阅读说明：本技术 一种氟比洛芬酯的纯化方法 (Method for purifying flurbiprofen axetil ) 是由 李文明 张斌 刘祥伟 姜丽华 秦建政 于 2020-05-11 设计创作，主要内容包括：本发明公开了一种氟比洛芬酯的纯化方法,首次将高压制备的方法应用于氟比洛芬酯的纯化工艺,开发了一种高效、稳定、更易于工业化生产的氟比洛芬酯纯化工艺。(The invention discloses a purification method of flurbiprofen axetil, which is characterized in that a high-pressure preparation method is applied to a purification process of flurbiprofen axetil for the first time, and a high-efficiency, stable and easily industrialized purification process of flurbiprofen axetil is developed.)

1. The method comprises the step of purifying a crude flurbiprofen axetil product by adopting a high-pressure preparation process, wherein a mobile phase in the high-pressure preparation process comprises a first mobile phase and a second mobile phase, the first mobile phase is ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, isopropyl ether, tetrahydrofuran or acetone, the second mobile phase is n-heptane, n-hexane or petroleum ether, and the volume ratio of the first mobile phase to the second mobile phase is 35: 65-2: 98.

2. The method for purifying flurbiprofen axetil according to claim 1, wherein the volume ratio of the first mobile phase to the second mobile phase in the high pressure preparation is 30:70 to 3: 97.

3. The method for purifying flurbiprofen axetil according to claim 1, wherein the volume ratio of the first mobile phase to the second mobile phase in the high pressure preparation is 5: 95.

4. The method of purifying flurbiprofen axetil according to claim 1, wherein the first mobile phase in the high pressure preparation is ethyl acetate.

5. The method of purifying flurbiprofen axetil according to claim 1, wherein the second mobile phase in the high pressure preparation is n-heptane.

6. The method for purifying flurbiprofen axetil according to claim 1, wherein the filler used for the high pressure preparation is a silica gel filler having a particle size of 5 to 50 μm, preferably 10 to 20 μm.

7. The method for purifying flurbiprofen axetil according to claim 1, characterized in that it comprises the following steps:

(1) adding (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid and 1-chloroethyl acetate into a solvent, controlling the temperature to react under the action of inorganic base, and filtering a product after the reaction is finished;

(2) decompressing the filtrate obtained in the step (1) to remove the solvent, raising the temperature to 80-170 ℃, and stirring for 1-36 hours under the vacuum condition of 0-30 mbar to obtain a crude flurbiprofen axetil product;

(3) preparing a crude flurbiprofen axetil product at high pressure, and collecting product components;

(4) decompressing the collected product components to remove the solvent to obtain flurbiprofen axetil;

the method for purifying flurbiprofen axetil according to claim 7, wherein: and (3) in the step (2), the high-temperature vacuum stirring temperature is 90-110 ℃, the high-temperature vacuum stirring vacuum degree is 0-10 mbar, and the high-temperature vacuum stirring duration time is 6-12 hours.

8. The method for purifying flurbiprofen axetil according to claim 7, characterized in that: and (4) performing reduced pressure rotary evaporation at the temperature of 40-120 ℃, the vacuum degree of the reduced pressure rotary evaporation of 0-10 mbar, and the duration of the reduced pressure rotary evaporation of 1-36 hours.

9. The method for purifying flurbiprofen axetil according to claim 7, characterized in that: and (4) performing reduced pressure rotary evaporation at the temperature of 60-80 ℃, the vacuum degree of the reduced pressure rotary evaporation of 0-5 mbar, and the duration of the reduced pressure rotary evaporation of 8-16 hours.

10. The method for purifying flurbiprofen axetil according to any one of claims 1 to 10, characterized in that the method produces the flurbiprofen axetil with a purity of greater than or equal to 99.9%, said method purifying the flurbiprofen axetil with a yield of greater than 69%.

11. The method for purifying flurbiprofen axetil according to any one of claims 1 to 10, characterized in that the method produces the flurbiprofen axetil in a purity of greater than or equal to 99.9%, said method purifying the flurbiprofen axetil in a yield of greater than 90%.

Technical Field

The invention belongs to the field of drug synthesis, and mainly relates to a method for purifying flurbiprofen axetil.

