Preparation method of ilaprazole
By dissolving sodium esprazole in a mixed solution of purified water and triethylamine, and performing free extraction and crystallization treatment, the existing esprazole preparation method has solved the problems of low yield and high calcination residue, and the high efficiency and low residue preparation process has been achieved, and high purity and excellent color esprazole is obtained.
Patent Information
- Application Number
- CN202411618216.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-13
- Publication Date
- 2025-02-28
AI Technical Summary
The existing preparation methods for esapraprazole have low yields and the product burning residue is too high.
Sodium esprazole was dissolved in a mixed solution of purified water and triethylamine, and free extraction was performed by aqueous solution of dichloromethane and tartaric acid, followed by crystallization treatment to obtain esprazole.
The yield of esaprazole is increased, the burning residue of the product is reduced, and a high-purity and excellent color product is obtained.
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Figure CN119528882A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing ilaprazole. Background Art
[0002] Ilaprazole is a potent proton pump inhibitor that works by interfering with the proton pumps that secrete gastric acid on the gastric parietal cells, thereby inhibiting gastric acid secretion.
[0003] In the prior art, the synthesis process of ilaprazole sodium to ilaprazole is to post-treat ilaprazole with dichloromethane and acetic acid, and the yield is only 66.79%. The ilaprazole obtained by this method has a low yield, a high ignition residue (about 0.2%-0.3%), and a poor product color. Summary of the invention
[0004] The purpose of the embodiments of the present application is to provide a method for preparing ilaprazole, aiming to solve the problems of low yield and excessively high ignition residue of the product in the existing synthesis process from ilaprazole sodium to ilaprazole.
[0005] The present application embodiment is implemented as follows: a method for preparing ilaprazole, comprising:
[0006] Adding ilaprazole sodium to a mixed solution of purified water and triethylamine to obtain a first mixed solution;
[0007] Adding dichloromethane and tartaric acid aqueous solution to the first mixed solution for free extraction, and collecting the organic phase;
[0008] The obtained organic phase is washed, and then purified water and n-heptane are added for crystallization. The mixture is filtered and dried to obtain ilaprazole.
[0009] Preferably, the step of adding ilaprazole sodium to a mixed solution of purified water and triethylamine to obtain a first mixed solution comprises:
[0010] Purified water and triethylamine were added to the reaction device, stirring was started, and then ilaprazole sodium was added. The temperature of the reaction solution was controlled at 15-25° C. and stirred until the solid was completely dissolved to obtain a first mixed solution.
[0011] Preferably, the step of adding dichloromethane and tartaric acid aqueous solution to the first mixed solution for free extraction and collecting the organic phase comprises:
[0012] Add dichloromethane to the first mixed solution, cool to 0-10°C, add tartaric acid aqueous solution dropwise, control the temperature of the reaction solution at -5 to 15°C, and after the addition is complete, continue stirring the reaction for 5-25 minutes, control the temperature of the reaction solution at -5 to 15°C, stand for stratification, and collect the organic phase.
[0013] Preferably, the obtained organic phase is washed, purified water and n-heptane are added for crystallization, and filtered and dried to obtain ilaprazole, comprising:
[0014] The obtained organic phase is washed, cooled to -5 to 15°C and stirred, then purified water is added, the temperature is controlled at -5 to 15°C, n-heptane is slowly added dropwise, when 30% to 50% of n-heptane is added dropwise, stirring is performed for 0.5 to 2.5 hours, when a large amount of solid is precipitated, n-heptane is slowly added dropwise, after the addition is completed, stirring and crystallizing for 0.5 to 2.5 hours, the crystallization temperature is controlled at -5 to 15°C, filtered, and dried to obtain ilaprazole;
[0015] The mass ratio of the purified water, n-heptane and ilaprazole sodium is (2-10):(8-12):1.
