Preparation method of fenoprofen calcium
By improving the preparation method of fenofofen calcium, the intermediate is generated by reacting m-hydroxyacetophenone with bromobenzene, which is then oxidized with ethyl chloroacetate and sodium chlorite, and finally recrystallized from ethyl acetate. This method solves the problems of high impurity content and low yield in the existing technology, and achieves the preparation of fenofofen calcium with high purity and high yield.
Patent Information
- Application Number
- CN202511016783.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-23
- Publication Date
- 2025-11-21
AI Technical Summary
Existing methods for preparing fenprofen calcium suffer from high impurity content and low yield, especially since phenylpropionic acid impurities are difficult to remove, affecting product purity and yield.
m-hydroxyacetophenone was reacted with bromobenzene to generate intermediate 1, which was then reacted with ethyl chloroacetate to generate intermediate 2. After oxidation, fenprofen was obtained, which was then reacted with sodium hydroxide to prepare fenprofen sodium. Finally, it was reacted with calcium chloride to form a salt to prepare fenprofen calcium. Sodium chlorite was used as the oxidant, and the mixture was purified by recrystallization using a mixed solvent of ethyl acetate and water.
It effectively reduced preparation costs, avoided the use of highly toxic reagents, improved the purity and yield of fenprofen calcium, removed major impurities, and met pharmaceutical requirements.
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Figure CN120987752A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a preparation method of fenoprofen calcium. BACKGROUND
[0002] Fenoprofen calcium (Fenoprofen Calcuim) is (±)-α-methyl-3-phenoxy-benzoic acid calcium dihydrate, which is a phenylpropionic acid compound, an excellent non-steroidal anti-inflammatory, antipyretic and analgesic drug, and has strong anti-prostaglandin effect, anti-inflammatory, analgesic and antipyretic effects.
[0003] The reported synthesis routes of fenoprofen calcium mainly include the following: Route one: taking m-phenoxytoluene as a starting material, bromination is carried out, then sodium cyanide is reacted to generate m-phenoxyphenylacetonitrile, m-phenoxyphenylacetic acid is obtained by hydrolysis of m-phenoxyphenylacetonitrile, selective α-monomethylation of m-phenoxyphenylacetic acid is carried out by dimethyl sulfate to generate fenoprofen, and fenoprofen is directly salified with calcium chloride to obtain fenoprofen calcium, and the total yield is 30%-40%. This method has the advantages of easy availability of raw materials and low cost, but uses toxic sodium cyanide and dimethyl sulfate. The reaction route is as follows:
[0004] Route two: taking phenylacetone as a raw material, bromination of the benzene ring is carried out, etherification is carried out to generate m-phenoxyphenylacetone, hydrogenation and chlorination are carried out to generate 1-(1-chloroethyl)-3-(phenoxy)benzene, then sodium cyanide is reacted to generate 2-(3-phenoxyphenyl)propionitrile, and finally hydrolysis and salification are carried out to obtain the product fenoprofen calcium. This route has the disadvantages of long steps and use of toxic sodium cyanide. The reaction route is as follows:
[0005] Route three: taking phenylacetone as a raw material, bromination of the benzene ring is carried out, etherification is carried out, Darzens condensation reaction, hydrolysis and decarboxylation are carried out to generate 2-(3-phenoxyphenyl)propionaldehyde, then hydrogen peroxide is used for oxidation to obtain fenoprofen, and salification of fenoprofen with calcium chloride generates the product fenoprofen calcium. This route has the advantages of low cost, but has the disadvantages of long steps, low yield of the hydrogen peroxide oxidation step of 2-(3-phenoxyphenyl)propionaldehyde, the total yield of the route is 10-20%, and after direct oxidation of the aldehyde group to form an acid, the product has high phenylpropionic acid impurities due to lack of intermediate purification steps, and it is difficult to meet the pharmaceutical requirements. The reaction route is as follows:
[0006] When obtaining fenoprofen sodium, there are more phenylpropionic acid homologous impurities with similar molecular weights, which can enter the final product, and reduce the yield and purity of the product. SUMMARY
[0007] The technical problem solved by the present application is to provide a preparation method of fenoprofen calcium, improve the yield and purity of the product, and reduce the impurity content.