Background

Postoperative pain is a series of physiological, psychological and behavioral responses that occur after the body is injured by surgical stimulation or the like. The effective postoperative pain treatment not only relieves the pain of patients, but also is beneficial to the recovery of diseases, and has great social and economic benefits. Pain is one of the most common symptoms of cancer patients, and seriously affects the life quality of the cancer patients, if the cancer pain is not relieved, the patients feel extremely uncomfortable, the symptoms of anxiety, depression, hypodynamia, insomnia, anorexia and the like of the patients can be caused or aggravated, and the daily activities, the self-care ability, the communication ability and the whole life quality of the patients are seriously affected.

The flurbiprofen axetil is a novel nonsteroidal anti-inflammatory analgesic, is a prodrug of flurbiprofen, and is a first nonsteroidal targeted analgesic approved by SFDA. The flurbiprofen axetil has certain lipophilicity, and the characteristics of targeting effect and lipid solubility of the flurbiprofen axetil enable the flurbiprofen to easily cross cells, can be targeted and gathered at surgical incisions and inflammation parts after entering a human body, can be rapidly hydrolyzed under the action of carboxylesterase to generate flurbiprofen, reduces prostaglandin synthesis by inhibiting Cyclooxygenase (COX) at spinal cords and periphery, and simultaneously reduces the sensitivity of sensory nerve fibers to noxious stimulation and raises the pain threshold so as to play a role in advanced analgesia. The research finds that the advanced use of the cyclooxygenase inhibitor can eliminate the latent period before the onset of action, so that the cyclooxygenase inhibitor becomes an ideal medicament for advanced analgesia, and the flurbiprofen axetil can also reduce the rising level of bradykinin which is an immune response medium in tissues. The traditional Chinese medicine composition has wide application in postoperative pain relief and cancer patients of orthopedic patients, general surgery patients, neurosurgery patients, obstetrics and gynecology patients and thoracic surgery patients in recent years, and has long action time and low adverse reaction.

Flurbiprofen axetil was marketed domestically in 2004 by beijing tide pharmaceutical corporation under the trade name "kaifen" for the treatment of postoperative and cancer pain. Once the Kaifen comes into the market, the Kaifen has the advantages of short response time, strong drug effect, long drug effect duration and the like, relieves the pain of a plurality of patients suffering from surgical wounds and cancers, creates great social benefit, makes up for the market shortage of the non-steroidal anti-inflammatory drug injection in the market, and has great clinical application value.

The chemical name of flurbiprofen axetil is: (+/-) -2- (2-fluoro-4-biphenyl) propionic acid-1-acetoxy ethyl ester with molecular formula of C₁₉H₁₉FO₄Molecular weight of 330.36, and structural formula as follows:

the flurbiprofen axetil synthesis process is reported in a mature route, the flurbiprofen axetil is liquid in the purification aspect, and the currently reported purification method mainly comprises silica gel column chromatography, reduced pressure distillation and molecular distillation. For example, document cn201310079429.x employs a method of distillation under reduced pressure; document CN201210574448.5 reports a method for purifying flurbiprofen axetil by two molecular distillations; documents CN201510023365.0 and CN2018106098321.1 report purification methods using common silica gel for column chromatography; document CN201110404346.4 reports a purification method by adsorption on silica gel and activated carbon, and the like. In actual operation, the temperature of reduced pressure distillation is too high, the heat transfer efficiency is low, and the sample is exposed to high temperature for a long time to cause the decomposition of the flurbiprofen axetil. The molecular distillation equipment is expensive, the productivity is low, the yield of industrial production is limited, the molecular distillation device must ensure high vacuum degree of system pressure, the requirement on material sealing is high, the distance between an evaporation surface and a condensation surface is moderate, the equipment processing difficulty is high, and the manufacturing cost is high. The silica gel column chromatography has the defects of long purification period, large solvent amount and the like, so that the production cost of the product is high. Therefore, it is very important to develop a more efficient purification method which is easy to be industrialized.

With the progress of high-pressure preparation and separation technology and the reduction of material equipment cost, the application of the flurbiprofen axetil in the purification of the flurbiprofen axetil becomes a high-efficiency, stable and high-purity purification method, and has very important industrial application value.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to improve the production efficiency and the product quality so as to realize a purification method with simple operation, stable production and high efficiency.

