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【结 构 式】 
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【分子编号】40612 【品名】(3R)-3-(tetradecanoyloxy)tetradecanoic acid 【CA登记号】 |
【 分 子 式 】C28H54O4 【 分 子 量 】454.73436 【元素组成】C 73.96% H 11.97% O 14.07% |
合成路线1
该中间体在本合成路线中的序号：(II)Acylation of amino alcohol (I) with (R)-3-(n-tetradecanoyloxy)tetradecanoic acid (II) employing 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (EDC.MeI) provided amide (III). After hydroxyl group protection with 2,2,2-trichloroethyl chloroformate (A), the resulting acetonide (IV) was hydrolyzed with aqueous AcOH to give (V).
| 【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (I) | 16046 | (4aR,6R,7R,8R,8aS)-7-amino-6-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-8-ol | C16H23NO5 | 详情 | 详情 | |
| (II) | 40612 | (3R)-3-(tetradecanoyloxy)tetradecanoic acid | C28H54O4 | 详情 | 详情 | |
| (III) | 40613 | (1R)-1-(2-[[(4aR,6R,7R,8R,8aS)-6-(benzyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]amino]-2-oxoethyl)dodecyl myristate | C44H75NO8 | 详情 | 详情 | |
| (IV) | 40614 | (1R)-1-[2-[((4aR,6R,7R,8R,8aR)-6-(benzyloxy)-2,2-dimethyl-8-[[(2,2,2-trichloroethoxy)carbonyl]oxy]hexahydropyrano[3,2-d][1,3]dioxin-7-yl)amino]-2-oxoethyl]dodecyl myristate | C47H76Cl3NO10 | 详情 | 详情 | |
| (V) | 40615 | (1R)-1-[2-[((2R,3R,4R,5R,6R)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-4-[[(2,2,2-trichloroethoxy)carbonyl]oxy]tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl]dodecyl myristate | C44H72Cl3NO10 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)N-Protection of amino alcohol (VI) under Schotten-Baumann conditions with 2,2,2-trichloroethyl chloroformate (B) aforded carbamate (VII). Subsequent esterification of (VII) with acid (II) provided (VIII), which was followed by acetonide hydrolysis to give diol (IX). Selective protection of the primary hydroxyl of (IX) with 1,1-dimethyl-2,2,2-trichloroethyl chloroformate (C) furnished carbonate (X). Further phosphorylation of the free secondary hydroxyl of (X) with diphenylphosphoryl chloride (D) produced phosphate ester (XI). Conversion of the trimethylsily-ethyl glycoside (XI) into the desired glycosyl chloride (XII) was then accomplished by treatment with alpha,alpha-dichloromethyl methyl ether and ZnCl2.
| 【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 |
| (D) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (II) | 40612 | (3R)-3-(tetradecanoyloxy)tetradecanoic acid | C28H54O4 | 详情 | 详情 | |
| (VI) | 39769 | (4aR,6R,7R,8R,8aS)-7-amino-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-ol | C14H29NO5Si | 详情 | 详情 | |
| (VII) | 39770 | 2,2,2-trichloroethyl (4aR,6R,7R,8R,8aS)-8-hydroxy-2,2-dimethyl-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-7-ylcarbamate | C17H30Cl3NO7Si | 详情 | 详情 | |
| (VIII) | 39772 | (4aR,6R,7R,8R,8aR)-2,2-dimethyl-7-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]hexahydropyrano[3,2-d][1,3]dioxin-8-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C45H82Cl3NO10Si | 详情 | 详情 | |
| (IX) | 39773 | (2R,3R,4R,5R,6R)-3-hydroxy-2-(hydroxymethyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C42H78Cl3NO10Si | 详情 | 详情 | |
| (X) | 39774 | (2R,3R,4R,5R,6R)-3-hydroxy-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C47H83Cl6NO12Si | 详情 | 详情 | |
| (XI) | 39775 | (2R,3R,4R,5R,6R)-3-[(diphenoxyphosphoryl)oxy]-2-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C59H92Cl6NO15PSi | 详情 | 详情 | |
| (XII) | 40616 | (2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C54H79Cl7NO14P | 详情 | 详情 | |
| (C) | 38221 | 1,1,1-trichloro-2-[(chlorocarbonyl)oxy]-2-methylpropane | C5H6Cl4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)Coupling of glycosyl chloride (XII) with glycoside (V) in the presence of silver triflate gave rise to the corresponding beta-disaccharide and subsequent reductive cleavage of the trichloro ethyl-based protecting groups with Zn/AcOH yielded disaccharide (XIII). Further N-acylation of (XIII) with acid (II) in the presence of 2-ethoxy-1-(ethoxycarbonyl)-1,2-dihydroquinoline (EEDQ) furnished amide (XIV). Finally, two-step hydrogenolytic deprotection of the benzyl and phenyl groups of (XIV) and lyophilization in the presence of triethylamine provided the title compound.
