Synthesis method of chloroprocaine hydrochloride intermediate impurity
Preparation of chlorprocaine hydrochloride intermediate impurities through acid chloride, amidation and salt formation reactions has solved the problem of lack of synthesis methods in the existing literature, provided a reference product for drug quality control, and improved drug quality and safety sex.
Patent Information
- Application Number
- CN202411687001.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-25
- Publication Date
- 2025-01-03
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of medicines, and in particular relates to a method for synthesizing chloroprocaine hydrochloride intermediate impurities. Background Art
[0002] The English name of chloroprocaine hydrochloride is Chloroprocaine hydrochloride, the chemical name is 2-chloro-4-aminobenzoic acid-2-(diethylamino)ethyl ester hydrochloride, and the molecular formula is C 13 H 20 Cl 2 N 2 O 2 , molecular weight is 307.22, CAS registration number is 3858-89-7, and the structural formula is shown in Formula I: .
[0003] Chloroprocaine hydrochloride is an anesthetic and the main component of chloroprocaine hydrochloride for injection used in local excision surgery. Chloroprocaine hydrochloride has the characteristics of small side effects, rapid anesthetic effect, strong and stable analgesic and muscle relaxant effects, and almost no rapid drug resistance. With the increasing demand for anesthetics in medical treatment, surgery, local anesthesia and other aspects around the world, chloroprocaine hydrochloride has a strong and stable analgesic and muscle relaxant effect.
[0004] Drug impurity research is an important aspect in drug development and preparation. The research and control of impurities is related to the clinical safety of drugs, and thus becomes one of the key links in drug quality control. In addition to being determined by the pharmacological activity of the drug itself, adverse reactions in the clinical use of drugs are sometimes closely related to the impurities in the drugs and must be strictly controlled. Whether the impurities in the drugs are fully and accurately controlled is directly related to the quality controllability and safety of the drugs. Therefore, impurity research and control is the premise and key link to ensure the safety and quality controllability of drugs, and is an important indicator for drug consistency evaluation.
[0005] In the process of quality research on chloroprocaine hydrochloride, we conducted research on a key material, 2-chloro-4-nitrobenzoic acid, by tracing and deriving impurities. After consulting the literature and information provided by the manufacturer, 2-chloro-4-nitrobenzoic acid will produce a small amount of byproduct 5-chloro-2-nitrobenzoic acid during the industrial production process. According to the synthesis process, 5-chloro-2-nitrobenzoic acid will be introduced into the intermediate after 2-chloro-4-nitrobenzoic acid is converted into acyl chloride and reacts with N, N-diethylethanolamine hydrochloride to form an ester. After salt formation, 5-chloro-2-nitrobenzoic acid 2-(diethylamino) ethyl ester hydrochloride (TM) is produced.
[0006] The structure of the impurity is as follows. Currently, there is no literature report on the synthesis method of this impurity (TM); Summary of the invention
[0007] The present invention discloses a method for preparing a chloroprocaine hydrochloride intermediate impurity, wherein the structural formula of the chloroprocaine hydrochloride intermediate impurity is as follows: .
[0008] The present invention is achieved through the following technical scheme: a method for synthesizing chloroprocaine hydrochloride intermediate impurities, which comprises the following steps.
[0009] S1. Acid chloride reaction: Add dichloromethane and 5-chloro-2-nitrobenzoic acid to the reaction kettle, control the reaction temperature at 15±5℃, add thionyl chloride dropwise, add N,N-dimethylformamide after the addition is complete, raise the temperature to 35-45℃, and reflux for 10-15h until the 5-chloro-2-nitrobenzoic acid reacts completely. The reaction solution is cooled, concentrated, and dissolved to obtain a dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride.
[0010] S2. Add N, N-diethylethanolamine hydrochloride, dichloromethane and triethylamine to the reaction kettle, control the temperature at 10-20°C, add the dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride dropwise, raise the temperature to 30-35°C after the addition is complete, and keep the temperature for 2-3 hours. The reaction solution is filtered, washed with water, dried and concentrated to obtain 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester (IM II).
[0011] S3. Salt-forming reaction: After dissolving IMII in ethyl acetate, control the temperature at 10-20°C, add ethyl acetate hydrochloride (4M) dropwise to form salt, keep the temperature and stir for 1-2 hours to obtain 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester hydrochloride (TM); The synthetic route is as follows: .
[0012] Furthermore, the molar ratio of the 5-chloro-2-nitrobenzoic acid, thionyl chloride and N,N-dimethylformamide is 1:1.1-1.5:2%-8%.
[0013] Furthermore, the synthesis method of the chloroprocaine hydrochloride intermediate impurity is characterized in that the molar ratio of 5-chloro-2-nitrobenzoyl chloride (IM I) to triethylamine and N,N-diethylethanolamine hydrochloride in step S2 is 1:2.5-3.5:1.0-1.2, and the reaction is carried out at 30-35°C for 2-3 hours. The reaction solution is filtered, washed with water twice, dried with anhydrous sodium sulfate, and concentrated to dryness to obtain an oily substance 5-chloro-2-nitrobenzoic acid 2-(diethylamino)-ethyl ester (IM II).
