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【结 构 式】 
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【分子编号】10459 【品名】(3R,4S)-3-Hydroxy-4-phenyl-2-azetanone 【CA登记号】 |
【 分 子 式 】C9H9NO2 【 分 子 量 】163.176 【元素组成】C 66.25% H 5.56% N 8.58% O 19.61% |
合成路线1
该中间体在本合成路线中的序号：(VI)A new partial synthesis for taxol has been reported: The cyclization of N-(4-methoxyphenyl)benzylideneimine (I) with acetoxyacetyl chloride (II) by means of triethylamine in dichloromethane gives cis-3-acetoxy-1-(4-methoxyphenyl)-4-phenylazetidin-2-one (III), which is treated with ceric ammonium nitrate in acetonitrile to afford cis-3-acetoxy-4-phenylazetidin-2-one (IV). Hydrolysis of (IV) with KOH in THF-water yields cis-3-hydroxy-4-phenylazetidin-2-one (V), which is submitted to optical resolution giving the (3R,4S)-isomer (VI). The reaction of (VI) with ethyl vinyl ether (VII) by means of methanesulfonic acid in THF affords (3R,4S)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one (VIII), which is benzoylated with benzoyl chloride (IX) and butyllithium in hexane to give (X). Opening of the azetidine ring of (X) with KOH in THF-water gives (2R,3S)-3-(benzamido)-2-(1-ethoxyethoxy)propanoic acid (XI), which is cyclized with potassium tert-butoxide and methanesulfonyl chloride to (4S,5R)-5-(1-ethoxyethoxy)-2,4-diphenyl-5,6-dihydro-4H-1,3-oxazin-6-one (XII). Finally, this compound is condensed with 7-O-(triethylsilyl)baccatin III (XIV) [prepared from 10-deacetylbaccatin III (XIII) by successive reaction with triethylsilyl chloride and acetyl chloride] by means of dimethylaminopyridine (DMAP) in pyridine.
| 【1】 Holton, R.A. (University of Florida); Method for preparation of taxol using an oxazinone. US 5015744 . |
| 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) | 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) | 18762 | 1-Ethoxyethylene; Ethyl vinyl ether；Ethoxyethene | 109-92-2 | C4H8O | 详情 | 详情 |
| (VIII) | 10462 | (3R,4S)-3-(1-Ethoxyethoxy)-4-phenyl-2-azetanone | C13H17NO3 | 详情 | 详情 | |
| (IX) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (X) | 10464 | (3R,4S)-1-Benzoyl-3-(1-ethoxyethoxy)-4-phenyl-2-azetanone | C20H21NO4 | 详情 | 详情 | |
| (XI) | 10465 | (2R,3S)-3-(Benzoylamino)-2-(1-ethoxyethoxy)-3-phenylpropionic acid | C20H23NO5 | 详情 | 详情 | |
| (XII) | 10466 | (4S,5R)-5-(1-Ethoxyethoxy)-2,4-diphenyl-4,5-dihydro-6H-1,3-oxazin-6-one | C20H21NO4 | 详情 | 详情 | |
| (XIII) | 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 |
| (XIV) | 10468 | (1S,2S,3R,4S,7R,9R,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 |
合成路线2
该中间体在本合成路线中的序号：(IX)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3
该中间体在本合成路线中的序号：(VI)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4
该中间体在本合成路线中的序号：(XI)A new synthesis of [14C]-labeled paclitaxel has been published: The protection of L-threonine methyl ester (I) with tert-butoxydiphenylchlorosilane (BPS-Cl) gives the compound (II), which is condensed with [14C]-labeled benzaldehyde (III), yielding the imine (IV). The cyclization of (IV) with acetoxyacetyl chloride (V) by means of triethylamine affords the azetidinone (VI), which is deprotected with tetrabutylammonium fluoride to the hydroxy ester (VII). The dehydration of (VII) with p-toluenesulfonyl chloride and triethylamine affords the unsaturated ester (VIII), which by ozonolysis is converted to the oxalimide (IX). Elimination of the oxalyl group with hydrazine gives the labeled azetidinone (X), which is deacetylated to the hydroxyazetidinone (XI) and protected with triethylchlorosilane (TES-Cl) to (XII). The benzoylation of (XII) with benzoyl chloride (XIII) and dimethylaminopyridine (DMAP) yields the corresponding benzoylated compound (XIV), which is then condensed with triethylsilyl-baccatin III (XV) by means of butyllithium to afford silylated labeled paclitaxel (XVI). Finally, this compound is deprotected with HCl. The intermediate silylated baccatin III (XV) is obtained from paclitaxel (XVII) by hydrogenolysis with NaBH4 to baccatin III (XVIII) and silylation with triethylsilyl chloride to (XV).
