Preparation method of S-flurbiprofen

Abstract

The invention belongs to the field of medical technology and drug analysis, and discloses a preparation method of S-flurbiprofen, which sequentially comprises the following steps: S1, carrying out salt forming reaction on flurbiprofen and a resolving agent in an alcohol solvent, and crystallizing to obtain an S-flurbiprofen phenylethylamine salt crude product; s2, taking the S-flurbiprofen phenylethylamine salt crude product, and carrying out recrystallization, so as to obtain the S-flurbiprofen phenylethylamine salt; and S3, taking the S-flurbiprofen phenylethylamine salt, adding hydrochloric acid, and filtering to obtain the S-flurbiprofen. The method can be used for preparing the S-flurbiprofen with high purity and high yield. The method is suitable for industrial production of S-flurbiprofen.

Description

Technical Field

[0001] The invention belongs to the fields of medical technology and drug analysis, and relates to a preparation method of S-flurbiprofen. Background Art

[0002] Flurbiprofen, chemically known as (±)-2-(2-fluoro-4-biphenyl)propionic acid, is a racemic compound and a fluorinated nonsteroidal anti-inflammatory drug (NSAID) that holds a significant position in the pharmaceutical field. Clinically, it is primarily indicated for the treatment of various inflammatory diseases, including rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis, effectively alleviating pain and inflammatory symptoms and improving patients' quality of life.

[0003] At present, the flurbiprofen sold on the market and used clinically is mainly its racemate. However, relevant studies have shown that there are significant differences in the effects of different enantiomers in the racemate. Research by Brume and other scholars found that the anti-inflammatory activity of flurbiprofen mainly comes from its S-enantiomer, namely S-flurbiprofen. This is because S-flurbiprofen can more effectively inhibit the activity of cyclooxygenase, which plays a key role in the inflammatory response. After cyclooxygenase is inhibited, the synthesis of inflammatory mediators prostaglandins is reduced, thereby exerting an anti-inflammatory effect. In sharp contrast, R-flurbiprofen lacks significant cyclooxygenase inhibitory activity and makes almost no contribution to anti-inflammatory effects.

[0004] Of particular concern is the close association between flurbiprofen's gastrointestinal adverse reactions and the presence of R-flurbiprofen. While the specific mechanism of action remains unclear, studies have shown that R-flurbiprofen may irritate or damage the gastrointestinal mucosa, leading to an increased incidence of gastrointestinal adverse reactions such as gastric ulcers and gastric bleeding, posing certain risks to patient treatment.

[0005] Furthermore, due to the excellent anti-inflammatory activity of S-flurbiprofen, half the amount of S-flurbiprofen can achieve the same therapeutic effect. This not only reduces the amount of drug used, but also reduces the adverse reactions caused by the use of the racemic R-flurbiprofen, thereby improving the safety and effectiveness of the drug. Therefore, research on the preparation method of S-flurbiprofen is of great significance. Summary of the Invention

[0006] In order to solve the above deficiencies in the prior art, the present invention aims to provide a method for preparing S-flurbiprofen, so as to achieve the purpose of preparing high-purity and high-yield S-flurbiprofen.

[0007] To achieve the above object, the technical solutions adopted by the present invention are as follows:

[0008] A method for preparing S-flurbiprofen comprises the following steps performed in sequence:

[0009] S1, flurbiprofen and a resolving agent undergo salt-forming reaction in an alcohol solvent, followed by crystallization to obtain a crude product of S-flurbiprofen phenethylamine salt;

[0010] S2, taking the crude product of S-flurbiprofen phenethylamine salt, and recrystallizing it to obtain S-flurbiprofen phenethylamine salt;

[0011] S3, take S-flurbiprofen phenethylamine salt, add hydrochloric acid, filter, and prepare S-flurbiprofen.

[0012] As a limitation of the present invention, the recrystallization comprises the following steps: taking a crude product of S-flurbiprofen phenethylamine salt, adding an alcohol solvent, heating to 30-80°C, stirring for 0.5-1h, cooling to 0-30°C, filtering, taking a filter cake, adding an alcohol solvent, heating to 30-80°C, stirring for 0.5-1h, cooling to 0-30°C, filtering to obtain S-flurbiprofen phenethylamine salt.

[0013] As a further limitation of the present invention, the recrystallization comprises the following steps: taking a crude product of S-flurbiprofen phenethylamine salt, adding an alcohol solvent, heating to 50-70°C, stirring for 0.5-1h, cooling to 0-30°C, filtering, taking a filter cake, adding an alcohol solvent, heating to 50-70°C, stirring for 0.5-1h, cooling to 0-30°C, filtering to obtain S-flurbiprofen phenethylamine salt.

[0014] As a further limitation of the present invention, the resolving agent is S-1-phenylethylamine;

[0015] The alcohol solvent includes at least one of methanol, ethanol, isopropanol or n-propanol.

