Synthetic method of intermediate for preparing vaccine adjuvant MPLA

Abstract

The invention relates to a synthetic method of an intermediate for preparing a vaccine adjuvant MPLA, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: starting from 1, 3, 4, 6-tetra-O-acetyl-2-deoxy-2-phthalimide group-alpha-D-glucose, and carrying out three steps of benzyl glycosylation, deacetylation and acetal exchange, so as to synthesize an intermediate benzyl 4, 6-di-O-benzal-2-deoxy-2-phthalimide group-beta-D-glucoside of the novel vaccine adjuvant MPLA. The method has the advantages of mild reaction, low reagent cost, few reaction byproducts, simple post-treatment, recrystallization of the product and environmental friendliness, and is a synthetic route suitable for industrial production of MPLA.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing a novel vaccine adjuvant MPLA intermediate benzyl 4,6-di-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucoside. Background Art

[0002] Vaccine adjuvants refer to auxiliary substances that are used in combination with vaccines to enhance the immune response or change the type of immune response, and they themselves have no antigenicity or pathogenic risk. In 1926, Alexander Glenny discovered that adding aluminum salts to antigens can enhance their immune activity. Since then, aluminum adjuvants have become the only adjuvants licensed to be added to human vaccines in the 60 years since then. In 1997, the water-in-oil emulsion MF59 was licensed to be added to influenza vaccines. Since then, more and more vaccine adjuvants have been developed and put into use in vaccines. Lipid A, the hydrophobic domain of lipopolysaccharide (LPS) in the cell wall of Gram-negative bacteria, is a strong immunostimulant, but it also has strong endotoxicity, which limits the application of lipid A in the field of vaccine adjuvants. Ribi et al. hydrolyzed the anomeric carbon-terminal phosphate group of lipid A to obtain monophosphoryl lipid A (MPLA), which has a 99.92% decrease in toxicity compared to lipid A and retained its immune activity. High immune activity and low toxicity make MPLA a strong candidate molecule for new vaccine adjuvants.

[0003]

[0004]

[0005] Simplifying vaccine ingredients is conducive to improving vaccine safety, so the production of MPLA should also ensure its purity. The current mainstream method for preparing MPLA is biological fermentation, which is not only expensive, but also cannot ensure the heterogeneity of the number and length of the acyl side chains of the disaccharide during the fermentation process. That is, the resulting MPLA is actually a mixture of disaccharides with different side chains, which is extremely difficult to separate, posing a safety hazard to the vaccine. Therefore, it is necessary to prepare MPLA with a single structure through chemical synthesis. As shown in the above structural formula, MPL TM The 3-position of P.gingivalis MPLA is a hydroxyl group, while the 3-position of E.coli MPLA and monophosphorylS.minnesota lipid A is an ester group. For different glycosyl acceptor residues of different MPLAs, it is necessary to develop intermediates that can be used for the synthesis of 3-hydroxyl and 3-ester glycosyl acceptors at the same time, and solve the problems of low reaction efficiency, low yield, dangerous reagents or reaction conditions, and difficult separation and purification in the synthesis route, so that the synthesis method of the MPLA intermediate can be more economical and efficient and suitable for industrial production. Summary of the invention

[0006] In view of the above problems, the present invention provides a method for synthesizing a novel vaccine adjuvant MPLA intermediate benzyl 4,6-di-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucoside, using 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-α-D-glucose as a starting material, and synthesizing the required MPLA intermediate through a three-step reaction.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A method for synthesizing an intermediate for preparing a vaccine adjuvant MPLA comprises the following steps:

[0009] Step (1), in an argon atmosphere and in the presence of an acid, in an organic solvent, reacting compound 1 and benzyl alcohol at 25 to 102° C. for 15 min to 24 h to obtain intermediate 2; the molar ratio of benzyl alcohol to compound 1 is 1.2 to 5:1; the molar ratio of acid to compound 1 is 1 to 5:1; the compound 1 is 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-α-D-glucose, and has the following structural formula:

[0010]

[0011] Step (2), in the presence of an argon atmosphere and a base, intermediate 2 is reacted in an organic solvent to obtain intermediate 3; the molar ratio of the base to intermediate 3 is 0.1 to 5:1;

[0012] Step (3), in an argon atmosphere and in the presence of an acid, in an organic solvent, reacting intermediate 3 and benzaldehyde dimethyl acetal at 25 to 102° C. for 10 min to 12 h to obtain intermediate 4, i.e., the intermediate for preparing the vaccine adjuvant MPLA; the molar ratio of benzaldehyde dimethyl acetal to intermediate 3 is 2 to 10:1.

