Synthesis process of N-(4-phenylthiazole-2-yl)-3-(4-benzyl piperazine-1-yl) propanamide monohydrochloride

Abstract

The invention relates to a synthesis process of N-(4-phenylthiazole-2-yl)-3-(4-benzyl piperazine-1-yl) propanamide monohydrochloride, which comprises the following steps: taking 4-phenyl-2-aminothiazole as an initial raw material, and carrying out acylation reaction to obtain an intermediate I; the intermediate I and N-Boc piperazine are subjected to a substitution reaction, BOC is removed, and an intermediate II is obtained; and dissolving the intermediate II and benzyl chloride in a reaction solvent, carrying out nucleophilic substitution reaction to obtain an intermediate III, adding a hydrochloric acid-acetone mixed solution into the reaction solvent in which the intermediate III is dissolved, carrying out salt forming reaction, recrystallizing after the reaction, filtering, and drying to constant weight to obtain a final product. The whole process route only comprises four steps, the synthesis steps are few, the method is simple and easy to control, additional complex purification and separation are not needed in each step, intermediates and final products with high purity and high yield can be directly obtained through mother liquor recrystallization, and the method is suitable for commercialized large-scale production.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a synthesis process of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazine-1-yl)propionamide monohydrochloride. Background Art

[0002] N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propionamide monohydrochloride is a 2-aminothiazole derivative, which can inhibit the dimerization of myeloid differentiation primary response 88 (MyD88), block the TLR / MyD88 / NF-κB signaling pathway, inhibit the migration of DCs and reduce the infiltration of inflammatory cells, and effectively reduce the expression and release of pathogenic inflammatory cytokines such as IL-17, IL-23, TNF-α in diseases related to excessive activation of innate immune responses, thereby achieving the purpose of preventing or curing related diseases.

[0003] Therefore, in view of the fact that the current N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl) propionamide monohydrochloride will play an increasingly important role in the field of biomedicine, and will even be used as a new chemical drug in various major diseases, it is necessary to develop a high-yield, high-purity, simple and easy-to-obtain synthesis process of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl) propionamide monohydrochloride. Therefore, the present invention aims to develop a synthesis process of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl) propionamide monohydrochloride with fewer synthesis steps, simple, easy to control and easy to obtain, which is more suitable for commercial scale-up production. Summary of the invention

[0004] The purpose of the present invention is to develop a synthesis process of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazine-1-yl)propionamide monohydrochloride.

[0005] The solution adopted by the present invention to solve the above technical problems is:

[0006] The synthesis process of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazine-1-yl)propionamide monohydrochloride mainly comprises the following steps:

[0007] S1: 4-phenyl-2-aminothiazole is used as a starting material, and 3-chloropropionyl chloride is dissolved in a reaction solvent, and in the presence of an alkaline substance, an acylation reaction is performed to obtain an intermediate I, namely N-(4-phenylthiazol-2-yl)-3-chloropropionamide;

[0008] S2: Dissolve intermediate I and N-Boc piperazine in a reaction solvent, carry out a substitution reaction in the presence of an alkaline substance, and then carry out a Boc removal reaction under acidic conditions to obtain intermediate II, namely N-(4-phenylthiazol-2-yl)-3-(piperazine-1-yl) propionamide trihydrochloride;

[0009] S3: Intermediate II and benzyl chloride are dissolved in a reaction solvent, and in the presence of an alkaline substance, a nucleophilic substitution reaction is carried out to obtain intermediate III, namely N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propionamide;

[0010] S4: adding hydrochloric acid to acetone to prepare a hydrochloric acid-acetone mixed solution; then adding the hydrochloric acid-acetone mixed solution to a reaction solvent containing intermediate III to carry out a salt-forming reaction, and after the reaction is completed, recrystallizing, filtering, and drying to constant weight to obtain the final product: N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazine-1-yl)propionamide monohydrochloride.

[0011] Furthermore, the alkaline substance is selected from one of diisopropylethylamine and potassium carbonate.

[0012] Furthermore, the alkaline substance in S1 is diisopropylethylamine, wherein the ratio of diisopropylethylamine to 4-phenyl-2-aminothiazole (w / w) is 1:1-2, preferably 1:1.47.

