Ixabepilone, 16-Aza-epothilone B, BMS 247550-01, NSC-710428, BMS-247550, -Drug Synthesis Database

【结构式】

【药物名称】Ixabepilone, 16-Aza-epothilone B, BMS 247550-01, NSC-710428, BMS-247550

【化学名称】(1S,3S,7S,10R,11S,12S,16R)-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methylthiazol-4-yl)vinyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione
　　　　　　(4S,7R,8S,9S,13R,14S,16S)-13,14-Epoxy-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-[1-methyl-2(E)-(2-methylthiazol-4-yl)vinyl]-1-azacyclohexadecane-2,6-dione

【CA登记号】219989-84-1

【分子式】C₂₇H₄₂N₂O₅S

【分子量】506.71019

【开发单位】Bristol-Myers Squibb (Originator), National Cancer Institute (Not Determined)

【药理作用】Brain Cancer Therapy, Breast Cancer Therapy, Colorectal Cancer Therapy, Lung Cancer Therapy, Melanoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Prostate Cancer Therapy, Renal Cancer Therapy, Solid Tumors Therapy, Antimitotic Drugs, Epothilones, Microtubule-Stabilizing Agents

合成路线1 合成路线2 合成路线3

合成路线1

The cleavage of the lactone group of epothilone B (I) by means of Na-N3 and tetrakis triphenylphosphine palladium (0) in THF gives the azido carboxylic acid (II), which is reduced with polymer-supported PPH3 (or in solution) or with H2 over PtO2 in ethanol to yield the amino acid (III). Finally, this compound is cyclized by means of diphenylphosphoryl azide (DPPA) in DMF.

参考文献中间体

【2】 Vite, G.D.; Kim, S.-H.; Johnson, J.A.; Borzilleri, R.M. (Bristol-Myers Squibb Co.); Epothilone derivs.. WO 9902514 .
【3】 Borzilleri, R.M.; Soong-Hoon, K. (Bristol-Myers Squibb Co.); A process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs. WO 9927890 .
【1】 Borzilleri, R.M.; Zheng, X.; Schmidt, R.J.; et al.; A novel application of a Pd(0)-catalyzed nucleophilic substitution reaction to the regio- and stereoselective synthesis of lactam analogues of the epothilone natural products. J Am Chem Soc 2000, 122, 37, 8890.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	42208	(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione	C₂₇H₄₁NO₆S	详情	详情
(II)	47825	(3S,6R,7S,8S)-11-[(2R,3S)-3-[(2S,3E)-2-azido-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid	C₂₇H₄₂N₄O₆S	详情	详情
(III)	47826	(3S,6R,7S,8S)-11-[(2R,3S)-3-[(2S,3E)-2-amino-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid	C₂₇H₄₄N₂O₆S	详情	详情

合成路线2

参考文献中间体

【1】 Borzilleri RM, Zheng X, Schmidt RJ, et al. 2000. A novel applicant pf a Pd(0)-catalyzed nucleophilic substitution reaction to the regio-and stereoselective synthesis of lactam analogues of the Epothilone natural products. J Am Chem Soc, 122: 8890～8897.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	42208	(1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione	C₂₇H₄₁NO₆S	详情	详情
(II)	47825	(3S,6R,7S,8S)-11-[(2R,3S)-3-[(2S,3E)-2-azido-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid	C₂₇H₄₂N₄O₆S	详情	详情
(III)	47826	(3S,6R,7S,8S)-11-[(2R,3S)-3-[(2S,3E)-2-amino-3-methyl-4-(2-methyl-1,3-thiazol-4-yl)-3-butenyl]-2-methyloxiranyl]-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid	C₂₇H₄₄N₂O₆S	详情	详情

