A method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate

Abstract

The invention discloses a method for synthesizing 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester, and belongs to the technical field of drug intermediate synthesis. The synthesis method uses 2-methylthiazole-5-carboxylic acid as the initial raw material, and sequentially obtains the target compound 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester through the classical chemical reactions of esterification, bromination, single reduction, double Boc amination and de-Boc, with a purity of more than 97%, a total yield of up to 48.3%, good stability, and solves the problems of low yield, difficult purification, strong reagent taste, difficult availability of cyclization raw materials, and inappropriate amplification of the overall process in the synthesis of similar compounds in the prior art, while promoting the application of the target compound in the field of medicine.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for synthesizing 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester. Background Art

[0002] Thiazole and its derivatives are an important class of heterocyclic compounds, which have been proven to have excellent pharmacological and biological activities. They can be used as key intermediates to synthesize anti-tumor, antiviral and antibacterial drugs, and are widely used in the fields of medicine, pesticides, etc. Methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate is an important thiazole derivative and can be used as a key raw material to prepare HDAC6 inhibitors for the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases (as described in WO2011106627A1). Therefore, it is necessary to study its synthesis.

[0003] There is no report on the synthesis of methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate in the prior art, but the synthesis of its similar compound ethyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate is mentioned in patent application CN111848546A, and the synthesis route is shown in Formula I below:

[0004]

[0005] The method uses aminoacetonitrile hydrochloride as a raw material, reacts with diethyl dithiophosphate under the protection of phthalic anhydride to obtain a thioamide intermediate, and then cyclizes with ethyl 2-chloro-3-oxopropionate, and deprotects to obtain the target compound 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid ethyl ester. This method not only has a low yield, but also the diethyl dithiophosphate used in the second step of the synthesis has a foul odor, which seriously pollutes the environment during use and affects the quality of life of the surrounding residents. The ethyl 2-chloro-3-oxopropionate used in the third step has not been produced on an industrial scale, the supply is scarce, and the price is expensive. In addition, the method requires purification by adding Boc to the amino group and then removing Boc, which is difficult to purify and cumbersome to operate. Summary of the invention

[0006] In view of the problems of low yield, difficulty in purification, strong reagent smell, difficulty in obtaining cyclization raw materials and unsuitability for industrial scale-up of the overall process in the synthesis of similar compounds in the prior art, the main purpose of the present invention is to provide a method for synthesizing 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester, which uses 2-methylthiazole-5-carboxylic acid as an initial raw material, and undergoes the classical chemical reaction steps of esterification, bromination, single reduction, double Boc amination and de-Boc to obtain the target product 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester with a purity of more than 97% under mild and suitable conditions.

[0007] To achieve the above object, the technical solution adopted by the present invention is:

[0008] The present invention provides a method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate, and the synthesis route is shown in formula (II):

[0009]

[0010] The synthesis steps include:

[0011] (1) Esterification reaction: Compound A 2-methylthiazole-5-carboxylic acid is added to methanol, and then concentrated sulfuric acid is added, and the mixture is heated under reflux overnight. After the reaction is completed, Compound B 2-methylthiazole-5-carboxylic acid methyl ester is obtained;

[0012] (2) Bromination reaction: Compound B 2-methylthiazole-5-carboxylic acid methyl ester is added to a first solvent, and then a bromination reagent and a catalytic amount of azobisisobutyronitrile (AIBN) are added and heated under reflux overnight. After the reaction is completed, a solution of Compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester is obtained;

[0013] (3) Single reduction reaction: Add a solution of compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester to a reaction vessel, then add phosphite and base, and react at room temperature overnight to obtain compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester;

[0014] (4) Bis-Boc amination reaction: Compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester is added to a second solvent, and then a base and an aminating agent are added. The reaction is carried out at room temperature overnight. After the reaction is completed, compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester is obtained;

[0015] (5) De-Boc reaction: Compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester) was added to a hydrochloric acid solution and stirred at room temperature overnight. After the reaction was completed, the mixture was spin-dried and methanol was added until the product was dissolved. A base was added to adjust the reaction system to alkaline, and the compound 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester (CP) was obtained by purification.