[0016] The present application provides a method for preparing ilaprazole, which has a simple process and is easy to operate. The method comprises dissolving ilaprazole sodium in a mixed solution of purified water and triethylamine, adding dichloromethane and tartaric acid aqueous solution for free extraction, and adding purified water and n-heptane to the obtained organic phase for crystallization to obtain ilaprazole. The present application innovatively uses tartaric acid for acidification, and adds water and n-heptane for two-phase crystallization during crystallization, which reduces the ignition residue of the product while achieving an improved yield, and the obtained product has a high purity and excellent color. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 The HPLC chromatogram of ilaprazole provided in Example 10 of the present application;
[0018] Figure 2 The X-ray powder diffraction pattern of ilaprazole provided in Example 10 of the present application;
[0019] Figure 3 The HPLC chromatogram of ilaprazole provided in Comparative Example 1 of the present application;
[0020] Figure 4 The HPLC chromatogram of ilaprazole provided for Comparative Example 2 of the present application;
[0021] Figure 5 The HPLC chromatogram of ilaprazole provided for Comparative Example 3 of the present application;
[0022] Figure 6 The HPLC chromatogram of ilaprazole provided for Comparative Example 4 of the present application;
[0023] Figure 7 The HPLC chromatogram of ilaprazole provided in Comparative Example 5 of the present application. DETAILED DESCRIPTION
[0024] In order to make the purpose, technical solution and advantages of the present application more clearly understood, the present application is further described in detail below in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and are not used to limit the present application.
[0025] The present application provides a method for preparing ilaprazole, comprising:
[0026] Adding ilaprazole sodium to a mixed solution of purified water and triethylamine to obtain a first mixed solution;
[0027] Adding dichloromethane and tartaric acid aqueous solution to the first mixed solution for free extraction, and collecting the organic phase;
[0028] The obtained organic phase is washed, and then purified water and n-heptane are added for crystallization. The mixture is filtered and dried to obtain ilaprazole.
[0029] In a preferred embodiment of the present application, the step of adding ilaprazole sodium to a mixed solution of purified water and triethylamine to obtain a first mixed solution comprises:
[0030] Purified water and triethylamine are added to the reaction apparatus, stirring is started, and then ilaprazole sodium is added. The temperature of the reaction liquid is controlled at 15-25°C (the temperature in the actual reaction process has certain fluctuations and can be controlled to 20±5°C), and stirring is performed until the solid is completely dissolved to obtain a first mixed solution; the mass ratio of purified water, triethylamine and ilaprazole sodium is (6-8):(0.08-0.16):1.
[0031] In a preferred embodiment of the present application, the step of adding dichloromethane and tartaric acid aqueous solution to the first mixed solution for free extraction and collecting the organic phase comprises:
[0032] Add dichloromethane to the first mixed solution, cool to 0-10°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to 5-10°C), drip tartaric acid aqueous solution, control the temperature of the reaction solution to -5 to 15°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to 5±5°C), after the dripping is completed, continue stirring the reaction for 5-25 minutes, control the temperature of the reaction solution to -5 to 15°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to 5±5°C), stand for stratification, and collect the organic phase. The mass ratio of dichloromethane, tartaric acid aqueous solution and ilaprazole sodium is (6-8): (2-3): 1. The mass fraction of the tartaric acid aqueous solution is 12%.
[0033] In a preferred embodiment of the present application, the obtained organic phase is washed, purified water and n-heptane are added for crystallization, and filtered and dried to obtain ilaprazole, comprising:
[0034] The obtained organic phase is washed and cooled to -5 to 15°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to 5±5°C) and stirred, and then purified water is added, and the temperature is controlled to -5 to 15°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to 5±5°C), and n-heptane is slowly added dropwise. When 30% to 50% of n-heptane is added dropwise, stirring is performed for 0.5 to 2.5 hours. When a large amount of solid is precipitated, n-heptane is continued to be slowly added dropwise. After the addition is completed, stirring and crystallization is performed for 0.5 to 2.5 hours, and the crystallization temperature is controlled to -5 to 15°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to 5±5°C). After filtering and drying, ilaprazole is obtained;
[0035] The mass ratio of the purified water, n-heptane and ilaprazole sodium is (2-10):(8-12):1.
