Synthesis method of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl) methyl] aminocarbonyl]-L-valine and methyl ester thereof
By using the one-pot reaction method in an air environment, the problems of nitrogen protection and low yield in the prior art were solved, and efficient and high-purity ritonavir intermediate synthesis was achieved, which was suitable for industrial production.
Patent Information
- Application Number
- CN202411176110.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-26
- Publication Date
- 2025-01-03
AI Technical Summary
The existing ritonavir intermediate synthesis method needs to be carried out under a nitrogen atmosphere, and the yield of the product is low, which increases the production cost and process difficulty.
The one-pot method is used to react L-valine methyl ester, triphosgene and alkali in an air environment to produce N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl] Aminocarbonyl]-L-valine methyl ester avoids nitrogen protection and intermediate separation, and improves yield and purity.
It realizes the efficient synthesis of high-purity ritonavir intermediates in air environments, simplifies the process flow, reduces production costs, and is suitable for industrial production.
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Figure CN119241467A_ABST
Abstract
Description
Technical Field
[0001] The present invention belongs to the technical field of compound synthesis, and more specifically, relates to a method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine and its methyl ester. Background Art
[0002] Ritonavir, chemical name: N-[(2S,3S,5R)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-isopropyl-1,3-thiazol-4-yl)methyl]carbamoyl]amino]butyryl]amino]-1,6-diphenyl-hexan-2-yl]carbamic acid 5-thiazolylmethyl ester, its structure is shown below:
[0003]
[0004] Ritonavir is an oral, effective inhibitor of human immunodeficiency virus-1 (HIV-1) and human immunodeficiency virus-2 (HIV-2) aspartic protease, blocking the enzyme from producing polyproteins required for morphologically mature HIV particles, thereby maintaining HIV particles in an immature state and slowing the spread of HIV in cells.
[0005] One of the intermediates of ritonavir is N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester or N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine. In view of the synthesis of the above-mentioned ritonavir intermediate, patent publication number CN105753806A discloses a heterogeneous synthesis method of a ritonavir intermediate, wherein L-valine methyl ester hydrochloride and triphosgene are dissolved in dichloromethane, and an aqueous solution of an inorganic base is added dropwise thereto at 5 to 28° C. under nitrogen protection; then, the mixture is stirred at 20 to 40° C. for 0.8 to 1.2 h to react to generate an isocyanate compound 3(S)-(-)-2-isocyanato-3-methylbutyric acid methyl ester; then, 2-isopropyl-4-(methylaminomethyl)thiazole is added thereto in batches at 20 to 40° C., and the reaction is carried out at the temperature for 0.8 to 1.2 h; thus, N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester is obtained, wherein the inorganic base is sodium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate. The above method can synthesize ((2-isopropylthiazol-4-yl)methyl)(methyl)carbamoyl)-L-valine methyl ester in one pot. However, the above reaction must be carried out under the protection of nitrogen atmosphere, and the yield of the product acid or methyl ester is low, which greatly increases the production cost and process difficulty.
[0006] Therefore, how to provide a synthesis method of the above-mentioned ritonavir intermediate that is more conducive to practical application has become a technical problem that needs to be solved urgently. Summary of the invention
[0007] In view of the above-mentioned existing technical problems, the primary purpose of the present invention is to provide a method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester, which can achieve one-pot synthesis without the need for a nitrogen atmosphere and has a high yield and purity.
[0008] In order to achieve the above object, the present invention is implemented by the following technical solutions:
[0009] The present invention claims a method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester, comprising the following steps: using a one-pot method to mix and react a compound of formula (I) or its acid salt, triphosgene, a base and a solvent, and then adding a compound of formula (III) to react to obtain a compound of formula (IV) N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester;
[0010] The base is selected from one or more of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylformamide, N,N-diisopropylethylamine, N-methylmorpholine, p-dimethylaminopyridine, and pyridine;
[0011] The reaction formula of the synthesis method is as follows:
[0012]
[0013] The present invention provides a one-pot method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester, wherein the above-mentioned specific base is used as the alkaline reagent of the reaction system, so that the compound of formula (I) and triphosgene can react in an air environment to prepare a ritonavir intermediate. The synthesis method provided by the present invention does not need to be prepared in a specific nitrogen atmosphere, and is not afraid of moisture in the air (5% moisture is added, which has no effect on the reaction); in addition, the one-pot method is used for preparation, and the intermediate does not need to be separated, so that a high-yield and high-purity ritonavir intermediate can be prepared. The synthesis method has the advantages of simple operation, high efficiency, good process stability, environmental friendliness, high atomic utilization rate, etc., and can be applied to industrial scale-up production, and has a good application prospect.
