合成路线:1) The reaction of 3-(tert-butoxycarbonyl)thiazolidine-4(R)-carboxylic acid (I) with tert-butylamine by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding protected amide (II),which is deprotected with HCl or methanesulfonic acid to the free amide (III).The condensation of (III) with (2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid (IV) by means of 1-hydroxybenzotriazole (HOBT) and DCC in DMF affords the dipeptide (V),which by deprotection with HCl in dioxane and condensation with 2(R)-(tert-butoxycarbonylamino)-3-(methylsulfanyl)propionic acid (VI) by means of HBOT and DCC as before yields the tripeptide (VII).Finally,this compound is deprotected with HCl as before and condensed with 2-(5-isoquinolinyloxy)acetic acid (VIII) by means of HBOT and DCC or HBOT and 5-norbornene-2,3-dicarboxyimide (NDPP) in DMF.
参考文献标题:Manufacturing method for peptide derivs.and their salts
文献作者:Maeda,S.; Moriwaki,H.(Hamari Chemicals Ltd.; Japan Energy Corp.)
参考来源:JP 1994220031
合成路线:1) The reaction of 3-(tert-butoxycarbonyl)thiazolidine-4(R)-carboxylic acid (I) with tert-butylamine by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding protected amide (II),which is deprotected with HCl or methanesulfonic acid to the free amide (III).The condensation of (III) with (2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid (IV) by means of 1-hydroxybenzotriazole (HOBT) and DCC in DMF affords the dipeptide (V),which by deprotection with HCl in dioxane and condensation with 2(R)-(tert-butoxycarbonylamino)-3-(methylsulfanyl)propionic acid (VI) by means of HBOT and DCC as before yields the tripeptide (VII).Finally,this compound is deprotected with HCl as before and condensed with 2-(5-isoquinolinyloxy)acetic acid (VIII) by means of HBOT and DCC or HBOT and 5-norbornene-2,3-dicarboxyimide (NDPP) in DMF.
合成路线:2) The intermediate (V) of the preceding synthesis is submitted to a deprotection - protection sequence [hydrolysis with HCl in dioxane and protection with benzyl succinimidyl carbonate (PhCH2-OSu)] giving the benzyloxycarbonyl protected compound (IX),which is condensed with (VI) by means of DCC and dimethylaminopyridine (DMAP) to yield (X) [the ester isomer of (VII)].The deprotection of (X) with HCl and condensation with (VIII) by means of HBOT and DCC as before affords (XI) [the benzyloxycarbonyl protected prodrug of KNI-272],which is deprotected with trifluoroacetic acid (TFA)/anisole and HCl affording the ester prodrug (XII).Finally,this compound is converted into KNI-272 by incubation at 37 C in a phosphate buffered saline at pH 7.4.
参考文献标题:KNI-272
文献作者:Ireland,C.D.; Castar,J.
参考来源:Drugs Fut 1996,21(10),1022
合成路线:1) The reaction of 3-(tert-butoxycarbonyl)thiazolidine-4(R)-carboxylic acid (I) with tert-butylamine by means of dicyclohexylcarbodiimide (DCC) in THF gives the corresponding protected amide (II),which is deprotected with HCl or methanesulfonic acid to the free amide (III).The condensation of (III) with (2S,3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid (IV) by means of 1-hydroxybenzotriazole (HOBT) and DCC in DMF affords the dipeptide (V),which by deprotection with HCl in dioxane and condensation with 2(R)-(tert-butoxycarbonylamino)-3-(methylsulfanyl)propionic acid (VI) by means of HBOT and DCC as before yields the tripeptide (VII).Finally,this compound is deprotected with HCl as before and condensed with 2-(5-isoquinolinyloxy)acetic acid (VIII) by means of HBOT and DCC or HBOT and 5-norbornene-2,3-dicarboxyimide (NDPP) in DMF.
参考文献标题:Design and synthesis of HIV protease inhibitors containing allophenylorstatine as a transition-state mimic
文献作者:Kiso,Y.
参考来源:Adv Exp Med Biol 1995,362(Aspartic Proteinases)(Aspartic Proteinases),413-23
合成路线:2) The intermediate (V) of the preceding synthesis is submitted to a deprotection - protection sequence [hydrolysis with HCl in dioxane and protection with benzyl succinimidyl carbonate (PhCH2-OSu)] giving the benzyloxycarbonyl protected compound (IX),which is condensed with (VI) by means of DCC and dimethylaminopyridine (DMAP) to yield (X) [the ester isomer of (VII)].The deprotection of (X) with HCl and condensation with (VIII) by means of HBOT and DCC as before affords (XI) [the benzyloxycarbonyl protected prodrug of KNI-272],which is deprotected with trifluoroacetic acid (TFA)/anisole and HCl affording the ester prodrug (XII).Finally,this compound is converted into KNI-272 by incubation at 37 C in a phosphate buffered saline at pH 7.4.
参考文献标题:Synthesis and prodrugs of HIV protease inhibitors
文献作者:Kimura,T.; Ohtake,J.; Nakata,S.; Enomoto,H.; Moriwaki,H.; Akaji,K.; Kiso,Y.
参考来源:Peptide Chem 1994,157-60
产品链接: CAS No. 147318-81-8››