Method for preparing flurbiprofen by recycling and reusing resolution mother liquor

Abstract

The invention relates to a method for recovering a solution rich in R-configuration flurbiprofen and then racemizing, the method is low in cost and simple to operate, continuous recovery and reuse of the R-configuration-rich flurbiprofen are realized, and the quality requirement of subsequent preparation of S-configuration flurbiprofen through further resolution of the flurbiprofen can be met.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to a method for recycling flurbiprofen split mother liquor. Background Art

[0002] Flurbiprofen is a nonsteroidal anti-inflammatory drug widely used in clinical practice for the treatment of rheumatoid arthritis, osteoarthritis, pain and other diseases. It mainly works by inhibiting COX (cyclooxygenase).

[0003] Flurbiprofen contains a pair of enantiomers (R)-flurbiprofen and (S)-flurbiprofen. A large number of public literature data show that the pharmacological activities and side effects of (R)-flurbiprofen and (S)-flurbiprofen are different. (S)-flurbiprofen has anti-inflammatory and analgesic effects, while (R)-flurbiprofen lacks significant cyclooxygenase inhibitory activity and has no anti-inflammatory effect. In addition, the presence of R-configuration enantiomers will increase the gastrointestinal side effects of flurbiprofen. Therefore, it is important to separate and use the flurbiprofen enantiomers.

[0004] Ifluprofen is the S-isomer of flurbiprofen, also known as S-flurbiprofen, and its chemical name is (S)-(+)-2-fluoro-α-methyl-4-felbinacetic acid. Ifluprofen patches are used for local joint osteoarthritis. The chemical structures of flurbiprofen (FP), S-flurbiprofen (SFP), and R-flurbiprofen (RFP) are as follows:

[0005]

[0006] A large number of documents have reported on the preparation method of (S)-flurbiprofen, which is mainly through the splitting of racemic flurbiprofen, and the splitting reagents include S(-)phenylethylamine, (S)-3-methyl-2-phenylbutylamine, glucamine, etc. The main problem of the existing flurbiprofen chemical splitting process is that flurbiprofen is prepared through multiple steps and the cost is relatively high. The ratio of R configuration and S configuration in flurbiprofen is 1:1, and S configuration flurbiprofen is obtained after splitting. At this time, the flurbiprofen salt in the mother liquor is rich in R configuration. The proportion of R configuration in the recovered flurbiprofen salt is generally greater than 70%, and the rest is S configuration flurbiprofen. This means that a large amount of raw materials are needed to obtain the target product (S)-flurbiprofen, and a large amount of waste will also be generated. The environmental cost and material cost of this method are both high. The existing technical situation is reported as follows:

[0007] Patent document CN118307400A discloses a method for preparing S-flurbiprofen using CIDT technology, using S-1-(4-substituted phenyl)ethylamine, and performing dynamic splitting under an organic base such as DBU (chemical name: 1,8-diazabicyclo[5.4.0]undec-7-ene), and then acid hydrolyzing the salt to obtain S-flurbiprofen. Studies have shown that the splitting efficiency of this method is low, the conversion rate of the R configuration to the S configuration is low, and the R configuration still accounts for the main proportion after racemization, which is greater than 70%, and it takes a long time, is not suitable for large-scale production, and has no industrial application value.

[0008] Patent document CN17430475A discloses a S-flurbiprofen crystal form, preparation method and application, wherein the resolving agent is glucosamine, and flurbiprofen rich in S configuration is obtained through three steps of salification, freeing and recrystallization. According to the embodiment, 2kg flurbiprofen can produce about 0.58Kg S-flurbiprofen. The document does not further disclose the high process cost of the recovery method of flurbiprofen rich in R configuration after salification.

[0009] Patent WO2010001103A1, page 16, reports a method for reclaiming flurbiprofen by splitting disease: using aniline to split flurbiprofen, then decompressing the filtrate enriched with R-flurbiprofen salt to remove methanol, treating the toluene layer with acid to remove the resolving agent, adding alkali and methanol to reflux in toluene for racemization, then concentrating at normal pressure to remove methanol, cooling, and adjusting pH to about 1.0 to obtain racemic flurbiprofen. However, operations such as filtrate recovery, removal of the resolving agent, and high-temperature racemization all require manual operation to complete. The whole process is extremely cumbersome and complicated, and is not suitable for industrial production.

[0010] Therefore, it is of positive significance to further racemize the R-configuration-rich flurbiprofen and use it as a starting material for chemical separation to prepare S-flurbiprofen, thereby reducing the preparation cost of S-flurbiprofen.

[0011] Therefore, it is very necessary to develop a low-cost method for recovering and applying R-rich flurbiprofen that can solve the above-mentioned technical problems and further racemize the R-rich flurbiprofen. Summary of the invention

[0012] In order to address the deficiencies in the prior art, the invention provides a method for recovering a solution of flurbiprofen rich in R-configuration and then racemizing it. The method has low cost and simple operation, realizes the continuous recovery and utilization of flurbiprofen rich in R-configuration, and can meet the quality requirements for the subsequent further separation of flurbiprofen to prepare S-configuration flurbiprofen.

