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【结 构 式】

【分子编号】52380

【品名】[(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate

【CA登记号】

【 分 子 式 】C27H56O7Si2

【 分 子 量 】548.90844

【元素组成】C 59.08% H 10.28% O 20.4% Si 10.23%
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：(XVII)

After silylation of diol (XII) to give (XIII), the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman’s catalyst, yielding alcohol (XIV). Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP). Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe's reagent, generated from bis(cyclopentadienyl)titanium and trimethylaluminum. Olefin (XVI) hydroboration by means of 9-borabicyclononane, followed by oxidative work-up with sodium perborate, provided the primary alcohol (XVII) as the undesired diastereoisomer. Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde, which was epimerized to (XVIII) under basic conditions. Further, aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX). This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX). The pivaloyl ester of (XXI) was then removed by reductive cleavage with LiAlH4, affording alcohol (XXII).

参考文献 中间体
合成目标
【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 52375 {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate C21H32O7 详情 详情
(XIII) 52376 {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate C33H60O7Si2 详情 详情
(XIV) 52377 [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate C26H54O7Si2 详情 详情
(XV) 52378 [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate C26H52O7Si2 详情 详情
(XVI) 52379 [(2R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate C27H54O6Si2 详情 详情
(XVII) 52380 [(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate C27H56O7Si2 详情 详情
(XVIII) 52381 [(2R,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate C27H54O7Si2 详情 详情
(XIX) 52382 [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate C27H56O7Si2 详情 详情
(XX) 52385 [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate C10H10Cl3NO2 详情 详情
(XXI) 52383 {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate C35H64O8Si2 详情 详情
(XXII) 52384 {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol C30H56O7Si2 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

After silylation of diol (XII) to yield (XIII), the O-benzyl group of (XIII) was removed by hydrogenolysis in the presence of Pearlman’s catalyst, yielding alcohol (XIV). Oxidation of alcohol (XIV) to the corresponding ketone (XV) was carried out by means of N-methylmorpholine-N-oxide in the presence of a catalytic amount of tetrapropylammonium perruthenate (TPAP). Ketone (XV) was then converted to the methylene derivative (XVI) by treatment with Tebbe’s reagent, generated from bis(cyclopentadienyl)titanium and trimethylaluminum. Olefin (XVI) hydroboration by means of 9-borabicyclononane, followed by oxidative work-up with sodium perborate, provided the primary alcohol (XVII) as the undesired diastereoisomer. Configuration of alcohol (XVII) was inverted via Swern oxidation to the corresponding aldehyde, which was epimerized to (XVIII) under basic conditions. Further, aldehyde (XVIII) reduction with NaBH4 at 0 C generated alcohol (XIX). This was protected as the methoxybenzyl ether (XXI) by condensation with p-methoxybenzyl trichloroacetimidate (XX). The pivaloyl ester (XXI) was then removed by reductive cleavage with LiAlH4, affording alcohol (XXII).

参考文献 中间体
合成目标
【1】 Littlefield, B.A.; Zheng, W.; Seletsky, B.M.; Yu, M.J.; Palme, M.H.; Towle, M.J. (Eisai Co., Ltd.); Macrocyclic analogs and methods of their use and preparation. US 6214865; WO 9965894 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XII) 52375 {5-(2,3-dihydroxypropyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate C21H32O7 详情 详情
(XIII) 52376 {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[(phenylmethyl)oxy]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate C33H60O7Si2 详情 详情
(XIV) 52377 [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-hydroxy-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate C26H54O7Si2 详情 详情
(XV) 52378 [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-oxotetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate C26H52O7Si2 详情 详情
(XVI) 52379 [(2R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-4-methoxy-3-methylenetetrahydro-2-furanyl]methyl pivalate C27H54O6Si2 详情 详情
(XVII) 52380 [(2R,3S,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-methoxytetrahydro-2-furanyl]methyl pivalate C27H56O7Si2 详情 详情
(XVIII) 52381 [(2R,3R,4R,5R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-formyl-4-methoxytetrahydro-2-furanyl]methyl pivalate C27H54O7Si2 详情 详情
(XIX) 52382 [5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-3-(hydroxymethyl)-4-(methyloxy)tetrahydro-2-furanyl]methyl 2,2-dimethylpropanoate C27H56O7Si2 详情 详情
(XX) 52385 [4-(methyloxy)phenyl]methyl 2,2,2-trichloroethanimidoate C10H10Cl3NO2 详情 详情
(XXI) 52383 {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methyl 2,2-dimethylpropanoate C35H64O8Si2 详情 详情
(XXII) 52384 {5-(2,3-bis{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-4-(methyloxy)-3-[({[4-(methyloxy)phenyl]methyl}oxy)methyl]tetrahydro-2-furanyl}methanol C30H56O7Si2 详情 详情
Extended Information