A refining method for reducing the content of N-nitrosoprolol impurities in crude propranolol hydrochloride

Abstract

The application discloses a refining method of propranolol hydrochloride. The method comprises the following steps: refining propranolol hydrochloride crude products containing N-nitroso propranolol impurities to prepare propranolol hydrochloride finished products meeting quality standards. The application provides a simple purification method of propranolol hydrochloride. The purification method can completely remove N-nitroso propranolol impurities, the yield reaches 95.2%, and meanwhile, the method can provide strong support for large-scale industrial production of propranolol hydrochloride.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis and preparation technology, and in particular to a purification method and application for reducing the content of N-nitrosoprene impurities in crude propranolol hydrochloride. Background Technology

[0002] Propranolol hydrochloride was the first beta-blocker invented by scientists James Black and others. Its mechanism of action is the competitive inhibition of catecholamines. It is commonly used to prevent and treat arrhythmias and angina pectoris, and has good efficacy in treating hypertension, myocardial infarction, and coronary heart disease, making it a blockbuster drug. With increased clinical application, many new uses have been discovered in recent years, including the treatment of sinus tachycardia during anesthesia, migraines, and the prevention of esophageal variceal rupture. Its clinical applications are extremely wide-ranging.

[0003] Propranolol hydrochloride, characterized by having the following structure:

[0004] Propranolol Hydrochloride Propranolol hydrochloride contains a secondary amine structure, which may lead to trace amounts of N-nitrosopranolol impurities during the production and storage of raw materials and formulations. Nitrosamine impurities are mutagenic impurities in the concern cohort and have been listed as possible human carcinogens. The presence of such impurities can significantly affect drug safety. Pfizer announced on March 1, 2022, a recall of 15 batches of its long-acting antihypertensive drug propranolol hydrochloride in Canada due to excessive nitrosamine levels. Therefore, establishing appropriate purification methods is of great significance for the quality of raw materials and related formulations. Following the regulatory guidelines issued by the European Medicines Agency (EMA), and reviewing the research progress of domestic and international drug regulatory authorities on mutagenic impurities such as nitrosamines that may be present in propranolol hydrochloride, and based on the EMA's latest published maximum daily intake of N-nitrosopranolol of 1500 ng, a detection method for N-nitrosopranolol was studied and validated. The final proposed control limit is 0.0006% (i.e., 6 ppm). This limit places extremely high demands on the purification method.

[0005] Currently, no literature addresses the purification of N-nitrosoprene from propranolol hydrochloride. Therefore, providing an efficient, simple purification method suitable for large-scale production to effectively control genotoxic impurities in propranolol hydrochloride and ensure drug safety is of great research significance.

[0006] The chemical structural formula of N-nitrosopropranolol impurity is shown below: Summary of the Invention

[0007] This invention provides a purification method for reducing the content of N-nitrosoprene impurities in crude propranolol hydrochloride. This method is efficient, simple, and suitable for large-scale production, achieving effective control of genotoxic impurities in propranolol hydrochloride and ensuring medication safety.

[0008] To achieve the above objectives, the present invention provides the following technical solution: Crude propranolol hydrochloride contains the genotoxic impurity N-nitrosopranolol. A purification method using an acidic degradation agent is employed to reduce the content of N-nitrosopranolol, thereby improving the quality of the product.

[0009] This invention involved extensive experimental research. Conventional recrystallization, relying solely on solubility differences, showed low efficiency in removing trace amounts of N-nitrosoprepranolol, leading to excessive impurities. Research into the structural characteristics of N-nitrosoprepranolol revealed that this impurity is alkaline; adding acidic substances can reduce its content to some extent. Inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid and acetic acid were screened. Hydrochloric acid was found to be the most effective, as it can break the nitroso bonds of N-nitrosoprepranolol under strongly acidic heating conditions, decomposing the genotoxic impurity into small molecules soluble in the mother liquor. Simultaneously, the high chloride ion environment reduces the low-temperature solubility of propranolol hydrochloride, leaving trace amounts of undecomposed nitrosamine impurities in the mother liquor during crystallization. This dual mechanism reduces N-nitrosoprepranolol to below the limit. Formic acid can reduce the content of N-nitrosoprepranolol, but it also has a reducing effect, reducing some N-nitrosoprepranolol to aminopropranolol, generating new impurities. Therefore, hydrochloric acid was ultimately determined to be the acidic degradation reagent of this invention.

