NK-611

3-羟基-4H-吡喃-4-酮 3-羟甲基-1,2,3,4-四氢异喹啉 Chemical Name: 4-O-[2-Deoxy-2-(dimethylamino)-4:6-O-ethylidene-beta-D-glucopyranosyl]-4'-O-demethyl-1-epipodophyllotoxin; [5R-[5alpha,5abeta,8aalpha,9beta(R*)]]-9-[[2-Deoxy-2-(dimethylamino)-4,6-O-ethylidene-beta-D-glucopyranosyl]oxy]-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d]-1,3-dioxol-6(5aH)-one; 2''-Deoxy-2''-(dimethylamino)etoposide
CAS No. 105655-99-0, 105760-98-3 (HCl)
项目整合开发状态: Phase II
项目研究机构: Nippon Kayaku (Originator), Asta Medica (Licensee)
合成路线:The partial demethylation of (?-podophyllotoxin (I) with HBr in ether - dichloromethane,followed by alkaline hydrolysis with BaCO3 in aqueous acetone,gives (?-4'-O-demethyl-1-epipodophyllotoxin (II),which is partially esterified with chloroacetyl chloride and pyridine,yielding (?-4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (III).The glycosidation of (III) with 2-(benzyloxocarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (IV) by means of BF3 ethearate in dichloromethane affords (?-1-O-[2-(benzyloxycarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl]-4'-O-(chloroacetyl)-4'-O-demethyl-1-epipodophyllotoxin (?-(V) which,after separation of the diastereomers and elimination of the protecting groups with zinc acetate in refluxing methanol and H2 over Pd/C in ethyl acetate - ethanol,gives 1-O-(2-amino-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (VI).Finally,this compound is methylated with formaldehyde and sodium cyanoborohydride in methanol.The sugar moiety has been obtained as follows: The reaction of 2-(benzyloxycarbonylamino)-2-deoxy-beta-D-glucopyranose (VII) with acetaldehyde and concentrated H2SO4 gives 2-(benzyloxycarbonylamino)-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (VIII),which is then esterified with chloroacetyl chloride to (IV).
📌 参考资料/链接:
参考文献标题:4'-Demethyl-4-epipodophyllotoxin derivs.,a process for their preparation and their use as medicaments
文献作者:Umezawa,H.; Takeuchi,T.; Kondo,S.; Tanaka,W.; Takita,T.; Nishimura,Y.; Yoshikawa,H.(Microbial Chemistry Research Foundation)
参考来源:EP 0196618; ES 8706713; JP 1986227590; US 4716221

📄 详细内容


合成路线:The partial demethylation of (?-podophyllotoxin (I) with HBr in ether - dichloromethane,followed by alkaline hydrolysis with BaCO3 in aqueous acetone,gives (?-4'-O-demethyl-1-epipodophyllotoxin (II),which is partially esterified with chloroacetyl chloride and pyridine,yielding (?-4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (III).The glycosidation of (III) with 2-(benzyloxocarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (IV) by means of BF3 ethearate in dichloromethane affords (?-1-O-[2-(benzyloxycarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl]-4'-O-(chloroacetyl)-4'-O-demethyl-1-epipodophyllotoxin (?-(V) which,after separation of the diastereomers and elimination of the protecting groups with zinc acetate in refluxing methanol and H2 over Pd/C in ethyl acetate - ethanol,gives 1-O-(2-amino-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (VI).Finally,this compound is methylated with formaldehyde and sodium cyanoborohydride in methanol.The sugar moiety has been obtained as follows: The reaction of 2-(benzyloxycarbonylamino)-2-deoxy-beta-D-glucopyranose (VII) with acetaldehyde and concentrated H2SO4 gives 2-(benzyloxycarbonylamino)-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (VIII),which is then esterified with chloroacetyl chloride to (IV).

参考文献标题:Studies on lignan lactone antitumor agents.II.Synthesis of N-alkylamino- and 2,6-dideoxy-2-aminoglycosidic lignan variants related to podophyllotoxin
文献作者:Saito,H.; Yoshikawa,H.; Nishimura,Y.; Kondo,S.; Takeuchi,T.; Umezawa,H.
参考来源:Chem Pharm Bull 1986,34(9),3741-46


合成路线:The partial demethylation of (?-podophyllotoxin (I) with HBr in ether - dichloromethane,followed by alkaline hydrolysis with BaCO3 in aqueous acetone,gives (?-4'-O-demethyl-1-epipodophyllotoxin (II),which is partially esterified with chloroacetyl chloride and pyridine,yielding (?-4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (III).The glycosidation of (III) with 2-(benzyloxocarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (IV) by means of BF3 ethearate in dichloromethane affords (?-1-O-[2-(benzyloxycarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl]-4'-O-(chloroacetyl)-4'-O-demethyl-1-epipodophyllotoxin (?-(V) which,after separation of the diastereomers and elimination of the protecting groups with zinc acetate in refluxing methanol and H2 over Pd/C in ethyl acetate - ethanol,gives 1-O-(2-amino-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (VI).Finally,this compound is methylated with formaldehyde and sodium cyanoborohydride in methanol.The sugar moiety has been obtained as follows: The reaction of 2-(benzyloxycarbonylamino)-2-deoxy-beta-D-glucopyranose (VII) with acetaldehyde and concentrated H2SO4 gives 2-(benzyloxycarbonylamino)-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (VIII),which is then esterified with chloroacetyl chloride to (IV).

参考文献标题:Syntheses of all four possible diastereomers of etoposide and its aminoglycosidic analogues via optical resolution of (?-podophyllotoxin by glucosidation with D- and L-sugars
文献作者:Saito,H.; Nishimura,Y.; Kondo,S.; Umezawa,H.
参考来源:Chem Lett 1987,5(5),799-802


合成路线:The partial demethylation of (?-podophyllotoxin (I) with HBr in ether - dichloromethane,followed by alkaline hydrolysis with BaCO3 in aqueous acetone,gives (?-4'-O-demethyl-1-epipodophyllotoxin (II),which is partially esterified with chloroacetyl chloride and pyridine,yielding (?-4'-O-chloroacetyl-4'-O-demethyl-1-epipodophyllotoxin (III).The glycosidation of (III) with 2-(benzyloxocarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (IV) by means of BF3 ethearate in dichloromethane affords (?-1-O-[2-(benzyloxycarbonylamino)-3-O-chloroacetyl-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl]-4'-O-(chloroacetyl)-4'-O-demethyl-1-epipodophyllotoxin (?-(V) which,after separation of the diastereomers and elimination of the protecting groups with zinc acetate in refluxing methanol and H2 over Pd/C in ethyl acetate - ethanol,gives 1-O-(2-amino-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranosyl)-4'-O-demethyl-1-epipodophyllotoxin (VI).Finally,this compound is methylated with formaldehyde and sodium cyanoborohydride in methanol.The sugar moiety has been obtained as follows: The reaction of 2-(benzyloxycarbonylamino)-2-deoxy-beta-D-glucopyranose (VII) with acetaldehyde and concentrated H2SO4 gives 2-(benzyloxycarbonylamino)-2-deoxy-4,6-O-ethylidene-beta-D-glucopyranose (VIII),which is then esterified with chloroacetyl chloride to (IV).
参考文献标题:NK-611
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1991,16(2),113


产品链接: CAS No. 105655-99-0››

产品链接: CAS No.105760-98-3››