[0013] Furthermore, the alkaline substance in S2 is potassium carbonate, wherein the ratio of potassium carbonate to 4-phenyl-2-aminothiazole (w / w) is 1:4-5, preferably 1:4.75;

[0014] Furthermore, the alkaline substance in S3 is potassium carbonate, wherein the ratio of potassium carbonate to 4-phenyl-2-aminothiazole (w / w) is 1:0.5-1, preferably 1:0.97.

[0015] Furthermore, the reaction solvent is selected from one of 2-methyltetrahydrofuran, N,N-dimethylformamide and acetone.

[0016] Furthermore, the reaction solvent in S1 is 2-methyltetrahydrofuran; the reaction solvent in S2 is N,N-dimethylformamide; the reaction solvent in S3 is N,N-dimethylformamide; and the reaction solvent in S4 is acetone.

[0017] Furthermore, intermediates I, II, III and the final product in S1-S4 are directly obtained from the mother liquor by filtering, recrystallizing and drying.

[0018] Further, the conditions of the S1 acylation reaction include: temperature 0-20°C; stirring reaction; reaction time 0.5-1 hour. When the temperature is increased, the reaction time will be shortened accordingly. On the contrary, when the temperature is appropriately reduced, the reaction time will be prolonged.

[0019] Furthermore, the molar ratio of 4-phenyl-2-aminothiazole to 3-chloropropionyl chloride in S1 is 1:1-2, preferably 1:1.8.

[0020] Furthermore, the acidic condition in S2 is achieved by adding methanolic hydrogen chloride.

[0021] Furthermore, the conditions of the substitution reaction in S2 include controlling the temperature at 10-40°C, stirring the reaction, and reacting for 3-6 hours; the conditions of the de-BOC reaction include controlling the temperature at 10-30°C, stirring the reaction, and reacting for 1.5-6 hours.

[0022] Furthermore, the molar ratio of intermediate I and N-Boc piperazine in S2 is 1:0.6-1, preferably 1:0.77.

[0023] Furthermore, the molar ratio of intermediate II and benzyl chloride in S3 is 1:0.2-0.5, preferably 1:0.31.

[0024] Furthermore, the conditions for the S3 nucleophilic substitution reaction include: temperature 45-55° C.; reaction time 5 to 6 hours.

[0025] Furthermore, the molar ratio of the intermediate III to the hydrochloric acid in S4 is 1:0.2-0.4, preferably 1:0.24.

[0026] Furthermore, the reaction conditions for preparing the hydrochloric acid-acetone mixed solution in S4 include: reaction temperature of 20-30° C.; including: reaction temperature of 0-10° C., stirring reaction, and reaction time of 12-20 hours.

[0027] Furthermore, the reaction conditions in the salt-forming reaction in S4, i.e., the addition of the hydrochloric acid-acetone mixed solution to the reaction solvent containing the intermediate III, include: a reaction temperature of 0-10° C., stirring the reaction, and a reaction time of 12-20 hours.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] 1. The entire process route of the present invention has only four steps, with few synthetic steps, simple and easy to control, and no additional complex purification and separation is required in each step. Intermediates and final products with high purity and high yield can be directly obtained through recrystallization of the mother liquor, which is suitable for commercial scale-up production.

[0030] 2. The equipment used in this route can be a conventional reactor, without special high temperature and high pressure requirements, no special toxic catalysts, etc., and is easy to industrialize.

[0031] 3. The alkali, acid and solvent used in this process can adopt conventional industrial reagents, and there is no three waste products after the reaction. The solvent can be easily recovered after the reaction, and the degree of industrialization is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Attached Figure 1 This is a graph showing the nuclear magnetic resonance detection result of the intermediate I synthesized in Example 1 of the present invention;

[0033] Attached Figure 2 This is a graph showing the nuclear magnetic resonance detection result of the intermediate II synthesized in Example 1 of the present invention;

[0034] Attached Figure 3 This is a graph showing the nuclear magnetic resonance detection result of the intermediate III synthesized in Example 1 of the present invention;

[0035] Attached Figure 4 This is the hydrogen nuclear magnetic resonance spectrum of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propanamide monohydrochloride synthesized in Example 1 of the present invention;

[0036] Attached Figure 5 This is the carbon nuclear magnetic resonance spectrum of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propanamide monohydrochloride synthesized in Example 1 of the present invention. DETAILED DESCRIPTION

[0037] For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.

[0038] Unless otherwise specified, the test methods used in the embodiments of the present invention are all conventional methods.

