SB-T-101187, -Drug Synthesis Database

【结构式】

【药物名称】SB-T-101187

【化学名称】[2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3S),10beta,11beta,12alpha,12aalpha,12balpha]]-6,12b-Diacetoxy-9-[3-(tert-butoxycarbonylamino)-3-[2,2-dimethyl-1(R)-cyclopropyl]-2-hydroxypropionyloxy]-10,11-(carbonyldioxy)-4-hydroxy-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】

【分子式】C₄₅H₅₇NO₁₇

【分子量】883.95254

【开发单位】State University of New York,Stony Brook (Originator)

【药理作用】ONCOLYTIC DRUGS, Antimitotic Drugs, Microtubule-Stabilizing Agents, Taxanes

合成路线1 合成路线2

合成路线1

Lithium enolate (II), generated from chiral ester (I) and LDA at -84 C, was cyclocondensed with imine (III) to furnish azetidinone (IV). After removal of the triisopropylsilyl group of (IV) using HF in pyridine, the resulting lactam was treated with CH2I2 and Et2Zn in 1,2-dichloroethane to give the dimethylcyclopropyl azetidinone (V). The C-3 hydroxyl group was reprotected as the triisopropylsilyl ether (VI). Then, the N-p-methoxyphenyl group of (VI) was removed by oxidative treatment with ceric ammonium nitrate at -10 C, and the resulting azetidinone was N-protected with Boc2O to afford tert-butyl carbamate (VII).

参考文献中间体

【1】 Lin, S.; et al.; Syntheses and biological activity of advanced second-generation taxoids. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 315.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	19161	(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate	C₃₈H₅₀O₁₃Si	详情	详情
(II)	21730	2-(Triisopropylsilyloxy)-1-(2(S)-phenyl-1(R)-cyclohexyl)vinyl-1-ol lithium salt	C₂₃H₃₇LiO₃Si	详情	详情
(IV)	21740	(3R,4S)-1-(4-hydroxyphenyl)-4-(2-methyl-1-propenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone	C₂₂H₃₅NO₃Si	详情	详情
(V)	21741	(3R,4S)-4-[(1S)-2,2-dimethylcyclopropyl]-3-hydroxy-1-(4-methoxyphenyl)-2-azetidinone	C₁₅H₁₉NO₃	详情	详情
(VI)	21742	(3R,4S)-4-[(1S)-2,2-dimethylcyclopropyl]-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone	C₂₄H₃₉NO₃Si	详情	详情
(VII)	21743	tert-butyl (2S,3R)-2-[(1S)-2,2-dimethylcyclopropyl]-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate	C₂₂H₄₁NO₄Si	详情	详情

合成路线2

Protection of the C-7 hydroxyl group of 14-b-hydroxy-10-deacetyl baccatin III (VIII) with triethylsilyl chloride and imidazole yielded silyl ether (IX). Then, the 1,14-diol of (IX) was converted to cyclic carbonate (X) by treatment with diphosgene in the presence of pyridine. Subsequent selective acetylation of (X) at C-10 hydroxyl group with acetyl chloride in the presence of LiN(SiMe3)2 afforded ester (XI). The title taxoid was then obtained by further coupling of (XI) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine.

参考文献中间体

【1】 Toyoshi, T.; Nomura, T.; Ogawa, A.; et al.; A four-week intravenous toxicity study of flecainide acetate in rats with a two-week recovery phase. Clin Rep 1994, 28, 6, 13.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	21743	tert-butyl (2S,3R)-2-[(1S)-2,2-dimethylcyclopropyl]-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate		C₂₂H₄₁NO₄Si	详情	详情
(VIII)	21744	(1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,9,12,15,16-pentahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₂₉H₃₆O₁₁	详情	详情
(IX)	19169	tert-butyl N-[3-(aminomethyl)benzyl]carbamate; tert-butyl 3-(aminomethyl)benzylcarbamate	108467-99-8	C₁₃H₂₀N₂O₂	详情	详情
(X)	19160	(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-12,15-dihydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate		C₃₆H₄₈O₁₂Si	详情	详情
(XI)	19161	(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-9-[(triethylsilyl)oxy]-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate		C₃₈H₅₀O₁₃Si	详情	详情

Extended Information