A preparation method of L-histidine betaine

Abstract

The present invention belongs to the field of fine chemical technology, and specifically relates to a method for preparing L-histidine betaine. The present invention uses L-histidine as a raw material, methanol and water as a solvent, and dimethyl carbonate and a base are added to react in a microwave reactor to obtain L-histidine betaine. The reaction equation is shown below. The present invention uses a microwave reactor and adds an appropriate amount of dimethyl carbonate to carry out a methylation reaction, which has the characteristics of fast reaction efficiency, high product yield, low toxicity, environmental protection, and low cost.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing L-histidine betaine. Background Art

[0002] L-histidine betaine is an alkaloid with a chemical structure similar to amino acids. It belongs to the quaternary ammonium class and is widely found in plants and animals. L-histidine betaine is a methyl donor in living organisms, regulating osmotic pressure and stabilizing vitamins. It is widely used in cleansing and skincare products.

[0003] Patent CN116102502A uses methanol as solvent, potassium carbonate as base, and dimethyl sulfate as methylating agent, and reacts under heating conditions, and the product is obtained after purification. This process has the disadvantages of low yield, high toxicity, high energy consumption, and high cost.

[0004] Patent CN114409608A uses water as solvent, sodium hydroxide as base, dimethyl sulfate as methylating agent, and reacts at 0°C to obtain the product after purification. This process has the disadvantages of low yield, high toxicity, and high cost.

[0005] Patent CN111574458A uses tetrahydrofuran as solvent, potassium carbonate as base, methyl iodide as methylating agent, and the reaction is completed at room temperature for 12 hours. This process has the disadvantages of low yield, low purity, and high toxicity.

[0006] Furthermore, it is necessary to provide a related preparation method with fast reaction, high yield, high purity, low toxicity, environmental protection and reduced cost. Summary of the Invention

[0007] The invention provides a preparation method of L-histidine betaine.

[0008] The technical solution adopted in the present invention is:

[0009] A method for preparing L-histidine betaine, the reaction formula is as follows:

[0010]

[0011] L-histidine is used as a raw material, methanol and water are used as solvents, dimethyl carbonate is used as a methylating agent, and the reaction is carried out in a microwave reactor at 50-200° C. for 15-45 minutes under alkaline conditions. After the reaction, purification is performed to obtain high-yield and high-purity L-histidine betaine.

[0012] The volume mass ratio of methanol to raw materials in the reaction system is 6 to 10, the volume mass ratio of water to raw materials is 8 to 12, the equivalent of dimethyl carbonate in the reaction system is 2 to 4, and the equivalent of alkali is 4 to 6.5 degrees or less

[0013] The L-histidine, methanol and water are mixed, and then alkali is added, and dimethyl carbonate is added at 0-5 degrees, and mixed for use.

[0014] The alkali is one or more of ammonia water, potassium hydroxide and calcium hydroxide.

[0015] The purification comprises concentrating the reaction, adding methanol to the concentrated product, then adding methyl tert-butyl ether under heating and stirring conditions, thoroughly mixing, cooling to room temperature, and filtering to obtain a high-purity product; wherein the mass volume ratio between the reaction product, methanol, and methyl tert-butyl ether is 3-5 mL of methanol and 9-13 mL of methyl tert-butyl ether per 1 g of reactant.

[0016] After the above reaction, the reaction liquid was collected by filtration, separated and purified, and each reagent was recycled.

[0017] The advantages of the present invention are:

[0018] The invention uses a microwave reactor and adds an appropriate amount of dimethyl carbonate to carry out a methylation reaction, and has the advantages of fast reaction efficiency, high product yield, low toxicity and environmental protection, and low solvent recovery and reuse cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is the NMR image of the product prepared in the embodiment of the present invention. DETAILED DESCRIPTION

[0020] The specific embodiments of the present invention are further described below with reference to examples. It should be noted that the specific embodiments described here are only for illustrating and explaining the present invention, and are not intended to limit the present invention.

[0021] Example 1

[0022] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 30mL of methanol, and 5 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.2% and a yield of 98.2%.

[0023] Example 2

[0024] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.4% and a yield of 98.9%.

[0025] Example 3

[0026] To a 100mL three-necked flask, add 3.1g of L-histidine, 45mL of water, 20mL of methanol, and 5 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete by distillation under reduced pressure to dryness. Add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.6% and a yield of 96.2%.

[0027] Example 4:

[0028] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 3 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.2% and a yield of 97.2%.

[0029] Example 5:

[0030] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of aqueous ammonia. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 15 minutes to complete the reaction. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.5% and a yield of 96.8%.

[0031] Example 6:

[0032] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 7 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.7% and a yield of 98.4%.

[0033] Example 7:

[0034] Add 3.1 g of L-histidine, 30 mL of water, 20 mL of methanol, and 5 equivalents of sodium hydroxide to a 100 mL three-necked flask, cool to 0°C, add 2 equivalents of dimethyl carbonate dropwise, transfer to a microwave reactor, heat to 150°C, and react for 30 minutes until the reaction is complete. Concentrate to dryness by vacuum distillation, add 15 mL of methanol, stir, heat to 50°C, add 37.5 mL of methyl tert-butyl ether dropwise, keep warm and stir for 1 hour, then cool to 25°C, collect the filter cake by filtration, and dry the filter cake to obtain

[0035] The purity was 99.1% product and the yield was 98.2%.

