A kind of refining method of pranoprofen

Abstract

The invention provides a method for refining and purifying pranoprofen. The method increases the property difference between pranoprofen and impurities by salt formation, and can effectively remove impurities A and impurity B. The prepared pranoprofen has high purity, simple and convenient process, high yield, and is suitable for large-scale production and preparation.

Description

Technical Field

[0001] The invention relates to the field of drug production, and in particular to a method for refining 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] For the preparation of pranoprofen, the current mainstream process is to use 5H-[1]benzopyran[2,3-b]pyridine as the raw material, replace it with 2-chloropropionyl chloride to obtain 7-(2-chloropropionyl)-5H-[1]benzopyran[2,3-b]pyridine, and complete the two reactions of ketalization and hydrolysis under alkaline conditions. Then rearrangement occurs in the presence of sulfonyl chloride, and then hydrolysis is performed to obtain pranoprofen. The purity of the crude pranoprofen obtained by this process can generally reach 92%-98%, and it contains a large number of impurities. At the same time, pranoprofen is sensitive to factors such as light and oxygen, so in addition to the need for a systematic study of the stability of the product in the subsequent formulation direction, it is also necessary to reduce the impurities in the raw materials as much as possible.

[0004] The impurities that may exist in pranoprofen include starting materials, intermediates, degradation products, process impurities and some unknown impurities, etc. Most of these impurities can be controlled within the limit requirements by conventional recrystallization refining methods, but some impurities are difficult to control. For example Figure 1 As shown, impurity A, whose retention time is immediately after that of pranoprofen, is an olefin impurity (Formula I) generated by eliminating the side reaction in the chlorination rearrangement reaction; the impurity content is relatively high, and it is difficult to remove the impurity through process control; at the same time, the impurity structure is similar to that of pranoprofen, and direct recrystallization of pranoprofen cannot remove impurity A. Figure 1 As shown, the impurity B before the main peak has a retention time of 16.18 min. This impurity is an oxidized impurity of pranoprofen and impurity B will continue to be produced during production.

[0005] Among the reported methods, different refining methods such as ethanol-water recrystallization, methanol-water beating followed by methanol-water recrystallization, and dioxane-water recrystallization are mentioned, as shown in the table below; most of the reported refining methods do not have a good yield, and only a few refining yields are about 80%. After investigation, the methods reported in the literature cannot achieve effective refining, and the yields are generally low. For example, the refining methods reported in JPH03271290A and JPH0495094A cannot achieve recrystallization, and beating has no refining effect; the methods reported in US3931205A and CN110372713B have no substantial refining possibility, and the yield loss is large. The yields of the two refining methods are 40-55%.

[0006]

[0007] Summary of the invention

[0008] In view of the deficiencies in the prior art, the present invention provides a method for refining pranoprofen.

[0009] The technical solution of the present invention is as follows: A method for refining pranoprofen comprises the following steps:

[0010] a) heating the crude pranoprofen in solvent A under reflux until the solution becomes clear;

[0011] b) adding a solution of alkali A or salt A, continuing heating and stirring to salify pranoprofen, and cooling and crystallizing;

[0012] c) filtering to obtain the pranoprofen salt, washing the filter cake with solvent A, and draining;

[0013] d) stirring the filter cake in solvent B until it is dissolved, filtering to obtain a filtrate, adjusting the pH of the filtrate with an acid, and precipitating a solid;

[0014] e) filtering and drying to obtain high-purity pranoprofen;

[0015] In some embodiments, the solvent A in step a) is selected from one or more of ethanol, acetone, and methanol, preferably ethanol.

[0016] In some embodiments, the volume mass ratio of solvent A to crude pranoprofen in step a) is 6:1.

[0017] In some embodiments, in step b), the base A is selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide; and the salt A is selected from magnesium chloride.

[0018] In some embodiments, the molar ratio of the crude pranoprofen to the base A or the salt A is 1:1 to 1.1.

[0019] In some embodiments, the volume mass ratio of the solution of base A or salt A to the crude pranoprofen is 2:1.

[0020] In some embodiments, the crystallization condition in step b) is cooling to 20° C. and crystallizing for 2 hours.

