Efficient synthesis method of chloroprocaine hydrochloride

Abstract

The invention discloses a synthesis method of chloroprocaine hydrochloride, and belongs to the technical field of medicines.The synthesis method comprises the steps that N, N-diethylethanolamine hydrochloride is used as a starting raw material, and synthesis of the target product chloroprocaine hydrochloride is achieved through chlorination, substitution, reduction and salt forming reactions; the method has the beneficial effects that the method has the advantages of simple synthetic route, mild reaction conditions, convenience in operation, low cost, small environmental pollution and high yield, and is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to a high-efficiency synthesis method of 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 Figure 2 .

[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] At present, the preparation method of chloroprocaine hydrochloride can be divided into the following two categories according to the different starting materials: a preparation method using 2-chloro-4-aminobenzoic acid as a starting material, a preparation method using 2-chloro-4-nitrobenzoic acid methyl ester as a starting material, and a preparation method using 2-chloro-4-nitrobenzoic acid as a starting material.

[0005] The literature reports a preparation method using 2-chloro-4-aminobenzoic acid as the starting material. The hydrochloride of 2-chloro-4-aminobenzoyl chloride is obtained by refluxing thionyl chloride and cooling with ether and hydrochloric acid. Then, chloroprocaine hydrochloride is obtained by refluxing with N,N-diethylethanolamine in toluene and tetrachloroethane. This method directly uses thionyl chloride as a solvent, which is highly irritating. It decomposes into sulfur dioxide and hydrogen chloride when it comes into contact with water or alcohol, which can burn the skin and irritate the mucous membrane. It has high requirements for equipment and is more harmful to operators. There are also literature reports that directly using 2-chloro-4-aminobenzoic acid as a raw material, heating and refluxing with N,N-diethylethanolamine at 40~100mmHg to obtain the final product. However, this method has high requirements for equipment and requires synthesis under pressure conditions.

[0006] Literature reports a preparation method using 2-chloro-4-nitrobenzoic acid as the starting material. One method is to form an ester with N,N-diethylethanolamine, and then reduce it with a Fe / HCl system to form a hydrochloride. The other method is to first reduce it with a Fe / HCl system, then form an ester with N,N-diethylethanolamine, and finally form a hydrochloride. The disadvantage of this route is that xylene is used as a solvent to react to form an ester, the reaction temperature is high, and the energy consumption during the production process is high. In addition, the iron sludge generated after Fe / HCl reduction is difficult to handle and the operation is complicated. Therefore, the industrial scale of this route has certain limitations. Summary of the invention

[0007] The present invention aims to overcome the shortcomings of the prior art and provide a highly efficient synthesis method of chloroprocaine hydrochloride, which has the advantages of simple synthesis route, mild reaction conditions, convenient operation, high yield, low cost and low environmental pollution, and is suitable for large-scale factory production.

[0008] The present invention is achieved through the following technical scheme: a method for synthesizing chloroprocaine hydrochloride, which comprises the following steps.

[0009] S1. Chlorination reaction: Add dichloromethane and N,N-diethylethanolamine hydrochloride to the reaction kettle, control the reaction temperature to 0~25℃, add thionyl chloride dropwise, and after the addition is complete, heat to 30~40℃, reflux for 5~20h until the N,N-diethylethanolamine hydrochloride reacts completely. The reaction solution is cooled, concentrated, dissolved and crystallized to obtain 2-diethylamino chloroethane hydrochloride solid, i.e., chloroprocaine hydrochloride intermediate I.

[0010] S2. Substitution reaction: Add N,N-dimethylformamide, 2-diethylaminoethyl chloride hydrochloride, and 2-chloro-4-nitrobenzoic acid to the reaction kettle, control the temperature at 0-30°C, add potassium carbonate, raise the temperature to 80-120°C, and continue to react for 2-8 hours. The reaction solution is diluted, extracted, washed with brine, dried, concentrated, and salted to obtain chloroprocaine hydrochloride intermediate II.

[0011] S3. Reduction reaction: tetrahydrofuran, chloroprocaine hydrochloride intermediate II, and stannous chloride dihydrate are added to a reaction kettle, the temperature is raised to 50-70°C, and the reaction is carried out for 2-8 hours until the chloroprocaine hydrochloride intermediate II is completely reacted. The reaction solution is adjusted to pH, filtered, extracted, washed with water, dried, and concentrated to obtain chloroprocaine hydrochloride intermediate III.

[0012] S4. Salt-forming reaction: After dissolving the chloroprocaine hydrochloride intermediate III in anhydrous ethanol, control the temperature at 0-20°C, add hydrochloric acid ethyl acetate solution dropwise to form a salt, keep the temperature and stir for 2-4 hours to obtain crude chloroprocaine hydrochloride.

