Method for refining pranoprofen

Abstract

The invention provides a pranoprofen refining and purifying method, which comprises the following steps: salifying a pranoprofen crude product and dicyclohexylamine, and refining through a tetrahydrofuran / n-heptane system to obtain pranoprofen. According to the method, no alcohol or alcohol / water system is used, so that generation of pranoprofen axetil is avoided, the pranoprofen refined product obtained through the method is high in purity, high in yield and excellent in impurity condition, industrialization is easy to achieve, and the yield is high.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for refining pranoprofen that is efficient and can be industrially scaled up. Background Art

[0002] Among non-steroidal anti-inflammatory drugs, propionic acid compounds represented by pranoprofen, ketoprofen, and ibuprofen have excellent antipyretic and anti-inflammatory balance and fewer side effects compared with other non-steroidal anti-inflammatory drugs. Pranoprofen, CAS: 52549-17-4, trade name propranopolin, chemical name 2-5H-[1] chromeno[2,3-b]pyridin-7-ylpropanoic acid, chemical structure is as follows:

[0003]

[0004] Pranoprofen was developed and marketed by Welfide (formerly Yoshitomi Pharmaceutical Co., Ltd., now Mitsubishi Pharmaceutical) in 1981, and then developed into eye drops by Senju Pharmaceutical Co., Ltd., which was launched in Japan in 1988. It is mainly used for the symptomatic treatment of inflammation of the external eye and anterior segment. Pranoprofen has a stronger anti-inflammatory effect than aspirin and ibuprofen, has a low and mild adverse reaction rate, a high efficacy rate, good tolerance, and does not increase intraocular pressure.

[0005] The quality standard of pranoprofen (YBH00632013) issued by the State Food and Drug Administration stipulates that the maximum single impurity shall not exceed 0.2% and the total impurities shall not exceed 1.0%. National drug standards are the minimum standards for drugs. In order to ensure the safety, effectiveness and quality controllability of drugs, each drug manufacturer usually formulates more stringent internal control standards. The impurities that may exist in pranoprofen include starting materials, intermediates, degradation products, process impurities and some unknown impurities, etc. These impurities can be controlled within the limit requirements by conventional recrystallization refining methods, but some impurities are difficult to control.

[0006] Chinese patent ZL201910751771.7 disclosed a method for refining and purifying pranoprofen on October 25, 2019, wherein pranoprofen powder is added to a methanol aqueous solution, and finally the filtered pranoprofen is mixed with the methanol aqueous solution to dissolve it, and then filtered, crystallized, and dried while hot to obtain the pranoprofen finished product.

[0007] Chinese patent CN202310054317.2 disclosed a method for preparing pranoprofen on May 2, 2023, which involves using ethanol to recrystallize to obtain a refined pranoprofen product.

[0008] Chinese patent CN201910341924.0 disclosed a method for preparing pranoprofen on June 28, 2019, which involves using ethanol water to purify pranoprofen refined products.

[0009] Chinese patent CN202310068855.7 disclosed a method for refining pranoprofen on April 11, 2023, in which pranoprofen is refined and purified by salification, wherein one or more of ethanol, acetone, and methanol are used as solvents.

[0010] As can be seen from the above, ethanol-water recrystallization, methanol-water beating and then methanol-water recrystallization are mentioned in the reported methods, but because there is a carboxyl structure in the structure of pranoprofen, when an alcohol solvent is used for recrystallization, the corresponding pranoprofen ester impurity will be produced, and the impurity is difficult to be refined and removed by using alcohol or alcohol / water system. At present, the literature reports less on the removal of this impurity, and the presence of this impurity may be related to the safety of subsequent preparations, such as adverse reactions. The preparation can cause eye discomfort for eye drops, and may also affect the stability of subsequent preparations and the bulk drug itself. Therefore, it is a technical problem that this area expects to solve to develop a method for refining pranoprofen ester that can reduce or avoid pranoprofen ester impurities, while ensuring that a high yield, high purity and less impurity content can be obtained. After salification of the crude product of pranoprofen with dicyclohexylamine, tetrahydrofuran / n-heptane is added, and the pranoprofen fine product obtained is high in purity and high in yield, and the resulting pranoprofen bulk drug is used for the preparation of preparations, especially liquid preparations, and is left for a long time without precipitation and turbidity. Summary of the invention

[0011] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for refining pranoprofen with high purity and high yield, so that pranoprofen with higher purity can be obtained, and the obtained pranoprofen raw material meets the requirements of subsequent preparation processes.

