(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 -Drug Synthesis Database

【结构式】

【分子编号】19160

【品名】(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

【CA登记号】

【分子式】C₃₆H₄₈O₁₂Si

【分子量】700.85542

【元素组成】C 61.7% H 6.9% O 27.39% Si 4.01%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XIII)

Protection of 14b-hydroxy-10-deacetylbaccatin (XI) with triethylsilyl chloride in pyridine-DMF provided the 7-silyl ether (XII). This compound was condensed with phosgene in CH2Cl2 to give cyclic carbonate (XIII), which was deprotonated with lithium hexamethyldisilazide (LiHMDS) in THF at -40 C, and then selectively acetylated at the 10 hydroxyl group with AcCl. The resulting baccatin derivative (XIV) was coupled with azetidinone (X) in the presence of LiHMDS in THF at -40 C to provide ester (XV), which was then desilylated by treatment with HF. Finally, the resulting isobutenyl compound (XVI) was hydrogenated in the presence of Pd/C to produce the target isobutyl derivative.

参考文献中间体

合成目标

【1】 Ojima, I.; et al.; Syntheses and structure-activity relationships of taxoids derived from 14beta-hydroxy-10-deacetylbaccatin III. J Med Chem 1997, 40, 3, 267.
【2】 Takahashi, N.; et al.; Growth inhibition of gastric cancer cells by troglitazone, a ligand for peroxisome proliferator-activated receptor. Dig Dis Week (May 16 1999, Orlando) 1999, Abst 3684.
【3】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	19157	tert-butyl (2S,3R)-2-(2-methyl-1-propenyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate	C₂₁H₃₉NO₄Si	详情	详情
(XI)	19158	(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
(XII)	19159	(1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-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	C₃₅H₅₀O₁₁Si	详情	详情
(XIII)	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
(XIV)	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
(XV)	19162	(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-5-methyl-2-[(triisopropylsilyl)oxy]-4-hexenoyl]oxy)-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	C₅₉H₈₉NO₁₇Si₂	详情	详情
(XVI)	19163	(1S,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-5-methyl-4-hexenoyl]oxy)-9-hydroxy-10,14,20,20-tetramethyl-11,18-dioxo-6,17,19-trioxapentacyclo[11.6.1.0(1,16).0(3,10).0(4,7)]icos-13-en-2-yl benzoate	C₄₄H₅₅NO₁₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

Semisynthesis of the first synthon: The diterpene 14beta-hydroxy-10-deacetylbaccatin III (I) was extracted in a highly purified form from the needles of Taxus wallichiana cultivated in the Himalayan region. It was then converted in 7-O-(triethylsilyl)-14beta-hydroxybaccatin III-1,14-carbonate (IV) according to the following scheme: 14beta-hydroxy-10-deacetylbaccatin III (I) was dissolved in anhydrous DMF and treated with N-methylimidazole and chlorotriethylsilane to provide 7-O-(triethylsilyl)-10-deacetyl-14beta-hydroxybaccatin III (II) in an almost quantitative yield. Compound (II) was dissolved in a mixture of methylene chloride and dry pyridine and added slowly to a cooled phosgene solution giving 7-O-(triethylsilyl-10-deacetyl-14beta-hydroxybaccatin III-1,14-carbonate (III). After acetylation of compound (III) in pyridine and acetyl chloride, the synthon (IV) was obtained and was ready for coupling.

参考文献中间体

合成目标

【1】 Laccabue, D.; Pratesi, G.; BAY 59-8862. Drugs Fut 2001, 26, 6, 533.
【2】 Ojima, I.; Bombardelli, E. (Affymax Technologies, NV; State University of New York, Albany); Anti-tumor cpds., pharmaceutical compsns., methods for preparation thereof and for treatment. US 5705508 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	19158	(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
(II)	19159	(1R,2S,3R,4S,7R,9S,10S,12R,15R,16S)-4-(acetoxy)-1,12,15,16-tetrahydroxy-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	C₃₅H₅₀O₁₁Si	详情	详情
(III)	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
(IV)	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

合成路线3

该中间体在本合成路线中的序号：(X)

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

合成目标

【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