[0008] The present application provides a preparation method of fenoprofen calcium, comprising the following steps, 1) m-hydroxyacetophenone and bromobenzene are reacted under the action of a base and cuprous iodide to generate an intermediate 1, i.e. m-phenoxyacetophenone; 2) the intermediate 1 is reacted with ethyl chloroacetate under the action of a strong base, and then subjected to hydrolysis and decarboxylation to generate an intermediate 2, i.e. 2-(3-phenoxyphenyl)propanal; 3) the intermediate 2 is subjected to an oxidation reaction to obtain fenoprofen; 4) fenoprofen is reacted with a sodium hydroxide solution to prepare sodium fenoprofen; 5) sodium fenoprofen is subjected to salt formation with a calcium chloride solution to prepare fenoprofen calcium; The reaction route is as follows: .
[0009] Preferably, in step 1), the base is one or more of cesium carbonate, potassium hydroxide and potassium tert-butoxide, and the solvent is one or more of N,N-dimethylformamide and tetrahydrofuran; the reaction temperature is 80-140℃, and the molar ratio of m-hydroxyacetophenone to bromobenzene is 1:0.8-1.
[0010] Preferably, in step 1), the base is cesium carbonate, the solvent is N,N-dimethylformamide, the reaction temperature is 120℃, and the molar ratio of m-hydroxyacetophenone to bromobenzene is 1:1.
[0011] Preferably, in step 2), the strong base is sodium isopropoxide, and the molar ratio of the intermediate 1 to ethyl chloroacetate is 1:2.
[0012] Preferably, in step 3), the oxidant used in the oxidation reaction is one or more of potassium dichromate, hydrogen peroxide and sodium chlorite (preferably sodium chlorite), the reaction temperature is 10-40℃ (preferably 25℃), and the reaction time is preferably 0.5-2h (more preferably 1h).
[0013] Preferably, in step 4), the molar ratio of fenoprofen to sodium hydroxide is 1:0.9-1:1.2, and the reaction temperature is 15-45℃.
[0014] Preferably, in step 4), the molar ratio of fenoprofen to sodium hydroxide is 1:1, and the reaction temperature is 25℃.
[0015] Preferably, in step 4), after the reaction is completed, the reaction solution is concentrated, a refined solvent is added, crystallization is performed, filtration is performed, and drying is performed to obtain non-steroidal anti-inflammatory drug sodium fine product, the refined solvent is a mixture of one or more of ethyl acetate, isopropyl alcohol, and ethanol combined with water, and the crystallization temperature is 0-35℃.
[0016] Preferably, the refined solvent is a mixture of ethyl acetate and water, and the crystallization temperature is 0-5℃.
[0017] Preferably, in step 5), the solvent used for salt formation is a mixture of one or more of methanol, ethanol, and acetone combined with water (preferably an ethanol aqueous solution), the reaction temperature is 30-70℃ (preferably 50℃), after the reaction is completed, crystallization is performed, the crystallization temperature is 0-30℃ (preferably 15-2℃), filtration is performed, and drying is performed (the drying temperature is 40-60℃, preferably 55℃) to obtain non-steroidal anti-inflammatory drug calcium fine product.
[0018] The present application has the advantages that the starting materials used are inexpensive and easy to obtain, the reagents avoid the use of highly toxic sodium cyanide and dimethyl sulfate, the oxidation step uses relatively mild sodium chlorite, and the non-steroidal anti-inflammatory drug sodium salt is purified, which can improve the purity of the final product non-steroidal anti-inflammatory drug calcium. The present application effectively reduces the cost, avoids the use of highly toxic compounds, effectively removes impurities, and improves the purity and yield.
[0019] The present application overcomes the deficiencies of the prior art non-steroidal anti-inflammatory drug calcium preparation method and preparation technology, adopts non-steroidal anti-inflammatory drug sodium salt formation with sodium hydroxide, and uses a mixed solvent of ethyl acetate and water to effectively remove the largest single impurity and improve the purity of the finished product non-steroidal anti-inflammatory drug calcium. BRIEF DESCRIPTION OF DRAWINGS
[0020] Figure 1 The HPLC chart of the non-steroidal anti-inflammatory drug calcium fine product prepared for Example 1 is shown in the figure.
[0021] Figure 2 The HPLC chart of the non-steroidal anti-inflammatory drug calcium fine product prepared for Comparative Example 1 is shown in the figure.