[0012] Specifically, the pranoprofen purification method of the present invention adopts salt formation with dicyclohexylamine, and after adding hydrochloric acid, tetrahydrofuran and n-heptane are added to precipitate suitable pranoprofen crystals. The obtained pranoprofen has high purity and high yield. When the obtained pranoprofen raw material is used to prepare preparations, especially liquid preparations, no precipitation and turbidity will occur after long-term storage.

[0013] The above beneficial effects of the present invention are achieved through the following technical solutions.

[0014] A method for refining pranoprofen, characterized in that the method for refining pranoprofen comprises the following steps:

[0015] a) dissolving the crude pranoprofen product in an organic solvent, stirring, heating to dissolve, adding dicyclohexylamine, precipitating a solid, cooling, stirring, filtering, and drying to obtain pranoprofen dicyclohexylamine salt;

[0016] b) adding pranoprofen dicyclohexylamine salt to dichloromethane, stirring, adding hydrochloric acid to dissolve, stirring at room temperature, separating the liquids, concentrating the organic phase, adding tetrahydrofuran to the concentrate, stirring, heating, adding n-heptane, cooling, crystallizing, filtering, and drying to obtain pranoprofen fine product.

[0017] The dicyclohexylamine used in step a) of the present invention is one of the important keys to achieve technical effects. The inventor found by high performance liquid chromatography when preparing pranoprofen that in the chromatogram, before and after the pranoprofen elution time, i.e. before and after the pranoprofen main peak, there are impurity peaks, and alcohol or alcohol / water system is used for refinement, although the elution time can be removed earlier, i.e. the impurities before the pranoprofen main peak, but the elution time is late, i.e. the impurities after the pranoprofen main peak, and the removal ability is poor, thereby affecting product quality. Using dicyclohexylamine and pranoprofen crude product salification, the impurities after the pranoprofen main peak can be effectively removed in the salification stage, and dicyclohexylamine is better combined with pranoprofen, and the salt formation rate is high, and the subsequent acidification desalination has less loss. When the mol ratio of pranoprofen crude product to dicyclohexylamine is 1:1.05-1.3, pranoprofen and dicyclohexylamine salification are sufficient, and the subsequent dicyclohexylamine that is not salified can be simply removed, and preferably, the mol ratio of pranoprofen crude product to dicyclohexylamine is 1:1.1.

[0018] The tetrahydrofuran / n-heptane used in step b) of the present invention is one of the important keys to achieve the technical effect. Prior art for the refining of pranoprofen, usually uses ethanol-water recrystallization, methanol-water pulping and then methanol-water recrystallization. Alcohol or alcohol / water system has poor removal ability for impurities after the main peak of pranoprofen. Repeated crystallization and refining using alcohol or alcohol / water system, the corresponding ester impurities accumulate and increase instead, therefore, a suitable refining solvent system is very critical. The inventors found that when the tetrahydrofuran / n-heptane system is used for refining, specifically, in step b) pranoprofen concentrate, tetrahydrofuran is added, stirred, heated to reflux, and n-heptane is added dropwise under reflux, the drop rate is 8-15mL / min, the temperature is controlled at 60-70°C, and solids are gradually precipitated. Tetrahydrofuran as a good solvent, n-heptane as a poor solvent, has an unexpected refining effect on the impurities before and after the main peak of pranoprofen. The use of tetrahydrofuran / n-heptane system for refining can avoid ester impurities produced by pranoprofen and alcohol, which plays an important role in further improving the quality of pranoprofen bulk drug. When pranoprofen concentrate is added with tetrahydrofuran, the mass volume ratio of pranoprofen dicyclohexylamine salt to tetrahydrofuran is 1:10-25, and the mass volume ratio of pranoprofen dicyclohexylamine salt to n-heptane is 1:20-35, the pranoprofen impurity removal effect is the best, and the pranoprofen fine product yield reaches the highest at the same time, and the obtained pranoprofen crystal properties are better, preferably, pranoprofen concentrate is added with tetrahydrofuran, the mass volume ratio of pranoprofen dicyclohexylamine salt to tetrahydrofuran is 1:15, and the mass volume ratio of pranoprofen dicyclohexylamine salt to n-heptane is 1:30.

