Preparation of 4-(dipropyl sulfamoyl)-N, N-dipropyl benzamide impurity reference substance
Through the preparation of probenecidyl chloride and the synthesis of 4-(dipropysulfamoyl)-N,N-dipropylbenzamide, combined with water as the solvent of the reaction system and purified by repeated adjustment of acid and alkalinity, the problem of lack of high-purity preparation methods in the prior art was solved, and the preparation of high-purity impurity reference products was achieved, and the quality control ability of probenecidyl (sodium) products was improved.
Patent Information
- Application Number
- CN202411788042.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-06
- Publication Date
- 2025-03-21
AI Technical Summary
The lack of a high-purity preparation method for 4-(dipropysulfamoyl)-N,N-dipropybenzamide impurities in the prior art has resulted in increasing the difficulty of quality control of probenecid (sodium) raw materials and preparations.
Through the preparation of probenecisilyl chloride and the synthesis of 4-(dipropylamylamino)-N,N-dipropylbenzamide, water is combined as the solvent of the reaction system, and purification is carried out by repeatedly adjusting the acid and alkalinity, avoiding the use of organic solvents, and the preparation of high-purity impurity reference products is achieved.
The high purity preparation of 4-(dipropysulfamoyl)-N,N-dipropybenzamide is achieved, and the quality standards and technical specifications as impurity reference materials are met, and the effectiveness, safety and quality controllability of probenecid (sodium) products are improved.
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Figure CN119661406A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the preparation of a 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide impurity reference substance, in particular to a method for purifying probenecid (sodium) impurity 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide, and the obtained impurity reference substance is used for the detection and quality control of probenecid sodium raw materials and preparations. Background Art
[0002] Probenecid is a white crystalline powder and is an anti-gout drug and an adjuvant drug for antibiotic treatment. Probenecid sodium is its sodium salt, a white crystalline powder, odorless, slightly bitter, and very soluble in water. In addition to its role in treating chronic gout, probenecid can also significantly optimize the pharmacokinetic properties of various β-lactam antibiotics. Currently, a compound preparation consisting of probenecid and ampicillin has been used clinically. Combined use of probenecid (sodium) and various β-lactam antibiotics [1] , which can not only significantly reduce the dosage of corresponding antibiotics, thereby reducing the incidence of adverse reactions to antibiotics, but also increase the compliance of antibiotic treatment and reduce the selection of drug-resistant bacteria. The development of the combined use of probenecid (sodium) and various β-lactam antibiotics has extremely important clinical value and also has a very positive social significance for reducing the use of antibiotics and alleviating bacterial resistance.
[0003] Reference standards (also called reference substances) refer to standard substances used for drug identification, inspection and content determination. They are special measuring tools for testing drug quality and have a direct impact on the accuracy and reproducibility of test results. For most chemical drugs, reference standards are an integral part of the drug quality control system and must be used throughout the life cycle of the drug. The quality standards (such as purity, content, residual solvents, inorganic impurities, stability, etc.) and technical requirements of reference substances must meet the relevant specifications for drug development and registration. [2] As an impurity reference substance, the purity is generally required to be no less than 98% and the content is no less than 95%. Referring to the "9102 Guidelines for the Analysis of Impurities in Pharmaceuticals" in the "Chinese Pharmacopoeia" (2020 Edition, Part IV), the ICH Guidelines for Impurities in New APIs (Q3A) and Impurities in New Preparations (Q3B), the research and control of impurities in drugs, especially innovative drugs, is one of the important contents of pharmaceutical research. Any impurities in drugs will affect the effectiveness, safety and quality controllability of drugs; all impurities should be quantitatively and qualitatively analyzed, and safety limits should be established to ensure drug safety.