[0016] Preferably, in step (1), the mass ratio of compound A to concentrated sulfuric acid is 1:(0.5-1); and preferably 1:1.

[0017] Preferably, in step (2), the first solvent is selected from one or a combination of two or more of carbon tetrachloride, chloroform, dichloromethane, dichloroethane or N,N-dimethylformamide, the bromination reagent is selected from N-bromosuccinimide or dibromohydantoin, the reaction temperature is 60-150°C, and the reaction time is 10-14h.

[0018] More preferably, in step (2), the first solvent is carbon tetrachloride, the bromination reagent is N-bromosuccinimide, the molar ratio of compound B, N-bromosuccinimide and AIBN is 1:(2.0-2.5):(0.3-0.66), and preferably 1:2.5:0.66; the reaction temperature is 77°C, and the reaction time is 12h.

[0019] Preferably, in step (3), the phosphite is selected from dimethyl phosphite or diethyl phosphite, the base is selected from N,N-diisopropylethylamine (DIPEA) or triethylamine, the reaction temperature is 0-40°C, and the reaction time is 10-14h.

[0020] More preferably, in step (3), the phosphite is dimethyl phosphite, the base is DIPEA, the molar ratio of compound C, dimethyl phosphate and DIPEA is 1:(1.0-1.5):(1.0-1.5), and preferably 1:1.3:1.3, the reaction temperature is 25°C, and the reaction time is 12h.

[0021] Preferably, in step (4), the second reagent is selected from one or more of N,N-dimethylformamide, acetonitrile, 1,4-dioxane or dimethyl sulfoxide, the base is selected from one of potassium carbonate, sodium carbonate or sodium bicarbonate, the aminating agent is selected from one or more of bis(tert-butyloxycarbonyl)amine, phthalimide, urotropine or tert-butylcarbamate, the reaction temperature is 10-60°C, and the reaction time is 10-14h.

[0022] More preferably, in step (4), the second reagent is N,N-dimethylformamide, the base is potassium carbonate, the aminating agent is bis(tert-butyloxycarbonyl)amine, the molar ratio of compound D, potassium carbonate and bis(tert-butyloxycarbonyl)amine is 1:(1.0-1.2):(1.0-1.1), and preferably 1:1.2:1.05, the reaction temperature is 25°C, and the reaction time is 12h.

[0023] Preferably, in step (5), the hydrochloric acid solution is selected from one of hydrochloric acid-ethyl acetate solution, hydrochloric acid-1,4-dioxane solution or hydrochloric acid-methanol solution, with a molar concentration of 3-5 mol / L; the base is selected from one of potassium carbonate, sodium carbonate or sodium bicarbonate, the reaction temperature is 0-40°C, and the reaction time is 10-14h.

[0024] More preferably, in step (5), the hydrochloric acid solution is a hydrochloric acid-ethyl acetate solution with a molar concentration of 4 mol / L, the base is potassium carbonate, the reaction temperature is 25°C, and the reaction time is 12 hours. As a preferred technical solution, the above-mentioned method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate comprises the following steps:

[0025] (a) adding compound A 2-methylthiazole-5-carboxylic acid to methanol, and then adding concentrated sulfuric acid, the mass ratio of compound A to concentrated sulfuric acid is 1:1, heating and reflux overnight, and after the reaction is completed, obtaining compound B 2-methylthiazole-5-carboxylic acid methyl ester;

[0026] (b) Compound B 2-methylthiazole-5-carboxylic acid methyl ester is added to carbon tetrachloride, and then N-bromosuccinimide and a catalytic amount of AIBN are added, and the mixture is heated under reflux overnight. The reaction temperature is 77° C., and the reaction time is 12 h. After the reaction, a solution of compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester is obtained; wherein the molar ratio of compound B, N-bromosuccinimide and AIBN is 1:2.5:0.66;

