tert-butyl (2S,3R)-2-(3-fluoro-2-pyridinyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate -Drug Synthesis Database

【结构式】

【分子编号】56387

【品名】tert-butyl (2S,3R)-2-(3-fluoro-2-pyridinyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate

【CA登记号】

【分子式】C₂₂H₃₅FN₂O₄Si

【分子量】438.6148832

【元素组成】C 60.24% H 8.04% F 4.33% N 6.39% O 14.59% Si 6.4%

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：(II)

The title taxane derivative is prepared by two related ways. Taxane (I) is condensed with azetidinone (II) in the presence of lithium hexamethyldisilazide to afford ester (III). The triisopropylsilyl protecting group of (III) is then removed by using a solution of tetrabutylammonium fluoride in THF, yielding (IV). Dihydroxylation of the vinyl group of (IV) with N-methylmorpholine N-oxide in the presence of osmium tetroxide produces diol (V), which is subsequently cleaved to aldehyde (VI) by means of NaIO4. Finally, reductive amination of aldehyde (VI) with dimethylamine and NaBH3CN gives rise to the target amine.

参考文献中间体

合成目标

【1】 Soga, T.; Takeda, Y.; Uoto, K. (Daiichi Pharmaceutical Co., Ltd.); Pentacyclic taxane cpds.. EP 1221445; WO 0127115 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	56386	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-16,18-dihydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate	C₃₂H₄₀O₉	详情	详情
(II)	56387	tert-butyl (2S,3R)-2-(3-fluoro-2-pyridinyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate	C₂₂H₃₅FN₂O₄Si	详情	详情
(III)	56388	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-16-hydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate	C₅₄H₇₅FN₂O₁₃Si	详情	详情
(IV)	56389	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-{[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-hydroxypropanoyl]oxy}-16-hydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate	C₄₅H₅₅FN₂O₁₃	详情	详情
(V)	56390	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-{[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-hydroxypropanoyl]oxy}-4-[(1R)-1,2-dihydroxyethyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate	C₄₅H₅₇FN₂O₁₅	详情	详情
(VI)	56391	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-{[(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-hydroxypropanoyl]oxy}-4-formyl-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate	C₄₄H₅₃FN₂O₁₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Similarly, condensation of taxane (I) with azetidinone (II) in the presence of lithium hexamethyldisilazide affords ester (III). The terminal vinyl group of (III) is converted to aldehyde (IV) by dihydroxylation with NMMO/OsO4, followed by oxidative cleavage with NaIO4. Reductive amination of aldehyde (IV) with dimethylamine and NaBH3CN yields amine (V). Selective catalytic hydrogenation of the disubstituted olefin of (V) produces taxane (VI), which is finally O-desilylated employing tetrabutylammonium fluoride in cold THF.

参考文献中间体

合成目标

【1】 Soga, T.; Takeda, Y.; Uoto, K. (Daiichi Pharmaceutical Co., Ltd.); Pentacyclic taxane cpds.. EP 1221445; WO 0127115 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	56392	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-16,18-dihydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate	C₃₂H₃₈O₉	详情	详情
(II)	56387	tert-butyl (2S,3R)-2-(3-fluoro-2-pyridinyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate	C₂₂H₃₅FN₂O₄Si	详情	详情
(III)	56393	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-16-hydroxy-7,19,20,20-tetramethyl-4-vinyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate	C₅₄H₇₃FN₂O₁₃Si	详情	详情
(IV)	56394	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-formyl-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate	C₅₃H₇₁FN₂O₁₄Si	详情	详情
(V)	56395	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate	C₅₅H₇₈FN₃O₁₃Si	详情	详情
(VI)	56396	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icos-1(19)-en-15-yl benzoate	C₅₅H₈₀FN₃O₁₃Si	详情	详情

Extended Information