BMS-188797, -Drug Synthesis Database

【结构式】

【药物名称】BMS-188797

【化学名称】4-O-Deacetyl-4-O-(methoxycarbonyl)paclitaxel
　　　　　　3(S)-Benzamido-2(R)-hydroxybenzenepropionic acid (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-6-acetoxy-12-(benzoyloxy)-4,11-dihydroxy-12b-(methoxycarbonyloxy)-4a,8,13,13-tetramethyl-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】172481-83-3

【分子式】C₄₇H₅₁NO₁₅

【分子量】869.92822

【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1

The silyl-protected 4-deacetyl baccatin (I) was deprotonated with lithium bis(trimethylsilyl) amide and then condensed with methyl chloroformate to produce carbonate (II). Desilylation of (II) using HF in pyridine afforded triol (III), which was selectively resilylated at the 7-hydroxyl group to furnish (IV). Attachment of the C-13 side-chain of (IV) was achieved by treatment with lactam (V) and lithium bis(trimethylsilyl)amide, yielding ester (VI). Finally, the silyl protecting groups of (VI) were removed by treatment with HF in pyridine.

参考文献中间体

【1】 Long, B.H.; Chen, S.H.; Wei, J.-M.; et al.; Novel C-4 paclitaxel (Taxol) analogs: Potent antitumor agents. Bioorg Med Chem Lett 1995, 5, 22, 2741.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	41096	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1-[(dimethylsilyl)oxy]-4-hydroxy-10,14,17,17-tetramethyl-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₄₃H₇₀O₁₀Si₃	详情	详情
(II)	41097	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1-[(dimethylsilyl)oxy]-4-[(methoxycarbonyl)oxy]-10,14,17,17-tetramethyl-11-oxo-9,15-bis[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₄₅H₇₂O₁₂Si₃	详情	详情
(III)	41098	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1,9,15-trihydroxy-4-[(methoxycarbonyl)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	C₃₁H₃₈O₁₂	详情	详情
(IV)	41099	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1,15-dihydroxy-4-[(methoxycarbonyl)oxy]-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	C₃₇H₅₂O₁₂Si	详情	详情
(V)	10490	(3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone	C₂₂H₂₇NO₃Si	详情	详情
(VI)	41100		C₅₉H₇₉NO₁₅Si₂	详情	详情

合成路线2

In an alternative procedure, paclitaxel (VII) was sequentially protected at the 2’ hydroxyl with tert-butyldimethylsilyl chloride and then at the 7-hydroxyl with triethylsilyl chloride, yielding the disilylated derivative (VIII). Selective hydrolysis of the C-2 benzoate and the C-4 acetate esters of (VIII) with Triton B afforded the triol (IX). Protection of the C-1 and C-2 hydroxy groups of (IX) with carbonyldiimidazole gave the 1,2-cyclic carbonate derivative (X). Subsequent treatment of (X) with methyl chloroformate and lithium bis(trimethylsilyl)amide introduced the 4-O-methoxycarbonyl group to furnish (XI). Opening of the cyclic carbonate group of (XI) with phenyllithium produced the benzoate ester (XII). The silyl protecting groups of (XII) were then removed by means of HF-pyridine.

参考文献中间体

【1】 Gunatilaka, A.A.; Kingston, D.G.I.; Sarragiotto, M.H.; Ramdayal, F.D.; Synthesis and biological evaluation of novel paclitaxel (Taxol) D-ring modified analogs. J Org Chem 1999, 64, 8, 2694.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VII)	41101	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[[(2R,3R)-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
(VIII)	41102	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-[((2R,3R)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-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)]heptade	C₅₉H₇₉NO₁₄Si₂	详情	详情
(IX)	41103	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-12-(acetoxy)-1,2,4-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-15-yl (2R,3R)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-phenylprop	C₅₀H₇₃NO₁₂Si₂	详情	详情
(X)	41104	(1S,5S,6R,7S,10R,12S,13S,15R,18S)-15-(acetoxy)-7-hydroxy-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-18-yl (2R,3R)-3-(benzoylamino)-2-[[tert-butyl(dimethyl)silyl]oxy]-3	C₅₁H₇₁NO₁₃Si₂	详情	详情
(XI)	41105	(1S,5S,6R,7S,10R,12S,13S,15R,18S)-15-(acetoxy)-7-[(methoxycarbonyl)oxy]-13,17,20,20-tetramethyl-3,14-dioxo-12-[(triethylsilyl)oxy]-2,4,9-trioxapentacyclo[14.3.1.0(1,5).0(6,13).0(7,10)]icos-16-en-18-yl (2R,3R)-3-(benzoylamino)-2-[[tert-butyl(dimeth	C₅₃H₇₃NO₁₅Si₂	详情	详情
(XII)	41106		C₅₉H₇₉NO₁₅Si₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)