[0022] Figure 3 The HPLC chart of the non-steroidal anti-inflammatory drug calcium fine product prepared for Comparative Example 2 is shown in the figure.
[0023] Figure 4 The HPLC chart of the non-steroidal anti-inflammatory drug calcium fine product prepared for Comparative Example 3 is shown in the figure. DETAILED DESCRIPTION
[0024] The following examples are only for further illustrating the present application, and do not limit the scope of the present application in any form.
[0025] Example 1 A non-steroidal anti-inflammatory drug calcium preparation method comprises the following steps: Step 1: Preparation of Intermediate 1: 3-phenoxyacetophenone A reaction flask was charged with cuprous iodide (5.7 g, 30.00 mmol), cesium carbonate (10.25 g, 60 mmol), 3-hydroxyacetophenone (63.6 g, 0.30 mol), bromobenzene (47.1 g, 0.30 mol) and N,N-dimethylformamide (1.2 L), vacuumed and replaced with nitrogen for three times, the reaction was heated to 120 °C under stirring, and the temperature was kept at 120 °C. TLC was used to monitor the reaction until the starting material bromobenzene was consumed completely. After the reaction was completed, the reaction was cooled to room temperature, filtered, and the filter cake was washed with 100 ml of DMF. The solvent DMF was recovered, and the fraction with a boiling point of 160-170 °C / 600-700 Pa was collected by distillation under reduced pressure to obtain 52.8 g of colorless liquid with a molar yield of 82.9% and a purity of 99.2%.
[0026] Step 2: Preparation of Intermediate 2: 2-(3-phenoxyphenyl)propanal The freshly prepared sodium isopropoxide (32.8 g, 0.4 mol), intermediate 1 (42.4 g, 0.2 mol) and ethyl chloroacetate (49.0 g, 0.4 mol) were added to isopropyl alcohol (800 ml), vacuumed and replaced with nitrogen for three times, stirred and heated to reflux for 4 hours. After cooling to room temperature, 50% sodium hydroxide solution (120 g) was added, stirred for 2 hours, and isopropyl alcohol was recovered by concentration under reduced pressure. Concentrated hydrochloric acid (80 ml) was added, heated to reflux, and the reaction was continued until no gas bubbles were generated. After the reaction solution was cooled to room temperature, it was extracted with ethyl acetate (2*80 ml). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(3-phenoxyphenyl)propanal as a brown oil, 37.2 g, with a molar yield of 82.3% and a purity of 92.1%.
[0027] Step 3: Preparation of Fenoprofen A reaction flask was charged with tert-butanol (120 ml), intermediate 2 (0.15 mol, 33.9 g) and 2-methyl-2-butene (1.5 mol, 105 g), stirred and cooled to 0 °C, then sodium phosphate monobasic aqueous solution (150 mL, 5 M, 0.75 mol) and sodium chlorite aqueous solution (90 mL, 5.0 M, 0.45 mol) were added in sequence. After stirring vigorously at 25 °C for 1 hour, the reaction mixture was quenched with 4.0 M hydrochloric acid aqueous solution (350 mL), extracted with 500 ml*3 of ethyl acetate, combined the organic phase, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 31.3 g of light yellow viscous liquid with a molar yield of 86.2% and a purity of 90.8%.
[0028] Step 4: Preparation of Fenoprofen Sodium A reaction bottle was added with sodium hydroxide (4.8 g, 0.12 mol) and water (90 g) and stirred to dissolve, then cooled to 25 °C, and then added with fenoprofen (29 g, 0.12 mol) and stirred at 25 °C for 30 min, and then the reaction solution was concentrated under reduced pressure to dryness, and then added with 70 ml of ethyl acetate and 0.4 ml of water, and then warmed to 60 °C, and then stirred to dissolve, and then cooled to 0-5 °C, and then kept at 0-5 °C for 1 h, and then filtered and dried to obtain white solid, i.e. fenoprofen sodium dihydrate 33.66 g, with a molar yield of 93.5% and a purity of 98.2%.
