Synthetic method of propranolol hydrochloride

Abstract

The invention discloses a propranolol hydrochloride synthesis method, which is characterized in that a salt forming reaction is carried out in a mixed solution system, and the mixed solution system is obtained by adding acetyl chloride into a chlorinated alkane / alcohol system and stirring; hydrochloric acid or thionyl chloride is avoided from being used in a salt forming reaction through the mixed solution, so that water in a reaction system is reduced, and sulfur dioxide is prevented from being generated; the content of the impurity B is reduced, and the crystallization and separation time of the product is greatly shortened; the purity of the obtained propranolol hydrochloride product is not lower than 99.95%, the content of impurity B in the product does not exceed 0.02%, and the method has the advantages of being easy to operate, controllable in quality, suitable for industrial production and the like.

Description

Technical Field

[0001] The invention relates to the technical field of chemical pharmacy, in particular to a method for synthesizing propranolol hydrochloride. Background Art

[0002] Propranolol Hydrochloride, chemical name: 1-isopropylamino-3-(1-naphthyloxy)-2-propanol hydrochloride, is a white or off-white crystalline powder, soluble in water or ethanol, slightly soluble in chloroform. Its structural formula is as follows:

[0003]

[0004] Propranolol hydrochloride is commonly used to prevent and treat arrhythmias, angina pectoris, hypertension, myocardial infarction, coronary heart disease, hyperthyroidism and other diseases. With the increase in clinical applications, it has been further discovered that it can also be used to treat sinus tachycardia and migraine during anesthesia, as well as to prevent esophageal varicose vein rupture, and has extremely wide clinical applications. The Chinese Pharmacopoeia, the United States Pharmacopoeia, the British Pharmacopoeia, the European Pharmacopoeia and the Japanese Pharmacopoeia all include propranolol hydrochloride APIs. Many pharmacopoeias, including the Chinese Pharmacopoeia and the European Pharmacopoeia, stipulate that the single impurity limit under the relevant substance is 0.1%. The European Pharmacopoeia 11.0 contains 3 known impurities, among which the structural formula of EP impurity B is as follows:

[0005]

[0006] The existing technology for the synthesis of propranolol hydrochloride is: using 1-naphthol and epichlorohydrin as raw materials to undergo an etherification reaction to obtain intermediate II - 3-(1-naphthyloxy)-1,2-epoxypropane, and then undergoing a ring-opening reaction under the action of isopropylamine to obtain intermediate III (propranolol) - 1-isopropylamino-3-(1-naphthyloxy)-2-propanol, and then reacting with hydrochloric acid to obtain propranolol hydrochloride. This process has the following problems in industrial scale-up production: a by-product - 3,3'-(disubstituted isopropylamino)di-((1-naphthyloxy)propan-2-ol) is generated during the second step of the ring-opening reaction. This by-product is the European Pharmacopoeia impurity B of propranolol hydrochloride. The content of impurity B in the intermediate product - propranolol is about 0.5%. The impurity removal capacity in the second step of the ring-opening reaction and the third step of the hydrochloric acid salt-forming reaction is limited. As the largest single impurity in the finished product of propranolol hydrochloride, it directly affects the quality of the final product. The third step uses concentrated hydrochloric acid to form a salt, but due to the dissolution property of propranolol hydrochloride in water or ethanol, the product dissolution loss is caused, thereby affecting the product yield. The synthesis route is as follows:

[0007]

[0008] In the preparation process of intermediate III (propranolol), intermediate II reacts with isopropylamine to generate European Pharmacopoeia impurity B. The reaction process is as follows:

[0009]

[0010] The EP impurity B of propranolol hydrochloride is the main process impurity of the product. The second step of the ring-opening reaction in the prior art adopts different process conditions: different reaction temperatures, different raw material ratios, different post-treatment methods, or different feeding methods - adding intermediate II to isopropylamine or adding isopropylamine to intermediate II, but none of them can effectively control the formation of by-products. The limited removal ability of the hydrochloric acid salt-forming reaction system in the third step of the prior art to the by-product makes the content of EP impurity B in the product close to the limit of 0.1%.

[0011] Chinese patent document CN108586273A discloses a method for preparing propranolol hydrochloride, which uses 1-naphthol and 1,3-dibromo(iodo)acetone as raw materials to obtain an intermediate through an alkylation reaction, and then obtains propranolol hydrochloride through a sodium borohydride reduction reaction, a nucleophilic substitution reaction with isopropylamine, and a hydrochloric acid salt reaction, and the process route avoids the use of epichlorohydrin. However, 1,3-dibromo(iodo)acetone is expensive, resulting in a high production cost of the technical solution; in the alkylation reaction, due to the high activity of 1,3-dibromo(iodo)acetone, disubstituted etherification byproducts are easily generated, which is not conducive to the separation and purification of the intermediate product and is difficult to implement and apply in the large-scale production stage.