[0021] In some embodiments, the volume ratio of the solvent A used in step c) to the mass ratio of the crude pranoprofen product is 1:1. In some embodiments, the volume ratio of the solvent B used in step d) to the mass ratio of the crude pranoprofen product is 8:1.

[0022] In some embodiments, in step d), the acid is selected from hydrochloric acid or acetic acid, and the pH is adjusted to 4-5.

[0023] In some embodiments, the drying temperature in step e) is 50°C.

[0024] Beneficial effects of the present invention: The present invention provides a method for refining and purifying pranoprofen, which increases the property difference between pranoprofen and impurities by salt formation, can effectively remove impurities A and impurity B, and the prepared pranoprofen has high purity. The purification method is simple to operate and has a high yield.

[0025] 1. The refining and purification method of pranoprofen of the present invention is a simple, easy and low-cost refining and purification method, which can effectively reduce impurities in pranoprofen and meet the preparation requirements.

[0026] 2. The pranoprofen finished product obtained by the method of the present invention has a chromatographic purity higher than 99.90%, wherein the content of impurity A is less than 0.10%, the content of impurity B is less than 0.10%, the total impurities are less than 0.10%, and the single refining yield is greater than 90%.

[0027] 3. The salt-forming step in the present invention has a significant effect on the removal of various impurities, especially the removal of impurity A. The effect is very significant. One salt-forming step can reduce impurity A by about 70-80%. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is the impurity chromatogram of the untreated crude pranoprofen of the embodiment

[0029] Figure 2 It is the impurity chromatogram of pranoprofen of embodiment 1 of the present invention

[0030] Figure 3 It is the impurity chromatogram of pranoprofen of embodiment 2 of the present invention

[0031] Figure 4 It is the impurity chromatogram of pranoprofen of embodiment 3 of the present invention

[0032] Figure 5It is the impurity chromatogram of pranoprofen of comparative example 1 of the present invention

[0033] Figure 6 It is the impurity chromatogram of pranoprofen of comparative example 2 of the present invention

[0034] Figure 7 It is the impurity chromatogram of pranoprofen of comparative example 3 of the present invention

[0035] Figure 8 It is the impurity chromatogram of pranoprofen of comparative example 4 of the present invention DETAILED DESCRIPTION

[0036] 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.

[0037] The detection methods used in the examples and comparative examples are shown in the following table, and the method is determined by referring to the high performance liquid chromatography method (General Rules 0512 of the 2020 edition of the Chinese Pharmacopoeia).

[0038]

[0039]

[0040] In the embodiment, the crude pranoprofen product to be refined and purified was prepared with reference to "Study and Improvement of the Synthesis of Pranoprofen" (Fine Chemical Intermediates 2009, 39 (3), 3739). The preparation method is as follows: 5H-[1]benzopyrano[2,3-b]pyridine is used as a raw material, dichloromethane (10V) is used as a reaction solvent, and in the presence of aluminum chloride (2.5eq), it is reacted with 2-chloropropionyl chloride (1.2eq) to obtain 7-(2-chloropropionyl)-5H-[1]benzopyrano[2,3-b]pyridine by Friedel-Crafts acylation reaction. , 3-b] pyridine; then, the ketal was prepared under the conditions of methanol (5V)-sodium methoxide (1.5eq) and hydrolyzed to obtain 1-(5H-benzopyrano[2,3-b]pyridin-7-yl)-1,1-dimethoxypropyl-2-ol; 1-(5H-benzopyrano[2,3-b]pyridin-7-yl)-1,1-dimethoxypropyl-2-ol was rearranged in the presence of sulfonyl chloride (1.2eq) and triethylamine (2.4eq) to obtain pranoprofen methyl ester, and finally, the crude pranoprofen was obtained through hydrolysis and post-treatment.

[0041] The HPLC spectrum of the crude unrefined pranoprofen is shown in Figure 1 As shown, the chromatographic purity is 98.78%, wherein the main impurity contents are: impurity A 0.23%, impurity B 0.11%, and total impurities 1.22%.

