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【结 构 式】 
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【分子编号】10505 【品名】(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-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 【CA登记号】 |
【 分 子 式 】C57H73NO15Si 【 分 子 量 】1040.28986 【元素组成】C 65.81% H 7.07% N 1.35% O 23.07% Si 2.7% |
合成路线1
该中间体在本合成路线中的序号：(XIV)A new partial synthesis of taxol has been described: The esterification of (1S,2R)-2-phenylcyclohexanol (I) with benzyloxyacetyl chloride (II) gives the corresponding chiral ester (III), which is deprotected by hydrogenolysis to the hydroxy ester (IV). Silylation of (IV) with triisopropylsilyl chloride affords the silylated ester (V), which is cyclized with trimethylsilylbenzaldimine (VI) [obtained from benzaldehyde (VII) and hexamethyldisilazane (HMSA)] by means of butyllithium in THF giving (3R,4S)-3-(triisopropylsilyloxy)-4-phenylazetidin-2-one (VIII). The deprotection of (VIII) with tetrabutylammonium fluoride affords (3R,4S)-3-hydroxy-4-phenylazetidin-2-one (IX), which is treated with ethyl vinyl ether to give the 1-ethoxyethyl ether (X). The benzoylation of (X) with benzoyl chloride (XI) by means of dimethylaminopyridine and triethylamine yields (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (XII), which is condensed with 7-O-(triethylsilyl)baccatin III (XIII) by means of NaH in THF, affording 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIV). Finally, this compound is deprotected with HCl in ethanol.
| 【1】 Habus, I.; Zhao, M.; Brigaud, T.; Zucco, M.; Ojima, I.; Sun, C.M.; Park, Y.H.; New and efficient approaches to the semisynthesis of taxol and its C-13 side chain analogs by means of beta-lactam synthon method. Tetrahedron 1992, 48, 34, 6985. |
| 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) | 10492 | (1S,2R)-(+)-trans-2-Phenyl-1-cyclohexanol; (1S,2R)-2-Phenylcyclohexanol | 2362-61-0 | C12H16O | 详情 | 详情 |
| (II) | 10493 | 2-(Benzyloxy)acetyl chloride; Benzyloxyacetyl chloride | 19810-31-2 | C9H9ClO2 | 详情 | 详情 |
| (III) | 10494 | (1S,2R)-2-phenylcyclohexyl 2-(benzyloxy)acetate | C21H24O3 | 详情 | 详情 | |
| (IV) | 10495 | (1S,2R)-2-phenylcyclohexyl 2-hydroxyacetate | C14H18O3 | 详情 | 详情 | |
| (V) | 10496 | (1S,2R)-2-phenylcyclohexyl 2-(triisopropylsilyl)acetate | C23H38O2Si | 详情 | 详情 | |
| (VI) | 10507 | Trimethyl-N-[(E)-benzylidene]silanamine; N-[(E)-Benzylidene]-N-(trimethylsilyl)amine | 17599-61-0 | C10H15NSi | 详情 | 详情 |
| (VII) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VIII) | 10499 | (3R,4S)-4-Phenyl-3-[(triisopropylsilyl)oxy]-2-azetanone | C18H29NO2Si | 详情 | 详情 | |
| (IX) | 10459 | (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone | C9H9NO2 | 详情 | 详情 | |
| (X) | 10462 | (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone | C13H17NO3 | 详情 | 详情 | |
| (XI) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XII) | 10464 | (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone | C20H21NO4 | 详情 | 详情 | |
| (XIII) | 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 | |
| (XIV) | 10505 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-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 | C57H73NO15Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)A new synthesis of paclitaxel has been reported: The cyclization of the 4-methoxyphenylimine of benzaldehyde (I) with acetoxyacetyl chloride (II) by means of triethylamine gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III), which is treated with ceric ammonium nitrate to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV). The hydrolysis of (IV) with KOH in THF/water affords the corresponding hydroxy compound (V), which is submitted to optical resolution by crystallization of the 2-methoxy-2-[2-(trifluoromethyl)phenyl]acetic esters. The (3R,4S)-regioisomer (VI) is protected with ethyl vinyl ether, giving the 1-ethoxyethyl derivative (VII), which is benzoylated with benzoyl chloride and butyllithium to afford (3R,4S)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII). The condensation of (VIII) with baccatin III (IX) by means of dimethylaminopyridine (DMAP) in pyridine yields the protected paclitaxel derivative (X), which is finally deprotected with HCl in ethanol/water.
| 【1】 Holton, R.A. (University of Florida); Method for preparation of taxol. EP 0400971; US 5336785 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| (I) | 10455 | N-(4-Methoxyphenyl)-N-[(Z)-benzylidene]amine; 4-Methoxy-N-[(Z)-benzylidene]aniline | 783-08-4 | C14H13NO | 详情 | 详情 |
| (II) | 10456 | Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate | 13831-31-7 | C4H5ClO3 | 详情 | 详情 |
| (III) | 10457 | (3R,4S)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetanyl acetate | C18H17NO4 | 详情 | 详情 | |
| (IV) | 10458 | (3R,4S)-2-oxo-4-phenylazetanyl acetate | C11H11NO3 | 详情 | 详情 | |
| (V) | 63030 | cis-3-Hydroxy-4-phenyl-2-azetanone; (3R*,4S*)-3-Hydroxy-4-phenyl-2-azetanone | C9H9NO2 | 详情 | 详情 | |
| (VI) | 10459 | (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone | C9H9NO2 | 详情 | 详情 | |
| (VII) | 10462 | (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 10464 | (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone | C20H21NO4 | 详情 | 详情 | |
| (IX) | 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 | |
| (X) | 10505 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-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 | C57H73NO15Si | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)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 azetidine (XI) by means of LiHMDS In THF affords 2'-O-(1-ethoxyethyl)-7-O-(triethylsilyl)taxol (XIII), which is treated with HF and pyridine to provide the desilylated taxol derivative (XIV). The reaction of (XIV) with DMSO, Ac2O and HOAc gives the 2'-O-protected 7-O-(methylsulfanylmethyl) derivative (XII), which is finally deprotected by means of HCl in ethanol to yield the target 7-O-(methylsulfanylmethyl)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 | |
| (XI) | 10464 | (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone | C20H21NO4 | 详情 | 详情 | |
| (XII) | 57908 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy}-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-2-yl benzoate | C53H63NO15S | 详情 | 详情 | |
| (XIII) | 10505 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-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 | C57H73NO15Si | 详情 | 详情 | |
| (XIV) | 10540 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-(1-ethoxyethoxy)-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 | C57H73NO15Si | 详情 | 详情 |