[0012] Chinese patent document CN113336656A discloses a method for synthesizing propranolol hydrochloride. In the isopropylamine ring-opening reaction process, a metal salt catalyst is added to reduce the amount of isopropylamine used; in the salt-forming reaction, anhydrous ethanol is used as a solvent, propranolol is dissolved, refluxed for decolorization, and hydrochloric acid is added to form a salt to prepare the product. In order to ensure sufficient crystallization, the salt-forming process needs to be cooled to below 10°C and frozen for crystallization for more than 12 hours. This process scheme cannot avoid the generation of EP impurity B in the ring-opening reaction process; the salt-forming reaction process uses ethanol as a solvent and hydrochloric acid to adjust the pH. Since propranolol hydrochloride dissolves in water or ethanol, the dissolution loss of the product in the solvent system is large, and even if the amount of ethanol is controlled, low-temperature and long-term crystallization is adopted, it will still affect the process yield level.

[0013] Chinese patent document CN111253267A discloses a method for synthesizing propranolol hydrochloride. In the isopropylamine ring-opening reaction process, a tertiary amine alkaline catalyst is added to reduce the amount of isopropylamine used; the salt-forming reaction process is carried out in an alcohol solvent using thionyl chloride, and a large amount of hydrogen chloride and sulfur dioxide are released during the reaction. Sulfur dioxide is a Class 3 carcinogen and is highly toxic to the respiratory system of operators. This patented technology also cannot avoid the generation of EP impurity B in the ring-opening reaction process; since the salt-forming reaction uses alcohols such as ethanol as solvents, it is necessary to crystallize for a long time at 5°C to 15°C, and no solid is precipitated after 7.5 hours of crystallization, and a small amount of crystals are precipitated after 16 hours of crystallization. It takes 24 hours or even longer for a large amount of crystals to precipitate; the crude product obtained by salt formation needs to be recrystallized in an alcohol solvent, which further reduces the yield level of the process scheme.

[0014] Therefore, it is necessary to design a synthesis method of propranolol hydrochloride to improve the defects of long crystallization time, low efficiency and high impurity B of propranolol hydrochloride. Summary of the invention

[0015] The present invention aims to provide a method for synthesizing propranolol hydrochloride, which is used to solve the defects of the prior art preparation method of propranolol hydrochloride, such as long crystallization time, low efficiency and high impurity B.

[0016] In view of this, the scheme of the present invention is:

[0017] A method for synthesizing propranolol hydrochloride, comprising the steps of:

[0018] Add the mixed solution dropwise to a solution system of propranolol or its crude product, react at 30-40° C. for 1-2 hours to form a salt, then add a diluent, cool and crystallize, filter and dry to obtain propranolol hydrochloride;

[0019] The mixed solution is obtained by adding acetyl chloride to a mixed solvent at 10-15° C. and keeping the mixture warm for 0.5-1h under stirring; the mixed solvent contains chlorinated alkanes and alcohols; the specific reaction process is as follows:

[0020]

[0021] Furthermore, the mass ratio of propranolol to acetyl chloride is 1:(0.31-0.36) g.

[0022] Furthermore, the temperature of the mixed solution dropwise addition process is controlled at 30-35°C.

[0023] Furthermore, the solvent used in the solution system of propranolol or its crude product is acetone or ethyl acetate.

[0024] Further, the chlorinated alkane is selected from at least one of dichloromethane and chloroform; and / or the alcohol is selected from at least one of methanol, ethanol or isopropanol.

[0025] Furthermore, the alcohol is ethanol, and the usage of acetyl chloride and ethanol is (0.31-0.36) g: (0.36-0.43) mL.

[0026] Furthermore, the diluent is n-hexane or n-heptane.

[0027] Furthermore, before the mixed solution is added dropwise, activated carbon is added to the crude propranolol solution system for decolorization, and the filtrate is filtered to obtain the filtrate.

[0028] Furthermore, the content of impurity B in the crude propranolol product is greater than 0.4%.

[0029] Furthermore, the cooling crystallization process is crystallization at 15-20°C for 1 hour, the cooling crystallization process is crystallization at 15-20°C for 1 hour, the content of impurity B in the finished propranolol hydrochloride product is less than 0.02%; the crystal purity is above 99.95%, and the yield of propranolol hydrochloride is above 99%.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The synthesis method of propranolol hydrochloride of the present invention avoids the use of hydrochloric acid or thionyl chloride in the salt-forming reaction, which is beneficial to reducing the moisture in the reaction system and avoiding the generation of sulfur dioxide; the salt-forming reaction is carried out in a mixed solution system, which is beneficial to reducing the content of impurity B and greatly shortening the crystallization time of the product; the purity of the obtained propranolol hydrochloride product is not less than 99.95%, and the content of impurity B in the product does not exceed 0.02%. The method has the advantages of simple operation, controllable quality, suitability for industrial production, and the like. DETAILED DESCRIPTION

[0032] The technical solution of the present invention will be clearly and completely described and verified in conjunction with the preferred embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] If the manufacturer of reagents or instruments is not specified in the examples, conventional products can be purchased from the market. If specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer can be used.