[0013] Preferably, in step (1), the acid is one of p-toluenesulfonic acid monohydrate, trifluoroacetic acid, trifluoromethanesulfonic acid, ether solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trimethylchlorosilane, trimethylbromosilane, triethylchlorosilane, boron trifluoride etherate, boron trifluoride tetrahydrofuran, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, ferric chloride, aluminum chloride, zinc chloride, copper trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, silver trifluoromethanesulfonate, iron trifluoromethanesulfonate, perfluorosulfonic acid resin Nafion and solid acid HND-580;

[0014] The organic solvent is one of dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl ether, methyl tert-butyl ether, butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, dimethyl carbonate, diethyl carbonate and acetonitrile.

[0015] Preferably, in step (2), the base is one of sodium, aqueous ammonia, methanol solution of ammonia, methanol solution of methylamine, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide;

[0016] The organic solvent is methanol, ethanol, dichloromethane / methanol with a volume ratio of 0.5 to 4:1, dichloromethane / ethanol with a volume ratio of 0.5 to 4:1, chloroform / methanol with a volume ratio of 0.5 to 4:1, chloroform / ethanol with a volume ratio of 0.5 to 4:1, 1,2-dichloroethane / methanol with a volume ratio of 0.5 to 4:1, 1,2-dichloroethane / ethanol with a volume ratio of 0.5 to 4:1, tetrahydrofuran / methanol with a volume ratio of 1 to 6:1, and tetrahydrofuran / methanol with a volume ratio of 1 to 6:1. :1 tetrahydrofuran / ethanol in a volume ratio of 1 to 6:1, 2-methyltetrahydrofuran / methanol in a volume ratio of 1 to 6:1, 2-methyltetrahydrofuran / ethanol in a volume ratio of 1 to 6:1, cyclopentyl methyl ether / methanol in a volume ratio of 1 to 6:1, cyclopentyl methyl ether / ethanol in a volume ratio of 1 to 6:1, ethyl acetate / methanol in a volume ratio of 2 to 8:1, ethyl acetate / ethanol in a volume ratio of 2 to 8:1, acetonitrile / methanol in a volume ratio of 3 to 10:1, and acetonitrile / ethanol in a volume ratio of 3 to 10:1.

[0017] Preferably, in step (3), the acid is one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, ether solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, zinc chloride, ferric chloride, aluminum chloride, titanium tetrachloride, cobalt chloride, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, iron trifluoromethanesulfonate, copper trifluoromethanesulfonate, perfluorosulfonic acid resin Nafion and solid acid HND-580;

[0018] The organic solvent is one of dichloromethane, ethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, pyridine, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide;