[0016] As a further limitation of the present invention, the molar ratio of flurbiprofen to the resolving agent is 1:0.5-1.

[0017] As a further limitation of the present invention, the ratio of flurbiprofen to alcohol solvent is 1 g: 5 to 15 mL;

[0018] The temperature of the salt formation reaction is 30-80° C., and the time is 0.5-1 h.

[0019] As a further limitation of the present invention, the ratio of flurbiprofen to alcohol solvent is 1 g: 5-10 mL;

[0020] The temperature of the salt formation reaction is 50-70°C.

[0021] As a further limitation of the present invention, the crystallization temperature is 0-30°C.

[0022] As a further limitation of the present invention, the usage ratio of the crude S-flurbiprofen phenethylamine salt to the alcohol solvent is 1 g:5-25 mL, and the usage ratio of the filter cake to the alcohol solvent is 1 g:5-25 mL.

[0023] As a further limitation of the present invention, the usage ratio of the crude S-flurbiprofen phenethylamine salt to the alcohol solvent is 1 g:10-20 mL, and the usage ratio of the filter cake to the alcohol solvent is 1 g:10-20 mL.

[0024] Due to the adoption of the above technical solution, the present invention has the following beneficial effects compared with the prior art:

[0025] (1) The present invention can improve the purity of the product S-flurbiprofen and reduce the residual amount of the isomer R-flurbiprofen. The content of S-flurbiprofen in the prepared product is greater than 99.8%, and the content of R-flurbiprofen is less than 0.2%.

[0026] (2) The present invention improves the product yield, and the total product yield can reach 35-45% (the theoretical yield is 50%).

[0027] (3) The present invention uses a single alcohol solvent for separation and purification, which is simple to operate.

[0028] (4) The preparation method of the present invention is simple to operate, has a short reaction time, and has high product purity and high yield, and is suitable for industrial production.

[0029] The invention is suitable for preparing S-flurbiprofen and is used for industrial production of S-flurbiprofen. DETAILED DESCRIPTION

[0030] The present invention is further described in detail below through specific examples. It should be understood that the described examples are only used to illustrate the present invention and are not intended to limit the present invention.

[0031] Unless otherwise specified, the materials and reagents used in the examples of the present invention can be obtained from commercial sources. Experimental methods without specific conditions in the examples are generally performed under conventional conditions or the conditions recommended by the manufacturer.

[0032] Example 1 A method for preparing S-flurbiprofen

[0033] This embodiment includes the following steps:

[0034] S1. Weigh 50 g, 0.2 mol, flurbiprofen and add it to 250 ml of isopropanol. After the addition is complete, heat it to 70° C. and stir to dissolve. Then add (24.8 g, 0.2 mol) of S-1-phenylethylamine. After the addition is complete, keep warm and stir for 1 hour, then cool it to 30° C., stir and crystallize, filter, and dry to obtain 37 g of crude S-flurbiprofen phenylethylamine salt, with a yield of 99%.

[0035] S2, weighed (35 g, 95.5 mmol) of crude S-flurbiprofen phenethylamine salt, added to 350 ml of ethanol, heated to 50 ° C, stirred and dissolved for 0.8 h, then cooled to 30 ° C, stirred and crystallized, filtered, the filter cake was added to 350 ml of ethanol, heated to 70 ° C, stirred and dissolved for 0.8 h, then cooled to 30 ° C, stirred and crystallized, filtered, and dried to obtain 29.5 g of S-flurbiprofen phenethylamine salt, with a yield of 84.3%.

[0036] S3, take (29 g, 78.9 mmol) of S-flurbiprofen phenethylamine salt, add hydrochloric acid, filter, and obtain 18.8 g of S-flurbiprofen with a yield of 95.3%. After testing, the chiral purity of S-flurbiprofen is 99.85%, R-flurbiprofen is 0.15%, and the purity of related substances is 99.793%.

[0037] Example 2 A method for preparing S-flurbiprofen

[0038] This embodiment includes the following steps:

[0039] S1. Weigh 50 g, 0.2 mol, flurbiprofen and add it to 500 ml of methanol. After the addition is complete, heat it to 60 ° C and stir to dissolve. Then add (12.4 g, 0.1 mol) of S-1-phenylethylamine. After the addition is complete, keep warm and stir for 1 hour, then cool it to 0 ° C, stir and crystallize, filter, and dry to obtain 37 g of crude S-flurbiprofen phenylethylamine salt, with a yield of 99%.

[0040] S2, weighed (35g, 95.5mmol) of crude S-flurbiprofen phenethylamine salt was added to 700ml of isopropanol, heated to 70°C, stirred and dissolved for 1h, then cooled to 0°C, stirred and crystallized, filtered, and the filter cake was added to 700ml of isopropanol, heated to 50°C, stirred and dissolved for 1h, then cooled to 15°C, stirred and crystallized, filtered, and dried to obtain 30.2g of S-flurbiprofen phenethylamine salt, with a yield of 86.3%.

