TAX-109, 109881, XRP-9881, RPR-109881A, -Drug Synthesis Database

【结构式】

【药物名称】TAX-109, 109881, XRP-9881, RPR-109881A

【化学名称】(2aR,3aR,4aR,6R,9S,11S,12S,12aR,12bS)-6,12b-Diacetoxy-9-[3(S)-(tert-butoxycarbonylamino)-2(R)-hydroxy-3-phenylpropionyloxy]-12-benzoyloxy-11-hydroxy-8,13,13-trimethyl-2a,3,3a,4,5,6,9,10,11,12,12a,12b-dodecahydro-1H-7,11-methanocyclodeca[3,4]cyclopropa[4,5]benz[1,2-b]oxet-5-one dihydrate

【CA登记号】192573-38-9, 156294-36-9 (anhydrous)

【分子式】C₄₅H₅₇NO₁₆

【分子量】867.95314

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

【药理作用】Brain Cancer Therapy, Breast Cancer Therapy, Oncolytic Drugs, 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1

The reaction of the taxane derivative (I) with trifluoromethanesulfonic anhydride gives the monotriflate (II), which is treated with sodium azide in hot acetonitrile to yield the cyclopropa derivative (III). The cleavage of the oxazolidine ring of (III) by means of formic acid affords the 3-amino-2-hydroxy derivative (IV), which is finally acylated with tert-butoxycarbonyl anhydride to provide the target taxoid derivative.

参考文献中间体

【1】 Bouchard, H.; Buourzat, J.-D.; Commercon, A. (Aventis Pharma SA); Novel taxoids, preparation thereof and pharmaceutical compsns. containing same. EP 0673372; FR 2698871; JP 1996504425; JP 1998291930; US 5814658; WO 9413654 .
【2】 Renard, A.; Bissery, M.-C. (Aventis Pharma SA); Method for treating abnormal cell proliferation in the brain. US 6156789 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	49338	5-[(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-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] 3-(tert-butyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate	C₄₈H₅₉NO₁₅	详情	详情
(II)	49339	5-((1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-2-(benzoyloxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(trifluoromethyl)sulfonyl]oxy]-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	C₄₉H₅₈F₃NO₁₇S	详情	详情
(III)	49340	5-[(1S,2S,3R,4S,7R,9S,11R,13R,16S)-4,13-bis(acetoxy)-2-(benzoyloxy)-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-16-yl] 3-(tert-butyl) (4S,5R)-2,2-dimethyl-4-phenyl-1,3-oxazolidine-3,5-dicarboxylate	C₄₈H₅₇NO₁₄	详情	详情
(IV)	39341	methyl 2-(5-chloro-2-methoxyphenyl)acetate	C₁₀H₁₁ClO₃	详情	详情

合成路线2

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.

参考文献中间体

【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3

The reaction of the taxoid compound (I) with DAST gives the cyclopropataxoid compound (II), which is finally deprotected with Zn and HOAc to yield the target compound.

参考文献中间体

【1】 Skulnick, H.I.; Johnson, R.A.; Midy, E.G.; Kelly, R.C.; Hester, J.B. Jr. (Pharmacia Corp.); 7-Halo and 7beta,8beta-methano-taxols, antineoplastic use and pharmaceutical compsns. containing them. EP 0674630; WO 9413655 .

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)	49348	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[((2R,3S)-3-[(tert-butoxycarbonyl)amino]-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 benzoate		C₄₈H₅₆Cl₃NO₁₇	详情	详情
(II)	49349	(1S,2S,3R,4S,7R,9S,11R,13R,16S)-4,13-bis(acetoxy)-16-[((2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-phenyl-2-[[(2,2,2-trichloroethoxy)carbonyl]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		C₄₈H₅₄Cl₃NO₁₆	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)