合成路线3

参考文献中间体

【1】 Chappel MD, Stachel SJ, Lee CB, et al.2000. En route to a plant scale synthesis of the promising antitumor agent 12,13-desoxyepothilone B. Org Lett,2: 1633～1636.
【2】 Harris CR, Kuduk SD, Balog A, et al. 1999. New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation. J Am Chem Soc, 121: 7050～7062.
【3】 Stachel SJ, Lee CB,Spassova M, et al, 2001. On the interactivity of complex synthesis and tumor pharmacology in the drug discovery process: total synthesis and comparative in vivo evaluations of the 15-azaepothilones. J Org Chem, 66: 4369～4378.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	26239	tert-butyl 4,4-dimethyl-3,5-dioxoheptanoate	C₁₃H₂₂O₄	详情	详情
(II)	26240	tert-butyl (Z)-3-methoxy-4,4-dimethyl-5-oxo-2-heptenoate	C₁₄H₂₄O₄	详情	详情
(III)	26242	tert-butyl (2Z,6R,7S,8S)-7-hydroxy-3-methoxy-4,4,6,8-tetramethyl-5-oxo-2,10-undecadienoate	C₂₀H₃₄O₅	详情	详情
(IV)	26243	tert-butyl (2Z,6R,7S,8S)-3-methoxy-4,4,6,8-tetramethyl-5-oxo-7-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-2,10-undecadienoate	C₂₃H₃₅Cl₃O₇	详情	详情
(V)	67166	(S)-4-benzyl-3-(2-((triethylsilyl)oxy)acetyl)oxazolidin-2-one	C₁₈H₂₇NO₄Si	详情	详情
(VI)	67167	(4S)-4-benzyl-3-((Z)-5-iodo-2-((triethylsilyl)oxy)hex-4-enoyl)oxazolidin-2-one	C₂₂H₃₂INO₄Si	详情	详情
(VII)	67168	(S,Z)-N-ethyl-5-iodo-N-methyl-2-((triethylsilyl)oxy)hex-4-enamide	C₁₄H₂₈INO₃Si	详情	详情
(VIII)	67169	(S,Z)-6-iodo-3-((triethylsilyl)oxy)hept-5-en-2-one	C₁₃H₂₅IO₂Si	详情	详情
(IX)	67170	4-((S,1E,5Z)-6-iodo-2-methyl-3-((triethylsilyl)oxy)hepta-1,5-dien-1-yl)-2-methylthiazole	C₁₈H₃₀INOSiS	详情	详情
(X)	67171	(S,1E,5Z)-6-iodo-2-methyl-1-(2-methylthiazol-4-yl)hepta-1,5-dien-3-ol	C₁₂H₁₆INOS	详情	详情
(XI)	67172	4-((S,1E,5Z)-3-azido-6-iodo-2-methylhepta-1,5-dien-1-yl)-2-methylthiazole	C₁₂H₁₅IN₄S	详情	详情
(XII)	67173	(2Z,6S,7R,8R,12Z,15R,16E)-tert-butyl 15-azido-3-methoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxo-7-((4,4,4-trichlorobutanoyl)oxy)heptadeca-2,12,16-trienoate	C₃₅H₅₁Cl₃N₄O₇S	详情	详情
(XIII)	67174	(2Z,6S,7R,8R,12Z,15R,16E)-tert-butyl 15-((tert-butoxycarbonyl)amino)-3-methoxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxo-7-((4,4,4-trichlorobutanoyl)oxy)heptadeca-2,12,16-trienoate	C₄₀H₆₁Cl₃N₂O₉S	详情	详情
(XIV)	67175	(6S,7R,8R,12Z,15R,16E)-tert-butyl 15-((tert-butoxycarbonyl)amino)-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-3,5-dioxo-7-((4,4,4-trichlorobutanoyl)oxy)heptadeca-12,16-dienoate	C₃₉H₅₉Cl₃N₂O₉S	详情	详情
(XV)	67176	(6S,7R,8R,12Z,15R,16E)-1-(tert-butoxy)-15-((tert-butoxycarbonyl)amino)-1-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-3,5-dioxoheptadeca-12,16-dien-7-yl 4,4,4-trichlorobutanoate	C₃₉H₆₁Cl₃N₂O₉S	详情	详情
(XVI)	67177	(6S,7R,8R,12Z,15R,16E)-15-amino-3-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxo-7-((4,4,4-trichlorobutanoyl)oxy)heptadeca-12,16-dienoic acid	C₃₀H₄₅Cl₃N₂O₇S	详情	详情
(XVII)	67178	(4R,7S,8R,9R,16R)-4-hydroxy-5,5,7,9,13-pentamethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-2,6-dioxoazacyclohexadec-13-en-8-yl 4,4,4-trichlorobutanoate	C₃₁H₄₅Cl₃N₂O₅S	详情	详情
(XVIII)	67179	4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)azacyclohexadec-13-ene-2,6-dione	C₂₇H₄₂N₂O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)