[0013] In order to achieve the purpose of the present invention, the present invention provides the following technical solution, comprising the following steps:

[0014] 1) cooling and precipitating a methanol solution of flurbiprofen octylglucamine salt rich in R-configuration, and desalting with a hydrochloric acid solution;

[0015] 2) After the desalting is completed, the product is extracted with an organic solvent and concentrated to obtain a product rich in R-flurbiprofen;

[0016] 3) adding the R-configuration-rich flurbiprofen to an aqueous solution of an inorganic base and heating for racemization reaction;

[0017] 4) After the reaction is completed, add acid to adjust the pH to 1-3, cool and filter to obtain flurbiprofen;

[0018] Furthermore, in step 1), the flurbiprofen glucamine salt is rich in R-configuration, wherein the R configuration is significantly greater than the S configuration, and the R configuration is greater than 70%; the desalting solution is a 1-8 mol / L hydrochloric acid solution, preferably 2-5 mol / L; the mass volume ratio of flurbiprofen glucamine salt and hydrochloric acid solution is 1:3-10, preferably 1:5, and the cooling temperature is 5-10°C.

[0019] Studies have shown that the solubility of flurbiprofen glucamine salt in the resolution solvent methanol is closely related to temperature. When the temperature is higher than 30°C, S-flurbiprofen glucamine salt is mainly precipitated, and when the temperature is further reduced to 5-10°C, R-flurbiprofen glucamine salt begins to precipitate in large quantities. The present invention uses the difference in solubility of two different configurations of flurbiprofen glucamine salt in methanol to

[0020] The product is separated and quickly recovered to obtain R-flurbiprofen octylglucamine salt.

[0021] Furthermore, in step 2), the organic solvent is selected from ethyl acetate, dichloromethane, methyl tert-butyl ether, diethyl ether, etc., preferably dichloromethane.

[0022] Furthermore, in step 3), the inorganic base is selected from sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; the concentration of the sodium hydroxide aqueous solution is 10-40%, preferably 25%; the mass volume ratio of flurbiprofen to the alkaline solution is 1:3-10, preferably 1:5;

[0023] The reaction temperature is selected from 50 to 100°C, preferably 70 to 90°C.

[0024] Furthermore, after the racemization reaction in step 4) is completed, the pH is adjusted to 1-3 with 1-8 mol / L hydrochloric acid solution, cooled to 0-10° C. to precipitate flurbiprofen, filtered and dried to obtain flurbiprofen, with an HPLC purity of more than 99% and an R / S ratio of 1:1.

[0025] The beneficial effects of the present invention are:

[0026] 1) The provided method for racemization of flurbiprofen octylglucamine salt rich in R-configuration realizes the recovery and application of flurbiprofen, and theoretically realizes that flurbiprofen can be 100% converted into S-flurbiprofen, while greatly reducing the treatment cost of waste salt, which is conducive to green industrial production.

[0027] 2) The recovered flurbiprofen has a high purity of greater than 99%, and can be directly used for the subsequent separation of S-flurbiprofen without further purification, thereby reducing the production cost of S-flurbiprofen.

[0028] 3) R-flurbiprofen octyl glucamine salt is obtained by cooling and splitting the mother liquor, and racemization is carried out by using an inorganic alkali aqueous solution. The recovery process is simple, easy to operate, and suitable for industrial operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 HPLC purity test diagram of R / S configuration prepared in Comparative Example 1

[0030] Figure 2 The R / S configuration HPLC purity test diagram of Example 1

[0031] Figure 3 HPLC purity test diagram of flurbiprofen octyl glucamine salt rich in R configuration of Example 2

[0032] Figure 4 HPLC purity test chart of S-type flurbiprofen obtained in Example 2

[0033] Figure 5 HPLC purity test chart of flurbiprofen obtained in Example 3 DETAILED DESCRIPTION

[0034] In order to further illustrate the present invention, the continuous recovery and application of R-rich flurbiprofen provided by the present invention is described in detail below in conjunction with the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0035] Comparative Example 1 Preparation of S-flurbiprofen by racemization of flurbiprofen recovered from DBU

[0036] 0.1 kg of solid containing 81% R-configuration flurbiprofen glucamine salt was dissolved in 0.5 L 4 mol / L hydrochloric acid solution, stirred at room temperature for about 1 hour, and then 0.5 L × 3 dichloromethane was added to the solution for extraction, and the organic phases were combined and concentrated under reduced pressure to obtain 40.1 g of solid rich in R-flurbiprofen. The solid rich in R-flurbiprofen was added to 50 g DBU, heated to 95 ° C, stirred for 24 hours, and the reaction was monitored by HPLC to find that the R / S configuration was 71:29, and the conversion rate was low compared with the initial.