[0027] (c) adding a solution of compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester to a reaction vessel, and then adding dimethyl phosphite and DIPEA, and reacting at room temperature overnight at 25° C. for 12 h to obtain compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester; wherein the molar ratio of compound C, dimethyl phosphate and DIPEA is 1:1.3:1.3;

[0028] (d) Compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester was added to N,N-dimethylformamide, and potassium carbonate and bis(tert-butyloxycarbonyl)amine were added, and the reaction was carried out at room temperature overnight. The reaction temperature was 25° C. and the reaction time was 12 h. After the reaction, compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester was obtained; wherein the molar ratio of compound D, potassium carbonate and bis(tert-butyloxycarbonyl)amine was 1:1.2:1.05;

[0029] (e) Compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester) was added to a 4 mol / L hydrochloric acid-ethyl acetate solution and stirred at room temperature overnight. The reaction temperature was 25°C and the reaction time was 12 h. After the reaction was completed, the product was dried by rotation and methanol was added until the product was dissolved. Potassium carbonate was added to adjust the reaction system to alkalinity, and the compound 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester was obtained by purification.

[0030] The present invention also provides the use of 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester as an intermediate in the preparation of drugs for treating proliferative, inflammatory, infectious, neurological or cardiovascular diseases.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) The present invention proposes a stable route for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate by optimizing the design of the synthesis method. 2-Methylthiazole-5-carboxylic acid is used as the initial raw material, and the target compound is obtained through the reaction steps of esterification, bromination, single reduction, double Boc amination and de-Boc. The reactions involved in the synthesis route are all classical chemical reactions with good stability.

[0033] (2) The present invention can obtain the target product 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester with a purity of more than 97% under mild and suitable conditions, and the total yield is as high as 48.3%. The raw materials and reagents used are all industrially produced and easily available on the market. No malodorous reagents are used, which has little pollution to the environment and low material cost. The problems of low yield, difficult purification, strong reagent smell, difficult availability of cyclization raw materials and overall process not suitable for industrial scale-up in the synthesis of similar compounds in the prior art are solved.

[0034] (3) In the synthesis method of the present invention, the intermediate obtained in step 2 can be directly used in the next reaction without separation, thereby improving the continuity of the reaction. Steps 4 and 5 are treated by double Boc amination and de-Boc, wherein the pure product is directly extracted after acid-base adjustment, and the target compound is purified while achieving amination, without the need for complicated purification treatment, thereby improving production efficiency and reducing costs.

[0035] (4) The synthesis method of the present invention is convenient for feeding, simple to operate, and has been successfully verified for preparation at the 100-gram level. It is suitable for industrial production and is expected to reduce the production cost of the intermediate and promote the application of the target compound in the medical field, thereby improving the quality of life of patients with proliferative, inflammatory, infectious, neurological or cardiovascular diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the nuclear magnetic resonance spectrum of methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate in Example 1. DETAILED DESCRIPTION

[0037] In order to make the purpose, technical solution and advantages of the embodiment of the present invention clearer, the technical solution of the embodiment of the present invention is clearly and completely described below in conjunction with the accompanying drawings of the embodiment of the present invention. Obviously, the described embodiment is a part of the embodiment of the present invention, not all of the embodiments. Based on the described embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the scope of protection of the present invention.

[0038] Unless otherwise specified in the following examples, all reagents and materials used were commercially available.

[0039] Example 1

[0040] This example prepares 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester, and the synthesis route is as follows:

[0041]

[0042] The specific steps are as follows:

[0043] Step 1: Add compound A (100 g, 0.70 mol, 1 eq) to 1000 ml of methanol, then add concentrated sulfuric acid (100 g, 1 mol, 1.4 eq), heat to reflux overnight, and detect by TLC that the reaction is complete. Pour into ice water, extract with ethyl acetate, backwash with sodium bicarbonate solution and spin dry to obtain 106 g of brown liquid compound B with a yield of 91.8% and a purity of 95%.