[0036] Example 8:

[0037] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete by distillation under reduced pressure to dryness. Add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.4% and a yield of 98.6%.

[0038] Example 9:

[0039] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of sodium hydroxide. Cool to 0°C and add 4 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.6% and a yield of 98.5%.

[0040] Example 10:

[0041] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of aqueous ammonia. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 45 minutes to complete the reaction. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.5% and a yield of 99.5%.

[0042] Example 11:

[0043] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of potassium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 150°C for 30 minutes. The reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.6% and a yield of 98.1%.

[0044] Example 12:

[0045] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of aqueous ammonia. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After complete dropwise addition, transfer to a microwave reactor and heat to 100°C for 45 minutes to complete the reaction. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After complete dropwise addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a purity of 99.3% and a yield of 97.5%.

[0046] Example 13: Solvent Recovery and Application

[0047] After the reaction of Example 10, methanol was recovered: the distillate and filtrate of the vacuum distillation were collected, and the 67° C. fraction was collected by atmospheric distillation. The methanol content was above 95% as determined by gas chromatography.

[0048] Add 3.1g of L-histidine, 30mL of water, 20mL of recovered methanol, and 5 equivalents of ammonia water to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate dropwise, transfer to a microwave reactor, heat to 150℃ and react for 30 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of recovered methanol, stir, heat to 50℃, add 37.5mL of methyl tert-butyl ether dropwise, keep warm and stir for 1 hour, then cool to 25℃, collect the filter cake by filtration, and dry the filter cake to obtain a product with a purity of 99.4% and a yield of 98.3%. The product was identified by nuclear magnetic resonance as follows Figure 1 .

[0049] Comparative Example 1

[0050] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 10mL of methanol, and 5 equivalents of sodium hydroxide. Cool to 0°C and add 3 equivalents of dimethyl carbonate dropwise. After addition, heat to 90°C and stir for 8 hours to complete the reaction. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a yield of 75.2% and a purity of 94.3%.

[0051] Comparative Example 2

[0052] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of aqueous ammonia. Cool to 0°C and add 5 equivalents of dimethyl carbonate dropwise. After addition, warm to 25°C and react for 24 hours until the reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, heat to 50°C, and add 37.5mL of methyl tert-butyl ether dropwise. After addition, heat and stir for 1 hour, then cool to 25°C. Filter and collect the filter cake, which is then dried to obtain the product with a yield of 88.5% and a purity of 96.1%.

[0053] Comparative Example 3

[0054] To a 100mL three-necked flask, add 3.1g of L-histidine, 30mL of water, 20mL of methanol, and 5 equivalents of aqueous ammonia. Add 5 equivalents of dimethyl carbonate dropwise at 25°C. Allow to react for 24 hours until the reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL of methanol, stir, and heat to 50°C. Then, add 37.5mL of methyl tert-butyl ether dropwise. After stirring for 1 hour, cool to 25°C, collect the filter cake by filtration, and dry it to obtain the product with a yield of 66.2% and a purity of 93.1%.

[0055] As can be seen from the above examples and comparative examples, using a microwave reactor and adding an appropriate amount of dimethyl carbonate and a specific base under specific conditions can accelerate the methylation reaction efficiency of L-histidine betaine, improve the reaction yield, and the solvent can be recycled to avoid material waste, effectively improve the product profit margin, and have the advantages of low toxicity and low pollution.

Claims

1. A method for preparing L-histidine betaine, characterized in that: The reaction formula is as follows: L-histidine is used as a raw material, methanol and water are used as solvents, dimethyl carbonate is used as a methylating agent, and the reaction is carried out in a microwave reactor at 50-200° C. for 15-45 minutes under alkaline conditions. After the reaction, purification is performed to obtain high-yield and high-purity L-histidine betaine.

2. The method for preparing L-histidine betaine according to claim 1, wherein: The volume mass ratio of methanol to raw materials in the reaction system is 3-10, the volume mass ratio of water to raw materials is 10-30, the equivalent of dimethyl carbonate in the reaction system is 2-4, and the equivalent of alkali is 4-6.

3. The method for preparing L-histidine betaine according to claim 1, wherein: The alkali is one or more of ammonia water, potassium hydroxide and calcium hydroxide.

4. The method for preparing L-histidine betaine according to claim 1, wherein: The purification comprises concentrating the reaction, adding methanol to the concentrated product, then adding methyl tert-butyl ether under heating and stirring conditions, thoroughly mixing, cooling to room temperature, and filtering to obtain a high-purity product; wherein the mass volume ratio between the reaction product, methanol, and methyl tert-butyl ether is 3-5 mL of methanol and 9-13 mL of methyl tert-butyl ether per 1 g of reactant.

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