Preparation method and application of choltheophylline bulk drug

Abstract

The invention provides a preparation method of a choltheophylline bulk drug with high yield and high purity. The method mainly comprises the following steps: firstly, dissolving theophylline in a first solvent, adding trimethylamine after cooling treatment, and carrying out heat preservation and stirring at a certain temperature; then adding a base catalyst, cooling again, then adding chloroethanol, continuously stirring and slowly heating; filtering while the solution is hot, slowly cooling filtrate, adding a second solvent for crystallization, and filtering to obtain a crude cholintheophylline product; and then, dissolving the crude cholintheophylline in a third solvent, heating and stirring for a period of time, filtering while hot, cooling filtrate for crystallization, and finally, carrying out suction filtration and vacuum drying to obtain a cholintheophylline finished product. The choltheophylline bulk drug prepared by the method has excellent yield and purity, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a preparation method and application of choline theophyllinate raw material drug. Background Art

[0002] Choline theophyllinate is an equimolecular compound of theophylline and choline, with high solubility, low irritation, rapid oral absorption and long duration of action; its effects are similar to those of aminophylline, and it shows better pharmacodynamic effects in some aspects. For example, the solubility of choline theophyllinate is 5 times greater than that of aminophylline, with rapid oral absorption, reaching the peak effect 3 hours later, less irritation to the gastric mucosa, good tolerance and long action time. These characteristics make choline theophyllinate have broad application prospects in the treatment of diseases such as bronchial asthma, angina pectoris, biliary colic and cardiac edema.

[0003] Existing preparation methods of choline theophyllinate mostly focus on the preparation of preparations such as tablets and capsules, while detailed reports on the preparation of raw material drugs are relatively scarce. British Patent GB800171A once mentioned that ethylene oxide was used for the synthesis of choline theophyllinate, but ethylene oxide, as a toxic, flammable and explosive chemical, has extremely high safety risks during its use. When preparing choline theophyllinate raw material drug, if the feeding amount of ethylene oxide, reaction conditions and subsequent treatment steps cannot be properly controlled, serious accidents such as fire, explosion or poisoning of personnel are likely to occur, which undoubtedly increases the uncertainty and potential hazards in the production process. Summary of the Invention

[0004] Aiming at the problems existing in the prior art, the present invention provides a preparation method of choline theophyllinate raw material drug, which uses chloroethanol as the starting material, is safe and efficient in the preparation process, and has high product yield, high purity, high safety, low cost and is suitable for industrial production.

[0005] The present invention is realized through the following technical solutions: The present invention provides a preparation method of choline theophyllinate raw material drug, comprising the following steps: (1) Dissolve anhydrous theophylline in a first solvent, add trimethylamine after cooling, and keep stirring at a certain temperature for a period of time; (2) Cool the system to a certain temperature, add an alkali catalyst and chloroethanol while controlling the temperature, keep stirring for a period of time, and then slowly heat up to a suitable temperature; (3) Filter, slowly cool the filtrate to a certain temperature during stirring, add a second solvent for crystallization, and filter to obtain the crude choline theophyllinate; (4) Dissolve the crude choline theophyllinate in a third solvent, heat up and stir for a period of time, then filter while it is hot, cool the filtrate for crystallization, and finally obtain choline theophyllinate through suction filtration and vacuum drying.

[0006] Preferably, in step (1), the first solvent is one or more of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; preferably, the first solvent is methanol; the mass ratio of anhydrous theophylline to the first solvent is 1:4 - 20; preferably, the mass ratio is 1:4.

[0007] Preferably, in step (1), the molar ratio of anhydrous theophylline to trimethylamine is 1:(1 - 2); preferably, the molar ratio is 1:1.05; the temperature reduction treatment is to reduce the temperature to below 15°C, preferably 5 - 10°C; the temperature of the heat preservation and stirring is below 30°C, preferably 15 - 20°C, and the stirring time is more than 30 minutes, preferably 1 - 2 h.

[0008] Preferably, in step (2), the molar ratio of anhydrous theophylline, base catalyst, and chloroethanol is 1:(1 - 2):(1 - 2); preferably, the molar ratio is 1:1.05:1.05; the temperature reduction to a certain temperature is to reduce the system temperature to below 15°C, preferably 5 - 10°C; the base catalyst is a mixture of one or more bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; preferably, the base catalyst is sodium hydroxide or potassium hydroxide; the heat preservation and stirring time is more than 1 h, preferably 2 - 3 h; slowly raise the temperature to above 40°C, preferably 55 - 60°C.

