Intermediate, synthesis and application of vaccine adjuvant MPLA

A reaction and solvent technology, applied in the field of intermediates of vaccine adjuvant MPLA, can solve the problems of lack of preparation methods of vaccine adjuvant MPLA, and achieve the effect of short route and increased total yield

Pending Publication Date: 2021-10-22
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide an intermediate, synthesis and application o

Method used

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  • Intermediate, synthesis and application of vaccine adjuvant MPLA
  • Intermediate, synthesis and application of vaccine adjuvant MPLA
  • Intermediate, synthesis and application of vaccine adjuvant MPLA

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0241] Preparation of starting compound 1

[0242]

[0243] Add 2-deoxy-1-oxo-(1,1-dimethylethyl)dimethylsilyl-2-[(2,2,2-trichloroethoxy)carbonyl]amino-3,4 , 6-triacetyl-β-D-glucose (10g, 16.8mmol) was slowly added to a reaction flask of guanidine hydrochloride buffer solution (100mL, pH = 8), stirred at room temperature for 3.5h, and TLC detected that the raw material was consumed , the reaction solution was neutralized with a cationic resin, filtered and concentrated, the product was extracted with dichloromethane and saturated sodium bicarbonate solution, the organic layer was collected and concentrated to obtain 2-deoxy-1-oxo-(1,1-dimethylethyl) di Methylsilyl-2-[(2,2,2-trichloroethoxy)carbonyl]amino-β-D-glucose (1-1, 8.23 ​​g).

[0244] In a reaction flask, 1-1 and 2-(dimethoxymethyl)-naphthalene (5.1g, 25mmol, 1.5eq) were dissolved in 50mL of acetonitrile, and camphorsulfonic acid (0.39g, 1.69mmol, 0.1eq) was added , Stir at room temperature for 4h to react, add tri...

Embodiment 1

[0264] The preparation of embodiment 1 compound 24

[0265]

[0266] Compound 23 (10g, 39mmol, 1eq) and 2-naphthaldehyde (18.14g, 116mmol, 3eq) were dissolved in THF (100mL), and TMSOTf (6.88g, 31mmol, 0.8eq) was added under ice-cooling, (TMS) 2 O (37.68g, 232mmol, 6eq) and Et 3 SiH (15.7 g, 135 mmol, 3.5 eq). Reacted at 0°C for 1.5 hours, and the reaction solution was washed with CH 2 Cl 2 (150mL) and dilute with saturated NaHCO 3 washing. The organic layer was spin-dried and recrystallized (to obtain methylnaphthalene as a white solid at room temperature) (petroleum ether: ethyl acetate = 5:1), and filtered to remove impurities (methylnaphthalene). The filtrate (containing compound 24) was collected and spin-dried to obtain the crude product 24 as a pale yellow oily liquid, which was directly used in the next step without purification. 1 H NMR (400MHz, CDCl 3 )0.89(3H,t,J6.7),1.27–1.64(18H,m),2.35(2H,dd,J8.4)2.49(1H,dd,J15.0,5.3),2.62(1H,dd,J15 .0,7.3),3.68(3H,s),...

Embodiment 2

[0267] The preparation of embodiment 2 compound 20

[0268]

[0269] Compound 24 prepared in Example 1 was dissolved in THF-H 2 O solution (5:1, 100 mL), was added aqueous lithium hydroxide solution (9.41 g, 224 mmol, 94 mL), and refluxed for 12 h. After the starting material disappeared, it was cooled to room temperature and quenched to pH 7 by adding 1.5M HCl aqueous solution. The mixture was washed with CH 2 Cl 2 (150mL) diluted with saturated NaHCO 3 washing. The organic phase was dried and spin-dried. Purification by silica gel column chromatography (petroleum ether / ethyl acetate=5:1) gave compound 20 (11.6 g, 77.9% yield in two steps, colorless syrup).

[0270] 1 H NMR (400MHz, CDCl 3 )δ10.00 (1H, s, OH), 7.85 (4H, dd, J = 14.5, 10.8), 7.53 (3H, d, J = 4.2), 4.85–4.71 (2H, m, NapCH 2 O), 4.08–3.94 (1H, m, H-3), 2.76 (1H, dd, J = 15.2, 6.9, H-2), 2.64 (1H, dd, J = 15.2, 4.3, H-2), 1.84–1.58(2H,m,H-4),1.57–1.31(18H,m),1.00(3H,t,J=6.0).

[0271] 13 C NMR (101...

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Abstract

The invention discloses an intermediate, synthesis and application of a vaccine adjuvant MPLA. According to the intermediate provided by the invention, an allyl phosphate ligand is used as a phosphate group source in MPLA, and Nap is used as a protecting group, so that the allyl phosphate ligand and the protecting group can be conveniently removed in subsequent operation; the synthesis route of the intermediate is short, and the total yield is obviously increased. A basis is provided for synthesis and amplification of MPLA.

Description

technical field [0001] The invention relates to an intermediate, synthesis and application of a vaccine adjuvant MPLA. Background technique [0002] MPLA is derived from the innermost liposome (lipidA) part of endotoxin (LPS) in the cell wall of Gram-negative bacteria, monophosphoryl lipid A (Monophosphoryl Lipid A, hereinafter referred to as MPL). Lipid A is an amphiphilic structure, and it is also a key structure for the toxicity and immunogenicity of Gram-negative bacteria, which can cause the body's immune response. Therefore, it can be added to the vaccine as an adjuvant to increase the immunogenicity of the vaccine; generally speaking, although the attenuated live vaccine has strong immunogenicity, it is also highly toxic and may cause disease risk; while non-toxic The inactivated vaccine has weak immunogenicity. The addition of adjuvants can enhance the immunogenicity of inactivated vaccines, and will not bring the risk of disease to weaker people. At the same time...

Claims

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Application Information

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IPC IPC(8): C07H23/00C07H13/06C07H1/00C07H1/06
CPCC07H23/00C07H13/06C07H1/00C07H1/06Y02P20/55
Inventor 高祺隋强李根郑致伟韩子怡薛俊娣
Owner SHANGHAI INST OF PHARMA IND
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