[0036] In a preferred embodiment of the present application, the drying temperature is 30-50°C.
[0037] In a preferred embodiment of the present application, the obtained organic phase is subjected to a washing treatment, comprising:
[0038] Add triethylamine to the obtained organic phase, maintain the reaction solution at -5 to 15°C (the temperature in the actual reaction process fluctuates to a certain extent and can be controlled to be 5±5°C), stir and react for 5-25 minutes, then add purified water, start stirring and washing, and collect the organic phase in layers.
[0039] In a preferred embodiment of the present application, 6M-8M of purified water (M is the weight of ilaprazole sodium) and 0.08-0.16M of triethylamine are added to the reaction bottle, stirring is started, and then 1M of ilaprazole sodium is added, the reaction solution is temperature controlled at 20±5°C, and stirred until the solid is completely dissolved, and then 6M-8M of dichloromethane is added to the reaction bottle, the temperature is lowered to 0-10°C, 2M-3M of 12% tartaric acid aqueous solution is added dropwise, the temperature of the reaction solution is controlled at 5±10°C, after the addition is completed, the reaction is continued to stir for 15±10 minutes, the temperature of the reaction solution is controlled at 5±10°C, the organic layer is collected, and the aqueous phase is extracted with 3.5M-3.9M of dichloromethane, and the resultant is collected. The organic layer is added with 0.04M-0.08M triethylamine, the reaction solution is kept stirring at 5±10°C for 15±10 minutes, and then 0.5M-1.5M purified water is added, stirring and washing are started, the organic phase is collected in layers, and the reaction bottle is cooled to 5±10°C and stirred, and then 2M-10M purified water is added, and the temperature is controlled at 5±10°C; 8M-12M n-heptane is slowly added dropwise, and when about 30%-50% of n-heptane is added dropwise, stirring is performed for 1.5±1 hour, and when a large amount of solid is precipitated, n-heptane is slowly added dropwise, and the crystallization is stirred for 1.5±1 hour, and the crystallization temperature is controlled at 5±10°C, filtered, and dried at 30-50°C to obtain the finished product. The molar yield of the finished product is between 80% and 85%.
[0040] The following is a detailed description of the preparation method of ilaprazole with specific examples, as shown below. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are all commercially available unless otherwise specified.
[0041] Embodiment 1:
[0042] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (46 g, 37.05 mmol, 0.72 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, extract the aqueous phase with 75 g of dichloromethane, collect and combine the organic layers , add triethylamine (1.2 g, 11.86 mmol, 0.23 eq) and keep the reaction solution at 5±5°C for 15 minutes, then add 20 g of purified water, start stirring and washing, collect the organic phase in layers, add it to the reaction bottle and stir at 5±5°C, then add 120 g of purified water, and cool to 5±5°C; slowly add 194 g of n-heptane, and control the dropping temperature to 5±5°C; when about 40% of n-heptane is added, stir for 1 hour, then continue to add n-heptane, after the dropwise addition, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5°C, filter, and dry at 35-45°C for 12 hours to obtain 15.55 g of white solid, with a yield of 82.51% and an ignition residue of 0.03%.
[0043] Embodiment 2:
[0044] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20 ± 5 ° C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10 ° C, slowly add 12% tartaric acid aqueous solution (58 g, 46.26 mmol, 0.9 eq) dropwise to control the temperature of the reaction solution to 5 ± 5 ° C. After the addition is complete, continue to stir and react for 15 minutes, control the temperature of the reaction solution to 5 ± 5 ° C, let it stand for stratification, collect the organic layer, extract the aqueous phase with 75 g of dichloromethane, collect and combine the organic layer, and then add 100 g of tartaric acid to the reaction flask. layer, add triethylamine (1.2g, 11.86mmol, 0.23eq) and keep the reaction solution at 5±5℃ stirring for 15 minutes, then add 20g of purified water, start stirring and washing, collect the organic phase in layers, add it to the reaction bottle and stir at 5±5℃, then add 120g of purified water, cool to 5±5℃; slowly add 194g of n-heptane dropwise, and control the dropping temperature to 5±5℃; when about 40% of n-heptane is added, stir for 1 hour, then continue to add n-heptane dropwise, after the dropwise addition is completed, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5℃, filter, and dry at 35-45℃ for 12 hours to obtain 15.14g of light yellow solid, with a yield of 80.34% and an ignition residue of 0.04%.
