|
【结 构 式】 
|
【分子编号】13053 【品名】(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 【CA登记号】6559-91-7 |
【 分 子 式 】C21H20O8 【 分 子 量 】400.385 【元素组成】C 63% H 5.03% O 31.97% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of dibenzyl-sugar (II) with 4'-demethyl-epipodophyllotoxin (I) by means of BF3·Et2O in acetonitrile gives a mixture of the alpha and beta coupled products (IV) + (III), which by crystallization in dichloromethane/methanol afforded pure diastereomer beta (III). Finally this compound is debenzylated by hydrogenolysis with H2 over Pd/C in THF.
| 【1】 Silverberg, L.J.; et al.; A crystallization-induced steroselective glycosidation reaction in the synthesis of the anticancer drug etoposide. Org Lett 2000, 2, 21, 3281. |
| 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) | 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 |
| (II) | 13055 | (2R,4aR,6S,7R,8R,8aS)-7,8-Bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-ol | C22H26O6 | 详情 | 详情 | |
| (III) | 41886 | (5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-bis(benzyloxy)-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 | C43H44O13 | 详情 | 详情 | |
| (IV) | 41891 | (5R,5aR,8aR,9S)-9-[[(2R,4aR,6S,7R,8R,8aS)-7,8-bis(benzyloxy)-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 | C43H44O13 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)3) The reaction of podophyllotoxin (V) with diphenyl chlorophosphate by means of ethyl diisopropylamine and dimethylaminopyridine (DMAP) gives the diphenylphosphoryloxy derivative (VI), which is glycosylated with 4,6-O-ethylidene-2,3-O-bis(2,2,2-trichloroethoxycarbonyl)-beta-D-glycopyranose (VII) by means of BF3/ethyl ether, yielding the protected etoposide derivative (VIII). The cleavage of the protecting groups of the carbohydrate moiety with Zn/acetic acid affords the free etoposide phosphate diphenyl ester (IX), already obtained (compound (III) of scheme 14675903a). The reductive cleavage of (IX) as before gives the free acid (X) (compound (IV) of scheme 14675903a), which is finally treated with NaHCO3. 4) The preceding reaction pathway carried out with dibenzyl chlorophosphate instead of diphenyl chlorophosphate yields compounds (XI), (XII), and finally (XIII), which by hydrogenolysis with H2 over Pd/C affords the free acid (X), already obtained.
| 【1】 Saulnier, M.G.; Tun, M.M.; Langley, D.R.; Knipe, J.O.; Doyle, T.W.; Senter, P.D.; Kadow, J.F.; Vyas, D.M.; Synthesis of etoposide phosphate, BMY-40481: A water-soluble clinically active prodrug of etoposide. Bioorg Med Chem Lett 1994, 4, 21, 2567. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 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 |
| (VI) | 13045 | 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 diphenyl phosphate | C33H29O11P | 详情 | 详情 | |
| (VII) | 13046 | (2R,4aR,6R,7R,8S,8aR)-6-hydroxy-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate | C14H16Cl6O10 | 详情 | 详情 | |
| (VIII) | 13047 | (2R,4aR,6R,7R,8S,8aR)-6-[((5S,5aR,8aR,9R)-9-[4-[(diphenoxyphosphoryl)oxy]-3,5-dimethoxyphenyl]-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)oxy]-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate | C47H43Cl6O20P | 详情 | 详情 | |
| (IX) | 13043 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-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 diphenyl phosphate | C41H41O16P | 详情 | 详情 | |
| (X) | 13044 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-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 dihydrogen phosphate | C29H33O16P | 详情 | 详情 | |
| (XI) | 13050 | 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 dibenzyl phosphate | C35H33O11P | 详情 | 详情 | |
| (XII) | 13051 | (2R,4aR,6R,7R,8S,8aR)-6-[[(5S,5aR,8aR,9R)-9-(4-[[bis(benzyloxy)phosphoryl]oxy]-3,5-dimethoxyphenyl)-8-oxo-5,5a,6,8,8a,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl]oxy]-2-methyl-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl 2,2,2-trichloroethyl carbonate | C49H47Cl6O20P | 详情 | 详情 | |
| (XIII) | 13052 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-dihydroxy-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 dibenzyl phosphate | C43H45O16P | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A new synthesis for etoposide phosphate disodium salt has been reported: The reaction of 4'-demethylepipodophpyllotoxin (I) with dibenzyl phosphite and diisopropylethylamine (DIEA) in acetonitrile gives the corresponding 4'-dibenzyl phosphate ester (II), which is condensed with 2,3-di-O-benzyl-4,6-O-ethylidene-alpha,beta-D-glucose (alpha:beta ratio = 85:15) by means of boron trifluoride ethearate in acetonitrile to afford the tetrabenzylated compound (IV). Finally, this compound is deprotected by hydrogenolysis with H2 over Pd/C in methanol/THF.
