RX-77368

L-焦谷氨酰-L-组氨酰-3,3-二甲基脯氨酰胺Chemical Name: L-Pyroglutamyl-L-Histidyl-L-3,3-dimethylprolinamide; 5-Oxo-L-prolyl-L-histidyl-3,3-dimethyl-L-prolinamide
CAS No. 76820-40-1
项目整合开发状态: Phase III
项目研究机构: Reckitt & Colman (Originator)
合成路线:The cyclization of diethyl benzyloxycarbonylaminomalonate (I) with 3-methyl-2-butenal (II) by means of sodium ethoxide in ethanol,followed by hydrogenation with H2 over Pd/C in acetic acid gives 2,2-dicarbethoxy-3,3-dimethylpyrrolidine (III),which by a decarboxylative hydrolysis with refluxing aqueous 5M HCl is converted into 3,3-dimethylproline (IV).The protection of the amino group of (IV) with tert-butyl-2,4,5-trichlorophenyl carbonate (V) in hot tert-butanol - water yields N-tert-butoxycarbonyl-3,3-dimethylproline (VI),which by reaction with NH3 by means of isobutyl chloroformate and N-methylmorpholine in THF is converted into N-tert-butoxycarbonyl-3,3-dimethylprolinamide (VII).The deprotection of (VII) with HCl in dioxane affords 3,3-dimethylprolinamide (VIII),which is finally condensed with benzyloxycarbonyl-L-pyroglutamylhistidine (IX) by means of 1-hydroxybenzotriazole (HBT) and dicyclohexylcarbodiimide (DCCD) in THF,and deprotected by hydrogenation with H2 over Pd/C in THF - water.