[0019] After the reaction is completed, the acid is quenched and the reaction system is concentrated, and the resulting crude product is purified by recrystallization; the solvent used for recrystallization is n-hexane / ethyl acetate with a volume ratio of 1 to 6:1, methylcyclopentane / ethyl acetate with a volume ratio of 1 to 6:1, cyclohexane / ethyl acetate with a volume ratio of 1 to 6:1, n-heptane / ethyl acetate with a volume ratio of 1 to 6:1, n-heptane / dimethyl carbonate with a volume ratio of 1 to 6:1, n-octane / diethyl carbonate with a volume ratio of 1 to 6:1, methanol, ethanol, isopropanol, n-butanol, 2-butanol, dichloromethane / methanol with a volume ratio of 4 to 10:1, chloroform / methanol with a volume ratio of 4 to 10:1, chloroform / ethanol with a volume ratio of 4 to 10:1, 1,2-dichloroethane / ethanol with a volume ratio of 4 to 10:1, chloroform / isopropanol with a volume ratio of 4 to 10:1, 1,2-dichloroethane / isopropanol in a ratio of 4 to 10:1, 1,2-dichloroethane / n-butanol in a ratio of 4 to 10:1, 1,2-dichloroethane / 2-butanol in a ratio of 4 to 10:1, 1,2-dichloroethane / isobutanol in a ratio of 4 to 10:1, methyl tert-butyl ether / tetrahydrofuran in a ratio of 1 to 8:1, n-hexane / tetrahydrofuran in a ratio of 1 to 10:1, One of cyclohexane / tetrahydrofuran in a volume ratio of 1 to 10:1, n-hexane / 2-methyltetrahydrofuran in a volume ratio of 1 to 10:1, cyclohexane / 2-methyltetrahydrofuran in a volume ratio of 1 to 10:1, n-heptane / 2-methyltetrahydrofuran in a volume ratio of 1 to 10:1, n-heptane / cyclopentyl methyl ether in a volume ratio of 1 to 10:1, and n-octane / cyclopentyl methyl ether in a volume ratio of 1 to 10:1.

[0020] Preferably, the synthesis method of compound 1 is as follows:

[0021] 2-deoxy-2-glucosamine hydrochloride, phthalic anhydride and a base are reacted in water to obtain compound 5; the molar ratio of phthalic anhydride to 2-deoxy-2-glucosamine hydrochloride is 1.05-1.5:1; the molar ratio of the base to 2-deoxy-2-glucosamine hydrochloride is 1.05-2.5:1; the base is one of lithium hydroxide, lithium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, cesium hydroxide, cesium carbonate, calcium hydroxide, barium hydroxide, tetramethylammonium hydroxide and tetrabutylammonium hydroxide;

[0022] Compound 5, 4-dimethylaminopyridine, acetic anhydride and a base are dissolved in an organic solvent and reacted at 0-50°C for 1.5h-12h to obtain compound 1; the molar ratio of acetic anhydride to compound 5 is 5-10:1; the molar ratio of the base to compound 5 is 5-12:1; the base is one of pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethylamine, diisopropylethylamine, tetramethylethylenediamine and triethylenediamine; the organic solvent is one of dichloromethane, ethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, pyridine, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0023] Beneficial effects:

[0024] The present invention starts from 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-α-D-glucose, and obtains the intermediate benzyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucoside of the novel vaccine adjuvant MPLA through three steps of reaction. Compared with the existing synthesis method, the present invention has high synthesis efficiency, the reagents used are cheap, easy to obtain and safe, the reaction conditions of each step are green and mild, the operation is simple, environmentally friendly, and the target product can be recrystallized, which is a synthesis route suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of compound 2 synthesized in Example 1 of the present invention.

[0026] Figure 2 This is the hydrogen nuclear magnetic resonance spectrum of compound 3 synthesized in Example 2 of the present invention.

[0027] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of compound 4 synthesized in Example 3 of the present invention. DETAILED DESCRIPTION

[0028] The overall synthetic route of the present invention is:

[0029]

[0030] The technical solution of the present invention is further described below using specific embodiments, but the present invention is not limited to the scope of the embodiments. The experimental methods in the following embodiments without specifying specific conditions are selected according to conventional methods and conditions, or according to the product instructions.

[0031] Example 1: Synthesis of benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucoside (Compound 2)

[0032]

[0033] Under argon atmosphere, benzyl alcohol (41 mL, 0.4 mol, 5 eq) and trimethylsilyl trifluoromethanesulfonate (72 mL, 0.4 mol, 5 eq) were added to a solution of compound 1 (38.19 g, 80 mmol, 1 eq) in 1,2-dichloroethane (800 mL) and stirred. The mixture was heated to reflux. After the reaction was completed under TLC monitoring, the reaction was quenched with a saturated sodium bicarbonate solution. The liquids were separated, and the aqueous phase was extracted with ethyl acetate three times. The organic phases were combined, and the organic phases were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and the solvent was removed by distillation under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 2 (29.43 g, 70%). Its hydrogen nuclear magnetic resonance spectrum is as follows: Figure 1 shown. 1 H NMR(500MHz,Chloroform-d)δ7.81–7.66(m,4H),7.12–7.01(m,5H),5.77(dd,J= 10.7,9.1Hz,1H),5.36(d,J=8.5Hz,1H),5.16(dd,J=10.1,9.0Hz,1H),4.82(d,J=

[0034] 12.2Hz,1H),4.51(d,J=12.2Hz,1H),4.39–4.29(m,2H),4.18(dd,J=12.3,2.3Hz ,1H),3.85(ddd,J=10.2,4.6,2.3Hz,1H),2.10(s,3H),1.99(s,3H),1.82(s,3H).

