Preparation method of amisulpride impurity
By introducing a hydrolysis reaction during the preparation of ammoniasulfonamide impurities, the problems of low purity and yield in existing technologies have been solved, achieving efficient preparation of high-purity ammoniasulfonamide impurities, which is suitable for industrial production and quality research.
Patent Information
- Application Number
- CN202511165198.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-20
- Publication Date
- 2025-11-18
AI Technical Summary
Existing methods for preparing ammonia sulfadiazine impurities suffer from low purity and low yield, and traditional separation methods are time-consuming, labor-intensive, and costly to purchase standard products.
The optimization process uses hydrolysis as a key intermediate. After oxidation, hydrolysis is performed to remove the protecting group, improve the reactivity of the compound, and then a condensation reaction is carried out to prepare the ammoniasulfapyr impurity.
This significantly improved the purity and yield of impurities in amisulpride, making it suitable for industrial production, reducing costs, and providing high-purity impurity compounds for quality studies of amisulpride.
Smart Images
Figure CN120965546A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of compound synthesis, and particularly relates to a preparation method of an amisulpride impurity. BACKGROUND
[0002] Schizophrenia is a complex and severe mental disorder, usually onset in late adolescence and early adulthood and high recurrence rate. 40%~50% of schizophrenic patients relapse after the first year of treatment. This shows the difficulty of treating schizophrenia, and the treatment of schizophrenia puts high requirements on the efficacy, adverse reactions and standard application of drugs, and it is urgent to improve the patient compliance and establish a good doctor-patient relationship.
[0003] Amisulpride is developed by Sanofi, which is a selective dopamine D2 and D3 receptor antagonist, mainly used for schizophrenia, and has been marketed in many countries around the world. It is the second generation of atypical antipsychotic drugs, which greatly improves the patient compliance, reduces the recurrence rate and improves the quality of life of patients due to less adverse reactions, and is favored by the medical field. In September 2009, Sanofi developed amisulpride tablets entered China, and the trade name is “Solian”.
[0004] Amisulpride is a derivative of benzamide and also a new generation of atypical antipsychotic drug. At a low dose, it can relieve negative symptoms, and at a high dose, it can treat positive symptoms. It is considered to have the characteristics of dual DNA receptor blocking. It can improve the positive and negative symptoms of patients. And its antidepressant effect is not only stronger than haloperidol, but also better than risperidone.
[0005] The synthesis route of amisulpride is as follows:
[0006] When amisulpride is prepared in this route, impurity I may be produced in the amisulpride product due to incomplete reaction of the starting material, and the impurity is very similar to amisulpride in structure, and the removal rate is very low in the subsequent impurity removal process. Therefore, in the development of amisulpride analysis method and the subsequent finished product inspection process, the standard of the impurity is needed for positioning and quantitative research of the impurity in amisulpride, and therefore a large amount of impurity standard is needed. However, the cost of purchasing the impurity standard is high. We try to use the traditional impurity separation method to separate the impurity in the amisulpride bulk drug, but the yield and content of the target product are low and the time and labor are wasted. Therefore, it is of great significance to develop a preparation method of amisulpride impurity.
[0007]
[0008] Amisulpride
[0009] Amisulpride impurity SUMMARY In view of this, the present application provides a preparation method of amisulpride impurity. The preparation method provided by the present application effectively makes up for the defects of direct condensation in the prior art by selecting hydrolysis as the optimization link of the key intermediate, thereby realizing the dual improvement of the purity and yield of the amisulpride impurity.
[0010] To achieve the above-mentioned application purposes, the present application adopts the following technical solutions: The present application provides a preparation method of amisulpride impurity, comprising the following steps: Oxidizing the compound shown in formula 1 with an oxidizing agent to obtain a compound shown in formula 2; Hydrolyzing the compound shown in formula 2 to obtain a compound shown in formula 3; Condensing the compound shown in formula 3 with N-ethyl-2-aminomethylpyrrolidine to obtain the amisulpride impurity shown in formula 4;
[0011] Formula 1;
[0012] Formula 2;
[0013] Formula 3;
[0014] Formula 4.
