Continuous flow synthesis method of chloracetyl-L-glutamine and glycyl-glutamine

Abstract

The invention discloses a continuous flow synthesis method of chloracetyl-L-glutamine and glycyl-glutamine, and belongs to the technical field of organic synthesis. According to the invention, molecular-level efficient mixing and heat conduction of materials are realized, so that the reaction materials are fully mixed, the reaction is more sufficient, the conversion rate is further improved, and the process operation is safe and controllable. The micro-channel reactor has the advantages that equipment is relatively small, the reaction is continuous flow, the feed flux is large, the occupied area of the equipment is reduced, and the productivity is improved. Through a micro-channel continuous flow method, ammonia water or ammonia gas is directly adopted without adding ammonium bicarbonate, the problem that the ammonia water cannot be used mechanically is solved, the recycled ammonia water treated after reaction can be directly used mechanically, three wastes are thoroughly solved, and the production process is green and environment-friendly. The glycyl-L-glutamine is totally synthesized through micro-channel continuous flow, the product purity HPLC (High Performance Liquid Chromatography) of the glycyl-L-glutamine reaches 99.5% or above, and the single impurity content is less than 0.1%.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a continuous flow synthesis method of chloroacetyl-L-glutamine and glycylglutamine. Background Art

[0002] Glycylglutamine is a synthetic amino acid peptide and one of the main ingredients in the 15-compound amino acid dipeptide injection. Glycylglutamine is primarily used to provide glutamine to promote protein synthesis. Glutamine plays a crucial role in parenteral nutrition, alleviating intestinal mucosal atrophy and enhancing the activity of small intestinal and colonic cells, thereby strengthening intestinal mucosal function and reducing bacterial and endotoxin translocation in the intestine. Therefore, glycyl-L-glutamine has broad potential for development in the medical field.

[0003] At present, a variety of preparation methods for glycyl-L-glutamine have been disclosed both at home and abroad. For example, chloroacetyl chloride is reacted with glutamic acid-γ-methyl ester to generate chloroacetylglutamate-γ-methyl ester, and then aminolysis is performed to obtain glycyl-glutamine (JP63051399). However, this method has high raw material costs and is difficult to remove the intermediate. Another example is the use of benzyloxycarbonylglycine and N-hydroxysuccinimide as raw materials, the addition of dicyclohexylcarbodiimide (DCC) to obtain the corresponding activated ester, and the reaction with glutamine to obtain benzyloxycarbonylglycylglutamine; and then, under the catalysis of a palladium catalyst, hydrogenolysis and recrystallization to obtain glycylglutamine (CN1532204). This method has a complex production process and strict equipment requirements, making it difficult to industrialize.

[0004] Zhang Zhe etc. adopt the method for dripping phthalylglycyl and sodium hydroxide aqueous solution simultaneously to first prepare phthalylglycyl-L-glutamine, then use triethylamine and hydrazine hydrate hydrazinolysis to prepare glycyl-L-glutamine (Chemical Reagent, 2011,33,177).Double dropping in the method has higher requirement to reaction control, and the pH value of reaction system is susceptible to the drop rate influence of acyl chlorides and sodium hydroxide, easily causes pH value too low and causes reaction to be difficult to forward to carry out, has a strong impact on productive rate, even causes reaction failure.And this method is also higher to equipment requirements, does not utilize to reduce production cost and realize industrialization.In addition, the triethylamine that this method adds in hydrazinolysis process is difficult to remove in subsequent purification step, causes product yield and purity to reduce.

[0005] For example, patent application number CN202011441553.2 discloses an industrial preparation method for glycyl-L-glutamine. Chloroacetyl chloride and L-glutamine are first subjected to an acylation reaction at low temperature and alkaline conditions. After phase separation, an N-chloroacetyl-L-glutamine aqueous solution is obtained. The N-chloroacetyl-L-glutamine aqueous solution is then treated using electrodialysis membrane separation technology. Ammonia gas is introduced into the treated N-chloroacetyl-L-glutamine aqueous solution for pressurized aminolysis. After concentration, crystallization, filtration, and drying, crude glycyl-L-glutamine is obtained. Finally, the crude glycyl-L-glutamine is dissolved in water and purified using WA-30 resin. High-purity glycyl-L-glutamine is obtained by crystallization. This patent uses a very complex purification process, including electrodialysis membrane separation technology, WA-30 resin purification, multiple crystallizations, and multi-stage reactions, and the reaction time is particularly long.

[0006] For example, the patent application number CN201410706801.X discloses a process for synthesizing high-purity glycyl-L-glutamine dipeptide in a mixed solvent, comprising the following steps: using high-content N-chloroacetyl-L-glutamine to react with (NH4)2CO3 in a mixed solvent of a non-protonated polar solvent and ammonia water, adding a mixed solvent of a non-protonated polar solvent and ammonia water, ammonium carbonate and high-content N-chloroacetyl-L-glutamine to a closed reactor in sequence, and heating to react; after the reaction, recovering excess ammonia water under reduced pressure at room temperature, heating and decompressing the excess (NH4)2CO3, concentrating the reaction solution, crystallizing it with a mixed solvent of methanol and ester, filtering, and drying to obtain a high-purity crude glycyl-L-glutamine; suspending the crude product in water, heating to dissolve it, decolorizing it by adsorption on activated carbon, hot filtering, adding a mixed solvent of methanol and ester, crystallizing it, filtering it, and vacuum drying it to obtain high-purity glycyl-L-glutamine. This patent requires the use of ammonium carbonate and decolorization, and the reaction time is very long.

