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【结 构 式】 
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【分子编号】10729 【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]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 【CA登记号】 |
【 分 子 式 】C40H47NO13 【 分 子 量 】749.81212 【元素组成】C 64.07% H 6.32% N 1.87% O 27.74% |
合成路线1
该中间体在本合成路线中的序号：(IV)Three partial syntheses of Taxol are described starting from Taxol analogues such as Taxol C or Taxol B (cephalomannine): 1) The reaction of Taxol C (I) with triethylsilyl chloride (TES-Cl) in pyridine gives the bis(triethylsilyl) derivative (II), which by reduction with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in dry THF yields compound (III). The hydrolytic cleavage of (III) with simultaneous desilylation by means of HCl in ethanol affords [2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),11beta,12alpha,12aalpha,12balpha]]-6,12b-diacetoxy-9-(3-amino-2-hydroxy-3-phenylpropionyloxy)-1 2-benzoyloxy-4,11-dihydroxy-4a,8,13,13-tetramethyl-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-5-one (IV) with a free amino group, which is benzoylated with benzoyl chloride (V) and pyridine to Taxol.
| 【1】 Young, T.H. (Hauser, Inc.); Preparation of Taxol and docetaxel through primary amines. EP 0852581; WO 9623780 . |
| 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) | 10726 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(hexanoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C46H57NO14 | 详情 | 详情 | |
| (II) | 10727 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(hexanoylamino)-2-methoxy-3-phenylpropanoyl]oxy]-1-hydroxy-9-methoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C48H61NO14 | 详情 | 详情 | |
| (III) | 10728 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(E)hexylideneamino]-2-methoxy-3-phenylpropanoyl]oxy)-1-hydroxy-9-methoxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C48H61NO13 | 详情 | 详情 | |
| (IV) | 10729 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H47NO13 | 详情 | 详情 | |
| (V) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)2) The silylation of Taxol B (VI) with triethylsilyl chloride as before gives the bis(triethylsilyl) compound (VII), which by reduction with zirconocene chloride hydride as described yields compound (VIII). Finally, the hydrolytic cleavage of (VIII) with simultaneous desilylation with HCl in ethanol affords the previously reported compound (IV) with its free amino group easily benzoylated to Taxol. 3) The ozonolysis of the silylated Taxol B (VII) with O3 in methanol gives compound (IX), which is reduced with zirconocene as before yielding the 2-oxopropylideneimine (X). Finally, the hydrolytic cleavage of (X) with simultaneous desilylation with HCl in ethanol affords the previously reported compound (IX) with its free amino group easiely benzoylated to Taxol.
| 【1】 Young, T.H. (Hauser, Inc.); Preparation of Taxol and docetaxel through primary amines. EP 0852581; WO 9623780 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 10729 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H47NO13 | 详情 | 详情 | |
| (VI) | 10731 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9-dihydroxy-15-[((2R,3S)-2-hydroxy-3-[[(E)-2-methyl-2-butenoyl]amino]-3-phenylpropanoyl)oxy]-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C45H53NO14 | 详情 | 详情 | |
| (VII) | 10732 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-15-([(2R,3S)-3-[[(E)-2-methyl-2-butenoyl]amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C57H81NO14Si2 | 详情 | 详情 | |
| (VIII) | 10733 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9-dihydroxy-15-[((2R,3S)-2-hydroxy-3-[[(E,2E)-2-methyl-2-butenylidene]amino]-3-phenylpropanoyl)oxy]-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C45H53NO13 | 详情 | 详情 | |
| (IX) | 10734 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-15-([(2R,3S)-3-phenyl-3-(pyruvoylamino)-2-[(triethylsilyl)oxy]propanoyl]oxy)-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H77NO15Si2 | 详情 | 详情 | |
| (X) | 10735 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-15-([(2R,3S)-3-[[(E)-2-oxopropylidene]amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H77NO14Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The benzoylation of (IV) with benzoyl chloride (V) and triethylamine in ethyl acetate affords the fully protected Taxol derivative (VI), which is desillylated with HF in acetonitrile giving the partially protected Taxol derivative (VII). Finally, this compound is fully deprotected by hydrogenation with H2 over Pd/C in isopropanal at 40 atm to give taxol.