[0039] Unless otherwise specified, the raw materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0040] The synthetic route adopted in the following examples is:

[0041] Step S1:

[0042]

[0043] Step S2:

[0044]

[0045] Step S3:

[0046]

[0047] Step S4:

[0048]

[0049] Example 1: Synthesis of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propanamide monohydrochloride.

[0050] Step S1:

[0051] 1) Add 2-methyltetrahydrofuran (22.37 kg) to the reaction kettle and stir, then add 4-phenyl-2-aminothiazole (1.30 kg) to the reaction bottle and stir to dissolve, and control the reaction temperature at 7±1°C;

[0052] 2) 3-chloropropionyl chloride (2.34 kg) was added to a 250 mL constant pressure dropping funnel and added dropwise to the reaction kettle, and the reaction temperature was controlled at 8 ± 1 °C;

[0053] 3) After the dropwise addition, diisopropylethylamine (1.91 kg) was continued to be added dropwise, and the reaction temperature was controlled at 6±1°C;

[0054] 4) After the addition, stir for 45 minutes and control the reaction temperature at 4±1°C;

[0055] 5) Take a sample and send it to HPLC for central control, and stop the reaction after the reaction is completed;

[0056] 6) Filter the reaction solution, set the filtrate aside, and add the filter cake to purified water (6.50 kg) and 2-methyltetrahydrofuran (5.59 kg).

[0057] Stir the mixture to dissolve and let it stand;

[0058] 7) Separate the liquid to obtain an organic phase, combine the organic phase with the previously placed filtrate, and wash twice with the prepared sodium bicarbonate solution (16.84 kg);

[0059] 8) Add 2.60 kg of anhydrous sodium sulfate to the organic phase and dry for 1.5 hours;

[0060] 9) filtering, rinsing the filter cake with 2-methyltetrahydrofuran (1.12 kg), and concentrating the filtrate under vacuum at 45±5°C and vacuum degree ≤-0.07 MPa to a total volume of 3.2 L (first concentration), adding n-heptane (5.30 kg) to the concentrate, and concentrating under vacuum at 45±5°C and vacuum degree ≤-0.07 MPa to a total volume of 2.9 L (second concentration);

[0061] 10) Add methyl tert-butyl ether (1.92 kg) to the second concentrated solution and recrystallize at 25° C. for 1.5 hours;

[0062] 11) filtering, and rinsing the filter cake with a mixture of methyl tert-butyl ether (0.48 kg) and n-heptane (0.44 kg);

[0063] 12) Filter cake drying: Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0064] 13) Collect the material and weigh the intermediate I (1.83 kg), yield: 93.0%, take a sample and send it to the analysis department for detection.

[0065] Step S2:

[0066] 1) Add N,N-dimethylformamide (7.12 kg) into a 50 L reactor;

[0067] 2) Add intermediate I (1.50 kg) and N-Boc (1.16 kg) into the reactor and stir to dissolve;

[0068] 3) Weigh potassium carbonate (0.86 kg) and add it to the reaction system, stirring;

[0069] 4) Control the temperature at 32±1°C and stir for 3.5 hours;

[0070] 5) HPLC control, stop the reaction after the reaction is completed;

[0071] 6) Stop the reaction, filter, rinse the filter cake with N,N-dimethylformamide (1.42 kg), and add the filtrate dropwise into a 50 L reactor filled with tap water (27.00 kg);

[0072] 7) After the dropwise addition, stir at 25°C for 1.5 hours to recrystallize;

[0073] 8) Filter by suction, rinse the filter cake four times with pure water (18.00 kg), until the pH of the last rinse liquid is 7-8;

[0074] 9) Add 4M methanolic hydrogen chloride (16.92 kg) to a 50L reactor, add the filter cake in batches, and stir at 27°C for 2 hours after the addition is complete;

[0075] 10) HPLC control, stop the reaction after the reaction is completed;

[0076] 11) Ethyl acetate (16.20 kg) was added to the reaction solution, stirred at 24°C for 1.5 hours, and recrystallized;

[0077] 12) Filter, and rinse the filter cake twice with ethyl acetate (2.70 kg);

[0078] 13) Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0079] 14) Collect the material and weigh the intermediate II (2.24 kg), with a yield of 93.6%. Take a sample and send it to the analysis department for detection.