[0007] The applicant has experimentally found that the reaction of chloroacetyl-L-glutamine with ammonia gas or aqueous ammonia in a reactor (without using ammonium carbonate) not only has a slow reaction rate but also undergoes a large number of side reactions (the content of certain side reaction products reaches 20%). Summary of the Invention

[0008] This patent achieves efficient mixing and heat transfer at the molecular level, ensuring thorough mixing of the reaction materials, a more complete reaction, further improving conversion rates, and ensuring safe and controllable process operations. Microchannel reactors offer the advantages of relatively small equipment, continuous flow reaction, high feed throughput, reduced equipment footprint, and increased production capacity. The ammonolysis reaction of chloroacetyl-L-glutamine currently utilizes aqueous ammonia and ammonium bicarbonate. The recovered ammonia contains a large amount of ammonium bicarbonate, which cannot be recycled in industrial production, making the treatment of the three wastes difficult and severely restricting the product's industrialization and capacity expansion. The present invention utilizes a microchannel continuous flow method, eliminating the need for ammonium bicarbonate and directly using aqueous ammonia or ammonia gas. This solves the problem of aqueous ammonia being incompatible with conventional methods. The recovered ammonia from post-reaction treatment can be directly reused, completely eliminating the three wastes and achieving a green and environmentally friendly production process. Glycyl-L-glutamine synthesized using microchannel continuous flow has a product purity exceeding 99.5% by HPLC, with impurities less than 0.1%.

[0009] In one aspect, a continuous flow synthesis method for chloroacetyl-L-glutamine in an embodiment of the present invention comprises: dissolving glutamine in a polar solvent and adding a base A for dissolution to obtain component A; dissolving chloroacetyl chloride in an organic solvent A to obtain component B, with the base B serving as component C. Components A and B are fed into a first reaction module of a first microchannel reactor, and the base B (component C) is fed into a third reaction module or a fourth reaction module of the first microchannel reactor. The reaction pressure is 0.1-0.5 MPa (preferably 0.1-0.3 MPa), the pH of the effluent is 10-12, the reaction temperature before the addition of the base B is -5-30°C (preferably 10-20°C), and the reaction temperature after the addition of the base B (including during the addition, and the same applies thereto) is 10-60°C (preferably 25-40°C), and the reaction residence time is 30-90 seconds. After completion of the reaction, the aqueous layer is separated to obtain chloroacetyl-L-glutamine.

[0010] In this method, chloroacetyl chloride and glutamine are first reacted in a low-base, low-temperature environment. After a period of reaction (most of the reactants are consumed, and the raw materials and products are less likely to undergo side reactions with the base under these conditions and in the microchannel reactor), base is added and the reaction is continued at a higher temperature to allow the reaction to proceed fully. The microchannel reactor allows the raw materials to be fully mixed according to their proportions, resulting in a product purity greater than 98% after solid-liquid separation.

[0011] The first microchannel reactor comprises 4-10 reaction modules connected in series, and the polar solvent is water or a non-aqueous solvent. When the polar solvent is a non-aqueous solvent, at least one of base A and base B is an aqueous solution. The polar solvent is water, and base A and base B are not limited.

[0012] Among them, the polar solvent in the embodiment of the present invention is selected from water, acetone, DMF, DMAC or DMSO, etc., preferably water, acetone or DMF, and most preferably water.

[0013] The organic solvent A is selected from toluene, benzene, hexane, heptane, petroleum ether, tetrahydrofuran or dioxane, preferably toluene, heptane or tetrahydrofuran, and most preferably toluene.

[0014] Wherein, base A is selected from sodium hydroxide solution, potassium hydroxide solution, ammonia water, sodium carbonate solution or triethylamine, etc., preferably sodium hydroxide solution, most preferably 20-35wt% sodium hydroxide solution.

[0015] Wherein, the base B is selected from sodium hydroxide solution, potassium hydroxide solution, ammonia water, sodium carbonate solution or triethylamine, etc., preferably sodium hydroxide solution, and most preferably 20-35wt% sodium hydroxide solution.

[0016] The mass ratio of glutamine to polar solvent is 1:2-10, the mass ratio of chloroacetyl chloride to organic solvent A is 1:1-5, and the mass flow ratio of component A, base B and component B is 1:0.3-1.5:0.2-1.2.

[0017] Preferably, in the embodiments of the present invention, the polar solvent is water, the organic solvent A is toluene, and the base A and base B are 20-35 wt% sodium hydroxide solutions. The mass ratio of glutamine to the polar solvent is 1:2-10, preferably 1:4-6. The mass ratio of chloroacetyl chloride to organic solvent A is 1:1-5, preferably 1:1-2. Preferably, the mass flow ratio of component A to base B to component B is 1:0.5-1.0:0.3-0.9.