[0045] Embodiment 3:
[0046] Add 140 g of purified water and triethylamine (2.16 g, 21.34 mmol, 0.41 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20 ± 5 ° C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10 ° C, slowly add 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) dropwise to control the temperature of the reaction solution to 5 ± 5 ° C. After the addition is complete, continue to stir and react for 15 minutes, control the temperature of the reaction solution to 5 ± 5 ° C, stand for stratification, collect the organic layer, extract the aqueous phase with 75 g of dichloromethane, collect and combine the organic layer. To the organic layer, triethylamine (1.2 g, 11.86 mmol, 0.23 eq) was added, and the reaction solution was stirred at 5±5°C for 15 minutes. Then 20 g of purified water was added, and stirring and washing were started. The organic phase was collected by layers, added to a reaction bottle and stirred at 5±5°C, and then 120 g of purified water was added, and the temperature was lowered to 5±5°C; 194.2 g of n-heptane was slowly added dropwise, and the dropping temperature was controlled at 5±5°C; when about 40% of n-heptane was added dropwise, it was stirred for 1 hour, and then n-heptane was continued to be added dropwise. After the dropping was completed, it was stirred for crystallization for 1.5 hours, and the crystallization temperature was controlled at 5±5°C. It was filtered and dried at 35-45°C for 12 hours to obtain 15.10 g of an off-white solid with a yield of 80.12% and an ignition residue of 0.05%.
[0047] Embodiment 4:
[0048] Add 140 g of purified water and triethylamine (2.64 g, 26.09 mmol, 0.51 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, extract the aqueous phase with 75 g of dichloromethane, collect and combine To the organic layer, triethylamine (1.2 g, 11.86 mmol, 0.23 eq) was added, and the reaction solution was stirred at 5±5°C for 15 minutes. Then 20 g of purified water was added, and stirring and washing were started. The organic phase was collected by layers, added to a reaction bottle and stirred at 5±5°C, and then 120 g of purified water was added, and the temperature was lowered to 5±5°C; 194.2 g of n-heptane was slowly added dropwise, and the dropping temperature was controlled at 5±5°C; when about 40% of n-heptane was added dropwise, it was stirred for 1 hour, and then n-heptane was continued to be added dropwise. After the dropping was completed, it was stirred for crystallization for 1.5 hours, and the crystallization temperature was controlled at 5±5°C. It was filtered and dried at 35-45°C for 12 hours to obtain 14.8 g of a white solid with a yield of 78.54% and an ignition residue of 0.05%.
[0049] Embodiment 5:
[0050] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, extract the aqueous phase with 75 g of dichloromethane, collect and combine To the organic layer, triethylamine (1.2 g, 11.86 mmol, 0.23 eq) was added, and the reaction solution was stirred at 5±5°C for 15 minutes. Then 20 g of purified water was added, and stirring and washing were started. The organic phase was collected by layers, added to a reaction bottle and stirred at 5±5°C, and then 80 g of purified water was added, and the temperature was lowered to 5±5°C; 194.2 g of n-heptane was slowly added dropwise, and the dropping temperature was controlled at 5±5°C; when about 40% of n-heptane was added dropwise, it was stirred for 1 hour, and then n-heptane was continued to be added dropwise. After the dropping was completed, it was stirred for crystallization for 1.5 hours, and the crystallization temperature was controlled at 5±5°C. It was filtered and dried at 35-45°C for 12 hours to obtain 16.5 g of a white solid with a yield of 87.53% and an ignition residue of 0.07%.
