Method for removing probenecid sodium halogenated alkyl toxic impurities

Abstract

The invention relates to a method for removing halogenated alkyl toxic impurities in probenecid sodium, which is characterized by comprising the following steps of: 1, heating and hydrolyzing excessive halogenated alkyl under an alkaline condition to remove the halogenated alkyl toxic impurities; 2, organic solvent extraction and removal; 3, adsorption removal by a specific adsorption column; after the treatment by the method, the residue of haloalkane is reduced to be not detected from 15-100ppm, and the limit requirements of related genotoxic impurities in Chinese drug registration regulations and ICH guidance principles are completely met.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for removing genotoxic impurities of halogenated alkyl in propene sulfonate sodium, in particular to a method for removing genotoxic impurities of 1-bromopropane and 2-bromopropane in propene sulfonate sodium, and the prepared propene sulfonate (sodium) fully meets the requirements of the Chinese drug registration regulations and ICH guidelines on the limits of genotoxic impurities. BACKGROUND

[0002] Propene sulfonate is a white crystalline powder, which is an antirheumatic drug and an adjuvant drug for antibiotic treatment. Propene sulfonate sodium is its sodium salt, a white crystalline powder, odorless, slightly bitter, and extremely soluble in water. In addition to its effect on chronic gout, propene sulfonate can significantly optimize the pharmacokinetic properties of various β-lactam antibiotics. Currently, there are compound preparations composed of propene sulfonate and ampicillin used in clinical practice. The combination of propene sulfonate (sodium) and various β-lactam antibiotics not only significantly reduces the dosage of the corresponding antibiotic, thereby reducing the incidence of antibiotic adverse reactions, but also increases the treatment adherence of antibiotics and reduces the selection of drug-resistant bacteria. The development of propene sulfonate (sodium) combined with various β-lactam antibiotics has extremely important clinical value and very positive social significance in reducing antibiotic use and alleviating bacterial resistance.

[0003] The most commonly used synthetic process route for propene sulfonate sodium is p-methylbenzenesulfonylamine-halopropane. The literature [1]、[2] This process route has been reported in detail.

[0004]

[0005] Among them, halogenated alkyl as an alkylating agent for alkylation reaction, generally commonly used brominated alkyl, namely 1-bromopropane. Halogenated alkyl as an alkylating agent for alkylation reaction, generally commonly used brominated alkyl, namely 1-bromopropane. 2-bromopropane is an isomer of 1-bromopropane, which may be present in trace amounts during the preparation of 1-bromopropane.

[0006] Genotoxic impurities (GTIs) are a class of impurities in drugs that can directly or indirectly cause genotoxicity or carcinogenicity, and have the characteristic of producing risk at extremely low exposure. Typical representatives include nitrosamines (such as NDMA), sulfonates and compounds containing warning structures. According to ICH M7(R2) and global regulatory consensus, genotoxic impurities are divided into five categories:

[0007] According to the carcinogen list published by the International Agency for Research on Cancer of the World Health Organization, 1-bromopropane is a 2B carcinogen; 2-bromopropane is predicted by Derek and Sarah software to be classified as a 2-type impurity according to ICH M7 rules, and is a mutagenic impurity.

[0008]

[0009] In recent years, with the gradual improvement of the regulations on genotoxic impurities, the supervision requirements of the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) and other departments on genotoxic impurities are becoming higher and higher, and the control requirements of Chinese drug research and development and registration regulations on genetic toxic impurities in drugs are also becoming more and more strict. If the genetic toxic impurities in drugs are not properly controlled, it may cause clinical hidden dangers and affect drug safety, so the removal of genetic toxic impurities is very important.

[0010]

[0011] In the synthesis process of propene sulfonate sodium, 1-bromopropane is used as a starting material to participate in the alkylation reaction to prepare propene sulfonate crude product. According to the reaction mechanism, the alkylation reaction is an incomplete reaction. In order to improve the reaction conversion rate, 1-bromopropane should be excessive, and part of the unreacted material will remain in the crude product after the reaction is completed. According to the ICH M7 guidelines, the residual amount of 1-bromopropane and 2-bromopropane in propene sulfonate (sodium) should not exceed 5 ppm. SUMMARY

[0012] The purpose of the present application is to provide a method for removing halogenated alkyl genotoxic impurities in propene sulfonate sodium, in particular a method for removing 1-bromopropane and 2-bromopropane in propene sulfonate sodium bulk drug, to meet the requirements of ICH and registration regulations and ensure the safety of drugs.