In order to achieve the purpose of the invention, the technical scheme provided by the invention is as follows:

(1) adding (+/-) -2- (2-fluoro-4-biphenyl) -propionic acid and 1-chloroethyl acetate into a solvent, controlling the temperature to react under the action of inorganic base, filtering a reaction system after the reaction is finished, and keeping a filtrate;

(2) decompressing the filtrate obtained in the step (1) to remove the solvent, raising the temperature, and keeping vacuum stirring to obtain a flurbiprofen axetil crude product;

(3) preparing the crude flurbiprofen axetil obtained in the step (2) at high pressure, and collecting product components;

(4) and (4) removing the solvent from the product components collected in the step (3) under reduced pressure to obtain the flurbiprofen axetil.

Wherein the high-temperature vacuum stirring temperature in the step (2) is 80-170 ℃, and the further optimization is 90-110 ℃; the vacuum degree of the high-temperature vacuum stirring in the step (2) is 0-30 mbar, and 0-10 mbar is further preferred; and (3) the duration time of the high-temperature vacuum stirring in the step (2) is 1-36 hours, preferably 6-12 hours.

Wherein the high pressure preparation in step (3) comprises two mobile phases, wherein the first mobile phase is a solvent such as ethyl acetate, isopropyl acetate, butyl acetate, dichloromethane, isopropyl ether, tetrahydrofuran, acetone, etc., and in some embodiments, the first mobile phase is ethyl acetate; wherein the second mobile phase is selected from n-heptane, n-hexane, or petroleum ether, in certain embodiments the second mobile phase is n-heptane, and in certain embodiments the high pressure preparation uses a mobile phase consisting of ethyl acetate and n-heptane.

Wherein the volume ratio of the first mobile phase to the second mobile phase in the mobile phase prepared under high pressure in the step (3) is 35: 65-2: 98, and in some embodiments, the volume ratio of the first mobile phase to the second mobile phase is 30: 70-3: 97, and the volume ratio of the first mobile phase to the second mobile phase is about 5: 95.

The filler used in the high-pressure preparation in the step (3) is a silica gel filler, and the particle size is 5-50 μm, preferably 10-20 μm.

Wherein the reduced pressure rotary evaporation temperature in the step (4) of the invention is 40-120 ℃, preferably 60-80 ℃; in the step (4), the reduced pressure rotary evaporation vacuum degree is 0-10 mbar, preferably 0-5 mbar; in the step (4), the duration of the reduced pressure rotary evaporation is 1-36 hours, and more preferably 8-16 hours.

The method has a good purification effect on the crude flurbiprofen axetil, and the purity of the flurbiprofen axetil prepared by the method is more than or equal to 99.9 percent; the method provides a yield of purified flurbiprofen axetil of greater than 69%, the method provides a yield of purified flurbiprofen axetil of greater than 85%, and in certain embodiments, the method provides a yield of purified flurbiprofen axetil of greater than 90%.

The synthetic route of the invention is shown as the following formula:

。

drawings

Figure 1 high resolution mass spectrum of flurbiprofen axetil;

FIG. 2 is a nuclear magnetic-H spectrum of flurbiprofen axetil;

FIG. 3 is a nuclear magnetic-C spectrum of flurbiprofen axetil;

FIG. 4 is a liquid phase spectrum of flurbiprofen axetil in example 2;

fig. 5 is a liquid phase spectrum of flurbiprofen axetil of the comparative example.

Detailed Description

The present invention will be further described with reference to the following examples. It should be noted that the following examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, as many insubstantial modifications and variations of the invention may be made by those skilled in the art in light of the above teachings.

Experimental materials:

1. reagent:

2. instrumentation and equipment

Electronic balance, rotary evaporator, magnetic stirrer, three-mouth bottle, Buchner funnel, filter flask, Agilent liquid chromatograph-mass spectrometer, Waters high performance liquid chromatograph, Bruker nuclear magnetic resonance apparatus (400M), thermometer, high pressure liquid preparation.

Example 1: and (3) synthesizing flurbiprofen axetil.