[0051] Embodiment 6:
[0052] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, extract the aqueous phase with 75.00 g of dichloromethane, collect and combine the organic layers. , add triethylamine (1.20 g, 11.86 mmol, 0.23 eq) and keep the reaction solution at 5±5°C for 15 minutes, then add 20.00 g of purified water, start stirring and washing, collect the organic phase in layers, add it to the reaction bottle and stir at 5±5°C, then add 160 g of purified water, and cool to 5±5°C; slowly add 194.2 g of n-heptane dropwise, and control the dropping temperature to 5±5°C; when about 40% of n-heptane is added, stir for 1 hour, then continue to add n-heptane dropwise, after the dropwise addition is completed, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5°C, filter, and dry at 35-45°C for 12 hours to obtain 15.3 g of white solid, with a yield of 81.17% and an ignition residue of 0.05%.
[0053] Embodiment 7:
[0054] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20 ± 5 ° C. Stir until the solid is completely dissolved. Then add 140 g of dichloromethane to the reaction flask, cool to 5-10 ° C, slowly add 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) dropwise to control the temperature of the reaction solution to 5 ± 5 ° C. After the addition is complete, continue to stir and react for 15 minutes, control the temperature of the reaction solution to 5 ± 5 ° C, stand for stratification, collect the organic layer, extract the aqueous phase with 75 g of dichloromethane, collect and combine the organic layer. To the organic layer, triethylamine (1.20 g, 11.86 mmol, 0.23 eq) was added, and the reaction solution was stirred at 5±5°C for 15 minutes. Then 20 g of purified water was added, and stirring and washing were started. The organic phase was collected by layers, added to a reaction bottle and stirred at 5±5°C, and then 120 g of purified water was added, and the temperature was lowered to 5±5°C; 160 g of n-heptane was slowly added dropwise, and the dropping temperature was controlled at 5±5°C; when about 40% of n-heptane was added dropwise, it was stirred for 1 hour, and then n-heptane was continued to be added dropwise. After the dropping was completed, it was stirred for crystallization for 1.5 hours, and the crystallization temperature was controlled at 5±5°C. It was filtered and dried at 35-45°C for 12 hours to obtain 14.77 g of a white solid with a yield of 78.34% and an ignition residue of 0.04%.
[0055] Embodiment 8:
[0056] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140.00 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, extract the aqueous phase with 75.00 g of dichloromethane, and collect The organic layers were combined, triethylamine (1.2 g, 11.86 mmol, 0.23 eq) was added, and the reaction solution was stirred at 5±5°C for 15 minutes. Then 20 g of purified water was added, stirring and washing were started, the organic phase was collected in layers, added to a reaction bottle and stirred at 5±5°C, and then 120 g of purified water was added, and the temperature was lowered to 5±5°C; 240 g of n-heptane was slowly added dropwise, and the dropping temperature was controlled at 5±5°C; when about 40% of n-heptane was added dropwise, stirring was performed for 1 hour, and then n-heptane was continued to be added dropwise. After the dropping was completed, stirring and crystallizing was performed for 1.5 hours, and the crystallization temperature was controlled at 5±5°C. The mixture was filtered and dried at 35-45°C for 12 hours to obtain 16.25 g of a white solid with a yield of 86.21% and an ignition residue of 0.06%.
[0057] Embodiment 9:
[0058] Add 140 g of purified water and triethylamine (2.4 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20 g, 51.49 mmol, 1 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 95 g of ethyl acetate to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, extract the aqueous phase with 50 g of ethyl acetate, collect and combine the organic layers, Triethylamine (1.2 g, 11.86 mmol, 0.23 eq) was added, and the reaction solution was stirred at 5±5°C for 15 minutes. Then 20 g of purified water was added, and stirring and washing were started. The organic phase was collected by layers, added to a reaction bottle and stirred at 5±5°C, and then 120 g of purified water was added, and the temperature was lowered to 5±5°C; 194.2 g of n-heptane was slowly added dropwise, and the dropping temperature was controlled at 5±5°C; when about 40% of n-heptane was added dropwise, it was stirred for 1 hour, and then n-heptane was continued to be added dropwise. After the dropping was completed, it was stirred for crystallization for 1.5 hours, and the crystallization temperature was controlled at 5±5°C. It was filtered and dried at 35-45°C for 12 hours to obtain 14.16 g of a light yellow solid with a yield of 75.12% and an ignition residue of 0.08%.