[0044] Step 2: Add compound B (106 g, 0.64 mol, 1 eq) to 1000 ml of carbon tetrachloride, then add N-bromosuccinimide (214 g, 2.12 mol, 2.5 eq), heat to reflux, add azobisisobutyronitrile (69.36, 0.42 mol, 0.66 eq) in batches, continue to reflux overnight after addition, TLC detection, the reaction is complete, cool and filter, wash the filter cake with dichloromethane, combine the organic phases, and obtain 1500 ml of compound C solution with a quantitative content of 12.10% and a yield of 90%, for standby use.

[0045] Step 3: Add the above-obtained compound C solution (1500 ml, quantitative content 12.10%, 0.58 mol, 1 eq) into a three-necked flask, then add dimethyl phosphite (82.94 g, 0.75 mol, 1.3 eq) and N,N-diisopropylethylamine (97.45 g, 0.75 mol, 1.3 eq), stir at room temperature overnight, detect by TLC, the reaction is complete, pour into ice water, extract with dichloromethane, backwash, dry and column to obtain 102.87 g of compound D, with a yield of 71.78% and a purity of 95%.

[0046] Step 4: Add compound D (102.87 g, 0.42 mol, 1 eq) to 1000 ml of N,N-dimethylformamide, and then add potassium carbonate (69.00 g, 0.5 mol, 1.2 eq) and bis(tert-butyloxycarbonyl)amine (94.90 g, 0.44 mol, 1.05 eq). Stir at room temperature overnight. After TLC detection, the reaction was complete. Pour into ice water, stir, filter, wash with water, and dry to obtain 146.76 g of compound E. The yield was 86.26% and the purity was 91%.

[0047] Step 5: Add compound E (146.76 g, 0.36 mol, 1 eq) to 1.5 l 4 mol / l hydrochloric acid-ethyl acetate solution, stir at room temperature overnight, and detect by TLC that the reaction is complete. Dried up by spin, then add a small amount of methanol until the product is completely dissolved, then add potassium carbonate powder until the system is alkaline, add a large amount of ethyl acetate, filter, and dried to obtain 60.3 g of compound CP with a yield of 94.5% and a purity of 97%.

[0048] Its NMR spectrum is Figure 1 As shown, 1 HNMR (600MHz, DMSO) δ8.47(s,1H),8.26(s,2H),4.44(s,2H),3.86(s,3H).

[0049] Example 2

[0050] This example prepares 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester, and the specific steps are as follows:

[0051] Step 1: Add compound A (10 g, 70 mmol, 1 eq) to 100 ml of methanol, then add concentrated sulfuric acid (10 g, 100 mmol, 1.4 eq), heat to reflux overnight, and detect by TLC that the reaction is complete. Pour into ice water, extract with ethyl acetate, backwash with sodium bicarbonate solution and spin dry to obtain 9.42 g of compound B as a brown liquid with a yield of 78% and a purity of 91%.

[0052] Step 2: Add compound B (9.42 g, 55 mmol, 1 eq) to 100 ml of carbon tetrachloride, then add N-bromosuccinimide (19.58 g, 110 mmol, 2.0 eq), heat to reflux, add azobisisobutyronitrile (2.71 g, 16.5 mmol, 0.3 eq) in batches, continue to reflux overnight after addition, TLC detection, the reaction is complete, cool and filter, wash the filter cake with dichloromethane, combine the organic phases, and obtain 150 ml of compound C solution with a quantitative content of 8.16% and a yield of 71.14%, for standby use.