[0080] Step S3:

[0081] 1) Weigh N,N-dimethylformamide (9.72 kg) and add it into a 50L reactor. Weigh intermediate II (2.20 kg) and add it into the reactor, and stir.

[0082] 2) Weigh potassium carbonate (1.97 kg) and add it to the reaction system, stirring at 25±5°C for 5-10 minutes;

[0083] 3) Weigh benzyl chloride (0.63 kg) and add it into the reaction kettle, stirring;

[0084] 4) Control the temperature to 50±5°C and react for 5.5 hours;

[0085] 5) HPLC control, stop the reaction after the reaction is completed;

[0086] 6) Filter, rinse the filter cake with N,N-dimethylformamide (1.93 kg), add purified water (12.20 kg) dropwise to the filtrate, and then stir at 25° C. for 1.5 hours;

[0087] 7) Filter and rinse the filter cake once with pure water (6.10 kg);

[0088] 8) Add dichloromethane (26.83 kg) to the reactor, transfer the filter cake to the reactor, stir to dissolve, and rinse the organic phase with purified water (12.20 kg) twice;

[0089] 9) Add anhydrous sodium sulfate (2.03 kg) to the organic phase solution and dry for 1.5 hours, filter, and rinse the filter cake once with dichloromethane (2.03 kg);

[0090] 10) The organic phase was concentrated to 6.75 L at 45±5°C and vacuum degree ≤-0.07 MPa (first concentration); tetrahydrofuran (32.71 kg) was weighed and divided into three equal parts by mass, the first part of tetrahydrofuran was added to the concentrated solution, and the solution was concentrated to 7.8 L; the second part of tetrahydrofuran was added to the concentrated solution, and the solution was concentrated to 7.2 L; the third part of tetrahydrofuran was added to the concentrated solution, and the solution was concentrated to 6.8 L (fourth concentration);

[0091] 11) Weigh pure water (0.61 kg) and add it to the above concentrate. Stir and heat until the system is dissolved. Stop heating and continue stirring for 30 minutes.

[0092] 12) adding methyl tert-butyl ether (4.52 kg) dropwise, and stirring for 12 hours at a temperature of 6±1°C for recrystallization;

[0093] 13) Filter, rinse the filter cake with a mixture of tetrahydrofuran (0.46 kg) and methyl tert-butyl ether (0.36 kg) cooled to 5.5°C, dry at 45±5°C and vacuum ≤-0.07 MPa until the difference between two consecutive weighings is ≤0.5%, collect the material, and weigh to obtain

[0094] M3=1.40kg.

[0095] 14) Add 2.67M3kg of tetrahydrofuran and 0.3M3kg of purified water to the reactor, then add M3 solid, stir and heat to 38°C until the system is dissolved;

[0096] 15) Add 2.22M3kg methyl tert-butyl ether dropwise, cool to 4°C and stir for 13 hours;

[0097] 16) Filter, and rinse the filter cake once with a mixture of 0.22 M3 tetrahydrofuran and 0.18 M3 methyl tert-butyl ether cooled to 5°C;

[0098] 17) Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0099] 15) The material was collected and weighed to obtain intermediate III (1.19 kg), with a yield of 56.7%. A sample was taken and sent to the analysis department for detection.

[0100] Step S4:

[0101] 1) Weigh acetone (45.24 kg) and add intermediate III (1.16 kg) to the reaction flask, heat to 32 °C and stir to dissolve, then cool to 24 °C and stir for 15 minutes;

[0102] 2) Filter, transfer the filtrate to reaction bottle 1, control the temperature at 25±5°C, and stir for 25 minutes;

[0103] 3) Weigh concentrated hydrochloric acid (0.28 kg) and acetone (43.98 kg) and add them to reaction bottle 2, control the temperature at 25±5°C, shake well to make a mixed solution, and set aside for later use;

[0104] 4) Add the hydrochloric acid and acetone mixture prepared in 3) dropwise into the reaction bottle 1 under stirring at 5±5°C for recrystallization;

[0105] 5) Monitor the pH of the reaction solution at 7-8, filter, and rinse the filter cake twice with acetone (0.91 kg) cooled to 5°C;

[0106] 6) Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0107] 7) Collect the material and weigh the final product (1.15 kg) with a yield of 91.0%. Take a sample and send it to the analysis department for detection.

