Mannitol monocarboxylic ester, preparation method and application

Abstract

The invention provides mannitol monocarboxylate as well as a preparation method and application thereof, and belongs to the field of organic synthesis. The molecular structural formula of the mannitol monocarboxylic ester is as follows: # imgabs0 #, according to the mannitol monocarboxylate disclosed by the invention, while the defects of the existing mannitol monooleate are effectively overcome, the dispersity of vaccine drug molecules in an oil phase and a water phase can be effectively improved, and the thermal stability of the vaccine drug molecules is effectively improved.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and particularly to a mannitol monocarboxylate, a preparation method thereof, and an application thereof. Background Art

[0002] Mannitol monooleate is a lipophilic surfactant with stable chemical properties; mannitol monooleate can be used in vaccine preparation, tracer preparation, and other potential fields (such as cosmetics, coatings, plastics, textiles, etc.).

[0003] In the prior art, mannitol monooleate as an adjuvant for water-in-oil vaccines can also be used in Freund's adjuvant. Although mannitol monooleate has been widely used in formulation adjuvants at present, its safety for humans has always been a concern and questioned. Currently, studies on the biological properties of mannitol monooleate show that the level of free fatty acids in the emulsifier prepared with mannitol monooleate is correlated with its toxicity level; at the same time, studies on sorbitan monofatty acid esters also show that such materials are heterogeneous (Journal of Pharmaceutical Sciences, 1972, 863 - 867).

[0004] Furthermore, in the preparation process of the existing mannitol monooleate, since the reaction needs to be carried out in a high-temperature environment, it directly results in a very dark color of the crude product of mannitol monooleate. To meet the usage requirements as a vaccine adjuvant, it is necessary to perform a decolorization treatment on the obtained crude product of mannitol monooleate, but the operation of its decolorization treatment is cumbersome, the treatment efficiency is low, and it is often difficult to meet the predetermined color requirements.

[0005] On the other hand, in the actual application process of the existing mannitol monooleate as a vaccine adjuvant, the improvement of the dispersion of vaccine drug molecules in the oil and water phases by mannitol monooleate needs to be further enhanced, and it also cannot help to improve the thermal stability of vaccine drug molecules.

[0006] Therefore, providing a brand-new preparation adjuvant applicable to the oil-water emulsion system, while effectively overcoming the defects of the existing mannitol monooleate, can effectively improve the dispersion of vaccine drug molecules in the oil and water phases, and effectively improve the thermal stability of vaccine drug molecules, which has important technical value and research significance. Summary of the Invention

[0007] To solve the technical problems existing in the prior art, the present invention provides a mannitol monocarboxylate, which can effectively overcome the defects of the existing mannitol monooleate, can effectively improve the dispersion of vaccine drug molecules in the oil and water phases, and can effectively improve the thermal stability of vaccine drug molecules; the present invention also provides a preparation method and an application of the mannitol monocarboxylate.

[0008] To solve the above technical problems, the technical solution adopted by the present invention is as follows: A mannitol monocarboxylate, the molecular structural formula is as follows: .

[0009] A preparation method of mannitol monocarboxylate, in which mannitol is converted into anhydro-mannitol before or during esterification, and then esterified with benzoic acid functionalized with oligoethylene glycol to obtain mannitol monocarboxylate; The mannitol monocarboxylate, the molecular structural formula is as follows: ; The benzoic acid functionalized with oligoethylene glycol is 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid, and the molecular structural formula is as follows: .

[0010] Preferably, in the presence of phosphoric acid, 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid is added to molten mannitol, and after heating and reacting, anhydro-mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate is obtained.

[0011] Preferably, the heating reaction temperature is not lower than 200 °C and the reaction time is not less than 2 h.

[0012] Further, the 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid is prepared by the following steps: the first reaction, the second reaction, and the third reaction; In the first reaction, in the presence of triethylamine, triethylene glycol monobutyl ether reacts with p-toluenesulfonyl chloride to obtain 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate; In the second reaction, 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate reacts with methyl p-hydroxybenzoate to obtain methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate; In the third reaction, methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate is hydrolyzed under alkaline conditions to obtain 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid.

[0013] Preferably, in the first reaction, the molar amount of p-toluenesulfonyl chloride is at least 1.1 times the molar amount of triethylene glycol monobutyl ether.

[0014] Preferably, in the second reaction, the molar ratio of 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate to methyl 4-hydroxybenzoate is 1:1.2-1.4.

[0015] Preferably, the reaction temperature of the first reaction is room temperature; the reaction temperature of the second reaction is not lower than 80 °C; the reaction temperature of the third reaction is not lower than 82 °C.

[0016] An oil-in-water emulsion is prepared at least by using the aforementioned mannitol monocarboxylate.

