Synthesis method of trimebutine maleate impurity

Abstract

A synthesis method of trimebutine maleate impurities belongs to the technical field of medicine manufacturing, and comprises the following steps: step 1, adding 3, 4, 5-trimethoxy benzoic acid acyl chloride and toluene into a reactor, mixing, then adding 2-diamino-2-phenyl butanol, dropwise adding triethylamine, and preserving heat; 2, heating the feed liquid for dissolving, cooling after dissolving the feed liquid, adding purified water, stirring, and filtering to obtain an impurity N-demethyltrimebutine crude product; step 3, adding the impurity N-demethylated trimebutine crude product and toluene into the reactor, heating for dissolving, carrying out heat preservation stirring and suction filtration, and leaching a filter cake by using toluene to obtain an impurity N-demethylated trimebutine wet product; and 4, putting the impurity N-demethylated trimebutine wet product obtained in the step 3 into a vacuum drying oven, and drying to obtain the impurity N-demethylated trimebutine. According to the method, the high-purity impurity N-demethylated trimebutine can be generated, so that the impurity N-demethylated trimebutine can be used as an impurity calibration substance in a trimebutine alkali purity detection process.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical manufacturing technology, specifically a method for synthesizing trimebutine maleate impurities. Background Technology

[0002] Trimebutine maleate is primarily used as an antispasmodic drug. It can inhibit K+ channels in cell membranes, thereby increasing the excitability of smooth muscle. Additionally, it can block Ca2+ channels in cell membranes. 2+ Channels that inhibit Ca 2+ Trimebutine maleate, by influx into the gastrointestinal tract, inhibits the excitability of smooth muscle. When gastrointestinal motility is low, it acts on adrenergic receptors, inhibiting adrenaline release and thus increasing motility rhythm. When in a high-motility state, it acts on cholinergic μ and K opioid receptors, inhibiting acetylcholine release and smooth muscle movement, thereby improving hyperactivity. This achieves a bidirectional regulatory effect on gastrointestinal motility. Because trimebutine maleate can regulate gastrointestinal dysfunction through the above pathways, it has become a highly effective drug for irritable bowel syndrome and other gastrointestinal motility disorders (abdominal pain, nausea, vomiting, abdominal distension, etc.).

[0003] When preparing trimebutine maleate using 2-dimethylamino-2-phenylbutanol as the starting material. This method produces the impurity N-demethyltrimebutine. Therefore, it is necessary to determine the liquid phase peak value of the impurity N-demethyltrimebutine during the subsequent purity detection process. Thus, it is now necessary to use high-purity impurity N-demethyltrimebutine as the standard for the impurity N-demethyltrimebutine in the purity detection process of trimebutine base. Summary of the Invention

[0004] This invention provides a method for synthesizing trimebutine maleate impurities to overcome the deficiencies in the prior art.

[0005] This invention is achieved through the following technical solution: A method for synthesizing trimebutine maleate impurity includes the following steps: Step 1: Add 3,4,5-trimethoxybenzoic acid chloride and toluene to the reactor, then add 2-diamino-2-phenylbutanol, heat to 40°C, slowly add triethylamine dropwise, and keep the reaction at this temperature for 2-3 hours after the addition is complete. Step 2: After the reaction is complete, heat the liquid to dissolve it completely. After the liquid is dissolved, cool it down, add purified water and stir. Filter to obtain crude N-demethyltrimebutine, which is used to remove impurities. Step 3: Add crude N-demethyltrimebutine and toluene to the reactor, heat to dissolve, keep warm and stir, filter, and wash the filter cake with toluene to obtain wet N-demethyltrimebutine. Step 4: Place the wet sample of impurity N-demethyltrimebutine obtained in Step 3 into a vacuum drying oven for drying to obtain impurity N-demethyltrimebutine.

[0006] In the method for synthesizing trimebutine maleate impurities as described above, the mass ratio of 3,4,5-trimethoxybenzoic acid chloride, toluene, 2-diamino-2-phenylbutanol and triethylamine in step one is 1:1.81:1:1.05.

