Preparation method of fenbufen bulk drug impurity I

Abstract

The invention discloses a preparation method of a fenbufen bulk drug impurity I. The preparation method of the fenbufen bulk drug impurity I comprises the following steps: mixing fenbufen, an alcohol substance and hydrochloric acid, stirring and heating for reaction; and after the reaction is finished, cooling and continuously stirring to crystallize, then carrying out suction filtration to obtain a filter cake, and directly drying or purifying the filter cake and then drying to obtain the fenbufen bulk drug impurity I. The feeding process is simple, the required raw materials are easy to obtain, and the preparation period is short. The purity of the fenbufen impurity I prepared by the method is high, and the preparation problem of the impurity I in fenbufen bulk drugs is effectively solved. The method can be applied to qualitative and quantitative research and detection of the fenbufen impurity I, and provides great convenience for quality control of fenbufen bulk drugs and related preparations thereof.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical industry, and in particular relates to a method for preparing impurity I of fenbufen raw material medicine. Background Art

[0002] Fenbufen (Formula I), chemically known as 3-(4-biphenylcarbonyl) propionic acid, is a white or off-white needle-shaped crystal and a long-acting non-steroidal anti-inflammatory analgesic. Its mechanism of action is to inhibit the synthesis of prostaglandins. It is used to treat symptoms such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and gout.

[0003] Fenbufen impurity I (Formula II), chemically named 4-(biphenyl-4-yl)-4-oxobutyric acid ethyl ester, is an esterified impurity that is difficult to avoid in the preparation of fenbufen. According to the Chinese Pharmacopoeia, the limit of this impurity shall not exceed 0.5%. The preparation and research of this impurity is of great significance for the process research and quality control of fenbufen API and its preparations.

[0004] The structural formulas of fenbufen and fenbufen impurity I are as follows:

[0005] Chinese patent CN110330427A provides a synthetic route for fenbufen methyl ester and fenbufen API. The scheme is to use N-(octaaminoquinoline) but-3-enamide and 4-bromobiphenyl as starting materials, anhydrous 2,3-butanediol as solvent, and allyl palladium (II) chloride dimer as catalyst under an inert atmosphere, and then stir vigorously in an oil bath at 125-135°C for 12 hours to obtain compound a with a directing group. After purification, compound a is added to an ethanol solvent containing sodium hydroxide and heated to reflux for 12 hours to obtain fenbufen butyric acid. Then fenbufen butyric acid, p-toluenesulfonic acid and methanol are mixed and refluxed for 6 hours to obtain fenbufen butyric acid methyl ester. Then fenbufen butyric acid methyl ester and potassium peroxymonosulfonate are added to nitromethane, and potassium bromide is added at the same time, and the reaction is carried out at 50°C for 24 hours. The reaction product is subjected to vacuum distillation (the pressure of the vacuum distillation is 100 mbar and the temperature is above 80°C) to remove the solvent, and then purified by silica gel column to obtain the fenbufen methyl ester product. This route has a long synthesis step, complicated operation, and expensive raw materials. The product is purified by column chromatography many times, and the overall yield is low.

[0006] The mainstream synthesis process of fenbufen is to use aluminum chloride as a catalyst, use biphenyl and succinic anhydride to carry out FC acylation reaction to prepare, and then fenbufen raw materials are obtained by refining. In this reaction process, impurity I is inevitably produced. At present, the acquisition scheme of impurity I is mainly to purify and separate the trace by-products in the preparation process of fenbufen, which is time-consuming and inefficient. At present, no effective preparation scheme of impurity I has been retrieved. It can be seen that there is an urgent need to design an efficient, economical and specific method for synthesizing fenbufen impurity I to meet the needs of fenbufen impurity process research. Summary of the invention

[0007] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing impurity I of fenbufen raw material drug, aiming to solve the problems existing in the above-mentioned background technology and propose a faster, lower-cost and more efficient synthesis scheme to prepare fenbufen impurity I to meet the high standard requirements of fenbufen impurity reference substances.

[0008] The purpose of the present invention is achieved through the following technical solutions: A method for preparing impurity I of fenbufen raw material medicine comprises the following steps: mixing fenbufen, an alcohol substance and hydrochloric acid, stirring and heating to react; after the reaction is completed, cooling and continuing stirring to crystallize, then filtering to obtain a filter cake, and directly drying the filter cake or drying it after purification to obtain impurity I of fenbufen raw material medicine.

[0009] Preferably, the alcohol substance is anhydrous ethanol or 95% ethanol.

[0010] Preferably, the mass ratio of fenbufen to alcohol is 1:10-30, more preferably 1:15.

[0011] Preferably, the mass ratio of hydrochloric acid to fenbufen is 1:1-3, more preferably 1:2.5.

[0012] Preferably, the concentration of hydrochloric acid is 21-37%, more preferably 37%.

