Synthesis method of chloroprocaine hydrochloride impurity

Abstract

The invention discloses a preparation method of a cloprocaine hydrochloride impurity and belongs to the technical field of medicines, and the cloprocaine hydrochloride impurity is used as a reference substance for quality research of cloprocaine hydrochloride. According to the present invention, the cloprocaine hydrochloride impurity is synthesized and is adopted as the reference substance for cloprocaine hydrochloride impurity detection so as to directly and effectively control the change condition of the impurity, such that the improvement of the quality standard of cloprocaine hydrochloride is easily achieved, and the product quality of cloprocaine hydrochloride can be well controlled.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a method for synthesizing chloroprocaine hydrochloride. 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 Cl2N2O2, molecular weight is 307.22, CAS registration number is 3858-89-7, structural formula is shown in formula I:

[0003]

[0004] 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.

[0005] 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.

[0006] In the process of quality research of chloroprocaine hydrochloride, we conducted research on a key material, N,N-diethylethanolamine hydrochloride, by tracing and deriving the impurities. After consulting the literature and the information provided by the manufacturer, N,N-diethylethanolamine hydrochloride uses diethylamine in the industrial production process, and there will be a small amount of diethylamine residue in the product. According to the synthesis process, diethylamine will be introduced into the intermediate as the intermediate 2-chloro-4-nitrobenzoyl chloride of N,N-diethylethanolamine hydrochloride and chloroprocaine hydrochloride forms an ester. After reduction and salt formation, 2-chloro-4-amino-N,N-(diethyl)-benzamide hydrochloride (TM) is produced.

[0007] The structure of the impurity is as follows. Currently, there is no literature report on the synthesis method of this impurity (TM).

[0008] Summary of the invention

[0009] The present invention discloses a method for preparing a chloroprocaine hydrochloride impurity, wherein the structural formula of the chloroprocaine hydrochloride impurity is as follows:

[0010] The present invention is achieved by the following technical scheme: a method for synthesizing chloroprocaine hydrochloride impurities, which comprises the following steps:

[0011] S1. Acid chloride reaction: Add dichloromethane and 2-chloro-4-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 2-chloro-4-nitrobenzoic acid reacts completely. The reaction solution is cooled, concentrated, and dissolved to obtain a dichloromethane solution of 2-chloro-4-nitrobenzoyl chloride;

[0012] S2. Condensation reaction: Add dichloromethane and diethylamine to the reaction kettle, control the temperature at 10-20°C, dropwise add the dichloromethane solution of 2-chloro-4-nitrobenzoyl chloride, after the dropwise addition is complete, raise the temperature to 30-35°C, and keep the temperature for 2-3 hours. The reaction solution is washed with water, dried, and concentrated to obtain 2-chloro-4-nitro-N,N-(diethyl)benzamide (IM II).

[0013] S3. Reduction reaction: Add tetrahydrofuran, 2-chloro-4-nitro-N,N-(diethyl)benzamide (IMII) and stannous chloride dihydrate into the reaction kettle, raise the temperature to 70-80℃ and reflux, react for 4-6h, monitor by TLC (EA:Hept=1:2, 1 drop of triethylamine), until the reaction of IM II is complete, adjust the pH of the reaction solution, extract, wash with water, dry and concentrate to obtain 2-chloro-4-amino-N,N-(diethyl)benzamide (IM III).

[0014] S4. Salt-forming reaction: Dissolve IMIII in anhydrous ethanol, control the temperature at 10-20°C, add ethyl acetate (4M) hydrochloride dropwise to form salt, keep warm and stir for 1-2 hours to obtain 2-chloro-4-amino-N,N-(diethyl)benzamide hydrochloride (TM).

[0015] The synthetic route is as follows:

[0016]

[0017] Furthermore, the molar ratio of the 2-chloro-4-nitrobenzoic acid, thionyl chloride and N,N-dimethylformamide is 1:1.1-1.5:2%-8%.

