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【结 构 式】

【药物名称】Docetaxol, Docetaxel, XRP-6976L, NSC-628503, RP-56976, Taxotere

【化学名称】N-Debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol
　　　　　　[2aR-[2aalpha,4beta,4abeta,6beta,9alpha(alphaR*,betaS*),11beta,12alpha,12aalpha,12balpha]]-beta-(tert-Butoxycarbonylamino)-alpha-hydroxybenzenepropanoic acid 12b-(acetyloxy)-12-(benzyloxy)-1,2,3,4,4a,6,9,10,11,12,12a,12b-dodecahydro-4,6,11-trihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-5H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl ester
　　　　　　(2R,3S)-N-Carboxy-3-phenylisoserine,N-tert-butyl ester,13-ester with 5beta,20-epoxy-1,2alpha,4,7beta,10beta,13alpha-hexahydrotax-11-en-9-one 4-acetate 2-benzoate
　　　　　　(2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-12b-(Acetoxy)-12-(benzoyloxy)-9-[3(S)-(tert-butoxycarbonylamino)-2(R)-hydroxy-3-phenylpropionyloxy]-4,6,11-trihydroxy-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

【CA登记号】114977-28-5, 148408-66-6 (trihydrate)

【 分 子 式 】C43H53NO14

【 分 子 量 】807.90016

【开发单位】Aventis Pharma (Originator), Chugai (Licensee)

【药理作用】Breast Cancer Therapy, Gastric Cancer Therapy, Head and Neck Cancer Therapy, Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Solid Tumors Therapy, Squamous Cell Carcinoma Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents, Taxanes
合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

Docetaxel is a synthetic derivative of 10-deacetylbaccatin III (10-DAB; RP 61387). The crystalline active ingredient is synthesized by a sequence of more than 10 chemical steps. The optically active side-chain (RPR 108278) is first fully synthesized and coupled with suitably protected 10-DAB. The resulting intermediate is then deprotected to give docetaxel which is crystallized.

参考文献 中间体
【1】 Locci-Tonelli, D.; Spiridonidis, C.H.; Fabre, J.L.; Docetaxel. Drugs Fut 1995, 20, 5, 464.
【2】 Colin, M.; Guenard, D.; Gueritte-Voegelein, F.; Potier, P. (Aventis SA); Process for preparing derivs. of baccatine III and of 10-deacetyl baccatine III. US 4924012 .
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) 12479 (1S,2S,3R,4S,7R,9R,10R,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[2-oxo-2-(trityloxy)ethyl]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C71H68O12 详情 详情
(II) 12481 (1S,2S,3R,4S,7R,9R,10R,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-(1-ethoxyethoxy)-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[2-oxo-2-(trityloxy)ethyl]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C89H93NO17 详情 详情

合成路线2

A new method for the synthesis of the docetaxel side-chain has been reported: The esterification of (S)-phenylglycine (I) with SOCl2 and methanol gives the corresponding methyl ester (II), which is acylated with tert-butoxycarbonyl anhydride to the tert-butoxycarbonyl derivative (III). The reduction of (III) with dibutylaluminum hydride (DIBAL) in toluene yields the corresponding aldehyde (IV), which is condensed with 2-(trimethylsilyl)thiazole (V) by means of tetrabutylammonium fluoride (TBAF) to afford the (1R,2S)-N-[2-hydroxy-1-phenyl-2-(2-thiazolyl)ethyl]carbamic acid tert-butyl ester (VI) with 88% enantiomeric purity. The cyclization of (VI) with 2,2-dimethoxypropane (VII) catalyzed by camphosulfonic acid (CSA) gives (4S,5R)-3-(tert-butoxycarbonyl)-2,3-dimethyl-4-phenyl-5-(2-thiazolyl)ox azolidine (VIII), which is treated with methyl trifluoromethanesulfonate to afford (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb aldehyde (IX). Finally, this compound is oxidized with KMnO4 in tert-butanol/aqueous potassium phosphate buffer to yield the corresponding carboxylic acid, the (4S,5R)-3-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyloxazolidine-5-carb oxylic acid (X), the side-chain of taxotere suitably protected.