[0004] There are very few impurities of probenecid (sodium) included in the pharmacopoeias of various countries. Only the European Pharmacopoeia (EP / BP) has controls on specific impurities. The impurity control limits of other pharmacopoeias are very loose, among which EP / BP impurity C, namely 4-(dipropylaminosulfonyl)-N, N-dipropylbenzamide, is shown in the following table:
[0005] Probenecid impurities are included in the pharmacopoeias of various countries
[0006]
[0007] Bo Jincai [3] et al. prepared four genotoxic impurities of probenecid sodium, but the preparation of 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide impurity has not been reported. Therefore, it is necessary to develop a high-purity preparation and purification method of 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide as an impurity reference substance. Summary of the invention
[0008] The invention aims to provide a preparation method for a 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide impurity reference substance. The prepared and purified product can be used as a reference substance for the impurity and is used for the detection and quality control of probenecid (sodium) raw materials and preparations, and has a very important application in improving the effectiveness, safety and quality controllability of probenecid (sodium) series products.
[0009] The technical solution of the present invention is achieved by preparing a 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide impurity reference substance, characterized in that the specific steps are as follows:
[0010] 1. Preparation of Probenecidyl Chloride
[0011]
[0012] 1. Add probenecid and DMF (N, N-dimethylformamide) to thionyl chloride in proportion, stir and heat, and keep warm for reaction; the weight ratio of probenecid, thionyl chloride and DMF is 1:1-2:0.2-0.4;
[0013] 2. The reaction temperature is 40-60°C, and the reaction is kept warm for 2-4 hours;
[0014] 3. The reaction solution was distilled under reduced pressure at 40-50°C until obvious crystals precipitated on the bottle wall, the distillation was terminated, the temperature was lowered and crystallization was carried out, and the precipitate was the intermediate 4-(dipropylsulfamoyl)-benzoyl chloride (hereinafter referred to as probenecidyl chloride).
[0015] 2. Preparation of 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide
[0016]
[0017] 1. Add purified water to dipropylamine in proportion, add probenecidyl chloride in portions under stirring and cooling protection, and keep warm for reaction after adding; the weight ratio of probenecidyl chloride to dipropylamine is 1:3-4, and the amount of water is 5-10% of dipropylamine;
[0018] 2. The reaction temperature is 10-20°C and the reaction time is 1-2h;
[0019] 3. Obtain the product 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide reaction solution.
[0020] 3. Product Purification
[0021]
[0022] 1. The pH of the reaction solution is adjusted to alkaline with sodium hydroxide solution, and the feed solution is extracted with purified water, and the upper organic phase is taken. Hydrochloric acid is added to the organic phase to precipitate solids, which are filtered and the filter cake is washed with purified water, and then dried at low temperature to obtain the product 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide;
[0023] 2. The solubility of the sodium hydroxide solution is 10%-15%, and the pH value of the reaction solution is adjusted to 9-10, 40-50°C
[0024] Stir for 20-30 minutes and let stand to separate into layers;
[0025] 3. Remove the lower aqueous phase, take the upper organic phase, add 2-3 times the amount of dipropylamine in purified water in batches, stir and wash the organic phase at room temperature for 10-20 minutes, and let it stand to separate;
[0026] 4. Take the upper yellow organic phase again, slowly add 10-15% dilute hydrochloric acid, stir continuously, adjust the pH value to 3-4, the yellow organic phase gradually disappears, and an off-white solid precipitates;
[0027] 5. Filter the reaction solution and rinse the filter cake with purified water until the pH of the washing solution is 5-6.
[0028] 6. Collect the filter cake and dry it at 30-35°C to obtain 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide.
[0029] Compared with the prior art, the present invention has outstanding technical advantages and positive effects:
[0030] 1. In the product purification process, water is used as the solvent of the reaction system, and the solubility differences of the product, each reactant, and the intermediates and by-reaction products in the reaction process are cleverly utilized. By repeatedly adjusting the acidity and alkalinity of the reaction system, the residual reactants, intermediates, and by-products are removed, achieving the purpose of product separation and purification.
