(1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-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 -Drug Synthesis Database

【结构式】

【分子编号】10531

【品名】(1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-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

【CA登记号】

【分子式】C₃₇H₅₂O₁₀Si

【分子量】684.89938

【元素组成】C 64.89% H 7.65% O 23.36% Si 4.1%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XX)

Compound (XV) is selectively acetylated with acetic anhydride and DMAP to the diol (XVI). The replacement of the benzyl protecting group by a triethylsilyl (TES) group in (XVI) by debenzylation with H2 over Pd(OH)2/C followed by treatment with TESCl in pyridine and deacetylation with K2CO3 in methanol affords the silylated triol (XVII). The formation of the oxetane ring is carried out by treatment of (XVII) with trimethylsilyl chloride (TMSCl) and pyridine (silylation of the primary alcohol), subsequent reaction with Tf2O (activation of the secondary alcohol), and cyclization by acidic treatment with CSA to give compound (XVIII) with the oxetane ring and a tertiary OH group. The acetylation of (XVIII) with acetic anhydride and DMAP affords compound (XIX) with the tertiary acetoxy group. The reaction of (XIX) with phenyllithium gives the benzoyloxy derivative (XX), which is oxidized with pyridinium chlorochromate (PCC) to yield the diketone (XXI). The reduction of (XXI) with NaBH4 in methanol affords compound (XXII) with the appropriate secondary hydroxy group, which is acylated with Ojima's beta-lactam (XXIII) by means of sodium bis(trimethylsilyl)amide to give the silylated paclitaxel (XXIV). Finally, this compound is deprotected with HF/pyridine.

参考文献中间体

合成目标

【1】 Yang, Z.; Liu, J.J.; Nicolaou, K.C.; et al.; Total synthesis of taxol. Nature 1994, 367, 6464, 630.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XV)	10526	(1S,5S,6R,7S,8S,10S,11S,13R)-7,8,10-trihydroxy-7-(hydroxymethyl)-11,15,18,18-tetramethyl-3,12-dioxo-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate		C₂₃H₃₂O₁₀	详情	详情
(XVI)	10527	(1S,5S,6R,7S,8S,10S,11S,13R)-7-[(acetoxy)methyl]-7,8,10-trihydroxy-11,15,18,18-tetramethyl-3,12-dioxo-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate		C₂₅H₃₄O₁₁	详情	详情
(XVII)	10528	(1S,5S,6R,7S,8S,10S,11S,13R)-7,8-dihydroxy-7-(hydroxymethyl)-11,15,18,18-tetramethyl-3,12-dioxo-10-[(triethylsilyl)oxy]-2,4-dioxatetracyclo[12.3.1.0(1,5).0(6,11)]octadec-14-en-13-yl acetate		C₂₉H₄₆O₁₀Si	详情	详情
(XVIII)	10529	(1S,5S,6R,7S,10R,12S,13S,15R)-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-15-yl acetate		C₂₉H₄₄O₉Si	详情	详情
(XIX)	10530	(1S,5S,6R,10R,12S,13S,15R)-15-(acetoxy)-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-7-yl acetate		C₃₁H₄₆O₁₀Si	详情	详情
(XX)	10531	(1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-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		C₃₇H₅₂O₁₀Si	详情	详情
(XXI)	10488	(1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-10,14,17,17-tetramethyl-11,15-dioxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate		C₃₇H₅₀O₁₁Si	详情	详情
(XXII)	10473	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-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		C₃₇H₅₂O₁₁Si	详情	详情
(XXIII)	10490	(3R,4S)-1-Benzoyl-4-phenyl-3-[(triethylsilyl)oxy]-2-azetanone		C₂₂H₂₇NO₃Si	详情	详情
(XXIV)	10535	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-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	n/a	AB	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXII)

Epoxide (XVIII) is debenzylated by hydrogenation and acetylated with acetic anhydride and dimethylaminopyridine (DMAP) to compound (XIX). The ring opening of the cyclic carbonate group of (XIX) with phenyllithium affords compound (XX) with the secondary benzoate group and the tertiary hydroxy substituent of paclitaxel. The oxidation of the methylene group of (XX) with OsO4 and lead tetraacetate affords the epoxy ketone (XXI). The deoxygenation of the epoxy group of (XXI) is performed with SmI2 and acetic anhydride, and after oxidation, alpha-ketol interchange and acetylation, compound (XXII) with almost all the functionality of paclitaxel is obtained. The allylic oxidation of (XXII) with pyridinium chlorochromate (PCC) followed by reduction with NaBH4 affords triethylsilyl-baccatin III (XXIII), which is deprotected with HF.pyridine to baccatin III (XXIV). Finally, both compounds (XXIII) and (XXIV) are converted to paclitaxel by known methods (J Org Chem 1991, 56: 1681).

参考文献中间体

合成目标

【1】 Masters, J.J.; Young, W.B.; Snyder, L.B.; Link, J.T.; Danishefsky, S.J.; A total synthesis of Taxol. Angew Chem. Int Ed Engl 1995, 34, 16, 1723.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XVIII)	10709	(1S,4S,5S,7R,10S,11R,12S,16S,19R)-10-(Benzyloxy)-4,19,21,21-tetramethyl-2-methylene-5-[(triethylsilyl)oxy]-8,13,15,20-tetraoxahexacyclo[14.4.1.0(1,19).0(4,11).0(7,10).0(12,16)]henicosan-14-one	C₃₅H₅₀O₇Si	详情	详情
(XIX)	10710	(1S,4S,5S,7R,11R,12S,16S,19R)-4,19,21,21-tetramethyl-2-methylene-14-oxo-5-[(triethylsilyl)oxy]-8,13,15,20-tetraoxahexacyclo[14.4.1.0(1,19).0(4,11).0(7,10).0(12,16)]henicos-10-yl acetate	C₃₀H₄₆O₈Si	详情	详情
(XX)	10711	(1S,4S,5S,7R,10S,11R,12S,13S,16R)-10-(acetoxy)-13-hydroxy-4,16,18,18-tetramethyl-2-methylene-5-[(triethylsilyl)oxy]-8,17-dioxapentacyclo[11.4.1.0(1,16).0(4,11).0(7,10)]octadec-12-yl benzoate	C₃₆H₅₂O₈Si	详情	详情
(XXI)	10712	(1S,4S,5S,7R,10S,11R,12S,13S,16R)-10-(acetoxy)-13-hydroxy-4,16,18,18-tetramethyl-2-oxo-5-[(triethylsilyl)oxy]-8,17-dioxapentacyclo[11.4.1.0(1,16).0(4,11).0(7,10)]octadec-12-yl benzoate	C₃₅H₅₀O₉Si	详情	详情
(XXII)	10531	(1S,2S,3R,4S,7R,9S,10S,12R)-4,12-bis(acetoxy)-1-hydroxy-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	C₃₇H₅₂O₁₀Si	详情	详情
(XXIII)	10473	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-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	C₃₇H₅₂O₁₁Si	详情	详情
(XXIV)	10447	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-1,9,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate	C₃₁H₃₈O₁₁	详情	详情

Extended Information