[0035] Example 2: Synthesis of benzyl 2-deoxy-2-phthalimido-β-D-glucoside (Compound 3)

[0036]

[0037] Under argon atmosphere, methanol (560 mL) was added to compound 2 (29.43 g, 56 mmol, 1 eq) and potassium carbonate (2.32 g, 16.8 mmol, 0.3 eq) and stirred. After the reaction was completed by TLC monitoring, the reaction was quenched with sodium acetate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by short silica gel column chromatography to obtain compound 3 (21.47 g, 96%). Its hydrogen nuclear magnetic resonance spectrum is as follows: Figure 2 shown. 1H NMR(500MHz, Methanol-d4)δ7.90–7.70(m,4H),7.12–6.99(m,5H),5.15(d,J=8.5Hz,1H),4.80(d,J=12.3Hz,1H),4.55(d,J=12.3Hz,1H), 4.26(dd,J=10.7,8.0Hz,1H), 4.01(dd,J=10.7,8.5Hz,1H), 3.97(dd,J=11.9,2.0Hz,1H), 3.77(dd,J=11.9,5.4Hz,1H), 3.46–3.36(m,2H).

[0038] Example 3: Synthesis of benzyl 4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-glucoside

[0039]

[0040] Under argon atmosphere, tetrahydrofuran (540 mL) was added to compound 3 (21.47 g, 54 mmol, 1 eq) and p-toluenesulfonic acid monohydrate (1.03 g, 5.4 mmol, 0.1 eq), stirred, and then benzaldehyde dimethyl acetal (41 mL, 0.27 mol, 5 eq) was added, heated to reflux, and the reaction was monitored by TLC. After the reaction was completed, it was quenched with a saturated sodium bicarbonate solution, separated, extracted with ethyl acetate three times, and the organic phases were combined. The organic phases were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed by distillation under reduced pressure. The crude product was recrystallized in chloroform / isopropanol (4:1) to obtain the target compound 4 (22.90 g, 87%), a novel vaccine adjuvant MPLA intermediate, whose hydrogen nuclear magnetic resonance spectrum is as follows Figure 3 shown. 1 H NMR(500MHz,Chloroform-d)δ7.89–7.68(m,4H),7.53–7.47(m,2H),7.42–7.35 (m,3H),7.12–7.01(m,5H),5.58(s,1H),5.28(d,J=8.5Hz,1H),4.85(d,J=12.3H z,1H),4.69–4.61(m,1H),4.53(d,J=12.3Hz,1H),4.46–4.39(m,1H),4.31(dd,J =10.5,8.5Hz,1H),3.91–3.83(m,1H),3.70–3.60(m,2H),2.37(d,J=3.5Hz,1H).

[0041] Example 4: Synthesis of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-α-D-glucose (Compound 1)

[0042]

[0043] 2-Deoxy-2-glucosamine hydrochloride (107.82 g, 0.5 mol, 1 eq) and sodium hydroxide (21.00 g, 0.525 mol, 1.05 eq) were mixed, water (500 mL) was added, and the mixture was stirred. Then, phthalic anhydride (88.87 g, 0.6 mol, 1.2 eq) was added, and the mixture was stirred for 6 h. The mixture was filtered under reduced pressure, and the solid was washed with a small amount of water and tetrahydrofuran. The solid was dried under reduced pressure using an oil pump to obtain compound 2 (117.82 g, 72%).