[0018] Furthermore, the synthesis method of chloroprocaine hydrochloride impurities is characterized in that the molar ratio of 2-chloro-4-nitrobenzoyl chloride (IM I) to diethylamine in step S2 is 1:2.0-3.0, and the reaction is carried out at 30-35° C. for 2-3 hours. The reaction solution is washed with water twice, dried by adding anhydrous sodium sulfate, and concentrated to dryness to obtain an oily substance 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IM II).

[0019] Furthermore, the synthesis method of chloroprocaine hydrochloride impurities is characterized in that the molar ratio of 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IM II) and stannous chloride dihydrate in step S3 is 1:3~4, refluxed at 70~80°C for 4~6h, adjusted to pH 8~9 with saturated sodium carbonate solution, extracted, washed with water, dried, and concentrated to obtain 2-chloro-4-amino-N,N-(diethyl)-benzamide (IM III).

[0020] Furthermore, the impurity synthesis method of chloroprocaine hydrochloride is characterized in that the 2-chloro-4-amino-N, N-(diethyl)-benzamide (IMIII) described in step S4 is dissolved with anhydrous ethanol, the mass ratio of IM III to anhydrous ethanol is 1:10-15, and hydrochloric acid ethyl acetate solution is added dropwise at 10-20°C, the mass ratio of IM III to hydrochloric acid ethyl acetate solution is 1:0.8-1.2, and the mixture is kept warm and stirred for 1-2h to obtain 2-chloro-4-amino-N, N-(diethyl)-benzamide hydrochloride (TM).

[0021] Furthermore, the chloroprocaine hydrochloride impurity is suitable for use as a reference substance in quality research of chloroprocaine hydrochloride.

[0022] In summary, the beneficial effects of the present invention are as follows: a preparation method of chloroprocaine hydrochloride impurities is disclosed, and the impurities are used as reference substances for quality research of chloroprocaine hydrochloride. The present invention synthesizes the impurities of chloroprocaine hydrochloride 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 the product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the embodiments or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art are briefly introduced below.

[0024] Figure 1 The HPLC spectrum of chloroprocaine hydrochloride impurities of Inventive Example 2 is shown.

[0025] Figure 2This is the MS spectrum of the impurity positive ion of chloroprocaine hydrochloride in Inventive Example 2.

[0026] Figure 3 This is the MS spectrum of the impurity anion of chloroprocaine hydrochloride in Inventive Example 2.

[0027] Figure 4 For the impurities of chloroprocaine hydrochloride in Invention Example 2 1 H NMR spectrum. DETAILED DESCRIPTION

[0028] 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.

[0029] The present invention uses 2-chloro-4-nitrobenzoic acid as a starting material, and synthesizes the target product chloroprocaine hydrochloride impurities by forming an acyl chloride, amidation, reduction, and forming a hydrochloride. The synthetic route is as follows:

[0030]

[0031] Embodiment 1: A method for synthesizing chloroprocaine hydrochloride impurities, comprising the following steps:

[0032] S1. Acid chloride reaction: Add 50mL of dichloromethane and 10g of 2-chloro-4-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, sample every 1h, add methanol to derive into methyl ester, monitor once by TLC (EA: Hept=1:3), react until the 2-chloro-4-nitrobenzoic acid spot disappears on TLC monitoring, that is, the reaction of 2-chloro-4-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 2-chloro-4-nitrobenzoyl chloride (IM I);

[0033] S2. Esterification reaction: Add 80mL of dichloromethane and 10.9g of diethylamine to the reaction flask, control the temperature at 10-20℃, add a dichloromethane solution of 2-chloro-4-nitrobenzoyl chloride (IM I) dropwise, stir for about 30min after the addition is complete, raise the temperature to 30-35℃, keep the temperature for 2h~3h, take a sample and add water every 0.5h, monitor once by TLC (EA: Hept=1:1), and react until the 2-chloro-4-nitrobenzoic acid spot disappears. Wash the filtrate twice with purified water (100mL*2), add 10g of anhydrous sodium sulfate and dry. Concentrate under reduced pressure (≤-0.08MPa) at 35-40℃ until no condensate drips out, and obtain 10.5g of 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IM II), with a yield of 81.7%.