| 【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 40612 | (3R)-3-(tetradecanoyloxy)tetradecanoic acid | C28H54O4 | 详情 | 详情 | |
| (V) | 40615 | (1R)-1-[2-[((2R,3R,4R,5R,6R)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-4-[[(2,2,2-trichloroethoxy)carbonyl]oxy]tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl]dodecyl myristate | C44H72Cl3NO10 | 详情 | 详情 | |
| (XII) | 40616 | (2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C54H79Cl7NO14P | 详情 | 详情 | |
| (XIII) | 40617 | C87H143N2O18P | 详情 | 详情 | ||
| (XIV) | 40618 | C115H195N2O21P | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)In a related procedure for the synthesis of the protected precursor (XIV), the known bis(trichloroethoxycarbonyl) derivative (XV) was coupled with glycosyl chloride (XII) to give the corresponding disaccharide which was deprotected to (XVI) upon treatment with Zn/AcOH. Bis N-acylation of (XV) with acid (II) in the presence of EEDQ then provided the target intermediate (XIV).
| 【1】 Sowell, C.G.; Johnson, D.A.; Keegan, D.S.; et al.; 3-O-Desacyl monophosphoryl lipid A derivatives: Synthesis and immunostimulant activities. J Med Chem 1999, 42, 22, 4640. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 40612 | (3R)-3-(tetradecanoyloxy)tetradecanoic acid | C28H54O4 | 详情 | 详情 | |
| (XII) | 40616 | (2R,3R,4R,5S,6R)-2-chloro-5-[(diphenoxyphosphoryl)oxy]-6-([[(2,2,2-trichloro-1,1-dimethylethoxy)carbonyl]oxy]methyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C54H79Cl7NO14P | 详情 | 详情 | |
| (XIV) | 40618 | C115H195N2O21P | 详情 | 详情 | ||
| (XV) | 40619 | (2R,3R,4R,5R,6R)-2-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl 2,2,2-trichloroethyl carbonate | C19H21Cl6NO9 | 详情 | 详情 | |
| (XVI) | 40620 | (2R,3R,4R,5R,6R)-3-amino-2-[[(2R,3S,4R,5R,6R)-5-amino-6-(benzyloxy)-3,4-dihydroxytetrahydro-2H-pyran-2-yl]methoxy]-5-[(diphenoxyphosphoryl)oxy]-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl (3R)-3-(tetradecanoyloxy)tetradecanoate | C59H91N2O15P | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(V)Phenylsulfanyl glycoside (I) was coupled with serine derivative (II) in the presence of N-bromosuccinimide, iodine and tetrabutylammonium triflate yielding the serine glycoside (III). Reductive cleavage of the trichloroethoxy carbonyl group of (III) with Zn and HOAc afforded amine (IV), which was acylated with (R)-3-(tetradecanoyloxy)tetradecanoic acid (V) using DCC and HOBt. Hydrogenolysis of the benzyl ester (VI) over palladium black provided carboxylic acid (VII).
| 【1】 Ikeda, K.; et al.; Lipid A and related compounds. XXXVII. Determination of favorable binding linkages of lipid A analog to antigen moiety for synthetic vaccines. Chem Pharm Bull 2000, 48, 1, 32. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 41407 | (2R,3S,4R,5R,6S)-3-(acetoxy)-2-[(acetoxy)methyl]-6-(phenylsulfanyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-4-yl acetate | C21H24Cl3NO9S | 详情 | 详情 | |
| (II) | 41408 | benzyl (2S)-3-hydroxy-2-(tetradecanoylamino)propanoate | C24H39NO4 | 详情 | 详情 | |
| (III) | 41409 | benzyl (2S)-3-[((2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-3-[[(2,2,2-trichloroethoxy)carbonyl]amino]tetrahydro-2H-pyran-2-yl)oxy]-2-(tetradecanoylamino)propanoate | C39H57Cl3N2O13 | 详情 | 详情 | |
| (IV) | 41410 | benzyl (2S)-3-([(2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-3-aminotetrahydro-2H-pyran-2-yl]oxy)-2-(tetradecanoylamino)propanoate | C36H56N2O11 | 详情 | 详情 | |
| (V) | 40612 | (3R)-3-(tetradecanoyloxy)tetradecanoic acid | C28H54O4 | 详情 | 详情 | |
| (VI) | 41411 | (1R)-1-[2-[((2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-2-[[(2S)-3-(benzyloxy)-3-oxo-2-(tetradecanoylamino)propyl]oxy]tetrahydro-2H-pyran-3-yl)amino]-2-oxoethyl]dodecyl myristate | C64H108N2O14 | 详情 | 详情 | |
| (VII) | 41412 | (2S)-3-[((2R,3R,4R,5R,6R)-4,5-bis(acetoxy)-6-[(acetoxy)methyl]-3-[[(3R)-3-(tetradecanoyloxy)tetradecanoyl]amino]tetrahydro-2H-pyran-2-yl)oxy]-2-(tetradecanoylamino)propionic acid | C57H102N2O14 | 详情 | 详情 |