Purification method for removing ibuprofen impurities

Abstract

The invention relates to the technical field of medicine preparation, in particular to a purification method for removing ibuprofen impurities, which comprises the following steps: mixing and heating an ibuprofen crude product, an alcohol solvent and a catalyst, and after the reaction is finished, cooling to obtain a reactant; the method comprises the following steps: adding an organic solvent into a reactant, layering, extracting, combining organic phases, concentrating under reduced pressure, adding a proper amount of water to crystallize, filtering and washing to obtain ibuprofen, thereby inhibiting the esterification reaction of ibuprofen under an acidic condition, accelerating the conversion rate, reducing the generation of byproducts, controlling the reaction temperature, reducing the generation of impurities, and improving the yield of ibuprofen. According to the present invention, the excessive alcohol compound (ROH) and the catalyst are added, such that the target product selectivity is improved, the product purity is high, the purification is easy, and the method has advantages of low production cost, simple operation and high product purity.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparation, and particularly relates to a method for purifying ibuprofen by removing impurities. Background Art

[0002] Ibuprofen, chemically named 2-(4-isobutylphenyl)propanoic acid, belongs to arylpropionic acid non-steroidal anti-inflammatory drugs. As a widely used non-steroidal anti-inflammatory drug, compared with drugs such as aspirin and corticosteroids, ibuprofen shows stronger pain and inflammation relief effects and fewer side effects, and has quickly become one of the first-choice drugs for treating pain and inflammation globally.

[0003] Ibuprofen can effectively relieve various types of pain, including headache, toothache, arthritis pain, and menstrual pain, etc., and is also a good choice for treating fever caused by cold or flu.

[0004] Drug impurities refer to other substances that do not belong to the active ingredients of the drug. Impurities may pose potential risks to human health, such as possible toxicity, allergic reactions, or other adverse reactions, threatening the safety of patients' medication. In the production process of ibuprofen, due to the need to add reagents, solvents, or catalysts, etc., these substances may not be completely removed due to reasons such as solubility, adsorption, occlusion, coprecipitation, and mixed crystal formation, and thus exist as impurities in the product. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for purifying ibuprofen by removing impurities, aiming to accelerate the conversion rate of ibuprofen and reduce the generation of by-products.

[0006] To achieve the above purpose, the present invention provides a method for purifying ibuprofen by removing impurities, including the following steps:

[0007] Mix and heat ibuprofen crude product, alcohol solvent, and catalyst, and after the reaction ends, cool down to obtain a reaction product;

[0008] Add an organic solvent to the reaction product, separate layers, extract, combine the organic phases, concentrate under reduced pressure, add an appropriate amount of water for crystallization, filter, and wash with water to obtain ibuprofen.

[0009] Among them, the alcohol solvent is methanol or a mixed solution of ethanol and water, and the catalyst is hydrochloride, sulfate, or phosphate.

[0010] Among them, the mass ratio of methanol or ethanol to water is 1:0.5 - 2.

[0011] Among them, the molar ratio of ibuprofen, alcohol solvent, and catalyst is 1:10 - 100:0.1 - 1, the mixed heating temperature is 20 - 78°C, and the reaction time is 0.5 - 18h.

[0012] Among them, the specific method of mixing the crude ibuprofen, an alcohol solvent and a catalyst, heating, and cooling after the reaction to obtain the reactant is as follows:

[0013] Mix the crude ibuprofen, an alcohol compound and a catalyst in a molar ratio of 1:30 - 60:0.5 - 1 in a mixing tank to obtain a mixture;

[0014] Heat the mixture to 40 - 70 °C, react for 0.5 - 18 h, and then cool to obtain the reactant.

[0015] Among them, the organic solvent is dichloromethane and acetone.

[0016] Among them, the specific method of adding an organic solvent to the reactant, layering, extracting, combining the organic phases, concentrating under reduced pressure, adding an appropriate amount of water for crystallization, filtering, and washing with water to obtain ibuprofen is as follows:

[0017] Add dichloromethane to the reactant, separate the layers by liquid separation, extract the aqueous phase with dichloromethane, and combine the organic phases;

[0018] Concentrate the organic phase to less than half of its volume under a vacuum of 0.06 - 0.1 MPa, add 3 - 10 times the volume of water for crystallization for 2 h while stirring, filter, and wash the filter cake with a small amount of water to obtain ibuprofen.

