【结 构 式】 |
【分子编号】31241 【品名】4-[(5R,5aR,8aR,9S)-9-([(2R,4aR,6R,7R,8R,8aR)-7-[[(benzyloxy)carbonyl]amino]-8-[(2-chloroacetyl)oxy]-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl 2 【CA登记号】 |
【 分 子 式 】C41H41Cl2NO16 【 分 子 量 】874.67908 【元素组成】C 56.3% H 4.72% Cl 8.11% N 1.6% O 29.27% |
合成路线1
该中间体在本合成路线中的序号:(V)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).
【1】 Umezawa, H.; Takeuchi, T.; Kondo, S.; Tanaka, W.; Takita, T.; Nishimura, Y.; Yoshikawa, H. (Microbial Chemistry Research Foundation); 4'-Demethyl-4-epipodophyllotoxin derivs., a process for their preparation and their use as medicaments. EP 0196618; ES 8706713; JP 1986227590; US 4716221 . |
【2】 Prous, J.; Castaner, J.; NK-611. Drugs Fut 1991, 16, 2, 113. |
【3】 Saito, H.; Nishimura, Y.; Kondo, S.; Umezawa, H.; Syntheses of all four possible diastereomers of etoposide and its aminoglycosidic analogues via optical resolution of (±)-podophyllotoxin by glucosidation with D- and L-sugars. Chem Lett 1987, 5, 5, 799-802. |
【4】 Saito, H.; Yoshikawa, H.; Nishimura, Y.; Kondo, S.; Takeuchi, T.; Umezawa, H.; Studies on lignan lactone antitumor agents. II. Synthesis of N-alkylamino- and 2,6-dideoxy-2-aminoglycosidic lignan variants related to podophyllotoxin. Chem Pharm Bull 1986, 34, 9, 3741-46. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 14608 | (5R,5aR,8aR,9R)-9-hydroxy-5-(3,4,5-trimethoxyphenyl)-5,8,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(5aH)-one; Podophyllotoxin | 518-28-5 | C22H22O8 | 详情 | 详情 |
(II) | 13053 | (5R,5aR,8aR,9S)-9-Hydroxy-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 | 6559-91-7 | C21H20O8 | 详情 | 详情 |
(III) | 31239 | 4-[(5R,5aR,8aR,9S)-9-hydroxy-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl 2-chloroacetate | C23H21ClO9 | 详情 | 详情 | |
(IV) | 31240 | (2R,4aR,7R,8R,8aR)-7-[[(benzyloxy)carbonyl]amino]-6-hydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-8-yl 2-chloroacetate | C18H22ClNO8 | 详情 | 详情 | |
(V) | 31241 | 4-[(5R,5aR,8aR,9S)-9-([(2R,4aR,6R,7R,8R,8aR)-7-[[(benzyloxy)carbonyl]amino]-8-[(2-chloroacetyl)oxy]-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy)-6-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]-2,6-dimethoxyphenyl 2 | C41H41Cl2NO16 | 详情 | 详情 | |
(VI) | 31242 | (5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7-amino-8-hydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]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 | C29H33NO12 | 详情 | 详情 | |
(VII) | 31243 | benzyl (3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | 16684-31-4 | C14H19NO7 | 详情 | 详情 |
(VIII) | 31244 | benzyl (2R,4aR,7R,8R,8aS)-6,8-dihydroxy-2-methylhexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate | C16H21NO7 | 详情 | 详情 |