[0010] In this invention, the method of adding acidic degradation agent was investigated. Initially, it was added directly, but it was finally determined to be added dropwise after dissolution. This method ensures the removal effect of N-nitrosoprene propranolol in the product while also ensuring the product yield.

[0011] This invention screens purification solvents such as acetone, water, methanol, ethanol, dichloromethane, and chloroform, as well as mixed solvents in different proportions. Based on the dissolution state of crude propranolol, a mixed solvent of acetone and water is finally selected as the solvent.

[0012] This invention screens the acid addition temperature, examines the reaction of adding hydrochloric acid at a temperature of 30–50°C, and confirms that adding hydrochloric acid at a temperature of 40–50°C can more effectively remove N-nitrosoprene impurities.

[0013] This invention screens crystallization temperatures, examines the yield and quality of products at temperatures between -10 and 10°C, and ultimately optimizes the crystallization temperature to be between 0 and 5°C.

[0014] This invention screens reaction temperatures, comparing yields and quality at temperatures between 30 and 60°C. Temperatures that are too high or too low will reduce the yield. Although the N-nitrosoprene impurities are degraded to within limits, cooling the reaction is not recommended considering process stability; a preferred reaction temperature is 40–50°C.

[0015] This invention screens the ratio of acetone to water, examining a ratio between 80:1 and 16:5. A ratio that is too low will result in a significant decrease in yield, while a ratio that is too high may cause the N-nitrosopropranolol impurity to degrade beyond the limit. To ensure that both the yield and quality meet the requirements, the preferred acetone-to-water ratio is 40:1.

[0016] The present invention screened a molar ratio of crude product to acidic degradation reagent of 1:0.27 to 0.99, with a preferred molar ratio of crude product to acidic degradation reagent of 1:0.66.

[0017] This invention further discloses the application of purified propranolol hydrochloride in the production of propranolol hydrochloride. Experimental results show that the synthetic method is simple and effective. The purified propranolol hydrochloride method effectively addresses the shortcomings of low purity and yield of key intermediates and stringent purification equipment requirements in production.

[0018] The positive effects of the purification method for producing propranolol hydrochloride disclosed in this invention are as follows: This invention provides a purification method for reducing the content of N-nitrosoprene impurities in crude propranolol hydrochloride.

[0019] Existing methods of recrystallizing propranolol using acetone-water rely solely on solubility differences, resulting in low efficiency in removing trace amounts of N-nitrosoprepranolol and a tendency for impurities to exceed limits. The innovation of this invention lies in using acetone-water as a refining mixed solvent. After dissolution, hydrochloric acid is added dropwise and the mixture is kept at 40-50°C. Hydrochloric acid, acting as an acidic degradation aid rather than a solvent component, breaks the nitroso bonds of N-nitrosoprepranolol under strongly acidic heating conditions, decomposing genotoxic impurities into small molecules soluble in the mother liquor. Simultaneously, the high chloride ion environment reduces the low-temperature solubility of propranolol hydrochloride, ensuring that trace amounts of undecomposed nitrosamine impurities remain in the mother liquor during crystallization. This dual mechanism reduces N-nitrosoprepranolol levels below the limit. The key advantages of the proposed method for preparing propranolol hydrochloride are high purity and high yield, simple synthesis, and effective reduction of N-nitrosoprepranolol impurity content. This purification method can completely remove N-nitrosoprene impurities, with a yield of 95.2%, providing strong support for the large-scale industrial production of propranolol hydrochloride. Attached Figure Description

[0020] Figure 1 Propranolol hydrochloride 1H NMR spectrum; Figure 2 Nuclear magnetic resonance mass spectrometry of propranolol hydrochloride. Detailed Implementation

[0021] For the sake of simplicity and clarity, descriptions of well-known technologies are appropriately omitted below to avoid unnecessary details affecting the description of the present technical solution. The following, in conjunction with preferred embodiments, further illustrates a purification method for reducing the content of N-nitrosoprene impurities in crude propranolol hydrochloride according to the present invention. It is particularly noted that the acetone, hydrochloric acid, methanol, and ethanol used are all commercially available.

