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【结 构 式】 
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【分子编号】10554 【品名】(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 【CA登记号】 |
【 分 子 式 】C43H48Cl3NO15 【 分 子 量 】925.20996 【元素组成】C 55.82% H 5.23% Cl 11.5% N 1.51% O 25.94% |
合成路线1
该中间体在本合成路线中的序号：(XII)3) The condensation of (4S,5R)-3-(bromoacetyl)-4-methyl-5-phenyloxazolidin-2-one (I) with benzaldehyde (II) by means of dibutylboron triflate gives intermediate (III), which by treatment with lithium ethoxide yields (R,R)-3-phenyloxirane-2-carboxylic acid ethyl ester (IV). The reaction of (IV) with sodium azide in ethanol affords the hydroxy ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate, giving the amino ester (VI). The protection of (VI) with tert-butoxycarbonyl anhydride affords the protected amino ester (VII), which is treated with 2-methoxypropene and pyridinium p-toluenesulfonate to give the oxazolidine (VIII). The hydrolysis of (VIII) with LiOH in ethanol/water yields (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carboxylic acid (IX), which is condensed with the protected baccatin III (X) by means of dicyclohexylcarbodiimide (DCC) and DMAP to afford the oxazolidine ester (XI). The treatment of (XI) with formic acid gives the amino ester (XII), which is benzoylated with benzoyl chloride and NaHCO3 to the protected paclitaxel (XIII). Finally, this compound is deprotected by treatment with Zn/acetic acid. (Commercon, A. et al. Tetrahedron Lett 1992, 33(36): 5185).
| 【1】 Guy, R.K.; Nicolaou, K.C.; Dai, W.M.; Chemistry and biology of taxol. Angew Chem. Int Ed Engl 1994, 33, 1, 15. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 63033 | 2-(ethyloxy)-1-propene; ethyl 1-methylethenyl ether | C5H10O | 详情 | 详情 | ||
| (I) | 10544 | (4S,5R)-3-(2-Bromoacetyl)-4-methyl-5-phenyl-1,3-oxazolan-2-one | C12H12BrNO3 | 详情 | 详情 | |
| (II) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 10545 | (4S,5R)-3-[(2S,3R)-2-Bromo-3-hydroxy-3-phenylpropanoyl]-4-methyl-5-phenyl-1,3-oxazolan-2-one | C19H18BrNO4 | 详情 | 详情 | |
| (IV) | 10546 | ethyl (2R,3R)-3-phenyl-2-oxiranecarboxylate | 121-39-1 | C11H12O3 | 详情 | 详情 |
| (V) | 10547 | ethyl (2R,3S)-3-azido-2-hydroxy-3-phenylpropanoate | C11H13N3O3 | 详情 | 详情 | |
| (VI) | 10548 | ethyl (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoate | C11H15NO3 | 详情 | 详情 | |
| (VII) | 10549 | ethyl (2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate | C16H23NO5 | 详情 | 详情 | |
| (VIII) | 10550 | 3-(tert-butyl) 5-ethyl (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate | C19H27NO5 | 详情 | 详情 | |
| (IX) | 10551 | (4S,5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-phenyl-1,3-oxazolane-5-carboxylic acid | C17H23NO5 | 详情 | 详情 | |
| (X) | 10448 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C34H39Cl3O13 | 详情 | 详情 | |
| (XI) | 10553 | 5-((1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl) 3-(tert-butyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate | C51H60Cl3NO17 | 详情 | 详情 | |
| (XII) | 10554 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H48Cl3NO15 | 详情 | 详情 | |
| (XIII) | 10555 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H48Cl3NO15 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of (2R,3S)-phenylisoserine (I) with 2-propynyl chloroformate (II) in aq. NaHCO3 gives the N-acylated compound (III), which is treated with diazomethane in ethyl ether (CDI and methanol) to yield the corresponding methyl ester (IV). The reaction of (IV) with 2-methoxypropene (V) and pyridinium p-toluenesulfonate in toluene affords the oxazolidine (VI), which is treated with LiOH in water to provide the oxazolidine-5-carboxylic acid (VII). The esterification of 7-O-(trichloroethoxycarbonyl)baccatin (VIII) with acid (VII) by means of DCC in toluene gives the corresponding ester (IX), which is treated with ammonium tetrathiomolybdate to cleave the oxazolidine ring and yield the 3-amino-2-hydroxypropionyl ester (X). The reaction of (X) with benzoyl chloride (XI) and NaHCO3 in ethyl acetate affords the expected benzamido derivative (XII), which is finally deprotected by means of Zn and AcOH to afford the target paclitaxel.
| 【1】 Sharma, A.P.; Sarkar, S. (Dabur India Ltd.); Method of preparation of paclitaxel (Taxol) using 3-(alk-2-ynyloxy)carbonyl-5-oxazolidine carboxylic acid. WO 0266448 . |
| 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) | 54908 | (2R,3S)-3-amino-2-hydroxy-3-phenylpropanoic acid | 136561-53-0 | C9H11NO3 | 详情 | 详情 |
| (II) | 55690 | Propargyl chloroformate | C4H3ClO2 | 详情 | 详情 | |
| (III) | 55691 | (2R,3S)-2-hydroxy-3-phenyl-3-{[(2-propynyloxy)carbonyl]amino}propanoic acid | C13H13NO5 | 详情 | 详情 | |
| (IV) | 55692 | methyl (2R,3S)-2-hydroxy-3-phenyl-3-{[(2-propynyloxy)carbonyl]amino}propanoate | C14H15NO5 | 详情 | 详情 | |
| (V) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (VI) | 55693 | 5-methyl 3-(2-propynyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate | C17H19NO5 | 详情 | 详情 | |
| (VII) | 55694 | (4S,5R)-2,2-dimethyl-4-phenyl-3-[(2-propynyloxy)carbonyl]-1,3-oxazolidine-5-carboxylic acid | C16H17NO5 | 详情 | 详情 | |
| (VIII) | 10448 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C34H39Cl3O13 | 详情 | 详情 | |
| (IX) | 55695 | 5-((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-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl) 3-(2-propynyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate | C50H54Cl3NO17 | 详情 | 详情 | |
| (X) | 10554 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H48Cl3NO15 | 详情 | 详情 | |
| (XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XII) | 55696 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-1,4-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-{[(2,2,2-trichloroethoxy)carbonyl]oxy}-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C48H50Cl3NO15 | 详情 | 详情 |