[0019] In the present invention, the type and ratio of organic solvent are one of the keys to achieve technical effect. As previously mentioned, using alcohol or alcohol / water system crystallization and purification, corresponding pranoprofen ester impurities will be produced. Therefore, while avoiding the use of alcohol solvents, it is equally critical to find an organic solvent that is conducive to the efficient refining of pranoprofen. When the organic solvent is tetrahydrofuran, one or more of dichloromethane or chloroform, the dissolution effect of pranoprofen and its impurities is better, and it is conducive to the precipitation of pranoprofen dicyclohexylamine salt, and preferably, the organic solvent is tetrahydrofuran. There are too few organic solvents, and pranoprofen and its impurities are not dissolved sufficiently, and there are too many organic solvents, which are not conducive to pranoprofen dicyclohexylamine salt and cause waste simultaneously. When in step a), the mass volume ratio of pranoprofen crude product to organic solvent is 1:5-15, and in step b), the mass volume ratio of pranoprofen dicyclohexylamine salt to dichloromethane is 1:10-25, the organic solvent can achieve the best dissolution effect on pranoprofen and its impurities, and the yield of pranoprofen dicyclohexylamine salt reaches the highest. Preferably, in step a), the mass volume ratio of pranoprofen crude product to organic solvent is 1:10, and in step b), the mass volume ratio of pranoprofen dicyclohexylamine salt to dichloromethane is 1:20.

[0020] In the present invention, reaction conditions, temperature and time are one of the keys to achieve technical effect. Suitable reaction conditions, temperature and time can further improve the effect of refining and the yield of product, shorten the reaction time, and be energy-efficient. When step a), cooling, stirring is to be cooled to room temperature, and when insulated and stirred for 0.5-3h, it is conducive to the dissolution of some impurities and the precipitation of pranoprofen dicyclohexylamine salt. Preferably, when insulated and stirred for 1h, yield and efficiency can reach the best. When step b), hydrochloric acid is dilute hydrochloric acid, and the volume ratio of methylene chloride and hydrochloric acid is 1:0.5-0.8, and pranoprofen dicyclohexylamine salt reacts fully with hydrochloric acid, and simultaneously, avoids the generation of acidified impurities, and preferably, the volume ratio of methylene chloride and hydrochloric acid is 1:0.5. In step b), stirring at room temperature is stirring at room temperature for 0.5-1h, adding n-heptane is dropping n-heptane under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, cooling is cooling to room temperature, and when being incubated for 1h, pranoprofen dicyclohexylamine salt reacts fully with hydrochloric acid, which is conducive to the desalination reaction of pranoprofen dicyclohexylamine salt, n-heptane is dropped under reflux, the dropping rate is 8-15mL / min, and the temperature is controlled at 60-70°C, which is conducive to the precipitation of pranoprofen high-quality crystals, avoiding the occurrence of violent precipitation phenomenon, cooling to room temperature, and being incubated for 1h is conducive to the continuous precipitation of pranoprofen fine products, and obtaining high yield, high purity and pranoprofen fine products with good crystal form. Preferably, in the step b), stirring at room temperature is stirring at room temperature for 0.5h.

[0021] A preferred method for refining pranoprofen of the present invention comprises the following steps:

[0022] a) Add crude pranoprofen to tetrahydrofuran, stir, heat to reflux, dissolve, slowly add dicyclohexylamine, precipitate solid, cool to room temperature, keep stirring for 1 hour, filter, rinse the filter cake with tetrahydrofuran, and dry at 50°C to obtain pranoprofen dicyclohexylamine salt.

[0023] In step a), the mass volume ratio of the crude pranoprofen to tetrahydrofuran is 1:10, and the molar ratio of the crude pranoprofen to dicyclohexylamine is 1:1.1.

[0024] b) Add pranoprofen dicyclohexylamine salt to dichloromethane, stir at room temperature, add dilute hydrochloric acid to dissolve, stir to dissolve, stir at room temperature for 0.5h, stand for separation, retain the organic phase, concentrate the organic phase under reduced pressure to dryness, add tetrahydrofuran to the concentrate, stir, raise the temperature to reflux, add n-heptane dropwise under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dropping is completed, the temperature is lowered to room temperature, the temperature is kept for 1h, filtered, the filter cake is rinsed with a mixed solution of tetrahydrofuran and n-heptane, and dried at 50°C to obtain pranoprofen fine product.

[0025] In step b), the mass volume ratio of pranoprofen dicyclohexylamine salt to dichloromethane is 1:20, tetrahydrofuran is added to the concentrate, the mass volume ratio of pranoprofen dicyclohexylamine salt to tetrahydrofuran is 1:15, the mass volume ratio of pranoprofen dicyclohexylamine salt to n-heptane is 1:30, and the volume ratio of dichloromethane to hydrochloric acid is 1:0.5.

[0026] The present invention provides a pranoprofen dicyclohexylamine salt, the structure of which is:

[0027]

[0028] The pranoprofen dicyclohexylamine salt provided by the present invention is used for preparing pranoprofen fine product.

[0029] Compared with the prior art, the present invention has the following outstanding advantages and beneficial effects:

[0030] 1. The refining and purification method of pranoprofen of the present invention uses crude pranoprofen and dicyclohexylamine to form salt, and then refines it through a tetrahydrofuran / n-heptane system without using alcohol or alcohol / water system, thereby avoiding the generation of pranoprofen ester, further improving the quality of pranoprofen, and the pranoprofen fine product obtained by the method has high purity, high yield, and excellent impurity situation.