[0022] A method for synthesizing propranolol hydrochloride includes the following steps: 1) 460 g (3.18 mol) of 1-naphthol, 1225 g (13.3 mol) of epichlorohydrin, and 16 mL of triethylamine were added sequentially to a 5.0 L three-necked flask equipped with a thermometer, reflux tube, and mechanical stirrer. The mixture was kept at 65 °C for 8 hours, and the reaction was monitored by TLC. After the reaction was completed, the epichlorohydrin in the reaction solution was evaporated at 100 °C. 640 g of intermediate 1 was obtained, HPLC: 94.7%.

[0023] 2) Add 640 g (theoretical yield 636 g, 3.2 mol) of intermediate 1 to a 5.0 L three-necked flask equipped with a thermometer and mechanical stirrer. Add 1280 mL of water dropwise over 30 minutes. React for 3 hours, monitoring the reaction with TLC. After the reaction is complete, evaporate the isopropylamine to dryness. Dissolve the material in 2560 mL of a 3 / 1 toluene / cyclohexane mixture and stir for 30 minutes. Cool to 10°C, filter, and wash the filter cake with a small amount of a 3 / 1 benzene / cyclohexane mixture. Dry the filter cake. Obtain 590 g of propranolol, yield 73.7%, HPLC: 99.3%, N-nitrosopranolol impurity content 83.7429 ppm.

[0024] 3) Add 580g of propranolol and 1740mL of isopropanol to a 2.0L three-necked flask equipped with a thermometer and mechanical stirrer. Heat to 50℃, add 60g of hydrochloric acid dropwise, maintain the reaction temperature for 30 minutes, then cool to 0-5℃, filter, wash with cold isopropanol, and dry the filter cake. 569g of crude propranolol hydrochloride was obtained, yield 86.0%, HPLC: 99.3%, with N-nitrosopranolol impurity content of 12.4946ppm. The limit for N-nitrosopranolol impurity control should be 6ppm; the excess was approximately 108.2%.

[0025] Below, we will use examples to refine crude propranolol hydrochloride.

[0026] Example 1 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C and reacted for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 37.2 g of propranolol hydrochloride was obtained, with a yield of 93.0% and an N-nitrosopranolol impurity content of 12.9782 ppm.

[0027] Example 2 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone, 40 mL of water, and 4 mL of hydrochloric acid were added to the reaction flask. The mixture was heated to 40–50 °C and reacted for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 30.24 g of propranolol hydrochloride was obtained, with a yield of 75.6% and an N-nitrosopranolol impurity content of 7.4662 ppm.

[0028] Example 3 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone, 40 mL of water, and 10 mL of hydrochloric acid were then added to the reaction flask. The mixture was heated to 40–50 °C and reacted for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 34.4 g of propranolol hydrochloride was obtained, with a yield of 86.0% and an N-nitrosopranolol impurity content of 6.7640 ppm.

[0029] Example 4 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1200 mL of acetone and 60 mL of ethanol were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 34.9 g of propranolol hydrochloride was obtained, with a yield of 87.25%. The N-nitrosopranolol impurity was not detected.

[0030] Example 5 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the temperature was maintained at 40–50 °C for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 38.08 g of propranolol hydrochloride was obtained, with a yield of 95.2%. The N-nitrosoprene impurity was not detected.

[0031] Example 6 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 30-40 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0-5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 36.6 g of propranolol hydrochloride was obtained, with a yield of 91.5% and an N-nitrosopranolol impurity content of 9.7878 ppm.

[0032] Example 7 40 g of crude propranolol hydrochloride was added to a 2 L three-necked flask equipped with a thermometer and mechanical stirrer. 1200 mL of acetone and 60 mL of methanol were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 34.0 g of propranolol hydrochloride was obtained, with a yield of 85.0% and an N-nitrosopranolol impurity content of 3.2172 ppm.

