Suproclone(Rec INN, USAN), 37162-RP, RP-37162

舒普罗酮Chemical Name: 4-(1-Oxopropyl)-1-piperazinecarboxylic acid (?-6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7-oxo-5H-1,4-dithiino[2,3-c]pyrrol-5-yl ester; 4-Propionyl-1-piperazinecarboxylic acid,ester with (?-6-(7-chloro-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-7-hydroxy-5H-p-dithiino[2,3-c]pyrrol-5-one; 6-(7-Chloro-1,8-naphthyridin-2-yl)-5-[(4-propionylpiperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrol-7-one
CAS No. 77590-92-2
项目整合开发状态: Biological Testing
项目研究机构: Aventis Pharma (Originator)
合成路线:The condensation of 2-amino-7-hydroxy-1,8-naphthyridine (I) with 5,6-dihydro-1,7-dithiin-2,3-dicarboxylic acid anhydride (II) in biphenyl-diphenyl ether at 230 C gives 5,7-dioxo-8-(7-hydroxy-1,8-naphthyridin-2-yl)-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (III),which by reaction with POCl3 at 100 C is converted to the corresponding 7-chloro derivative (IV).Partial reduction of (IV) with KBH4 in methanol yields 6-(7-chloro-1,8-naphthyridin 2-yl)-5-hydroxy-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (V),which is condensed with 4-chlorocarbonyl-1-(tert-butoxycarbonyl)piperazin (VI) by means of NaH in DMF affording 5-[(4-tert-butoxycarbonylpiperazin-1-yl)carbonyloxy]-6-(7-chloro-1,8-naphthyndin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (VII) Deprotection of (VII) by means of trifluoroacetic acid gives 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-[(piperazin-1-yl)carbonyloxy]-2,3,6,7-tetrahydro-5H-1,4-dithino[2,3-c]pyrrole (VIII),which is finally acetylated with propionic acid (IX) by means of dicyclohexylcarbodiimide in methylene chloride.The piperazine derivative (VI) is prepared as follows: The condensation of piperazine (X) with tert-butyl azidoformate (XI) in aqueous HCl gives 1-(tert-butoxycarbonyl)piperazine (XII),which is then condensed with phosgene in anhydrous toluene.

合成路线:Condensation of 7-hydroxy-1,8-naphthyridin-2-amine (I) with phthalic anhydride (II) in refluxing acetic acid gives N-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide (III),which is treated with refluxing POCl3 to yield the 7-chloro derivative (IV).Reduction of compound (IV) with KBH4 in dioxane affords 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (V),which is condensed with 5-methyl-2-hexanone (VI) by means of NaH in DMF to give (?-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxohexyl)isoindolin-1-one (VII) (racemic pagoclone).The treatment of (VII) with NaOH in dioxane/water yields the racemic benzoic acid (VIII).Optical resolution of racemic (VIII) by means of (+)-ephedrine or cinchonine affords the (+)-isomer (IX),which is finally cyclized to the chiral (+)-indolinone derivative pagoclone by means of SOCl2 and imidazole in dichloromethane.