[0031] 2. The pranoprofen fine product obtained by the present invention is suitable for use in subsequent preparations. When the obtained pranoprofen bulk drug is used to prepare preparations, especially liquid preparations, no precipitation or turbidity occurs after long-term storage.

[0032] 3. The overall design of the process of the present invention is reasonable, the operation is simple, and repeated crystallization is not required, so it is easy to realize industrialization and high production capacity. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 Impurity chromatogram of untreated crude pranoprofen.

[0034] Figure 2 The impurity chromatogram of the pranoprofen fine product prepared in Example 1 of the present invention.

[0035] Figure 3 The impurity chromatogram of the pranoprofen fine product prepared in Comparative Example 5 of the present invention.

[0036] Figure 4 The impurity chromatogram of the pranoprofen fine product prepared in Comparative Example 6 of the present invention.

[0037] Figure 5 Mass spectrum of pranoprofen dicyclohexylamine salt prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0038] The present invention is further described in detail below with reference to examples, but the embodiments of the present invention are not limited thereto.

[0039] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

[0040] Example 1

[0041] Step a) 10.00 g of crude pranoprofen was added to 100.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, 7.81 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 1 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 16.56 g of pranoprofen dicyclohexylamine salt, with a yield of about 96.8% and a purity of 99.5%. 1 H NMR (600MHz, Methanol-d4) δ8.06 (dd, J=5.0, 1.8Hz, 1H), 7.73 (dd, J=7.4, 1.9Hz, 1H), 7.23 (d, J= 7.7Hz,2H),7.12(dd,J=7.4,4.9Hz,1H),6.99(d,J=8.1Hz,1H),4.10(s,2H),3.54(q,J=7.1Hz,1H) ,3.10(tt,J=11.1,3.9Hz,2H),2.00(dd,J=9.2,4.7Hz,4H),1.80(dt,J=13.0,3.1Hz,4H),1.65(dp ,J=10.1,3.5,3.0Hz,2H),1.41(d,J=7.2Hz,3H),1.37–1.22(m,8H),1.15(qt,J=12.9,3.7Hz,2H). 13 C NMR(600MHz,Methanol-d4)δ182.62,159.73,151.00,146.72,141.41,140.76,128.94,12 8.37,121.24,120.50,117.87,117.17,54.30,49.59,30.54,28.64,26.14,25.51,19.92.

[0042] Step b) 16.56g of pranoprofen dicyclohexylamine salt is added to 331.12mL of dichloromethane, stirred at room temperature, 165.56mL of 5% dilute hydrochloric acid is added to dissolve, stirred to dissolve clearly, stirred at room temperature for 0.5h, and the liquid is separated and the organic phase is retained. The organic phase is concentrated to dryness under reduced pressure, and the concentrate is added with 248.34mL of tetrahydrofuran, stirred, heated to reflux, and 496.68mL of normal heptane is added dropwise under reflux, and the dropping rate is 8-15mL / min, and the temperature is controlled at 60-70°C, and solid is gradually precipitated. After dripping, the mixture is cooled to room temperature, kept warm for 1h, filtered, and the filter cake is washed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 9.53g of pranoprofen fine product, with a yield of 98.5% and a purity of 99.9%. The chromatogram of the product is shown in Figure 2 shown.

[0043] Example 2

[0044] Step a) 10.00 g of pranoprofen crude product was added to 50.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, 7.46 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 0.5 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 16.20 g of pranoprofen dicyclohexylamine salt, with a yield of about 94.7% and a purity of 99.4%.

[0045] Step b) 16.20g of pranoprofen dicyclohexylamine salt is added to 161.97mL of dichloromethane, stirred at room temperature, 129.58mL of 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 0.6h, leaving liquid separation, retaining organic phase, the organic phase is concentrated to dryness under reduced pressure, 161.97mL of tetrahydrofuran is added to the concentrate, stirred, the temperature is raised to reflux, 323.94mL of normal heptane is added dropwise under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dripping is completed, the temperature is cooled to room temperature, insulation 1h, filter, the filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 9.24g of pranoprofen fine product, with a yield of 97.6% and a purity of 99.9%.

[0046] Example 3

[0047] Step a) 10.00 g of crude pranoprofen was added to 150.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, slowly added 9.23 g of dicyclohexylamine, precipitated solid, cooled to room temperature, stirred for 3 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 16.45 g of pranoprofen dicyclohexylamine salt, with a yield of about 96.2% and a purity of 99.3%.