[0108] Detection of the intermediate 1 synthesized in Example 1: The appearance is a white solid. The retention time of the main peak of the sample solution is compared with the retention time of the main peak of the separation solution. The retention times are consistent, which has identification significance.

[0109] Detection of intermediate II synthesized in Example 1: The appearance is a white solid. The retention time of the main peak of the sample solution is compared with the retention time of the main peak of the separation solution. The retention times are consistent, which has identification significance.

[0110] Detection of intermediate III synthesized in Example 1: The appearance is a white solid. The retention time of the main peak of the sample solution is compared with the retention time of the main peak of the separation solution. The retention times are consistent, which has identification significance.

[0111] The NMR data of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazine-1-yl)propionamide monohydrochloride synthesized in Example 1: 1 H NMR (400MHz, DMSO-d6) δ12.32-12.56 (m, 1H), 11.10-11.34 (m, 1H), 7.89 -7.91 (m, 2H), 7.52-7.63 (m, 2H), 7.30-7.45 (m, 7H), 4.278 (s, 1H), 2.89-3.55 (m, 10H), 2.08-2.72 (m, 3H).

[0112] 13 C NMR (400MHz, DMSO-d6) δ170.76, 168.74, 158.25, 149.26, 137.78, 134.72, 132.01, 129.87, 129.21, 129 .13, 128.83, 128.28, 126.13, 108.64, 61.43, 58.77, 53.01, 51.61, 50.82, 49.35, 40.61, 33.25, 29.86.

[0113] Example 2: Synthesis of N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propanamide monohydrochloride.

[0114] Step S1:

[0115] 1) Add 2-methyltetrahydrofuran (29.08 kg) to the reaction kettle and stir, then add 4-phenyl-2-aminothiazole (1.69 kg) to the reaction bottle and stir to dissolve, and control the temperature at 7±1°C;

[0116] 2) 3-chloropropionyl chloride (3.04 kg) was added to a 250 mL constant pressure dropping funnel and added dropwise to the reaction kettle, and the reaction temperature was controlled at 8 ± 1 °C;

[0117] 3) After the dropwise addition, diisopropylethylamine (2.48 kg) was continued to be added dropwise, and the reaction temperature was controlled at 6±1°C;

[0118] 4) After the dropwise addition, stir at 12°C for 0.5 hours;

[0119] 5) Take a sample and send it to HPLC for central control, and stop the reaction after the reaction is completed;

[0120] 6) Filter the reaction solution, set the filtrate aside, and add the filter cake to purified water (6.50 kg) and 2-methyltetrahydrofuran (5.59 kg).

[0121] Stir the mixture to dissolve and let it stand;

[0122] 7) Separate the liquid to obtain an organic phase, combine the organic phase with the previously placed filtrate, and wash twice with the prepared sodium bicarbonate solution (21.89 kg);

[0123] 8) Add 2.60 kg of anhydrous sodium sulfate to the organic phase and dry for 1.5 hours;

[0124] 9) filtering, rinsing the filter cake with 2-methyltetrahydrofuran (1.12 kg), and concentrating the filtrate under vacuum at 45±5°C and vacuum degree ≤-0.07 MPa to a total volume of 3.2 L (first concentration), adding n-heptane (5.30 kg) to the concentrate, and concentrating under vacuum at 45±5°C and vacuum degree ≤-0.07 MPa to a total volume of 2.9 L (second concentration);

[0125] 10) Add methyl tert-butyl ether (1.92 kg) to the second concentrated solution and recrystallize at 25° C. for 1.5 hours;

[0126] 11) filtering, and rinsing the filter cake with a mixture of methyl tert-butyl ether (0.48 kg) and n-heptane (0.44 kg);

[0127] 12) Filter cake drying: Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0128] 13) Collect the material and weigh the intermediate I (2.37 kg), with a yield of 92.6%. Take a sample and send it to the analysis department for detection.