[0033] Example 8 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 5–10 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 32.52 g of propranolol hydrochloride was obtained, with a yield of 81.3%. The N-nitrosopranolol impurity was not detected.

[0034] Example 9 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to -10–0 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 36.96 g of propranolol hydrochloride was obtained, with a yield of 92.4% and an N-nitrosopranolol impurity content of 7.6602 ppm.

[0035] Example 10 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added. The mixture was heated to 40–50 °C, and 15 mL of hydrochloric acid was added dropwise to the reaction flask. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 28.48 g of propranolol hydrochloride was obtained, with a yield of 71.2%, and the N-nitrosopranolol impurity content was 1.2622 ppm.

[0036] Example 11 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 30–40 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 36.92 g of propranolol hydrochloride was obtained, with a yield of 92.3% and an N-nitrosopranolol impurity content of 5.3664 ppm.

[0037] Example 12 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 50–60 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 34.24 g of propranolol hydrochloride was obtained, with a yield of 85.6% and an N-nitrosopranolol impurity content of 1.3652 ppm.

[0038] Example 13 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 20 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 36.80 g of propranolol hydrochloride was obtained, with a yield of 92.0% and an N-nitrosopranolol impurity content of 6.5654 ppm.

[0039] Example 14 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 50 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 20.7 g of propranolol hydrochloride was obtained, with a yield of 51.75%. The N-nitrosopranolol impurity was not detected.

[0040] Example 15 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 4 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 35.8 g of propranolol hydrochloride was obtained, with a yield of 89.5%, and the N-nitrosopranolol impurity content was 5.5456 ppm.

[0041] Example 16 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of formic acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 34.16 g of propranolol hydrochloride was obtained, with a yield of 85.4%. The N-nitrosopranolol impurity content was 3.5764 ppm. HPLC showed a single impurity of 0.85%, exceeding the limit by 0.10%.

[0042] Example 17 40 g of crude propranolol hydrochloride was added to a 3 L three-necked flask equipped with a thermometer and mechanical stirrer. 0.3 mg of N-nitrosopranolol impurity was then added to bring the N-nitrosopranolol impurity content in the crude product to approximately 20 ppm. 1600 mL of acetone and 40 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 10 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 50 mL of acetone and dried. 37.92 g of propranolol hydrochloride was obtained, with a yield of 94.8%. The N-nitrosopranolol impurity content was undetectable.

[0043] Example 18 30 g of crude propranolol hydrochloride (Example 8) was added to a 2 L three-necked flask equipped with a thermometer and mechanical stirrer. 0.15 mg of N-nitrosopranolol impurity was then added to bring the N-nitrosopranolol impurity content in the crude product to approximately 5 ppm. 1200 mL of acetone and 30 mL of water were added to the reaction flask. The mixture was heated to 40–50 °C, and 7.5 mL of hydrochloric acid was added dropwise. After the addition was complete, the reaction was allowed to proceed for 2 hours. The reaction system was then cooled to 0–5 °C and stirred to induce crystallization for 1 hour. The mixture was filtered, and the filter cake was washed with 40 mL of acetone and dried. 28.74 g of propranolol hydrochloride was obtained, with a yield of 95.8%. The N-nitrosopranolol impurity content was undetectable.

[0044] Summary of test results for each embodiment:

[0045]

[0046] Experimental Summary: The above experiments show that the conditions in Example 5 were optimal. The 1H NMR and mass spectrometry analyses of propranolol hydrochloride are as follows: 1 HNMR(CDCl3)9.348(s,1H),8.863(s,1H),8.828(d,1H),7.886(d,1H),7.491-7.555(m,2H),7.441(d,1H),7.415( t,1H),6.982(d,1H),6.052(d,1H),4.460(m,1H),4.191(d,2H),3.388(q,1H),3.092-3.273(m,2H),1.309(m,6H). [M-Cl - ] + =260.1.