[0014] Preferably, the molar ratio of the compound of formula (I) to triphosgene is 1:0.1 to 1.0. More preferably, the molar ratio of the compound of formula (I) to triphosgene is 1:0.2 to 0.5.
[0015] Preferably, the molar ratio of the compound of formula (I) to triethylamine is 1:1.0-6.0.
[0016] Preferably, the molar ratio of the compound of formula (I) to the compound of formula (III) is 1:0.6-1.2.
[0017] Preferably, the solvent is selected from one or more of halogenated hydrocarbons, carboxylates, C3-C8 cycloalkanes, alkylbenzenes, ethers, and ketones. More specifically, in the present invention, halogenated hydrocarbon solvents include but are not limited to dichloromethane, etc.; carboxylates include but are not limited to ethyl acetate, propyl acetate, etc.; C3-C8 cycloalkanes include but are not limited to cyclohexane, etc.; alkylbenzenes include but are not limited to toluene, xylene, etc.; ethers include but are not limited to methyl tert-butyl ether, tetrahydrofuran, etc.; ketones include but are not limited to acetone, butanone, methyl ethyl ketone, etc.
[0018] Preferably, the temperature of the mixed reaction is -10°C to 40°C. More preferably, the temperature of the mixed reaction is 20 to 35°C.
[0019] Preferably, the reaction temperature after adding the compound of formula (III) is 20-30°C.
[0020] Preferably, the acid salt of the compound of formula (I) is one or more of hydrochloride and hydrobromide.
[0021] Preferably, the method further comprises a purification step of subjecting the product to recrystallization.
[0022] Preferably, the purification treatment can be carried out by a recrystallization method conventional in the art, more specifically, a recrystallization method such as volatilization crystallization, evaporation crystallization, anti-solvent crystallization, etc.
[0023] In some embodiments, the present invention provides an anti-solvent crystallization method for recrystallizing the compound of formula (V), comprising the following operations: dissolving the compound of formula (V) in a good solvent, cooling, adding a poor solvent, and cooling and crystallizing. More specifically, the good solvent includes but is not limited to toluene, and the poor solvent includes but is not limited to n-heptane.
[0024] Preferably, the base is triethylamine. In the present invention, the triethylamine can be added in multiple times. More specifically, the triethylamine can be added in two times, and the mass ratio of the first added triethylamine to the second added triethylamine is 0.8 to 1.2:2.
[0025] Furthermore, the ritonavir intermediate N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester can also be used in the industry as an acid intermediate. Based on this, the present invention claims a method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine, comprising the following steps:
[0026] S1. A one-pot method is used to react a compound of formula (I) or an acid salt thereof, triphosgene, a base and a solvent, followed by adding a compound of formula (III) to react to obtain a compound of formula (IV);
[0027] S2. The compound of formula (IV) is subjected to saponification reaction and acidification to prepare the compound of formula (V) N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine;
[0028] The base is selected from one or more of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylformamide, N,N-diisopropylethylamine, N-methylmorpholine, p-dimethylaminopyridine, and pyridine;
[0029] The reaction formula of the synthesis method is as follows:
[0030]
[0031] Preferably, the saponification reaction can be carried out with reference to conventional saponification reactions in the art. More specifically, the alkali added in the saponification reaction includes but is not limited to sodium hydroxide and the like.
[0032] Compared with the prior art, the present invention has the following beneficial effects:
[0033] The invention provides a method for synthesizing a ritonavir intermediate. The method does not need to be prepared under a specific nitrogen atmosphere, and a one-pot method is adopted to prepare the ritonavir intermediate with high yield and high purity without separation of the intermediate. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] Figure 1 This is the mass spectrum of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine prepared in Example 1.
[0035] Figure 2 This is the hydrogen spectrum of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine prepared in Example 1.
[0036] Figure 3This is the carbon spectrum of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine prepared in Example 1. DETAILED DESCRIPTION
[0037] The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.
[0038] Compound I-1 is a commonly used chemical raw material in pharmaceutical chemistry, which can be easily obtained from the market, or can be synthesized by referring to patent EP3564214. Compound III is a commonly used pharmaceutical intermediate, which can be easily obtained from the market, or can be synthesized by referring to patent EP0657442.
