A kind of preparation method of pranoprofen

Abstract

The present invention provides a method for preparing pranoprofen. The present invention uses p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and the like as activation reagents, rearranges under alkaline conditions, and then hydrolyzes, thereby reducing the generation of by-products, especially substantially eliminating the generation of impurities A that are difficult to remove; at the same time, the requirements for temperature control are greatly reduced, the overall process level is significantly improved, and an economical and efficient effect is achieved.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of pranoprofen. Background Art

[0002] Pranoprofen is a tricyclic propionic acid derivative with the chemical name of 2-5H-[1]benzopyrano[2,3-b]pyridin-7-ylpropionic acid. It contains two mirror-image isomers and the commercially available product is a racemate. It is a non-steroidal anti-inflammatory analgesic drug developed by Welfide (formerly Gifu Pharmaceutical Co., Ltd., now Mitsubishi Pharmaceutical).

[0003] Japanese patent JP1992288081A discloses a method for preparing pranoprofen, using 5H-[1]-benzopyrano[2,3-b]pyridine in the presence of anhydrous aluminum chloride, reacting with 2-bromopropionyl bromide at 10°C or lower, and then hydrolyzing with a methanol solution of sodium methoxide. The resulting compound is rearranged in a dichloromethane solvent at -20°C in the presence of pyridine and sulfonyl chloride and then hydrolyzed to obtain pranoprofen. As shown in route 1:

[0004]

[0005] Patent CN109942589A discloses a new preparation method, and its process route is shown in the following formula (Route 2). This route changes the synthesis method of the halogenated intermediate, but does not change the rearrangement reaction.

[0006]

[0007] The rearrangement reaction using sulfonyl chloride or thionyl chloride requires low temperature, and both will undergo a chlorination elimination side reaction to generate pranoprofen olefin impurity A (Formula I). ​​The impurity structure is similar to pranoprofen and is extremely difficult to remove. The impurity increases significantly when the temperature is higher than -20°C.

[0008] Summary of the invention

[0009] In view of the deficiencies in the prior art, the present invention provides a method for preparing pranoprofen.

[0010] The technical scheme of the present invention is as follows: A method for preparing pranoprofen, the reaction scheme of which is as follows:

[0011]

[0012] 1) dissolving compound 1 and base A in dry solvent A, adding a sulfonation activation reagent under the protection of an inert gas, and reacting to obtain a pranoprofen methyl ester intermediate; wherein the sulfonation activation reagent is selected from p-toluenesulfonyl chloride, methanesulfonic anhydride or trifluoromethanesulfonic anhydride;

[0013] 2) Adding base B to hydrolyze the intermediate pranoprofen methyl ester to obtain pranoprofen.

[0014] Furthermore, the base A in step 1) is selected from one or more of triethylamine, N,N-diisopropylethylamine, pyridine or N-methylmorpholine, preferably triethylamine or pyridine.

[0015] Furthermore, the solvent A in step 1) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide, preferably dichloromethane.

[0016] Furthermore, the reaction temperature of step 1) is -20 to 50°C, preferably -5 to 30°C.

[0017] Furthermore, the base B in step 2) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

[0018] Furthermore, the post-treatment method of step 2) is: adding water to dilute the reaction solution, washing twice with dichloromethane, adding acetic acid to the aqueous phase to adjust the pH to 4-5, a large amount of solid precipitates, filtering, drying to obtain a crude pranoprofen product, and recrystallizing with ethanol to obtain a refined pranoprofen product.

[0019] Beneficial effects of the present invention: The present invention uses p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and the like as activation reagents, rearranges under alkaline conditions, and then hydrolyzes, thereby reducing the generation of by-products, especially achieving substantially no generation of impurity A that is difficult to remove; at the same time, the requirements for temperature control are greatly reduced, the overall process level is significantly improved, and an economical and efficient effect is achieved. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 Example 1 Product 1 H-NMR spectrum.

[0021] Figure 2 Example 1 Product 13 C-NMR spectrum.

[0022] Figure 3 HPLC spectrum of the product of Example 1.

[0023] Figure 4 HPLC spectrum of the product of Comparative Example 1.

[0024] Figure 5 HPLC spectrum of the product of Comparative Example 2. DETAILED DESCRIPTION

[0025] The following embodiments can enable those skilled in the art to more fully understand the present invention, but the present invention is not limited to the scope of the embodiments.

[0026] The preparation of compound 1 refers to "Research and Improvement of the Synthesis of Pranoprofen" (Jin Rongqing, Fine Chemical Intermediates, 2009, 39(3), 3739).