[0018] Furthermore, in the embodiment of the present invention, glutamine is dissolved in water at 30-50°C and a 20-35 wt% sodium hydroxide solution is added to dissolve the component A. Component A and component B are then fed into different inlets of the first reaction module of the first microchannel reactor. Heating the solvent can reduce the amount of sodium hydroxide solution added, control the reaction progress, and reduce the generation of impurities.

[0019] Preferably, the continuous flow synthesis method of chloroacetyl-L-glutamine in the present invention comprises: dissolving glutamine in water at 30-50°C and adding 20-35wt% sodium hydroxide solution to dissolve to obtain component A, dissolving chloroacetyl chloride in toluene to obtain component B, respectively feeding component A and component B into different inlets of a first reaction module of a first microchannel reactor, feeding alkali B to a third reaction module of the first microchannel reactor, the reaction pressure being 0.1-0.3 MPa, the pH value of the effluent being 10-12, the reaction temperature before the addition of alkali B being 10-20°C, the reaction temperature after the addition of alkali B being 25-40°C, and the reaction residence time being 30-90s. The first microchannel reactor comprises 6-8 reaction modules connected in series, which are silicon carbide microchannel reactors. The mass ratio of glutamine to water is 1:4-6, the mass ratio of chloroacetyl chloride to toluene is 1:1-2, and the mass flow ratio of component A, base B, and component B is 1:0.5-1.0:0.3-0.9. Base B is a 20-35 wt% sodium hydroxide solution. After the reaction is completed, the aqueous layer is separated to obtain chloroacetyl-L-glutamine.

[0020] Furthermore, acid A is added to the aqueous layer to adjust the pH to 1-2, and solid-liquid separation is performed to obtain the acid salt of chloroacetyl-L-glutamine. Acid A is selected from hydrochloric acid, sulfuric acid, or nitric acid, and acid A is preferably hydrochloric acid.

[0021] Specifically, the first microchannel reactor includes 6 reaction modules connected in series, the refrigerant channels of the first two reaction modules are connected in series; and the refrigerant channels of the last four reaction modules are connected in series.

[0022] On the other hand, an embodiment of the present invention further provides a continuous flow synthesis method for glycylglutamine, comprising: feeding a chloroacetyl-L-glutamine reaction solution and concentrated ammonia water (concentration of 20-30 wt%, specifically 25 wt%) or ammonia gas into a first reaction module of a second microchannel reactor for reaction, the reaction temperature being 20-80 ° C (preferably 40-60 ° C), the reaction pressure being 0.2-1.5 MPa (preferably 0.5-0.7 MPa), and the reaction residence time being 60-200 s. The chloroacetyl-L-glutamine reaction solution is obtained by dissolving chloroacetyl-L-glutamine in solvent B, adjusting the pH of the reaction solution obtained by the above method to 6-8 (adding acid, the acid can be selected from hydrochloric acid, sulfuric acid, dilute nitric acid, phosphoric acid, acetic acid, or formic acid, preferably hydrochloric acid, specifically 30 wt % hydrochloric acid), or adjusting the pH of the reaction solution obtained by the above method to 1-2 (adding acid, the acid can be selected from hydrochloric acid, sulfuric acid, or dilute nitric acid, preferably hydrochloric acid, specifically 30 wt % hydrochloric acid), solid-liquid separation, and dissolving in solvent B. The second microchannel reactor includes 4-8 reaction modules, and a strong mixing module is provided between the first reaction module and the second reaction module or between the second reaction module and the third reaction module.

[0023] The intensive mixing module ensures thorough mixing of the raw materials, and the microchannel reactor allows the raw materials to react in the correct proportions, achieving high-speed and high-purity product production without the addition of ammonium carbonate. The crude product purity is greater than 98%.

[0024] The solvent B in the embodiment of the present invention is selected from water, acetone, DMF, DMAC or DMSO, preferably water, acetone or DMF, and most preferably water.

[0025] The mass ratio of chloroacetyl-L-glutamine to solvent B is 1:2-10, preferably 1:4-6. If concentrated aqueous ammonia is used, the mass flow ratio of the chloroacetyl-L-glutamine reaction solution to the concentrated aqueous ammonia is 1:1-15, preferably 1:4-6. If ammonia gas is used, the volume flow ratio of the chloroacetyl-L-glutamine reaction solution to the ammonia gas is 1:15-90, preferably 1:45-60.

[0026] Preferably, the second microchannel reactor in the embodiment of the present invention includes 5-7 reaction modules and is a Hastelloy microchannel reactor. A strong mixing module is provided between the first reaction module and the second reaction module. The reaction temperature is 40-60°C, the reaction pressure is 0.5-0.7 MPa, and the solvent B is water; the mass ratio of chloroacetyl-L-glutamine to solvent B is 1:4-6; if it is concentrated ammonia water, the mass flow ratio of the chloroacetyl-L-glutamine reaction liquid to the concentrated ammonia water is 1:5-10; if it is ammonia gas, the volume flow ratio of the chloroacetyl-L-glutamine reaction liquid to the concentrated ammonia water is 1:45-60.

[0027] Furthermore, after the reaction is completed, concentration, solid-liquid separation and recrystallization (specifically, methanol can be used) are performed to obtain glycylglutamine, which is consistent with the existing technology.