参考文献 中间体
【1】 Semola, T.; Dondoni, A.; Perrone, D.; Synthesis of Taxol and Taxotere side chains by 2-(trimethylsilyl)thiazole based homologation of L-phenylglycine. Synthesis 1995, 2, 2, 181.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
13214 Di-tert-butyldicarbonate; Dicarbonic acid bis(1,1-dimethylethyl) ester; dicarbonic acid di-tert-butyl ester pyrocarbonic acid di-tert-butyl ester; bis(1,1-dimethylethyl) dicarbonate di-tert-butyl pyrocarbonate 24424-99-5 C10H18O5 详情 详情
(I) 10716 (2S)-2-Amino-2-phenylethanoic acid; L-(+)-alpha-Phenylglycine 2935-35-5 C8H9NO2 详情 详情
(II) 10717 methyl (2S)-2-amino-2-phenylethanoate C9H11NO2 详情 详情
(III) 12485 methyl (2S)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoate C14H19NO4 详情 详情
(IV) 45428 tert-butyl (1S)-2-oxo-1-phenylethylcarbamate C13H17NO3 详情 详情
(V) 10720 2-(Trimethylsilyl)-1,3-thiazole 79265-30-8 C6H11NSSi 详情 详情
(VI) 12488 tert-butyl N-[(1S,2R)-2-hydroxy-1-phenyl-2-(1,3-thiazol-2-yl)ethyl]carbamate C16H20N2O3S 详情 详情
(VII) 10722 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane 77-76-9 C5H12O2 详情 详情
(VIII) 12490 tert-butyl (4S,5R)-2,2-dimethyl-4-phenyl-5-(1,3-thiazol-2-yl)-1,3-oxazolane-3-carboxylate C19H24N2O3S 详情 详情
(IX) 12491 tert-butyl (4S,5R)-5-formyl-2,2-dimethyl-4-phenyl-1,3-oxazolane-3-carboxylate C17H23NO4 详情 详情
(X) 12492 (4S,5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-phenyl-1,3-oxazolane-5-carboxylic acid C17H23NO5 详情 详情

合成路线3

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.

参考文献 中间体
【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

A new synthesis of docetaxel has been developed: The stereoselective dihydroxylation of methyl cinnamate (I) by the Sharpless AD process gives the enantiopure diol (II), which was treated first with tosyl chloride/triethylamine and then with K2CO3 in DMF yielding epoxide (III). Hydrolysis of the ester group of (III) with LiOH in methanol/water affords the epoxy-acid (IV), which is coupled with 7,10-bis(2,2,2-trichloroethoxycarbonyl)-10-deacetylbaccatin III (V) by means of dicyclohexylcarbodiimide (CDD) and dimethylaminopyridine in hot toluene to give the ester (VI). Regioselective cleavage of the epoxide ring of (VI) with NaN3 in aqueous methanol yielded the azide derivative (VII), which was treated with triphenylphosphine in the presence of tert-butoxycarbonyl anhydride and K2CO3 in dichloromethane affording the tert-butoxycarbonylamino derivative (VIII). Finally, (VIII) was submitted to a reductive deprotection with zinc powder in acetic acid.

参考文献 中间体
【1】 Harada, N.; Yamaguchi, T.; Hashiyama, T.; Ozaki, K.; Synthesis of taxoids 3. A novel and efficient method for preparation of taxoids employing cis-glycidic acid. Tetrahedron Lett 1998, 39, 5575.
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) 23888 methyl (E)-3-phenyl-2-propenoate 103-26-4 C10H10O2 详情 详情
(II) 23889 methyl (2S,3R)-2,3-dihydroxy-3-phenylpropanoate C10H12O4 详情 详情
(III) 23890 methyl (2R,3R)-3-phenyl-2-oxiranecarboxylate 99528-65-1 C10H10O3 详情 详情
(IV) 23891 (2R,3R)-3-phenyl-2-oxiranecarboxylic acid C9H8O3 详情 详情
(V) 23892 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C35H38Cl6O14 详情 详情
(VI) 23893 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-15-yl (2R,3R)-3-phenyl-2-oxiranecarboxylate C44H44Cl6O16 详情 详情
(VII) 23894 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-[[(2R,3S)-3-azido-2-hydroxy-3-phenylpropanoyl]oxy]-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl ben C44H45Cl6N3O16 详情 详情
(VIII) 23895 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,12-bis[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)] C49H55Cl6NO18 详情 详情

合成路线5

The acylation of 10-deacetylbaccatin III (I) with CDI in chloroform gives the 7,10-bis-O-(imidazolylcarbonyl) derivative (II), which is condensed with the chiral oxazolidinecarboxylic acid (III) by means of DCC and DMAP in hot toluene to yield the corresponding ester (IV). The hydrolysis of (IV) with aqueous TFA affords compound (V), which is finally treated with (Boc)2O and NaHCO3 in THF to provide the target docetaxel.

参考文献 中间体
【1】 Duvvuri, S.; Puranik, R. (Dr. Reddy's Research Foundation); An improved process for the preparation of docetaxel. WO 0212216 .
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) 54926 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetyloxy)-2-(benzoyloxy)-1,15-dihydroxy-9-[(1H-imidazol-1-ylcarbonyl)oxy]-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-12-yl 1H-imidazole-1-carboxylate C37H40N4O12 详情 详情
(III) 10551 (4S,5R)-3-(tert-Butoxycarbonyl)-2,2-dimethyl-4-phenyl-1,3-oxazolane-5-carboxylic acid C17H23NO5 详情 详情
(IV) 54927 5-{(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetyloxy)-2-(benzoyloxy)-1-hydroxy-9,12-bis[(1H-imidazol-1-ylcarbonyl)oxy]-10,14,17,17-tetramethyl-11-oxo-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 C54H61N5O16 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
Extended Information