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【结 构 式】 
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【分子编号】10595 【品名】(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 【CA登记号】33069-62-4 |
【 分 子 式 】C47H51NO14 【 分 子 量 】853.92028 【元素组成】C 66.11% H 6.02% N 1.64% O 26.23% |
合成路线1
该中间体在本合成路线中的序号：(XXXVIII)The secondary alcohol (XXXII) is treated with phenyllithium in THF (to open the cyclic carbonate and form the benzoyloxy group) and oxidized with tetrapropylammonium perruthenate (TPAP) to give the benzoyloxyketone (XXXIII). Enolization of ketone (XXXIII) with potassium tert-butoxide affords the potassium enolate (XXXIV), which is oxidized with phenylseleninic anhydride and acetylated with acetic anhydride in DMAP to give the alpha-acetoxyketone (XXXV). Further desilylation of (XXXV) with tris(diethylamino)sulfoxonium difluorotrimethylsiliconate (TASF) in THF yields the secondary alcohol (XXXVI), which is condensed with Ojima's beta-lactam (XXXVII) by means of lithium hexamethyldisilazane (LHMDS) in THF to afford protected paclitaxel (XXXVIII). Finally, this compound is deprotected first with HF in pyridine to eliminate the triethylsilyl (TES) group and then hydrogenated with H2 over Pd/C in ethanol to eliminate the BOM group.
| 【1】 Kim, H.-B.; Holton, R.A.; Somoza, C.; et al.; First total synthesis of taxol. 2. Completion of the C and D rings. J Am Chem Soc 1994, 116, 4, 1599. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXII) | 10589 | (1S,5S,6R,10R,12S,13R,15R,18S)-12-[(benzyloxy)methyl]-18-[[tert-butyl(dimethyl)silyl]oxy]-15-hydroxy-13,17,20,20-tetramethyl-3-oxo-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-7-yl acetate | C37H54O9Si | 详情 | 详情 | |
| (XXXIII) | 10590 | (1S,2S,3R,4S,7R,9S,10R,15S)-4-(acetoxy)-9-[(benzyloxy)methyl]-15-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-12-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C43H58O9Si | 详情 | 详情 | |
| (XXXIV) | 10591 | potassium (1S,2S,3R,4S,7R,9S,10S,15S)-4-(acetoxy)-2-(benzoyloxy)-9-[(benzyloxy)methyl]-15-[[tert-butyl(dimethyl)silyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadeca-11,13-dien-12-olate | C43H57KO9Si | 详情 | 详情 | |
| (XXXV) | 10592 | (1S,2S,3R,4S,7R,9S,10R,12R,15S)-4,12-bis(acetoxy)-9-[(benzyloxy)methyl]-15-[[tert-butyl(dimethyl)silyl]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 | C45H60O11Si | 详情 | 详情 | |
| (XXXVI) | 10593 | (1S,2S,3R,4S,7R,9S,10R,12R,15S)-4,12-bis(acetoxy)-9-[(benzyloxy)methyl]-1,15-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 | C39H46O11 | 详情 | 详情 | |
| (XXXVII) | 10490 | (3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone | C22H27NO3Si | 详情 | 详情 | |
| (XXXVIII) | 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 |
合成路线2
该中间体在本合成路线中的序号：(XVII)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 |
合成路线3
该中间体在本合成路线中的序号：(Ia)Several partial syntheses of docetaxel have been described: The selective hydrolysis of Taxol A (I, R = Ph), Taxol B (I, R = C(Me)=CHMe) or Taxol C (I, R = C5H11) with NaHCO3 in THF/water gives the corresponding 10-deacetyl derivatives (II), which by selective silylation with triethylsilyl chloride in pyridine are converted into the 10-deacetyl-2',7-bis(triethylsilyl) compounds (III). The reaction of compounds (III) with zirconocene chloride hydride [bis(cyclopentadienyl)zirconium chloride hydride] in THF afford the corresponding imino derivatives (IV), which, without isolation are hydrolyzed and desilylated by a treatment with concentrated aqueous HCl in ethanol giving 10-deacetyltaxolamine (V). Finally, this compound is acylated at the amino group by a treatment by di-tert-butyl dicarbonate and NaHCO3 in ethyl acetate/water.
