A process for the preparation of chlorpheniramine maleate
By using a continuous flow microchannel reactor and organic solvent extraction in the synthesis of chlorpheniramine maleate, the problems of low yield and high energy consumption in the prior art have been solved, and a highly efficient and safe production process has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
- Filing Date
- 2022-09-30
- Publication Date
- 2026-06-05
AI Technical Summary
Existing methods for synthesizing chlorpheniramine maleate suffer from problems such as low yield of the target product, high energy consumption, high equipment requirements, and complex operation.
Hydrolysis and decarboxylation reactions were carried out using a continuous flow microchannel reactor, combined with alkali neutralization and organic solvent extraction, avoiding high-temperature long-term reactions and high-vacuum distillation. After dissolving, hydrolyzing and decarboxylating compound III in the continuous flow microchannel reactor, the pH value was adjusted with alkali and extracted. Subsequently, it was salted with maleic acid to obtain chlorpheniramine maleate.
It significantly improved the yield of the target product, simplified the operation process, reduced energy consumption, avoided the generation of impurities and carbonization, and provided a safe and reliable production foundation.
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Figure CN117843555B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing chlorpheniramine maleate. Background Technology
[0002] Chlorpheniramine maleate, also known as Chlorpheniramine, is an antihistamine that exerts its anti-allergic effect by antagonizing H1 receptors. It is mainly used to treat allergic rhinitis, skin and mucous membrane allergies, urticaria, vasodilatory rhinitis, hay fever, contact dermatitis, and drug- and food-induced allergic diseases. Newer antihistamines are inexpensive, have a stronger antihistamine effect and a weaker central sedative effect, require smaller doses, have fewer adverse reactions, and are suitable for children; therefore, they are still widely used clinically.
[0003] US Patent 2567245 discloses a method for synthesizing chlorpheniramine. Compound III is reacted with 80% sulfuric acid at 140–150°C for 24 hours. After the reaction, it is added to ice water, neutralized with ammonia, and extracted with diethyl ether. After removing the diethyl ether, the fraction collected at 139–142°C under a high vacuum of 1–2 mmHg yields compound II. The drawbacks of this method are: due to the prolonged high-temperature reaction, significant impurities are generated and carbonization occurs during the reaction; furthermore, high-vacuum distillation requires sophisticated equipment, is energy-intensive and time-consuming, results in low yield of the target product, and carries high production risk. Summary of the Invention
[0004] The purpose of this invention is to address the shortcomings of existing technologies by providing a method for synthesizing chlorpheniramine maleate with high yield of the target product, low energy consumption, and simple operation.
[0005] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:
[0006] A method for preparing chlorpheniramine maleate comprises the following steps:
[0007]
[0008] (1) Compound III was dissolved in sulfuric acid. The dissolved solution was fed into a continuous flow microchannel reactor for hydrolysis and decarboxylation. The reaction solution was neutralized with alkali solution after flowing out of the continuous flow reactor. Then, an organic solvent was used to extract the compound II solution.
[0009] (2) The solution of compound II was added to an alcohol solvent to form a salt with maleic acid to obtain chlorpheniramine maleate (compound I).
[0010] Furthermore, compound III was added to 70-80% sulfuric acid and stirred to dissolve. The mass ratio of compound III to 70-80% sulfuric acid was 1:2.5 to 1:5.
[0011] Furthermore, the dissolved liquid enters a continuous flow microchannel reactor and reacts at 120–140°C.
[0012] Furthermore, the material after reaction in the continuous flow microchannel reactor is injected into a reaction vessel containing ice water, the pH is adjusted to 8-9 with alkali solution, extraction solvent is added for extraction, and the organic phase is washed and dried to obtain a solution of compound II.
[0013] Furthermore, the alkaline solution is 10-20% sodium hydroxide.
[0014] Furthermore, the extraction solvent in step (1) is one or more of toluene, xylene, ethyl acetate, and isopropyl acetate.
[0015] Furthermore, the alcohol solvent in step (2) is one or more of methanol, ethanol or isopropanol.
[0016] Furthermore, the reaction temperature in step (2) is 60–90 °C.
[0017] Beneficial effects
[0018] Compared with the prior art, the beneficial effects of the present invention are as follows:
[0019] 1. This synthesis method avoids the problems of numerous impurities and carbonization caused by prolonged high-temperature reactions;
[0020] 2. This method avoids the use of high-vacuum distillation, simplifies post-processing, and significantly improves yield and quality;
[0021] 3. The reaction operation of this invention is easy to control, safe and reliable, and can lay the foundation for subsequent industrial-scale production. Attached Figure Description
[0022] Figure 1 The HPLC chromatogram of compound II from Example 1 is shown below.
[0023] Figure 2 The HPLC chromatogram of compound I in Example 1 is shown below.
[0024] Figure 3 The HPLC chromatogram of compound II in Example 2 is shown below.
[0025] Figure 4 The HPLC chromatogram of compound I in Example 2 is shown below.
[0026] Figure 5 For comparison, the HPLC chromatogram of compound II in Example 1;
[0027] Figure 6 The HPLC chromatogram of compound I in Comparative Example 1 is shown. Detailed Implementation
[0028] The embodiments of the present invention are described in detail below. These embodiments are implemented based on the technical solution of the present invention, and provide detailed implementation methods and specific operation processes. However, the scope of protection of the present invention is not limited to the following embodiments.
[0029] Example 1
[0030] Preparation of Compound II solution:
[0031] Add 100g of compound III to a reaction flask containing 500g of 70% sulfuric acid and stir to dissolve.
[0032] The external heat exchanger is turned on to control the temperature of the continuous flow microchannel reactor at 120℃.
