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【结 构 式】 
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【药物名称】 【化学名称】N-[3(R)-(Decanoyloxy)tetradecanoyl]-O3-[2-[3(R)-(decanoyloxy)tetradecanamido]-3-O-[3(R)-(decanoyloxy)tetradecanoyl]-2-deoxy-4-O-phosphono-beta-D-glucopyranosyl]-L-serine triethylammonium salt 【CA登记号】216014-15-2 【 分 子 式 】C87H168N3O20P 【 分 子 量 】1607.29091 |
【开发单位】Corixa (Originator) 【药理作用】IMMUNOMODULATING AGENTS, Immunostimulants |
合成路线1
The reaction of the glucopyranosyl bromide (I) (or its chloride analogue) with the N-acyl-L-serine benzyl ester (II) by means of Ag-OTf in dichloroethane gives the glucoside (III), which is deprotected at the amino group with Zn and AcOH yielding the 2-aminoglucoside (IV). The condensation of (IV) with the tetradecanoic acid (V) by means of EDDQ in dichloromethane affords the amide (VI), which is finally deprotected by hydrogenation with H2 over PtO2 in THF/AcOH.
| 【1】 Ulrich, J.T.; Keegan, D.S.; Rhodes, M.J.; Johnson, D.A.; Johnson, G.L.; Ward, J.R.; Cantrell, J.L.; Sowell, C.G.; Brookshire, V.G.; Livesay, M.T.; Synthesis and biological evaluation of a new class of vaccine adjuvants: Aminoalkyl glucosaminide 4-phosphates. Bioorg Med Chem Lett 1999, 9, 15, 2273. |
| 【2】 Johnson, D.A.; Sowell, C.G. (Corixa Corp.); Aminoalkyl glucosamine phosphate cpds. and their use as adjuvants and immunoeffectors. EP 0983286; US 6113918; WO 9850399 . |
| 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) | 38211 | (2R,3R,4R,5S,6R)-2-bromo-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-(decanoyloxy)tetradecanoate | C50H71BrCl6NO14P | 详情 | 详情 | |
| (II) | 38225 | (1R)-1-(2-[[(1S)-2-(benzyloxy)-1-(hydroxymethyl)-2-oxoethyl]amino]-2-oxoethyl)dodecyl decanoate | C34H57NO6 | 详情 | 详情 | |
| (III) | 38226 | C84H127Cl6N2O20P | 详情 | 详情 | ||
| (IV) | 38227 | C76H121N2O16P | 详情 | 详情 | ||
| (V) | 38215 | (3R)-3-(decanoyloxy)tetradecanoic acid | C24H46O4 | 详情 | 详情 | |
| (VI) | 38228 | C100H165N2O19P | 详情 | 详情 |
合成路线2
The intermediate, the glucopyranosyl bromide (I) has been obtained as follows: The reaction of 2-(trimethylsilylethyl)-2-amino-2-deoxy-4,6-O-isopropylidene-beta-D-glucopyranoside (VII) with Troc-Cl and NaHCO3 gives the N-protected glucoside (VIII), which is acylated with the tetradecanoic acid (IX) by means of EDC and 4-(1-pyrrolidinyl)pyridine in dichloromethane to yield the 3-O-acylated glucoside (X). The hydrolysis of the isopropylidene group of (X) with AcOH affords the diol (XI), which is selectively protected at the primary OH group with 2,2,2-trichloro-1,1-dimethylethyl chloroformate (XII) in pyridine to provide (XIII). The phosphorylation of the remaining OH group of (XIII) with diphenyl chlorophosphate (XIV) by means of DIEA in dichloromethane gives the phosphoric ester (XV), which is finally desilylated and hydrolyzed with TFA in dichloromethane, and treated with oxalyl bromide in dichloromethane/DMF to furnish the target glucopyranosyl bromide (I).
| 【1】 Johnson, D.A.; Sowell, C.G. (Corixa Corp.); Aminoalkyl glucosamine phosphate cpds. and their use as adjuvants and immunoeffectors. EP 0983286; US 6113918; WO 9850399 . |
| 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) | 38211 | (2R,3R,4R,5S,6R)-2-bromo-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-(decanoyloxy)tetradecanoate | C50H71BrCl6NO14P | 详情 | 详情 | |
| (VII) | 38217 | (4aR,6S,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 | |
| (VIII) | 38218 | 2,2,2-trichloroethyl (4aR,6S,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 | |
| (IX) | 38215 | (3R)-3-(decanoyloxy)tetradecanoic acid | C24H46O4 | 详情 | 详情 | |
| (X) | 38219 | (4aR,6S,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-(decanoyloxy)tetradecanoate | C41H74Cl3NO10Si | 详情 | 详情 | |
| (XI) | 38220 | (2R,3R,4R,5R,6S)-3-hydroxy-2-(hydroxymethyl)-5-[[(2,2,2-trichloroethoxy)carbonyl]amino]-6-[2-(trimethylsilyl)ethoxy]tetrahydro-2H-pyran-4-yl (3R)-3-(decanoyloxy)tetradecanoate | C38H70Cl3NO10Si | 详情 | 详情 | |
| (XII) | 38221 | 1,1,1-trichloro-2-[(chlorocarbonyl)oxy]-2-methylpropane | C5H6Cl4O2 | 详情 | 详情 | |
| (XIII) | 38222 | (2R,3R,4R,5R,6S)-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-(decanoyloxy)tetradecanoate | C43H75Cl6NO12Si | 详情 | 详情 | |
| (XIV) | 16074 | Diphenyl phosphoryl chloride; 1,1'-Diphenylphosphoryl chloride; Chlorodiphenyl Phosphate; Diphenyl chlorophosphate; Diphenylchlorophosphate | 2524-64-3 | C12H10ClO3P | 详情 | 详情 |
| (XV) | 38223 | (2R,3R,4R,5R,6S)-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-(decanoyloxy)tetradecanoate | C55H84Cl6NO15PSi | 详情 | 详情 |
合成路线3
The intermediate, the N-acyl-L-serine benzyl ester (II) has been obtained by N-acylation of L-serine benzyl ester (XVI) with the tetradecanoic acid (V) by means of EDDQ in dichloromethane.
| 【1】 Johnson, D.A.; Sowell, C.G. (Corixa Corp.); Aminoalkyl glucosamine phosphate cpds. and their use as adjuvants and immunoeffectors. EP 0983286; US 6113918; WO 9850399 . |