[0029] Step 5: Preparation of fenoprofen calcium A reaction bottle was added with 66 g of water, 52 g of ethanol and fenoprofen sodium (0.1 mol, 30.0 g) in sequence, and then stirred to warm to 50 °C, and then added dropwise with a calcium chloride solution (anhydrous calcium chloride 5.55 g, water 31.45 g), and then added dropwise for about 20 min, and then the reaction solution was continuously stirred at 50 °C for 30 min, and then cooled to 15-25 °C, and then kept at 15-25 °C for 1 h, and then filtered and dried at 55 °C to obtain white solid, i.e. fenoprofen calcium dihydrate 23.5 g, with a yield of 84.1% and a purity of 99.67% and a maximum single impurity of 0.22%.
[0030] The total yield of the five steps was 46.3%, with a purity of 99.67% and a maximum single impurity of 0.22%.
[0031] Comparative Example 1 The preparation of intermediate 1 in step 1 and the preparation of intermediate 2 in step 2 were the same as in Example 1. The amounts of the raw materials were adjusted synchronously to obtain intermediate 2, i.e. (2-(3-phenoxyphenyl)propanal) 50 g.
[0032] Step 3: Preparation of fenoprofen A reaction bottle was added with 45.2 g of intermediate 2 (2-(3-phenoxyphenyl)propanal), 100 ml of 10% sodium hydroxide solution, and then cooled to 0 °C, and then added dropwise with 36 g of 30% hydrogen peroxide under stirring, and then the temperature during the dropwise addition was not more than 5 °C, and then after the dropwise addition was completed, the temperature was warmed to 25 °C and reacted for 20 h. After the reaction was completed, the pH was adjusted to <3 with 10% hydrochloric acid, and then the reaction solution was allowed to stand, and then the organic phase was separated, and then the aqueous phase was extracted with 100 ml of ethyl acetate twice, and then the combined organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to dryness to obtain light yellow oil 13.2 g, with a yield of 27.3%, a purity of 88.65% and a maximum single impurity of 0.20%.
[0033] Steps 4 and 5 were the same as in Example 1. The yield of step 5 in this example was 83.9%, with a purity of 99.48%, a total yield of 14.6% and a maximum single impurity of 0.20%.
[0034] Comparative Example 2 Steps 1, 2 and 3 were the same as in Example 1. The amounts of the raw materials were adjusted synchronously to obtain fenoprofen 51 g.
[0035] Step 4: Preparation of Fenolofen Calcium Product 52 g of ethanol and fenofoprofen (0.1 mol, 24.2 g) were added sequentially to the reaction flask. After stirring until dissolved, sodium hydroxide solution (4 g sodium hydroxide, 0.1 mol, 66 g water) was added. After the addition was complete, the mixture was stirred and heated to 50 °C. Calcium chloride solution (5.55 g anhydrous calcium chloride, 31.45 g water) was added dropwise over approximately 20 minutes. The reaction mixture was then stirred at 50 °C for another 30 minutes. The temperature was lowered to 15–25 °C and kept at this temperature for approximately 1 hour to allow crystals to precipitate. The mixture was filtered and dried at 55 °C to obtain 23.1 g of white solid fenofoprofen calcium dihydrate, with a molar yield of 82.7%, a purity of 97.73%, and a maximum single impurity of 1.45%.
[0036] The overall yield was 48.6%, the purity was 97.73%, and the maximum single impurity was 1.45%.
[0037] Comparative Example 3 Steps 1, 2, 3, and 4 are the same as in Example 1, with the amounts of each raw material adjusted synchronously to obtain 60g of fenprofen sodium dihydrate.
[0038] Step 4: Preparation of Fenolofen Calcium Product 200g of water and 45g of fenofofen sodium (0.15mol) were added sequentially to the reaction flask and stirred until dissolved. Calcium chloride solution (8.33g of anhydrous calcium chloride and 47g of water) was then added dropwise over approximately 20 minutes. The mixture was stirred for another 30 minutes and kept at this temperature for approximately 1 hour to allow crystals to precipitate. The solution was then filtered and dried at 55°C to obtain 40.35g of white solid fenofofen calcium dihydrate, with a molar yield of 96.3%, a purity of 98.58%, and a maximum single impurity of 0.73%.
[0039] The overall yield of the five steps was 53.0%, the purity was 98.58%, and the maximum single impurity was 0.73%.