[0013] S5. Refining: Add 95% ethanol and crude chloroprocaine hydrochloride to the reactor, control the temperature at 60-70°C to completely dissolve the crude chloroprocaine hydrochloride, add activated carbon and sodium dithionite and keep warm for 0.5-2h, and filter while hot. Cool the filtrate to 0-20°C, keep warm and stir for 1-4h to obtain the finished chloroprocaine hydrochloride. Synthesis route see Figure 1 .

[0014] Furthermore, in step S1, the molar ratio of N,N-diethylethanolamine hydrochloride to thionyl chloride is 1:1.0-3.0.

[0015] Furthermore, in step S2, the molar ratio of the chloroprocaine hydrochloride intermediate I, 2-chloro-4-nitrobenzoic acid and potassium carbonate is 1:0.8-1.2:1.0-4.0, and the reaction is carried out at 80-120°C for 2-8 hours. The reaction solution is diluted, extracted, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain an oily substance. The mixture is dissolved in ethyl acetate, and a hydrochloric acid ethyl acetate solution is added dropwise, and the mass ratio of the oily substance to the hydrochloric acid ethyl acetate solution is 1:0.8-1.5.

[0016] Furthermore, in step S3, the molar ratio of the chloroprocaine hydrochloride intermediate II and stannous chloride dihydrate is 1:1-6, the reaction is carried out at 50-70° C. for 2-8 hours, the pH value is adjusted to 9-11 with a 5% sodium hydroxide solution, and the mixture is extracted, washed with water, dried, and concentrated to obtain the chloroprocaine hydrochloride intermediate III.

[0017] Furthermore, the chloroprocaine hydrochloride intermediate III in step S4 is dissolved in anhydrous ethanol, the mass ratio of chloroprocaine hydrochloride intermediate III to anhydrous ethanol is 1:5-20, and hydrochloric acid ethyl acetate solution is added dropwise at 0-20° C., the mass ratio of chloroprocaine hydrochloride intermediate III to hydrochloric acid ethanol solution is 1:0.8-1.5, and the mixture is stirred at this temperature for 2-4 hours to obtain crude chloroprocaine hydrochloride.

[0018] Further, the refining method described in step S5 is as follows: 95% ethanol is added to the crude chloroprocaine hydrochloride, the mass ratio of the crude product to 95% ethanol is 1:5-20, refluxed at a temperature of 60-70°C until the crude chloroprocaine hydrochloride is completely dissolved, activated carbon and sodium dithionite are added, and the mass ratio of the crude product to activated carbon and sodium dithionite is 1:0.05-0.20:0.01-0.10. Keep warm for 0.5-2h, and filter while hot. The filtrate is cooled to 0-20°C, stirred for 1-4h, and the obtained solid is washed with anhydrous ethanol and dried to obtain the finished chloroprocaine hydrochloride.

[0019] The invention has the following advantages: N,N-diethylethanolamine hydrochloride is used as a starting material, and the target product chloroprocaine hydrochloride is synthesized through chlorination, substitution, reduction and hydrochloride formation reactions; the method of the invention has the advantages of simple synthesis route, mild reaction conditions, convenient operation, high yield, low cost and low environmental pollution, and is suitable for large-scale factory production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 This is a synthetic route for chloroprocaine hydrochloride.

[0021] Figure 2 It is the structural formula of chloroprocaine hydrochloride.

[0022] Figure 3 This is the H NMR spectrum of chloroprocaine hydrochloride.

[0023] Figure 4 This is the mass spectrum of chloroprocaine hydrochloride. DETAILED DESCRIPTION

[0024] 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.

[0025] The present invention uses N,N-diethylethanolamine hydrochloride as the starting material, and synthesizes the target product chloroprocaine hydrochloride through chlorination, substitution, reduction, hydrochloride formation, and refining. The synthetic route is shown in Figure 1 .

[0026] Embodiment 1: A method for synthesizing chloroprocaine hydrochloride comprises the following steps.

[0027] S1. Chlorination reaction: Add 10.0L dichloromethane and 1.0Kg N,N-diethylethanolamine hydrochloride to the reaction kettle, control the temperature below 10°C, add 1.5Kg thionyl chloride dropwise, raise the temperature to 30-40°C, react for 10h, and monitor until the N,N-diethylethanolamine hydrochloride reacts completely. Cool the reaction solution, concentrate to dryness, add 1L anhydrous ethanol and heat to dissolve, then add 5L methyl tert-butyl ether to crystallize, filter, and dry to obtain 1.03Kg of chloroprocaine hydrochloride intermediate I, with a yield of 92.0%.