[0034] The starting material propranolol described in the following examples was prepared according to the preparation method described in Chinese patent document CN113511979A. The HPLC purity of propranolol was 97.9%, the drying loss was 0.09%, and the content of impurity B in propranolol was 0.6%.

[0035] Example 1

[0036] Add 36 ml of ethanol and 120 ml of dichloromethane into the reaction bottle, cool to 10°C with stirring, control the temperature to 10-15°C with stirring, and add 31 g of acetyl chloride dropwise. After the addition is completed, continue stirring at 10-15°C for 0.5 hour to obtain a mixed solution.

[0037] Add 100g of propranolol to 200ml of acetone, stir and heat to 45-50℃ to dissolve for 1 hour, add 2g of activated carbon, continue to decolorize at 45-50℃ for 1 hour, filter, cool the filtrate to 35℃, add the mixed solution dropwise to the filtrate, and control the dropping temperature to 30-35℃. After the dropwise addition is completed, continue to form salt at 30-40℃ and keep warm for 2 hours. After the salt-forming reaction is completed, add 100ml of n-hexane at 30-40℃, continue to stir for 0.5 hour after the addition, cool to 15-20℃ for crystallization for 1 hour, filter and dry to obtain 113.1g of propranolol hydrochloride, HPLC purity 99.97%, impurity B is 0.01%.

[0038] Example 2

[0039] Add 43 ml of ethanol and 150 ml of chloroform into the reaction bottle, cool to 10°C with stirring, control the temperature to 10-15°C with stirring, add 36 g of acetyl chloride dropwise, continue stirring at 10-15°C for 1 hour after the addition is completed, to obtain a mixed solution.

[0040] 100g of propranolol was added to 200ml of ethyl acetate, stirred and heated to 45-50℃ for 1 hour, 2g of activated carbon was added, and decolorization was continued at 45-50℃ for 1 hour, filtered, the filtrate was cooled to 35℃, and the mixed solution was added dropwise to the filtrate, and the dropping temperature was controlled to 30-35℃. After the dropwise addition was completed, the salt was kept warm at 30-40℃ for 2 hours. After the salt-forming reaction was completed, 100ml of n-heptane was added at 30-40℃, and stirring was continued for 0.5 hours after the addition was completed. The temperature was cooled to 15-20℃ for crystallization for 1 hour, filtered and dried to obtain 113.0g of propranolol hydrochloride, HPLC purity 99.96%, and impurity B was 0.02%.

[0041] Example 3

[0042] Add 40 ml of ethanol and 140 ml of dichloromethane into the reaction bottle, cool to 10°C with stirring, control the temperature to 10-15°C with stirring, and add 33 g of acetyl chloride dropwise. After the addition is completed, continue stirring at 10-15°C for 1 hour to obtain a mixed solution.

[0043] Add 100g of propranolol to 200ml of acetone, stir and heat to 45-50℃ to dissolve for 1 hour, add 2g of activated carbon, continue to decolorize at 45-50℃ for 1 hour, filter, cool the filtrate to 35℃, add the mixed solution dropwise to the filtrate, and control the dropping temperature to 30℃-35℃. After the dropwise addition is completed, continue to form salt at 30-40℃ and keep warm for 1 hour. After the salt-forming reaction is completed, add 100ml of n-hexane at 30-40℃, continue to stir for 0.5 hour after the addition, cool to 15-20℃ for crystallization for 1 hour, filter and dry to obtain 113.2g of propranolol hydrochloride, HPLC purity 99.96%, impurity B is not detected.

[0044] Comparative Example 1

[0045] 100 g of propranolol was added to 200 ml of anhydrous ethanol, stirred and heated to 70-78°C to dissolve for 0.5 hour, 5 g of activated carbon was added, and decolorization was continued at 75-78°C for 1.5 hours. The mixture was filtered while hot, and the filtrate was cooled to 30°C. Concentrated hydrochloric acid was added dropwise to adjust the pH to 1.5, and the temperature was continued to be cooled to 0-5°C. No obvious solid precipitation was observed after crystallization for 20 hours. Solid precipitation was observed after crystallization for 24 hours (total crystallization time was 44 hours). A large amount of crystals were precipitated after crystallization for 68 hours. The mixture was filtered, rinsed with a small amount of anhydrous ethanol, and dried to obtain 69.8 g of propranolol hydrochloride with HPLC purity of 99.59% and impurity B of 0.08%. Since ethanol has a high solubility in propranolol hydrochloride, it takes several days to precipitate a large amount of crystals. The water content of the concentrated hydrochloric acid in the salt-forming reaction system further affects the yield of the salt-forming process. The solvent ethanol in the salt-forming reaction system has limited ability to remove impurity B, which is close to the limit value of impurity B of 0.1%.