[0015] At present, the amisulpride impurity The common preparation method includes condensing Oxidizing under the condition of an oxidizing agent, and then further condensing the intermediate to obtain the amisulpride impurity. However, the yield and purity of the amisulpride impurity prepared by using the above synthesis method are not ideal. Therefore, it is necessary to provide a preparation method of amisulpride impurity to solve the problems of low purity and low yield in the preparation of the existing amisulpride impurity.
[0016] The method for preparing amisulpride impurities provided by this invention involves hydrolyzing the compound shown in Formula 2 obtained after oxidation. This hydrolysis removes the protecting group from the compound shown in Formula 2, eliminating steric hindrance that interferes with the condensation reaction and significantly improving the reactivity of the compound shown in Formula 3 with N-ethyl-2-aminomethylpyrrolidine. This greatly enhances the selectivity and efficiency of the condensation reaction, reducing the formation of non-target byproducts, increasing the purity of the target product, accelerating the main reaction process, and improving the yield of the target product. By selecting hydrolysis as a key intermediate, this invention effectively overcomes the shortcomings of direct condensation in existing technologies, achieving a dual improvement in the purity and yield of amisulpride impurities.
[0017] Preferably, the preparation method of the amisulpride impurity specifically includes the following steps: S1. Add the compound shown in Formula 1 and the oxidant to the first solvent and carry out the oxidation reaction at 15~35℃ to obtain the compound shown in Formula 2. S2. Add the compound shown in Formula 2 and a strong base to water and carry out a hydrolysis reaction at 15~40℃ to obtain the compound shown in Formula 3. S3. The compound shown in Formula 3, the condensing agent, the organic base and N-ethyl-2-aminomethylpyrrolidine are added to the second solvent and a condensation reaction is carried out at 25~30℃ to obtain the ammoniasulfapyr impurity shown in Formula 4.
[0018] This invention further defines the preparation method of amisulpride impurities, which is beneficial to further improve the purity and yield of amisulpride impurities.
[0019] Preferably, in S1, the oxidant is at least one of 28-32 wt% hydrogen peroxide aqueous solution or 9-12 wt% sodium hypochlorite aqueous solution.
[0020] More preferably, in S1, the oxidant is a 30wt% hydrogen peroxide aqueous solution.
[0021] Preferably, in S1, the first solvent is acetone.
[0022] The preferred solvent facilitates thorough mixing of the reactants, improves the utilization rate of the reactants, reduces the occurrence of side reactions, and also helps the products obtained from each step of the reaction to dissolve in the reaction system, ensuring the smooth progress of the next step of the reaction.
[0023] Preferably, in S1, the mass ratio of the compound shown in Formula 1 to the oxidant is 1:(0.5~2).
[0024] By limiting the proportions of the materials, the reaction can be ensured to occur fully, thereby improving the purity and yield of the target product.
[0025] More preferably, in S1, the mass ratio of the compound shown in Formula 1 to the oxidant is 1:1.5.
[0026] Preferably, in S1, the temperature of the oxidation reaction is 20°C.
[0027] This invention further limits the reaction temperature, which can reduce the occurrence of side reactions and improve the purity and yield of the target product while ensuring that the reaction occurs fully.
[0028] Preferably, in S1, the oxidation reaction takes 1 to 6 hours.
[0029] More preferably, in S1, the oxidation reaction takes 2 hours.
[0030] Preferably, in S1, the mass-to-volume ratio of the compound shown in Formula 1 to the first solvent is 1 g: (2~10) mL.
[0031] More preferably, in S1, the mass-to-volume ratio of the compound shown in Formula 1 to the first solvent is 1 g: 5 mL.
[0032] For example, in S1, the reaction system after the reaction is completed is crystallized at 15~35°C, filtered, and then the filtrate is purified by silica gel column chromatography using dichloromethane and methanol to obtain the compound shown in Formula 2.
[0033] Preferably, in S2, the strong base is at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
[0034] More preferably, in S2, the strong base is sodium hydroxide.
[0035] Preferably, in S2, the molar ratio of the compound shown in Formula 2 to the strong base is 1:(1~1.05).
[0036] By limiting the proportions of the materials, the reaction can be ensured to occur fully, thereby improving the purity and yield of the target product.