[0013] The technical solution of the present application is as follows: a method for removing halogenated alkyl genotoxic impurities in propene sulfonate sodium, characterized by the following specific steps: 1) Excessive halogenated alkyl is heated under strong alkaline conditions and removed by hydrolysis reaction: in the synthesis process of propene sulfonate sodium, the intermediate propene sulfonate crude product is added to water with alkaline substances, the pH of the reaction solution is adjusted to ≥14, the temperature is controlled at 70-90°C, and the hydrolysis is carried out for ≥2h. The pH of the reaction solution is monitored in time, and alkaline substances are added to keep the pH of the reaction solution ≥14; most of the halogenated alkyl residues are converted into non-genotoxic impurities under the conditions of alkalinity and heating through hydrolysis reaction; the hydrolysis of different bromopropanes is as follows: ‌1-bromopropane: hydrolysis product is 1-propanol

[0014] ‌2-bromopropane: hydrolysis product is 2-propanol (isopropyl alcohol) :

[0015] 2) Organic solvent extraction removal: After hydrolysis, the reaction solution is cooled to 50-70℃, and an organic solvent is added. After stirring for 1h, the solution is allowed to stand for ≥30min, and the extraction liquid is separated. The organic solvent is added again, and the above operation is repeated.

[0016] 3) Specific adsorption removal: After extraction, the reaction solution is passed through a specific adsorption column at room temperature. The activated carbon fiber membrane (ACF) in the adsorption column has very good adsorption effect on low concentration of halogenated alkane. The specific and efficient adsorption of ACF on low concentration of halogenated alkane is as follows: ACF is activated at high temperature to form a dense microporous structure (selective pore size of about 0.5-2nm), and the specific surface area can reach 1600㎡ / g, which provides sufficient adsorption sites for bromopropane molecules; the inner wall of the micropore can efficiently capture bromopropane molecules through intermolecular van der Waals force, especially for low concentration of bromopropane; the surface of ACF contains carboxyl, hydroxyl and other oxygen-containing groups, which can enhance the selective adsorption of bromine atoms in bromopropane through polar action.

[0017] wherein: The basic substance in step (1) is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, and potassium ethoxide; preferably sodium hydroxide and potassium hydroxide.

[0018] The hydrolysis reaction temperature in step (1) is 70-90℃, and the hydrolysis time is ≥2h.

[0019] The organic solvent in step (2) is a non-polar or weakly polar solvent that is not miscible with water, which can be one or more of dichloroethane, dichloromethane, n-hexane, toluene, xylene, and methyl tert-butyl ether; preferably toluene, xylene, and methyl tert-butyl ether. The ratio of organic solvent to water is 1-2:5; the stirring time is ≥1h, and the stirring temperature is 50-70℃.

[0020] The specific adsorption column filler in step (3) is an activated carbon fiber (ACF) membrane, and the micropore size of the activated carbon fiber is 0.5-2nm, and the flow rate is 0.5kg / min.

[0021] The positive effects of the present application are 1. By controlling the basicity of the reaction solution and the specific reaction temperature, the hydrolysis of halogenated alkane is maximized; 2. By controlling the extraction temperature and selecting a good solvent for halogenated alkane, the residual halogenated alkane is effectively separated from the reaction solution; 3. By developing and utilizing a specific and efficient adsorption column, selecting a special adsorption column pore size, and controlling the reaction solution column speed, trace amounts of halogenated alkane are specifically adsorbed.

[0022] The residual halogenated alkane in the obtained propenecid and the propenecid crude product is reduced from about 15-100 ppm to undetectable, which fully meets the limit requirements of the Chinese drug registration regulations and ICH guidelines on genotoxic impurities. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 is a GC-MS chromatogram of the halogenated alkane content of the propenecid crude product in Example 1. Figure 1 Figure 2 is a GC-MS chromatogram of the halogenated alkane content of the propenecid fine product in Example 1.