[0059] Embodiment 10:
[0060] To the reaction flask, 140 g of purified water and triethylamine (2.40 g, 23.72 mmol, 0.46 eq) were added and stirred. Then, ilaprazole sodium (20 g, 51.49 mmol, 1 eq) was added. The reaction solution was kept at a temperature of 20 ± 5 °C and stirred until the solid was completely dissolved. Then, 140.00 g of dichloromethane was added to the reaction flask, the temperature was lowered to 5-10 °C, and 12% tartaric acid aqueous solution (52.6 g, 42.05 mmol, 0.82 eq) was slowly added dropwise to control the temperature of the reaction solution to 5 ± 5 °C. After the addition was complete, the reaction was continued to stir for 15 minutes, the temperature of the reaction solution was controlled to 5 ± 5 °C, the layers were allowed to stand and the organic layer was collected. The aqueous phase was extracted with 75 g of dichloromethane, the organic layers were collected and combined, and triethylamine was added. Ethylamine (1.2 g, 11.86 mmol, 0.23 eq) kept the reaction solution at 5±5°C and stirred for 15 minutes, then added 20 g of purified water, started stirring and washing, collected the organic phase by layers, added it to the reaction bottle and stirred at 5±5°C, then added 120 g of purified water, and cooled to 5±5°C; slowly added n-heptane 194.2 g, and controlled the dropping temperature at 5±5°C; when n-heptane was added by about 40%, stirred for 1 hour, and then continued to add n-heptane, after the dropping was completed, stirred for crystallization for 1.5 hours, controlled the crystallization temperature at 5±5°C, filtered, and dried at 35-45°C for 12 hours to obtain 15.69 g of white solid, with a yield of 83.24%, 0.02% ignition residue, and 99.07% HPLC purity. Figure 1 , X-ray powder diffraction results are shown in Figure 2 .
[0061] In the early stage of research and development, this application conducted a series of studies on acid types, base types and crystallization systems. Some comparative experiments are shown below:
[0062] Comparative Example 1:
[0063] Add 140.00 g of purified water to the reaction flask, start stirring, then add ilaprazole sodium (20.00 g, 51.49 mmol, 1.00 eq), control the temperature of the reaction solution to 20±5°C, stir until the solid is completely dissolved, then add 140.00 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 6.40% dilute hydrochloric acid solution (48.50 g, 85.20 mmol, 1.65 eq) to control the temperature of the reaction solution to 5±5°C, after the addition is complete, continue stirring the reaction for 15 minutes, control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, and the aqueous phase is washed with dichloromethane. Extract with 75.00g chloromethane, collect and combine the organic layers, add 20.00g purified water, start stirring and washing, collect the organic phase in layers, add it to the reaction bottle, stir and cool to 5±5℃; slowly add 194.20g n-heptane, control the dropping temperature to 5±5℃; when about 40% of n-heptane is added, stir for 1 hour, then continue to add n-heptane, after the drop is completed, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5℃, filter, and dry at 35-45℃ for 12 hours to obtain 13.80g of light yellow solid, with a yield of 73.25%, 0.19% ignition residue, 93.05% HPLC purity, see Figure 3 .