[0027] Example 1

[0028] Compound 1 (50 g, 0.17 mol) was added to a three-necked flask, followed by 500 mL of dichloromethane. After complete dissolution, pyridine (32 g, 0.40 mol) was added. Trifluoromethanesulfonic anhydride (57 g, 0.20 mol) was added dropwise under nitrogen protection and reacted at 0-10°C for 3 h. Water was added to wash the separated liquid. The organic phase was concentrated under reduced pressure. Methanol 200 mL and sodium hydroxide (20.0 g, 0.51 mol) 50 mL water solution were added to the oily substance. The mixture was reacted at room temperature for 1 h under nitrogen protection. Water 450 mL was added and washed twice with 500 mL of dichloromethane. Acetic acid was added to the aqueous phase to adjust the pH to 4-5. A large amount of solid precipitated. The mixture was filtered and dried to obtain 32.2 g of crude pranoprofen. The pranoprofen refined product 32.9 g was obtained by recrystallization from ethanol. The total yield was 76% and the purity was 99.96% (olefin impurity A was detected at 0.01%).

[0029] Example 2

[0030] Compound 1 (5 g, 0.017 mol) was added to a three-necked flask, followed by 50 mL of dichloromethane. After complete dissolution, pyridine (3.2 g, 0.040 mol) was added, and p-toluenesulfonyl chloride (3.8 g, 0.020 mol) was added dropwise under nitrogen protection, and the mixture was refluxed for 3 h. After washing with water, the organic phase was concentrated under reduced pressure. Methanol 20 mL and sodium hydroxide (2.0 g, 0.051 mol) 5 mL water solution were added to the oily substance, and the mixture was reacted at room temperature for 1 h under nitrogen protection. Water 45 mL was added, and the mixture was washed twice with 50 mL of dichloromethane. Acetic acid was added to the aqueous phase to adjust the pH to 4-5. A large amount of solid was precipitated, which was filtered, dried, and recrystallized from ethanol to obtain 1.90 g of pranoprofen refined product with a yield of 45%.

[0031] Example 3

[0032] Compound 1 (5 g, 0.017 mol) was added to a three-necked flask, followed by 50 mL of dichloromethane. After complete dissolution, pyridine (3.2 g, 0.040 mol) was added, and methanesulfonic anhydride (3.5 g, 0.020 mol) was added dropwise under nitrogen protection, and the mixture was refluxed for 6 h. After washing with water, the organic phase was concentrated under reduced pressure. Methanol 20 mL and sodium hydroxide (2.0 g, 0.051 mol) 5 mL water solution were added to the oily substance, and the mixture was reacted at room temperature for 1 h under nitrogen protection. Water 45 mL was added, and the mixture was washed twice with 50 mL of dichloromethane. Acetic acid was added to the aqueous phase to adjust the pH to 4-5. A large amount of solid was precipitated, which was filtered, dried, and recrystallized from ethanol to obtain 2.37 g of pranoprofen refined product with a yield of 56%.

[0033] Example 4

[0034] Compound 1 (5 g, 0.017 mol) was added to a three-necked flask, followed by 50 mL of dichloromethane. After complete dissolution, pyridine (3.2 g, 0.040 mol) was added, and trifluoromethanesulfonic anhydride (5.7 g, 0.020 mol) was added dropwise under nitrogen protection, and the mixture was reacted at -20 to 0°C for 3 h. Water was added to wash the separated liquid, and the organic phase was concentrated under reduced pressure. Methanol 20 mL and sodium hydroxide (2.0 g, 0.051 mol) 5 mL water solution were added to the oily substance, and the mixture was reacted at room temperature for 1 h under nitrogen protection. Water 45 mL was added, and the mixture was washed twice with 50 mL of dichloromethane. Acetic acid was added to the aqueous phase to adjust the pH to 4 to 5. A large amount of solid was precipitated, which was filtered, dried, and recrystallized from ethanol to obtain 3.09 g of crude pranoprofen with a yield of 73% and a purity of 99.90%.

[0035] Example 5

[0036] Compound 1 (5 g, 0.017 mol) was added to a three-necked flask, followed by 50 mL of dichloromethane. After complete dissolution, pyridine (3.2 g, 0.040 mol) was added, and trifluoromethanesulfonic anhydride (5.7 g, 0.020 mol) was added dropwise under nitrogen protection, and the mixture was reacted at -20 to 0°C for 3 h. After washing the separated liquid with water, the organic phase was concentrated under reduced pressure. Methanol 20 mL and sodium hydroxide (2.0 g, 0.051 mol) 5 mL water solution were added to the oily substance, and the mixture was reacted at room temperature for 1 h under nitrogen protection. Water 45 mL was added, and the mixture was washed twice with 50 mL of dichloromethane. Acetic acid was added to the aqueous phase to adjust the pH to 4 to 5. A large amount of solid was precipitated, which was filtered, dried, and recrystallized from ethanol to obtain 2.92 g of crude pranoprofen with a yield of 69% and a purity of 99.93%.

