CN116041358A - Preparation method of pranoprofen - Google Patents

Abstract

The invention provides a preparation method of pranoprofen. According to the invention, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and the like are used as activating reagents, rearranged under alkaline conditions and hydrolyzed, so that the generation of byproducts is reduced, and particularly, the impurity A which is basically not difficult to remove is realized; meanwhile, the requirement on temperature control is greatly reduced, the overall process level is obviously improved, and the economic and efficient effects are achieved.

Description

Preparation method of pranoprofen

Technical Field

The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of pranoprofen.

Background

Pranoprofen is a tricyclic propionic acid derivative, having the chemical name 2-5H 1 benzopyran 2,3-b pyridin-7-yl propionic acid, containing two mirror image isomers, and is commercially available as racemate. Is a non-steroidal anti-inflammatory analgesic developed by welfide company (Yuanjifu pharmaceutical Co., ltd., mitsubishi pharmaceutical).

Japanese patent JP1992288081A discloses a process for preparing pranoprofen by reacting 5H 1-benzopyran [2,3-b ] pyridine with 2-bromopropionyl bromide in the presence of anhydrous aluminum chloride at a temperature of 10 ℃ or less, then hydrolyzing with a methanol solution of sodium methoxide, and subjecting the resulting compound to rearrangement reaction in a methylene chloride solvent at a temperature of-20 ℃ in the presence of pyridine and sulfonyl chloride, followed by hydrolysis. As shown in route one:

a novel preparation method is disclosed in patent CN109942589A, and the process route is shown in the following formula (route II). This route changes the way in which the halogenated intermediates are synthesized, and does not alter the rearrangement reaction.

The rearrangement reaction using sulfonyl chloride or thionyl chloride requires low temperature, and both can generate chloride elimination side reaction, to generate pranoprofen olefin impurity A (formula I), the structure of the impurity is similar to pranoprofen, the impurity is extremely difficult to remove, and the impurity is obviously increased at the temperature higher than-20 ℃.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a preparation method of pranoprofen.

The technical scheme of the invention is as follows: the preparation method of pranoprofen comprises the following reaction routes:

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

2) And adding alkali B into the pranoprofen methyl ester intermediate to hydrolyze to obtain the pranoprofen.

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

Further, the solvent A in the step 1) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tertiary butyl ether, ethyl acetate, N-dimethylformamide, N-dimethylacetamide or dimethyl sulfoxide, and is preferably dichloromethane.

Further, the reaction temperature of the step 1) is-20 to 50 ℃, preferably-5 to 30 ℃.

Further, the base B of step 2) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

Further, the post-treatment method of the step 2) comprises the following steps: adding water to dilute the reaction solution, washing twice with dichloromethane, adding acetic acid into the water phase to adjust the pH to 4-5, precipitating a large amount of solids, filtering, drying to obtain a pranoprofen refined product, and recrystallizing with ethanol to obtain the pranoprofen refined product.

The invention has the beneficial effects that: according to the invention, p-toluenesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride and the like are used as activating reagents, rearranged under alkaline conditions and hydrolyzed, so that the generation of byproducts is reduced, and particularly, the impurity A which is basically not difficult to remove is realized; meanwhile, the requirement on temperature control is greatly reduced, the overall process level is obviously improved, and the economic and efficient effects are achieved.

Drawings

FIG. 1 example 1 product ¹ H-NMR spectrum.

FIG. 2 example 1 product ¹³ C-NMR spectrum.

FIG. 3 HPLC profile of the product of example 1.

FIG. 4 is an HPLC chromatogram of the product of comparative example 1.

FIG. 5 is an HPLC chromatogram of the product of comparative example 2.

Detailed Description

The following examples will provide those skilled in the art with a more complete understanding of the present invention and are not intended to limit the invention to the embodiments described.

The preparation of compound 1 is described in "improvement of synthesis studies of pranoprofen" (Jin Rongqing, fine chemical intermediate, 2009, 39 (3), 3739).