Adding 200ml of tetrahydrofuran, 200.00g of flurbiprofen, 177.75g of ethyl 1-bromoacetate and 124.48g of anhydrous potassium carbonate, stirring and heating, keeping the temperature of a reaction system at 50 ℃ for reaction for 12 hours (monitoring the reaction by TLC) until the reaction is complete, cooling the reaction system to room temperature, carrying out suction filtration, leaching a filter cake with 200ml of tetrahydrofuran, combining filtrates, carrying out reduced pressure rotary evaporation at 60 ℃ to obtain 256.60g of crude flurbiprofen axetil as a colorless liquid, wherein the yield is 94.9%. Detection by HPLC: purity 99.449%; high scoreMass spectrum discrimination: 353.1163 [ M + Na ]]⁺；HNMR（400M，DMSO-d6）：1.37 (m, 6H)；1.92 (s, 1.5H)；2.05 (s, 1.5H)；3.93 (m, 1H)；6.79 (m, 1H)；7.22 (m, 2H)；7.24 (m, 1H)；7.49 (m, 3H)；7.54 (m, 2H)；CNMR（400M，DMSO-d6）：18.1855；19.0630；20.4066；43.6811；88.4700；115.2435；123.9570；127.7284；128.5027；128.6362；130.6661；134.7209；141.7928；157.6352；160.0844；168.5392；171.5338。

Example 2: purification of flurbiprofen axetil

Configuration of mobile phase: measuring 19L of n-heptane and 1L of ethyl acetate, and uniformly mixing the two for later use;

the preparation and separation method comprises the following steps: the instrument model is as follows: DAC100, detection wavelength: 254nm, flow rate: 200ml/min, mobile phase: ethyl acetate/n-heptane = 5/95; weighing a crude flurbiprofen axetil (120.00g) and dissolving in n-heptane (2400ml) for sample loading, performing separation preparation, collecting main peak components, performing reduced pressure rotary evaporation at 60 ℃, and obtaining 111.83g of flurbiprofen axetil colorless oily matter with the yield of 93.2% and the purity of 99.948% by HPLC detection.

Example 3: purification of flurbiprofen axetil

The preparation and separation method comprises the following steps: the instrument model is as follows: DAC50, detection wavelength: 254nm, flow rate: 50ml/min, mobile phase: ethyl acetate/n-heptane = 3/97; weighing a crude flurbiprofen axetil (9.60g) and dissolving in n-heptane (192ml) for sample loading, performing separation preparation, collecting main peak components, and performing rotary evaporation at 60 ℃ under reduced pressure to obtain 8.66g of flurbiprofen axetil colorless oily matter, wherein the yield is 90.2%, and the purity is 99.915% by HPLC detection.

Example 4: purification of flurbiprofen axetil

The preparation and separation method comprises the following steps: the instrument model is as follows: DAC50, detection wavelength: 254nm, flow rate: 50ml/min, mobile phase: isopropyl ether/n-heptane = 30/70; weighing the crude flurbiprofen axetil (2.50g) and dissolving in n-heptane (50ml), separating and preparing, collecting the main peak component, and carrying out rotary evaporation at 60 ℃ under reduced pressure to obtain 2.30g of flurbiprofen axetil colorless oily matter with yield of 92.0% and purity of 99.901% by HPLC detection.

Example 5: purification of flurbiprofen axetil

The preparation and separation method comprises the following steps: the instrument model is as follows: DAC50, detection wavelength: 254nm, flow rate: 50ml/min, mobile phase: dichloromethane/n-heptane = 35/65; weighing a crude flurbiprofen axetil (3.00g) and dissolving in n-heptane (60ml) for sample loading, performing separation preparation, collecting main peak components, and performing reduced pressure rotary evaporation at 60 ℃ to obtain 2.08g of flurbiprofen axetil colorless oily matter, wherein the yield is 69.3%, and the purity is 99.960% by HPLC detection.

Comparative example: purification of flurbiprofen axetil

Separation by ordinary silica gel column, eluent: ethyl acetate/n-heptane = 1/15; weighing a crude flurbiprofen axetil (10.00g), loading, separating, collecting a main peak component, and carrying out rotary evaporation at 60 ℃ under reduced pressure to obtain 4.85g of flurbiprofen axetil colorless oily matter, wherein the yield is 48.5%, and the purity is 99.760% by HPLC (high performance liquid chromatography).