[0014] Furthermore, the method for synthesizing chloroprocaine hydrochloride intermediate impurities is characterized in that the 5-chloro-2-nitrobenzoic acid 2-(diethylamino)-ethyl ester (IMII) described in step S3 is dissolved in ethyl acetate, the mass ratio of IM II to ethyl acetate is 1:10-15, and hydrochloric acid ethyl acetate solution is added dropwise at 10-20° C., the mass ratio of IM II to hydrochloric acid ethyl acetate solution is 1:0.8-1.2, and the mixture is stirred for 1-2 hours to obtain 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester hydrochloride (TM).
[0015] Furthermore, the chloroprocaine hydrochloride intermediate impurity is suitable for use as a reference substance in quality research of chloroprocaine hydrochloride.
[0016] In summary, the beneficial effects of the present invention are as follows: a preparation method of chloroprocaine hydrochloride intermediate impurities is disclosed, and the impurities are used as reference substances for chloroprocaine hydrochloride quality research. The present invention synthesizes chloroprocaine hydrochloride intermediate impurities and uses them as impurity reference substances to directly and effectively control the changes of impurities in chloroprocaine hydrochloride, which helps to improve the quality standard of chloroprocaine hydrochloride, thereby better controlling product quality. BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 The HPLC spectrum of the impurities of the chloroprocaine hydrochloride intermediate of Inventive Example 2 is shown.
[0018] Figure 2 This is the MS spectrum of the impurity positive ion of the chloroprocaine hydrochloride intermediate in Inventive Example 2.
[0019] Figure 3 For the impurities of the intermediate of chloroprocaine hydrochloride in Invention Example 2 1 H NMR spectrum. DETAILED DESCRIPTION
[0020] The present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to the following.
[0021] The present invention uses 5-chloro-2-nitrobenzoic acid as a starting material, and synthesizes the target product chloroprocaine hydrochloride intermediate impurity by forming an acyl chloride, amidation, and hydrochloride. The synthetic route is as follows: .
[0022] Example 1: A method for synthesizing chloroprocaine hydrochloride intermediate impurities, comprising the following steps.
[0023] S1. Acid chloride reaction: Add 50mL of dichloromethane and 10g of 5-chloro-2-nitrobenzoic acid to the reaction flask, control the reaction temperature at 15±5℃, add 7.14g of thionyl chloride dropwise, add 0.5mL of N,N-dimethylformamide after the addition is complete, heat to 35-45℃, reflux for 10h, take samples every 1h, add methanol to derive into methyl ester, monitor once by TLC (EA: Hept=1:3), react until the 5-chloro-2-nitrobenzoic acid spot disappears on TLC monitoring, that is, the reaction of 5-chloro-2-nitrobenzoic acid is complete. Cool the reaction solution to room temperature, concentrate to dryness, add 20mL of dichloromethane to dissolve, and obtain a dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride (IM I).
[0024] S2. Esterification reaction: Add 80mL of dichloromethane, 8.4g of N,N-diethylethanolamine hydrochloride, and 15.1g of triethylamine to the reaction flask, control the temperature at 10-20℃, dropwise add the dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride (IM I), stir for about 30min after the addition is complete, raise the temperature to 30-35℃, keep the temperature for 2h~3h, take samples and add water every 0.5h, monitor once with TLC (EA: Hept=1:1), and react until the 5-chloro-2-nitrobenzoic acid spot disappears. Filter the reaction solution and wash the filtrate twice with purified water (100mL*2), add 10g of anhydrous sodium sulfate and dry. The product was concentrated under reduced pressure (≤-0.08 MPa) at 35-40°C until no condensate dropped out, to obtain 12.09 g of 2-(diethylamino)ethyl 5-chloro-2-nitrobenzoate (IMII), with a yield of 81.07%.
[0025] S3. Salt-forming reaction: Add 5.0 g of 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester (IMII) and 75 mL of ethyl acetate to the reaction flask, stir to dissolve, cool to 10-20°C, add 6 mL of hydrochloric acid ethyl acetate solution dropwise, and a light yellow solid is precipitated. Keep stirring at 10-20°C for 1-2 hours, filter, and rinse with glacial ethyl acetate. The filter cake is dried under reduced pressure at 50°C for 10 hours to obtain 4.9 g of 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester hydrochloride (TM), with a yield of 87.39% and a liquid phase purity of 98.87%.
[0026] Example 2: A method for synthesizing chloroprocaine hydrochloride intermediate impurities, comprising the following steps.