[0028] S2. Substitution reaction: Add 10LN,N-dimethylformamide, 1.0Kg chloroprocaine hydrochloride intermediate I and 1.0Kg 2-chloro-4-nitrobenzoic acid to the reactor, control the temperature at 20-30℃, add 2.4Kg potassium carbonate, stir for 1h after adding, heat to 100-110℃, keep warm for 3h, and monitor until the 2-chloro-4-nitrobenzoic acid reacts completely. Dilute with water, extract, wash with brine, dry with anhydrous sodium sulfate, and concentrate to dryness. Add 15L ethyl acetate to the concentrated solution, stir to dissolve, cool to 10-20℃, add 1.2L hydrochloric acid ethyl acetate solution dropwise, and precipitate solid. After the drop is completed, control the temperature at 10-20℃ and stir for 2h, filter and rinse with ethyl acetate, and dry the filter cake for 12h to obtain 1.4Kg chloroprocaine hydrochloride intermediate II with a yield of 71.4%.

[0029] S3. Reduction reaction: Add 0.92kg of intermediate II and 7.4L of tetrahydrofuran to the reactor, add 2.5Kg of stannous chloride dihydrate under stirring, and the reaction system gradually becomes clear. Heat to 50-60℃, react for 4h, and monitor until the reaction of chloroprocaine hydrochloride intermediate II is complete. Cool the reaction solution to 20-30℃, add 5% sodium hydroxide solution, adjust the pH to 10-11, filter, extract the filtrate with ethyl acetate, dry it with anhydrous sodium sulfate, and concentrate to dryness to obtain chloroprocaine hydrochloride intermediate III.

[0030] S4. Salt-forming reaction: Add intermediate III and 10L of anhydrous ethanol to the reaction kettle, stir to dissolve, cool to 10-20°C, drop 1L of hydrochloric acid ethyl acetate solution to precipitate solid. Keep stirring at 10-20°C for 2-3h, filter, rinse with anhydrous ethanol, dry the filter cake for 10h to obtain 680g of crude chloroprocaine hydrochloride, with a yield of 81.2%.

[0031] S5. Crude product purification: Add 600g crude chloroprocaine hydrochloride and 7L 95% ethanol to the reactor, heat to 60-70℃, keep warm to dissolve, and stir for 1h. Add 38g activated carbon and 13g sodium dithionite, and keep warm for 1h. Filter while hot and rinse with a small amount of 95% ethanol. Cool the filtrate to 10-20℃, keep warm and stir for 2-3h, filter, and dry the filter cake for 15h to obtain 499g of chloroprocaine hydrochloride finished product with a yield of 83.1%. Figure 3 and Figure 4 As shown, the obtained product was confirmed by mass spectrometry and nuclear magnetic resonance hydrogen spectrum, showing that it was chloroprocaine hydrochloride.

[0032] Embodiment 2: A method for synthesizing chloroprocaine hydrochloride comprises the following steps.

[0033] S1. Chlorination reaction: add 15.0L of dichloromethane and 3.0Kg of N,N-diethylethanolamine hydrochloride to the reaction kettle, control the temperature below 20°C, add 2.7Kg of thionyl chloride dropwise, raise the temperature to 30-40°C and react for 10h, monitor until the N,N-diethylethanolamine hydrochloride reacts completely, cool the reaction solution, concentrate to dryness, add 4.5L of anhydrous ethanol and heat to dissolve, then add 27L of methyl tert-butyl ether to crystallize, filter, and dry to obtain 3.1Kg of chloroprocaine hydrochloride intermediate I with a yield of 92.3%.

[0034] S2. Substitution reaction: Add 18LN,N-dimethylformamide, 3.0Kg chloroprocaine hydrochloride intermediate I and 3.0Kg 2-chloro-4-nitrobenzoic acid to the reactor, control the temperature at 20-30℃, add 3.6Kg potassium carbonate, stir for 0.5h after adding, heat to 80-90℃, keep warm for 3h, monitor until 2-chloro-4-nitrobenzoic acid reacts completely. Dilute with water, extract, wash with brine, dry with anhydrous sodium sulfate, concentrate to dryness, add 60L ethyl acetate to the concentrate, stir to dissolve, cool to 10-20℃, add 3.6L hydrochloric acid ethyl acetate solution dropwise, and precipitate solid. After dropping, control the temperature at 10-20℃, keep warm and stir for 2h, filter and rinse with ethyl acetate, dry the filter cake for 12h, and obtain 4.4Kg chloroprocaine hydrochloride intermediate II, with a yield of 74.9%.

[0035] S3. Reduction reaction: Add 3.2Kg of intermediate II and 24L of tetrahydrofuran to the reactor, add 8Kg of stannous chloride dihydrate under stirring, and the reaction system gradually becomes clear. Heat to 50-60℃, react for 4h, and monitor until the reaction of chloroprocaine hydrochloride intermediate II is complete. Cool the reaction solution to 20-30℃, add 5% sodium hydroxide solution, adjust the pH to 10-11, filter, extract the filtrate with ethyl acetate, dry it with anhydrous sodium sulfate, and concentrate to dryness to obtain chloroprocaine hydrochloride intermediate III.