Example 1

Adding compound 1 (50 g,0.17 mol) into a three-port bottle, adding dichloromethane 500mL, adding pyridine (32 g,0.40 mol) after complete dissolution, dropwise adding trifluoromethanesulfonic anhydride (57 g,0.20 mol) under the protection of nitrogen, reacting for 3h at 0-10 ℃, adding water washing liquid, concentrating an organic phase under reduced pressure, adding methanol 200mL and sodium hydroxide (20.0 g,0.51 mol) water 50mL solution into oily matters, reacting for 1h at room temperature under the protection of nitrogen, adding water 450mL, washing twice with dichloromethane 500mL in sequence, adding acetic acid into the aqueous phase to adjust the pH to 4-5, precipitating a large amount of solids, filtering, drying to obtain 32.2g of pranoprofen crude product, recrystallizing with ethanol to obtain 32.9g of pranoprofen refined product, wherein the total yield is 76%, and the purity is 99.96% (olefin impurity A is detected to be 0.01%).

Example 2

Compound 1 (5 g,0.017 mol) is added into a three-mouth bottle, 50mL of dichloromethane is added, pyridine (3.2 g,0.040 mol) is added after complete dissolution, p-toluenesulfonyl chloride (3.8 g, 0.020mol) is added dropwise under the protection of nitrogen gas for reaction for 3 hours at reflux temperature, water washing and liquid separation are added, an organic phase is concentrated under reduced pressure, solution of 20mL of methanol and 5mL of sodium hydroxide (2.0 g,0.051 mol) in water is added into oily matter, reaction is carried out for 1 hour at room temperature under the protection of nitrogen gas, 45mL of water is added, and dichloromethane is sequentially used for washing twice with 50mL of dichloromethane, acetic acid is added into the aqueous phase for regulating pH to 4-5, a large amount of solids are separated out, filtration and drying are carried out, ethanol recrystallization is carried out, and pranoprofen refined product 1.90g is obtained, and the yield is 45%.

Example 3

Adding compound 1 (5 g,0.017 mol) into a three-port bottle, adding 50mL of dichloromethane, adding pyridine (3.2 g,0.040 mol) after complete dissolution, dropwise adding methanesulfonic anhydride (3.5 g, 0.020mol) under nitrogen protection, reacting for 6h at reflux temperature, adding water for washing liquid separation, decompressing and concentrating an organic phase, adding a solution of 20mL of methanol and 5mL of sodium hydroxide (2.0 g,0.051 mol) in oily substance, reacting for 1h at room temperature under nitrogen protection, adding 45mL of water, washing twice with 50mL of dichloromethane, adding acetic acid into the aqueous phase to adjust pH to 4-5, precipitating a large amount of solids, filtering, drying, recrystallizing with ethanol to obtain 2.37g of pranoprofen refined product, wherein the yield is 56%.

Example 4

Adding compound 1 (5 g,0.017 mol) into a three-port bottle, adding 50mL of dichloromethane, adding pyridine (3.2 g,0.040 mol) after complete dissolution, dropwise adding trifluoromethanesulfonic anhydride (5.7 g, 0.020mol) under nitrogen protection, reacting for 3h at the temperature of-20-0 ℃, adding water for washing and separating liquid, decompressing and concentrating an organic phase, adding 20mL of methanol and 5mL of sodium hydroxide (2.0 g,0.051 mol) into oily substance, reacting for 1h at room temperature under nitrogen protection, adding 45mL of water, washing twice with 50mL of dichloromethane, adding acetic acid into the aqueous phase to adjust the pH to 4-5, precipitating a large amount of solids, filtering, drying, recrystallizing with ethanol to obtain 3.09g of pranoprofen crude product with the yield of 73%, and the purity of 99.90%.

Example 5

Adding compound 1 (5 g,0.017 mol) into a three-port bottle, adding 50mL of dichloromethane, adding pyridine (3.2 g,0.040 mol) after complete dissolution, dropwise adding trifluoromethanesulfonic anhydride (5.7 g, 0.020mol) under nitrogen protection, reacting for 3 hours at the temperature of-20-0 ℃, adding water for washing and separating liquid, decompressing and concentrating an organic phase, adding 20mL of methanol and 5mL of sodium hydroxide (2.0 g,0.051 mol) water into oily matter, reacting for 1 hour at room temperature under nitrogen protection, adding 45mL of water, washing twice with 50mL of dichloromethane, adding acetic acid into the aqueous phase to adjust the pH to 4-5, precipitating a large amount of solids, filtering, drying, recrystallizing with ethanol to obtain 2.92g of pranoprofen crude product with the yield of 69%, and the purity of 99.93%.

