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【结 构 式】 
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【分子编号】64148 【品名】{(2R,3S,4R,5R)-6-(allyloxy)-3-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl}methyl 4-methylbenzenesulfonate 【CA登记号】 |
【 分 子 式 】C29H44F3NO9S 【 分 子 量 】639.7309096 【元素组成】C 54.45% H 6.93% F 8.91% N 2.19% O 22.51% S 5.01% |
合成路线1
该中间体在本合成路线中的序号：(XV)Treatment of D-glucosamine•HCl (VI) with ethyl trifluoroacetate and NaOMe produced the trifluoroacetamide (VII), which was subsequently acetylated with Ac2O yielding the tetraacetate (VIII). Displacement of the anomeric acetoxy group of (VIII) by allyl alcohol (IX) in the presence of SnCl4 furnished the allyl glucoside (X). After methanolysis of the acetate ester groups of (X), the resultant triol (XI) was protected as the acetonide (XII) by treatment with 2,2-dimethoxypropane and camphorsulfonic acid. Alkylation of the free hydroxyl group of (XII) with tosylate (V) under Williamson's ether synthesis conditions produced adduct (XIII). Selective hydrolysis of the acetonide moiety of (XIII) was accomplished by treatment with hydrofluoric acid to give diol (XIV). The primary hydroxyl of (XIV) was then converted to tosylate (XV) upon treatment with p-toluenesulfonyl chloride and DMAP.
| 【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 64141 | (3R)-3-methoxydecyl 4-methylbenzenesulfonate | C18H30O4S | 详情 | 详情 | |
| (VI) | 24036 | (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol; Glucosamine | 3416-24-8 | C6H13NO5 | 详情 | 详情 |
| (VII) | 64142 | 2,2,2-trifluoro-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]acetamide | C8H12F3NO6 | 详情 | 详情 | |
| (VIII) | 64143 | (2R,3R,4R,5R)-4,6-bis(acetyloxy)-2-[(acetyloxy)methyl]-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-3-yl acetate | C16H20F3NO10 | 详情 | 详情 | |
| (IX) | 12234 | 2-Propen-1-ol; Allyl alcohol | 107-18-6 | C3H6O | 详情 | 详情 |
| (X) | 64144 | (2R,3R,4R,5R)-3-(acetyloxy)-2-[(acetyloxy)methyl]-6-(allyloxy)-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-4-yl acetate | C17H22F3NO9 | 详情 | 详情 | |
| (XI) | 64145 | N-[(3R,4R,5S,6R)-2-(allyloxy)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-2,2,2-trifluoroacetamide | C11H16F3NO6 | 详情 | 详情 | |
| (XII) | 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 | |
| (XIII) | 64146 | N-((4aR,7R,8R,8aS)-6-(allyloxy)-8-{[(3R)-3-methoxydecyl]oxy}-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)-2,2,2-trifluoroacetamide | C25H42F3NO7 | 详情 | 详情 | |
| (XIV) | 64147 | N-((3R,4R,5S,6R)-2-(allyloxy)-5-hydroxy-6-(hydroxymethyl)-4-{[(3R)-3-methoxydecyl]oxy}tetrahydro-2H-pyran-3-yl)-2,2,2-trifluoroacetamide | C22H38F3NO7 | 详情 | 详情 | |
| (XV) | 64148 | {(2R,3S,4R,5R)-6-(allyloxy)-3-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl}methyl 4-methylbenzenesulfonate | C29H44F3NO9S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XV)Displacement of the tosylate group of (XV) by sodium methoxide produced the methyl ether (XVI). Hydrolysis of the trifluoroacetamide function of (XVI) using potassium tert-butoxide in hot DMSO took place with simultaneous allylic double bond isomerization, leading to enol ether (XVII). After protection of the amino group of (XVII) as the trichloroethyl carbamate (XVIII), phosphitylation of the secondary hydroxyl group of (XVIII) with diallyl N,N-diisopropylphosphoramidite in the presence of tetrazole-generated phosphite (XIX), which was further oxidized to phosphate (XX) employing Oxone (R). The O-propenyl group of (XX) was then hydrolyzed by means of HF to provide the monosaccharide building block (XXI).
| 【1】 Kobayashi, S.; Kawata, T.; Christ, W.J.; Rossignol, D.P. (Eisai Co., Ltd.); Substd. liposaccharides useful in the treatment and prevention of endotoxemia. US 5750664; WO 9639411 . |
| 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) | 64148 | {(2R,3S,4R,5R)-6-(allyloxy)-3-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-5-[(2,2,2-trifluoroacetyl)amino]tetrahydro-2H-pyran-2-yl}methyl 4-methylbenzenesulfonate | C29H44F3NO9S | 详情 | 详情 | |
| (XVI) | 64149 | N-[(3R,4R,5S,6R)-2-(allyloxy)-5-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-yl]-2,2,2-trifluoroacetamide | C23H40F3NO7 | 详情 | 详情 | |
| (XVII) | 64150 | (2R,3S,4R,5R)-5-amino-4-{[(3R)-3-methoxydecyl]oxy}-2-(methoxymethyl)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ol | C21H41NO6 | 详情 | 详情 | |
| (XVIII) | 64151 | 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate | C24H42Cl3NO8 | 详情 | 详情 | |
| (XIX) | 64152 | 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphino]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate | C30H51Cl3NO10P | 详情 | 详情 | |
| (XX) | 64153 | 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-2-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ylcarbamate | C30H51Cl3NO11P | 详情 | 详情 | |
| (XXI) | 64154 | 2,2,2-trichloroethyl (3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-2-hydroxy-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)tetrahydro-2H-pyran-3-ylcarbamate | C27H47Cl3NO11P | 详情 | 详情 |