[0019] A method for removing impurities and purifying ibuprofen according to the present invention, which mixes the crude ibuprofen, an alcohol solvent and a catalyst, heats, cools after the reaction to obtain the reactant, adds an organic solvent to the reactant, layers, extracts, combines the organic phases, concentrates under reduced pressure, adds an appropriate amount of water for crystallization, filters, and washes with water to obtain ibuprofen. This method can inhibit the esterification reaction of ibuprofen under acidic conditions. To accelerate the conversion rate while reducing the generation of by-products, control the reaction temperature, reduce the generation of impurities, add an excessive amount of alcohol compound (ROH) and a catalyst at the same time to improve the selectivity of the target product. The product has high purity and is easy to purify. This method has the advantages of low production cost, simple operation, and high product purity, and the purity of the prepared ibuprofen can reach more than 95%. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can be obtained based on these drawings.

[0021] Figure 1It is a flow chart of a method for removing impurities and purifying ibuprofen provided by the present invention.

[0022] Figure 2 It is a flow chart of the specific method of mixing crude ibuprofen, an alcohol solvent and a catalyst, heating them, and after the reaction ends, cooling to obtain the reaction product.

[0023] Figure 3 It is a flow chart of the specific method of adding an organic solvent to the reaction product, separating layers, extracting, combining the organic phases, concentrating under reduced pressure, adding an appropriate amount of water for crystallization, filtering, and washing with water to obtain ibuprofen. Specific Embodiments

[0024] The embodiments of the present invention will be described in detail below. The examples of the embodiments are shown in the accompanying drawings, where the same or similar reference numerals represent the same or similar elements or elements with the same or similar functions throughout. The embodiments described below by referring to the accompanying drawings are exemplary and are intended to explain the present invention, and should not be construed as limiting the present invention.

[0025] Please refer to Figures 1 to 3 , the present invention provides a method for removing impurities and purifying ibuprofen, including the following steps:

[0026] S1 Mix crude ibuprofen, an alcohol solvent and a catalyst, heat them, and after the reaction ends, cool to obtain the reaction product;

[0027] In the embodiments of the present invention, the alcohol solvent is methanol or a mixed solution of ethanol and water with a mass ratio of 1:0.5 - 2, the catalyst is hydrochloride, sulfate or phosphate, the molar ratio of ibuprofen, the alcohol compound and the catalyst is 1:10 - 100:0.1 - 1, the temperature of the mixed heating is 20 - 78°C, and the reaction time is 0.5 - 18 h.

[0028] Specific method:

[0029] S11 Put crude ibuprofen, the alcohol compound and the catalyst into a mixing tank according to a molar ratio of 1:30 - 60:0.5 - 1, mix them evenly to obtain a mixture;

[0030] S12 Heat the mixture to 40 - 70°C, after reacting for 0.5 - 18 h, cool to obtain the reaction product;

[0031] S2 Add an organic solvent to the reaction product, separate layers, extract, combine the organic phases, concentrate under reduced pressure, add an appropriate amount of water for crystallization, filter, and wash with water to obtain ibuprofen;

[0032] In the embodiments of the present invention, the organic solvent is dichloromethane or acetone.

[0033] Specific method:

[0034] S21 Add dichloromethane to the neutral mixture, separate the layers by liquid separation, extract the aqueous phase with dichloromethane, and combine the organic phases.

[0035] In the embodiment of the present invention, pour an appropriate amount of dichloromethane slowly into a container containing the reactants, such as a conical flask or a separatory funnel, and stir or shake simultaneously to promote full contact between the reactants and the organic solvent. Generally, stir or shake for 5 - 15 minutes, then let it stand still to separate the layers naturally under the action of gravity. Slowly release and collect the separated organic phase from the lower outlet of the separatory funnel. After the organic phase is released completely, close the piston, and then pour the aqueous phase out from the upper outlet of the separatory funnel into a clean container. Combine the organic phases obtained from each extraction into the same clean container to ensure that no other impurities are mixed in.

[0036] S22 Concentrate the organic phase under reduced pressure, add an appropriate amount of water for crystallization, filter, and wash with water to obtain ibuprofen.

[0037] In the embodiment of the present invention, transfer the organic phase to the eggplant-shaped flask of a rotary evaporator, connect the device, turn on the vacuum pump, and adjust the vacuum degree and temperature. It can be evaporated quickly under a vacuum degree of 0.06 - 0.1 MPa. When the solution is concentrated to less than half of the original volume, stop the concentration, and the crude product can be obtained after natural cooling.