| 【1】 Walker, D.G.; Swigor, J.E.; Standridge, R.T.; Synthesis of paclitaxel-C3'-C-14. J Label Compd Radiopharm 1995, 36, 5, 479. |
| 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) | 10674 | (2S,3R)-3-Hydroxy-1-methoxy-1-oxo-2-butanaminium chloride | C5H12ClNO3 | 详情 | 详情 | |
| (II) | 10675 | methyl (2S,3R)-2-amino-3-methoxybutanoate | C21H29NO4Si | 详情 | 详情 | |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (III) | 44663 | benzaldehyde | C7H6O | 详情 | 详情 | |
| (IV) | 10677 | methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate | C28H33NO4Si | 详情 | 详情 | |
| (IV) | 44664 | methyl (2S,3R)-3-methoxy-2-[[(E)-benzylidene]amino]butanoate | C13H17NO3 | 详情 | 详情 | |
| (V) | 10456 | Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate | 13831-31-7 | C4H5ClO3 | 详情 | 详情 |
| (VI) | 10679 | methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate | C32H37NO7Si | 详情 | 详情 | |
| (VI) | 44665 | methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-methoxybutanoate | C17H21NO6 | 详情 | 详情 | |
| (VII) | 10680 | methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate | C16H19NO6 | 详情 | 详情 | |
| (VII) | 44666 | methyl (2S,3R)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-3-hydroxybutanoate | C16H19NO6 | 详情 | 详情 | |
| (VIII) | 10681 | methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate | C16H17NO5 | 详情 | 详情 | |
| (VIII) | 44667 | methyl (Z)-2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-butenoate | C16H17NO5 | 详情 | 详情 | |
| (IX) | 10682 | methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate | C14H13NO6 | 详情 | 详情 | |
| (IX) | 44668 | methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate | C14H13NO6 | 详情 | 详情 | |
| (X) | 10683 | methyl 2-[(3R,4S)-3-(acetoxy)-2-oxo-4-phenylazetidinyl]-2-oxoacetate | C14H13NO6 | 详情 | 详情 | |
| (X) | 44669 | (3R,4S)-2-oxo-4-phenylazetidinyl acetate | C11H11NO3 | 详情 | 详情 | |
| (XI) | 10459 | (3R,4S)-3-Hydroxy-4-phenyl-2-azetanone | C9H9NO2 | 详情 | 详情 | |
| (XI) | 44670 | (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone | C9H9NO2 | 详情 | 详情 | |
| (XII) | 10685 | (3R,4S)-4-Phenyl-3-[(triethylsilyl)oxy]-2-azetidinone | C15H23NO2Si | 详情 | 详情 | |
| (XII) | 44673 | (3R,4S)-3-hydroxy-4-phenyl-2-azetidinone | C9H9NO2 | 详情 | 详情 | |
| (XIII) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (XIV) | 10687 | (3R,4S)-1-Benzoyl-3-hydroxy-4-phenyl-2-azetidinone | C16H13NO3 | 详情 | 详情 | |
| (XIV) | 44671 | (3R,4S)-1-benzoyl-3-hydroxy-4-phenyl-2-azetidinone | C16H13NO3 | 详情 | 详情 | |
| (XV) | 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 | |
| (XVI) | 10689 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]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 | n/a | AB | 详情 | 详情 |
| (XVI) | 44672 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-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 | C47H51NO14 | 详情 | 详情 | |
| (XVII) | 10595 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-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 | 33069-62-4 | C47H51NO14 | 详情 | 详情 |
| (XVIII) | 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 |