[0028] The method in the embodiment of the present invention includes: S101: Glutamine is dissolved in water at 30-50°C and 20-35wt% sodium hydroxide solution is added for dissolution to obtain component A, chloroacetyl chloride is dissolved in toluene to obtain component B, components A and B are fed into different inlets of the first reaction module of the first microchannel reactor, alkali B is fed to the third reaction module of the first microchannel reactor, the reaction pressure is 0.1-0.3 MPa, the pH value of the effluent is 10-12, the reaction temperature before the addition of alkali B is 10-20°C, the reaction temperature after the addition of alkali B is 25-40°C, and the reaction residence time is 30-90s. The first microchannel reactor includes 6-8 reaction modules connected in series, which are silicon carbide microchannel reactors. The mass ratio of glutamine to water is 1:4-6, the mass ratio of chloroacetyl chloride to toluene is 1:1-2, the mass flow ratio of component A to base B to component B is 1:0.5-1.0 to 0.3-0.9, and base B is a 20-35 wt% sodium hydroxide solution. After the reaction is completed, the aqueous layer is separated and the pH value is adjusted to 6-8 by adding hydrochloric acid to obtain a chloroacetyl-L-glutamine reaction solution, or the aqueous layer is separated, the pH value is adjusted to 1-2 by adding hydrochloric acid, and the solution is dissolved in 4-6 times the mass of water to obtain the chloroacetyl-L-glutamine reaction solution.

[0029] S102: The chloroacetyl-L-glutamine reaction liquid and concentrated ammonia water or ammonia gas are fed into the first reaction module of the second microchannel reactor for reaction at a reaction temperature of 40-60°C, a reaction pressure of 0.5-0.7 MPa, and a reaction residence time of 60-200 seconds. After the reaction is completed, the reaction is concentrated, solid-liquid separated, and recrystallized to obtain glycylglutamine. The second microchannel reactor includes 5-7 reaction modules and is a Hastelloy alloy microchannel reactor. A strong mixing module is provided between the first reaction module and the second reaction module. The mass ratio of chloroacetyl-L-glutamine to water is 1:4-6. If concentrated ammonia water is used, the mass flow ratio of the chloroacetyl-L-glutamine reaction liquid to the concentrated ammonia water is 1:5-10. If ammonia gas is used, the volume flow ratio of the chloroacetyl-L-glutamine reaction liquid to the ammonia gas is 1:45-60.

[0030] Specifically, the first microchannel reactor includes five reaction modules connected in series, and the heat medium channels of the last four reaction modules are connected in series.

[0031] This invention utilizes a microchannel reaction module to achieve thorough mixing of materials, ensuring complete reaction, resulting in a purity exceeding 99% (and exceeding 99.99% after refining). This significantly increases production capacity (with a two-step reaction residence time of less than 30 minutes). This replaces existing kettle-type reactions, addressing industrial issues such as incomplete reaction and low efficiency. By eliminating the use of ammonium bicarbonate as a raw material and reducing pollutant emissions, the process is safer, more controllable, and more environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 It is a schematic diagram of the first microchannel reactor for preparing chloroacetyl-L-glutamine in the present invention.

[0033] Figure 2 Schematic diagram of the second microchannel reactor for preparing glycylglutamine by using aqueous ammonia in the present invention.

[0034] Figure 3 Schematic diagram of the second microchannel reactor for preparing glycylglutamine by ammonia gas according to the present invention.

[0035] Figure 4 This is the HPLC detection spectrum of the chloroacetyl-L-glutamine reaction solution prepared in Scheme 1; Figure 5 This is the HPLC detection spectrum of the chloroacetyl-L-glutamine solid prepared in Scheme 1.

[0036] Figure 6 The HPLC detection spectrum of the crude glycylglutamine prepared by the present invention is shown.

[0037] Figure 7 The present invention provides an HPLC detection spectrum of the glycylglutamine fine product prepared by the present invention. DETAILED DESCRIPTION

[0038] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be described in further detail below with reference to the accompanying drawings.

[0039] This embodiment provides a method and microchannel reaction apparatus for synthesizing glycyl-L-glutamine using a microchannel continuous flow process. The microchannel reaction apparatus includes a metering pump or plunger pump (with an external weighing scale), multiple microchannel modules, a heating / cooling integrated unit, and a pressure display backpressure valve.

[0040] The synthesis method is as follows: Scheme 1 (the intermediate chloroacetyl-L-glutamine is used as a solid for the next reaction): 1. Microchannel continuous flow synthesis of chloroacetyl-L-glutamine (attached) Figure 1 shown) Component 1: Prepare a suspension of 200 g glutamine and 1000 g water, heat to 30-50°C, and add 25 wt% sodium hydroxide solution until the solution is completely clear.

[0041] Component 2: 25wt% sodium hydroxide solution.

[0042] Component 3: Mix 231g of chloroacetyl chloride and 350g of toluene.

[0043] The internal temperature of the pre-cooling medium control modules of reaction modules No. 1 and No. 2 is controlled to 10-30°C, and the internal temperature of the pre-cooling medium control modules of reaction modules No. 3 to No. 6 is controlled to 25-40°C.

