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【结 构 式】 
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【分子编号】57540 【品名】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 【CA登记号】 |
【 分 子 式 】C14H20F3NO6 【 分 子 量 】355.3111496 【元素组成】C 47.33% H 5.67% F 16.04% N 3.94% O 27.02% |
合成路线1
该中间体在本合成路线中的序号：(XII)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：(XII)The other monosaccharide building block (XXXIII) was also synthesized from the common intermediate (XII). Alkylation of (XII) with mesylate (XXIII), prepared from 1-decanol (XXII), gave the decyl ether (XXIV). After acidic acetonide hydrolysis of (XXIV) to yield (XXV), removal of the trifluoroacetamide by means of potassium tert-butoxide, with concomitant O-allyl group isomerization, furnished (XXVI). Imine (XXVII) was then obtained by exchange reaction of amine (XXVI) with benzophenone imine at 45 C. After silylation of the primary hydroxyl of (XXVII) with tert-butyldimethylsilyl chloride affording(XXVIII), the secondary hydroxyl group was protected as the allyl carbonate (XXIX) by sequential treatment with phosgene and then with allyl alcohol. Imine (XXIX) hydrolysis, followed by coupling of the resultant amine (XXX) with 3-oxotetradecanoic acid (XXXI) led to keto amide (XXXII). Precursor (XXXIII) was then obtained by desilylation of (XXXII) with HF.
| 【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 |
|---|---|---|---|---|---|---|
| (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 | |
| (XXII) | 40729 | 1-decanol | 112-30-1 | C10H22O | 详情 | 详情 |
| (XXIII) | 64156 | decyl methanesulfonate | C11H24O3S | 详情 | 详情 | |
| (XXIV) | 64157 | N-[(4aR,7R,8R,8aS)-6-(allyloxy)-8-(decyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-2,2,2-trifluoroacetamide | C24H40F3NO6 | 详情 | 详情 | |
| (XXV) | 64158 | N-[(3R,4R,5S,6R)-2-(allyloxy)-4-(decyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-2,2,2-trifluoroacetamide | C21H36F3NO6 | 详情 | 详情 | |
| (XXVI) | 64159 | (2R,3S,4R,5R)-5-amino-4-(decyloxy)-2-(hydroxymethyl)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ol | C19H37NO5 | 详情 | 详情 | |
| (XXVII) | 64160 | (2R,3S,4R,5R)-4-(decyloxy)-5-[(diphenylmethylene)amino]-2-(hydroxymethyl)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-ol | C32H45NO5 | 详情 | 详情 | |
| (XXVIII) | 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 | |
| (XXIX) | 64162 | allyl (2R,3S,4R,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)-5-[(diphenylmethylene)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate | C42H63NO7Si | 详情 | 详情 | |
| (XXX) | 64163 | allyl (2R,3S,4R,5R)-5-amino-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate | C29H55NO7Si | 详情 | 详情 | |
| (XXXI) | 59107 | 3-oxotetradecanoic acid | C14H26O3 | 详情 | 详情 | |
| (XXXII) | 64164 | allyl (2R,3S,4R,5R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate | C43H79NO9Si | 详情 | 详情 | |
| (XXXIII) | 64165 | allyl (2R,3S,4R,5R)-4-(decyloxy)-2-(hydroxymethyl)-5-[(3-oxotetradecanoyl)amino]-6-[(Z)-1-propenyloxy]tetrahydro-2H-pyran-3-yl carbonate | C37H65NO9 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XVII)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 |