[0039] Example 1 Synthesis of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine
[0040]
[0041] (1) Synthesis of Compound I: 60.00 g of Compound I-1 and 200 mL of dichloromethane were added to a 1000 mL reaction bottle at room temperature, and ammonia was introduced under stirring at room temperature. The reaction was carried out for 2 h and the raw material was detected by TLC until the reaction was completed. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 46.25 g of a colorless transparent oil with a yield of 98.5%. The obtained oily concentrate was directly used in the next step.
[0042] (2) Synthesis of Compound IV: 200 mL of dichloromethane was added to the oily concentrate of step (1), and 150 mL of triphosgene (0.38 eq) dichloromethane solution was added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 15 min. Then, 28.55 g of triethylamine was added dropwise. The internal temperature was controlled to be less than 35°C during the addition. After the addition was completed, the mixture was stirred at room temperature for 1 to 2 h. 53.50 g of triethylamine was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 15 min, and then 57.03 g of Compound III was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3 h.
[0043] The raw material was detected by TLC until the reaction was completed, 350 mL of prepared 3% citric acid solution was added, and the mixture was stirred at room temperature for 30 min. The liquids were separated, and the organic phase was concentrated to dryness under reduced pressure to obtain 109.44 g of compound IV with a yield of 94.8%. The crude product was directly used in the next reaction.
[0044] (3) Synthesis of crude compound V: Add 220 mL of methanol and 110 mL of water to the crude product, stir at room temperature for 30 min, add a prepared 20% sodium hydroxide solution (2.0 eq), and react at room temperature for 3 h. TLC detects the raw material until the reaction is complete, adds a prepared 10% hydrochloric acid solution to adjust the system to pH = 8-9, extracts twice with methyl tert-butyl ether (440 mL × 2), separates the liquids, and retains the aqueous phase; then adds 550 mL of dichloromethane to the aqueous phase, and adjusts the pH to 2-4 with 10% hydrochloric acid, separates the liquids, adds 330 mL of dichloromethane to the aqueous phase for back extraction, combines the organic phases, and concentrates the organic phases under reduced pressure to dryness to obtain 100 g of crude compound V, with a yield of 95.5%.
[0045] (4) Purification: 200 mL of toluene was added to the crude product of Compound V, the temperature was raised to 60° C. and stirred for 1 h, then the temperature was lowered to 20° C. 800 mL of n-heptane was added dropwise, and the mixture was kept warm and stirred for 1 to 2 h, and the temperature was gradually lowered to 5° C. and kept warm and stirred for 2 h, filtered, and the wet product was dried at 40° C. to obtain ritonavir intermediate N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine, 96.20 g of Compound V, a yield of 96.2%, and a purity of 99.9% (the mass spectrum of the ritonavir intermediate is shown in FIG. 2 ). Figure 1 As shown, the hydrogen spectrum of ritonavir intermediate is as follows Figure 2 As shown, the carbon spectrum of ritonavir intermediate is as follows Figure 3 shown).
[0046] Example 2 Synthesis of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester
[0047]
[0048] (1) Synthesis of Compound I: 60.00 g of Compound I-1 and 200 mL of dichloromethane were added to a 1000 mL reaction bottle at room temperature, and ammonia was introduced under stirring at room temperature. The reaction was carried out for 2 h and the raw material was detected by TLC until the reaction was completed. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 46.25 g of a colorless transparent oil with a yield of 98.5%. The obtained oily concentrate was directly used in the next step.
[0049] (2) Synthesis of Compound IV: 200 mL of dichloromethane was added to the oily concentrate of step (1), and 150 mL of triphosgene (0.38 eq) dichloromethane solution was added dropwise at room temperature. After the addition was completed, the mixture was stirred at room temperature for 15 min. Then, 28.55 g of triethylamine was added dropwise. The internal temperature was controlled to be less than 35°C during the addition. After the addition was completed, the mixture was stirred at room temperature for 1 to 2 h. 53.50 g of triethylamine was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 15 min, and then 57.03 g of Compound III was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 3 h.