[0017] An application of the aforementioned mannitol monocarboxylate as a nonionic lipophilic surfactant.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The mannitol monocarboxylate of the present invention can effectively overcome the defects of the existing mannitol monooleate, and the oil-in-water (O / W) emulsion prepared by it has high stability; at the same time, the oligomeric ethylene glycol-functionalized benzoic acid in the mannitol monocarboxylate can be chemically bonded to the vaccine drug molecule, improving the dispersibility of the drug molecule in the oil and water phases and enhancing the thermal stability of the drug molecule (New J.Chem., 2023, 47, 4521–4528).

[0019] (2) The preparation method of the mannitol monocarboxylate of the present invention has a simple process, is easy to operate, the prepared mannitol monocarboxylate has stable properties, is easy to decolorize, and has high preparation efficiency.

[0020] (3) The oil-in-water (O / W) emulsion prepared by using the mannitol monocarboxylate of the present invention can maintain its original state after standing at room temperature for one week, and there is no obvious difference in appearance compared with that before standing. Description of the Drawings

[0021] Figure 1 1H NMR spectrum of the mannitol monocarboxylate prepared in Example 3, that is, mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate.

[0022] Figure 2 Appearance morphology diagram of the oil-in-water (O / W) emulsion prepared in Example 4.

[0023] Figure 3 Appearance morphology diagram of the oil-in-water (O / W) emulsion prepared in Example 4 after standing at room temperature for one week. Detailed Description of the Invention

[0024] To have a clearer understanding of the technical features, objectives, and effects of the present invention, the specific embodiments of the present invention will now be described. It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0025] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present invention. As used herein, "first", "second", etc. are used to distinguish similar objects and are not used to describe a specific order or sequence. In addition, it should also be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0026] An embodiment of the present invention provides a mannitol monocarboxylate, and its molecular structural formula is as follows: 。

[0027] An embodiment of the present invention also provides a preparation method of the mannitol monocarboxylate, which is prepared by the following method: Mannitol is converted into the corresponding monohydrate (anhydromannitol) before or during the esterification, and after an esterification reaction with oligomeric ethylene glycol-functionalized benzoic acid, the mannitol monocarboxylate is obtained.

[0028] Preferably, the oligomeric ethylene glycol-functionalized benzoic acid is 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid, and its molecular structural formula is as follows: 。

[0029] Furthermore, the 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid is prepared by the following steps: the first reaction, the second reaction, and the third reaction; In the first reaction, in the presence of triethylamine, triethylene glycol monobutyl ether reacts with p-toluenesulfonyl chloride to obtain the corresponding triethylene glycol monobutyl ether monotosylate, that is, 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate; In the second reaction, 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate reacts with methyl p-hydroxybenzoate to obtain methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate; In the third reaction, methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate is hydrolyzed under alkaline conditions to obtain 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid.

[0030] Preferably, in the first reaction, the molar addition amount of p-toluenesulfonyl chloride is at least 1.1 times the molar amount of triethylene glycol monobutyl ether; In the second reaction, the molar ratio of 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate to methyl p-hydroxybenzoate is 1:1.2 - 1.4.

[0031] Further, in the first reaction, in a dichloromethane solvent environment, in the presence of triethylamine and 4-dimethylaminopyridine, after triethylene glycol monobutyl ether and p-toluenesulfonyl chloride react at room temperature, it is concentrated after layering, washing, and drying to obtain 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate.

[0032] In the second reaction, in a DMF solvent environment, in the presence of potassium carbonate, after 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate and methyl p-hydroxybenzoate contact and react at a temperature not lower than 80 °C, it is desolvated after extraction, washing, and drying to obtain methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate.

[0033] In the third reaction, in an aqueous ethanol solution, in an alkaline environment, methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate is heated to reflux (not lower than 82 °C), and after hydrolysis under insulation, it is crystallized after extraction, washing, and drying to obtain 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid.

[0034] Preferably, the preparation method of the mannitol monocarboxylate is that in an acidic environment, 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid contacts and reacts with molten mannitol to obtain mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate.

[0035] Preferably, the preparation method of the mannitol monocarboxylate is: in the presence of phosphoric acid, 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid is added to molten mannitol, and after heating and reacting, mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate is obtained.

[0036] Preferably, in the preparation of the mannitol monocarboxylate, the reaction temperature is not lower than 200 °C and the reaction time is not less than 2 h.

[0037] The embodiment of the present invention also provides an oil-in-water emulsion, which is prepared at least by using the foregoing mannitol monocarboxylate.

[0038] The embodiments of the present invention also provide an application of the foregoing mannitol monocarboxylate as a nonionic lipophilic surfactant.

[0039] The present invention will be further described below in conjunction with some specific embodiments.