| 【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 |
|---|---|---|---|---|---|---|
| 14346 | di(tert-butyl) malonate; Di-tert-butyl malonate | 541-16-2 | C11H20O4 | 详情 | 详情 | |
| (IIa) | 10470 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1,9,12-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 | C45H49NO13 | 详情 | 详情 | |
| (Ia) | 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 |
| (Ib) | 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 | |
| (IIIa) | 12495 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,12-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 | C57H77NO13Si2 | 详情 | 详情 | |
| (IVa) | 12496 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-11-oxo-15-([(2R,3S)-3-phenyl-3-[[(E)-benzylidene]amino]-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 | C57H77NO12Si2 | 详情 | 详情 | |
| (Ic) | 28490 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(cyclopentylcarbonyl)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 | C46H55NO14 | 详情 | 详情 | |
| (IIb) | 28491 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12-trihydroxy-15-[((2R,3S)-2-hydroxy-3-[[(Z)-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 | C43H51NO13 | 详情 | 详情 | |
| (IIc) | 28492 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(cyclopentylcarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-1,9,12-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 | C44H53NO13 | 详情 | 详情 | |
| (IIIb) | 28493 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-15-([(2R,3S)-3-[[(Z)-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 | C55H79NO13Si2 | 详情 | 详情 | |
| (IIIc) | 28494 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(cyclopentylcarbonyl)amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,12-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 | C56H81NO13Si2 | 详情 | 详情 | |
| (IVb) | 28495 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12-dihydroxy-10,14,17,17-tetramethyl-15-([(2R,3S)-3-[[(E,2Z)-2-methyl-2-butenylidene]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 | C55H79NO12Si2 | 详情 | 详情 | |
| (IVc) | 28496 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[[(E)-cyclopentylmethylidene]amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1,12-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 | C56H81NO12Si2 | 详情 | 详情 | |
| (V) | 12497 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-amino-2-hydroxy-3-phenylpropanoyl]oxy]-1,9,12-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 | C38H45NO12 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reaction of taxol (I) with benzyloxycarbonyl chloride and DIEA in dichloromethane gives the protected compound (II), which is treated with DAST in the same solvent to yield the cyclopropa taxol (III). The hydrogenolysis of (III) with H2 over Pd/C affords compound (IV), which is deacylated with tetrabutylammonium borohydride in dichloromethane to provide the cyclopropa baccatin (V). The acylation of (V) with azetidinone (VI) by means of BuLi in THF gives the silylated taxoid (VII), which is finally desilylated with HCl in acetonitrile to afford the target compound.