[0013] Preferably, the reaction temperature is 50-80°C, more preferably 80°C.

[0014] Preferably, the reaction time is 4 to 8 hours, more preferably 5 hours.

[0015] Preferably, the cooling is to cool to 0-20°C and continue stirring to precipitate crystals, more preferably to cool to 0°C.

[0016] Preferably, the filter cake is directly dried under reduced pressure.

[0017] Preferably, the purification treatment method is: purification by silica gel column chromatography, the silica gel column is a normal phase silica gel column, the mobile phase is ethyl acetate / petroleum ether = 1 / 3 (v / v), and the flow rate is 30 mL / min.

[0018] The chemical reaction formula involved in the present invention is as follows:

[0019] The reaction mechanism involved in the present invention is: fenbufen raw material is used as the reaction raw material, ethanol is used as both the raw material and the reaction solvent, and hydrochloric acid is used as a catalyst. Under acidic conditions, carboxylic acid substances and alcohol substances undergo esterification reaction to obtain esterification products.

[0020] Compared with the prior art, the beneficial effects of the present invention include: (1) The method of the present invention has the characteristics of easy availability of raw materials, simple operation, short preparation cycle, high yield, and high purity of the prepared fenbufen impurity I. It meets the requirements of impurity reference materials and can be used as a fenbufen impurity I standard. It is suitable for qualitative and quantitative research and detection of fenbufen impurities, and has great significance for the quality control of fenbufen raw materials and related preparations.

[0021] (2) The present invention adopts the above technical solution to provide a method for preparing fenbufen impurity I. The fenbufen impurity I prepared by the above technical solution has a crude purity of up to 96%. After conventional column chromatography purification, the purity can reach 99.9%, which meets the requirements of impurity reference materials. This solution makes up for the shortcomings of the existing technology, has a reasonable design, and is easy to operate. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The HPLC spectrum of the product described in Example 1 is shown in FIG.

[0023] Figure 2 The HPLC spectrum of the product described in Example 2 is shown in FIG. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0025] If the manufacturer of the reagents or instruments is not specified in the examples, conventional products can be purchased from the market. If the specific conditions are not specified, conventional conditions or conditions recommended by the manufacturer can be used.

[0026] Example 1 A method for preparing impurity I of fenbufen bulk drug, comprising the following steps: Add 20 g of fenbufen and 300 g of anhydrous ethanol to a 500 mL reaction bottle, then slowly add 2.5 g of 37 wt% hydrochloric acid to the reaction bottle, heat to 80 ° C, stir and reflux for 5 hours; after the reaction is completed, place in an ice water bath, stir and crystallize for 2 hours, filter the crystallized material, rinse the filter cake with 20 mL of ethanol, and dry the filter cake under reduced pressure at 50 ° C for 5 hours.

[0027] The HPLC test showed that the product was impurity I of fenbufen raw material drug with a purity of 96% and a yield of 98%.

[0028] Example 2 A method for preparing impurity I of fenbufen bulk drug, comprising the following steps: Add 20g of fenbufen and 300g of anhydrous ethanol to a 500mL reaction bottle, then slowly add 2.5g of 37wt% hydrochloric acid to the reaction bottle, heat to 80°C, stir and reflux for 5h; after the reaction is completed, place in an ice water bath, stir and crystallize for 2h, filter the crystallized material, rinse the filter cake with 20mL of ethanol, and purify the filter cake by column chromatography, using reagent grade normal phase silica gel, 200~300 mesh, ethyl acetate / petroleum ether (volume ratio of 1:3) as the mobile phase, and the flow rate is 30 mL / min to obtain an eluent; the eluent is concentrated under reduced pressure and dried under reduced pressure at 50°C for 5h.

[0029] The HPLC test showed that the product was impurity I of fenbufen raw material drug with a purity of 99.9% and a yield of 95%.

[0030] Example 3 A method for preparing impurity I of fenbufen bulk drug, comprising the following steps: Add 20g of fenbufen and 300g of anhydrous ethanol to a 500mL reaction bottle, then slowly add 2.5g of 37wt% hydrochloric acid to the reaction bottle, heat to 50°C, stir and reflux for 5h; after the reaction is completed, place in an ice water bath, stir and crystallize for 2h, filter the crystallized material, rinse the filter cake with 20mL of ethanol, and purify the filter cake by column chromatography, using reagent grade normal phase silica gel, 200~300 mesh, ethyl acetate / petroleum ether (volume ratio of 1:3) as the mobile phase, and the flow rate is 30 mL / min to obtain an eluent; the eluent is concentrated under reduced pressure and dried under reduced pressure at 50°C for 5h.

[0031] The HPLC test confirmed that the product was impurity I of fenbufen raw material drug with a purity of 99.9% and a yield of 81%.