[0031] 2. In the acyl chlorination and amidation preparation process, thionyl chloride and di-n-propylamine are both reactants and solvents of the reaction system, thus avoiding the use of other organic solvents.
[0032] 3. No organic solvent was used in the entire subsequent purification process.
[0033] 4. The products prepared and purified by the present invention meet the quality standards and technical specifications for impurity reference substances in terms of purity, content, residual solvents, inorganic impurities and other quality indicators. BRIEF DESCRIPTION OF THE DRAWINGS
[0034] Figure 1 Probenecid structure.
[0035] Figure 2 The present invention discloses a self-made impurity 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide with the structural formula. In the research project of the present invention, the impurity is named Z17, hereinafter referred to as Z17.
[0036] Figure 3 The invention discloses a self-made impurity Z17 HPLC purity detection spectrum.
[0037] Figure 4 The self-made impurity Z17 reference substance of the present invention is used for testing impurities in probenecid sodium raw material medicine.
[0038] Figure 5 Nuclear magnetic resonance of the homemade impurity Z17 of the present invention 1 H-MNR.
[0039] Figure 6 The invention's homemade impurity Z17 nuclear magnetic resonance 13 CNMR spectrum. DETAILED DESCRIPTION
[0040] Embodiment 1:
[0041] (I) Preparation of homemade impurity Z17 intermediate
[0042] 1. Weigh 20g of probenecid into a 250ml reaction bottle, add 6ml of DMF into the reaction bottle, start stirring. Then slowly add 20g of dichlorothionyl, connect the four-necked bottle with a PTFE anchor stirrer, a condenser, a thermometer, and a water bath; the condenser is connected to the alkali liquid tail gas absorption device.
[0043] 2. Raise the temperature to 50°C while stirring, keep the temperature for 2 hours, and the reaction is complete.
[0044] 3. The temperature of the liquid was lowered to 40°C, and vacuum distillation was started until obvious crystals were precipitated on the bottle wall, and the vacuum distillation was completed.
[0045] 4. The feed liquid was cooled to 15°C to obtain the intermediate 4-(dipropylsulfamoyl)-benzoyl chloride (hereinafter referred to as probenecidyl chloride).
[0046] (II) Preparation of homemade impurity Z17
[0047] 5. Weigh 35 g of dipropylamine into a 500 ml four-necked reaction bottle, start stirring, and connect the four-necked bottle to a PTFE anchor stirrer, a condenser, and a thermometer.
[0048] 6. Control the reaction temperature at 15°C, slowly add 10 g of probenecidyl chloride into the reaction bottle and stir.
[0049] 7. Stir the reaction for half an hour, add 1.75 g of purified water as a catalyst to the reaction bottle, and continue stirring for 1 hour to obtain the homemade impurity Z174-(dipropylaminosulfonyl)-N,N-dipropylbenzamide reaction solution.
[0050] (III) Purification
[0051] 8. Slowly add 10% sodium hydroxide solution to the homemade impurity Z17 reaction solution, heat and stir at 40°C for 30 minutes, and adjust the pH to 9-10.
[0052] 9. Transfer to a separatory funnel, let stand to separate the layers, take the upper yellow organic phase and transfer it to a new 500 ml reaction bottle.
[0053] 10. Add 105 ml of purified water to the reaction bottle, stir and wash with water for 10 minutes at room temperature, and let it stand to separate the layers.
[0054] 11. Take the upper yellow organic phase, transfer it to a 250ml reaction bottle, and start stirring.
[0055] 12. Slowly add 10% dilute hydrochloric acid to the reaction bottle, stirring continuously, and adjust the pH value to 3. The yellow organic phase gradually disappears and an off-white solid precipitates.
[0056] 13. Filter the liquid in the reaction bottle and rinse the filter cake with purified water to pH 5-6.
[0057] 14. Collect the filter cake and dry it at 30°C to obtain 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide.