[0050] The raw material was tested by TLC until the reaction was completed, 350 mL of the prepared 3% citric acid solution was added, and the mixture was stirred at room temperature for 30 min. The organic phase was separated and concentrated to dryness under reduced pressure to obtain ritonavir intermediate N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester, 109.44 g of compound IV, and a yield of 94.8%. Example 3 Synthesis of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine
[0051] (1) Synthesis of Compound I: 4.00 kg of Compound I-1 and 12.00 kg of dichloromethane were added to a 50 L reactor at room temperature. The temperature in the reactor was set at 25°C. Ammonia gas was introduced under stirring. The reaction was continued for 2 h. TLC was used to detect the raw material until the reaction was completed. The filtrate was filtered and concentrated under reduced pressure at 35°C to dryness to obtain a colorless transparent oily compound I, which was directly used in the next step.
[0052] (2) Synthesis of Compound IV: 10.00 kg of dichloromethane was added to the above Compound I, and the temperature in the autoclave was set at 25°C and the atmosphere was air. 8.00 kg of triphosgene (0.38 eq) in dichloromethane solution was added dropwise. After the addition was completed, the mixture was stirred at 25°C for 30 min. Then 1.90 kg of triethylamine was added dropwise. The temperature in the autoclave was controlled to be less than 35°C during the addition. After the addition was completed, the mixture was stirred at 25°C for 1 to 2 h. 3.57 kg of triethylamine was added dropwise. After stirring at room temperature for 30 min, 3.80 kg of Compound III was added dropwise. After the addition was completed, the mixture was stirred at 25°C for 3 h.
[0053] The raw material was tested by TLC until the reaction was completed, 14.00 kg of prepared 3% citric acid solution was added, and the mixture was stirred at room temperature for 30 min. The organic phase was transferred to a 100 L reactor and concentrated to dryness under reduced pressure to obtain compound IV, and the crude product was directly used in the next reaction.
[0054] (3) Synthesis of crude compound V: Add 10.50 kg methanol and 6.70 kg water to the above compound IV, set the temperature in the kettle to 25°C, stir for 30 min, add the prepared 20% sodium hydroxide (2.0 eq) solution, and react at room temperature for 3 h. TLC detects the raw material until the reaction is complete, adds the prepared 10% hydrochloric acid solution to adjust the system to pH = 8-9, extracts twice with methyl tert-butyl ether (19.7 kg × 2), separates the liquids, and retains the aqueous phase; then adds 44.1 kg dichloromethane to the aqueous phase, and adjusts the pH to 2-4 with 10% hydrochloric acid, separates the liquids, adds 26.5 kg dichloromethane to the aqueous phase for back extraction, combines the organic phases, and concentrates the organic phases to dryness under reduced pressure to obtain a crude compound V, which will be further purified.
[0055] (4) Purification: 11.6 kg of toluene was added to the crude product of Compound V, the temperature was raised to 60°C and stirred for 1 hour, then the temperature was lowered to 20°C, and 36.4 kg of n-heptane was added dropwise. After the addition was completed, the mixture was kept warm and stirred for 1 to 2 hours, and the temperature was gradually lowered to 5°C and kept warm and stirred for 2 hours. The mixture was filtered and the wet product was dried at 40°C to obtain ritonavir intermediate N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine, i.e., Compound V (6.42 kg), with a yield of 85.86% (calculated based on the amount of Compound I-1 added) and a purity of 99.88%.
[0056] Example 4 Synthesis of N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine
[0057] (1) Synthesis of Compound I: 50.00 g of Compound I-1 and 150 mL of dichloromethane were added to a 1000 mL reaction bottle at room temperature, and ammonia was introduced under stirring at room temperature. The reaction was carried out for 2 h and the raw material was detected by TLC until the reaction was completed. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 38.33 g of a colorless transparent oil with a yield of 98.0%. The obtained oily concentrate was directly used in the next step.
[0058] (2) Synthesis of Compound IV: 150 mL of dichloromethane was added to the oily concentrate obtained in step (1), and 125 mL of a prepared dichloromethane solution of triphosgene (0.38 eq) was added dropwise at room temperature. The mixture was stirred at room temperature for 15 min. Then, 21.20 g of N-methylmorpholine was added dropwise. The internal temperature was controlled to be less than 35° C. During the addition, the mixture was stirred at room temperature for 1 to 2 h. 40.58 g of N-methylmorpholine was added dropwise. The mixture was stirred at room temperature for 15 min. Then, 47.53 g of Compound III was added dropwise. The mixture was stirred at room temperature for 3 h.