[0042]

[0043] The specific test data are shown in the following table:

[0044] Peak Retention time area area% Separation 1 5.897 1.0031 0.437 na 2 7.327 0.3856 0.168 5.53 3 10.390 0.1245 0.054 10.09 4 11.393 0.1325 0.058 3.28 5 12.678 0.2747 0.120 4.28 6 16.180 0.2571 0.112 8.32 7 16.673 0.0918 0.040 1.13 8 18.352 226.8452 98.782 5.56 9 19.598 0.5287 0.230 4.63

[0045] Example 1

[0046] Add 6 times the amount of ethanol (240 mL) to the crude product of Pranoprofen (40.00 g, 0.157 mol), heat to 80 ° C, and reflux the system. Add 2 times the amount of ethanol (80 mL) solution containing sodium hydroxide (6.14 g, 0.154 mol), continue heating and stirring; reflux for 3-5 minutes, solid precipitates, cool to 20 ° C, and crystallize for 2 hours. Filter, rinse the filter cake with ethanol (40 mL), and drain. The solid is returned to the reaction bottle, 8 times the amount of water (320 mL) is added, stirred until dissolved, filtered to obtain a filtrate, the filtrate is adjusted to pH 4-5 with acetic acid, solid precipitates, filtered, and the wet product is dried at 50 ° C to obtain 39.95 g of Pranoprofen finished product with a yield of 92.0%. The chromatogram of the product is as follows Figure 2 As shown, its chromatographic purity is 99.91%, of which impurity A is 0.03%, impurity B is 0.02%, and total impurities are 0.09%. Specific experimental data are shown in the following table:

[0047] Peak Retention time area area% Separation 1 7.312 0.0441 0.020 na 2 10.385 0.0545 0.014 10.31 3 12.663 0.0467 0.011 7.02 4 16.300 0.1400 0.022 5.94 5 18.342 225.2663 99.906 3.60 6 19.592 0.1519 0.027 4.56

[0048] Example 2

[0049] Add 8 times the amount of acetone (320 mL) to the crude product of Pranoprofen (40.00 g, 0.157 mol), heat to 60 ° C, reflux the system, add 2 times the amount of ethanol (80 mL) solution containing potassium hydroxide (8.61 g, 0.154 mol), continue heating and stirring, solid precipitates after 3 to 5 minutes, cool to 20 ° C, and crystallize for 2 hours. Filter, rinse the filter cake with acetone, and drain; return the filter cake to the reaction bottle, add 8 times the amount of water (320 mL), stir until it is clear, filter to obtain the filtrate, adjust the pH of the filtrate to 4 to 5 with acetic acid, solid precipitates, filter, and drain to obtain a wet product, which is dried at 50 ° C to obtain 39.13 g of Pranoprofen finished product with a yield of 90.1%. The chromatogram of the product is as follows Figure 3 As shown, its chromatographic purity is 99.84%, of which impurity A is 0.05%, impurity B is 0.05%, and total impurities are 0.16%. Specific experimental data are shown in the following table:

[0050] Peak Retention time area area% Separation 1 7.300 0.031 0.014 na 2 10.345 0.0454 0.020 9.99 3 12.652 0.0415 0.018 7.68 4 16.283 0.1212 0.054 7.44 5 18.323 225.2717 99.842 4.25 6 19.563 0.1171 0.052 4.55

[0051] Example 3

[0052] Add 6 times the amount of methanol (120 mL) to the crude product of Pranoprofen (20.00 g, 0.078 mol), heat to 65 ° C, reflux the system, add 2 times the amount of methanol (40 mL) solution containing magnesium chloride (7.31 g, 0.072 mol), continue heating and stirring, reflux for 3 to 5 minutes, solid precipitates, cool to 20 ° C, and crystallize for 2 hours. Filter, rinse the filter cake with methanol, and drain; return the filter cake to the reaction bottle, add 8 times the amount of water (160 mL), stir until it is dissolved, filter to obtain the filtrate, adjust the pH of the filtrate to 4 to 5 with hydrochloric acid, solid precipitates, filter, and drain to obtain a wet product, which is dried at 50 ° C to obtain 19.94 g of Pranoprofen finished product with a yield of 91.9%. The chromatogram of the product is as follows Figure 4 As shown, its chromatographic purity is 99.78%, of which impurity A is 0.071%, impurity B is 0.04%, and total impurities are 0.22%. Specific experimental data are shown in the following table:

[0053] Peak Retention time area area% Separation 1 10.548 0.0775 0.030 na 2 12.787 0.1156 0.045 4.67 3 16.232 0.1111 0.043 8.82 4 18.265 256.1611 99.781 7.12 5 19.500 0.1832 0.071 4.61 6 26.025 0.0180 0.007 23.3 7 28.718 0.0574 0.022 10.81

[0054] At the same time, the same batch of pranoprofen crude product in the example was refined with reference to various literatures, and the specific results are shown in Comparative Examples 1 to 4.

[0055] Comparative Example 1

[0056] References: Jin Rongqing, Zhang Haibo, Meng Ting, et al. Research and improvement on the synthesis of pranoprofen[J]. Fine Chemical Intermediates, 2009, 39(3):4.

[0057] Add 5 times the amount of ethanol (50 mL) to the crude product of Pranoprofen (10.00 g, 0.039 mol), heat and stir under nitrogen protection until reflux, and the system becomes clear; add purified water (50 mL) under nitrogen protection, keep warm and stir for 30 min, slowly cool to 20 ° C, and crystallize for 2 hours. Filter, rinse the filter cake with a small amount of ethanol, drain, and dry the filter cake at 50 ° C to obtain 5.12 g of Pranoprofen finished product, with a yield of 51.2%. The chromatogram of the product is shown in the figure below: Figure 5 As shown, its chromatographic purity is 98.80%, of which impurity A is 0.16%, impurity B is 0.015%, and total impurities are 1.20%. Specific experimental data are shown in the following table:

[0058] Peak Retention time area area% Separation 1 4.848 0.8085 0.467 na 2 5.953 0.2634 0.152 5.17 3 8.817 0.0986 0.057 10.51 4 11.31 0.1610 0.093 8.53 5 14.83 0.3027 0.175 12.94 6 15.132 0.0092 0.005 na 7 15.398 0.0255 0.015 na 8 16.382 0.1237 0.071 5.96 9 17.152 170.9714 98.803 2.92 10 18.48 0.2797 0.162 4.95

[0059] Comparative Example 2

[0060] References: Rao Hancai, Huang Nengzhang, Wang Shuo, et al. A method for refining and purifying pranoprofen. CN110372713B.

[0061] The crude product of Pranoprofen (15.00g) was ground through an 80-mesh sieve, and 8 times (80mL) of 50% methanol-water solution was added to (10.00g, 0.039mol), and the mixture was heated to 60-65°C, refluxed, and stirred for 4h, cooled to room temperature, filtered, and the filter cake was rinsed with a small amount of 50% methanol-water solution, drained, and dried at low temperature (30°C) to obtain 6.13g of product with a beating yield of 61.3%. The beating-treated Pranoprofen was added with 25 times of 50% methanol-water solution and placed in a three-necked flask, heated to reflux, stirred to dissolve, refluxed for 30 minutes for decolorization, filtered while hot, and the filtrate was added to a clean three-necked flask, stirred for 30 minutes, cooled to 25°C, and crystallized for 5h. Filter, rinse the filter cake with a small amount of recrystallization solvent (50% methanol solution), drain, and dry at 55°C to obtain 4.25 g of pranoprofen finished product. The total yield of the two operations is 42.5%. The chromatogram of the product is as follows Figure 6 As shown, its chromatographic purity is 99.26%, of which impurity A is 0.21%, impurity B is not detected, and total impurities are 0.74%. Specific experimental data are shown in the following table:

[0062] Peak Retention time area area% Separation 1 4.887 0.3960 0.237 na 2 6.003 0.3700 0.122 5.28 3 8.847 0.0877 0.053 11.16 4 11.303 0.1006 0.060 7.48 5 14.842 0.0868 0.052 10.74 6 17.172 165.4848 99.26 8.57 7 18.500 0.3545 0.212 4.94

[0063] By comparing the HPLC spectrum data of the related substances of the above samples with the HPLC spectrum data of the crude pranoprofen product, it can be seen that the refining method provided by CN110372713B has a certain refining effect on the crude pranoprofen product, but has no refining effect on the impurity A of 18.5min, and cannot effectively remove the impurities of 4.8min and 6.0min, and the yield of the entire operation process is low.

