Synthesis method of 1-(4-chlorphenyl)-2, 3-dihydro-1H-indolizine chloride
By using 2-(4'-chlorobenzyl)pyridine and tetrahydrofuran for substitution and halogenation cyclization reactions in chlorphenamine maleate, the high-purity 1-(4-chlorophenyl)-2,3-dihydro-1H-indolezine chloride was successfully synthesized, which solved the problem of difficulty in removing impurities in the prior art and improved product quality and detection accuracy.
Patent Information
- Application Number
- CN202411899311.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-23
- Publication Date
- 2025-03-21
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The prior art is difficult to effectively remove the impurity 1-(4-chlorophenyl)-2,3-dihydro-1H-indoleazine chloride in chlorphenamine maleate, affecting product quality.
1-(4-chlorophenyl)-2,3-dihydro-1H-indolezine chloride was successfully synthesized by substitution reaction and halocyclization reaction. This method is simple to operate, easy to obtain raw materials, high yield and high purity.
The high purity synthesis of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolezine chloride was achieved, providing chlorpheniramine maleate impurity standards, improving product quality and accurate positioning and qualitativeness of detection and analysis.
Smart Images
Figure FT_1 
Figure FT_2 
Figure FT_3
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of chemical pharmacy, and specifically relates to a method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride, wherein the compound is an impurity of chlorpheniramine maleate. Background Art
[0002] Allergic rhinitis refers to a non-infectious inflammatory disease of the nasal mucosa that occurs when an atopic individual is exposed to allergens, mainly mediated by IgE (mainly histamine) and involves the release of mediators. It also involves a variety of immune active cells and cytokines.
[0003] Chlorpheniramine maleate is an anti-allergic drug, which is effective for nasal congestion caused by allergic rhinitis and upper respiratory tract infection. It can also be used for colds or sinusitis and skin mucosal allergies. This drug is a histamine H1 receptor antagonist, which can counteract capillary dilation caused by allergic reactions, reduce capillary permeability, and relieve wheezing caused by bronchial smooth muscle contraction. In addition, this drug also has central inhibition and anti-M cholinergic receptor effects.
[0004] 1-(4-Chlorophenyl)-2,3-dihydro-1H-indolizine chloride is an impurity produced by the degradation of chlorpheniramine maleate. This impurity may remain in the final product of chlorpheniramine maleate and affect the product quality. Its structural formula is shown in Figure 2 . After searching, there is no literature report on this compound. Therefore, providing a synthesis method of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride for the preparation of chlorpheniramine maleate impurity standard has important practical significance. Summary of the invention
[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride. The method has the advantages of simple operation, cheap and readily available raw materials, high yield and high purity.
[0006] The purpose of the present invention is achieved by the following technical scheme: a method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride, which is an impurity of chlorpheniramine maleate. The synthetic route is shown in Figure 1 The specific preparation method includes the following steps.
[0007] S1. Substitution reaction: add 2-(4'-chlorobenzyl)pyridine and tetrahydrofuran to a reaction bottle, cool to -78~-10°C, add LDA and bromoethanol dropwise under temperature control, react for 1.5~4h under temperature control, and post-treat the reaction solution to obtain 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol.
[0008] S2. Halogenation cyclization reaction: Add the above-obtained 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol into a reaction flask, then add dichloromethane and thionyl chloride, and react at 20-40°C for 3-6 hours. The reaction solution is post-treated to obtain 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0009] Furthermore, in step S1, the equivalent ratio of 2-(4'-chlorobenzyl)pyridine, bromoethanol and LDA is 1:0.5~2:1~5.
[0010] Furthermore, in step S1, the weight ratio of 2-(4'-chlorobenzyl)pyridine to tetrahydrofuran is 1:5-20.
[0011] Furthermore, the post-treatment method in step S1 is: after the reaction is completed, water and ethyl acetate are added to the reaction solution, extracted, and concentrated to obtain 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol.
[0012] Furthermore, the reaction temperature in step S1 is -78~-10°C.
[0013] Furthermore, in step S2, the weight ratio of 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol, thionyl chloride and dichloromethane is 1:1~5:5~20.
[0014] The invention has the following advantages: the invention uses 2-(4'-chlorobenzyl)pyridine as a raw material, and obtains 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride through two substitution and cyclization reactions. The 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride is a high-purity target product for the synthesis of chlorpheniramine maleate impurities, and can be used as an impurity standard product in the detection and analysis of chlorpheniramine maleate finished products, thereby improving the accurate positioning and qualitative analysis of impurities in the detection and analysis of chlorpheniramine maleate finished products, which is conducive to strengthening the control of the impurities, and further improving the quality of chlorpheniramine maleate finished products. The method provided by the invention has easy-to-obtain raw materials and is simple to operate. The yield of the obtained product is 62%±5%, and the purity is greater than 98%. BRIEF DESCRIPTION OF THE DRAWINGS
[0015] Figure 1 This is a synthetic route for 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0016] Figure 2 It is the structural formula of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0017] Figure 3 This is the HPLC spectrum of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0018] Figure 4This is the mass spectrum of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0019] Figure 5 This is the H NMR spectrum of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride. DETAILED DESCRIPTION
[0020] The present invention is further described below in conjunction with the accompanying drawings and embodiments, but the protection scope of the present invention is not limited to the following description.