| 【1】 Sisti, N.J.; Swindell, C.S.; Chander, M.C. (NaPro BioTherapeutics, Inc.); Paclitaxel synthesis from precursor compounds and methods of producing the same. US 5675025 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 10729 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H47NO13 | 详情 | 详情 | |
| (V) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (VI) | 10746 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-2-[(benzyloxy)methoxy]-3-phenylpropanoyl]oxy)-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-2-yl benzoate | C61H73NO15Si | 详情 | 详情 | |
| (VII) | 10747 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-2-[(benzyloxy)methoxy]-3-phenylpropanoyl]oxy)-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H59NO15 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)The reaction of baccatine III (I) with trichloroacetyl chloride in pyridine gives 7-O-(trichloroacetyl)baccatine III (II), which is condensed with 2,3-epoxy-3-phenylpropionic acid (III) by means of DCC and DMAP in toluene to yield the ester (IV). Opening of the epoxide ring of (IV) by means of sodium azide and methyl formate in methanol affords the expected hydroxy azide (V), which is reduced with PPh3 in dichloromethane/water to provide the corresponding amino derivative (VI). Finally, the amino group of (VI) is benzoylated with benzoyl chloride (VII) and NaHCO3 in ethyl acetate/water to furnish the target paclitaxel.
| 【1】 Bombardelli, E.; Pontiroli, A.; Battaglia, A.; Dambruoso, P.; Guerrini, A. (Indena SpA); A process for the preparation of paclitaxel. WO 0246177 . |
| 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) | 10447 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C31H38O11 | 详情 | 详情 | |
| (II) | 38901 | (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-trichloroacetyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C33H37Cl3O12 | 详情 | 详情 | |
| (III) | 23891 | (2R,3R)-3-phenyl-2-oxiranecarboxylic acid | C9H8O3 | 详情 | 详情 | |
| (IV) | 54903 | (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-trichloroacetyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,3R)-3-phenyl-2-oxiranecarboxylate | C42H43Cl3O14 | 详情 | 详情 | |
| (V) | 54904 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-azido-2-hydroxy-3-phenylpropanoyl]oxy}-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C40H45N3O13 | 详情 | 详情 | |
| (VI) | 10729 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H47NO13 | 详情 | 详情 | |
| (VII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The Grignard reaction of phenylmagnesium bromide (I) with 11C labeled CO2 (II) in THF gives the radiolabeled benzoic acid (III), which is treated with phthaloyl dichloride (IV) in the same solvent to yield radiolabeled benzoyl chloride (V). Finally, this compound is treated with N-debenzoylated paclitaxel (VI) in acetonitrile to afford the target radiolabeled paclitaxel.
| 【1】 Ravert, H.T.; et al.; Radiosynthesis of [11C]paclitaxel. J Label Compd Radiopharm 2002, 45, 6, 471. |
| 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) | 17616 | bromo(phenyl)magnesium; Phenyl Magnesium Bromide | 100-58-3 | C6H5BrMg | 详情 | 详情 |
| (III) | 10202 | Benzoic acid | 65-85-0 | C7H6O2 | 详情 | 详情 |
| (III) | 55347 | benzoic acid | C7H6O2 | 详情 | 详情 | |
| (IV) | 23811 | phthaloyl dichloride;1,2-Benzenedicarbonyl dichloride;o-Phthaloyl chloride | 88-95-9 | C8H4Cl2O2 | 详情 | 详情 |
| (V) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (V) | 55348 | benzoyl chloride | C7H5ClO | 详情 | 详情 | |
| (VI) | 10729 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H47NO13 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(II)The hydrogenation of the protected taxol derivative (I) with H2 over Pd/C in aqueous THF in the presence of HCl gives the 3'-amino-taxol derivative (II), which is N-benzoylated by means of benzoyl chloride (III) and TEA to provide the target paclitaxel.
| 【1】 McChesney, J.D.; Zygmunt, J. (NaPro BioTherapeutics, Inc.); Two-step conversion of protected taxane ester to paclitaxel. WO 0285878 . |
| 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) | 56876 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-({(2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-[(benzyloxy)methoxy]-3-phenylpropanoyl}oxy)-9-{[(benzyloxy)carbonyl]oxy}-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C64H67NO18 | 详情 | 详情 | |
| (II) | 10729 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C40H47NO13 | 详情 | 详情 | |
| (III) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |