SB-T-12843, -Drug Synthesis Database

【结构式】

【药物名称】SB-T-12843

【化学名称】[2aR-[2aalpha,4beta,4abeta,6beta,9alpha(2R,3R),10beta,11beta,12alpha,12aalpha,12balpha]]-12b-Acetoxy-12-benzoyloxy-9-[3-(tert-butoxycarbonylamino)-4,4-difluoro-2-hydroxybutyryloxy]-6-(3,3-dimethylbutyryloxy)-4,11-dihydroxy-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】C₄₄H₅₉F₂NO₁₅

【分子量】879.95533

【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). Ozonolysis of the olefinic bond of (IV) at -78 C in CH2Cl2-MeOH, followed by reductive workup using Me2S afforded aldehyde (V). Subsequent treatment of (V) with diethylaminosulfur trifluoride in CH2Cl2 at r.t. yielded the difluoromethyl lactam (VI). Then, the N-p-methoxyphenyl group of (VI) was removed by oxidative treatment with ceric ammonium nitrate at -5 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.
【2】 Ferlini, C.; Scambia, G.; Lin, S.; Bernacki, R.J.; Ojima, I.; Wang, T.; Pera, P.; Slater, J.C.; Syntheses and biological activity of C3'-difluoromethyl taxoids. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 39.
【3】 Pera, P.; Scambia, G.; Ojima, I.; Lin, S.; Wang, T.; Ferlini, C.; Slater, J.C.; Bernacki, R.J.; Syntheses and biological activity of C-3'-difluoromethyl-taxoids. Bioorg Med Chem Lett 2000, 8, 7, 1619.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	19151	(1R,2S)-2-phenylcyclohexyl 2-[(triisopropylsilyl)oxy]acetate	C₂₃H₃₈O₃Si	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
(III)	19154	4-methoxy-N-[(E)-3-methyl-2-butenylidene]aniline; N-(4-methoxyphenyl)-N-[(E)-3-methyl-2-butenylidene]amine	C₁₂H₁₅NO	详情	详情
(IV)	21732	(3R,4S)-1-(4-methoxyphenyl)-4-[(E)-1-propenyl]-3-[(triisopropylsilyl)oxy]-2-azetidinone	C₂₂H₃₅NO₃Si	详情	详情
(V)	21733	(2R,3R)-1-(4-methoxyphenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-2-azetidinecarbaldehyde	C₂₀H₃₁NO₄Si	详情	详情
(VI)	21734	(3R,4R)-4-(difluoromethyl)-1-(4-methoxyphenyl)-3-[(triisopropylsilyl)oxy]-2-azetidinone	C₂₀H₃₁F₂NO₃Si	详情	详情
(VII)	21735	tert-butyl (2R,3R)-2-(difluoromethyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate	C₁₈H₃₃F₂NO₄Si	详情	详情

合成路线2

The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acylation of (IX) at C-10 hydroxyl group with acid chloride (X) 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】 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.
【2】 Ferlini, C.; Scambia, G.; Lin, S.; Bernacki, R.J.; Ojima, I.; Wang, T.; Pera, P.; Slater, J.C.; Syntheses and biological activity of C3'-difluoromethyl taxoids. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 39.
【3】 Pera, P.; Scambia, G.; Ojima, I.; Lin, S.; Wang, T.; Ferlini, C.; Slater, J.C.; Bernacki, R.J.; Syntheses and biological activity of C-3'-difluoromethyl-taxoids. Bioorg Med Chem Lett 2000, 8, 7, 1619.

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)	21735	tert-butyl (2R,3R)-2-(difluoromethyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate		C₁₈H₃₃F₂NO₄Si	详情	详情
(VIII)	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
(IX)	21737	(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
(X)	21738	3,3-dimethylbutanoyl chloride	7065-46-5	C₆H₁₁ClO	详情	详情
(XI)	21739	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-12-[(3,3-dimethylbutanoyl)oxy]-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		C₄₁H₆₀O₁₁Si	详情	详情

Extended Information