[0021] Example 1: Synthesis of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0022] Add 4 g of 2-(4'-chlorobenzyl)pyridine and 30 mL of tetrahydrofuran to a reaction bottle, cool to -60°C, stir, and add 30 mL of LDA (2.0 M tetrahydrofuran / n-hexane) dropwise at -50°C. After the addition is complete, keep warm and stir. Add 3 g of bromoethanol to the reaction solution, keep warm and stir. After the reaction is completed, pour the reaction solution into ice water to quench, extract with ethyl acetate, and concentrate the organic phase to obtain 3.9 g of 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol with a yield of 80.2%.
[0023] 3 g of the above 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol was added to a reaction bottle, 18 ml of thionyl chloride and 40 ml of dichloromethane were added, the temperature was raised to 35°C and stirred for reaction. After the reaction was completed, water was added to the reaction solution for extraction, and the aqueous phase was concentrated to obtain 2.7 g of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride with a yield of 84.4% and a purity of 99.1%.
[0024] The HPLC spectrum of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride is as follows Figure 3 As shown, the purity is 99.1%.
[0025] The mass spectrum of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride is shown in Figure 4 As shown, MS:230.07280(M + ).
[0026] The H NMR spectrum of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride is shown in Figure 5As shown, the H spectrum shows that the two peaks with chemical shifts of 2.97 and 2.53 are two hydrogens on the carbon that is not connected to the aromatic ring on the saturated five-membered ring of indolizine, the peak with a chemical shift of 4.86 is a hydrogen on the carbon that is connected to both aromatic rings, and the peak with a chemical shift of 4.99 is two hydrogens on the carbon connected to N on the saturated five-membered ring of indolizine. The chemical shifts are 7.28-8.82, with a total of eight hydrogens, which are hydrogens on the aromatic ring. The test results are consistent with the structure of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0027] Example 2: Synthesis of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
[0028] Add 5 g of 2-(4'-chlorobenzyl)pyridine and 40 mL of tetrahydrofuran to a reaction bottle, cool to -50°C, stir, and add 40 mL of LDA (2.0 M tetrahydrofuran / n-hexane) dropwise at -45°C. After the addition is complete, keep warm and stir. Add 4 g of bromoethanol to the reaction solution, keep warm and stir. After the reaction is completed, pour the reaction solution into ice water to quench, extract with ethyl acetate, and concentrate the organic phase to obtain 5.1 g of 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol with a yield of 83.6%.
[0029] 5 g of the above 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol was added to a reaction bottle, 30 ml of thionyl chloride and 60 ml of dichloromethane were added, the temperature was raised to 40°C and stirred for reaction. After the reaction was completed, water was added to the reaction solution for extraction, and the aqueous phase was concentrated to obtain 4.3 g of 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride with a yield of 79.6% and a purity of 98.9%.
Claims
1. A method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride, wherein the compound is a chlorpheniramine maleate impurity, and the synthesis route is shown in Figure 1. The specific preparation method comprises the following steps: S1. Substitution reaction: add 2-(4'-chlorobenzyl)pyridine and tetrahydrofuran to a reaction flask, cool to -78~-10°C, add LDA and bromoethanol dropwise under temperature control, react for 1.5~4h under temperature control, and post-treat the reaction solution to obtain 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol; S2. Halogenation cyclization reaction: Add the above-obtained 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol into a reaction flask, then add dichloromethane and thionyl chloride, and react at 20-40°C for 3-6 hours. The reaction solution is post-treated to obtain 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride.
2. A method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride as claimed in claim 1, characterized in that: In step S1, the equivalent ratio of 2-(4'-chlorobenzyl)pyridine, bromoethanol and LDA is 1:0.5~2:1~5.
3. The method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride according to claim 1, characterized in that: The weight ratio of 2-(4'-chlorobenzyl)pyridine to tetrahydrofuran in step S1 is 1:5-20.
4. The method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride according to claim 1, characterized in that: The post-treatment method in step S1 is: after the reaction is completed, water and ethyl acetate are added to the reaction solution, extracted, and concentrated to obtain an intermediate.
5. The method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride according to claim 1, characterized in that: The reaction temperature in step S1 is -78~-10°C.
6. A method for synthesizing 1-(4-chlorophenyl)-2,3-dihydro-1H-indolizine chloride as claimed in claim 1, characterized in that: The weight ratio of 3-(4-chlorophenyl)-3-(pyridin-2-yl)propanol, thionyl chloride and dichloromethane in step S2 is 1:1~5:5~20.