[0038] To better understand the present technical solution, the following examples are provided for further illustration:

[0039] Example 1

[0040] Add 20.6 g of ibuprofen crude product, 150 g of 50% ethanol aqueous solution, and 5 g of sodium chloride, heat to 40 - 50 °C, react for 2 h, cool to room temperature, add 50 mL of dichloromethane, separate the layers, extract the aqueous phase with 50 mL × 2 of dichloromethane, and combine the organic phases. Concentrate under reduced pressure to half of the volume, add 100 g of water with stirring, concentrate under reduced pressure, filter, to obtain 18.4 g of ibuprofen (GC), and the GC purity is 99.4%.

[0041] Example 2

[0042] Add 20.6 g of ibuprofen crude product, 120 g of 75% ethanol aqueous solution, and 7 g of sodium sulfate, heat to 50 - 60 °C, react for 4 h, cool to room temperature, add 50 mL of dichloromethane, separate the layers, extract the aqueous phase with 50 mL × 2 of dichloromethane, and combine the organic phases. Concentrate under reduced pressure to half of the volume, add 120 g of water with stirring, concentrate under reduced pressure, filter, to obtain 17.8 g of ibuprofen (GC), and the GC purity is 99.6%.

[0043] Example 3

[0044] Add 20.6 g of crude ibuprofen, 100 g of 50% methanol aqueous solution and 5 g of sodium chloride, heat up to 40 - 50 °C, react for 2 h, cool down to room temperature, add 50 mL of dichloromethane, separate the liquid, extract the aqueous phase with 50 mL * 2 of dichloromethane, and combine the organic phases. Concentrate under reduced pressure to half of the volume, add 100 g of water with stirring, concentrate under reduced pressure, filter, and obtain 19.2 g of ibuprofen (GC), with a GC purity of 99.1%.

[0045] The above-disclosed is only a preferred embodiment of a method for removing ibuprofen impurities and purifying, and of course, the scope of rights of the present invention cannot be limited thereby. Those of ordinary skill in the art can understand all or part of the processes of implementing the above embodiments, and the equivalent changes made according to the claims of the present invention still fall within the scope covered by the invention.

Claims

1. A method for purifying ibuprofen by removing impurities, characterized in that, It includes the following steps: Mix and heat the crude ibuprofen, alcohol solvent and catalyst, and after the reaction ends, cool down to obtain a reaction product; Add an organic solvent to the said reaction product, separate layers, extract, combine the organic phases, concentrate under reduced pressure, add an appropriate amount of water for crystallization, filter, and wash with water to obtain ibuprofen.

2. The method for purifying ibuprofen impurities according to claim 1, wherein ； The said alcohol solvent is methanol or a mixed solution of ethanol and water, and the said catalyst is sulfate, phosphate and hydrochloride.

3. The method for purifying ibuprofen impurities according to claim 2, wherein ； The mass ratio of the said alcohol solvent methanol or ethanol to water is 1:0.5 - 2.

4. The method for purifying ibuprofen by removing impurities as claimed in claim 1, wherein; The molar ratio of the said crude ibuprofen, alcohol compound and catalyst is 1:10 - 100:0.1 - 5, the heating temperature of the said mixed solution is 20 - 78°C, and the reaction time is 0.5 - 18 h.

5. The method for purifying ibuprofen by removing impurities as claimed in claim 3, wherein; The specific method of mixing and heating the crude ibuprofen, alcohol solvent and catalyst, and after the reaction ends, cooling down to obtain a reaction product: Mix the crude ibuprofen, alcohol compound and catalyst in a molar ratio of 1:30 - 60:0.5 - 1 in a mixing tank and mix evenly to obtain a mixture; Heat the said mixture, heat to 40 - 70°C, after reacting for 0.5 - 18 h, cool down to obtain a reaction product.

6. The method for purifying ibuprofen by removing impurities as claimed in claim 1, wherein ； The said organic solvent is dichloromethane and acetone.

7. The method for purifying ibuprofen by removing impurities as claimed in claim 5, wherein; The specific method of adding an organic solvent to the said reaction product, separating layers, extracting, combining the organic phases, concentrating under reduced pressure, adding an appropriate amount of water for crystallization, filtering, and washing with water to obtain ibuprofen: Add dichloromethane to the said reaction product, separate layers by liquid separation, extract the aqueous phase with dichloromethane, and combine the organic phases; Concentrate the said organic phase to less than half of its volume under a vacuum of 0.06 - 0.1 MPa, add 3 - 10 times of water for crystallization for 2 h while stirring, filter, and wash the filter cake with a small amount of water to obtain ibuprofen.

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