|
【结 构 式】 
|
【分子编号】57544 【品名】2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-ylcarbamate 【CA登记号】 |
【 分 子 式 】C40H58Cl3NO8 【 分 子 量 】787.26056 【元素组成】C 61.03% H 7.43% Cl 13.51% N 1.78% O 16.26% |
合成路线1
该中间体在本合成路线中的序号：(XXI)The chiral diol (XII) is converted to the dioxane derivative (XIV) by treatment with anisaldehyde dimethyl acetal (XIII) in the presence of p-toluenesulfonic acid. Reductive cleavage of dioxane (XIV) by means of DIBAL produces regioselectively the mono-p-methoxybenzyl ether (XV). The primary alcohol group of (XV) is then converted to the corresponding mesylate (XVI) employing methanesulfonyl chloride and triethylamine. Alkylation of the protected glucosamine (XVII) with mesylate (XVI) in the presence of NaH yields ether (XVIII). After basic hydrolysis of the trifluoroacetamide (XVIII), the resultant amine (XIX) is reprotected as the trichloroethyl carbamate (XX) by using trichloroethyl chloroformate and NaHCO3. Subsequent hydrolysis of the acetonide group of (XX) provides diol (XXI).
| 【1】 Nishijima, M.; Kurakata, S.-I.; Shiozaki, M.; Mochizuki, T.; Kanai, S.; Watanabe, Y.; Synthesis of lipid A type pyran carboxylic acids with ether chains and their biological activities. Carbohydr Res 2001, 333, 3, 203. |
| 【2】 Shiozaki, M.; Kurakata, S.; Kanai, S.; Kazama, Y. (Sankyo Co., Ltd.); Ether type lipid A1-carboxylic acid analogues. EP 1152007; JP 2000297096; US 2002161221; US 6511965; WO 0047595 . |
| 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) | 57536 | (3R)-1,3-tetradecanediol | C14H30O2 | 详情 | 详情 | |
| (XIII) | 26485 | 1-(dimethoxymethyl)-4-methoxybenzene | 2186-92-7 | C10H14O3 | 详情 | 详情 |
| (XIV) | 57537 | (4R)-2-(4-methoxyphenyl)-4-undecyl-1,3-dioxane; methyl 4-[(4R)-4-undecyl-1,3-dioxan-2-yl]phenyl ether | C22H36O3 | 详情 | 详情 | |
| (XV) | 57538 | (3R)-3-[(4-methoxybenzyl)oxy]-1-tetradecanol | C22H38O3 | 详情 | 详情 | |
| (XVI) | 57539 | (3R)-3-[(4-methoxybenzyl)oxy]tetradecyl methanesulfonate | C23H40O5S | 详情 | 详情 | |
| (XVII) | 57540 | N-[(4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-2,2,2-trifluoroacetamide | C14H20F3NO6 | 详情 | 详情 | |
| (XVIII) | 57541 | N-((4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)-2,2,2-trifluoroacetamide | C42H60F3NO7 | 详情 | 详情 | |
| (XIX) | 57542 | (4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-amine; (4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ylamine | C40H61NO6 | 详情 | 详情 | |
| (XX) | 57543 | 2,2,2-trichloroethyl (4aR,6S,7R,8R,8aS)-6-(allyloxy)-8-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate | C43H62Cl3NO8 | 详情 | 详情 | |
| (XXI) | 57544 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | C40H58Cl3NO8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXI)The primary hydroxyl of (XXI) is protected as the silyl ether (XXII) by means of t-butyldimethylsilyl chloride and DMAP. Subsequent phosphorylation of the remaining secondary hydroxyl group with diphenylphosphoryl chloride gives phosphate ester (XXIII). Removal of the p-methoxybenzyl protecting group of (XXIII) is accomplished by oxidative cleavage with DDQ, yielding alcohol (XXIV), which is acylated by myristoyl chloride, to produce ester (XXV). Desilylation of (XXV) under acidic conditions affords alcohol (XXVI), which is converted to methyl ether (XXVII) using trimethyloxonium fluoborate as the alkylating reagent. Iridium-catalyzed deallylation of the allyl glucoside (XXVII) furnishes the cyclic glucosamine (XXVIII).
| 【1】 Nishijima, M.; Kurakata, S.-I.; Shiozaki, M.; Mochizuki, T.; Kanai, S.; Watanabe, Y.; Synthesis of lipid A type pyran carboxylic acids with ether chains and their biological activities. Carbohydr Res 2001, 333, 3, 203. |
| 【2】 Shiozaki, M.; Kurakata, S.; Kanai, S.; Kazama, Y. (Sankyo Co., Ltd.); Ether type lipid A1-carboxylic acid analogues. EP 1152007; JP 2000297096; US 2002161221; US 6511965; WO 0047595 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 30295 | tetradecanoyl chloride | 112-64-1 | C14H27ClO | 详情 | 详情 | |
| (XXI) | 57544 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | C40H58Cl3NO8 | 详情 | 详情 | |
| (XXII) | 57545 | 4-{2-[((1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-hydroxy-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl)oxy]ethyl}-1,1'-biphenyl; 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-hydroxytetrahydro-2H-pyran-3-ylcarbamate | C46H72Cl3NO8Si | 详情 | 详情 | |
| (XXIII) | 57546 | 4-{2-[((1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl)oxy]ethyl}-1,1'-biphenyl; 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-4-{[(3R)-3-(2-[1,1'-biphenyl]-4-ylethoxy)tetradecyl]oxy}-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]tetrahydro-2H-pyran-3-ylcarbamate | C58H81Cl3NO11PSi | 详情 | 详情 | |
| (XXIV) | 57547 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]-4-{[(3R)-3-hydroxytetradecyl]oxy}tetrahydro-2H-pyran-3-ylcarbamate | C44H69Cl3NO11PSi | 详情 | 详情 | |
| (XXV) | 57548 | (1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-[(diphenoxyphosphoryl)oxy]-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl myristate | C58H95Cl3NO12PSi | 详情 | 详情 | |
| (XXVI) | 57549 | (1R)-1-{2-[((2S,3R,4R,5S,6R)-2-(allyloxy)-5-[(diphenoxyphosphoryl)oxy]-6-(hydroxymethyl)-3-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl myristate | C52H81Cl3NO12P | 详情 | 详情 | |
| (XXVII) | 57550 | 2,2,2-trichloroethyl (2S,3R,4R,5S,6R)-2-(allyloxy)-5-[(diphenoxyphosphoryl)oxy]-4-{[(3R)-3-(formyloxy)tetradecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | C40H57Cl3NO12P | 详情 | 详情 | |
| (XXVIII) | 57551 | (1R)-1-{2-[((2R,3S,4R,5R)-3-[(diphenoxyphosphoryl)oxy]-6-hydroxy-2-(methoxymethyl)-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}tetrahydro-2H-pyran-4-yl)oxy]ethyl}dodecyl myristate | C50H79Cl3NO12P | 详情 | 详情 |