[0024] Figure 2 Figure 2 is a GC-MS chromatogram of the halogenated alkane content of the propenecid fine product in Example 1. DETAILED DESCRIPTION

[0025] In order to make the purpose, technical scheme and advantages of the present application clearer, the present application will be further described in detail below in combination with the drawings and examples. It should be understood that the specific examples described herein are only used to explain the present application and do not limit the present application.

[0026] Example 1 (Batch No.: B2503001) 1) Bromopropane hydrolysis 100L dissolving kettle was sequentially added with 50kg purified water, 2kg sodium hydroxide, and 10kg propenecid crude product (Batch No.: B22503001), with water:sodium hydroxide:propenecid crude product being 5:0.2:1. The dissolving reactor condenser was opened to control the temperature and the material reflux valve was opened. The temperature was increased to 90℃ under stirring, and the reaction was controlled for 2h, and then the temperature was decreased.

[0027] 2) Organic solvent extraction After the hydrolysis was completed, the temperature was decreased to 50.1℃, and 20kg of toluene was added to the reaction solution, and the temperature was controlled at 65℃, After stirring for 1h, the reaction solution was allowed to stand for ≥30min, and the upper organic phase was separated. 20kg of toluene was added to the reaction solution again, and the above operation was repeated once.

[0028] Column adsorption After the extraction, the reaction solution was cooled to room temperature, and passed through the ACF adsorption column under the action of gravity, with a flow rate of 0.4-0.5kg / min and an adsorption time of 2h.

[0029] 4) Acid precipitation crystallization The adsorption solution was transferred into a crystallization kettle, and 50% acetic acid was added dropwise to obtain the propenecid fine product by acid precipitation.

[0030] ​The crude propene sulfonate is hydrolyzed by adding alkali, extracted by organic solvent, adsorbed by column, and acid precipitated to obtain the fine propene sulfonate. The crude propene sulfonate and the fine propene sulfonate are detected for halogenated alkane. The detection result shows that the content of 1-bromopropane in the crude propene sulfonate is 15 ppm, and the fine propene sulfonate is not detected. The detection result is shown in the following table Figure 1 , the following table Figure 2 .

[0031] Example 2 1) Hydrolysis of bromopropane In a 100 L dissolving kettle, 40 kg of purified water, 1.6 kg of sodium hydroxide and 8 kg of crude propene sulfonate are sequentially added, and the water, sodium hydroxide and crude propene sulfonate are in a ratio of 5:0.2:1. The inlet and outlet valves and the material reflux valve of the condenser of the dissolving kettle are opened, and the temperature is increased to 80 ℃ under stirring. The temperature is controlled for 2.5 h, and then the temperature is decreased.

[0032] 2) Extraction by organic solvent After the hydrolysis is completed, the temperature is decreased to 57 ℃, 8 kg of dimethylbenzene is added to the reaction solution, the temperature is controlled at 50 ℃, and the stirring is performed for 1.5 h. Then, the reaction solution is statically layered for ≥30 min, and the upper organic phase is separated. Then, 8 kg of dimethylbenzene is added again, and the above operation is repeated once.

[0033] Adsorption by column After the extraction, the reaction solution is cooled to room temperature, and is passed through an ACF adsorption column under the action of gravity at a flow rate of 0.4-0.5 kg / min. It takes about 100 min for the liquid to pass through the column.

[0034] 4) Acid precipitation and crystallization The adsorbed liquid is transferred into a crystallization kettle, and 50% acetic acid is added dropwise to obtain the fine propene sulfonate by acid precipitation.

[0035] Example 3 1) Hydrolysis of bromopropane In a 100 L dissolving kettle, 50 kg of purified water, 3 kg of potassium hydroxide and 10 kg of crude propene sulfonate are sequentially added, and the water, potassium hydroxide and crude propene sulfonate are in a ratio of 5:0.3:1. The inlet and outlet valves and the material reflux valve of the condenser of the dissolving kettle are opened, and the temperature is increased to 75 ℃ under stirring. The temperature is controlled for 3 h, and then the temperature is decreased.

[0036] 2) Extraction by organic solvent After the hydrolysis is completed, the temperature is decreased to 60 ℃, 15 kg of toluene is added to the reaction solution, the temperature is controlled at 70 ℃, and the stirring is performed for 1 h. Then, the reaction solution is statically layered for ≥30 min, and the upper organic phase is separated. Then, 15 kg of toluene is added again, and the above operation is repeated once.