[0064] Comparative Example 3

[0065] Add 3 times the amount of dimethyl sulfoxide (30 mL) to the crude product of Pralofen (10.00 g, 0.039 mol), stir at room temperature until the system is dissolved, add water dropwise until solids just precipitate out of the system, cool to 0-10°C, and crystallize for 1-2 hours. Filter, rinse the filter cake with a small amount of water, drain, and dry the filter cake at 50°C to obtain 5.17 g of Pralofen finished product. The chromatogram of the product is shown in the figure below: Figure 7 As shown, its chromatographic purity is 98.99%, of which impurity A is 0.17%, impurity B is 0.005%, total impurities are 0.49%, and the yield is 51.7%. The specific experimental data are shown in the following table:

[0066]

[0067]

[0068] Comparative Example 4

[0069] Reference: MITSUBISHI CHEMICAL HOLDINGS CORPORATION.Substitutedalkanoic acids and derivatives.US3931205,1976,A

[0070] Add 5 times the amount of dioxane (50 mL) to the crude product of Pralox (10.00 g, 0.039 mol), stir at room temperature until the system is clear, add water until the system just precipitates solids, cool to 0-10 ° C, and crystallize for 1-2 hours. Filter, rinse the filter cake with a small amount of water, drain, and dry the filter cake at 50 ° C to obtain 7.23 g of Pralox. Return the dried material to the reaction bottle again, add 5 times the amount of dioxane (36 mL), stir at room temperature until the system is clear, add water until the system just precipitates solids, cool to 0-10 ° C, and crystallize for 1-2 hours. Filter, rinse the filter cake with a small amount of water, drain, and dry the filter cake at 50 ° C to obtain 5.13 g of Pralox finished product, with a yield of 51.3%. The chromatogram of the product is as follows Figure 8 As shown, its chromatographic purity is 99.70%, of which impurity A is 0.18%, impurity B is ND, and total impurities are 0.30%. Specific experimental data are shown in the following table:

[0071] Peak Retention time area area% Separation 1 4.883 0.1984 0.113 na 2 17.163 175.2007 99.703 54.69 3 18.488 0.3229 0.184 4.94

[0072] As can be seen from the above comparative example, the recrystallization process of general pranoprofen can remove other impurities; however, the ordinary recrystallization process for impurity A has a very limited effect on the removal of the impurity, and even repeated refining operations cannot effectively reduce the content of impurity A, and the yield will be greatly reduced. The refining process in the present invention has a significant effect on the removal of each impurity, especially in terms of the removal of impurity A, and obtains unexpected effects, which can ensure that the product meets the expected quality requirements.

Claims

1. A method for refining pranoprofen, comprising the following steps: a) heating the crude pranoprofen in solvent A under reflux until the solution becomes clear; B) adding the solution of alkali A, continuing heating and stirring to make pranoprofen salify, cooling and crystallizing; c) filtering to obtain the pranoprofen salt, washing the filter cake with solvent A, and draining; d) stirring the filter cake in solvent B until it is dissolved, filtering to obtain a filtrate, adjusting the pH of the filtrate with an acid, and precipitating a solid; e) filtering and drying to obtain pranoprofen; In said step a), solvent A is selected from ethanol; In the step a), the volume mass ratio of solvent A to the crude pranoprofen is 6:1; In the step b), the base A is selected from sodium hydroxide; The crystallization condition in step b) is cooling to 20° C. and crystallizing for 2 hours; The molar ratio of the crude pranoprofen to the base A is 1:1-1.1, and the volume mass ratio of the solution of the base A or the salt A to the crude pranoprofen is 2:1; The mass ratio of the volume of the solvent A used in the step c) to the crude pranoprofen is 1:1; The solvent B used in step d) is water; The mass ratio of the volume of the solvent B used in the step d) to the crude pranoprofen is 8:1; In step d), the acid is selected from hydrochloric acid or acetic acid, and the pH is adjusted to 4-5.

2. The refining method according to claim 1, characterized in that The drying temperature in step e) is 50°C.

Images