[0046] Comparative Example 2

[0047] The salt-forming reaction of 100 g of propranolol was the same as that of Example 1, except that no n-hexane was added after the reaction, and the temperature was directly lowered to 15° C. for crystallization for 1 hour, and then filtered and dried to obtain 90.3 g of propranolol hydrochloride.

[0048] Comparative Example 3

[0049] Add 36 ml of ethanol and 120 ml of dichloromethane into the reaction bottle, cool to 10°C with stirring, control the temperature to 10°C with stirring, and add 31 g of acetyl chloride dropwise. After the addition is completed, continue stirring at 10°C for 0.5 hour to obtain a mixed solution.

[0050] 100g of propranolol was added to 200ml of anhydrous ethanol, stirred and heated to 45°C for 1 hour, 2g of activated carbon was added, and decolorization was continued at 45°C for 1 hour, filtered, and the filtrate was cooled to 35°C, and the mixed solution was added dropwise to the filtrate, and the dropping temperature was controlled to 30°C. After the dropwise addition was completed, the salt was kept at 30°C for 2 hours. After the salt-forming reaction was completed, 100ml of n-hexane was added at 30°C, and stirring was continued for 0.5 hours after the addition was completed. The temperature was cooled to 15°C for crystallization for 1 hour, filtered, and dried to obtain 23.1g of propranolol hydrochloride, with an HPLC purity of 99.78% and an impurity B content of 0.12%.

[0051] Examples 1 to 3 fully illustrate the use of acetyl chloride added to the chlorinated alkane / alcohol system to obtain a mixed solvent and stirred and added dropwise to the propranolol solution for salt formation reaction. Combined with simple dilution, a large amount of target crystals can be obtained in the normal temperature range in only 1h of crystallization, and the content of impurity B is effectively controlled below 0.02%, the crystal purity is above 99.95%, and the yield of propranolol hydrochloride is above 99%; the overall efficiency is high, and the quality is controllable, which is suitable for industrial production. Comparative Example 1 uses a traditional salt-forming method. Due to the introduction of a large amount of water, there is a significant impact on the crystallization process, resulting in the crystallization process time being extended to several days, and the purity and yield cannot meet industrial needs. In Comparative Example 2, no diluent was used before crystallization, resulting in a decrease in yield. In Comparative Example 3, anhydrous ethanol was used as a salt-forming reaction solvent, and only a small amount of propranolol hydrochloride was obtained under the same crystallization conditions, which was due to the excessive solubility of propranolol hydrochloride in the alcohol solution.

[0052] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing propranolol hydrochloride, characterized in that the steps include: Add the mixed solution dropwise to a solution system of propranolol or its crude product, react at 30-40° C. for 1-2 hours to form a salt, then add a diluent, cool and crystallize, filter and dry to obtain propranolol hydrochloride; The mixed solution is obtained by adding acetyl chloride into a mixed solvent at 10-15° C. and keeping the mixture warm for 0.5-1h under stirring; the mixed solvent contains chlorinated alkanes and alcohols.

2. The synthesis method according to claim 1, characterized in that The mass ratio of propranolol to acetyl chloride is 1:(0.31-0.36) g.

3. The synthesis method according to claim 1, characterized in that The temperature during the dropwise addition of the mixed solution is controlled at 30-35°C.

4. The synthesis method according to claim 1, characterized in that The solvent used in the solution system of propranolol or its crude product is acetone or ethyl acetate.

5. The synthesis method according to claim 1, characterized in that The chlorinated alkane is selected from at least one of dichloromethane and chloroform; and / or the alcohol is selected from at least one of methanol, ethanol or isopropanol.

6. The synthesis method according to claim 1, characterized in that The alcohol is ethanol, and the usage of acetyl chloride and ethanol is (0.31-0.36) g: (0.36-0.43) mL.

7. The synthesis method according to claim 1, characterized in that The diluent is n-hexane or n-heptane.

8. The synthesis method according to claim 1, characterized in that The crude propranolol solution system is decolorized by adding activated carbon before the mixed solution is added dropwise, and the filtrate is collected by filtration.

9. The synthesis method according to claim 1, characterized in that The content of impurity B in the crude propranolol product is above 0.4%.

10. The synthesis method according to claim 1, characterized in that The cooling and crystallization process is crystallization at 15-20° C. for 1 hour, and the content of impurity B in the finished propranolol hydrochloride product is less than 0.02%.

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