[0037] Adsorption by column After the extraction, the reaction solution is cooled to room temperature, and is passed through an ACF adsorption column under the action of gravity at a flow rate of 0.4-0.5 kg / min. It takes about 140 min for the liquid to pass through the column.

[0038] 4) Acid precipitation crystallization The adsorption liquid was transferred into the crystallization kettle, and 50% acetic acid was added dropwise to obtain propene sulfone fine product by acid precipitation.

[0039] Example 4 1) Bromopropane hydrolysis In a 100L dissolving kettle, 30kg of purified water, 1.6kg of potassium hydroxide and 6kg of propene sulfone crude product were added in sequence, and the water: potassium hydroxide: propene sulfone crude product was 5:0.27:1. The inlet and outlet valves and the material reflux valve of the condenser of the dissolving reaction kettle were opened, and the temperature was increased to 85℃ under stirring, and the temperature was controlled for 2h, and then the temperature was decreased.

[0040] 2) Organic solvent extraction After hydrolysis, the temperature was decreased to 60℃, and 9kg of dimethylbenzene was added to the reaction liquid, and the temperature was controlled at 68℃, and after stirring for 2h, it was statically layered for ≥30min, and the upper organic phase was separated; 9kg of dimethylbenzene was added again, and the above operation was repeated once.

[0041] Column adsorption After extraction, the reaction liquid was cooled to room temperature, and passed through the ACF adsorption column under the action of gravity, and the flow rate was 0.4-0.5kg / min, and about 90min of liquid was passed through.

[0042] 4) Acid precipitation crystallization The adsorption liquid was transferred into the crystallization kettle, and 50% acetic acid was added dropwise to obtain propene sulfone fine product by acid precipitation.

[0043] Reference: [1] National Raw Drug Process Compilation Writing Group. National Raw Drug Process Compilation [M]. Shanghai: China Pharmaceutical Industry Press, 1980: 760-761.

[0044] [2] CN107033038B, Wu Xiaohui, Preparation method of propene sulfone.

Claims

1. A method for removing halogenated alkyl toxic impurities in probenecid sodium, characterized in that The specific steps are: 1) Excess alkyl halide is heated under strong alkaline conditions and removed by hydrolysis: During the synthesis of probenecid sodium, the intermediate crude probenecid and an alkaline substance are added to water, the pH of the reaction solution is adjusted to ≥14, and the temperature is controlled for hydrolysis for ≥2 hours. The pH of the reaction solution is monitored during the reaction, and alkaline substances are added in time to maintain the pH of the reaction solution ≥14; 2) Extraction and removal of organic solvent: After the hydrolysis is completed, cool to 50-70°C, add organic solvent to the reaction solution, stir for 1 hour, let it stand for 30 minutes or more, and remove the extract; add organic solvent again and repeat the above steps once; 3) Specific adsorption removal: After extraction, the reaction liquid passes through a specific adsorption column at room temperature. The activated carbon fiber membrane (ACF) filled in the adsorption column has a very good adsorption effect on low concentrations of halogenated hydrocarbons.

2. A method for removing halogenated alkyl toxic impurities in probenecid sodium according to claim 1, characterized in that The alkaline substance in step (1) is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, and potassium ethoxide.

3. A method for removing halogenated alkyl toxic impurities in probenecid sodium according to claim 1, characterized in that The hydrolysis reaction temperature in step (1) is 70-90° C., and the hydrolysis reaction time is ≥2 h.

4. according to the removal method of the halogenated alkyl toxic impurities in a kind of probenecid sodium of claim 1, it is characterized in that The organic solvent in step (2) is a non-polar or weakly polar solvent that is immiscible with water, and is one or more of dichloroethane, dichloromethane, n-hexane, toluene, xylene, and methyl tert-butyl ether, and the ratio of the organic solvent to water is 1 to 2:5; the stirring temperature is 50-70° C., and the stirring time is ≥1 h.

5. A method for removing halogenated alkyl toxic impurities in probenecid sodium according to claim 1, characterized in that The specific adsorption column filler in step (3) is an activated carbon fiber (ACF) membrane, the pore size of the activated carbon fiber is 0.5-2nm, and the flow rate is 0.5kg / min.

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