[0037] Preferably, in S2, the mass ratio of the compound shown in Formula 2 to water is 1:(3~4).
[0038] More preferably, in S2, the temperature of the hydrolysis reaction is 35°C.
[0039] The optimal reaction temperature can reduce the occurrence of side reactions and improve the purity and yield of the target product while ensuring that the reaction occurs fully.
[0040] Preferably, in S2, the hydrolysis reaction takes 1 to 6 hours.
[0041] More preferably, in S2, the hydrolysis reaction takes 3 hours.
[0042] For example, in S2, the pH of the reaction system after the reaction is completed is adjusted to 2-3 with hydrochloric acid, crystallization is carried out for 2 hours, and then filtered to obtain the compound shown in Formula 3.
[0043] Preferably, in S3, the condensing agent is at least one of ethyl chloroformate, N,N'-carbonyldiimidazole (CDI) or 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU).
[0044] Preferably, in S3, the organic base is triethylamine.
[0045] Preferably, in S3, the second solvent is at least one of dichloromethane, acetone, or N,N-dimethylformamide (DMF).
[0046] More preferably, in S3, the second solvent is dichloromethane.
[0047] Preferably, in S3, the molar ratio of the compound shown in Formula 3 to the condensing agent is 1:(1~1.05).
[0048] Preferably, in S3, the molar ratio of the compound shown in Formula 3 to the organic base is 1:(1~1.05).
[0049] Preferably, in S3, the molar ratio of the compound shown in Formula 3 to N-ethyl-2-aminomethylpyrrolidine is 1:(1.05~1.1).
[0050] Preferably, in S3, the mass-to-volume ratio of the compound shown in Formula 3 and the second solvent is 1 g: (5~8) mL.
[0051] Preferably, in S3, the condensation reaction takes 3 to 5 hours.
[0052] For example, in S3, the reaction system after the reaction is completed is washed with water, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure. The concentrate is added to a crystallization solvent and crystallized at 20-25°C. After filtration, the ammoniasulfamethoxazole impurity shown in Formula 4 is obtained.
[0053] For example, the crystallization solvent is isopropanol, methanol or ethanol, preferably isopropanol.
[0054] For example, the crystallization time is 2 to 2.5 hours.
[0055] The method for preparing ammoniasulfapyridine impurities provided by this invention uses mild reaction conditions, simple and readily available reagents, and inexpensive reagents. It can also produce impurity compounds with both high purity and high yield, providing technical support for the quality research of ammoniasulfapyridine. The method provided by this invention overcomes the problem of low production efficiency in the original preparation of ammoniasulfapyridine impurities and is suitable for industrial production. Attached Figure Description
[0056] Figure 1 This is a partially magnified NMR image of compound 1 prepared in Example 1 of the present invention; Figure 2 This is a partially magnified NMR image of compound 1 prepared in Example 1 of the present invention; Figure 3 This is a partially magnified NMR image of compound 2 prepared in Example 1 of the present invention; Figure 4 This is a partially magnified NMR image of compound 2 prepared in Example 1 of the present invention; Figure 5 The NMR spectrum is shown for the ammonia sulfadiazine impurity prepared in Example 1 of this invention. Detailed Implementation
[0057] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0058] The inventors detected an impurity of amisulpride in a product manufactured by Hebei Longhai Pharmaceutical Co., Ltd., with batch number 220706. The structural formula of the amisulpride impurity is as follows: .
[0059] Example 1 This invention provides a method for preparing an impurity of amisulpride, comprising the following steps: S100, add to a 100mL four-necked flask 10 g of acetone (50 mL) and 30 wt% hydrogen peroxide solution (7 g) were added at 0 °C. The temperature was controlled at 20 °C and the mixture was stirred for 2 h. After the reaction was completed, 10 wt% sodium thiosulfate solution (100 mL) was added and crystallization was carried out for 2 h. The mixture was filtered to obtain 9.77 g of compound 1, with a yield of 91.6% and a purity of 84.62%. After purification by silica gel column chromatography, 9.15 g of white solid was obtained, with a yield of 93.65% and a purity of 99.66%.