Comparative example 1 (method of JP 1992288081A)

Compound 1 (30.1 g,0.10 mol) was put into a three-necked flask, 220mL of methylene chloride was added, triethylamine (24.3 g,0.24 mol) was added after complete dissolution, sulfonyl chloride (16.2 g,0.12 mol) was slowly added dropwise at-20℃and then the mixture was kept at room temperature for 2 hours, and then the mixture was slowly warmed to room temperature and reacted for 3 hours, and the resulting reaction solution was reacted in 2 hours

Drop wise to 20.2g (0.480 mol) sodium hydroxideIn a mixed solution of 150ml methanol and 50ml water. After the dropping, methanol was distilled off under reduced pressure, and 150ml of water was added to the concentrated residue for dissolution. The aqueous layer was washed with 50ml of methylene chloride, then the aqueous layer was combined for decolorization, acetic acid was added dropwise to adjust the pH to 5 to 6, a solid was precipitated, washed with water, and recrystallized from dioxane/water recrystallized from ethanol to give 16.1g of pranoprofen concentrate in a total yield of 63% and a purity of 98.78% (FIG. 4: oxidized impurity 0.44%, olefin impurity 0.23%).

Comparative example 2 (method of CN109942589 a)

Adding compound 1 (40 g,0.13 mol) into 200ml of dichloromethane, cooling to about 0 ℃, adding triethylamine (26 g) firstly, slowly dropwise adding thionyl chloride (23 g,0.19 mol), controlling the temperature to be less than or equal to 20 ℃, reacting for 3 hours at room temperature after the dropwise adding, concentrating under reduced pressure, adding 20ml of concentrated hydrochloric acid, heating to 60 ℃ for reacting for 3 hours, adding the reaction solution into 200ml of ice water, adding 10% sodium hydroxide solution to adjust the pH value to be 11, washing the system with 100ml of dichloromethane for 2 times, adjusting the pH value of a water layer with acetic acid to be 5, precipitating a large amount of solids, stirring for 2 hours at room temperature, and filtering to obtain a pranoprofen crude product. 200ml of ethanol is added for heating, refluxing and dissolving, then the temperature is reduced to room temperature, an equal amount of water is added, after solid precipitation, stirring is carried out for 2 hours, and then filtration is carried out, so that a white solid is obtained, 18.3g is dried, and the pranoprofen refined product is obtained, and the yield is 56%. (FIG. 5: 0.34% oxygenated impurity, 0.49% olefinic impurity).

The results and comparison of the preparation methods described in the examples and comparative examples of the present invention are as follows:

the method for preparing the pranoprofen does not need a severe low-temperature environment, has certain advantages in the yield and product purity methods, has the lowest content of the pranoprofen olefin impurity A which is difficult to remove, is easy to refine, and has the quality higher than the pharmacopoeia requirement.

Claims (6)

1. The preparation method of pranoprofen comprises the following reaction routes:

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

2) And adding alkali B into the pranoprofen methyl ester intermediate to hydrolyze to obtain the pranoprofen.

2. The preparation method according to claim 1, wherein the base a of step 1) is selected from one or more of triethylamine, N-diisopropylethylamine, pyridine or N-methylmorpholine, preferably triethylamine or pyridine.

3. The preparation method according to claim 1, wherein the solvent a of step 1) is selected from one or more of dichloromethane, chloroform, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, N-dimethylformamide, N-dimethylacetamide or dimethylsulfoxide, preferably dichloromethane.

4. The process according to claim 1, wherein the reaction temperature of step 1) is-20 to 50 ℃, preferably-5 to 30 ℃.

5. The process according to claim 1, wherein the base B of step 2) is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.

6. The method according to claim 1, wherein the post-treatment method of step 2) is: adding water to dilute the reaction solution, washing twice with dichloromethane, adding acetic acid into the water phase to adjust the pH to 4-5, precipitating a large amount of solids, filtering, drying to obtain a pranoprofen refined product, and recrystallizing with ethanol to obtain the pranoprofen refined product.

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