【结 构 式】 |
【分子编号】57903 【品名】(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate 【CA登记号】 |
【 分 子 式 】C61H71NO15Si 【 分 子 量 】1086.31798 【元素组成】C 67.45% H 6.59% N 1.29% O 22.09% Si 2.59% |
合成路线1
该中间体在本合成路线中的序号:(IX)A new synthesis of paclitaxel has been described: The condensation of Oppolzer's L-(+)-2,10-camphorsultam (I) with 2-(4-methoxybenzyloxy)acetyl chloride (II) by means of NaH gives the corresponding substituted sultam (III), which is condensed with N-benzoylbenzaldehydeimine (IV) by means of lithium bis(trimethylsilyl)amide, yielding the protected side-chain (V) of paclitaxel. The reaction of (V) with DDQ affords oxazolidine (VI), which is hydrolyzed with LiOH/H2O2 to the free oxazolidine-carboxylic acid (VII). The esterification of (VII) with baccatin III (VIII) by means of dicyclohexylcarbodiimide (DCC) affords the protected paclitaxel derivative (IX), which is finally treated with HCl in ethanol.
【1】 Kanazawa, A.M.; Greene, A.E.; Denis, J.-N.; Direct, stereoselective synthesis of the protected paclitaxel (Taxol) side chain and high-yield transformation to paclitaxel. J Chem Soc Chem Commun 1994, 2591. |
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) | 10609 | (1R,5S,7S)-10,10-Dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C10H17NO2S | 详情 | 详情 | |
(II) | 10610 | 2-[(4-Methoxybenzyl)oxy]acetyl chloride | C10H11ClO3 | 详情 | 详情 | |
(III) | 10611 | (1R,5S,7S)-4-[2-[(4-Methoxybenzyl)oxy]acetyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C20H27NO5S | 详情 | 详情 | |
(IV) | 10612 | N-[(Z)-Benzylidene]benzamide | C14H11NO | 详情 | 详情 | |
(V) | 10613 | N-[(1S,2R)-3-[(1R,5S,7S)-10,10-Dimethyl-3,3-dioxo-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]dec-4-yl]-2-[(4-methoxybenzyl)oxy]-3-oxo-1-phenylpropyl]benzamide | C34H38N2O6S | 详情 | 详情 | |
(VI) | 10614 | (1R,5S,7S)-4-[[(4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidin-5-yl]carbonyl]-10,10-dimethyl-3lambda(6)-thia-4-azatricyclo[5.2.1.0(1,5)]decane-3,3-dione | C34H36N2O6S | 详情 | 详情 | |
(VII) | 10615 | (4S,5R)-3-Benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid | C24H21NO5 | 详情 | 详情 | |
(VIII) | 10473 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H52O11Si | 详情 | 详情 | |
(IX) | 57903 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate | C61H71NO15Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(V)The reaction of 10-O-deacetyl-baccatin III (I) with triethylsilyl chloride and pyridine gives the 7-O-silyl derivative (II), which is acylated with Ac2O and pyridine to yield 7-O-(triethylsilyl)baccatin III (III). The condensation of (III) with the chiral oxazolidine-carboxylic acid (IV) by means of DCC and DMAP in ethyl acetate affords the 13-O-ester (V), which is desilylated by means of HF and TEA in dichloromethane to provide the free 7-hydroxy derivative (VI). The reaction of (VI) with dimethylsulfoxide, Ac2O and HOAc gives the 7-O-(methylsulfanylmethyl) derivative (VII), which is finally hydrolyzed at the oxazolidine ring by means of HCl in ethyl acetate to give rise to the target 7-O-(methlsulfanylmethyl)taxol.
【1】 Bourzat, J.-D.; Commercon, A.; Ojima, I.; Bouchard, H. (Aventis Pharma SA; State University of New York, Albany); Methods for preparing new taxoids and pharmaceutical compsns. containing them. WO 0270498 . |
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) | 10467 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | 32981-86-5 | C29H36O10 | 详情 | 详情 |
(II) | 10537 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C35H50O10Si | 详情 | 详情 | |
(III) | 10473 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C37H52O11Si | 详情 | 详情 | |
(IV) | 57902 | (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid | C24H21NO5 | 详情 | 详情 | |
(V) | 57903 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate | C61H71NO15Si | 详情 | 详情 | |
(VI) | 57904 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate | C55H57NO15 | 详情 | 详情 | |
(VII) | 57905 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-9-[(methylsulfanyl)methoxy]-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate | C57H61NO15S | 详情 | 详情 |