[0047] Screening degradation reagents and addition methods, and comparing Examples 1, 2, 3, and 16, reveals the following: Example 1, without hydrochloric acid, shows almost no removal effect on N-nitrosoprepranolol impurities; Example 16, while formic acid degrades N-nitrosoprepranolol impurities to within limits, also generates significant single impurities. Examples 2 and 3, with acetone, water, and hydrochloric acid added simultaneously, show partial removal of N-nitrosoprepranolol impurities. The amount of hydrochloric acid added also matters; Example 2, with insufficient hydrochloric acid, cannot degrade N-nitrosoprepranolol impurities to within limits.

[0048] Different proportions of hydrochloric acid were screened. In Examples 10 and 15, the proportion of hydrochloric acid added was adjusted based on Example 5. Adding too much hydrochloric acid would reduce the yield; adding too little hydrochloric acid would reduce the yield, but the N-nitrosoprene impurity would be degraded to within the limit, although the impurity content was still much higher than in Example 5.

[0049] By screening the acid addition temperature and comparing Examples 5 and 6, it was found that adding hydrochloric acid at a temperature of 40-50°C can more effectively remove N-nitrosoprene impurities.

[0050] By screening reaction solvents and comparing Examples 4, 5, and 7, acetone and water were found to be the optimal reaction system.

[0051] By screening the crystallization temperature, comparing Example 5 with Examples 8 and 9, it can be found that a crystallization temperature of 0-5℃ ensures qualified quality while maximizing yield.

[0052] By screening the reaction temperature, comparing Example 5 with Examples 11 and 12, it was found that a reaction temperature of 40-50℃ can achieve the maximum yield while ensuring quality. Too high or too low a temperature will reduce the yield. Although the N-nitrosoprene impurity in Example 11 has been degraded to within the limit, cooling the reaction is not recommended considering the stability of the process.

[0053] By screening the ratio of acetone to water, and comparing Examples 5, 13, and 14, it was found that a ratio of acetone to water of 40:1 yielded the maximum yield while ensuring quality. A ratio that was too low would result in a significant decrease in yield, while a ratio that was too high could cause the N-nitrosopropranolol impurities to degrade beyond the limit.

[0054] After optimizing the process, the adaptability of the process was further verified by doping experiments Example 17 and Example 18. The experiments proved that the process is stable and reliable and has high repeatability.

[0055] Meanwhile, a wealth of test results were accumulated through numerous experiments, from which typical and valuable experimental data were selected, listed, and analyzed.

[0056] The above formula can efficiently obtain propranolol hydrochloride with low N-nitrosopropranolol impurities, achieving a purification yield of 95.2% and high purity, with high operability. This provides a practical purification method for the production of propranolol hydrochloride.

[0057] After a detailed description of the preferred embodiments, those skilled in the art will clearly understand that various changes and modifications can be made without departing from the scope and spirit of the above-mentioned claims. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of this invention fall within the scope of this invention. Furthermore, this invention is not limited to the exemplary embodiments described in the specification.

Claims

1. A purification method for reducing the content of N-nitrosoprene impurities in crude propranolol hydrochloride, characterized in that, The steps are as follows: 1) Add crude propranolol hydrochloride to a mixed purification solvent of acetone and water, heat to 40-50℃ and stir until completely dissolved; 2) Slowly add the acidic degradation reagent dropwise to the solution at 40-50℃. After the addition is complete, keep the solution at 30-60℃ and stir for 2 hours to allow the N-nitrosopranolol impurities in the system to decompose acidically. 3) After the heat preservation is completed, the temperature is lowered to 0-10℃ to crystallize, filtered, washed with cold acetone, and vacuum dried to obtain the finished product propranolol hydrochloride; The volume ratio of acetone to water is 40:1; the molar ratio of crude product to acidic degradation reagent is 1:0.27 to 0.

99.

2. The refining method according to claim 1, characterized in that... The acidic degradation reagent is hydrochloric acid.

3. The refining method according to claim 1, characterized in that... The molar ratio of crude product to acidic degradation reagent is 1:0.

66.

4. The refining method according to claim 1, characterized in that... The crystallization temperature is 0–5℃.

Images