| 【1】 Chen, S.-H.; Farina, V. (Bristol-Myers Squibb Co.); 7,8-Cyclopropataxones. CA 2099211; EP 0577083; JP 1994179665; JP 1994179666; JP 2001199974; US 5254580 . |
| 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) | 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 |
| (II) | 49342 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[((2R,3S)-3-(benzoylamino)-2-[[(benzyloxy)carbonyl]oxy]-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 | C55H57NO16 | 详情 | 详情 | |
| (III) | 49343 | (1S,2S,3R,4S,7R,9S,11R,13R,16S)-4,13-bis(acetoxy)-16-[((2R,3S)-3-(benzoylamino)-2-[[(benzyloxy)carbonyl]oxy]-3-phenylpropanoyl)oxy]-1-hydroxy-15,18,18-trimethyl-12-oxo-6-oxapentacyclo[12.3.1.0(3,11).0(4,7).0(9,11)]octadec-14-en-2-yl benzoate | C55H55NO15 | 详情 | 详情 | |
| (IV) | 49344 | (1S,2S,3R,4S,7R,9S,11R,13R,16S)-4,13-bis(acetoxy)-16-[[(2R,3S)-3-(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-15,18,18-trimethyl-12-oxo-6-oxapentacyclo[12.3.1.0(3,11).0(4,7).0(9,11)]octadec-14-en-2-yl benzoate | C47H49NO13 | 详情 | 详情 | |
| (V) | 49345 | (1S,2S,3R,4S,7R,9S,11R,13R,16S)-4,13-bis(acetoxy)-1,16-dihydroxy-15,18,18-trimethyl-12-oxo-6-oxapentacyclo[12.3.1.0(3,11).0(4,7).0(9,11)]octadec-14-en-2-yl benzoate | C31H36O10 | 详情 | 详情 | |
| (VI) | 49346 | tert-butyl (3R,4S)-2-oxo-4-phenyl-3-[(triethylsilyl)oxy]-1-azetidinecarboxylate | C20H31NO4Si | 详情 | 详情 | |
| (VII) | 49347 | (1S,2S,3R,4S,7R,9S,11R,13R,16S)-4,13-bis(acetoxy)-16-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-15,18,18-trimethyl-12-oxo-6-oxapentacyclo[12.3.1.0(3,11).0(4,7).0(9,11)]octadec-14-en-2-yl benzoate | C51H67NO14Si | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Acylation of paclitaxel (I) with 2,3-O-isopropylideneglyceryl chloroformate (II) produced the 2',7-bis-carbonate (III). Subsequent acid hydrolysis of the acetonide groups of (III) furnished the corresponding bis-(dihydroxypropyl)carbonate (IV). The 2'-ester of (IV) was then selectively hydrolyzed using a phosphate buffer at pH 6.5.
| 【1】 Seligson, A.L.; et al.; A new prodrug of paclitaxel: Synthesis of Protaxel. Anti-Cancer Drugs 2001, 12, 4, 305. |
| 【2】 Sovak, M.; Douglass, J.G.; Bressi, J.C.; Seligson, A. (Biophysica Foundation); Novel taxoids. JP 1998509461; US 5801191; WO 9638138 . |
| 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) | 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 |
| (II) | 56226 | 4-{[(chlorocarbonyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolane | C7H11ClO4 | 详情 | 详情 | |
| (III) | 56227 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-{[(2R,3S)-3-(benzoylamino)-2-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl}oxy)-3-phenylpropanoyl]oxy}-9-({[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]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 | C61H71NO22 | 详情 | 详情 | |
| (IV) | 56228 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-2-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-3-phenylpropanoyl)oxy]-9-{[(2,3-dihydroxypropoxy)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 | C55H63NO22 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)In an alternative method, paclitaxel (I) was acylated with allyl chloroformate (V) to afford the bis-carbonate (VI). Dihydroxylation of both allyl groups of (VI) was accomplished by treatment with tert-butyl hydroperoxide producing (IV). The 2'-ester of (IV) was finally removed upon stirring in a NaHCO3-neutralized solution at room temperature.
| 【1】 Seligson, A.L.; et al.; A new prodrug of paclitaxel: Synthesis of Protaxel. Anti-Cancer Drugs 2001, 12, 4, 305. |
| 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) | 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 |
| (IV) | 56228 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-2-{[(2,3-dihydroxypropoxy)carbonyl]oxy}-3-phenylpropanoyl)oxy]-9-{[(2,3-dihydroxypropoxy)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 | C55H63NO22 | 详情 | 详情 | |
| (V) | 38115 | 3-[(chlorocarbonyl)oxy]-1-propene | 2937-50-0 | C4H5ClO2 | 详情 | 详情 |
| (VI) | 56229 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-9-{[(allyloxy)carbonyl]oxy}-15-{[(2R,3S)-2-{[(allyloxy)carbonyl]oxy}-3-(benzoylamino)-3-phenylpropanoyl]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 | C55H59NO18 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Paclitaxel (I) was protected as the 2'-(triethylsilyl) derivative (II) and then converted to the 7-methylsulfanylmethyl ether (III) by treatment with dimethyl sulfide and benzoyl peroxide. Subsequent desilylation of (III) using aqueous acetic acid or HCl in H2O/CH3CN furnished the desired 7-O-methylsulfanylmethyl paclitaxel. Alternatively, the title compound was also obtained by direct methylsulfanylmethylation of paclitaxel.
