Carprofen and a process for its preparation

Abstract

The application discloses a kind of carolic acid and preparation method thereof, and specifically relates to the field of medical technology.The method comprises the following steps: stirring catalyst H2WO4 / C with hydrogen peroxide, then adding dichloro chrysanthemic acid ethyl ester; oil bath heating is carried out, reaction temperature is controlled, repeated reflux is carried out, and oxidation reaction is carried out; after the reaction, homogeneous transparent solution is filtered, extracted, and subjected to reduced pressure distillation to obtain carolic acid product.In the application, when catalyzing and oxidizing dichloro chrysanthemic acid ethyl ester, a high-activity H2WO4 / C heteropoly acid is used as a catalyst, the reaction scheme is optimized, the selectivity of the reaction is greatly improved, the number of cycles of the catalyst is increased, and after 20 cycles of the new catalyst, the catalyst activity does not decrease obviously.Furthermore, due to the great improvement of selectivity, the loss of product is reduced, and the yield is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a calonic acid and its preparation method. Background Technology

[0002] Calonic acid is an important intermediate in the production of boceprevir, a hepatitis C protease inhibitor, and is also widely used in pesticide and other organic synthesis fields. Calonic acid is synthesized by catalytic synthesis of ethyl dichloroquine, with potassium permanganate used as an oxidant in the traditional process.

[0003] However, traditional processes have several drawbacks. Potassium permanganate exists in a lower valence state after the reaction, increasing the difficulty of product separation and purification. Furthermore, the discharge of these waste (liquid) products has a severe environmental impact. These factors not only increase costs but also bring unavoidable harm to humans and the environment. Therefore, key steps in the process need to be improved and optimized. Summary of the Invention

[0004] Therefore, the present invention provides a caronic acid and its preparation method to solve the problems of low purity and difficult separation when potassium permanganate is used as a catalyst.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] According to one aspect of the present invention, a method for preparing calonic acid is provided, the method comprising:

[0007] Ethyl dichloroquine was added after stirring the catalyst H2WO4 / C with hydrogen peroxide.

[0008] The oxidation reaction is carried out by heating in an oil bath, controlling the reaction temperature, and repeatedly refluxing.

[0009] After the homogeneous and transparent solution is allowed to stand, it is filtered, extracted, and then distilled under reduced pressure to obtain the caronic acid product.

[0010] Furthermore, the concentration of the hydrogen peroxide is 30%.

[0011] Furthermore, the molar ratio of hydrogen peroxide to ethyl dichloroquine is 4–5.

[0012] Furthermore, the temperature of the oil bath is 110-130℃.

[0013] Furthermore, the reaction temperature is 75-80℃ in the initial stage and 95-100℃ in the later stage.

[0014] Furthermore, the settling conditions are 0°C for 12 hours.

[0015] According to another aspect of the present invention, a calonic acid is prepared by any one of the methods of claims 1-6.

[0016] The present invention has the following advantages:

[0017] In this invention, a highly active H2WO4 / C heteropolyacid was used as a catalyst in the catalytic oxidation of ethyl dichloroquine. This optimized reaction scheme significantly improved the selectivity and increased the number of catalyst cycles. After 20 cycles, the activity of the novel catalyst did not show a significant decrease. Furthermore, the greatly improved selectivity reduced product loss and increased yield.

[0018] This invention utilizes hydrogen peroxide instead of potassium permanganate for the oxidation reaction, significantly improving operational safety, reducing synthesis costs, and lowering the reaction hazard factor. It also reduces environmental pollution, post-treatment difficulties, and operational hazards associated with waste (liquid) emissions. The optimized reaction scheme improves yield, reduces costs, and is environmentally friendly, meeting the requirements of green and modern production. Detailed Implementation

[0019] The following specific embodiments illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] Example 1

[0021] This embodiment provides a method for preparing calonic acid:

[0022] Add 0.625 g (H2WO4 / C 2.5) and 44.5 mL of 30% hydrogen peroxide to a 100 mL reaction flask; stir magnetically for 10 min at room temperature, then add 10.5 mL of ethyl dichloroquine (approximately 100 mmol, with a hydrogen peroxide / ethyl dichloroquine molar ratio of approximately 4.4). Control the oil bath heating temperature at 120 °C, keeping the initial reaction temperature at 75 °C and the later temperature at 95–100 °C, with the reactants always under reflux. Let the homogeneous and transparent solution obtained after the reaction stand at 0 °C for 12 h, then filter, extract, and distill under reduced pressure; no further purification is required.

[0023] The yield was 99.3%; the purity (HPLC) was greater than 99.8%.