[0064] Comparative Example 2:
[0065] Add 140.00 g of purified water to the reaction flask, start stirring, then add ilaprazole sodium (20.00 g, 51.49 mmol, 1.00 eq), control the temperature of the reaction solution to 20±5°C, stir until the solid is completely dissolved, then add 140.00 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 10% acetic acid solution (51.12 g, 85.20 mmol, 1.65 eq) to control the temperature of the reaction solution to 5±5°C, after the addition is complete, continue stirring the reaction for 15 minutes, control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, and wash the aqueous phase with dichloromethane. 75.00g of alkane was extracted, the organic layers were collected and combined, 20.00g of purified water was added, stirring and washing were started, the organic phase was collected in layers, added to the reaction bottle, stirred and cooled to 5±5℃; 194.20g of n-heptane was slowly added dropwise, and the dropping temperature was controlled to 5±5℃; when about 40% of n-heptane was added dropwise, stirring was performed for 1 hour, and then n-heptane was continued to be added dropwise. After the addition was completed, stirring and crystallizing for 1.5 hours, the crystallization temperature was controlled to 5±5℃, filtered, and dried at 35-45℃ for 12 hours to obtain 13.63g of off-white solid, with a yield of 72.31%, 0.26% of ignition residue, and 95.12% HPLC purity. Figure 4 .
[0066] Comparative Example 3:
[0067] Add 140.00 g of purified water to the reaction flask, start stirring, then add ilaprazole sodium (20.00 g, 51.49 mmol, 1.00 eq), control the temperature of the reaction solution to 20±5°C, stir until the solid is completely dissolved, then add 140.00 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.60 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C, after the addition is complete, continue stirring the reaction for 15 minutes, control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, and the aqueous phase is washed with dichloromethane. Extract with 75.00g chloroform, collect and combine the organic layers, add 20.00g purified water, start stirring and washing, collect the organic phase in layers, add it to the reaction bottle, stir and cool to 5±5℃; slowly add 194.20g n-heptane, control the dropping temperature to 5±5℃; when about 40% of n-heptane is added, stir for 1 hour, then continue to add n-heptane, after the drop is completed, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5℃, filter, and dry at 35-45℃ for 12 hours to obtain 13.95g of white solid, with a yield of 74.01%, 0.20% ignition residue, 96.52% HPLC purity, see Figure 5 .
[0068] Comparative Example 4:
[0069] Add 140.00 g of purified water and 26% ammonia water (1.55 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20.00 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140.00 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.60 g, 42.05 mmol, 0.82 eq) and control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, and extract the aqueous phase with 75.00 g of dichloromethane. Collect and combine the organic layers, add 26% ammonia water (0.78 g, 11.86 mmol, 0.23 eq), keep the reaction solution at 5±5°C and stir for 15±5 minutes, then add 20.00 g of purified water, start stirring and washing, collect the organic phase by layers, add it to the reaction bottle, stir and cool to 5±5°C; slowly add n-heptane 194.20 g, and control the dropping temperature to 5±5°C; when n-heptane is added by about 40%, stir for 1 hour, then continue to add n-heptane, after the drop is completed, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5°C, filter, and dry at 35-45°C for 12 hours to obtain 13.86 g of white solid, with a yield of 73.52%, 0.21% ignition residue, and HPLC purity of 96.53%. Figure 6 .
[0070] Comparative Example 5:
[0071] Add 140.00 g of purified water and triethylamine (2.40 g, 23.72 mmol, 0.46 eq) to the reaction flask and start stirring. Then add ilaprazole sodium (20.00 g, 51.49 mmol, 1.00 eq) and control the temperature of the reaction solution to 20±5°C. Stir until the solid is completely dissolved. Then add 140.00 g of dichloromethane to the reaction flask, cool to 5-10°C, slowly drop 12% tartaric acid aqueous solution (52.60 g, 42.05 mmol, 0.82 eq) to control the temperature of the reaction solution to 5±5°C. After the addition is complete, continue stirring and reacting for 15 minutes. Control the temperature of the reaction solution to 5±5°C, let stand for stratification, collect the organic layer, and extract the aqueous phase with 75.00 g of dichloromethane. , collect and combine the organic layers, add triethylamine (1.20 g, 11.86 mmol, 0.23 eq) and keep the reaction solution at 5±5°C for 15 minutes, then add 20.00 g of purified water, start stirring and washing, collect the organic phase by layers, add it to the reaction bottle, stir and cool to 5±5°C; slowly add 194.20 g of n-heptane, and control the dropping temperature to 5±5°C; when about 40% of n-heptane is added, stir for 1 hour, then continue to add n-heptane, after the drop is completed, stir and crystallize for 1.5 hours, control the crystallization temperature to 5±5°C, filter, and dry at 35-45°C for 12 hours to obtain 14.20 g of white solid, with a yield of 75.31%, 0.18% ignition residue, and 98.55% HPLC purity. Figure 7 .
