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【结 构 式】

【药物名称】BMS-184476

【化学名称】7-O-(Methylsulfanylmethyl)paclitaxel
　　　　　　3(S)-Benzamido-2(R)-hydroxybenzenepropionic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6,12b-diacetoxy-12-(benzoyloxy)-11-hydroxy-4a,8,13,13-tetramethyl-4-(methylsulfanylmethoxy)-5-oxo-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]benz[1,2-b]oxet-9-yl ester

【CA登记号】160237-25-2

【 分 子 式 】C49H55NO14S

【 分 子 量 】914.047

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】ONCOLYTIC DRUGS, Radiation Therapy, Radiosensitizers, 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1

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.

参考文献 中间体
【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2

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 oxazolidine-carboxylic acid (IV) by means of DCC and DMAP in ethyl acetate affords the 13-O-ester (V), which is desilylated by means of HF and TEA in dichloromethane to provide the free 7-hydroxy derivative (VI). The reaction of (VI) with dimethylsulfoxide, Ac2O and HOAc gives the 7-O-(methylsulfanylmethyl) derivative (VII), which is finally hydrolyzed at the oxazolidine ring by means of HCl in ethyl acetate to give rise to the target 7-O-(methlsulfanylmethyl)taxol.

参考文献 中间体
【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
(IV) 57902 (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylic acid C24H21NO5 详情 详情
(V) 57903 (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-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate C61H71NO15Si 详情 详情
(VI) 57904 (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 (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate C55H57NO15 详情 详情
(VII) 57905 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-2-(benzoyloxy)-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-15-yl (2R,4S,5R)-3-benzoyl-2-(4-methoxyphenyl)-4-phenyl-1,3-oxazolidine-5-carboxylate C57H61NO15S 详情 详情

合成路线3

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 desilylation of (III) by means of HCl in ethanol yields baccatin III (VIII), which is condensed with DMSO by means of Ac2O and HOAc to afford the ketonic derivative (IX). The reduction of (IX) by means of NaBH4 in ethanol affords 7-O-(methylsulfanylmethyl)baccatin III (X), which is condensed with the chiral azetidinone (XI) by means of LiHMDS in THF to provide 2'-O-(1-ethoxyethyl)-7-O-(methylsulfanylmethyl)taxol (XII). Finally, this compound is deprotected by means of HCl in ethanol to give the target 7-O-(methylsulfanylmethyl)taxol.

参考文献 中间体
【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
(VIII) 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
(IX) 57906 (1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetyloxy)-1-hydroxy-10,14,17,17-tetramethyl-9-[(methylsulfanyl)methoxy]-11,15-dioxo-6-oxatetracyclo[11.3.1.0~3,10~.0~4,7~]heptadec-13-en-2-yl benzoate C33H40O11S 详情 详情
(X) 57907 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetyloxy)-1,15-dihydroxy-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 C33H42O11S 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

合成路线4

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.

参考文献 中间体
【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
Extended Information
Drug NewChemical Entity Original Patent(1)