[0129] Step S2:

[0130] 1) Add N,N-dimethylformamide (9.25 kg) into a 50 L reactor;

[0131] 2) Add intermediate I (1.95 kg) and N-Boc (1.50 kg) into the reaction kettle and stir to dissolve;

[0132] 3) Weigh potassium carbonate (1.11 kg) and add it to the reaction system, stirring;

[0133] 4) Control the temperature at 13°C and stir for 4.5 hours;

[0134] 5) HPLC control, stop the reaction after the reaction is completed;

[0135] 6) Stop the reaction, filter, rinse the filter cake with N,N-dimethylformamide (1.42 kg), and add the filtrate dropwise into a 50 L reactor filled with tap water (27.00 kg);

[0136] 7) After the dropwise addition, stir at 25°C for 1.5 hours to recrystallize;

[0137] 8) Filter by suction, rinse the filter cake four times with pure water (18.00 kg), until the pH of the last rinse liquid is 7-8;

[0138] 9) Add 4M methanolic hydrogen chloride (21.99 kg) to a 50L reactor, add the filter cake in batches, and stir at 27°C for 2 hours after the addition is complete;

[0139] 10) HPLC control, stop the reaction after the reaction is completed;

[0140] 11) Ethyl acetate (16.20 kg) was added to the reaction solution, stirred at 24°C for 1.5 hours, and recrystallized;

[0141] 12) Filter, and rinse the filter cake twice with ethyl acetate (2.70 kg);

[0142] 13) Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0143] 14) Collect the material and weigh the intermediate II (2.91 kg), with a yield of 93.5%. Take a sample and send it to the analysis department for detection.

[0144] Step S3:

[0145] 1) Weigh N,N-dimethylformamide (12.60 kg) and add it into a 50L reactor. Weigh intermediate II (2.86 kg) and add it into the reactor, and stir.

[0146] 2) Weigh potassium carbonate (2.56 kg) and add it to the reaction system, and stir at 15±5°C for 30 minutes;

[0147] 3) Weigh benzyl chloride (0.81 kg) and add it into the reaction kettle, stirring;

[0148] 4) Control the temperature to 50±5°C and react for 5.5 hours;

[0149] 5) HPLC control, stop the reaction after the reaction is completed;

[0150] 6) Filter, rinse the filter cake with N,N-dimethylformamide (1.93 kg), add purified water (12.20 kg) dropwise to the filtrate, and then stir at 25° C. for 1-2 hours;

[0151] 7) Filter and rinse the filter cake once with pure water (6.10 kg);

[0152] 8) Add dichloromethane (26.83 kg) to the reactor, transfer the filter cake to the reactor, stir to dissolve, and rinse the organic phase with purified water (12.2 kg) twice;

[0153] 9) Add anhydrous sodium sulfate (2.63 kg) to the organic phase solution and dry for 1.5 hours, filter, and rinse the filter cake once with dichloromethane (2.03 kg);

[0154] 10) The organic phase was concentrated to 7.3 L at 45±5°C and vacuum degree ≤-0.07 MPa (first concentration); tetrahydrofuran (32.71 kg) was weighed and divided into three equal parts by mass, the first part of tetrahydrofuran was added to the concentrated solution, and the solution was concentrated to 7.8 L; the second part of tetrahydrofuran was added to the concentrated solution, and the solution was concentrated to 7.2 L; the third part of tetrahydrofuran was added to the concentrated solution, and the solution was concentrated to 6.8 L (fourth concentration);

[0155] 11) Weigh pure water (0.61 kg) and add it to the above concentrate. Stir and heat until the system is dissolved. Stop heating and continue stirring for 30 minutes.

[0156] 12) Add methyl tert-butyl ether (4.52 kg) dropwise, and after completion of the addition, stir at 12° C. for 6 hours to recrystallize;

[0157] 13) Filter, rinse the filter cake with a mixture of tetrahydrofuran (0.46 kg) and methyl tert-butyl ether (0.36 kg) cooled to 5.3°C, dry at 45±5°C and vacuum ≤-0.07 MPa until the difference between two consecutive weighings is ≤0.5%, collect the material, and weigh to obtain M3=1.40 kg;

[0158] 14) Add 2.67M3kg of tetrahydrofuran and 0.3M3kg of purified water to the reactor, then add M3 solid, stir and heat to 38°C until the system is dissolved;

[0159] 15) Add 2.22M3kg methyl tert-butyl ether dropwise, cool to 4°C and stir for 13 hours;

[0160] 16) Filter, and rinse the filter cake once with a mixture of 0.22 M3 tetrahydrofuran and 0.18 M3 methyl tert-butyl ether cooled to 5°C;

[0161] 17) Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0162] 18) The material was collected and weighed to obtain intermediate III (1.54 kg), with a yield of 56.4%. A sample was taken and sent to the analysis department for detection.