[0044] Use a weighing balance to calibrate the flow of the three groups of plunger pumps using drinking water as the medium, and check whether there is leakage and whether the back pressure valve is normal.

[0045] Component 1 is introduced into inlet 1# of reaction module 1 through the plunger pump line. Component 3 is introduced into inlet 2# of reaction module 1 through the plunger pump line. Component 2 is introduced into the inlet of reaction module 3 through the plunger pump line. After mixing, the mixture passes through all modules to complete the reaction. Check for leaks and that the pump pressure and back pressure valve pressure are normal.

[0046] Calibrate the mass flow rates (g / min) of the three components and maintain them within the following g / min ratios: component 1 (glutamine solution): component 2 (sodium hydroxide solution): component 3 (chloroacetyl chloride toluene solution): 1:0.5-1.0:0.3-0.9. Fine-tune the mass flow rate ratio of component 2 to control the pH of the effluent, aiming for a pH of 10-12 after exiting the main module. The reaction pressure was 0.1-0.3 MPa, the internal temperature of reaction modules 1 and 2 was 15±2°C, and the internal temperature of reaction modules 3 through 6 was 35±2°C. The reaction residence time was 45 seconds. The reaction solution was collected from the reaction modules. The reaction solution was allowed to stand for separation, and the toluene layer was removed. The aqueous layer was adjusted to a pH of 1-2 with 30 wt% hydrochloric acid to precipitate a large amount of solid. Solid-liquid separation was performed to yield Compound 1: chloroacetyl-L-glutamine hydrochloride.

[0047] 2. Microchannel continuous flow synthesis of glycyl-L-glutamine (Attachment Figure 2 shown) Component 1: 300g of chloroacetyl-L-glutamine, add 1500g of water and dissolve.

[0048] Component 2: Industrial concentrated ammonia solution.

[0049] Keep the preheating medium control module of the No. 1 reaction module, the No. 2 strong mixing module, and the No. 2 reaction module to the No. 5 reaction module at a temperature of 40-60°C. Use a weighing balance to verify the flow of the two sets of plunger pumps using drinking water as the medium, and check for leaks and whether the back pressure valve is functioning properly.

[0050] Pass component 1 and component 2 into different inlets of reaction module No. 1 through their respective plunger pump pipelines; check that there is no leakage and the pump pressure and back pressure display are normal.

[0051] Calibrate the mass flow rates (g / min) of the two components and maintain a mass flow rate ratio (g / min) of 1:5-10 for component 1 (chloroacetyl chloride-L-glutamine solution): component 2 (ammonia solution). Maintain stable flow rates, maintain the module temperature at 50°C ± 2°C, and the pressure at 0.5-0.7 MPa. The reaction residence time is 1 minute 50 seconds. The reaction solution exiting the module is collected, concentrated by distillation, and crystallized using recovered ammonia to obtain crude glycyl-L-glutamine. This crude product is then re-refined with water and methanol to yield the product. The total molar yield is 82%, the product liquid phase purity is 99.8%, and single impurity content is ≤ 0.1%.

[0052] Scheme 2 (the intermediate chloroacetyl-L-glutamine is used in solution for the next reaction. The impurities in the previous step do not affect the reaction in the next step according to the experiment): 1. Microchannel continuous flow synthesis of chloroacetyl-L-glutamine (attached) Figure 1 shown) Component 1: Prepare a suspension of 200 g glutamine and 1000 g water, heat to 30-50°C, and add 25 wt% sodium hydroxide solution until the solution is completely clear.

[0053] Component 2: 25wt% sodium hydroxide solution.

[0054] Component 3: Mix 231g of chloroacetyl chloride and 350g of toluene.

[0055] The internal temperature of the pre-cooling medium control modules of reaction modules No. 1 and No. 2 is controlled to 10-30°C, and the internal temperature of the pre-cooling medium control modules of reaction modules No. 3 to No. 6 is controlled to 25-40°C.

[0056] Use a weighing balance to calibrate the flow of the three groups of plunger pumps using drinking water as the medium, and check whether there is leakage and whether the back pressure valve is normal.

[0057] Component 1 enters inlet 1# of reaction module No. 1 through the plunger pump pipeline; component 3 enters inlet 2# of reaction module No. 1 through the plunger pump pipeline, and component 2 enters the inlet of reaction module No. 3 through the plunger pump pipeline. After mixing, the reaction is completed through all modules and checked for leakage and normal pump pressure and back pressure.

[0058] Calibrate the mass flow rates (g / min) of the three components and maintain them within the following ratios: component 1 (glutamine solution): component 2 (sodium hydroxide solution): component 3 (chloroacetyl chloride toluene solution): 1:0.5-1.0:0.3-0.9. Fine-tune the mass flow rate ratio of component 2 to control the pH of the effluent, aiming for a pH of 10-12 after exiting the main module. The reaction pressure is 0.1-0.3 MPa, the internal temperature of reaction modules 1 and 2 is 20±2°C, and the internal temperature of reaction modules 3 through 6 is 30±2°C. The reaction residence time is 45 seconds. Collect the reaction solution effluent from the reaction modules. Allow the reaction solution to stand and separate. Remove the toluene layer, and adjust the pH of the aqueous layer to 6-8 with 30 wt% hydrochloric acid to obtain a chloroacetyl-L-glutamine solution.