[0048] Step b) 16.45g of pranoprofen dicyclohexylamine salt is added to 411.34mL of dichloromethane, stirred at room temperature, 246.80mL of 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 1h, leaving liquid separation, retaining organic phase, the organic phase is concentrated to dryness under reduced pressure, 411.34mL of tetrahydrofuran is added to the concentrate, stirred, the temperature is raised to reflux, 575.87mL of normal heptane is added dropwise under reflux, the rate of addition is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dripping is completed, the temperature is cooled to room temperature, insulation is 1h, and filtering is performed, the filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 9.45g of pranoprofen fine product, with a yield of 98.2% and a purity of 99.9%.

[0049] Example 4

[0050] Step a) 10.00 g of crude pranoprofen was added to 80.00 mL of dichloromethane, stirred, heated to reflux, dissolved, 8.17 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 1.5 h, filtered, the filter cake was rinsed with dichloromethane, and dried at 50 ° C to obtain 16.04 g of pranoprofen dicyclohexylamine salt, with a yield of about 93.8% and a purity of 99.4%.

[0051] Step b) 16.04g pranoprofen dicyclohexylamine salt is added to 240.65mL dichloromethane, stirred at room temperature, 168.45mL 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 0.7h, leaving liquid separation, retaining organic phase, the organic phase is concentrated to dryness under reduced pressure, 192.52mL tetrahydrofuran is added to the concentrate, stirred, the temperature is raised to reflux, 352.95mL normal heptane is added dropwise under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dripping is completed, the temperature is cooled to room temperature, insulation 1h, filter, the filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 9.22g of pranoprofen fine product, with a yield of 98.3% and a purity of 99.9%.

[0052] Example 5

[0053] Step a) 10.00 g of crude pranoprofen was added to 120.00 mL of chloroform, stirred, heated to reflux, dissolved, 8.88 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 2 h, filtered, the filter cake was rinsed with chloroform, and dried at 50 ° C to obtain 16.11 g of pranoprofen dicyclohexylamine salt, with a yield of about 94.2% and a purity of 99.3%.

[0054] Step b) 16.11g pranoprofen dicyclohexylamine salt is added to 354.45mL dichloromethane, stirred at room temperature, 212.67mL 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 0.8h, standing liquid separation, retaining organic phase, organic phase is concentrated to dryness under reduced pressure, concentrate is added 354.45mL tetrahydrofuran, stirred, heated to reflux, 515.57mL normal heptane is added dropwise under reflux, the dropping rate is 8-15mL / min, temperature is controlled at 60-70°C, solid is gradually precipitated, dripping is completed, cooling to room temperature, insulation 1h, filtering, filter cake is rinsed with tetrahydrofuran and normal heptane mixed solution, 50°C drying, to obtain 9.23g pranoprofen fine product, yield 98.0%, purity 99.9%.

[0055] Comparative Example 1

[0056] Step a) 10.00 g of crude pranoprofen was added to 40.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, 7.10 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 1 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 15.41 g of pranoprofen dicyclohexylamine salt, with a yield of about 90.1% and a purity of 99.2%.

[0057] Step b) 15.41g pranoprofen dicyclohexylamine salt is added to 123.28mL dichloromethane, stirred at room temperature, 49.31mL 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 0.5h, leaving liquid separation, retaining organic phase, the organic phase is concentrated to dryness under reduced pressure, 123.28mL tetrahydrofuran is added to the concentrate, stirred, the temperature is raised to reflux, 277.38mL normal heptane is added dropwise under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dripping is completed, the temperature is cooled to room temperature, insulation 1h, filter, the filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 8.79g of pranoprofen fine product, with a yield of 97.6% and a purity of 97.5%.

[0058] Comparative Example 2

[0059] Step a) 10.00 g of crude pranoprofen was added to 180.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, 9.94 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 1 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 15.75 g of pranoprofen dicyclohexylamine salt, with a yield of about 92.1% and a purity of 99.1%.

[0060] Step b) 15.75g of pranoprofen dicyclohexylamine salt is added to 441.06mL of dichloromethane, stirred at room temperature, 441.06mL of 5% dilute hydrochloric acid is added to dissolve, and the solution is stirred and dissolved. The mixture is stirred at room temperature for 0.5h, and the liquid separation is allowed to stand. The organic phase is concentrated to dryness under reduced pressure, and 441.06mL of tetrahydrofuran is added to the concentrate, stirred, and the temperature is raised to reflux. 504.07mL of normal heptane is added dropwise under reflux, and the rate of addition is 8-15mL / min. The temperature is controlled at 60-70°C, and solid is gradually precipitated. After dripping, the mixture is cooled to room temperature, kept warm for 1h, filtered, and the filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 8.95g of pranoprofen fine product, with a yield of 97.2% and a purity of 98.5%.

