【药物名称】Belotecan hydrochloride, CKD-602, Camtobell
化学结构式(Chemical Structure):
参考文献No.170378
标题:Chemical modification of an antitumor alkaloid camptothecin: Synthesis and antitumor activity of 7-C-substituted camptothecins
作者:Sawada, S.; Nokata, K.; Furuta, T.; Yokokura, T.; Miyasaka, T.
来源:Chem Pharm Bull 1991,39(10),2574
合成路线图解说明:

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.

合成路线图解说明:

Radical hydroxymethylation of camptothecin (I) by means of MeOH in the presence of H2O2 and FeSO4 provided (II). Subsequent heating of alcohol (II) in acetic acid gave rise to 7-formylcamptothecine (III). Finally, condensation of aldehyde (III) with O-t-butylhydroxylamine afforded the corresponding oxime.

参考文献No.603114
标题:CKD-602
作者:Hong, C.I.; Kim, J.K.; Ahn, S.K.
来源:Drugs Fut 2000,25(12),1243
合成路线图解说明:

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.

合成路线图解说明:

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No.603374
标题:Synthesis and antitumor activity of 7-substituted 20(RS)-camptothecin analogues
作者:Jew, S.-S.; Kim, H.-J.; Kim, M.G.; et al.
来源:Bioorg Med Chem Lett 1996,6(7),845
合成路线图解说明:

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No.603377
标题:Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation
作者:Kim, J.M.; Jew, S.; Kim, M.G.; Kim, H.-J.; Hah, J.M.; Ok, K.; Cho, Y.
来源:Tetrahedron Asymmetry 1995,6(6),1245
合成路线图解说明:

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No.604518
标题:Practical synthesis of (S)-7-(2-isopropylamino)ethylcamptothecin hydrochloride, potent topoisomerase I inhibitor
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.
来源:J Heterocycl Chem 2000,371141
合成路线图解说明:

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.

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