heating compound (IV) with phosphorus oxychloride (POCl3),4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine (V) is obtained,which in turn is oxidized with peracetic acid in refluxing acetonitrile to afford N-oxide derivative (VI).Condensation of (VI) with 5-isopropylpyridine-2-sulfonamide potassium (VII) furnishes 5-isopropylpyridine-2-sulfonic acid 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide (VIII),which is then dissolved in dimethoxyethane and subjected to reaction with Na in hot ethylene glycol (IX) to provide N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-5-isopropylpyridine-2-sulfonamide (X).Refluxing of (X) with trimethylsilylcyanide and Et3N in acetonitrile yields cyano derivative (XI),which is then converted into the tetrazole derivative (XII) by reaction with sodium azide and NH4Cl in DMF at 70 C.Finally,the disodium salt of tezosentan is obtained by treatment of (XII) with Na/MeOH in THF.
合成路线:Reaction of 2-chloro-5-ispropylpyridine (VII) with thiourea (A) in aqueous HCl gives 5-isopropyl- pyridine-2-thiol (VIII),which is chlorinated with chlorine in acetic acid to yield 5-isopropylpyridine-2-sulfochloride (IX).This compound is converted into 5-isopropylpyridine-2-sulfonamide potassium salt (X).
参考文献标题:Process for the preparation of 2,5-disubstd.pyridines
文献作者:Spurr,P.(F.Hoffmann-La Roche AG)
参考来源:EP 0897914
合成路线:Reaction of 4-cyano-pyridine (I) with Na in methanol followed by treatment with ammonium chloride provides 4-amidino-pyridine hydrochloride (II),which is then converted into 5-(2-methoxyphenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (IV) by condensation with diethyl malonate derivative (III) by means of Na in MeOH.By heating compound (IV) with phosphorus oxychloride (POCl3),4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)pyrimidine (V) is obtained,which in turn is oxidized with peracetic acid in refluxing acetonitrile to afford N-oxide derivative (VI).Condensation of (VI) with 5-isopropylpyridine-2-sulfonamide potassium (VII) furnishes 5-isopropylpyridine-2-sulfonic acid 6-chloro-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl amide (VIII),which is then dissolved in dimethoxyethane and subjected to reaction with Na in hot ethylene glycol (IX) to provide N-[6-(2-hydroxyethoxy)-5-(2-methoxyphenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-5-isopropylpyridine-2-sulfonamide (X).Refluxing of (X) with trimethylsilylcyanide and Et3N in acetonitrile yields cyano derivative (XI),which is then converted into the tetrazole derivative (XII) by reaction with sodium azide and NH4Cl in DMF at 70 C.Finally,the disodium salt of tezosentan is obtained by treatment of (XII) with Na/MeOH in THF.
参考文献标题:Tezosentan Disodium
文献作者:Chilman-Blair,K.; Castar,J.; Leeson,P.A.; Bay閟,M.
参考来源:Drugs Fut 2003,28(8),754
产品链接: CAS No. 180384-58-1›› 产品链接: CAS No.180384-57-0››