[0034] S3. Reduction reaction: Add 10g IM II and 80mL tetrahydrofuran to the reaction flask, add 35g stannous chloride dihydrate under stirring, and stir for about 30min. Heat to 75±5℃, reflux for 5-6h, sample every 0.5h, monitor once by TLC (EA:Hept=1:2, 1 drop of triethylamine), and react until the IM II spot disappears. Cool the reaction solution to 15-25℃, add saturated sodium carbonate solution, adjust the pH to 8-9, add 50mL ethyl acetate, and stand for separation. Extract the aqueous phase twice with ethyl acetate (50mL*2), and combine the organic phases. Wash the organic phase twice with purified water (100mL*2), add 20g anhydrous sodium sulfate and dry. Concentrate at 40-50℃, ≤0.08MPa until no condensate drips out. Obtain 6.6g of 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII), with a yield of 74.6%.

[0035] S4. Salt-forming reaction: Add 5.0g 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII) and 75mL anhydrous ethanol to the reaction flask, stir to dissolve, cool to 10-20℃, add 6mL hydrochloric acid ethyl acetate solution dropwise, and a light yellow solid is precipitated. Keep stirring at 10-20℃ for 1-2h, filter, and rinse with ethanol. Dry the filter cake under reduced pressure at 50℃ for 10h to obtain 4.9g 2-chloro-4-amino-N,N-(diethyl)-benzamide hydrochloride (TM), with a yield of 85.1% and a liquid phase purity of 98.3%.

[0036] Embodiment 2: A method for synthesizing chloroprocaine hydrochloride impurities, comprising the following steps:

[0037] S1. Acid chloride reaction: Add 150mL of dichloromethane and 30g of 2-chloro-4-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, sample every 1h, add methanol to derive into methyl ester, monitor once by TLC (EA: Hept=1:3), react until the 2-chloro-4-nitrobenzoic acid spot disappears on TLC monitoring, that is, the reaction of 2-chloro-4-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 2-chloro-4-nitrobenzoyl chloride (IM I);

[0038] S2. Esterification reaction: Add 240mL of dichloromethane and 33g of diethylamine to the reaction flask, control the temperature at 10-20℃, add a dichloromethane solution of 2-chloro-4-nitrobenzoyl chloride (IM I) dropwise, stir for about 30min after the addition is complete, raise the temperature to 30-35℃, keep the temperature for 2h~3h, take a sample and add water every 0.5h, monitor once by TLC (EA: Hept=1:1), and react until the 2-chloro-4-nitrobenzoic acid spot disappears. Wash the filtrate twice with purified water (300mL*2), add 30g of anhydrous sodium sulfate and dry. Concentrate under reduced pressure (≤-0.08MPa) at 35-40℃ until no condensate drips out, and obtain 30.5g of 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IM II), with a yield of 79.8%.

[0039] S3. Reduction reaction: Add 30g IM II and 240mL tetrahydrofuran to the reaction flask, add 105.3g stannous chloride dihydrate under stirring, and stir for about 30min. Heat to 75±5℃, reflux for 5-6h, sample every 0.5h, monitor once by TLC (EA: Hept=1:2, 1 drop of triethylamine), and react until the IM II spot disappears. Cool the reaction solution to 15-25℃, add saturated sodium carbonate solution, adjust the pH to 8-9, add 150mL ethyl acetate, and stand for separation. Extract the aqueous phase twice with ethyl acetate (150mL*2), and combine the organic phases. Wash the organic phase twice with purified water (300mL*2), add 60g anhydrous sodium sulfate and dry. Concentrate at 40-50℃, ≤0.08MPa until no condensate drips out. 20.0 g of 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII) was obtained with a yield of 75.6%.