[0163] Step S4:

[0164] 1) Weigh acetone (58.81 kg) and add intermediate III (1.50 kg) to the reaction flask, heat to 14 °C and stir to dissolve, then cool to 25 °C and stir for 45 minutes;

[0165] 2) Filter, transfer the filtrate to reaction bottle 1, control the temperature at 25°C ± 5°C, and stir for 25 minutes;

[0166] 3) Weigh concentrated hydrochloric acid (0.36 kg) and acetone (57.18 kg) and add them to reaction bottle 2, control the temperature at 25±5°C, shake well to make a mixed solution, and set aside for later use;

[0167] 4) Add the hydrochloric acid and acetone mixture prepared in 3) dropwise into the reaction bottle 1 under stirring at 5±5℃ for recrystallization;

[0168] 5) Monitor the pH of the reaction solution at 7-8, filter, and rinse the filter cake twice with acetone (0.9 kg) cooled to 5°C;

[0169] 6) Dry at 45±5°C and vacuum ≤-0.07MPa until the difference between two consecutive weighings is ≤0.5%;

[0170] The material was collected and weighed to obtain the final product (1.49 kg), with a yield of 91.2%. Samples were taken and sent to the analysis department for testing.

[0171] The above is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and changes can be made without departing from the principle of the present invention, and these improvements and changes are also regarded as the protection scope of the present invention.

Claims

1. A process for synthesizing N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propionamide monohydrochloride, characterized in that: The following steps are involved: S1: 4-phenyl-2-aminothiazole is used as a starting material, and 3-chloropropionyl chloride is dissolved in a reaction solvent, and in the presence of an alkaline substance, an acylation reaction is performed to obtain an intermediate I, namely N-(4-phenylthiazol-2-yl)-3-chloropropionamide; S2: Dissolve intermediate I and N-Boc piperazine in a reaction solvent, carry out a substitution reaction in the presence of an alkaline substance, and then carry out a Boc removal reaction under acidic conditions to obtain intermediate II, namely N-(4-phenylthiazol-2-yl)-3-(piperazine-1-yl) propionamide trihydrochloride; S3: Intermediate II and benzyl chloride are dissolved in a reaction solvent, and in the presence of an alkaline substance, a nucleophilic substitution reaction is carried out to obtain intermediate III, namely N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazin-1-yl)propionamide; S4: adding hydrochloric acid to acetone to prepare a hydrochloric acid-acetone mixed solution; then adding the hydrochloric acid-acetone mixed solution to a reaction solvent containing intermediate III to carry out a salt-forming reaction, and after the reaction is completed, recrystallizing, filtering, and drying to constant weight to obtain the final product: N-(4-phenylthiazol-2-yl)-3-(4-benzylpiperazine-1-yl)propionamide monohydrochloride.

2. The synthesis process according to claim 1, characterized in that The alkaline substance is selected from diisopropylethylamine and potassium carbonate.

3. The synthesis process according to claim 1, characterized in that: The reaction solvent is selected from one of 2-methyltetrahydrofuran, N,N-dimethylformamide and acetone.

4. The synthesis process according to claim 1, characterized in that The conditions of S1 acylation reaction include: temperature 0-20°C; stirring reaction; reaction time 0.5-1 hour.

5. The synthesis process according to claim 1, characterized in that: The molar ratio of 4-phenyl-2-aminothiazole to 3-chloropropionyl chloride in S1 is 1:1-2.

6. The synthesis process according to claim 1, characterized in that: The molar ratio of intermediate I and N-Boc piperazine in S2 is 1:0.6-1.

7. The synthesis process according to claim 1, characterized in that: The molar ratio of intermediate II and benzyl chloride in S3 is 1:0.2-0.

5.

8. The synthesis process according to claim 1, characterized in that: The conditions of the S3 nucleophilic substitution reaction include: temperature 45-55° C.; reaction time 5 to 6 hours.

9. The synthesis process according to claim 1, characterized in that: The molar ratio of intermediate III and hydrochloric acid in S4 is 1:0.2-0.

4.

10. The synthesis process according to claim 1, characterized in that: The reaction conditions for preparing the hydrochloric acid-acetone mixed solution in S4 include: a reaction temperature of 20-30° C.; the conditions for the salt-forming reaction in S4 include: a reaction temperature of 0-10° C., stirring the reaction, and a reaction time of 12-20 hours.

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