[0044] Compound 2 (117.82 g, 0.36 mol, 1 eq) and 4-dimethylaminopyridine (21.99 g, 0.18 mol, 0.5 eq) were mixed, pyridine (500 mL) was added, and the mixture was stirred. The mixture was cooled in an ice-water bath, and acetic anhydride (255 mL, 2.7 mol, 7.5 eq) was added dropwise. The reaction was monitored by TLC after the addition was completed. After the reaction was completed, the reaction system was evaporated under reduced pressure. The concentrated reaction system was poured into water, extracted with ethyl acetate three times, and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 1 (113.43 g, 66%).

Claims

1. A method for synthesizing an intermediate for preparing a vaccine adjuvant MPLA, comprising the following steps: Step (1), in an argon atmosphere and in the presence of an acid, in an organic solvent, reacting compound 1 and benzyl alcohol at 25 to 102° C. for 15 min to 24 h to obtain intermediate 2; the molar ratio of benzyl alcohol to compound 1 is 1.2 to 5:1; the molar ratio of acid to compound 1 is 1 to 5:1; the compound 1 is 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-α-D-glucose, and has the following structural formula: Step (2), in the presence of an argon atmosphere and a base, intermediate 2 is reacted in an organic solvent to obtain intermediate 3; the molar ratio of the base to intermediate 3 is 0.1 to 5:1; Step (3), in an argon atmosphere and in the presence of an acid, in an organic solvent, reacting intermediate 3 and benzaldehyde dimethyl acetal at 25 to 102° C. for 10 min to 12 h to obtain intermediate 4, i.e., the intermediate for preparing the vaccine adjuvant MPLA; the molar ratio of benzaldehyde dimethyl acetal to intermediate 3 is 2 to 10:

1.

2. The method for synthesizing an intermediate for preparing the vaccine adjuvant MPLA according to claim 1, characterized in that: In step (1), the acid is one of p-toluenesulfonic acid monohydrate, trifluoroacetic acid, trifluoromethanesulfonic acid, ether solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trimethylchlorosilane, trimethylbromosilane, triethylchlorosilane, boron trifluoride etherate, boron trifluoride tetrahydrofuran, trimethylsilyl trifluoromethanesulfonate, triethylsilyl trifluoromethanesulfonate, ferric chloride, aluminum chloride, zinc chloride, copper trifluoromethanesulfonate, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, silver trifluoromethanesulfonate, iron trifluoromethanesulfonate, perfluorosulfonic acid resin Nafion and solid acid HND-580; The organic solvent is one of dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl ether, methyl tert-butyl ether, butyl ether, cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl acetate, ethyl acetate, dimethyl carbonate, diethyl carbonate and acetonitrile.

3. The method for synthesizing an intermediate for preparing the vaccine adjuvant MPLA according to claim 1, characterized in that: In step (2), the base is one of sodium, ammonia water, ammonia methanol solution, methylamine methanol solution, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, tetramethylammonium hydroxide, tetrabutylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide; The organic solvent is methanol, ethanol, dichloromethane / methanol with a volume ratio of 0.5 to 4:1, dichloromethane / ethanol with a volume ratio of 0.5 to 4:1, chloroform / methanol with a volume ratio of 0.5 to 4:1, chloroform / ethanol with a volume ratio of 0.5 to 4:1, 1,2-dichloroethane / methanol with a volume ratio of 0.5 to 4:1, 1,2-dichloroethane / ethanol with a volume ratio of 0.5 to 4:1, tetrahydrofuran / methanol with a volume ratio of 1 to 6:1, and tetrahydrofuran / methanol with a volume ratio of 1 to 6:

1. :1 tetrahydrofuran / ethanol in a volume ratio of 1 to 6:1, 2-methyltetrahydrofuran / methanol in a volume ratio of 1 to 6:1, 2-methyltetrahydrofuran / ethanol in a volume ratio of 1 to 6:1, cyclopentyl methyl ether / methanol in a volume ratio of 1 to 6:1, cyclopentyl methyl ether / ethanol in a volume ratio of 1 to 6:1, ethyl acetate / methanol in a volume ratio of 2 to 8:1, ethyl acetate / ethanol in a volume ratio of 2 to 8:1, acetonitrile / methanol in a volume ratio of 3 to 10:1, and acetonitrile / ethanol in a volume ratio of 3 to 10:

1.