[0032] Figure 1 is the HPLC spectrum of the product described in Example 1, Figure 2 The HPLC spectrum of the product described in Example 2 is shown in FIG. Figure 1~2All showed that the obtained product was impurity I of fenbufen raw material drug.

[0033] Comparing Examples 1 and 2, Example 2 adds a purification step, and although the yield is slightly reduced within an acceptable range, the purity of the product is improved. Comparing Examples 2 and 3, we can see that when the reaction temperature is set to 50°C, the raw materials fail to react completely due to insufficient temperature, and the final yield is low; while at 80°C, the yield is improved.

[0034] Example 4 A method for preparing impurity I of fenbufen bulk drug, comprising the following steps: Add 20g of fenbufen and 300g of anhydrous ethanol to a 500mL reaction bottle, then slowly add 2.5g of 37wt% hydrochloric acid to the reaction bottle, heat to 60°C, stir and reflux for 5h; after the reaction is completed, place in an ice water bath, stir and crystallize for 2h, filter the crystallized material, rinse the filter cake with 20mL of ethanol, and purify the filter cake by column chromatography, using reagent grade normal phase silica gel, 200~300 mesh, ethyl acetate / petroleum ether (volume ratio of 1:3) as the mobile phase, and the flow rate is 30 mL / min to obtain an eluent; the eluent is concentrated under reduced pressure and dried under reduced pressure at 50°C for 5h.

[0035] Example 5 A method for preparing impurity I of fenbufen bulk drug, comprising the following steps: Add 20g of fenbufen and 300g of anhydrous ethanol to a 500mL reaction bottle, then slowly add 2.5g of 37wt% hydrochloric acid to the reaction bottle, heat to 70°C, stir and reflux for 5h; after the reaction is completed, place in an ice water bath, stir and crystallize for 2h, filter the crystallized material, rinse the filter cake with 20mL of ethanol, and purify the filter cake by column chromatography, using reagent grade normal phase silica gel, 200~300 mesh, ethyl acetate / petroleum ether (volume ratio of 1:3) as the mobile phase, and the flow rate is 30 mL / min to obtain an eluent; the eluent is concentrated under reduced pressure and dried under reduced pressure at 50°C for 5h.

[0036] Example 6 A method for preparing impurity I of fenbufen bulk drug, comprising the following steps: Add 20g of fenbufen and 300g of anhydrous ethanol to a 500mL reaction bottle, then slowly add 2.5g of 37wt% hydrochloric acid to the reaction bottle, heat to 75°C, stir and reflux for 5h; after the reaction is completed, place in an ice water bath, stir and crystallize for 2h, filter the crystallized material, rinse the filter cake with 20mL of ethanol, and purify the filter cake by column chromatography, using reagent grade normal phase silica gel, 200~300 mesh, ethyl acetate / petroleum ether (volume ratio of 1:3) as the mobile phase, and the flow rate is 30 mL / min to obtain an eluent; the eluent is concentrated under reduced pressure and dried under reduced pressure at 50°C for 5h.

[0037] The HPLC test showed that the products prepared in Examples 4 to 6 were impurity I of fenbufen bulk drug with a purity of 99.9%.

[0038] The specific implementation of the present invention described above does not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and modifications made based on the technical concept of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing impurity I of fenbufen bulk drug, characterized in that: The method comprises the following steps: mixing fenbufen, an alcohol substance and hydrochloric acid, stirring and heating to react; after the reaction is completed, cooling and continuing stirring to crystallize, then filtering to obtain a filter cake, and directly drying the filter cake or drying it after purification to obtain the fenbufen raw material drug impurity I.

2. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The alcohol substance is anhydrous ethanol or 95% ethanol.

3. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The mass ratio of fenbufen to alcohol is 1:10-30; The mass ratio of hydrochloric acid to fenbufen is 1:1-3.

4. The method for preparing the impurity I of fenbufen bulk drug according to claim 3, characterized in that: The mass ratio of fenbufen to alcohol is 1:15; The mass ratio of hydrochloric acid to fenbufen is 1:2.

5.

5. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The concentration of the hydrochloric acid is 21-37%.

6. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The reaction temperature is 50-80°C; The reaction time is 4 to 8 hours.

7. The method for preparing the impurity I of fenbufen bulk drug according to claim 6, characterized in that: The reaction temperature is 80°C; The reaction time is 5 h.

8. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The cooling is to cool to 0-20°C and continue stirring to precipitate crystals.

9. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The filter cake is directly dried by reduced pressure drying.

10. The method for preparing the impurity I of fenbufen bulk drug according to claim 1, characterized in that: The purification treatment method is: purification by silica gel column chromatography, the silica gel column is a normal phase silica gel column, the mobile phase is ethyl acetate and petroleum ether in a volume ratio of 1 / 3, and the flow rate is 30 mL / min.

Images