合成路线:In a different strategy,N-Cbz-p-fluorophenylalanine (I) is activated as the mixed anhydride (II) employing isobutyl chloroformate and N-methylmorpholine.Coupling of anhydride (II) with phenylalanine methyl ester (III) leads to the dipeptide ester (IV),which is further treated with methanolic ammonia to produce amide (V).The dipeptide amide (V) is alternatively obtained by direct coupling of mixed anhydride (II) with phenylalanine amide (VI).Hydrogenolysis of the N-Cbz group of (V) in the presence of Pd/C furnishes the deprotected dipeptide (VII).
合成路线:N-Cbz-D-Alanine (VIII) is activated as the mixed anhydride (IX) and subsequently coupled to the dipeptide amide (VII),producing (X).Deprotection of the N-Cbz group of tripeptide (X) by hydrogenolysis over Pd/C yields (XI).The mixed anhydride (XIII) (prepared from N-Cbz-L-tyrosine (XII) and isobutyl chloroformate) is then coupled to tripeptide (XI),producing (XIV).Finally,removal of the N-Cbz group of (XIV) by catalytic hydrogenolysis furnishes the title compound.
参考文献标题:Process for the preparation of a tetrapeptide
文献作者:Franz閚,H.(AstraZeneca plc)
参考来源:WO 9947548
合成路线:In a different strategy,N-Cbz-p-fluorophenylalanine (I) is activated as the mixed anhydride (II) employing isobutyl chloroformate and N-methylmorpholine.Coupling of anhydride (II) with phenylalanine methyl ester (III) leads to the dipeptide ester (IV),which is further treated with methanolic ammonia to produce amide (V).The dipeptide amide (V) is alternatively obtained by direct coupling of mixed anhydride (II) with phenylalanine amide (VI).Hydrogenolysis of the N-Cbz group of (V) in the presence of Pd/C furnishes the deprotected dipeptide (VII).
合成路线:In an alternative procedure,N-Cbz-L-tyrosine (I) is condensed with D-alanine methyl ester (II),either employing TBTU as the coupling reagent or via previous activation as the mixed anhydride with isobutyl chloroformate,to produce dipeptide (III).After alkaline hydrolysis of the methyl ester function of (III),the resultant carboxylic acid (IV) is coupled to dipeptide amide (V) yielding the protected tetrapeptide (VI).Finally,deprotection of (VI) is carried out by catalytic hydrogenolysis over Pd/C.
参考文献标题:A process for the preparation of H-Tyr-D-Ala-Phe(F)-Phe-NH2
文献作者:Nilsson,M.; Ellburg,M.; Franz鑞,H.(AstraZeneca AB)
参考来源:EP 1212350; JP 2003509437; WO 0119849
合成路线:In a different strategy,N-Cbz-p-fluorophenylalanine (I) is activated as the mixed anhydride (II) employing isobutyl chloroformate and N-methylmorpholine.Coupling of anhydride (II) with phenylalanine methyl ester (III) leads to the dipeptide ester (IV),which is further treated with methanolic ammonia to produce amide (V).The dipeptide amide (V) is alternatively obtained by direct coupling of mixed anhydride (II) with phenylalanine amide (VI).Hydrogenolysis of the N-Cbz group of (V) in the presence of Pd/C furnishes the deprotected dipeptide (VII).
合成路线:In an alternative procedure,N-Cbz-L-tyrosine (I) is condensed with D-alanine methyl ester (II),either employing TBTU as the coupling reagent or via previous activation as the mixed anhydride with isobutyl chloroformate,to produce dipeptide (III).After alkaline hydrolysis of the methyl ester function of (III),the resultant carboxylic acid (IV) is coupled to dipeptide amide (V) yielding the protected tetrapeptide (VI).Finally,deprotection of (VI) is carried out by catalytic hydrogenolysis over Pd/C.
参考文献标题:Frakefamide,an analgesic tetrapeptide: Development of a pilot-plant-scale process
文献作者:Franz閚,H.M.; Bessidskaia,G.; Abedi,V.; Nilsson,A.; Nilsson,M.; Olsson,L.
参考来源:Org Process Res Dev 2002,6(6),788
产品链接: CAS No. 188196-22-7››