[0007] In the method for synthesizing trimebutine maleate impurities as described above, the temperature at which the feed solution is heated to dissolve in step two is 75-85℃.

[0008] In the method for synthesizing trimebutine maleate impurities as described above, the amount of purified water added in step two is 2.4-2.7 times the mass or volume of the feed solution.

[0009] In the above-described method for synthesizing trimebutine maleate impurity, in step two, after the solution is dissolved and cooled to 28-32°C, purified water is added, and the mixture is stirred for 10 minutes at a stirring speed of 200-350 rpm. The solution is then cooled again to 15°C and kept at this temperature for 15 minutes. After the reaction is completed, the mixture is filtered to obtain crude N-demethyltrimebutine impurity.

[0010] In the method for synthesizing trimebutine maleate impurity as described above, the mass ratio of crude N-demethyltrimebutine impurity to toluene in step three is 1:5-6.

[0011] In the method for synthesizing trimebutine maleate impurities as described above, the heating and dissolution temperature in step three is 70-85℃.

[0012] In the method for synthesizing trimebutine maleate impurities as described above, in step three, after heating to dissolve and stirring for 30 minutes, the temperature is lowered to 15-20°C, and crystallization is carried out for 20 minutes before filtration.

[0013] In the method for synthesizing trimebutine maleate impurities as described above, the mass ratio of toluene used for rinsing to filter cake in step three is 1:2.5-3.

[0014] In the method for synthesizing trimebutine maleate impurity as described above, in step four, the vacuum degree of the vacuum drying oven is not less than -0.070 MPa, the oven is cold-pumped for 1 hour, the temperature is raised to 55°C, and the oven is kept warm and dried for 4 hours to obtain the impurity N-demethyltrimebutine.

[0015] The advantages of this invention are: the present invention generates high-purity impurity N-demethyltrimebutine by reacting the acylchlorotoluene solution prepared from 3,4,5-trimethoxybenzoic acid with 2-amino-2-phenylbutanol, thereby enabling it to be used as a standard for the impurity N-demethyltrimebutine in the purity detection process of trimebutine base. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is the purity detection spectrum of Embodiment 1 of the present invention; Figure 2 This is the mass spectrometry detection spectrum of Embodiment 1 of the present invention; Figure 3 This is the 1H NMR spectrum of Example 1 of the present invention; Figure 4 This is the carbon NMR spectrum of Example 1 of the present invention; Figure 5 This is the NMR DOSY diffusion map of Embodiment 1 of the present invention; Figure 6 This is the purity detection spectrum of Example 2 of the present invention; Figure 7 This is the purity detection spectrum of Embodiment 3 of the present invention. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Example 1 Step 1: Add 3,4,5-trimethoxybenzoic acid chloride and toluene to the reactor, then add 2-diamino-2-phenylbutanol. Heat to 40°C and slowly add triethylamine. The mass ratio of 3,4,5-trimethoxybenzoic acid chloride, toluene, 2-diamino-2-phenylbutanol and triethylamine in Step 1 is 1:1.81:1:1.05. After the addition is complete, keep the reaction at this temperature for 2-3 hours. Step 2: After the reaction is complete, heat the liquid to 75°C to dissolve it. After the liquid is dissolved, cool it to 28°C and add purified water. The amount of purified water added is 2.4 times the mass or volume of the liquid. Stir for 10 minutes at a stirring speed of 200 rpm. Cool the liquid to 15°C again and keep it at this temperature for 15 minutes. After the reaction is completed, filter to obtain crude N-demethyltrimebutine. Step 3: Add crude N-demethyltrimebutine and toluene to the reactor. The mass-to-volume ratio of crude N-demethyltrimebutine to toluene is 1:5. Heat to 70°C and dissolve. After dissolving, keep warm and stir for 30 minutes. Then cool to 15°C and keep warm to grow crystals for 20 minutes. Filter and wash the filter cake with toluene. The mass ratio of toluene to filter cake is 1:2.5. Obtain wet N-demethyltrimebutine. Step 4: Place the wet sample of impurity N-demethyltrimebutine obtained in Step 3 into a vacuum drying oven for drying. The vacuum degree of the drying oven should not be less than -0.070 MPa. Perform cold suction for 1 hour, then heat to 55℃ and maintain this temperature for 4 hours to obtain impurity N-demethyltrimebutine. Its purity (e.g., ...) Figure 1 (As shown) is: 99.694%, through Figure 2 The mass spectrometry data shows that in positive ion mode, the measured mass-to-nucleus ratio is 360.18, and the theoretical mass-to-nucleus ratio is 360.17. The deviation between the measured and theoretical values ​​of the sample's eluted peaks and the structure to be confirmed is within ±1.0, which meets the requirements. Therefore, the HPLC-MS information of the sample and the structure to be confirmed is consistent. Figure 3-4 The NMR data shows that the 1H-NMR spectrum contains 13 groups (30 in total) of hydrogen signals in the sample structure, with an integration ratio of 1:2:2:2:1:1:1:7:3:2:2:3:33 from low field to high field. 1 The number of H-NMR spectra does not match the target structure, but when combined with the NMR DOSY diffusion map (such as...), the results are not consistent. Figure 5 As shown in the figure, the peaks at δH of 1.19 ppm and 3.05 ppm are not from the same component as the other peaks, and can be basically identified as other impurities. After removing these two sets of peaks, 1 The H-NMR spectrum contains 11 groups (25 in total) of hydrogen signals, which is consistent with the target structure. At the same time, the peak with δH of 3.85 ppm is a single peak of a methyl group, which overlaps with another group of dq peaks, resulting in a total integral of 7, which is consistent with the target structure.