[0058] Embodiment 2:
[0059] (I) Preparation of homemade impurity Z17 intermediate
[0060] 1. Weigh 20g of probenecid into a 250ml reaction bottle, add 8ml of DMF into the reaction bottle, start stirring. Then slowly add 40g of thionyl chloride, connect the four-necked bottle with a PTFE anchor stirrer, a condenser, a thermometer, and a water bath; the condenser is connected to the alkali liquid tail gas absorption device.
[0061] 2. Raise the temperature to 60°C while stirring, and keep the reaction for 3 hours. The reaction is complete.
[0062] 3. The temperature of the feed liquid is reduced to 45°C, and vacuum distillation is started until obvious crystals are precipitated on the bottle wall, and the vacuum distillation is completed.
[0063] 4. The feed liquid was cooled to 12°C to obtain the intermediate 4-(dipropylsulfamoyl)-benzoyl chloride (hereinafter referred to as probenecidyl chloride).
[0064] (II) Preparation of homemade impurity Z17
[0065] 5. Weigh 30g of dipropylamine into a 500ml four-necked reaction flask, start stirring, and connect the four-necked flask to a PTFE anchor stirrer, a condenser, and a thermometer.
[0066] 6. Control the reaction temperature at 13°C, slowly add 10 g of probenecidyl chloride into the reaction bottle and stir.
[0067] 7. Stir the reaction for half an hour, add 2.1g of catalyst and purified water to the reaction bottle, and continue stirring for 0.5h.
[0068] The reaction solution of the homemade impurity Z174-(dipropylaminosulfonyl)-N,N-dipropylbenzamide was obtained.
[0069] (III) Purification
[0070] 8. Slowly add 15% sodium hydroxide solution to the homemade impurity Z17 reaction solution, heat and stir at 40°C for 30 minutes, and adjust the pH to 9-10.
[0071] 9. Transfer to a separatory funnel, let stand to separate the layers, take the upper yellow organic phase and transfer it to a new 500 ml reaction bottle.
[0072] 10. Add 75 ml of purified water to the reaction bottle, stir and wash with water at room temperature for 20 minutes, and let it stand to separate the layers.
[0073] 11. Take the upper yellow organic phase, transfer it to a 250ml reaction bottle, and start stirring.
[0074] 12. Slowly add 13% dilute hydrochloric acid to the reaction bottle, stirring continuously, and adjust the pH value to 4. The yellow organic phase gradually disappears and an off-white solid precipitates.
[0075] 13. Filter the liquid in the reaction bottle and rinse the filter cake with purified water to pH 5-6.
[0076] 14. Collect the filter cake and dry it at 35°C to obtain 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide.
[0077] The specific applications are as follows:
[0078] 1. Purity test of homemade impurity Z17 (HPLC)
[0079] The purity of the product was 98.51% as determined by HPLC. Figure 3 The purity test spectrum of homemade impurity Z17 is shown in Table 1.
[0080] Table 1 Purity test of homemade impurity Z17
[0081]
[0082] 2. Self-made impurity Z17 reference substance is used for product impurity inspection and quality control
[0083] Accurately weigh an appropriate amount of probenecid (sodium) and add all the impurity reference substances (attached Figure 4 The homemade impurity Z17 reference substance shown is used for the inspection of impurities in probenecid sodium raw materials), containing an appropriate amount of homemade impurity Z17, see Table 2 below, the elution time of probenecid (sodium) is 29min, and the elution time of homemade impurity Z17 is 46.8min, which can meet the monitoring of impurities in probenecid (sodium) raw materials and related preparations and the quality control of products.
[0084] Table 2 Self-made impurity Z17 reference substance used for the detection of impurities in probenecid sodium raw materials
[0085]
[0086] 3. The homemade impurity Z17 was tested by the Shanghai Institute of Pharmaceutical Industry through quantitative nuclear magnetic resonance. The content of the impurity was 100.1%. The test results are shown in Table 3.