| 【1】 Silverberg, L.J.; Vemishetti, P.; Dillon, J.L. Jr.; Usher, J.J. (Bristol-Myers Squibb Co.); Process of preparing etoposide phosphate and etoposide. EP 0652226; JP 1995196680; JP 1998152499; US 5459248 . |
| 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) | 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 |
| (II) | 13050 | 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 dibenzyl phosphate | C35H33O11P | 详情 | 详情 | |
| (III) | 13055 | (2R,4aR,6S,7R,8R,8aS)-7,8-Bis(benzyloxy)-2-methylhexahydropyrano[3,2-d][1,3]dioxin-6-ol | C22H26O6 | 详情 | 详情 | |
| (IV) | 13056 | 4-((5R,5aR,8aR,9S)-9-[[(2R,4aR,6R,7R,8R,8aS)-7,8-bis(benzyloxy)-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 dibenzyl phosphate | C57H57O16P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)Reaction of propionic acid hydrazide (I) with CS-2 and KOH gave dithiocarbamate (II), which was cyclized to aminotriazole (III) upon treatment with hydrazine. Demethylation of podophyllotoxin (IV) with HBr, followed by treatment with BaCO3 afforded 4'-demethyl epipodophyllotoxin (V). Finally, condensation of (V) with triazole (III) in the presence of trifluoroacetic acid furnished the title compound.
| 【1】 Chen, Y.Z.; Lu, K.K.; Synthesis and antitumor activities of 4beta-S-(5''-alkyl-4''-amino-1'',2'',4''-triazole-3''-yl)-4-deoxy-4'-O-demethyl-epipodophyllotoxin derivatives. Acta Pharm Sin 1999, 34, 1, 63. |
| 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) | 25213 | propanohydrazide | C3H8N2O | 详情 | 详情 | |
| (II) | 25214 | 2-propionyl-1-hydrazinecarbodithioate | C4H7N2OS2 | 详情 | 详情 | |
| (III) | 25215 | 4-amino-5-ethyl-4H-1,2,4-triazol-3-ylhydrosulfide; 4-amino-5-ethyl-4H-1,2,4-triazole-3-thiol | C4H8N4S | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 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 |
合成路线5
该中间体在本合成路线中的序号：(V)Reaction of butyric acid hydrazide (I) with CS-2 and KOH gave dithiocarbamate (II), which was cyclized to aminotriazole (III) upon treatment with hydrazine. Demethylation of podophyllotoxin (IV) with HBr, followed by treatment with BaCO3 afforded 4'-demethyl epipodophyllotoxin (V). Finally, condensation of (V) with triazole (III) in the presence of trifluoroacetic acid furnished the title compound.
| 【1】 Chen, Y.Z.; Lu, K.K.; Synthesis and antitumor activities of 4beta-S-(5''-alkyl-4''-amino-1'',2'',4''-triazole-3''-yl)-4-deoxy-4'-O-demethyl-epipodophyllotoxin derivatives. Acta Pharm Sin 1999, 34, 1, 63. |
| 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) | 25210 | butanohydrazide | 3538-65-6 | C4H10N2O | 详情 | 详情 |
| (II) | 25211 | 2-butyryl-1-hydrazinecarbodithioate | C5H9N2OS2 | 详情 | 详情 | |
| (III) | 25212 | 1-amino-5-propyl-1H-pyrrol-2-ylhydrosulfide | C7H12N2S | 详情 | 详情 | |
| (IV) | 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 |
| (V) | 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 |
合成路线6
该中间体在本合成路线中的序号：(V)Oxidative oxidation of p-nitrobenzaldehyde (I) and 1,2-phenylenediamine (II) in DMF in the presence of nitrobenzene produced benzimidazole (III). Subsequent reduction of the nitro group of (III) by means of NaBH4 and CuCl afforded aniline (IV). Bromide (VI) was prepared by treatment of 4'-demethyl epipodophyllotoxin (V) with HBr. The title compound was then obtained by coupling aniline (IV) with bromide (VI) using BaCO3 in 1,2-dichloroethane.
| 【1】 Cheng, H.-H.; Guan, J.; Zhu, X.-K.; Cheng, Y.-C.; Tachibana, Y.; Bastow, K.F.; Lee, K.-H.; Gurwith, M.; Cho, S.J.; Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles. J Med Chem 1999, 42, 13, 2441. |
| 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) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (II) | 12824 | 2-Aminophenylamine; o-Phenylenediamine; 1,2-Benzenediamine | 95-54-5 | C6H8N2 | 详情 | 详情 |
| (III) | 33735 | 2-(4-nitrophenyl)-1H-benzimidazole | C13H9N3O2 | 详情 | 详情 | |
| (IV) | 33736 | 4-(1H-benzimidazol-2-yl)aniline; 4-(1H-benzimidazol-2-yl)phenylamine | C13H11N3 | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 14609 | (5R,5aR,8aR,9S)-9-bromo-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 | C21H19BrO7 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)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 |