[0040] Example 1 Preparation of methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate: The methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate has the following structural formula: The specific preparation method is as follows: 1. First reaction Add triethylene glycol monobutyl ether (41.2 g, 0.2 mol) to a reaction flask, then add dichloromethane (500 mL), triethylamine (30.3 g, 0.3 mol), 4-dimethylaminopyridine (1.0 g), and slowly add p-toluenesulfonyl chloride (46 g, 0.24 mol). Control the reaction temperature not higher than 30 °C. After reacting at room temperature for 3 h, monitor by thin-layer chromatography (take 0.5 ml of the reaction solution and place it in a sample bottle, add a few drops of triethylamine and 20 mg of p-nitrobenzenesulfonyl chloride, shake well and react for 10 min, then spot the plate together with the reaction solution for comparison. When the two are the same, it indicates that the reaction is complete); if the reaction is incomplete, first determine whether the reaction solution is alkaline. If it is not alkaline, add triethylamine. If the reaction is still incomplete, add p-toluenesulfonyl chloride; after the reaction is complete, add 1 mol / L hydrochloric acid until acidic, let it stand for layer separation, wash the dichloromethane layer with deionized water, then add sodium bicarbonate aqueous solution until alkaline, let it stand for layer separation, wash the dichloromethane layer with deionized water, dry over anhydrous sodium sulfate, filter and concentrate. The concentrated solution gives 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate, which is directly used for the next step of the reaction.

[0042] 2. Second reaction Dissolve 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (7.2 g, 20 mmol, 1.0 equiv) and methyl 4-hydroxybenzoate (4.15 g, 27 mmol, 1.35 equiv) in DMF (50 mL). After adding anhydrous potassium carbonate (9.9 g, 50 mmol, 2.5 equiv) to this solution, heat the mixture to 80 °C and stir for 16 h. After cooling, disperse the reaction mixture in water (200 mL) and ethyl acetate (200 mL). Extract the aqueous layer twice with ethyl acetate, 100 mL each time. Combine the organic phases and wash them once with dilute hydrochloric acid, deionized water, saturated sodium bicarbonate, and saturated brine respectively. After drying, remove the solvent under reduced pressure to obtain a colorless oil, namely methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate (6.6 g, 19.4 mmol, yield 97%).

[0043] The nuclear magnetic resonance detection results of methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate are as follows: 1 H NMR (CDCl 3 ) δ7.99 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H),4.19 (m, 2H), 3.89 (m, 5H), 3.75 (m, 2H), 3.70 (m, 2H), 3.66 (m, 2H), 3.59(m,2H), 3.46 (m, 2H), 1.58 (m, 2H), 1.38 (m, 2H), 0.92 (m, 3H); 13 C-NMR(CDCl 3 ) 166.9, 162.6, 131.6, 122.7, 114.2, 71.2, 70.9, 70.7, 70.6, 70.1,69.6, 67.6,51.9, 31.7, 19.3, 14.0。

[0044] Example 2 Preparation of 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid: The 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid has the following structural formula: The specific preparation method is as follows: To a solution of methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate (6.3 g, 18.5 mmol, 1.0 equiv) in an aqueous ethanol solution (50% by volume, 200 mL) was added KOH (2.6 g, 39 mmol). After heating under reflux and monitoring by thin-layer chromatography, ethanol was removed by concentration under reduced pressure after the reaction was completed. The pH was adjusted to 2 - 3 with 1 mol / L HCl, and then the mixture was extracted three times with ethyl acetate (50 mL each time). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to 20 mL, and then crystallized with n-hexane. After filtration and drying, a white solid, namely 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid (4.89 g, 15 mmol, yield 81%), was obtained. mp: 78 - 79 °C.

[0046] The nuclear magnetic resonance detection results of the said 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid are as follows: 1 H NMR (CDCl 3 ) δ12.64 (brs, 1H) 7.90 (d, J = 8.9 Hz, 2H), 7.04 (d, J =8.9 Hz, 2H), 4.18 (m, 2H),3.77 (m, 2H), 3.60 (m, 2H), 3.56 - 3.51 (m, 4H),3.47 (m, 2H), 3.37 (m, 2H), 1.46 (m, 2H), 1.30 (m, 2H), 0.87 (m, 3H); 13 C-NMR(CDCl 3 ) 167.5, 162.6, 131.8, 123.5, 114.7, 70.5, 70.4, 70.3, 70.0, 69.2,67.9, 31.8,19.3, 14.2.