[0061] Comparative Example 3

[0062] Step a) 10.00 g of crude pranoprofen was added to 100.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, 7.81 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 0.3 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 12.91 g of pranoprofen dicyclohexylamine salt, with a yield of about 75.5% and a purity of 99.1%.

[0063] Step b) 12.91g of pranoprofen dicyclohexylamine salt is added to 258.26mL of dichloromethane, stirred at room temperature, 129.13mL of 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 0.3h, standing liquid separation, retaining organic phase, the organic phase is concentrated to dryness under reduced pressure, 193.70mL of tetrahydrofuran is added to the concentrate, stirred, the temperature is raised to reflux, 387.39mL of normal heptane is added dropwise under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dripping is completed, the temperature is cooled to room temperature, insulation is 1h, and filtering is performed. The filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 7.14g of pranoprofen fine product, with a yield of 94.6% and a purity of 97.3%.

[0064] Comparative Example 4

[0065] Step a) 10.00 g of crude pranoprofen was added to 100.00 mL of tetrahydrofuran, stirred, heated to reflux, dissolved, 7.81 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 4 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 16.49 g of pranoprofen dicyclohexylamine salt, with a yield of about 96.4% and a purity of 99.2%.

[0066] Step b) 16.49g pranoprofen dicyclohexylamine salt is added to 329.75mL dichloromethane, stirred at room temperature, 164.88mL 5% dilute hydrochloric acid is added to dissolve, stirring is clear, stirring at room temperature for 2h, leaving liquid separation, retaining organic phase, the organic phase is concentrated to dryness under reduced pressure, 247.32mL tetrahydrofuran is added to the concentrate, stirred, the temperature is raised to reflux, 494.63mL normal heptane is added dropwise under reflux, the dropping rate is 8-15mL / min, the temperature is controlled at 60-70°C, solid is gradually precipitated, the dripping is completed, the temperature is cooled to room temperature, insulation 1h, filter, the filter cake is rinsed with a mixed solution of tetrahydrofuran and normal heptane, and dried at 50°C to obtain 9.47g pranoprofen fine product, with a yield of 98.2% and a purity of 98.7%.

[0067] Comparative Example 5

[0068] Step a) 10.00 g of crude pranoprofen was added to 100.00 mL of methanol, stirred, heated to reflux, dissolved, 7.81 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 1 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 15.63 g of pranoprofen dicyclohexylamine salt, with a yield of about 91.4% and a purity of 98.5%.

[0069] Step b) 15.63g of pranoprofen dicyclohexylamine salt is added to 312.65mL of dichloromethane, stirred at room temperature, 156.33mL of 5% dilute hydrochloric acid is added to dissolve, stirred to dissolve clearly, stirred at room temperature for 0.5h, and the liquid is separated and the organic phase is retained. The organic phase is concentrated to dryness under reduced pressure, and 156.33mL of 30% methanol aqueous solution is added, and the temperature is raised to 50°C, and the temperature is kept and stirred continuously for 3 hours, and the mixture is cooled to room temperature, filtered, and the filter cake is washed with a small amount of methanol aqueous solution of the same concentration, drained, and dried at low temperature, and dried at 50°C to obtain 9.01g of pranoprofen fine product, with a yield of 98.6% and a purity of 98.5%. The chromatogram of the product is shown in FIG. Figure 3 shown.

[0070] Comparative Example 6

[0071] Step a) 10.00 g of crude pranoprofen was added to 100.00 mL of ethanol, stirred, heated to reflux, dissolved, 7.81 g of dicyclohexylamine was slowly added, solid was precipitated, cooled to room temperature, stirred for 1 h, filtered, the filter cake was rinsed with tetrahydrofuran, and dried at 50 ° C to obtain 15.77 g of pranoprofen dicyclohexylamine salt, with a yield of about 92.2% and a purity of 98.6%.

[0072] Step b) 15.77g of pranoprofen dicyclohexylamine salt is added to 315.39mL of dichloromethane, stirred at room temperature, 157.69mL of 5% dilute hydrochloric acid is added to dissolve, stirred to dissolve clearly, stirred at room temperature for 0.5h, and the liquid is allowed to stand, and the organic phase is retained. The organic phase is concentrated to dryness under reduced pressure, and 157.69mL of 30% ethanol aqueous solution is added, and the temperature is raised to 50°C, and the temperature is kept and stirred continuously for 3 hours, and the mixture is cooled to room temperature, filtered, and the filter cake is washed with a small amount of ethanol aqueous solution of the same concentration, drained, and dried at low temperature, and dried at 50°C to obtain 9.07g of pranoprofen fine product, with a yield of 98.4% and a purity of 98.6%. The chromatogram of the product is shown in FIG. Figure 4 shown.