[0059] 2. Microchannel continuous flow synthesis of glycyl-L-glutamine (Attachment Figure 2 shown) Component 1: Chloroacetyl-L-glutamine solution from the previous step.

[0060] Component 2: Industrial concentrated ammonia solution.

[0061] The temperature inside the preheating medium control module of the No. 1 reaction module, the No. 2 strong mixing module, and the No. 2 reaction module to the No. 5 reaction module is 40-60°C.

[0062] Use a weighing balance to calibrate the flow of the two sets of plunger pumps used with drinking water as the medium, and check whether there is leakage and whether the back pressure valve is normal.

[0063] Pass component 1 and component 2 into different inlets of reaction module No. 1 through their respective plunger pump pipelines; check that there is no leakage and the pump pressure and back pressure display are normal.

[0064] Calibrate the mass flow rates (g / min) of the two components and maintain a mass flow ratio (g / min) of 1:5-10 for component 1 (chloroacetyl chloride-L-glutamine solution): component 2 (ammonia solution). Maintain stable flow calibration, maintain the module's measurement temperature at 55°C ± 2°C, and the pressure at 0.5-0.7 MPa. The reaction residence time is 1 minute 50 seconds. The reaction solution exiting the module is collected, concentrated by distillation, and crystallized using recovered ammonia solution to obtain crude glycyl-L-glutamine. This crude product is then re-refined with water and methanol to yield the product. The total molar yield is 82%, the product liquid phase purity is 99.8%, and single impurity content is ≤0.1%.

[0065] Scheme 3 (the intermediate chloroacetyl-L-glutamine is reacted with aqueous solution and ammonia gas for the next step): 1. Microchannel continuous flow synthesis of chloroacetyl-L-glutamine (attached) Figure 1 shown) Component 1: Prepare a suspension of 200 g glutamine and 1000 g water, heat to 30-50°C, and add 25 wt% sodium hydroxide solution until the solution is completely clear.

[0066] Component 2: 25% sodium hydroxide solution.

[0067] Component 3: Mix 231g of chloroacetyl chloride and 350g of toluene.

[0068] The internal temperature of the pre-cooling medium control modules of reaction modules No. 1 and No. 2 is controlled to 10-30°C, and the internal temperature of the pre-cooling medium control modules of reaction modules No. 3 to No. 6 is controlled to 25-40°C.

[0069] Use a weighing balance to calibrate the flow of the three groups of plunger pumps using drinking water as the medium, and check whether there is leakage and whether the back pressure valve is normal.

[0070] Component 1 is introduced into inlet #1 of reaction module #1 through the plunger pump tubing. Component 3 is introduced into inlet #2 of reaction module #1 through the plunger pump tubing. Component 2 is introduced into the inlet of reaction module #3 through the plunger pump tubing. After mixing, the mixture passes through all modules to complete the reaction. Check for leaks and that the pump pressure and back pressure are normal.

[0071] Calibrate the mass flow rates (g / min) of the three components and maintain them within the following g / min ratios: component 1 (glutamine solution): component 2 (sodium hydroxide solution): component 3 (chloroacetyl chloride toluene solution): 1:0.5-1.0:0.3-0.9. Fine-tune the mass flow rate ratio of component 2 to maintain a pH of 10-12 for the reaction solution exiting the master module. Maintain a reaction pressure of 0.1-0.3 MPa, internal temperatures of 25±2°C for reaction modules 1 and 2, and 35±2°C for reaction modules 3 through 6, with a residence time of 45 seconds. Collect the reaction solution exiting the reaction modules. Allow the reaction solution to stand and separate. Remove the toluene layer, and adjust the pH of the aqueous layer to 6-8 with 30 wt% hydrochloric acid to obtain a chloroacetyl-L-glutamine solution.

[0072] 2. Microchannel continuous flow synthesis of glycyl-L-glutamine (Attachment Figure 3 shown) Component 1: Chloroacetyl-L-glutamine solution from the previous step.

[0073] Component 2: Industrial concentrated ammonia solution.

[0074] The temperature inside the preheating medium control module of the No. 1 reaction module, the No. 2 strong mixing module, and the No. 2 reaction module to the No. 5 reaction module is 40-60°C.

[0075] Use a weighing balance to calibrate the flow of the two sets of plunger pumps used with drinking water as the medium, and check whether there is leakage and whether the back pressure valve is normal.

[0076] Components 1 and 2 were introduced into the different inlets of reaction module #1 via their respective plunger pump lines. Check for leaks and normal pump and backpressure pressures. Component 1 was introduced into inlet #1 of reaction module #1 via the plunger pump line. Component 2, ammonia gas, was introduced into inlet #2 of reaction module #1 via a pressure reducing valve and a gas flowmeter. Check for leaks and normal pump and backpressure pressures. Control: Component 1 (chloroacetyl chloride-L-glutamine solution, ml / min): Component 2 (ammonia gas, ml / min) = 1:45-60. Liquid and gas flow rates were stable, the module temperature was maintained at 40-60°C, and the pressure was maintained at 0.5-0.7 MPa. The reaction residence time was 2 minutes and 5 seconds. The reaction liquid outflow from the reaction module was collected, concentrated by distillation, and ammonia was recovered to crystallize crude glycyl-L-glutamine. The crude product was recrystallized from water and methanol to obtain the product. The total molar yield was 85%, the product liquid phase purity was 99.9%, and single impurity content was ≤0.1%.