[0027] S1. Acid chloride reaction: Add 150mL of dichloromethane and 30g of 5-chloro-2-nitrobenzoic acid to the reaction flask, control the reaction temperature at 15±5℃, add 21.5g of thionyl chloride dropwise, add 1.5mL of N,N-dimethylformamide after the addition is complete, heat to 35-45℃, reflux for 10h, take samples every 1h, add methanol to derive into methyl ester, monitor once by TLC (EA: Hept=1:3), react until the 5-chloro-2-nitrobenzoic acid spot disappears on TLC monitoring, that is, the reaction of 5-chloro-2-nitrobenzoic acid is complete. Cool the reaction solution to room temperature, concentrate to dryness, add 60mL of dichloromethane to dissolve, and obtain a dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride (IM I).
[0028] S2. Esterification reaction: Add 240mL of dichloromethane, 25.2g of N, N-diethylethanolamine hydrochloride, and 45.3g of triethylamine to the reaction flask, control the temperature at 10-20°C, dropwise add a dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride (IM I), stir for about 30 minutes after the addition is complete, raise the temperature to 30-35°C, keep the temperature for 2h~3h, take a sample every 0.5h and add water, monitor once with TLC (EA: Hept=1:1), and react until the 5-chloro-2-nitrobenzoic acid spot disappears. Filter the reaction solution and wash the filtrate twice with purified water (300mL*2), add 30g of anhydrous sodium sulfate and dry. The product was concentrated under reduced pressure (≤-0.08 MPa) at 35-40°C until no condensate dropped out, to obtain 37.4 g of 2-(diethylamino)ethyl 5-chloro-2-nitrobenzoate (IMII), with a yield of 83.54%.
[0029] S3. Salt-forming reaction: Add 20g of 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester (IMIII) and 300mL of ethyl acetate to the reaction flask, stir to dissolve, cool to 10-20°C, add 24mL of hydrochloric acid ethyl acetate solution dropwise, and a light yellow solid is precipitated. Keep stirring at 10-20°C for 1-2h, filter, and rinse with glacial ethyl acetate. Dry the filter cake under reduced pressure at 50°C for 10h to obtain 19.6g of 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester hydrochloride (TM), with a yield of 85.61% and a liquid phase purity of 99.25%.
Claims
1. A method for synthesizing chloroprocaine hydrochloride intermediate impurities, characterized in that: It includes the following steps: S1. Acid chloride reaction: Add dichloromethane and 5-chloro-2-nitrobenzoic acid to the reaction kettle, control the reaction temperature at 15±5°C, add thionyl chloride dropwise, add N,N-dimethylformamide after the addition is complete, raise the temperature to 35-45°C, and reflux for 10-15h until the 5-chloro-2-nitrobenzoic acid reacts completely. The reaction solution is cooled, concentrated, and dissolved to obtain a dichloromethane solution of 5-chloro-2-nitrobenzoyl chloride; S2. Condensation reaction: Add N, N-diethylethanolamine hydrochloride, dichloromethane, and triethylamine to the reaction kettle, control the temperature at 10-20°C, and drop 5-chloro-2-nitrobenzoyl chloride in dichloromethane. After the addition is complete, raise the temperature to 30-35°C and keep the temperature for 2-3 hours. The reaction solution is filtered, washed with water, dried, and concentrated to obtain 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester (IM II). 2.S3. Salt-forming reaction: After dissolving IMII in ethyl acetate, control the temperature at 10-20°C, add ethyl acetate (4M) hydrochloric acid dropwise to form salt, keep the temperature and stir for 1-2 hours to obtain 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester hydrochloride (TM); The synthetic route is as follows:
3. The method for synthesizing chloroprocaine hydrochloride intermediate impurities according to claim 1, characterized in that: The molar ratio of 5-chloro-2-nitrobenzoic acid, thionyl chloride and N,N-dimethylformamide in step S1 is 1:1.1-1.5:2%-8%.
4. The method for synthesizing chloroprocaine hydrochloride intermediate impurities according to claim 1, characterized in that: In step S2, the molar ratio of 5-chloro-2-nitrobenzoyl chloride (IM I) to triethylamine and N,N-diethylethanolamine hydrochloride is 1:2.5-3.5:1.0-1.2, and the reaction is carried out at 30-35° C. for 2-3 hours. The reaction solution is filtered, washed with water twice, dried by adding anhydrous sodium sulfate, and concentrated to dryness to obtain an oily substance, 5-chloro-2-nitrobenzoic acid 2-(diethylamino)-ethyl ester (IM II).
5. The method for synthesizing chloroprocaine hydrochloride intermediate impurities according to claim 1, characterized in that: The 5-chloro-2-nitrobenzoic acid 2-(diethylamino)-ethyl ester (IMII) described in step S3 is dissolved in ethyl acetate, the mass ratio of IM II to ethyl acetate is 1:10-15, and hydrochloric acid ethyl acetate solution is added dropwise at 10-20° C., the mass ratio of IM II to hydrochloric acid ethyl acetate solution is 1:0.8-1.2, and the mixture is stirred for 1-2 hours to obtain 5-chloro-2-nitrobenzoic acid 2-(diethylamino)ethyl ester hydrochloride (TM).