[0047] Example 3 Preparation of mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate (i.e., mannitol monocarboxylate): The said mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate has the following structural formula: The specific preparation method is as follows: Mannitol (18.2 g, 0.1 mol) was kept molten at 220 °C for 1 h; Phosphoric acid (0.7 g) and 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid (32.6 g, 0.1 mol) were added dropwise into the molten mannitol, and stirred and mixed; After the mixture was continuously heated and reacted at 220 °C for 2 h, the reaction mixture was cooled to room temperature and extracted with 50 mL of methanol, then neutralized with an aqueous NaOH solution, washed with deionized water to remove phosphate and free mannitol residues, and finally washed with n-hexane to remove free 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid and dried. After concentration, a pale yellow oil was obtained, namely mannitol anhydride 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate.

[0049] As Figure 1 shown, the nuclear magnetic resonance hydrogen spectrum detection results of the mannitol anhydride 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate prepared in this example are as follows: 1 H NMR (400 MHz, CDCl 3 ) δ 9.08 (brs, 1H), 7.83 (d, J = 8.7 Hz,2H),6.93 (d, J = 8.9 Hz, 2H), 6.20 (t, J = 5.7 Hz, 1H), 5.42-4.67 (brs, 1H), 4.56(d, J = 4.3 Hz, 2H), 4.24-4.05 (m, 3H), 4.05-3.80 (m, 4H), 3.79-3.55 (m, 9H),3.46 (t, J = 6.7 Hz, 2H), 2.59 (m, 1H), 2.26 (m, 1H), 1.57 (dt, J = 14.7, 6.9Hz, 2H), 1.43-1.18 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). Example 4 Preparation of oil-in-water (O / W) emulsion: The mannitol anhydride 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate (0.1 g) prepared in Example 3, the nonionic hydrophilic surfactant Tween-85 (1.0 g), and the pharmaceutical-grade white oil Marcol 82 (8.8 g) were stirred and mixed evenly by a magnetic stirrer; then 20 wt% aqueous solution of Tween 85 (1.0 g) and disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution with a concentration of 0.02 mol / L (pH 7.8, 8.6 g) were added, and the mixture was rapidly stirred for 1 min to obtain a milky white solution, that is, an oil-in-water (O / W) emulsion (as Figure 2 shown).

[0050] After the oil-in-water (O / W) emulsion was left standing at room temperature for one week, the milky white solution remained unchanged, and there was no obvious difference in the appearance of the emulsion before and after standing (as Figure 3 shown).

[0051] Unless otherwise specified, the percentages used in the present invention are all mass percentages.

[0052] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A mannitol monocarboxylate, characterized in that The molecular structure is shown below: 。 2. A method for preparing mannitol monocarboxylate, characterized in that: Mannitol is converted into dehydrated mannitol before or during esterification, and then esterified with benzoic acid functionalized with oligoethylene glycol to obtain mannitol monocarboxylic acid ester; The mannitol monocarboxylate has a molecular structural formula as shown below: ； The oligoethylene glycol functionalized benzoic acid is 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid, and the molecular structure is shown below: 。 3. The method for preparing mannitol monocarboxylate according to claim 2, characterized in that: In the presence of phosphoric acid, 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid is added to molten mannitol, and heated for reaction to obtain dehydrated mannitol 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate.

4. The method for preparing mannitol monocarboxylate according to claim 3, characterized in that: The heating reaction temperature is not lower than 200°C and the reaction time is not less than 2h.

5. The method for preparing mannitol monocarboxylate according to claim 2, characterized in that: The 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid is prepared by the following steps: a first reaction, a second reaction, and a third reaction; The first reaction comprises reacting triethylene glycol monobutyl ether with p-toluenesulfonyl chloride in the presence of triethylamine to obtain 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate; In the second reaction, 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate reacts with methyl p-hydroxybenzoate to obtain methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate; In the third reaction, methyl 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoate is hydrolyzed under alkaline conditions to obtain 4-(2-(2-(2-butoxyethoxy)ethoxy)ethoxy)benzoic acid.

6. The method for preparing mannitol monocarboxylate according to claim 5, characterized in that: In the first reaction, the molar amount of p-toluenesulfonyl chloride is at least 1.1 times the molar amount of triethylene glycol monobutyl ether.

7. The method for preparing mannitol monocarboxylate according to claim 5, characterized in that: In the second reaction, the molar ratio of 2-(2-(2-butoxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate to methyl paraben is 1:1.2-1.

4.

8. The method for preparing mannitol monocarboxylate according to claim 5, characterized in that: The reaction temperature of the first reaction is room temperature; the reaction temperature of the second reaction is not less than 80°C; and the reaction temperature of the third reaction is not less than 82°C.

9. An oil-in-water emulsion, characterized in that: The method is prepared by at least using the mannitol monocarboxylate according to claim 1.

10. Use of the mannitol monocarboxylate as claimed in claim 1 as a nonionic lipophilic surfactant.

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