[0040] Comparing Example 1 and Comparative Example 2 and Comparative Example 3, it was found that after fenoprofen was salted with sodium hydroxide and recrystallized from ethyl acetate-water, the impurities in fenoprofen calcium, with an RRT of 0.97 (15.9 min), were reduced to 0.01% and 0% (see Example 3). Figure 1 , Figure 2 The impurity was 1.45% without the sodium salt formation step of fenprofen, proving that the sodium salt purification step removed >99% of this specific impurity. Preparing the final product by purifying fenprofen into sodium salt improves product purity, significantly reduces the maximum single impurity, and maintains a relatively stable yield. Changing the oxidant in step 3 from hydrogen peroxide to sodium chlorite significantly increased the product yield. In the final salt formation step, using the method in Comparative Example 3 increased the yield but decreased product purity, with the maximum single impurity exceeding the limit.
[0041] Those skilled in the art should understand that the above discussion of any embodiment is only intended to be illustrative and is not intended to be limiting to the scope of the present application; the above embodiments or technical features among different embodiments can also be combined, the steps can be implemented in any order, and there are many other changes such as the different aspects of one or more embodiments of the present application as described above, which are not provided in details for the sake of brevity.
[0042] One or more embodiments of the present application are intended to cover all such alternatives, modifications, and variations as fall within the broad scope of the present application. Accordingly, any one of the above-cited examples, or any other unrecited example, can be prepared by any combination of the features thereof and by any method described herein or otherwise encompassed by the principles of the present application, without departing from the spirit and scope of one or more embodiments of the present application.
Claims
1. A method for preparing nonprofen calcium, characterized in that, Includes the following steps, 1) m-hydroxyacetophenone and bromobenzene react with a base and cuprous iodide to form intermediate 1, namely m-phenoxyacetophenone; 2) Intermediate 1 reacts with ethyl chloroacetate under the action of a strong base, and then undergoes hydrolysis and decarboxylation to generate intermediate 2, namely 2-(3-phenoxyphenyl)propanal; 3) Intermediate 2 undergoes an oxidation reaction to yield fenprofen; 4) Fenoprofen sodium is prepared by reacting fenprofen with sodium hydroxide solution; 5) Fenoprofen sodium reacts with calcium chloride solution to form a salt, thus preparing fenprofen calcium; The reaction route is as follows: 。 2. The preparation method according to claim 1, characterized in that, In step 1), the base is one or more of cesium carbonate, potassium hydroxide, and potassium tert-butoxide, and the solvent is one or more of N,N-dimethylformamide and tetrahydrofuran; the reaction temperature is 80-140℃, and the molar ratio of m-hydroxyacetophenone to bromobenzene is 1:0.8-1.
3. The preparation method according to claim 2, characterized in that, In step 1), the base is cesium carbonate, the solvent is N,N-dimethylformamide, the reaction temperature is 120℃, and the molar ratio of m-hydroxyacetophenone to bromobenzene is 1:
1.
4. The preparation method according to claim 1, characterized in that, In step 2), the strong base is sodium isopropoxide, and the molar ratio of intermediate 1 to ethyl chloroacetate is 1:
2.
5. The preparation method according to claim 1, characterized in that, In step 3), the oxidant used in the oxidation reaction is one or more of potassium dichromate, hydrogen peroxide, and sodium chlorite, and the reaction temperature is 10~40℃.
6. The preparation method according to claim 1, characterized in that, In step 4), the molar ratio of fenprofen to sodium hydroxide is 1:0.9 to 1:1.2, and the reaction temperature is 15 to 45°C.
7. The preparation method according to claim 6, characterized in that, In step 4), the molar ratio of fenprofen to sodium hydroxide is 1:1, and the reaction temperature is 25℃.
8. The preparation method according to claim 1, characterized in that, In step 4), after the reaction is completed, the reaction solution is concentrated, a refining solvent is added, crystallization occurs, the solution is filtered, and the solution is dried to obtain high-quality fenoprofen sodium. The refining solvent is a mixture of one or more of ethyl acetate, isopropanol, and ethanol with water, and the crystallization temperature is 0~35℃.
9. The preparation method according to claim 8, characterized in that, The refining solvent is a mixture of ethyl acetate and water, and the crystallization temperature is 0~5℃.
10. The preparation method according to claim 1, characterized in that, In step 5), the solvent used for salt formation is a mixture of one or more of methanol, ethanol, acetone and water. The reaction temperature is 30~70℃. After the reaction is completed, crystallization occurs at a temperature of 0~30℃. The mixture is then filtered and dried to obtain fine fenprofen calcium.