4. The method for synthesizing an intermediate for preparing the vaccine adjuvant MPLA according to claim 1, characterized in that: In step (3), the acid is one of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, ether solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, zinc chloride, ferric chloride, aluminum chloride, titanium tetrachloride, cobalt chloride, scandium trifluoromethanesulfonate, zinc trifluoromethanesulfonate, iron trifluoromethanesulfonate, copper trifluoromethanesulfonate, perfluorosulfonic acid resin Nafion and solid acid HND-580; The organic solvent is one of dichloromethane, ethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, pyridine, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide; After the reaction is completed, the acid is quenched and the reaction system is concentrated, and the resulting crude product is purified by recrystallization; the solvent used for recrystallization is n-hexane / ethyl acetate with a volume ratio of 1 to 6:1, methylcyclopentane / ethyl acetate with a volume ratio of 1 to 6:1, cyclohexane / ethyl acetate with a volume ratio of 1 to 6:1, n-heptane / ethyl acetate with a volume ratio of 1 to 6:1, n-heptane / dimethyl carbonate with a volume ratio of 1 to 6:1, n-octane / diethyl carbonate with a volume ratio of 1 to 6:1, methanol, ethanol, isopropanol, n-butanol, 2-butanol, dichloromethane / methanol with a volume ratio of 4 to 10:1, chloroform / methanol with a volume ratio of 4 to 10:1, chloroform / ethanol with a volume ratio of 4 to 10:1, 1,2-dichloroethane / ethanol with a volume ratio of 4 to 10:1, chloroform / isopropanol with a volume ratio of 4 to 10:1, 1,2-dichloroethane / isopropanol in a ratio of 4 to 10:1, 1,2-dichloroethane / n-butanol in a ratio of 4 to 10:1, 1,2-dichloroethane / 2-butanol in a ratio of 4 to 10:1, 1,2-dichloroethane / isobutanol in a ratio of 4 to 10:1, methyl tert-butyl ether / tetrahydrofuran in a ratio of 1 to 8:1, n-hexane / tetrahydrofuran in a ratio of 1 to 10:1, One of cyclohexane / tetrahydrofuran in a volume ratio of 1 to 10:1, n-hexane / 2-methyltetrahydrofuran in a volume ratio of 1 to 10:1, cyclohexane / 2-methyltetrahydrofuran in a volume ratio of 1 to 10:1, n-heptane / 2-methyltetrahydrofuran in a volume ratio of 1 to 10:1, n-heptane / cyclopentyl methyl ether in a volume ratio of 1 to 10:1, and n-octane / cyclopentyl methyl ether in a volume ratio of 1 to 10:

1.

5. The method for synthesizing an intermediate for preparing the vaccine adjuvant MPLA according to claim 1, characterized in that: The synthesis method of compound 1 is as follows: 2-deoxy-2-glucosamine hydrochloride, phthalic anhydride and a base are reacted in water to obtain compound 5; the molar ratio of phthalic anhydride to 2-deoxy-2-glucosamine hydrochloride is 1.05-1.5:1; the molar ratio of the base to 2-deoxy-2-glucosamine hydrochloride is 1.05-2.5:1; the base is one of lithium hydroxide, lithium carbonate, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium hydroxide, potassium bicarbonate, potassium carbonate, cesium hydroxide, cesium carbonate, calcium hydroxide, barium hydroxide, tetramethylammonium hydroxide and tetrabutylammonium hydroxide; Compound 5, 4-dimethylaminopyridine, acetic anhydride and a base are dissolved in an organic solvent and reacted at 0-50°C for 1.5h-12h to obtain compound 1; the molar ratio of acetic anhydride to compound 5 is 5-10:1; the molar ratio of the base to compound 5 is 5-12:1; the base is one of pyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, N-methylmorpholine, N-methylpiperidine, N-ethylpiperidine, triethylamine, diisopropylethylamine, tetramethylethylenediamine and triethylenediamine; the organic solvent is one of dichloromethane, ethyl ether, methyl tert-butyl ether, methyl cyclopentyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, pyridine, acetonitrile, N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

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