[0060]
[0061] Compound 1 S200. Add purified compound 1 (9g, 0.03mol) and sodium hydroxide (1.45g, 0.036mol) to a 100mL reaction flask, then add purified water (27g), maintain at 35℃, stir for 3h, after the reaction is complete, add hydrochloric acid to adjust the pH to 2~3, crystallize at 20℃ for 2h, filter, and obtain compound 2 8.13g, yield 90%, purity 99.36%.
[0062]
[0063] Compound 2 In reaction S300, compound 2 (8 g, 0.031 mol), dichloromethane (40 mL), ethyl chloroformate (3.47 g, 0.032 mol), triethylamine (3.29 g, 0.032 mol), and N-ethyl-2-aminomethylpyrrolidine (4.4 g, 0.034 mol) were added to a 100 mL reaction flask. The mixture was stirred at 25 °C for 3 h. After the reaction was completed, the mixture was washed twice with 50 mL of purified water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and 40 mL of isopropanol was added until completely dissolved. The mixture was then slowly cooled to 25 °C and allowed to crystallize for 2 h. After filtration, 10.15 g of amisulpride impurity was obtained, with a yield of 92.72% and a purity of 100.00%.
[0064]
[0065] Ammoniasulfamethoxazole Impurities Example 2 This invention provides a method for preparing an impurity of amisulpride, comprising the following steps: S100, add to a 100mL four-necked flask 10 g of acetone (20 mL) and 30 wt% hydrogen peroxide solution (7 g) were added at 0 °C. The temperature was controlled at 30 °C and the mixture was stirred for 5 h. After the reaction was completed, 10 wt% sodium thiosulfate solution (100 mL) was added and crystallization was carried out for 2 h. The mixture was filtered to obtain 9.56 g of compound 1, with a yield of 89.66% and a purity of 55.68%. After purification by silica gel column chromatography, 9.1 g of white solid was obtained, with a yield of 95.5% and a purity of 99.75%.
[0066]
[0067] Compound 1 S200. Add purified compound 1 (5.5 g, 0.021 mol) and potassium hydroxide (1.18 g, 0.021 mol) to a 100 mL reaction flask, then add purified water (22 g), maintain at 15 °C, stir for 2 h, after the reaction is complete, add hydrochloric acid to adjust the pH to 2-3, crystallize at 20 °C for 2 h, filter, and obtain compound 2 4.75 g, yield 86.03%, purity 99.56%.
[0068]
[0069] Compound 2 In reaction S300, compound 2 (4.5 g, 0.017 mol), acetone (36 mL), CDI (2.82 g, 0.017 mol), triethylamine (1.76 g, 0.017 mol), and N-ethyl-2-aminomethylpyrrolidine (2.23 g, 0.017 mol) were added to a 100 mL reaction flask. The mixture was stirred at 30 °C for 5 h. After the reaction was completed, the mixture was washed twice with 50 mL of purified water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and 40 mL of isopropanol was added until completely dissolved. The mixture was then slowly cooled to 25 °C and allowed to crystallize for 2 h. After filtration, 5.42 g of amisulpride impurity was obtained, with a yield of 88.02% and a purity of 99.85%.
[0070]
[0071] Ammonia sulfadiazine impurities Example 3 This invention provides a method for preparing an impurity of amisulpride, comprising the following steps: S100, add to a 100mL four-necked flask 10 g of acetone (90 mL) and 10 wt% sodium hypochlorite aqueous solution (18 g) were added at 0 °C. The temperature was controlled at 35 °C, and the mixture was stirred for 3 h. After the reaction was completed, 10 wt% sodium thiosulfate aqueous solution (100 mL) was added, and crystallization was carried out for 2 h. The mixture was filtered to obtain 9.64 g of compound 1, with a yield of 90.41% and a purity of 69.56%. After purification by silica gel column chromatography, 8.4 g of white solid was obtained, with a yield of 87.14% and a purity of 99.42%.