[0033] Turn on the constant flow pump and deliver the above solution to the microchannel reactor at a flow rate of 120 ml / min for hydrolysis and decarboxylation reaction. After the reaction, inject the material into a container filled with ice water, adjust the pH value to 8-9 with 20% sodium hydroxide, and then add 800 ml of toluene for extraction. After washing and drying the organic phase, obtain the compound II solution.
[0034] Preparation of compound I:
[0035] 600 ml of isopropanol and 35 g of maleic acid were added sequentially to the solution of compound II. The mixture was heated to 70-80 °C, stirred for 0.5 hours, cooled to room temperature, filtered, and dried under vacuum at 50-60 °C to obtain chlorpheniramine maleate I white powder. The total yield (based on compound III) was 81.5%.
[0036] Example 2
[0037] Preparation of Compound II solution:
[0038] Add 100g of compound III to a reaction flask containing 400g of 80% sulfuric acid and stir to dissolve.
[0039] The external heat exchanger was turned on to control the temperature of the continuous flow microchannel reactor at 130℃.
[0040] Turn on the constant flow pump and deliver the above solution to the microchannel reactor at a flow rate of 100 ml / min for hydrolysis and decarboxylation reaction. After the reaction, inject the material into a container filled with ice water, adjust the pH value to 8-9 with 20% sodium hydroxide, and then add 800 ml of toluene for extraction. After washing and drying the organic phase, obtain the compound II solution.
[0041] Preparation of compound I:
[0042] 600 ml of ethanol and 35 g of maleic acid were added sequentially to the solution of compound II. The mixture was heated to 70-80 °C, stirred for 0.5 hours, cooled to room temperature, filtered, and dried under vacuum at 50-60 °C to obtain a white powder of chlorpheniramine maleate I. The total yield (based on compound III) was 82.7%.
[0043] Example 3
[0044] Preparation of Compound II solution:
[0045] Add 100g of compound III to a reaction flask containing 250g of 80% sulfuric acid and stir to dissolve.
[0046] The external heat exchanger was turned on to control the temperature of the continuous flow microchannel reactor at 140℃.
[0047] Turn on the constant flow pump and deliver the above solution to the microchannel reactor at a flow rate of 50 ml / min for hydrolysis and decarboxylation reaction. After the reaction, inject the material into a container filled with ice water, adjust the pH value to 8-9 with 20% sodium hydroxide, and then add 800 ml of toluene for extraction. After washing and drying the organic phase, obtain the compound II solution.
[0048] Preparation of compound I:
[0049] 600 ml of ethanol and 35 g of maleic acid were added sequentially to the solution of compound II. The mixture was heated to 70-80 °C, stirred for 0.5 hours, cooled to room temperature, filtered, and dried under vacuum at 50-60 °C to obtain a white powder of chlorpheniramine maleate I. The total yield (based on compound III) was 75.8%.
[0050] Comparative Example 1
[0051] Compound II was prepared according to the method reported in patent US2567245.
[0052] 100g of compound III was added to a reaction flask containing 500g of 80% sulfuric acid. The mixture was heated to 140-150℃ and reacted for 24 hours. The reaction solution was then slowly added to ice water, and the sulfuric acid was neutralized by ammonia. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the ethyl acetate was evaporated. The mixture was then distilled under reduced pressure under a high vacuum of 1-2 mmHg. The fraction collected at 139-142℃ was the pale yellow oily compound II, with a yield of 56%.
[0053] 450 ml toluene, 335 ml isopropanol and 20 g maleic acid were added sequentially to a reaction flask containing compound II. The mixture was heated to 70-80 °C and stirred for 0.5 hours. After cooling to room temperature, the mixture was filtered and dried under vacuum at 50-60 °C to obtain a white powder of chlorpheniramine maleate I with a yield of 92%.
[0054] The overall yield for both steps was 51.5%.
Claims
1. A method for preparing chlorpheniramine maleate, characterized in that, To achieve this, follow these steps: a. Dissolve compound III in 70-80% sulfuric acid. The dissolved solution is fed into a continuous flow microchannel reactor for hydrolysis and decarboxylation. The reaction solution is neutralized with alkali solution after flowing out of the continuous flow reactor. Then, it is extracted with organic solvent to obtain compound II solution. b. The solution of compound II was added to an alcohol solvent to form a salt with maleic acid to obtain chlorpheniramine maleate (compound I); The mass ratio of compound III to 70-80% sulfuric acid is 1:2.5 to 1:
5. The dissolved liquid enters a continuous flow microchannel reactor and reacts at 120–140°C, with the flow rate of the dissolved liquid controlled at 120 ml / min or 100 ml / min.
2. The method for preparing chlorpheniramine maleate according to claim 1, characterized in that: After the reaction in the continuous flow microchannel reactor, the material is injected into a reaction vessel containing ice water, the pH is adjusted to 8-9 with alkali solution, extraction solvent is added for extraction, and the organic phase is washed and dried to obtain a solution of compound II.
3. The method for preparing chlorpheniramine maleate according to claim 2, characterized in that: The alkaline solution is 10-20% sodium hydroxide.
4. The method for preparing chlorpheniramine maleate according to claim 1, characterized in that: The extraction solvent in step a is one or more of toluene, xylene, ethyl acetate, and isopropyl acetate.
5. The method for preparing chlorpheniramine maleate according to claim 1, characterized in that, The alcohol solvent in step b is one or more of methanol, ethanol, or isopropanol.
6. The method for preparing chlorpheniramine maleate according to claim 1, characterized in that: The reaction temperature in step b is 60–90 °C.