[0053] Step 3: Add the above obtained compound C solution (150ml, quantitative content 8.16%, 39.13mmol, 1eq) to a three-necked flask, then add dimethyl phosphite (4.31g, 39.13mmol, 1.0eq) and N,N-diisopropylethylamine (5.06g, 39.13mmol, 1.0eq), and stir at room temperature overnight. TLC detection, the reaction is complete, poured into ice water, extracted with dichloromethane, backwashed, and dried through a column to obtain 4.6g of compound D, with a yield of 45% and a purity of 90%.

[0054] Step 4: Add compound D (4.6 g, 17.6 mmol, 1 eq) to 100 ml of N,N-dimethylformamide, and then add potassium carbonate (2.43 g, 17.6 mol, 1.0 eq) and bis(tert-butyloxycarbonyl)amine (3.82 g, 17.6 mmol, 1.0 eq), stir at room temperature overnight, and detect by TLC that the reaction is complete. Pour into ice water, stir, filter, wash with water, and dry to obtain 5.65 g of compound E with a yield of 75% and a purity of 87%.

[0055] Step 5: Add compound E (5.65 g, 13.2 mmol, 1 eq) to 55 ml of 4 mol / l hydrochloric acid-ethyl acetate solution, stir at room temperature overnight, and detect by TLC that the reaction is complete. Dried by spin drying, add a small amount of methanol until the product is completely dissolved, add potassium carbonate powder until the system is alkaline, add a large amount of ethyl acetate, filter, and dried by spin drying to obtain 2.18 g of compound CP with a yield of 91% and a purity of 95%.

[0056] Example 3

[0057] This example prepares 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester, and the specific steps are as follows:

[0058] Step 1: Add compound A (10 g, 70 mmol, 1 eq) to 100 ml of methanol, then add concentrated sulfuric acid (5 g, 50 mmol, 0.7 eq), heat to reflux overnight, and detect by TLC that the reaction is complete. Pour into ice water, extract with ethyl acetate, backwash with sodium bicarbonate solution and spin dry to obtain 6.2 g of compound B as a brown liquid with a yield of 50% and a purity of 89%.

[0059] Step 2: Add compound B (6.2g, 35mmol, 1eq) to 60ml carbon tetrachloride, then add dibromohydantoin (22.02g, 77mmol, 2.2eq), heat to reflux, add azobisisobutyronitrile (3.79g, 23.1mmol, 0.66eq) in batches, and continue to reflux overnight. TLC detection, the reaction is complete, cooled and filtered, the filter cake is washed with dichloromethane, and the organic phases are combined to obtain 90ml of compound C solution, with a quantitative content of 8.5% and a yield of 70.05%, for standby use.

[0060] Step 3: Add the above obtained compound C solution (90ml, quantitative content 8.5%, 24.52mmol, 1eq) to a three-necked flask, then add dimethyl phosphite (4.06g, 36.78mmol, 1.5eq) and N,N-diisopropylethylamine (4.75g, 36.78mmol, 1.5eq), and stir at room temperature overnight. TLC detection, the reaction is complete, poured into ice water, extracted with dichloromethane, backwashed, and dried through a column to obtain 4.32g of compound D, with a yield of 69% and a purity of 92%.

[0061] Step 4: Add compound D (4.32 g, 16.72 mmol, 1 eq) to 50 ml of N,N-dimethylformamide, and then add potassium carbonate (2.78 g, 20.06 mol, 1.2 eq) and bis(tert-butyloxycarbonyl)amine (3.63 g, 16.72 mmol, 1.0 eq), stir at room temperature overnight, and detect by TLC that the reaction is complete. Pour into ice water, stir, filter, wash with water, and dry to obtain 5.25 g of compound E with a yield of 76% and a purity of 90%.

[0062] Step 5: Add compound E (5.25 g, 12.3 mmol, 1 eq) to 55 ml of 4 mol / l methanol-ethyl acetate solution, stir at room temperature overnight, and detect by TLC that the reaction is complete. Dried out by spin drying, then add a small amount of methanol until the product is completely dissolved, then add potassium carbonate powder until the system is alkaline, add a large amount of ethyl acetate, filter, and dried to obtain 2.05 g of compound CP with a yield of 89% and a purity of 92%.