[0009] Preferably, in step (3), the cooling to a certain temperature is to below 10°C, preferably 0 - 5°C; the second solvent added is a mixture of one or more solvents such as ethanol, dichloromethane, chloroform, ether, and isopropanol; preferably, the second solvent is isopropanol or dichloromethane; the mass ratio of the second solvent to the first solvent is 1:5 - 40; preferably, the mass ratio is 1:10.

[0010] Preferably, in step (3), the crystallization time is more than 1 h, preferably 2 h.

[0011] Preferably, in step (4), the third solvent is a mixture of one or more solvents such as tetrahydrofuran, methanol, ethanol, acetone, and dichloromethane; preferably, the third solvent is ethanol; the mass ratio of crude choline theophyllinate to the third solvent is 1:4 - 10, preferably 1:4.

[0012] Preferably, in step (4), the heating and stirring is at a temperature above 50°C, preferably 70 - 80°C; the stirring time is more than 0.5 h, preferably 1 - 2 h; the crystallization temperature is below 20°C, preferably 0 - 5°C.

[0013] Preferably, in step (4), the crystallization time is more than 1 h, preferably 2 h.

[0014] The present invention also provides the use of choline theophyllinate prepared by the above preparation method in the preparation of choline theophyllinate preparations.

[0015] Compared with the prior art, the preparation method of choline theophyllinate of the present invention has the following beneficial effects: (1) The present invention uses chloroethanol as the starting material and introduces an alkali catalyst to synthesize choline theophyllinate by a one-pot method. The preparation process is simple, highly controllable, and has much lower cost, higher safety, more environmental friendliness, and is easier to carry out industrial production compared with the synthesis of choline theophyllinate using a series of choline salts such as choline chloride and choline bicarbonate as the starting materials; (2) The preparation method provided by the present invention has a high product yield and high purity, improving the safety of drug use. Detailed implementation manners

[0016] The following further elaborates on the present application in detail with specific examples, which are not used to limit the present invention. The described examples are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts fall within the protection scope of the present invention.

[0017] Example 1 This example provides a preparation method of choline theophyllinate raw material, and the synthesis route is as follows: Add 50 g of anhydrous theophylline and 200 g of anhydrous methanol into a reaction flask, and then start the stirring device. After the substances in the system are completely dissolved to form a clear solution, lower the temperature to 15 °C. At this time, add 18.9 g of trimethylamine to the reaction system, and continue to keep warm and stir at 15 °C for 1.5 h. Then further lower the system temperature to 0 °C, and slowly add 12.2 g of sodium hydroxide within this temperature range (0 - 5 °C). After the sodium hydroxide is completely added and the system temperature is stable, add 25.7 g of chloroethanol, and continue to keep warm and stir at 0 - 5 °C for 2 h. After the reaction is completed, raise the temperature of the system to 55 °C, and filter while it is hot at this temperature to remove insoluble impurities. Slowly cool the obtained filtrate to 0 °C, and then add 2 kg of isopropanol to promote the crystallization of choline theophyllinate. Stir and crystallize at 0 °C for 2 hours, and after filtration and drying, 86.4 g of crude choline theophyllinate is obtained.

[0018] 86.4 g of crude choline theophyllinate was placed in 259.2 g of absolute ethanol, and then the temperature was raised to 75 °C and stirred at this temperature for 1 h to ensure complete dissolution. Then, filtration was carried out while it was hot to remove insoluble impurities. Next, the solution was slowly cooled to 0 °C. During this process, choline theophyllinate gradually crystallized out from ethanol, and the crystallization continued for 2 h. After crystallization was completed, filtration was carried out again to separate the crystals, and they were dried. Finally, 73.1 g of choline theophyllinate product in the form of white crystals was obtained, with a melting point of 188.3 - 191.4 °C, a content of 99.57%, and a yield of approximately 93%.

[0019] Structure identification: The above-mentioned finished product was identified and confirmed to be choline theophyllinate as follows: 1 H-NMR(600MHz,DMSO-d6,25℃)δ:2.786(s,3H),3.148(s,3H),3.385(s,9H),3.527(t,2H),4.038(m,2H),4.283(s,1H),8.652(s,1H) 13 C-NMR(600MHz,DMSO-d6,25℃)δ:29.446,32.085,54.826,54.829,54.831,57.562,69.738,91.124,145.129,151.386,157.086,162.148。

[0020] LC-MS (m / z) : 284.3 [M+H] + 。

[0021] Example 2 50 g of anhydrous theophylline and 200 g of anhydrous methanol were added to a reaction flask, and then the stirring device was started. After the substances in the system were completely dissolved to form a clear solution, the temperature was lowered to 15 °C. At this time, 18.9 g of trimethylamine was added to the reaction system, and stirring was continued at 15 °C for 1.5 h. Then the system temperature was further lowered to 0 °C, and 12.2 g of sodium hydroxide was slowly added within this temperature range (0 - 5 °C). After the sodium hydroxide was completely added and the system temperature was stable, 25.7 g of chloroethanol was added, and stirring was continued at 0 - 5 °C for 2 h. After the reaction was completed, the system temperature was raised to 55 °C, and filtration was carried out while it was hot at this temperature to remove insoluble impurities. The obtained filtrate was slowly cooled to 0 °C, and then 2 kg of dichloromethane was added to promote the crystallization of choline theophyllinate. Stirring and crystallization were carried out at 0 °C for 2 hours, and 87.4 g of crude choline theophyllinate was obtained after filtration and drying.

[0022] 87.4 g of crude choline theophyllinate was placed in 262.2 g of absolute ethanol, and then the temperature was raised to 75 °C and stirred at this temperature for 1 h to ensure complete dissolution. Then, filtration was carried out while it was hot to remove insoluble impurities. Next, the solution was slowly cooled to 0 °C. During this process, choline theophyllinate gradually precipitated out of the ethanol as crystals, and the crystallization continued for 2 h. After the crystallization was completed, filtration was carried out again to separate the crystals, which were then dried. Finally, 74.7 g of choline theophyllinate product in the form of white crystals with a content of 99.17% and a yield of approximately 95% was obtained.

[0023] Comparative Example 1 50 g of anhydrous theophylline and 200 g of absolute ethanol were added to a reaction flask, and then the stirring device was started. After the substances in the system were completely dissolved to form a clear solution, the temperature was lowered to 15 °C. At this time, 18.9 g of trimethylamine was added to the reaction system, and stirring was continued at 15 °C for 1.5 h. Then the temperature of the system was further lowered to 0 °C, and 14 g of gaseous ethylene oxide was slowly introduced within this temperature range (0 - 5 °C). Stirring was continued at 0 - 5 °C for 2 h. After the reaction was completed, the temperature of the system was raised to 76 °C, and filtration was carried out while it was hot at this temperature to remove insoluble impurities. The obtained filtrate was slowly cooled to 0 °C, and crystallization was carried out by stirring at 0 °C for 2 hours. After filtration and drying, 64.7 g of crude choline theophyllinate was obtained.

[0024] 64.7 g of crude choline theophyllinate was placed in 194.1 g of absolute ethanol, and then the temperature was raised to 75 °C and stirred at this temperature for 1 h to ensure complete dissolution. Then, filtration was carried out while it was hot to remove insoluble impurities. Next, the solution was slowly cooled to 0 °C. During this process, choline theophyllinate gradually precipitated out of the ethanol as crystals, and the crystallization continued for 2 h. After the crystallization was completed, filtration was carried out again to separate the crystals, which were then dried. Finally, 58.7 g of choline theophyllinate product in the form of white crystals with a content of 99.28% and a yield of approximately 74.6% was obtained.

[0025] Comparative Example 2 36.9 g of choline chloride was added to 200 g of absolute methanol, and then 12.2 g of sodium hydroxide was added. The temperature was raised to 35 °C and stirred for 1 h, and then the reaction solution was cooled to 20 °C.

[0026] Then 50 g of theophylline was added to the above reaction solution and stirred for 2 h. After the reaction was completed, the temperature of the system was raised to 55 °C, and filtration was carried out while it was hot at this temperature to remove insoluble impurities. The obtained filtrate was slowly cooled to 0 °C, and then 2 kg of dichloromethane was added. Crystallization was carried out by stirring at 0 °C for 2 hours. After filtration and drying, 75.4 g of crude choline theophyllinate was obtained.

[0027] 75.4 g of crude choline theophyllinate was placed in 226.2 g of absolute ethanol, and then the temperature was raised to 75 °C and stirred at this temperature for 1 h to ensure complete dissolution. After that, filtration was carried out while it was hot to remove insoluble impurities. Then, the solution was slowly cooled to 0 °C and crystallization was continued for 2 h. After crystallization was completed, filtration and drying were carried out, and finally 67.8 g of choline theophyllinate product in the form of white crystals with a content of 98.23% and a yield of about 74.6% was obtained.

[0028] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these features, it should be considered as the scope recorded in this specification.

Claims

1. A preparation method of choline theophyllinate raw material drug, characterized in that, It includes the following steps: (1) Dissolve anhydrous theophylline in the first solvent, add trimethylamine after cooling treatment, and keep stirring at a certain temperature for a period of time; (2) Cool the system to a certain temperature, add an alkali catalyst and chloroethanol while controlling the temperature, keep stirring for a period of time, and then slowly heat up to a suitable temperature; (3) Filter, slowly cool the filtrate to a certain temperature during stirring, add the second solvent for crystallization, and filter to obtain the crude choline theophyllinate; (4) Dissolve the crude choline theophyllinate in the third solvent, heat up and stir for a period of time, then filter while it is hot, cool the filtrate for crystallization, and finally obtain choline theophyllinate through suction filtration and vacuum drying.

2. The preparation method according to claim 1, characterized in that, In step (1), the first solvent is one or more of methanol, ethanol, isopropanol, acetone, and tetrahydrofuran; preferably, the first solvent is methanol; the mass ratio of anhydrous theophylline to the first solvent is 1:4 - 20; preferably, the mass ratio is 1:

4.

3. The preparation method according to claim 1 or 2, characterized in that In step (1), the molar ratio of anhydrous theophylline to trimethylamine is 1:(1~2); preferably, the molar ratio is 1:1.05; the cooling treatment is to cool down to below 15°C, preferably 5~10°C; the temperature for keeping stirring is below 30°C, preferably 15~20°C, and the stirring time is more than 30 minutes, preferably 1~2 h.

4. The preparation method according to any one of claims 1-3, characterized in that, In step (2), the molar ratio of anhydrous theophylline, alkali catalyst, and chloroethanol is 1:(1~2):(1~2); preferably, the molar ratio is 1:1.05:1.05; the cooling to a certain temperature is to lower the system temperature to below 15°C, preferably 5~10°C; the alkali catalyst is a mixture of one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, and potassium tert-butoxide; preferably, the alkali catalyst is sodium hydroxide or potassium hydroxide; the time for keeping stirring is more than 1 h, preferably 2~3 h; slowly heat up to above 40°C, preferably 55~60°C.

5. The preparation method according to claim 1, characterized in that, In step (3), the cooling to a certain temperature is below 10°C, preferably 0~5°C; the added second solvent is a mixture of one or more of ethanol, dichloromethane, chloroform, ether, and isopropanol; preferably, the second solvent is isopropanol or dichloromethane; the mass ratio of the second solvent to the first solvent is 1:5 - 40; preferably, the mass ratio is 1:

10.

6. The preparation method according to claim 1 or 5, characterized in that, In step (3), the crystallization time is more than 1 h, preferably 2 h.

7. The preparation method according to any one of claims 1-6, characterized in that, In step (4), the third solvent is a mixture of one or more of tetrahydrofuran, methanol, ethanol, acetone, and dichloromethane; preferably, the third solvent is ethanol; the mass ratio of the crude choline theophyllinate to the third solvent is 1:4 - 10, preferably 1:

4.

8. The preparation method according to claim 1 or 7, characterized in that In step (4), the heating and stirring is at a temperature above 50°C, preferably 70~80°C; the stirring time is more than 0.5 h, preferably 1~2 h; the crystallization temperature is below 20°C, preferably 0~5°C.

9. The preparation method according to claims 1-8, characterized in that, In step (4), the crystallization time is more than 1 h, preferably 2 h.

10. Use of choline theophyllinate prepared by the preparation method according to any one of claims 1 - 9 in the preparation of choline theophyllinate preparations.

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