Preparation method of fenoprofen and preparation method of fenoprofen calcium

Abstract

The invention belongs to the technical field of medicine preparation, and particularly relates to a fenoprofen preparation method and a fenoprofen calcium preparation method, and the fenoprofen preparation method comprises the following steps: mixing 1-(3-phenoxyphenyl) ethanol, palladium salt, sulfonic acid and a small molecule alcohol solution, vacuumizing to replace carbon monoxide, pressurizing, heating and reacting to obtain fenoprofen; the small molecular alcohol is methanol, ethanol or isopropanol; the method is simple in reaction, environment-friendly and high in purity and yield.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation, and particularly relates to a preparation method of fenoprofen and a preparation method of fenoprofen calcium. Background Art

[0002] Fenoprofen calcium, also known as benoxyibuprofen calcium, is a white crystalline powder. Fenoprofen calcium tablets are an excellent new type of non-steroidal anti-inflammatory, antipyretic and analgesic drug with strong anti-prostaglandin effect. It is suitable for various arthritis, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gouty arthritis and other soft tissue pain. It is also used for other pains such as dysmenorrhea, toothache, injury and traumatic pain.

[0003] At present, there are two common production process routes for fenoprofen calcium: ①Using 3-phenoxybenzaldehyde and trimethyl orthoformate as raw materials 3-Phenoxybenzaldehyde undergoes two-step Grignard and oxidation reactions to obtain 3-phenoxypropiophenone. In the presence of trimethyl orthoformate, iodine is used to cause 1,2-aryl rearrangement of 3-phenoxypropiophenone. After three steps of hydrolysis, fenoprofen is obtained, and then calcium salt is obtained. However, trimethyl orthoformate is expensive, and the reaction time is as long as 32 hours, the yield is low, the atom economy is not high, and the Grignard reaction conditions are harsh, requiring anhydrous and oxygen-free conditions, and high requirements for equipment, which is not easy to industrialize. The reaction route is as follows: .

[0004] ②Using 3-phenoxybenzyl alcohol, sodium cyanide and dimethyl sulfate as raw materials 3-Phenoxybenzyl alcohol reacts with thionyl chloride to generate 3-phenoxybenzyl chloride, which then reacts with sodium cyanide aqueous solution at 90°C to obtain 3-phenoxybenzyl cyanide. 3-Phenoxybenzyl cyanide reacts with diethyl carbonate, and dimethyl sulfate is added in one pot to generate 2-(3-phenoxyphenyl)-2-cyano-propionic acid ethyl ester, which is hydrolyzed, acidified, and extracted under the action of sodium hydroxide to obtain fenoprofen, which is then converted into calcium salt. The reaction steps are long and the yield is low. Highly toxic substances such as sodium cyanide and dimethyl sulfate are used in the process.

[0005] .

[0006] The existing synthetic routes have the following disadvantages: (1) They require the use of highly toxic compounds such as sodium cyanide and dimethyl sulfate, which increases the risk of the synthetic process; (2) The overall route is too long and complicated, which reduces the overall yield of the product and increases the synthesis cost; (3) Grignard reagents are used, the reaction conditions are harsh, and anhydrous and oxygen-free conditions are required, which places high demands on equipment and is not easy to industrialize; (4) The conversion rate is low and the atom economy is not high. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a preparation method of fenoprofen and a preparation method of fenoprofen calcium, which have simple reaction, are environmentally friendly, and have high purity and yield.

[0008] The embodiment of the present invention provides a method for preparing fenoprofen, comprising mixing 1-(3-phenoxyphenyl)ethanol, palladium salt, sulfonic acid and a small molecule alcohol solution, evacuating to displace carbon monoxide, pressurizing, heating and reacting to obtain fenoprofen; the small molecule alcohol is methanol, ethanol or isopropanol.

[0009] Preferably, the palladium salt is palladium chloride or palladium acetate (preferably palladium chloride), and the sulfonic acid is p-toluenesulfonic acid.

[0010] Preferably, the pressure is increased and controlled to reach 1.5-2.0 MPa; the temperature is increased and controlled to be 90-130°C.

[0011] Preferably, the small molecule alcohol solution is a small molecule alcohol aqueous solution, and the mass concentration of the small molecule alcohol is 75-100%.

[0012] Preferably, the weight-to-volume ratio of the 1-(3-phenoxyphenyl)ethanol to the small molecule alcohol solution is 1 g:5-8 mL.

[0013] Preferably, the molar ratio of the 1-(3-phenoxyphenyl)ethanol to the palladium salt is 10:0.1-2; the molar ratio of the 1-(3-phenoxyphenyl)ethanol to the sulfonic acid is 10:0.1-4.