[0087] Table 3 Quantitative NMR detection results of homemade impurity Z17
[0088]
[0089] 4. Self-made impurity Z17 was commissioned by Shanghai Institute of Pharmaceutical Industry to obtain NMR spectroscopy 1 H-MNR and 13 CNMR test, the test results are shown in Table 4 and Table 5 (Appendix Figure 5 , 6 The following are homemade impurity Z17 1 H-MNR and 13 CNMR detection spectrum)
[0090] Table 4 Quantitative NMR of homemade impurity Z17 1 H-MNR
[0091] Table 1 NMR 1HNMR spectrum data list
[0092]
[0093] Table 5 Quantitative NMR of homemade impurity Z17 13 CNMR
[0094] Table 2 NMR 13 CNMR spectrum data list
[0095]
[0096] References:
[0097] 1. Wang Zhanqing, Xu Jingfeng. Research progress of probenecid combination therapy [J]. Chinese Journal of Pharmaceutical Sciences, 2005, 40(21): 1607-1609
[0099] 2. Technical requirements for reference substances in chemical drug registration. Ren Lianjie, Zhang Ning, Chen Zhen. Chinese Journal of New Drugs, 2016(04):389-394404.
[0101] 3. Bai Jincai, Wang Xiaoyu, Xie Jing, et al. Synthesis of four genetic impurities of probenecid sodium [J]. Guangdong Chemical Industry, 2018, 45(10): 58).
Claims
1. Preparation of 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide impurity reference substance, characterized in that The specific steps are as follows:
1. Preparation of Probenecidyl Chloride 1) Add probenecid and DMF (N, N-dimethylformamide) to thionyl chloride in proportion, stir and heat, and keep the temperature for reaction; the weight ratio of probenecid, thionyl chloride and DMF is 1:1-2:0.2-0.4; 2) The reaction temperature is 40-60°C, and the reaction is kept warm for 2-4 hours; 3) The reaction solution is distilled under reduced pressure at 40-50°C until obvious crystals precipitate on the wall of the bottle, the distillation is terminated, the temperature is lowered and crystallization is carried out, and the precipitate is the intermediate 4-(dipropylsulfamoyl)-benzoyl chloride, hereinafter referred to as probenecidyl chloride; 2. Preparation of 4-(dipropylsulfamoyl)-N,N-dipropylbenzamide 1) Add purified water to dipropylamine in proportion, add probenecidyl chloride in portions under stirring and cooling protection, and keep warm for reaction after adding; the weight ratio of probenecidyl chloride to dipropylamine is 1:3-4, and the amount of water is 5-10% of dipropylamine; 2) The reaction temperature is 10-20°C and the reaction time is 1-2h; 3) Obtaining the product 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide reaction solution; 3. Product Purification 1) The pH of the reaction solution is adjusted to alkaline with sodium hydroxide solution, purified water is added to the feed solution for extraction, and the upper organic phase is taken. Hydrochloric acid is added to the organic phase to precipitate solids, which are filtered and the filter cake is washed with purified water and dried at low temperature to obtain the product 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide; 2) The solubility of the sodium hydroxide solution is 10%-15%, the pH value of the reaction solution is adjusted to 9-10, stirred at 40-50°C for 20-30 minutes, and allowed to stand for stratification; 3) Remove the lower aqueous phase, take the upper organic phase, add 2-3 times the amount of dipropylamine in purified water in batches, stir and wash the organic phase at room temperature for 10-20 minutes, and let it stand to separate the layers; 4) Take the upper yellow organic phase again, slowly add 10-15% dilute hydrochloric acid, stir continuously, adjust the pH value to 3-4, the yellow organic phase gradually disappears, and an off-white solid precipitates; 5) Filter the reaction solution and rinse the filter cake with purified water until the pH of the washing solution is 5-6; 6) Collect the filter cake and dry it at 30-35°C to obtain 4-(dipropylaminosulfonyl)-N,N-dipropylbenzamide.