[0063] It can be seen from the above embodiments that the synthesis method of the present invention can obtain the target compound under various conditions such as different amounts of concentrated sulfuric acid, brominating agents and different material ratios; wherein the optimal conditions for each step of the reaction are: in the first step of the esterification reaction, the mass ratio of compound A to concentrated sulfuric acid is 1:1; in the second step of the bromination reaction, the bromination agent is preferably N-bromosuccinimide, and the molar ratio of compound B to the brominating agent and azobisisobutyronitrile is 1:2.5:0.66; in the third step of the single reduction reaction, the molar ratio of compound C, dimethyl phosphate and base is 1:1.3:1.3; in the fourth step of the bis-Boc amination reaction, the molar ratio of compound D, base and aminating agent is 1:1.2:1.05, and the yield of the target product obtained under the preferred conditions is 48.3%.

Claims

1. A method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate, characterized in that: The synthetic route is shown in formula (II): The synthesis steps include: (1) Esterification reaction: Compound A 2-methylthiazole-5-carboxylic acid is added to methanol, and then concentrated sulfuric acid is added, and the mixture is heated under reflux overnight. After the reaction is completed, Compound B 2-methylthiazole-5-carboxylic acid methyl ester is obtained; (2) Bromination reaction: Compound B 2-methylthiazole-5-carboxylic acid methyl ester is added to a first solvent, and then a bromination reagent and a catalytic amount of azobisisobutyronitrile (AIBN) are added and heated under reflux overnight. After the reaction is completed, a solution of Compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester is obtained; (3) Single reduction reaction: Add a solution of compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester to a reaction vessel, then add phosphite and base, and react at room temperature overnight to obtain compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester; (4) Bis-Boc amination reaction: Compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester is added to a second solvent, and then a base and an aminating agent are added. The reaction is carried out at room temperature overnight. After the reaction is completed, compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester is obtained; (5) De-Boc reaction: Compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester) was added to a hydrochloric acid solution and stirred at room temperature overnight. After the reaction was completed, the product was dried by rotary evaporation and methanol was added until the product was dissolved. A base was added to adjust the reaction system to alkaline, and the compound 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester was obtained by purification.

2. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 1, characterized in that: In step (1), the mass ratio of compound A to concentrated sulfuric acid is 1:0.5-1.

3. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 1, characterized in that: In step (2), the first solvent is selected from one or more of carbon tetrachloride, chloroform, dichloromethane, dichloroethane or N,N-dimethylformamide, the bromination reagent is selected from N-bromosuccinimide or dibromohydantoin, the reaction temperature is 60-150° C., and the reaction time is 10-14 h.

4. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 3, characterized in that: In step (2), the first solvent is carbon tetrachloride, the bromination reagent is N-bromosuccinimide, the molar ratio of compound B, N-bromosuccinimide and AIBN is 1:2.0-2.5:0.3-0.66, the reaction temperature is 77°C, and the reaction time is 12h.

5. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 1, characterized in that: In step (3), the phosphite is selected from dimethyl phosphite or diethyl phosphite, the base is selected from N,N-diisopropylethylamine (DIPEA) or triethylamine, the reaction temperature is 0-40°C, and the reaction time is 10-14h.

6. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 5, characterized in that: In step (3), the phosphite is dimethyl phosphite, the base is DIPEA, the molar ratio of compound C, dimethyl phosphate and DIPEA is 1:1.0-1.5:1.0-1.5, the reaction temperature is 25°C, and the reaction time is 12h.

7. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 1, characterized in that: In step (4), the second solvent is selected from one or more of N,N-dimethylformamide, acetonitrile, 1,4-dioxane or dimethyl sulfoxide, the base is selected from one of potassium carbonate, sodium carbonate or sodium bicarbonate, the aminating agent is selected from one or more of bis(tert-butyloxycarbonyl)amine, phthalimide, urotropine or tert-butylcarbamate, the reaction temperature is 10-60°C, and the reaction time is 10-14h.

8. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 7, characterized in that: In step (4), the second solvent is N,N-dimethylformamide, the base is potassium carbonate, the aminating agent is bis(tert-butyloxycarbonyl)amine, the molar ratio of compound D, potassium carbonate and bis(tert-butyloxycarbonyl)amine is 1:1.0-1.2:1.0-1.1, the reaction temperature is 25°C, and the reaction time is 12h.

9. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 1, characterized in that: In step (5), the hydrochloric acid solution is selected from one of hydrochloric acid-ethyl acetate solution, hydrochloric acid-1,4-dioxane solution or hydrochloric acid-methanol solution, with a molar concentration of 3-5 mol / L; the base is selected from one of potassium carbonate, sodium carbonate or sodium bicarbonate, the reaction temperature is 0-40°C, and the reaction time is 10-14h.

10. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 9, characterized in that: In step (5), the hydrochloric acid solution is a hydrochloric acid-ethyl acetate solution with a molar concentration of 4 mol / l, the base is potassium carbonate, the reaction temperature is 25° C., and the reaction time is 12 h.

11. The method for synthesizing methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate according to claim 1, characterized in that: The synthesis steps are as follows: (a) Compound A 2-methylthiazole-5-carboxylic acid is added to methanol, and then concentrated sulfuric acid is added, the mass ratio of compound A to concentrated sulfuric acid is 1:1, and heated under reflux overnight. After the reaction is completed, compound B 2-methylthiazole-5-carboxylic acid methyl ester is obtained; (b) Compound B 2-methylthiazole-5-carboxylic acid methyl ester is added to carbon tetrachloride, and then N-bromosuccinimide and a catalytic amount of AIBN are added and heated under reflux overnight. The reaction temperature is 77° C. and the reaction time is 12 h. After the reaction, a solution of compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester is obtained; wherein the molar ratio of compound B, N-bromosuccinimide and AIBN is 1:2.5:0.66; (c) adding a solution of compound C 2-(dibromomethyl)thiazole-5-carboxylic acid methyl ester to a reaction vessel, and then adding dimethyl phosphite and DIPEA, and reacting at room temperature overnight at 25° C. for 12 h. After the reaction, compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester is obtained; wherein the molar ratio of compound C, dimethyl phosphate and DIPEA is 1:1.3:1.3; (d) Compound D 2-(bromomethyl)thiazole-5-carboxylic acid methyl ester was added to N,N-dimethylformamide, and potassium carbonate and bis(tert-butyloxycarbonyl)amine were added, and the reaction was carried out at room temperature overnight. The reaction temperature was 25° C. and the reaction time was 12 h. After the reaction, compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester was obtained; wherein the molar ratio of compound D, potassium carbonate and bis(tert-butyloxycarbonyl)amine was 1:1.2:1.05; (e) Compound E ((5-(methoxycarbonyl)thiazol-2-yl)methyl)iminodicarboxylic acid di-tert-butyl ester) was added to a 4 mol / L hydrochloric acid-ethyl acetate solution and stirred at room temperature overnight. The reaction temperature was 25°C and the reaction time was 12 h. After the reaction was completed, the product was dried by rotation and methanol was added until the product was dissolved. Potassium carbonate was added to adjust the reaction system to alkalinity, and the compound 2-(aminomethyl)-1,3-thiazole-5-carboxylic acid methyl ester was obtained by purification.

12. Use of methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate in the preparation of drugs for treating proliferative, inflammatory, infectious, neurological or cardiovascular diseases, wherein methyl 2-(aminomethyl)-1,3-thiazole-5-carboxylate is prepared by the synthesis method described in any one of claims 1 to 11.

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