[0041] S3, take (29.5 g, 80.8 mmol) of S-flurbiprofen phenethylamine salt, add hydrochloric acid, filter, and obtain 19.2 g of S-flurbiprofen with a yield of 95.1%. After testing, the chiral purity of S-flurbiprofen is 99.83%, R-flurbiprofen is 0.17%, and the purity of related substances is 99.824%.

[0042] Example 3 A method for preparing S-flurbiprofen

[0043] This embodiment includes the following steps:

[0044] S1. Weigh 50 g, 0.2 mol, flurbiprofen and add it to 400 ml of ethanol. After the addition is complete, heat it to 50 ° C and stir to dissolve. Then add (18.6 g, 0.15 mol) of S-1-phenylethylamine. After the addition is complete, keep warm and stir for 0.8 h, then cool it to 15 ° C, stir and crystallize, filter, and dry to obtain 37 g of crude S-flurbiprofen phenylethylamine salt, with a yield of 99%.

[0045] S2, weighed (35g, 95.5mmol) of crude S-flurbiprofen phenethylamine salt was added to 600ml of isopropanol, heated to 60°C, stirred and dissolved for 0.5h, then cooled to 15°C, stirred and crystallized, filtered, and the filter cake was added to 600ml of isopropanol, heated to 60°C, stirred and dissolved for 0.5h, then cooled to 0°C, stirred and crystallized, filtered, and dried to obtain 30.6g of S-flurbiprofen phenethylamine salt, with a yield of 87.4%.

[0046] S3, take (30 g, 81.8 mmol) of S-flurbiprofen phenethylamine salt, add hydrochloric acid, filter, and obtain 19.8 g of S-flurbiprofen with a yield of 96.8%. After testing, the chiral purity of S-flurbiprofen is 99.85%, R-flurbiprofen is 0.15%, and the purity of related substances is 99.793%.

[0047] It should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art may still modify the technical solutions described in the above embodiments or replace some of the technical features therein with equivalents. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing S-flurbiprofen, characterized in that, The process includes the following steps: S1, flurbiprofen and a resolving agent undergo salt-forming reaction in an alcohol solvent, followed by crystallization to obtain a crude product of S-flurbiprofen phenethylamine salt; S2, taking crude S-flurbiprofen phenethylamine salt and recrystallizing it to obtain S-flurbiprofen phenethylamine salt; S3, taking S-flurbiprofen phenethylamine salt, adding hydrochloric acid, filtering, and preparing S-flurbiprofen.

2. The preparation method of S-flurbiprofen according to claim 1, wherein The recrystallization comprises the following steps: taking a crude product of S-flurbiprofen phenethylamine salt, adding an alcohol solvent, heating to 30-80° C., stirring for 0.5-1 hour, cooling to 0-30° C., filtering, taking a filter cake, adding an alcohol solvent, heating to 30-80° C., stirring for 0.5-1 hour, cooling to 0-30° C., filtering, and obtaining S-flurbiprofen phenethylamine salt.

3. The preparation method of S-flurbiprofen according to claim 2, wherein The recrystallization comprises the following steps: taking a crude product of S-flurbiprofen phenethylamine salt, adding an alcohol solvent, heating to 50-70° C., stirring for 0.5-1 hour, cooling to 0-30° C., filtering, taking a filter cake, adding an alcohol solvent, heating to 50-70° C., stirring for 0.5-1 hour, cooling to 0-30° C., filtering, and obtaining S-flurbiprofen phenethylamine salt.

4. The preparation method of S-flurbiprofen according to claim 3, wherein The resolving agent is S-1-phenylethylamine; The alcohol solvent includes at least one of methanol, ethanol, isopropanol or n-propanol.

5. The preparation method of S-flurbiprofen according to claim 4, wherein The molar ratio of flurbiprofen to the resolving agent is 1:0.5-1.

6. The preparation method of S-flurbiprofen according to claim 5, wherein The amount ratio of flurbiprofen to alcohol solvent is 1g:5~15mL; The temperature of the salt formation reaction is 30-80° C., and the time is 0.5-1 h.

7. The preparation method of S-flurbiprofen according to claim 6, wherein The amount ratio of flurbiprofen to alcohol solvent is 1g:5~10mL; The temperature of the salt formation reaction is 50-70°C.

8. The preparation method of S-flurbiprofen according to claim 7, wherein The crystallization temperature is 0-30°C.

9. The preparation method of S-flurbiprofen according to claim 8, wherein The usage ratio of the crude S-flurbiprofen phenethylamine salt to the alcohol solvent is 1 g: 5-25 mL, and the usage ratio of the filter cake to the alcohol solvent is 1 g: 5-25 mL.

10. The method for preparing S-flurbiprofen according to claim 9, wherein The usage ratio of the crude S-flurbiprofen phenethylamine salt to the alcohol solvent is 1 g:10-20 mL, and the usage ratio of the filter cake to the alcohol solvent is 1 g:10-20 mL.