[0020] Example 2 Step 1: Add 3,4,5-trimethoxybenzoic acid chloride and toluene to the reactor, then add 2-diamino-2-phenylbutanol. Heat to 40°C and slowly add triethylamine. The mass ratio of 3,4,5-trimethoxybenzoic acid chloride, toluene, 2-diamino-2-phenylbutanol and triethylamine in Step 1 is 1:1.81:1:1.05. After the addition is complete, keep the reaction at this temperature for 2-3 hours. Step 2: After the reaction is complete, heat the liquid to 85°C to dissolve it. After the liquid is dissolved, cool it to 32°C and add purified water. The amount of purified water added is 2.7 times the mass or volume of the liquid. Stir for 10 minutes at a stirring speed of 350 rpm. Cool the liquid to 15°C again and keep it at this temperature for 15 minutes. After the reaction is completed, filter to obtain crude N-demethyltrimebutine. Step 3: Add crude N-demethyltrimebutine and toluene to the reactor. The mass-to-volume ratio of crude N-demethyltrimebutine to toluene is 1:6. Heat to 85°C to dissolve the impurity. After dissolving, keep the temperature and stir for 30 minutes. Then, cool to 20°C and keep the temperature to allow crystals to grow for 20 minutes. Filter the mixture and wash the filter cake with toluene. The mass ratio of toluene to filter cake is 1:3. This yields wet N-demethyltrimebutine. Step 4: Place the wet sample of impurity N-demethyltrimebutine obtained in Step 3 into a vacuum drying oven for drying. The vacuum degree of the drying oven should not be less than -0.070 MPa. Perform cold suction for 1 hour, then heat to 55℃ and maintain this temperature for 4 hours to obtain impurity N-demethyltrimebutine. Its purity (e.g., ...) Figure 6 As shown, the percentage is 99.159%.