[0014] Preferably, the preparation method of 1-(3-phenoxyphenyl)ethanol is to mix 3-phenoxyacetophenone, Raney nickel and a solvent, evacuate to replace hydrogen, and react to obtain 1-(3-phenoxyphenyl)ethanol.

[0015] Preferably, in the preparation method of 1-(3-phenoxyphenyl)ethanol, the solvent is an alcohol, an ether or a halogenated hydrocarbon, the alcohol is preferably a small molecule alcohol, more preferably methanol, ethanol or isopropanol, most preferably methanol, the ether is preferably diethyl ether or tetrahydrofuran, the halogenated hydrocarbon is preferably dichloromethane or chloroform, the reaction temperature is 25-50°C, preferably 25°C, the molar ratio of 3-phenoxyacetophenone to Raney nickel is 1:0.05-0.2, more preferably 1:0.1; the weight volume ratio of 3-phenoxyacetophenone to small molecule alcohol is 1g:4-6mL.

[0016] The embodiment of the present invention provides a preparation method of fenoprofen calcium. The fenoprofen obtained by the preparation method is mixed with a small molecule alcohol to obtain a fenoprofen solution; a substance containing calcium ions is added to the fenoprofen solution, reacted, cooled for crystallization, filtered, washed, and dried to obtain fenoprofen calcium.

[0017] Preferably, the substance containing calcium ions is a calcium chloride aqueous solution. When adding, the temperature of the solution is controlled to be 50-60°C. After the addition is completed, the temperature is raised to 65-75°C for reaction.

[0018] The beneficial effect of the present invention is that the present invention uses 3-phenoxyacetophenone as a raw material, under the catalysis of Raney nickel, and hydrogen as a reducing agent. After the reaction is completed, the Raney nickel is directly filtered and recovered to obtain 1-(3-phenoxyphenyl)ethanol; 1-(3-phenoxyphenyl)ethanol reacts with CO under the catalyst of Pd salt to directly generate fenoprofen, which simplifies the synthesis route and is simple to operate. Both steps only require filtering and recovering the catalyst, and the remaining system is reduced pressure distilled to recover the solvent. The process is simple and easy to implement, suitable for industrial production, and the obtained product has a high yield and high purity. The reaction is green and environmentally friendly, has good atomic economy, and has little pollution. The catalytic hydrogenation reaction of the present invention does not need to be carried out under high pressure conditions, so the equipment requirements are not high, and conventional equipment can meet production needs.

[0019] The present invention directly avoids using highly toxic compounds such as sodium cyanide and dimethyl sulfate, thereby reducing the risk of poisoning of operators; the starting raw materials have been industrially produced with low cost, and Raney nickel and palladium salt can be recycled; the synthesis route is short, the process steps are shortened, the operation is simple, and industrial production is easy; the post-processing operation of each step is simple, saving labor and time; the two-step reaction is a catalytic reaction with high atom economy.

[0020] The invention uses 1-(3-phenoxyphenyl)ethanol as a raw material, adds palladium chloride and CO to convert hydroxyl into carboxylic acid, adds p-toluenesulfonic acid as a catalyst in the reaction, and uses small molecular alcohol as a solvent, so as to well control the purity and improve the yield, make the reaction simpler, and have higher purity and yield. DETAILED DESCRIPTION

[0021] Example 1 A method for preparing fenoprofen calcium, the specific reaction steps are as follows: (1) At room temperature, add 21.2 g (0.1 mol) of 3-phenoxyacetophenone, 5.8 g (0.01 mol) of Raney Ni, and 100 mL of methanol to the feed port of a 250 mL three-necked reaction flask. After the addition, put a glass stopper on it, start mechanical stirring, put a hydrogen balloon on the other feed port, evacuate and replace three times, stir and react at room temperature for 15 h, send samples for testing, and after the reaction is completed, turn off the hydrogen balloon, filter the reaction solution under reduced pressure, recover Raney Ni, and distill the filtrate under reduced pressure to obtain 20.3 g of 1-(3-phenoxyphenyl)ethanol, with a yield of 95%.

[0022] (2) At room temperature, 20 g (0.09 mol) of 1-(3-phenoxyphenyl)ethanol, 1.6 g (0.009 mol) of palladium chloride, 3.1 g (0.018 mol) of p-toluenesulfonic acid, 100 ml of methanol, and 20 ml of water were added to a 250 mL stainless steel high-pressure reactor. The CO was replaced by vacuum three times until the pressure reached 1.6 MPa. Stirring was started, the temperature was raised to 110°C, and the reaction was carried out for 15 h until the pressure was very low. The temperature was lowered, samples were taken for inspection, the reaction system was filtered, washed with saturated brine, and distilled under reduced pressure to obtain 21.4 g of fenoprofen with a yield of 98% and a purity of 97.3%.