[0073] As can be seen from Examples 1-5 and Comparative Examples 1-6, the selection of reaction conditions has a greater impact on the purity and yield of pranoprofen fine products. In Comparative Example 1, in step a), the addition of tetrahydrofuran is less, and the addition of dicyclohexylamine is less, resulting in a low salification rate of pranoprofen dicyclohexylamine salt, and a low yield, and in step b), the addition of tetrahydrofuran and normal heptane is less, and the addition of hydrochloric acid is less, resulting in insufficient desalination of pranoprofen dicyclohexylamine salt, and insufficient removal of impurities, therefore, yield and purity are low. In Comparative Example 2, in step a), the addition of tetrahydrofuran is more, and the addition of dicyclohexylamine is more, and solvent is more, resulting in a slight reduction in the precipitation amount of pranoprofen dicyclohexylamine salt, and in step b), the addition of tetrahydrofuran and normal heptane is more, and the addition of hydrochloric acid is more, and solvent is more, resulting in a slight reduction in the precipitation amount of pranoprofen fine products, and more hydrochloric acid is added at the same time, resulting in the growth of some impurities, thereby reducing purity. In comparative example 3, in step a) and step b), the stirring time is shorter, the reaction is insufficient, therefore, the pranoprofen dicyclohexylamine salt salt formation rate is low, the yield is low, and the refining is insufficient, resulting in the low yield and low purity of pranoprofen fine products. In comparative example 4, in step a) and step b), the stirring time is longer, and the purity of pranoprofen fine products is slightly lower. It can be seen from the analysis that the stirring time is too long, and some impurities are precipitated. In comparative examples 5 and 6, the organic solvent for dissolving is methanol or ethanol, and the refining solvent system is methanol / water or ethanol / water, and the purity of the pranoprofen fine products obtained is slightly poor. It can be seen from the analysis that alcohol or alcohol-water system is used to produce pranoprofen ester impurities, resulting in purity decline. And all parameters of embodiments 1 to 5 fall within the scope of the present invention, and pranoprofen and dicyclohexylamine are selected to form salts, and then suitable refining solvents and reaction conditions are selected to further improve the yield and purity of pranoprofen fine products. Especially the technical parameters of embodiment 1, the yield and purity of pranoprofen fine products, are optimal at the same time.

[0074] Comparative Example 7

[0075] Pranoprofen was refined according to the method reported in Example 1 of CN202310068855.7.

[0076] Add 10.0g of crude pranoprofen to 60mL of ethanol, heat to 80°C, and reflux the system. Add 20mL of ethanol solution containing 1.57g of sodium hydroxide, continue heating and stirring; reflux for 3-5 minutes, solid precipitates, cool to 20°C, and crystallize for 2 hours. Filter, rinse the filter cake with 10mL of ethanol, and drain. The solid is returned to the reaction bottle, 80mL of water is added, stirred until dissolved, filtered to obtain a filtrate, the filtrate is adjusted to pH 4-5 with acetic acid, solid precipitates, filtered, and the wet product is dried at 50°C to obtain 9.16g of pranoprofen finished product, with a yield of 91.6% and a purity of 99.1%.

[0077] Example 8

[0078] The pranoprofen prepared in Examples 1-5, Comparative Examples 4 and 7 was used as a raw material, and pranoprofen eye drops were prepared using the same prescription. The pranoprofen eye drops were observed at 25° C. for 3 months, and the number of particles of 10 μm and above and the number of particles of 25 μm and above in each test container (portion) were detected and recorded using the insoluble particle light obstruction method of the Chinese Pharmacopoeia General Rules (0903). The results are shown in Table 1.

[0079] Table 1 Detection results of insoluble particles of different pranoprofen eye drops

[0080]

[0081]

[0082] According to the Chinese Pharmacopoeia General Rules (0903), the number of insoluble particles in each test sample container (portion) shall not exceed 6,000 particles of 10 μm and above, and the number of particles of 25 μm and above shall not exceed 600. As shown in Table 1, the number of insoluble particles in the eye drops of pranoprofen prepared by this scheme is significantly lower than that of pranoprofen eye drops prepared by Comparative Example 4 and Comparative Example 7 (the method reported in Example 1 of CN202310068855.7), indicating that this scheme can effectively remove impurities generated in the preparation process of pranoprofen raw materials by salifying pranoprofen with dicyclohexylamine and using tetrahydrofuran / n-heptane as the solvent of the refining system.