[0040] S4. Salt-forming reaction: Add 20g 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII) and 75mL anhydrous ethanol to the reaction flask, stir to dissolve, cool to 10-20°C, add 24mL 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 ethanol. Dry the filter cake under reduced pressure at 50°C for 10h to obtain 19.6g of 2-chloro-4-amino-N,N-(diethyl)-benzamide hydrochloride (TM), with a yield of 84.3% and a liquid phase purity of 98.5%.

Claims

1. A method for synthesizing chloroprocaine hydrochloride impurities, characterized in that: It includes the following steps: S1. Acid chloride reaction: Add dichloromethane and 2-chloro-4-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 2-chloro-4-nitrobenzoic acid reacts completely. The reaction solution is cooled, concentrated, and dissolved to obtain a dichloromethane solution of 2-chloro-4-nitrobenzoyl chloride; S2. Condensation reaction: Add dichloromethane and diethylamine to the reaction kettle, control the temperature at 10-20°C, dropwise add the dichloromethane solution of 2-chloro-4-nitrobenzoyl chloride, after the dropwise addition is complete, raise the temperature to 30-35°C, and keep the temperature for 2-3 hours. The reaction solution is washed with water, dried, and concentrated to obtain 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IMII). S3. Reduction reaction: tetrahydrofuran, IMII and stannous chloride dihydrate were added to the reaction kettle, the temperature was raised to 70-80°C and refluxed, the reaction was carried out for 4-6 hours, and TLC monitoring (EA: Hept = 1:2, 1 drop of triethylamine) was performed until the reaction of IMII was complete. The reaction solution was adjusted to pH, extracted, washed with water, dried and concentrated to obtain 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII). S4. Salt-forming reaction: After dissolving IMIII in anhydrous ethanol, control the temperature at 10-20°C, add ethyl acetate (4M) hydrochloride dropwise to form salt, keep warm and stir for 1-2 hours to obtain 2-chloro-4-amino-N,N-(diethyl)benzamide hydrochloride (TM). The synthetic route is as follows: 。 2. The method for synthesizing chloroprocaine hydrochloride impurities according to claim 1, characterized in that: The molar ratio of 2-chloro-4-nitrobenzoic acid, thionyl chloride and N,N-dimethylformamide in step S1 is 1:1.1-1.5:2%-8%.

3. The method for synthesizing chloroprocaine hydrochloride impurities according to claim 1, characterized in that: In step S2, the molar ratio of 2-chloro-4-nitrobenzoyl chloride to diethylamine is 1:2.5-3.5, and the reaction is carried out at 30-35° C. for 2-3 hours. The reaction solution is washed with water twice, dried by adding anhydrous sodium sulfate, and concentrated to dryness to obtain an oily substance 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IMII).

4. The method for synthesizing chloroprocaine hydrochloride impurities according to claim 1, characterized in that: In step S3, the molar ratio of 2-chloro-4-nitro-N,N-(diethyl)-benzamide (IMII) and stannous chloride dihydrate is 1:3-4, refluxed at 70-80° C. for 4-6 hours, adjusted to pH 8-9 with saturated sodium carbonate solution, extracted, washed with water, dried and concentrated to obtain 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII).

5. The method for synthesizing chloroprocaine hydrochloride impurities according to claim 1, characterized in that: The 2-chloro-4-amino-N,N-(diethyl)-benzamide (IMIII) described in step S4 is dissolved in anhydrous ethanol, the mass ratio of IMIII to anhydrous ethanol is 1:10-15, and hydrochloric acid ethyl acetate solution is added dropwise at 10-20° C., the mass ratio of IMIII to hydrochloric acid ethyl acetate solution is 1:0.8-1.2, and the mixture is stirred for 1-2 hours to obtain 2-chloro-4-amino-N,N-(diethyl)-benzamide hydrochloride (TM).

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