[0077] Comparative Example 1 Components 1, 2, and 3 were introduced from different inlets in reaction module 1. The internal temperature of reaction modules 1 to 6 was maintained at 20 ± 2°C. Other procedures were consistent with those in Scheme 1. The resulting chloroacetyl-L-glutamine had a purity of 96.1%.

[0078] Comparative Example 2 Components 1, 2, and 3 were introduced into reaction module 1 through reaction modules 6 at different inlets. The internal temperature of reaction modules 1 through 6 was maintained at 35 ± 2°C. Other procedures were consistent with those in Scheme 1. The resulting chloroacetyl-L-glutamine had a purity of 94.7%.

[0079] Comparative Example 3 Components 1 and 3 were introduced through different inlets in reaction module 1, while component 2 was introduced through reaction module 2. The internal temperature of reaction module 1 was 20 ± 2°C, and the internal temperature of reaction modules 2 through 6 was 35 ± 2°C. All other conditions were the same as in Scheme 1. The resulting chloroacetyl-L-glutamine had a purity of 96.5%.

[0080] Comparative Example 4 Prepare a suspension of 200 g of glutamine and 1000 g of water. Add 25 wt% sodium hydroxide solution (or more) at room temperature until the solution is completely clear. All other steps are the same as in Scheme 1. The resulting chloroacetyl-L-glutamine has a purity of 96.3%.

[0081] Comparative Example 5 When preparing glycylglutamine, no strong mixing module was set, the purity of the crude product was 92.1%, and the total molar yield was less than 80%.

[0082] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A continuous flow synthesis method for chloroacetyl-L-glutamine, characterized in that: The method comprises: Glutamine is dissolved in a polar solvent and base A is added for dissolution to obtain component A, chloroacetyl chloride is dissolved in an organic solvent A to obtain component B, components A and B are fed into a first reaction module of a first microchannel reactor, and base B is fed into a third reaction module or a fourth reaction module of the first microchannel reactor. The reaction pressure is 0.1-0.5 MPa, the pH value of the effluent is 10-12, the reaction temperature before the addition of base B is -5-30°C, the reaction temperature after the addition of base B is 10-60°C, and the reaction residence time is 30-90 seconds. The first microchannel reactor includes 4-10 reaction modules connected in series. After the reaction is completed, the aqueous layer is separated to obtain chloroacetyl-L-glutamine. The polar solvent is water or a non-aqueous solvent. When the polar solvent is a non-aqueous solvent, at least one of the base A and the base B is an aqueous solution.

2. The continuous flow synthesis method of chloroacetyl-L-glutamine according to claim 1, characterized in that: The polar solvent is selected from water, acetone, DMF, DMAC or DMSO, the organic solvent A is selected from toluene, benzene, hexane, heptane, petroleum ether, tetrahydrofuran or dioxane, the base A is selected from sodium hydroxide solution, potassium hydroxide solution, ammonia water, sodium carbonate solution or triethylamine; the base B is selected from sodium hydroxide solution, potassium hydroxide solution, ammonia water, sodium carbonate solution or triethylamine.

3. The continuous flow synthesis method of chloroacetyl-L-glutamine according to claim 1, characterized in that: The polar solvent is water, the organic solvent A is toluene, the base A and the base B are 20-35wt% sodium hydroxide solution, the mass ratio of glutamine to the polar solvent is 1:2-10, the mass ratio of chloroacetyl chloride to the organic solvent A is 1:1-5, and the mass flow ratio of component A, base B and component B is =1:0.3-1.5:0.2-1.

2.

4. The continuous flow synthesis method of chloroacetyl-L-glutamine according to claim 3, characterized in that: Glutamine is dissolved in water at 30-50° C. and 20-35 wt % sodium hydroxide solution is added for dissolution to obtain component A. Component A and component B are respectively fed into different inlets of the first reaction module of the first microchannel reactor.

5. The continuous flow synthesis method of chloroacetyl-L-glutamine according to claim 1, characterized in that: The method comprises: Glutamine was dissolved in water at 30-50°C and 20-35 wt% sodium hydroxide solution was added to dissolve to obtain component A, chloroacetyl chloride was dissolved in toluene to obtain component B, components A and B were respectively fed into different inlets of the first reaction module of the first microchannel reactor, and alkali B was fed to the third reaction module of the first microchannel reactor. The reaction pressure was 0.1-0.3 MPa, the pH value of the effluent was 10-12, the reaction temperature before the addition of alkali B was 10-20°C, and the reaction temperature after the addition of alkali B was 20-30°C. 25-40° C., a reaction residence time of 30-90 s; the first microchannel reactor comprises 6-8 reaction modules connected in series, which is a silicon carbide microchannel reactor; the mass ratio of glutamine to water is 1:4-6, the mass ratio of chloroacetyl chloride to toluene is 1:1-2, the mass flow ratio of component A, base B and component B is =1:0.5-1.0:0.3-0.9, and the base B is 20-35wt% sodium hydroxide solution; after the reaction is completed, the water layer is separated to obtain chloroacetyl-L-glutamine.

