Preparation method of L-histidine betaine

Abstract

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of L-histidine betaine. According to the method, L-histidine is used as a raw material methanol, water is used as a solvent, dimethyl carbonate and alkali are added, and the L-histidine betaine is obtained through a reaction in a microwave reactor. The reaction equation is shown in the specification. The microwave reactor is used, a proper amount of dimethyl carbonate is added for methylation reaction, and the method has the advantages of being high in reaction efficiency, high in product yield, low in toxicity, environmentally friendly and low in cost. # imgabs0 #

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 animals and plants. L-histidine betaine is one of the methyl donors in living things. It has the functions of regulating the osmotic pressure in the body and stabilizing vitamins. It is widely used in cleansing skin care products.

[0003] Patent CN116102502A uses methanol as solvent, potassium carbonate as base, dimethyl sulfate as methylating agent, and reacts under heating conditions to obtain the product 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, reacts at 0°C, and obtains 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 reacts at room temperature for 12 hours to complete the reaction. 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 method for preparing L-histidine betaine.

[0008] The technical solution adopted by 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 material in the reaction system is 6 to 10, the volume mass ratio of water to raw material 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 after mixing, and mixed for use.

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

[0015] The purification is to concentrate the reaction, add methanol to the concentrated product, then add methyl tert-butyl ether under heating and stirring conditions, fully mix, cool to room temperature, and filter 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 solution is collected by filtration, separated and purified, and each reagent is recycled.

[0017] The advantages of the present invention are:

[0018] The invention uses a microwave reactor and adds a proper 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 application 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 implementation modes of the present invention are further described below in conjunction with examples. It should be noted that the specific implementation modes described here are only for illustrating and explaining the present invention, and are not limited to the present invention.

[0021] Example 1

[0022] Add 3.1g L-histidine, 30mL water, 30mL methanol, and 5 equivalents of sodium hydroxide to a 100mL three-necked flask, cool to 0°C, add 3 equivalents of dimethyl carbonate, transfer to a microwave reactor, heat to 150°C and react for 30 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL methanol, stir and heat to 50°C, add 37.5mL methyl tert-butyl ether, 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 a product with a purity of 99.2% and a yield of 98.2%.

[0023] Example 2

[0024] 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 3 equivalents of dimethyl carbonate, transfer to a microwave reactor, heat to 150°C and react for 30 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15 mL of methanol, stir and heat to 50°C, add 37.5 mL of methyl tert-butyl ether, 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 a product with a purity of 99.4% and a yield of 98.9%.

[0025] Example 3

[0026] Add 3.1g L-histidine, 45mL water, 20mL methanol, and 5 equivalents of sodium hydroxide to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, 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 methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 99.6% and a yield of 96.2%.

[0027] Embodiment 4:

[0028] Add 3.1 g of L-histidine, 30 mL of water, 20 mL of methanol, and 3 equivalents of sodium hydroxide to a 100 mL three-necked flask, cool to 0°C, add 3 equivalents of dimethyl carbonate, transfer to a microwave reactor, heat to 150°C, react for 30 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15 mL of methanol, stir and heat to 50°C, add 37.5 mL of methyl tert-butyl ether, 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 a product with a purity of 99.2% and a yield of 97.2%.

[0029] Embodiment 5:

[0030] Add 3.1g L-histidine, 30mL water, 20mL methanol, and 5 equivalents of ammonia water to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, transfer to a microwave reactor, heat to 150℃ and react for 15 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 99.5% and a yield of 96.8%.

[0031] Embodiment 6:

[0032] Add 3.1g L-histidine, 30mL water, 20mL methanol, and 7 equivalents of sodium hydroxide to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, 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 methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 99.7% and a yield of 98.4%.

[0033] Embodiment 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, transfer to a microwave reactor, heat to 150°C and react for 30 minutes, and 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, 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] Embodiment 8:

[0037] Add 3.1g L-histidine, 30mL water, 20mL methanol, and 5 equivalents of sodium hydroxide to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, 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 methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 98.6%.

[0038] Embodiment 9:

[0039] Add 3.1g L-histidine, 30mL water, 20mL methanol, and 5 equivalents of sodium hydroxide to a 100mL three-necked flask, cool to 0℃, add 4 equivalents of dimethyl carbonate, 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 methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 99.6% and a yield of 98.5%.

[0040] Embodiment 10:

[0041] Add 3.1g L-histidine, 30mL water, 20mL methanol, and 5 equivalents of ammonia water to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, transfer to a microwave reactor, heat to 150℃ and react for 45 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15mL methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 99.5%, and a yield of 99.5%.

[0042] Embodiment 11:

[0043] Add 3.1g L-histidine, 30mL water, 20mL methanol, and 5 equivalents of potassium hydroxide to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, 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 methanol, stir and heat to 50℃, add 37.5mL methyl tert-butyl ether, 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 99.6% and a yield of 98.1%.

[0044] Embodiment 12:

[0045] Add 3.1 g of L-histidine, 30 mL of water, 20 mL of methanol, and 5 equivalents of ammonia water to a 100 mL three-necked flask, cool to 0 ° C, add 3 equivalents of dimethyl carbonate, transfer to a microwave reactor, heat to 100 ° C and react for 45 minutes, and the reaction is complete. Concentrate to dryness by vacuum distillation, add 15 mL of methanol, stir and heat to 50 ° C, add 37.5 mL of methyl tert-butyl ether, keep warm and stir for 1 hour, then cool to 25 ° C, filter and collect the filter cake, dry the filter cake to obtain a 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 the above 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 detected by gas chromatography.

[0048] Add 3.1g L-histidine, 30mL water, 20mL recovered methanol, and 5 equivalents of ammonia water to a 100mL three-necked flask, cool to 0℃, add 3 equivalents of dimethyl carbonate, 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 and heat to 50℃, add 37.5mL of methyl tert-butyl ether, keep warm and stir for 1 hour, then cool to 25℃, filter and collect the filter cake, dry the filter cake to obtain a product with a purity of 99.4% and a yield of 98.3%. The product is identified by NMR as follows Figure 1 .

[0049] Comparative Example 1

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

[0051] Comparative Example 2

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

[0053] Comparative Example 3

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

[0055] It can be seen from the above embodiments and comparative examples that by using a microwave reactor and adding an appropriate amount of dimethyl carbonate and a specific base under specific conditions, the methylation reaction efficiency of L-histidine betaine can be accelerated, the reaction yield can be improved, the solvent can be recycled to avoid material waste, the product profit margin can be effectively improved, and it has 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 is to concentrate the reaction, add methanol to the concentrated product, then add methyl tert-butyl ether under heating and stirring conditions, fully mix, cool to room temperature, and filter 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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