[0072]
[0073] Compound 1 S200. In a 100 mL reaction flask, add purified compound 1 (6 g, 0.023 mol) and lithium hydroxide (0.56 g, 0.023 mol), then add purified water (24 g), maintain at 40 °C, stir for 3 h, and after the reaction is complete, add hydrochloric acid to adjust the pH to 2-3, crystallize at 20 °C for 2 h, filter, and obtain compound 2 5.39 g, yield 89.48%, purity 99.26%.
[0074]
[0075] Compound 2 In reaction S300, compound 2 (4.5 g, 0.017 mol), DMF (31.5 mL), HATU (6.62 g, 0.017 mol), triethylamine (1.76 g, 0.017 mol), and N-ethyl-2-aminomethylpyrrolidine (2.23 g, 0.017 mol) were added to a 100 mL reaction flask. The mixture was stirred at 30 °C for 5 h. After the reaction was completed, the mixture was washed twice with 50 mL of purified water, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and 40 mL of isopropanol was added until completely dissolved. The mixture was then slowly cooled to 25 °C and allowed to crystallize for 2 h. After filtration, 5.63 g of amisulpride impurity was obtained, with a yield of 91.43% and a purity of 99.63%.
[0076]
[0077] Ammoniasulfamethoxazole Impurities The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A method for preparing an impurity of ammoniasulfonamide, characterized in that, Includes the following steps: The compound shown in Formula 1 is subjected to an oxidation reaction with an oxidizing agent to obtain the compound shown in Formula 2. Hydrolysis of the compound shown in Formula 2 yields the compound shown in Formula 3. The compound shown in Formula 3 was condensed with N-ethyl-2-aminomethylpyrrolidine to obtain the ammoniasulfapyridine impurity shown in Formula 4. Formula 1; Formula 2; Formula 3; Formula 4.
2. The method for preparing the ammoniasulfonamide impurity as described in claim 1, characterized in that, Specifically, the steps include the following: S1. Add the compound shown in Formula 1 and the oxidant to the first solvent and carry out the oxidation reaction at 15~35℃ to obtain the compound shown in Formula 2. S2. Add the compound shown in Formula 2 and a strong base to water and carry out a hydrolysis reaction at 15~40℃ to obtain the compound shown in Formula 3. S3. The compound shown in Formula 3, the condensing agent, the organic base and N-ethyl-2-aminomethylpyrrolidine are added to the second solvent and a condensation reaction is carried out at 25~30℃ to obtain the ammoniasulfapyr impurity shown in Formula 4.
3. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S1, the oxidant is at least one of 28-32 wt% hydrogen peroxide aqueous solution or 9-12 wt% sodium hypochlorite aqueous solution; and / or In S1, the first solvent is acetone.
4. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S1, the mass ratio of the compound shown in Formula 1 to the oxidant is 1:(0.5~2); and / or In S1, the oxidation reaction takes 1-6 hours; and / or In S1, the mass-to-volume ratio of the compound shown in Formula 1 to the first solvent is 1 g: (2~10) mL.
5. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S2, the strong base is at least one of sodium hydroxide, potassium hydroxide, or lithium hydroxide.
6. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S2, the molar ratio of the compound shown in Formula 2 to the strong base is 1:(1~1.05); and / or In S2, the mass ratio of the compound shown in Formula 2 to water is 1:(3~4).
7. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S2, the hydrolysis reaction takes 1 to 6 hours.
8. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S3, the condensing agent is at least one selected from ethyl chloroformate, N,N'-carbonyldiimidazole, or 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; and / or In S3, the organic base is triethylamine; and / or In S3, the second solvent is at least one of dichloromethane, acetone, or N,N-dimethylformamide.
9. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S3, the molar ratio of the compound shown in Formula 3 to the condensing agent is 1:(1~1.05); and / or In S3, the molar ratio of the compound shown in Formula 3 to the organic base is 1:(1~1.05); and / or In S3, the molar ratio of the compound shown in Formula 3 to N-ethyl-2-aminomethylpyrrolidine is 1:(1.05~1.1); and / or In S3, the mass-to-volume ratio of the compound shown in Formula 3 and the second solvent is 1 g: (5~8) mL.
10. The method for preparing the ammoniasulfonamide impurity as described in claim 2, characterized in that, In S3, the condensation reaction takes 3 to 5 hours.