6. The continuous flow synthesis method of chloroacetyl-L-glutamine according to claim 1, characterized in that: Acid A is added to the aqueous layer to adjust the pH value to 1-2, and solid-liquid separation is performed to obtain the acid salt of chloroacetyl-L-glutamine, wherein the acid A is selected from hydrochloric acid, sulfuric acid or nitric acid.

7. A continuous flow synthesis method for glycylglutamine, characterized in that: The method comprises: The chloroacetyl-L-glutamine reaction liquid and concentrated ammonia water or ammonia gas are fed into the first reaction module of the second microchannel reactor for reaction, the reaction temperature is 20-80°C, the reaction pressure is 0.2-1.5 MPa, and the reaction residence time is 60-200 seconds; the chloroacetyl-L-glutamine reaction liquid is obtained by dissolving chloroacetyl-L-glutamine in solvent B, adjusting the pH of the reaction liquid obtained in claim 1 to 6-8, or adjusting the pH of the reaction liquid obtained in claim 1 to 1-2, performing solid-liquid separation, and dissolving the reaction liquid in solvent B; the second microchannel reactor includes 4-8 reaction modules, and a strong mixing module is provided between the first reaction module and the second reaction module or between the second reaction module and the third reaction module.

8. The continuous flow synthesis method of glycylglutamine according to claim 7, characterized in that The solvent B is selected from water, acetone, DMF, DMAC or DMSO, and the mass ratio of the chloroacetyl-L-glutamine to the solvent B is 1:2-10; if concentrated aqueous ammonia is used, the mass flow ratio of the chloroacetyl-L-glutamine reaction solution to the concentrated aqueous ammonia is 1:1-15; if ammonia gas is used, the volume flow ratio of the chloroacetyl-L-glutamine reaction solution to the ammonia gas is 1:15-90.

9. The continuous flow synthesis method of glycylglutamine according to claim 7, characterized in that: The second microchannel reactor includes 5-7 reaction modules and is a Hastelloy microchannel reactor. A strong mixing module is provided between the first reaction module and the second reaction module. The reaction temperature is 40-60°C, the reaction pressure is 0.5-0.7 MPa, and the solvent B is water. The mass ratio of the chloroacetyl-L-glutamine to the solvent B is 1:4-6. If it is concentrated ammonia water, the mass flow ratio of the chloroacetyl-L-glutamine reaction liquid to the concentrated ammonia water is 1:5-10; if it is ammonia gas, the volume flow ratio of the chloroacetyl-L-glutamine reaction liquid to the ammonia gas is 1:45-60.

10. The continuous flow synthesis method of glycylglutamine according to claim 7, characterized in that: The method comprises: S101: dissolving glutamine in water at 30-50°C and adding 20-35wt% sodium hydroxide solution to dissolve to obtain component A, dissolving chloroacetyl chloride in toluene to obtain component B, feeding components A and B into different inlets of the first reaction module of the first microchannel reactor, feeding alkali B to the third reaction module of the first microchannel reactor, the reaction pressure is 0.1-0.3Mpa, the pH value of the effluent is 10-12, the reaction temperature before the addition of alkali B is 10-20°C, the reaction temperature after the addition of alkali B is 25-40°C, and the reaction residence time is 30-90s; the first microchannel reactor The device comprises 6-8 reaction modules connected in series, which are silicon carbide microchannel reactors; the mass ratio of glutamine to water is 1:4-6, the mass ratio of chloroacetyl chloride to toluene is 1:1-2, the mass flow ratio of component A, alkali B and component B is 1:0.5-1.0:0.3-0.9, and the alkali B is a 20-35wt% sodium hydroxide solution; after the reaction is completed, the water layer is separated and the pH value is adjusted to 6-8 by adding hydrochloric acid to obtain a chloroacetyl-L-glutamine reaction solution, or the water layer is separated, the pH value is adjusted to 1-2 by adding hydrochloric acid, and the reaction solution is dissolved in 4-6 times the mass of water to obtain a chloroacetyl-L-glutamine reaction solution; S102: The chloroacetyl-L-glutamine reaction liquid and concentrated ammonia water or ammonia gas are fed into the first reaction module of the second microchannel reactor for reaction at a reaction temperature of 40-60° C., a reaction pressure of 0.5-0.7 MPa, and a reaction residence time of 60-200 s. After the reaction is completed, the reaction liquid is concentrated, solid-liquid separation and recrystallization are performed to obtain glycylglutamine. The second microchannel reactor includes 5-7 reaction modules and is a Hastelloy alloy microchannel reactor. A strong mixing module is provided between the first reaction module and the second reaction module. The mass ratio of the chloroacetyl-L-glutamine to water is 1:4-6. If concentrated ammonia water is used, the mass flow ratio of the chloroacetyl-L-glutamine reaction liquid to the concentrated ammonia water is 1:5-10. If ammonia gas is used, the volume flow ratio of the chloroacetyl-L-glutamine reaction liquid to the ammonia gas is 1:45-60.

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