[0037] Example 1 Preparation of Flurbiprofen from 75% R-configuration Flurbiprofen Octylglucamine Salt

[0038] 1.0 kg of solid containing 81% R-configuration flurbiprofen glucamine salt was dissolved in 5L 4mol / L hydrochloric acid solution, stirred at room temperature for about 1 hour, and then 5L×3 dichloromethane was added to the solution for extraction, the organic phases were combined, and concentrated under reduced pressure to obtain 412.7 g of solid rich in R-flurbiprofen. The solid rich in R-flurbiprofen was added to 2L of 25% sodium hydroxide aqueous solution, heated to 95°C, stirred for reaction for 3 hours, and the reaction was terminated when the R and S configurations were 1:1 by HPLC monitoring, and 2mol / L dilute hydrochloric acid was added to adjust the pH to 2.5, cooled to 5°C, flurbiprofen solid was precipitated, filtered, and dried to obtain 375.6 g of flurbiprofen, and the R / S configuration was 1:1 by HPLC detection.

[0039] Example 2 Preparation of S-flurbiprofen from recovered flurbiprofen

[0040] Weigh 245 g of recovered flurbiprofen and 300 g of octylglucamine into a reaction bottle, add 200 ml of methanol, stir and heat to 55-65 ° C for salt formation reaction; after reacting for 3 hours, cool to 35-40 ° C, add 0.5% seed crystals, continue to slowly cool to 30-35 ° C and stir for 1-2 hours, keep warm and filter to obtain 270 g of crude S-flurbiprofen octylglucamine salt.

[0041] The filtrate was further cooled to 5-10° C. to precipitate 470 g of R-configuration-rich flurbiprofen octyl glucamine salt solid (R / S configuration: 80.98% / 18.94%) for recycling.

[0042] Take 270g of crude S-flurbiprofen glucamine salt and recrystallize it with a 50% methanol-water mixed solution to obtain S-flurbiprofen glucamine salt. Add water to the S-flurbiprofen glucamine salt, adjust the pH to 2.0 with dilute hydrochloric acid, stir and react for 1 hour, add 600ml of dichloromethane, stand and separate the liquids, and concentrate the organic layer under reduced pressure at 40°C to obtain 110g of S-flurbiprofen with a chromatographic purity of 99.93%.

[0043] Example 3 Preparation of Flurbiprofen from 81% R-configuration Flurbiprofen Octylglucamine Salt

[0044] 0.2Kg of R-rich flurbiprofen glucamine salt (R / S configuration is 80.98% / 18.94%) solid was dissolved in 1L3mol / L hydrochloric acid aqueous solution, stirred at room temperature for about 0.5 hours, and then 1L×3 ethyl acetate was added to the solution for extraction, the organic phases were combined, and the solid was concentrated under reduced pressure to obtain 82.5g of R-rich flurbiprofen. The solid rich in R-flurbiprofen was added to 20% sodium hydroxide aqueous solution, heated to 85°C, stirred for reaction, and the reaction was terminated when the R and S configurations were 1:1 by HPLC monitoring, and 2mol / L dilute hydrochloric acid was added to adjust the pH to 2.0, cooled to 5°C, flurbiprofen solid was precipitated, filtered, and dried to obtain 72.6g of flurbiprofen, which was detected by HPLC, and the chromatographic purity was 99.87%.

[0045] The above description is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several improvements without departing from the principle of the present invention, and these improvements should also be regarded as within the protection scope of the present invention.

Claims

1. A method for recovering and applying flurbiprofen, characterized in that: The steps include: 1) cooling and precipitating a methanol solution of flurbiprofen octyl glucamine salt rich in R-configuration, and desalting with a hydrochloric acid solution; 2) extracting with organic solvent after desalting and concentrating to obtain flurbiprofen rich in R-configuration; 3) adding R-configuration-rich flurbiprofen to an aqueous solution of an inorganic base and heating for racemization reaction; 4) After the reaction is completed, the pH is adjusted to 1-3, cooled and filtered to obtain flurbiprofen; The inorganic acid is a 1-8 mol / L hydrochloric acid solution, and the inorganic base is a 10-40% sodium hydroxide solution; The R-configuration-rich flurbiprofen octyl glucamine salt has an R configuration greater than 70%.

2. The method for recovering and applying flurbiprofen according to claim 1, characterized in that: The mass volume ratio of R-flurbiprofen glucamine salt and hydrochloric acid in step 1) is 1:3-10.

3. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that: The mass volume ratio of R-flurbiprofen glucamine salt and hydrochloric acid in step 1) is 1:

5.

4. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that: The cooling temperature of step 1) is 5~10℃.

5. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that: The organic solvent in step 2) is selected from ethyl acetate, dichloromethane, methyl tert-butyl ether, and diethyl ether.

6. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that: The organic solvent in step 2) is selected from dichloromethane and ethyl acetate.

7. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that In step 3), the mass volume ratio of flurbiprofen to sodium hydroxide solution is 1:3-10; and the reaction temperature is 50-100°C.

8. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that: The concentration of the sodium hydroxide solution in step 3) is 25%; the mass volume ratio of flurbiprofen to the sodium hydroxide solution is 1:5; and the reaction temperature is 70-90°C.

9. The method for recovering and reusing flurbiprofen according to claim 1, characterized in that: In step 4), after the racemization reaction is completed, the pH is adjusted to 1-3 with 1-8 mol / L hydrochloric acid solution, and the mixture is cooled to 0-10° C. to precipitate flurbiprofen.

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