[0059] The raw material was detected by TLC until the reaction was completed, 350 mL of prepared 3% citric acid solution was added, and the mixture was stirred at room temperature for 30 min. The liquids were separated, and the organic phase was concentrated to dryness under reduced pressure to obtain 91.10 g of compound IV with a yield of 95.2%. The crude product was directly used in the next reaction.
[0060] (3) Synthesis of crude compound V: Add 200 mL of methanol and 100 mL of water to the crude product, stir at room temperature for 30 min, add a prepared 20% sodium hydroxide (2.0 eq) solution, and react at room temperature for 3 h. TLC detects the raw material until the reaction is complete, adds a prepared 10% hydrochloric acid solution to adjust the system to pH = 8-9, extracts twice with methyl tert-butyl ether (400 mL × 2), separates the liquids, and retains the aqueous phase; then adds 500 mL of dichloromethane to the aqueous phase, and adjusts the pH to 2-4 with 10% hydrochloric acid, separates the liquids, adds 300 mL of dichloromethane to the aqueous phase for back extraction, combines the organic phases, and concentrates the organic phases under reduced pressure to dryness to obtain 84.15 g of crude compound V, with a yield of 96.5%.
[0061] (4) Purification: 200 mL of toluene was added to the crude compound V, the temperature was raised to 60°C and stirred for 1 h, then the temperature was lowered to 20°C, and 800 mL of n-heptane was added dropwise. After the addition was completed, the mixture was kept warm and stirred for 1 to 2 h, and the temperature was gradually lowered to 5°C and kept warm and stirred for 2 h. The mixture was filtered and the wet product was dried at 40°C to obtain ritonavir intermediate N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine, 80.79 g of compound V, with a yield of 96.0% and a purity of 99.9%.
[0062] The foregoing examples are merely illustrative and are used to explain some features of the method of the present invention. The appended claims are intended to require the widest possible range that can be imagined, and the embodiments presented herein are demonstrated by the applicant's actual test results. Therefore, the applicant's intention is that the appended claims are not limited by the selection of examples that illustrate the features of the present invention. Some numerical ranges used in the claims also include sub-ranges therein, and changes in these ranges should also be interpreted as being covered by the appended claims where possible.
Claims
1. A method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester, characterized in that: The following steps are involved: A one-pot method is used to mix and react the compound of formula (I) or its acid salt, triphosgene, a base and a solvent, and then a compound of formula (III) is added to react to obtain a compound of formula (IV) N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine methyl ester; The base is selected from one or more of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylformamide, N,N-diisopropylethylamine, N-methylmorpholine, p-dimethylaminopyridine, and pyridine; The reaction formula of the synthesis method is as follows:
2. The synthesis method according to claim 1, characterized in that: The molar ratio of the compound of formula (I) to triphosgene is 1:0.1-1.
0.
3. The synthesis method according to claim 1, characterized in that: The molar ratio of the compound of formula (I) to the base is 1:1.0-6.
0.
4. The synthesis method according to claim 1, characterized in that: The molar ratio of the compound of formula (I) to the compound of formula (III) is 1:0.6-1.
2.
5. The synthesis method according to claim 1, characterized in that: The solvent is selected from one or more of halogenated hydrocarbons, carboxylates, C3-C8 cycloalkanes, alkylbenzenes, ethers, and ketones.
6. The synthesis method according to claim 1, characterized in that: The temperature of the mixed reaction is -10°C to 40°C.
7. The synthesis method according to claim 1, characterized in that: After adding the compound of formula (III), the reaction temperature is 20-30°C.
8. The synthesis method according to claim 1, characterized in that: The acid salt of the compound of formula (I) is one or both of hydrochloride and hydrobromide.
9. The synthesis method according to claim 1, characterized in that: The method also includes a purification step: the product is subjected to recrystallization treatment.
10. A method for synthesizing N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine, characterized in that: The following steps are involved: S1. A one-pot method is used to react a compound of formula (I) or an acid salt thereof, triphosgene, a base and a solvent, followed by adding a compound of formula (III) to react to obtain a compound of formula (IV); S2. The compound of formula (IV) is subjected to saponification reaction and acidification to prepare the compound of formula (V) N-[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]aminocarbonyl]-L-valine; The base is selected from one or more of triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, N,N-dimethylformamide, N,N-diisopropylethylamine, N-methylmorpholine, p-dimethylaminopyridine, and pyridine; The reaction formula of the synthesis method is as follows: