Preparation method of high-purity pentoxifylline

Abstract

The invention relates to the technical field of medicine preparation, in particular to a preparation method of high-purity pentoxifylline. Adding sodium hydroxide and potassium iodide into the methanol solution at room temperature, and adding theobromine for complete reaction; dropwise adding a 6-bromo-2-hexanone solution, cooling after reaction, filtering, reducing pressure, distilling, extracting, separating liquid, concentrating, recrystallizing, filtering and drying to obtain a crude product; pulping and filtering to obtain a finished product. Compared with the prior art, the method has the main differences that the reaction temperature and time are strictly controlled, the generation of side reaction impurities is reduced, the quality is good, 95% isopropanol is used for crystallization, the crystal is excellent, the appearance is good, the stability is high, the safety is good, the PH value and the osmotic pressure are basically consistent with those of the original research, the yield is high, and the quality is good.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and more specifically, to a method for preparing high-purity pentoxifylline. Background Art

[0002] Pentoxifylline, chemical name is 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione, is a blood rheology improver. It is an orally active, non-selective phosphodiesterase (PDE) inhibitor with immunomodulatory, anti-inflammatory, blood rheology improving, anti-fibrinolytic and anti-proliferative effects. It can be used to study peripheral vascular diseases, cerebrovascular diseases and other diseases involving local microcirculatory defects. Its chemical structure is: The related substances, content, pH value, osmotic pressure, clarity, heavy metals and other related parameters of the API are closely related to the difficulty of preparation. High-standard APIs are related to drug quality, safety and stability. The Chinese Pharmacopoeia standard for pentoxifylline is relatively wide, and in order to be close to the parameters of the original preparation, it is extremely important to improve the purity, content, osmotic pressure, pH value, clarity and heavy metals of the API pentoxifylline, which has become the focus of pharmaceutical research.

[0003] The Chinese invention patent publication number is CN117304190A, and the name is a method for preparing pentoxifylline, which discloses extracting theobromine crude product from cocoa beans as raw materials, obtaining theobromine with higher purity after refining and purification, and preparing pentoxifylline after synthesis reaction with the self-made bromohexanone with higher purity after refining, which can reduce the impurities in the prepared pentoxifylline, and can remove most of the impurities after washing with ethanol and adsorption with activated carbon, and then washing with an ethanol isopropanol mixed solvent prepared with ethanol and isopropanol, which can further improve the purity of the obtained pentoxifylline. However, the purity of the prepared finished product is between 99.1% and 99.4%, which obviously does not meet the European Pharmacopoeia and the Chinese Pharmacopoeia, and the crude product is refined with an isopropanol-anhydrous ethanol mixed solvent, and the solvent cannot be recovered, and chloroform is used as an extraction solvent, and the crude product purity is low, 98.65%. Summary of the invention

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art. To this end, an object of one aspect of the present invention is to provide a method for preparing high-purity pentoxifylline, and the specific steps of the preparation method are as follows: S1. Sodium hydroxide and potassium iodide are taken at room temperature, added to a mixed solution of purified water and methanol, and after dissolution, theobromine is added and heated to reflux, and after gradual dissolution, reflux and stirring are continued, and solution I is obtained after the reaction is complete; S2. Add 6-bromo-2-hexanone solution dropwise to the solution I prepared in S1. After the reaction is completed, cool and filter to obtain a clear filtrate. Distill methanol from the filtrate under reduced pressure until a residual aqueous solution is obtained. Extract with an extraction solvent, stir the extraction, separate the liquids, and obtain an organic phase. Concentrate the organic phase under reduced pressure to obtain an oily substance or a viscous solid. Recrystallize with a crystallization solvent, cool and crystallize, filter and dry to obtain a crude product of pentoxifylline. S3. The crude pentoxifylline prepared in S2 was slurried and filtered with 95% isopropanol at room temperature to obtain the finished pentoxifylline.

[0005] The reaction formula of the preparation method is as follows: .

[0006] Preferably, the molar ratio of sodium hydroxide to theobromine in S1 is 0.9-1.3:1; the molar ratio of potassium iodide to theobromine is 0.05-0.1:1; and the purity of theobromine is above 98.0%.

[0007] Preferably, the volume ratio of pure water to methanol in S1 is 60% to 70%.

[0008] Preferably, the temperature in S1 is raised to 65° C. to 75° C. and refluxed, and after the mixture is gradually dissolved, the mixture is refluxed and stirred for 0.5 h to 1 h.

[0009] Preferably, a 6-bromo-2-hexanone solution is added dropwise to S2, the reaction temperature is 65°C to 75°C, and the reaction time is 5h to 10h; the purity of the 6-bromo-2-hexanone is above 92.0%; 6-bromo-2-hexanone is dissolved in methanol, and the dissolution ratio is 1:1.6, and the mass ratio of 6-bromo-2-hexanone to theobromine is 1.3 to 1.5:1.

[0010] Preferably, in S2, the filtrate is subjected to reduced pressure distillation of methanol at 50° C., and the vacuum degree is ≥ 0.09 MPa.

[0011] Preferably, the extraction solvent in S2 is an organic reagent, such as dichloromethane, chloroform, ethyl acetate or toluene.

[0012] Preferably, the organic phase in S2 is concentrated under reduced pressure, the vacuum degree is ≥0.09 MPa, the crystallization solvent is 80% to 95% isopropanol, the mass volume ratio is 1:5, the crystallization temperature is 10°C to 20°C, the crystallization time is 1h to 2h, and the drying temperature is 50°C.

[0013] Preferably, the volume ratio of the S3 pentoxifylline crude product to 95% isopropanol is 5:1.

[0014] The beneficial effects of the present invention are as follows: The pentoxifylline prepared by the present invention is found to be made of theobromine and 6-bromo-2-hexanone as raw materials, and the amount of methanol aqueous solution and alkali is controlled. After condensation, the pentoxifylline purity is more than 99.7% through dichloromethane extraction, isopropanol solution recrystallization, cooling crystallization and a series of parameters such as the obtained pentoxifylline, and the related substances are less than 0.1%, which meets the quality requirements of the European Pharmacopoeia on pentoxifylline. It is also better than the pentoxifylline product of current technical conditions. In the pentoxifylline prepared by the method, in the stability experiment, the pentoxifylline content change is not obvious, and the related substances are almost unchanged, indicating that the pentoxifylline prepared by the method has good stability and is conducive to the use of preparation raw materials.

[0015] The pentoxifylline, related substances, content, osmotic pressure, pH, heavy metals and clarity obtained by the present invention are all in accordance with the Chinese Pharmacopoeia 2020 edition and the European Pharmacopoeia, and the pentoxifylline injection made from the raw material, the related substances, and the content are consistent with the original research. The pentoxifylline prepared by the present invention has a high yield, which can reach more than 39%, good alkali stability, and the content and related substances do not change significantly under high temperature and high humidity.

[0016] The main differences between the present invention and the prior art are: strictly controlling the reaction temperature and time, reducing the occurrence of side reaction impurities, having good quality, using 95% isopropanol for crystallization, having excellent crystals, good appearance, high stability, good safety, pH value, osmotic pressure being basically consistent with the original research, having high yield and good quality.

[0017] Additional aspects and advantages of the invention will become apparent from the following description, or may be learned by practice of the invention. DETAILED DESCRIPTION

[0018] In order to more clearly understand the above-mentioned purpose, features and advantages of the present invention, the present invention is further described in detail below in conjunction with specific embodiments. It should be noted that the embodiments of the present application and the features in the embodiments can be combined with each other without conflict.

[0019] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from the description. Therefore, the protection scope of the present invention is not limited to the specific embodiments disclosed below.

[0020] Embodiment 1 S1. Take 43.3g of sodium hydroxide and 13.9g of potassium iodide at room temperature, add them to 1200ml of 60% methanol solution, after dissolving, add 150.0g of theobromine (theobromine purity is more than 98.0%), heat to 75℃ and reflux, continue to reflux and stir for 0.5h~1h after gradually dissolving, and obtain solution I after the reaction is complete; S2. Add 6-bromo-2-hexanone solution (194.0 g of 6-bromo-2-hexanone dissolved in 310 ml of methanol, 6-bromo-2-hexanone purity of 92.0% or more) dropwise to the solution I prepared in S1, the reaction temperature is 70°C, the reaction time is 6 h, after the reaction is completed, cool and filter to obtain a clear filtrate, reduce the pressure of the filtrate at 70°C to a vacuum degree ≥ 0.09 MPa, distill methanol, distill to the remaining aqueous solution, control the temperature to 60°C, extract with 500 ml*2 (twice) of dichloromethane, separate the liquids to obtain an organic phase; the organic phase is concentrated at 60°C, vacuum degree ≥ 0.09 MPa until no obvious droplets fall from the condenser tube, and an oily substance or a viscous solid is obtained, which is recrystallized with 500 ml of 95% isopropanol, cooled to 10°C for crystallization for 1 h, filtered, and dried at 50°C to obtain 91.0 g of crude pentoxifylline; S3. The crude pentoxifylline prepared in S2 was slurried and filtered with 500 ml of 95% isopropanol at room temperature to obtain 73.5 g of pentoxifylline finished product.

[0021] Embodiment 2 S1. Take 29.9g of sodium hydroxide and 13.8g of potassium iodide at room temperature, add them to 1200ml of 60% methanol solution, after dissolving, add 150.0g of theobromine (theobromine purity is above 98.0%), heat to 75℃ and reflux, continue to reflux and stir for 0.5h~1h after gradually dissolving, and obtain solution I after the reaction is complete; S2. Add 6-bromo-2-hexanone methanol solution (208.0 g of 6-bromo-2-hexanone dissolved in 332 ml of methanol, 6-bromo-2-hexanone purity of 92.0% or more) dropwise to the solution I prepared in S1, the reaction temperature is 70°C, the reaction time is 6 h, after the reaction is completed, cool and filter to obtain a clear filtrate, the filtrate is decompressed to a vacuum degree of ≥0.09 MPa at 60°C, methanol is distilled, distilled to the remaining aqueous solution, the temperature is controlled to 60°C, extracted with 500 ml*2 (twice) of toluene, separated to obtain an organic phase; the organic phase is decompressed to a vacuum degree of ≥0.09 MPa at 80°C, condensed without obvious liquid dripping, concentrated to obtain an oily substance or a viscous solid, recrystallized with 450 ml of 80% isopropanol, cooled to 10°C for crystallization for 1 h, filtered, and dried at 50°C to obtain 88.0 g of crude pentoxifylline; S3. The crude pentoxifylline prepared in S2 was slurried and filtered with 450 ml of 95% isopropanol at room temperature to obtain 71.2 g of pentoxifylline finished product.

[0022] Embodiment 3 S1. Take 43.3g of sodium hydroxide and 13.9g of potassium iodide at room temperature, add them to 1200ml of 70% methanol solution, after dissolving, add 150.0g of theobromine (theobromine purity is above 98.0%), heat to 75℃ and reflux, continue to reflux and stir for 0.5h~1h after gradually dissolving, and obtain solution I after the reaction is complete; S2. Add 6-bromo-2-hexanone methanol solution (208.0 g of 6-bromo-2-hexanone dissolved in 332 ml of methanol, 6-bromo-2-hexanone purity of 92.0% or more) to the solution I prepared in S1, the reaction temperature is 60°C, the reaction time is 6h, after the reaction is completed, cool and filter to obtain a clear filtrate, distill the methanol from the filtrate at 50°C, vacuum degree ≥0.09Mpa, reduce the pressure until no obvious droplets fall from the condenser, distill to the remaining aqueous solution, control the temperature to 60°C, extract with 500ml*2 (twice) toluene, separate the liquids to obtain an organic phase; the organic phase is concentrated at 80°C, vacuum degree ≥0.09Mpa, and reduced pressure to obtain an oily substance or a viscous solid, which is recrystallized with 450ml of 95% isopropanol, cooled to 15°C, crystallized for 1h, filtered, and dried at 50°C to obtain 93.80g of crude pentoxifylline; S3. The crude pentoxifylline prepared in S2 was slurried and filtered with 450 ml of 95% isopropanol at room temperature to obtain 74.5 g of pentoxifylline finished product.

[0023] Embodiment 4 S1. Take 43.3g sodium hydroxide and 6.9g potassium iodide at room temperature, add them to 1200ml 70% methanol solution, after dissolving, add 150.0g theobromine (theobromine purity is more than 98.0%), heat to 75℃ and reflux, continue to reflux and stir for 0.5h~1h after gradually dissolving, and obtain solution I after the reaction is complete; S2. Add 6-bromo-2-hexanone methanol solution (222.9 g of 6-bromo-2-hexanone dissolved in 350 ml of methanol, 6-bromo-2-hexanone purity of 92.0% or more) dropwise to the solution I prepared in S1, the reaction temperature is 65°C, the reaction time is 10 h, after the reaction is completed, cool and filter to obtain a clear filtrate, distill the methanol from the filtrate at 60°C with a vacuum degree ≥0.09 MPa, reduce the pressure until no obvious droplets fall from the condenser, distill until the remaining aqueous solution, control the temperature to 60°C, extract with 500 ml*2 (twice) of dichloromethane, separate the liquids to obtain an organic phase; the organic phase is concentrated at 60°C with a vacuum degree ≥0.09 MPa, and no obvious droplets fall from the condenser to obtain an oily substance or a viscous solid, which is recrystallized with 450 ml of 90% isopropanol, cooled to 15°C for crystallization for 2 h, filtered, and dried at 50°C to obtain 88.9 g of crude pentoxifylline; S3. The crude pentoxifylline prepared in S2 was slurried and filtered with 450 ml of 90% isopropanol at room temperature to obtain 72.7 g of pentoxifylline finished product.

[0024] Embodiment 5 S1. Take 43.3g sodium hydroxide and 6.9g potassium iodide at room temperature, add them to 1200ml 60% methanol solution, after dissolving, add 150.0g theobromine (theobromine purity is more than 98.0%), heat to 75℃ and reflux, continue to reflux and stir for 0.5h~1h after gradually dissolving, and obtain solution I after the reaction is complete; S2. Add 6-bromo-2-hexanone methanol solution (222.9 g of 6-bromo-2-hexanone dissolved in 350 ml of methanol, 6-bromo-2-hexanone purity of 92.0% or more) to the solution I prepared in S1, the reaction temperature is 60°C, the reaction time is 6 hours, after the reaction is completed, cool and filter to obtain a clear filtrate, distill the methanol from the filtrate at 60°C with a vacuum degree of ≥0.09 MPa, reduce the pressure until no obvious droplets fall from the condenser, distill until the remaining aqueous solution, control the temperature to 60°C, extract with 500 ml*2 (twice) of toluene, separate the liquids to obtain an organic phase; the organic phase is concentrated at 80°C with a vacuum degree of ≥0.09 MPa, and no obvious droplets fall from the condenser to obtain an oily substance or a viscous solid, which is recrystallized with 550 ml of 95% isopropanol, cooled to 10°C for crystallization for 2 hours, filtered, and dried at 50°C to obtain 94.0 g of crude pentoxifylline; S3. The crude pentoxifylline prepared in S2 was slurried and filtered with 450 ml of 95% isopropanol at room temperature to obtain 74.7 g of pentoxifylline finished product.

[0025] The samples prepared in the embodiment were compared with the prior art samples, and the results are shown in Table 1 below: Table 1 The stability comparison test of the pentoxifylline crystals obtained by the present invention and the pentoxifylline crystals obtained by the prior art was carried out, and the results are shown in Table 2: Table 2 It can be seen from the above indicators that the technical solution of the present invention is superior to the prior art.

[0026] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may also have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing high-purity pentoxifylline, characterized in that: The specific steps of the preparation method are as follows: S1. Sodium hydroxide and potassium iodide are taken at room temperature, added to a mixed solution of purified water and methanol, and after dissolution, theobromine is added and heated to reflux, and after gradual dissolution, reflux and stirring are continued, and solution I is obtained after the reaction is complete; S2. Add 6-bromo-2-hexanone solution dropwise to the solution I prepared in S1. After the reaction is completed, cool and filter to obtain a clear filtrate. Distill methanol from the filtrate under reduced pressure until a residual aqueous solution is obtained. Extract with an extraction solvent, stir the extraction, separate the liquids, and obtain an organic phase. Concentrate the organic phase under reduced pressure to obtain an oily substance or a viscous solid. Recrystallize with a crystallization solvent, cool and crystallize, filter and dry to obtain a crude product of pentoxifylline. S3. The crude pentoxifylline prepared in S2 is slurried and filtered with 95% isopropanol at room temperature to obtain the finished pentoxifylline.

2. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The reaction formula of the preparation method is as follows: 。 3. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The molar ratio of sodium hydroxide to theobromine in S1 is 0.9-1.3:1; the molar ratio of potassium iodide to theobromine is 0.05-0.1:1; and the purity of theobromine is above 98.0%.

4. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The volume ratio of pure water to methanol in S1 is 60% to 70%.

5. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The S1 is heated to 65°C to 75°C and refluxed, and after gradually dissolving, reflux and stirring are continued for 0.5h to 1h.

6. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: A 6-bromo-2-hexanone solution is added dropwise to the S2, the reaction temperature is 65° C. to 75° C., and the reaction time is 5 h to 10 h; the purity of the 6-bromo-2-hexanone is above 92.0%; the 6-bromo-2-hexanone is dissolved in methanol, and the dissolution ratio is 1:1.6, and the mass ratio of 6-bromo-2-hexanone to theobromine is 1.3 to 1.5:

1.

7. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: In S2, the filtrate is subjected to reduced pressure distillation of methanol at 50° C., and the vacuum degree is ≥0.9 MPa.

8. A method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The extraction solvent in S2 is an organic reagent, such as dichloromethane, chloroform, ethyl acetate or toluene.

9. The method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The organic phase in S2 is concentrated under reduced pressure, the vacuum degree is ≥0.9 MPa, the crystallization solvent is 80% to 95% isopropanol, the mass volume ratio is 1:5, the crystallization temperature is 10°C to 20°C, the crystallization time is 1h to 2h, and the drying temperature is 50°C.

10. The method for preparing high-purity pentoxifylline according to claim 1, characterized in that: The volume ratio of the crude S3 pentoxifylline to 95% isopropanol is 5:1.

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