| 【1】 Altstadt, T.J.; et al.; Synthesis and antitumor activity of novel C-7 paclitaxel ethers: Discovery of BMS-184476. J Med Chem 2001, 44, 26, 4577. |
| 【2】 Golik, J.; et al.; Synthesis and antitumor evaluation of paclitaxel phosphonooxymethyl ethers: A novel class of water soluble paclitaxel pro-drugs. Bioorg Med Chem Lett 1996, 6, 15, 1837. |
| 【3】 Golik, J.; Kadow, J.F.; Kaplan, M.A.; Li, W.-S.; Perrone, R.K.; Thottahil, J.K.; Vyas, D.; Wittman, M.D.; Wong, H.; Wright, J.J. (Bristol-Myers Squibb Co.); Phosphonooxymethyl or methylthiomethyl ethers of taxane derivatives as antitumor agents. EP 0639577 . |
| 【4】 Kelly, R.C.; Gebhard, I. (Pharmacia Corp.); 7-Ether-taxol analogs, antineoplastic use and pharmaceutical compsns. containing them. EP 0767786; JP 1998502077; WO 9600724 . |
| 【5】 Wong, H.S.; Wittman, M.D. (Bristol-Myers Squibb Co.); 7-O-Ethers of taxane derivs.. CA 2152771; EP 0694539; JP 1996239373 . |
| 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) | 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 |
| (II) | 49369 | (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)-1,9-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 | C53H65NO14Si | 详情 | 详情 | |
| (III) | 49370 | (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-9-[(methylsulfanyl)methoxy]-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate | C55H69NO14SSi | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)Malic acid (I) was protected as the 1,2-O-isopropylidene derivative (II) upon treatment with acetone in the presence of acid catalyst. Condensation of (II) with paclitaxel (III) using diisopropylcarbodiimide and DMAP produced the 2'-ester (IV). After hydrolytic cleavage of the isopropylidene protecting group of (IV), conversion to the corresponding sodium carboxylate salt furnished the title compound.
| 【1】 Braamer, L.; Damen, E.W.P.; Wiegerinck, P.H.G.; Sperling, D.; de Vos, D.; Scheren, H.W.; Paclitaxel esters of malic acid as prodrugs with improved water solubility. Bioorg Med Chem 2000, 8, 2, 427. |
| 【2】 Wiegerinck, P.H.G.; Scheeren, J.W.; Damen, E.W.P.; Sperling, D.; Braamer, L.; De Vos, D. (Pharmachemie BV); Water soluble analogs and prodrugs of paclitaxel. WO 0010988 . |
| 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) | 11058 | (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid | 97-67-6 | C4H6O5 | 详情 | 详情 |
| (II) | 39221 | 2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid | 73991-95-4 | C7H10O5 | 详情 | 详情 |
| (III) | 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 |
| (IV) | 39222 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3S)-3-(benzoylamino)-2-([2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetyl]oxy)-3-phenylpropanoyl]oxy]-1,9-dihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)] | C54H59NO18 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)The target compound is obtained by esterification of Taxol (paclitaxel) (I) with hexadecanoic anhydride (II) by means of DCC in dichloromethane.