[0023] (3) In a 250 mL reaction bottle, add 100 mL of ethanol and 20 g (0.08 mol) of fenoprofen in sequence, stir for 10 minutes and dissolve. Stir and heat to 55 °C, continue stirring, and drop 28.5 g of the prepared 20% calcium chloride solution (5.7 g of calcium chloride) into the reaction bottle, control the temperature at 55 °C, and add the solution for less than 1 hour. After the addition, heat to 70 ± 2 °C and stir for 1 hour, cool to below 25 °C, and crystallize for 1 hour. Continue stirring, filter, wash with 15 mL of purified water until neutral, drain, and dry to obtain 21 g of fenoprofen calcium with a yield of 95%.

[0024] Comparative Example 1 Compared with Example 1, the difference is that in step (2), 0.018 mol of p-toluenesulfonic acid is replaced by 0.018 mol of hydrochloric acid, and the rest is the same as Example 1.

[0025] The yield of step (2) is 95% and the purity is 78%.

[0026] Comparative Example 2 Compared with Example 1, the difference is that the solvent in step (2) is a toluene aqueous solution, that is, the solvent is 100 ml toluene and 20 ml water, not 100 ml methanol and 20 ml water. The rest is the same as Example 1.

[0027] The yield of step (2) is 79% and the purity is 83%.

[0028] A person skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of protection of the present application is limited to these examples. In line with the concept of the present application, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of different aspects of one or more embodiments of the present application as described above, which are not provided in detail for the sake of simplicity.

[0029] One or more embodiments of the present application are intended to cover all such substitutions, modifications and variations that fall within the broad scope of the present application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing fenoprofen, characterized in that: 1-(3-phenoxyphenyl)ethanol, palladium salt, sulfonic acid and a small molecule alcohol solution are mixed, vacuumed to displace carbon monoxide, pressurized, heated, and reacted to obtain fenoprofen; the small molecule alcohol is methanol, ethanol or isopropanol.

2. The preparation method according to claim 1, characterized in that: The palladium salt is palladium chloride or palladium acetate, and the sulfonic acid is p-toluenesulfonic acid.

3. The preparation method according to claim 1 is characterized in that the pressure is controlled to reach 1.5-2.0 MPa during pressurization and the temperature is controlled to be 90-130°C during heating.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The small molecule alcohol solution is a small molecule alcohol aqueous solution, and the mass concentration of the small molecule alcohol is 75-100%.

5. The preparation method according to claim 4, characterized in that: The weight-to-volume ratio of the 1-(3-phenoxyphenyl)ethanol and the small molecule alcohol solution is 1 g:5-8 mL.

6. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the 1-(3-phenoxyphenyl)ethanol to the palladium salt is 10:0.1-2; the molar ratio of the 1-(3-phenoxyphenyl)ethanol to the sulfonic acid is 10:0.1-4.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The preparation method of 1-(3-phenoxyphenyl)ethanol comprises the following steps: mixing 3-phenoxyacetophenone, Raney nickel and a solvent, evacuating the mixture to replace hydrogen, and reacting the mixture to obtain 1-(3-phenoxyphenyl)ethanol.

8. The preparation method according to claim 7, characterized in that: In the preparation method of 1-(3-phenoxyphenyl)ethanol, the solvent is alcohol, ether or halogenated hydrocarbon, the reaction temperature is 25-50°C, the molar ratio of 3-phenoxyacetophenone to Raney nickel is 1:0.05-0.2, and the weight volume ratio of 3-phenoxyacetophenone to small molecule alcohol is 1g:4-6mL.

9. A method for preparing fenoprofen calcium, characterized in that: The fenoprofen obtained by the preparation method according to any one of claims 1 to 8 is mixed with a small molecule alcohol to obtain a fenoprofen solution; a substance containing calcium ions is added to the fenoprofen solution, reacted, cooled for crystallization, filtered, washed, and dried to obtain fenoprofen calcium.

10. The method for preparing fenoprofen calcium according to claim 9, characterized in that: The substance containing calcium ions is a calcium chloride aqueous solution. When adding, the temperature of the solution is controlled to be 50-60° C. After the addition is completed, the temperature is raised to 65-75° C. for reaction.