[0083] The above contents are further detailed descriptions of the present invention in combination with specific preferred embodiments, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the protection scope of the present invention.

Claims

1. A method for refining pranoprofen, characterized in that, The method for refining pranoprofen comprises the following steps: a) dissolving the crude pranoprofen product in an organic solvent, stirring, heating to dissolve, adding dicyclohexylamine, precipitating a solid, cooling, stirring, filtering, and drying to obtain pranoprofen dicyclohexylamine salt; b) adding the pranoprofen dicyclohexylamine salt obtained in step a) to dichloromethane, stirring, adding hydrochloric acid to dissolve, stirring at room temperature, separating the liquids, concentrating the organic phase, adding tetrahydrofuran to the concentrate, stirring, heating, adding n-heptane, cooling, crystallizing, filtering, and drying to obtain pranoprofen fine product.

2. The method for refining pranoprofen according to claim 1, wherein In the step a), the mass volume ratio of the crude pranoprofen to the organic solvent is 1:5-15, preferably 1:

10.

3. The method for refining pranoprofen according to claim 1 or 2, characterized in that, In step a), the organic solvent is one or more of tetrahydrofuran, dichloromethane or chloroform, preferably tetrahydrofuran.

4. The method for refining pranoprofen according to claim 1, wherein In step a), the molar ratio of the crude pranoprofen to dicyclohexylamine is 1:1.05-1.3, preferably 1:1.

1.

5. The method for refining pranoprofen according to claim 1, wherein: In step a), the cooling and stirring are cooling to room temperature, and stirring at this temperature for 0.5-3 hours, preferably stirring for 1 hour.

6. The method for refining pranoprofen according to claim 1, characterized in that: In step b), the mass volume ratio of the pranoprofen dicyclohexylamine salt to dichloromethane is 1:10-25, preferably 1:20, tetrahydrofuran is added to the concentrate, the mass volume ratio of the pranoprofen dicyclohexylamine salt to tetrahydrofuran is 1:10-25, preferably 1:15, and the mass volume ratio of the pranoprofen dicyclohexylamine salt to n-heptane is 1:20-35, preferably 1:

30.

7. The method for refining pranoprofen according to claim 1, characterized in that: In step b), the hydrochloric acid is dilute hydrochloric acid, and the volume ratio of dichloromethane to hydrochloric acid is 1:0.5-0.8, preferably 1:0.

5.

8. The method for refining pranoprofen according to claim 1, characterized in that: In step b), the stirring at room temperature is stirring at room temperature for 0.5-1h, preferably 0.5h, the adding of n-heptane is adding n-heptane dropwise under reflux, the dropping speed is 8-15mL / min, the temperature is controlled at 60-70°C, and the cooling is cooling to room temperature and keeping warm for 1h.

9. A method for refining pranoprofen, characterized in that: The method for refining pranoprofen comprises the following steps: a) adding crude pranoprofen to tetrahydrofuran, stirring, heating to reflux, dissolving, slowly adding dicyclohexylamine, precipitating solid, cooling to room temperature, keeping warm and stirring for 1 hour, filtering, rinsing the filter cake with tetrahydrofuran, and drying at 50° C. to obtain pranoprofen dicyclohexylamine salt; In step a), the mass volume ratio of the crude pranoprofen to tetrahydrofuran is 1:10, and the molar ratio of the crude pranoprofen to dicyclohexylamine is 1:1.1; b) adding pranoprofen dicyclohexylamine salt to dichloromethane, stirring at room temperature, adding dilute hydrochloric acid to dissolve, stirring and dissolving, stirring and clearing, stirring at room temperature for 0.5h, standing and separating, retaining the organic phase, the organic phase was concentrated to dryness under reduced pressure, tetrahydrofuran was added to the concentrate, stirred, heated to reflux, and n-heptane was added dropwise under reflux, the dropping rate was 8-15mL / min, the temperature was controlled at 60-70°C, solid was gradually precipitated, the dripping was completed, the temperature was cooled to room temperature, and the temperature was kept for 1h, filtered, the filter cake was rinsed with a mixed solution of tetrahydrofuran and n-heptane, and dried at 50°C to obtain pranoprofen fine product; In step b), the mass volume ratio of the pranoprofen dicyclohexylamine salt to dichloromethane is 1:20, tetrahydrofuran is added to the concentrate, the mass volume ratio of the pranoprofen dicyclohexylamine salt to tetrahydrofuran is 1:15, the mass volume ratio of the pranoprofen dicyclohexylamine salt to n-heptane is 1:30, and the volume ratio of dichloromethane to hydrochloric acid is 1:0.

5.

10. A pranoprofen dicyclohexylamine salt, having the structure:

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