[0021] Example 3 Step 1: Add 3,4,5-trimethoxybenzoic acid chloride and toluene to the reactor, then add 2-diamino-2-phenylbutanol. Heat to 40°C and slowly add triethylamine. The mass ratio of 3,4,5-trimethoxybenzoic acid chloride, toluene, 2-diamino-2-phenylbutanol and triethylamine in Step 1 is 1:1.81:1:1.05. After the addition is complete, keep the reaction at this temperature for 2-3 hours. Step 2: After the reaction is complete, heat the liquid to 80°C to dissolve it. After the liquid is dissolved, cool it to 30°C and add purified water. The amount of purified water added is 2.5 times the mass or volume of the liquid. Stir for 10 minutes at a stirring speed of 280 rpm. Cool the liquid to 15°C again and keep it at this temperature for 15 minutes. After the reaction is complete, filter to obtain crude N-demethyltrimebutine. Step 3: Add crude N-demethyltrimebutine and toluene to the reactor. The mass-to-volume ratio of crude N-demethyltrimebutine to toluene is 1:5.5. Heat to 80℃ to dissolve the impurity. After dissolving, keep the temperature and stir for 30 minutes. Then, cool to 18℃ and keep the temperature to allow crystals to grow for 20 minutes. Filter the mixture and wash the filter cake with toluene. The mass ratio of toluene to filter cake is 1:2.7. Obtain wet N-demethyltrimebutine. Step 4: Place the wet sample of impurity N-demethyltrimebutine obtained in Step 3 into a vacuum drying oven for drying. The vacuum degree of the drying oven should not be less than -0.070 MPa. Perform cold suction for 1 hour, then heat to 55℃ and maintain this temperature for 4 hours to obtain impurity N-demethyltrimebutine. Its purity (e.g., ...) Figure 7 As shown in the figure, the percentage is 98.183%.

[0022] As shown in Examples 1-3, the impurity N-demethyltrimebutine prepared by the present invention has high purity and meets the requirements for use as a calibrator for impurity N-demethyltrimebutine in the purity detection process of trimebutine base.

[0023] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing trimebutine maleate impurities, characterized in that: Includes the following steps: Step 1: Add 3,4,5-trimethoxybenzoic acid chloride and toluene to the reactor, then add 2-diamino-2-phenylbutanol, heat to 40°C, slowly add triethylamine dropwise, and keep the reaction at this temperature for 2-3 hours after the addition is complete. Step 2: After the reaction is complete, heat the liquid to dissolve it completely. After the liquid is dissolved, cool it down, add purified water and stir. Filter to obtain crude N-demethyltrimebutine, which is used to remove impurities. Step 3: Add crude N-demethyltrimebutine and toluene to the reactor, heat to dissolve, keep warm and stir, filter, and wash the filter cake with toluene to obtain wet N-demethyltrimebutine. Step 4: Place the wet sample of impurity N-demethyltrimebutine obtained in Step 3 into a vacuum drying oven for drying to obtain impurity N-demethyltrimebutine.

2. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: The mass ratio of 3,4,5-trimethoxybenzoic acid chloride, toluene, 2-diamino-2-phenylbutanol and triethylamine in step one is 1:1.81:1:1.

05.

3. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: In step two, the temperature at which the liquid is heated to dissolve is 75-85℃.

4. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: In step two, the amount of purified water added is 2.4-2.7 times the mass or volume of the liquid.

5. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: In step two, after the solution is dissolved, it is cooled to 28-32℃, purified water is added, and the mixture is stirred for 10 minutes at a speed of 200-350 rpm. The solution is then cooled to 15℃ again and kept at this temperature for 15 minutes. After the reaction is completed, the mixture is filtered to obtain crude N-demethyltrimebutine.

6. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: The mass ratio of crude N-demethyltrimebutine to toluene in step three is 1:5-6.

7. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: The heating temperature for step three is 70-85℃.

8. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: In step three, after heating and dissolving, the mixture is kept at this temperature and stirred for 30 minutes. Then, the temperature is lowered to 15-20°C, and the mixture is kept at this temperature for 20 minutes to allow crystals to grow before being filtered.

9. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: In step three, the mass ratio of toluene used for rinsing to filter cake is 1:2.5-3.

10. The method for synthesizing trimebutine maleate impurities according to claim 1, characterized in that: In step four, the vacuum degree of the vacuum drying oven is not less than -0.070 MPa. After cold evacuation for 1 hour, the temperature is raised to 55°C and kept warm for 4 hours to obtain the impurity N-demethyltrimebutine.

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