[0072] The experimental systems and test results of the above-mentioned Example 10 and Comparative Examples 1-5 are summarized in the following Table 1:
[0073] Table 1
[0074]
[0075]
[0076] The above-mentioned embodiments only express several implementation methods of the present application, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the present application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the protection scope of the present application shall be subject to the attached claims.
[0077] The above description is only a preferred embodiment of the present application and is not intended to limit the present application. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present application should be included in the protection scope of the present application.
Claims
1. A method for preparing ilaprazole, characterized in that: include: Adding ilaprazole sodium to a mixed solution of purified water and triethylamine to obtain a first mixed solution; Adding dichloromethane and tartaric acid aqueous solution to the first mixed solution for free extraction, and collecting the organic phase; The obtained organic phase is washed, and then purified water and n-heptane are added for crystallization. The mixture is filtered and dried to obtain ilaprazole.
2. The method for preparing ilaprazole according to claim 1, characterized in that: The step of adding ilaprazole sodium to a mixed solution of purified water and triethylamine to obtain a first mixed solution comprises: Purified water and triethylamine were added to the reaction device, stirring was started, and then ilaprazole sodium was added. The temperature of the reaction solution was controlled at 15-25° C. and stirred until the solid was completely dissolved to obtain a first mixed solution.
3. The method for preparing ilaprazole according to claim 2, characterized in that: The mass ratio of the purified water, triethylamine and ilaprazole sodium is (6-8):(0.08-0.16):
1.
4. The method for preparing ilaprazole according to claim 1, characterized in that: The step of adding dichloromethane and tartaric acid aqueous solution to the first mixed solution for free extraction and collecting the organic phase comprises: Add dichloromethane to the first mixed solution, cool to 0-10°C, add tartaric acid aqueous solution dropwise, control the temperature of the reaction solution at -5 to 15°C, and after the addition is complete, continue stirring the reaction for 5-25 minutes, control the temperature of the reaction solution at -5 to 15°C, stand for stratification, and collect the organic phase.
5. The method for preparing ilaprazole according to claim 4, characterized in that: The mass ratio of the dichloromethane, the tartaric acid aqueous solution and ilaprazole sodium is (6-8):(2-3):
1.
6. The method for preparing ilaprazole according to claim 4, characterized in that: The mass fraction of the tartaric acid aqueous solution is 12%.
7. The method for preparing ilaprazole according to claim 1, characterized in that: The obtained organic phase is washed, purified water and n-heptane are added for crystallization, and then filtered and dried to obtain ilaprazole, comprising: The obtained organic phase is washed, cooled to -5 to 15°C and stirred, then purified water is added, the temperature is controlled at -5 to 15°C, n-heptane is slowly added dropwise, when 30% to 50% of n-heptane is added dropwise, stirring is performed for 0.5 to 2.5 hours, when a large amount of solid is precipitated, n-heptane is slowly added dropwise, after the addition is completed, stirring and crystallizing for 0.5 to 2.5 hours, the crystallization temperature is controlled at -5 to 15°C, filtered, and dried to obtain ilaprazole; The mass ratio of the purified water, n-heptane and ilaprazole sodium is (2-10):(8-12):
1.
8. The method for preparing ilaprazole according to claim 7, characterized in that: The drying temperature is 30-50℃.
9. The method for preparing ilaprazole according to claim 1, characterized in that: The obtained organic phase is subjected to a washing treatment, comprising: Triethylamine was added to the obtained organic phase, and the reaction solution was kept at -5 to 15°C and stirred for reaction for 5 to 25 minutes. Purified water was then added, and stirring and washing were started. The organic phase was collected by layers.