| 【1】 Ali, S.; et al.; Hydrolyzable hydrophobic taxanes: Synthesis and anti-cancer activities. Anti-Cancer Drugs 2001, 12, 2, 117. |
| 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) | 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 |
| (II) | 27916 | hexadecanoic anhydride | 623-65-4 | C32H62O3 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(I)Esterification of Taxol (paclitaxel) (I) with 2-bromohexadecanoic acid (II) by means of DCC in dichloromethane yields the target 2'-(2-bromohexadecanoyl)paclitaxel.
| 【1】 Ali, S.; et al.; Hydrolyzable hydrophobic taxanes: Synthesis and anti-cancer activities. Anti-Cancer Drugs 2001, 12, 2, 117. |
| 【2】 Mayhew, E.; Janoff, A.S.; Bhattacharya, S.; Kehane, G.; Ahmad, I.; Franklin, J.C.; Ali, S. (The Liposome Company, Ltd.); Hydrolysis-promoting hydrophobic taxane derivs.. US 6107332 . |
| 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) | 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 |
| (II) | 47926 | 2-bromohexadecanoic acid | 18263-25-7 | C16H31BrO2 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(I)Paclitaxel (I) is selectively protected at the side-chain hydroxyl group with 2,2,2-trichloroethyl chloroformate in pyridine to afford the carbonate ester (II). Subsequent acylation of (II) with 3-methyl-3-[(2,4,6-trimethoxybenzyl)thio]butyric acid (III) provides ester (IV). Removal of the trimethoxybenzyl protecting group of (IV) by means of formic acid in the presence of L-cysteine gives rise to thiol (V).
| 【1】 Lin, C.-E.; et al.; Design and synthesis of nitrosylated paclitaxel (NO-paclitaxel) and adamantanyl nitric oxide donor as antirestenosis agents. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 36. |
| 【2】 Garvey, D.S.; Letts, L.G.; Wang, T.; Richardson, S.K.; Lin, C.-E. (NitroMed Inc.); Nitrosated and nitrosylated taxanes, compsns. and methods of use. WO 0198286 . |
| 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) | 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 |
| (II) | 58359 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-3-phenyl-2-{[(2,2,2-trichloroethoxy)carbonyl]oxy}propanoyl)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 | C50H52Cl3NO16 | 详情 | 详情 | |
| (III) | 38878 | 3-methyl-3-[(2,4,6-trimethoxybenzyl)sulfanyl]butyric acid | C15H22O5S | 详情 | 详情 | |
| (IV) | 58360 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-3-phenyl-2-{[(2,2,2-trichloroethoxy)carbonyl]oxy}propanoyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-9-({3-methyl-3-[(2,4,6-trimethoxybenzyl)sulfanyl]butanoyl}oxy)-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C65H72Cl3NO20S | 详情 | 详情 | |
| (V) | 58361 | (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-15-[((2R,3S)-3-(benzoylamino)-3-phenyl-2-{[(2,2,2-trichloroethoxy)carbonyl]oxy}propanoyl)oxy]-1-hydroxy-10,14,17,17-tetramethyl-9-[(3-methyl-3-sulfanylbutanoyl)oxy]-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate | C55H60Cl3NO17S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(V)Condensation of paclitaxel (V) with succinic anhydride (VI) affords the hemisuccinate ester (VII). This is subsequently coupled with amino ester (IV) in the presence of DCC to furnish the title compound.
| 【1】 Jacob, J.N. (Organomed Corporation); Paclitaxel-carbohydrate conjugates: Design, synthesis and biological evaluations. US 6218367 . |
| 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) | 59013 | (3R,4S,5R,6R)-2,3,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl 4-aminobutanoate | C10H19NO7 | 详情 | 详情 | |
| (V) | 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 |
| (VI) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (VII) | 59014 | 4-{[(1R,2S)-2-(benzoylamino)-1-({[(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]oxy}carbonyl)-2-phenylethyl]oxy}-4-oxobutano | C51H55NO17 | 详情 | 详情 |