[0037] Comparative Example 1 (method of JP1992288081A)

[0038] Compound 1 (30.1 g, 0.10 mol) was added to a three-necked flask, followed by 220 mL of dichloromethane. After complete dissolution, triethylamine (24.3 g, 0.24 mol) was added. Sulfonyl chloride (16.2 g, 0.12 mol) was slowly added dropwise at -20 °C and kept warm for 2 h. The temperature was then slowly raised to room temperature for reaction for 3 h. Within 2 hours, the reaction solution was stirred at room temperature. The mixture was added dropwise to a mixed solution of 20.2 g (0.480 mol) of sodium hydroxide in 150 ml of methanol and 50 ml of water. After the addition, the methanol was removed by distillation under reduced pressure, and 150 ml of water was added to the concentrated residue to dissolve. The water layer was washed with 50 ml of dichloromethane, and then the water layers were combined for decolorization. Acetic acid was added dropwise to adjust the pH to 5 to 6, and a solid was precipitated. The solid was washed with water, and recrystallized from dioxane / water. Ethanol recrystallization gave 16.1 g of pranoprofen refined product, with a total yield of 63% and a purity of 98.78% ( Figure 4 : Oxidation impurities 0.44%, olefin impurities 0.23%).

[0039] Comparative Example 2 (method of CN109942589A)

[0040] Compound 1 (40g, 0.13mol) was added to 200ml of dichloromethane, and then cooled to about 0°C. Triethylamine (26g) was added first, and then dichlorothionyl (23g, 0.19mol) was slowly added dropwise, and the temperature was controlled to ≤20°C. After the addition was completed, the mixture was reacted at room temperature for 3h. After concentration under reduced pressure, 20ml of concentrated hydrochloric acid was added, and the mixture was heated to 60°C for reaction for 3h. The reaction solution was then added to 200ml of ice water, and 10% sodium hydroxide solution was added to adjust the pH to 11. The system was washed twice with 100ml of dichloromethane, and the pH of the water layer was adjusted to 5 with acetic acid. A large amount of solid was precipitated, and then stirred at room temperature for 2h, and filtered to obtain a crude product of pranoprofen. 200ml of ethanol was added, heated to reflux and dissolved, and then the temperature was lowered to room temperature and an equal amount of water was added. After the solid precipitated, it was stirred for 2h and filtered to obtain 18.3g of dried white solid, which was a fine product of pranoprofen with a yield of 56%. ( Figure 5 : Oxidation impurities 0.34%, olefin impurities 0.49%).

[0041] The results and comparisons of the preparation methods described in the examples and comparative examples of the present invention are as follows:

[0042]

[0043]

[0044] The method of the present invention does not require a harsh low-temperature environment to prepare pranoprofen, has certain advantages in yield and product purity, has the lowest content of the difficult-to-remove pranoprofen olefin impurity A, is easy to purify, and has a quality of pranoprofen higher than the pharmacopoeia requirement. The method is suitable for large-scale production.

Claims

1. A method for preparing pranoprofen, the reaction scheme is as follows: 1) dissolving compound 1 and base A in dry solvent A, adding a sulfonation activation reagent under inert gas protection, and reacting to obtain pranoprofen methyl ester intermediate; wherein the sulfonation activation reagent is selected from trifluoromethanesulfonic anhydride; 2) adding base B to the pranoprofen methyl ester intermediate for hydrolysis to obtain pranoprofen; The base A in step 1) is selected from pyridine; The base B in step 2) is selected from sodium hydroxide or potassium hydroxide.

2. The preparation method according to claim 1, characterized in that: The solvent A in step 1) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.

3. The preparation method according to claim 1, characterized in that: The reaction temperature of step 1) is -5 to 30°C.

4. The preparation method according to claim 1, characterized in that: The post-treatment method of step 2) is: adding water to dilute the reaction solution, washing twice with dichloromethane, adding acetic acid to the aqueous phase to adjust the pH to 4-5, a large amount of solid precipitates, filtering, drying to obtain a crude pranoprofen product, and recrystallizing with ethanol to obtain a refined pranoprofen product.

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