合成路线:Total synthesis: Reaction of ethyl acetopyruvate (I) with triethyl orthoformate gives compound (II),which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1H)-pyridone (III).The reaction of (III) with methyl acrylate (A) gives compound (IV),which is sequentially submitted to decarboxylation,ketalization and treatment with diethylcarbonate,giving the functionalized tetrahydroindolizine (V).Ethylation of (V) followed by reduction in the presence of acetic anhydride gives the amide (VI),which is reacted with sodium nitrite,refluxed in CCl4,hydrolyzed and acidified to give the tricyclic compound (VII).The DIBAL reduction of (VII) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (VIII).Asymmetric dihydroxylation of compound (VIII) with (DHQD)2PHAL,K2OsO4 and K3Fe(CN)6 in t-BuOH gives the diol (IX).The oxidation and deketalization of compound (IX) gives (S)-hydroxylactone (X).Finally,Friedlander condensation of the lactone (X) with 3-[N-isopropyl-N-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (B) followed by deprotection gives CKD-602.
合成路线:Semisynthesis: Treatment of camptothecin (XI) with tert-butylhydroperoxide in the presence of FeSO4,conc.H2SO4 and acetic acid in water gives (S)-7-methylcamptothecin (XII).Mannich reaction of compound (XII) with isopropylamine hydrochloride in DMSO as a formaldehyde source gives CKD-602.
参考文献标题:CKD-602
文献作者:Hong,C.I.; Kim,J.K.; Ahn,S.K.
参考来源:Drugs Fut 2000,25(12),1243
合成路线:Total synthesis: Reaction of ethyl acetopyruvate (I) with triethyl orthoformate gives compound (II),which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1H)-pyridone (III).The reaction of (III) with methyl acrylate (A) gives compound (IV),which is sequentially submitted to decarboxylation,ketalization and treatment with diethylcarbonate,giving the functionalized tetrahydroindolizine (V).Ethylation of (V) followed by reduction in the presence of acetic anhydride gives the amide (VI),which is reacted with sodium nitrite,refluxed in CCl4,hydrolyzed and acidified to give the tricyclic compound (VII).The DIBAL reduction of (VII) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (VIII).Asymmetric dihydroxylation of compound (VIII) with (DHQD)2PHAL,K2OsO4 and K3Fe(CN)6 in t-BuOH gives the diol (IX).The oxidation and deketalization of compound (IX) gives (S)-hydroxylactone (X).Finally,Friedlander condensation of the lactone (X) with 3-[N-isopropyl-N-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (B) followed by deprotection gives CKD-602.
参考文献标题:Synthesis and antitumor activity of 7-substituted 20(RS)-camptothecin analogues
文献作者:Jew,S.-S.; Kim,H.-J.; Kim,M.G.; et al.
参考来源:Bioorg Med Chem Lett 1996,6(7),845
合成路线:Total synthesis: Reaction of ethyl acetopyruvate (I) with triethyl orthoformate gives compound (II),which is then treated with cyanoacetamide to yield 3-cyano-4-methyl-6-(carbethoxy)-2(1H)-pyridone (III).The reaction of (III) with methyl acrylate (A) gives compound (IV),which is sequentially submitted to decarboxylation,ketalization and treatment with diethylcarbonate,giving the functionalized tetrahydroindolizine (V).Ethylation of (V) followed by reduction in the presence of acetic anhydride gives the amide (VI),which is reacted with sodium nitrite,refluxed in CCl4,hydrolyzed and acidified to give the tricyclic compound (VII).The DIBAL reduction of (VII) and subsequent elimination of the hydroxyl group gives the cyclic enol ether (VIII).Asymmetric dihydroxylation of compound (VIII) with (DHQD)2PHAL,K2OsO4 and K3Fe(CN)6 in t-BuOH gives the diol (IX).The oxidation and deketalization of compound (IX) gives (S)-hydroxylactone (X).Finally,Friedlander condensation of the lactone (X) with 3-[N-isopropyl-N-(carbobenzyloxy)amino]-1-(2-aminophenyl)propan-1-one (B) followed by deprotection gives CKD-602.
参考文献标题:Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation
文献作者:Kim,J.M.; Jew,S.; Kim,M.G.; Kim,H.-J.; Hah,J.M.; Ok,K.; Cho,Y.
参考来源:Tetrahedron Asymmetry 1995,6(6),1245
合成路线:Semisynthesis: Treatment of camptothecin (XI) with tert-butylhydroperoxide in the presence of FeSO4,conc.H2SO4 and acetic acid in water gives (S)-7-methylcamptothecin (XII).Mannich reaction of compound (XII) with isopropylamine hydrochloride in DMSO as a formaldehyde source gives CKD-602.
参考文献标题:Practical synthesis of (S)-7-(2-isopropylamino)ethylcamptothecin hydrochloride,potent topoisomerase I inhibitor
文献作者:Kim,K.K.; Kim,J.W.; Journ,D.J.; Jeong,B.S.; Choi,N.S.; Hong,C.I.; Ahn,S.K.; Kim,J.K.; Lee,S.J.; Jew,S.-S.
参考来源:J Heterocycl Chem 2000,371141
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