[0024] Example 2

[0025] This embodiment provides a method for preparing calonic acid:

[0026] Add 0.626 g (H2WO4 / C 2.5) and 44.5 mL of 30% hydrogen peroxide to a 100 mL reaction flask; stir magnetically for 10 min at room temperature, then add 10.5 mL of ethyl dichloroquine (approximately 100 mmol, with a hydrogen peroxide / ethyl dichloroquine molar ratio of approximately 4.4). Control the oil bath heating temperature at 120 °C, keeping the initial reaction temperature at 80 °C and the later temperature at 95–100 °C, with the reactants always under reflux. Let the homogeneous and transparent solution obtained after the reaction stand at 0 °C for 12 h, then filter, extract, and distill under reduced pressure; no further purification is required.

[0027] The yield was 99.3%; the purity (HPLC) was greater than 99.9%.

[0028] Example 3

[0029] This embodiment provides a method for preparing calonic acid:

[0030] Add 0.624 g (H2WO4 / C 2.5) and 44.5 mL of 30% hydrogen peroxide to a 100 mL reaction flask; stir magnetically for 10 min at room temperature, then add 10.5 mL of ethyl dichloroquine (approximately 100 mmol, with a hydrogen peroxide / ethyl dichloroquine molar ratio of approximately 4.4). Control the oil bath heating temperature at 120 °C, keeping the initial reaction temperature at 78 °C and the later temperature at 95–100 °C, with the reactants always under reflux. Let the homogeneous and transparent solution obtained after the reaction stand at 0 °C for 12 h, then filter, extract, and distill under reduced pressure; no further purification is required.

[0031] The yield was 99.3%; the purity (HPLC) was greater than 99.8%.

[0032] Comparative Example 1

[0033] Patent CN202210144740.7, Preparation method of Example 1:

[0034] a. Add 200.00 g (1.00 eq.) of nitric acid, 138.75 g (3.00 eq.) of potassium hydroxide, and 2 L (10.0 V) of water to a 3000 mL reaction flask and stir until the solid dissolves. Lower the internal temperature to 10℃~20℃. Add potassium permanganate (390.81 g (3.00 eq.) in portions over a period of 2 hours. After the addition is complete, maintain the reaction temperature at 30℃~40℃ and stir for at least 3 hours.

[0035] b. Cool the reaction system to 20℃~30℃, filter, wash the filter cake twice with water (400mL*2), collect the filtrate, add solid sodium sulfite (103.90g, 1.00eq.) to the filtrate for quenching, control the quenching temperature below 40℃, after quenching, stir at 20℃~30℃ for 30min, adjust the pH to 1~2 with 6M hydrochloric acid, stir at 20℃~30℃ for 30~40min, add sodium chloride (700.00g), then add ethyl acetate (2L*2) for extraction twice, collect the organic layer and concentrate under reduced pressure, add methyl tert-butyl ether (400mL) and beat at 20~30℃ for 3~4 hours, then slowly cool to 0℃~5℃ and beat for 3~4 hours, filter, collect the filter cake, dry the filter cake to obtain 100.00g of white solid, yield: 76.70%, purity: 99%. HNMR (300MHz, D2O) 1.23 (s, 3H), 1.31 (s, 3H), 2.08 (s, 2H).

[0036] Compared to Comparative Example 1, this invention utilizes hydrogen peroxide instead of potassium permanganate for the oxidation reaction, significantly improving operational safety, reducing synthesis costs, and lowering the reaction hazard factor. It also reduces environmental pollution from waste (liquid) emissions, the difficulty of post-treatment, and operational hazards. The optimized reaction scheme improves yield, reduces costs, and is environmentally friendly, meeting the requirements of green and modern production.

[0037] Experimental Example 1

[0038] The catalyst was repeatedly used, and its catalytic activity was tested. The results are shown in Table 1.

[0039] Table 1

[0040] 5 times 10 times 20 times <![CDATA[H3PMo 12 O 40 / C]]> 99 98.7 98.3

[0041] The catalyst used in this invention has an increased number of cycles; after 20 cycles, the activity of the novel catalyst did not decrease significantly.

[0042] Although the present invention has been described in detail above with general descriptions and specific embodiments, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, all such modifications or improvements made without departing from the spirit of the present invention fall within the scope of protection claimed by the present invention.

Claims

1. A method for preparing calonic acid, characterized in that, The method includes: Ethyl dichloroquine was added after stirring the catalyst H2WO4 / C with hydrogen peroxide. The oxidation reaction is carried out by heating in an oil bath, controlling the reaction temperature, and repeatedly refluxing. After the homogeneous and transparent solution was allowed to stand, it was filtered, extracted, and then distilled under reduced pressure to obtain the calonic acid product. The concentration of the hydrogen peroxide is 30%; The reaction temperature is 75-80 ℃ in the initial stage and 95-100 ℃ in the later stage.

2. The method for preparing calonic acid according to claim 1, characterized in that, The molar ratio of hydrogen peroxide to ethyl dichloroquine is 4-5.

3. The method for preparing calonic acid according to claim 1, characterized in that, The temperature of the oil bath is 110-130℃.

4. The method for preparing calonic acid according to claim 1, characterized in that, The settling conditions were 0℃ for 12 hours.