[0036] S4. Salt-forming reaction: Add intermediate III and 30L of anhydrous ethanol to the reactor, stir to dissolve, cool to 10-20°C, drop 3L of hydrochloric acid ethyl acetate solution, and precipitate solid. Keep stirring at 10-20°C for 2-3h, filter, rinse with anhydrous ethanol, and dry the filter cake for 12h to obtain 2.5Kg of crude chloroprocaine hydrochloride, with a yield of 85.4%.

[0037] S5. Crude product purification: Add 2Kg crude chloroprocaine hydrochloride and 25L 95% ethanol to the reactor, heat to 60-70℃, keep warm to dissolve, and stir for 1h. Add 120g activated carbon and 80g sodium dithionite, keep warm for 1h. Filter while hot and rinse with a small amount of 95% ethanol. Cool the filtrate to 10-20℃, keep warm and stir for 2-3h, filter, and dry the filter cake for 14h to obtain 1.7Kg of chloroprocaine hydrochloride finished product with a yield of 83.3%.

Claims

1. An efficient synthesis method of chloroprocaine hydrochloride, characterized in that: It includes the following steps: S1. Chlorination reaction: Add dichloromethane and N,N-diethylethanolamine hydrochloride to the reaction kettle, control the reaction temperature to 0~25℃, add thionyl chloride dropwise, and after the addition is complete, heat to 30~40℃, reflux for 5~20h until the N,N-diethylethanolamine hydrochloride reacts completely. The reaction solution is cooled, concentrated, dissolved and crystallized to obtain 2-diethylamino chloroethane hydrochloride solid, i.e., chloroprocaine hydrochloride intermediate I. 2.S2. Substitution reaction: Add N,N-dimethylformamide, 2-diethylaminoethyl chloride hydrochloride, and 2-chloro-4-nitrobenzoic acid to the reaction kettle, control the temperature at 0-30°C, add potassium carbonate, raise the temperature to 80-120°C, and continue to react at this temperature for 2-8 hours. The reaction solution is diluted, extracted, washed with brine, dried, concentrated, and salted to obtain chloroprocaine hydrochloride intermediate II. 3.S3. Reduction reaction: tetrahydrofuran, chloroprocaine hydrochloride intermediate II and stannous chloride dihydrate are added to the reaction kettle, the temperature is raised to 50-70°C, and the reaction is carried out for 2-8 hours until the chloroprocaine hydrochloride intermediate II is completely reacted. The reaction solution is adjusted to pH, filtered, extracted, washed with water, dried, and concentrated to obtain chloroprocaine hydrochloride intermediate III. 4.S4. Salt-forming reaction: Dissolve the chloroprocaine hydrochloride intermediate III in anhydrous ethanol, control the temperature at 0-20°C, add hydrochloric acid ethyl acetate solution dropwise to form salt, keep warm and stir for 2-4 hours to obtain crude chloroprocaine hydrochloride. 5.S5. Refining: Add 95% ethanol and crude chloroprocaine hydrochloride to the reactor, control the temperature at 60-70°C to completely dissolve the crude chloroprocaine hydrochloride, add activated carbon and sodium dithionite and keep warm for 0.5-2h, and filter while hot. Cool the filtrate to 0-20°C, keep warm and stir for 1-4h to obtain the finished chloroprocaine hydrochloride. The synthesis route is shown in Figure 1.

6. The method for synthesizing chloroprocaine hydrochloride according to claim 1, characterized in that: The molar ratio of N,N-diethylethanolamine hydrochloride to thionyl chloride in step S1 is 1:1.0-3.

0.

7. The method for synthesizing chloroprocaine hydrochloride according to claim 1, characterized in that: The molar ratio of the chloroprocaine hydrochloride intermediate I, 2-chloro-4-nitrobenzoic acid and potassium carbonate in step S2 is 1:0.8-1.2:1.0-4.0, and the reaction is carried out at 80-120°C for 2-8 hours. The reaction solution is diluted, extracted, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain an oily substance. The mixture is dissolved in ethyl acetate, and a hydrochloric acid ethyl acetate solution is added dropwise, and the mass ratio of the oily substance to the hydrochloric acid ethyl acetate solution is 1:0.8-1.

5.

8. The method for synthesizing chloroprocaine hydrochloride according to claim 1, characterized in that: In step S3, the molar ratio of the chloroprocaine hydrochloride intermediate II and stannous chloride dihydrate is 1:1-6, the reaction is carried out at 50-70° C. for 2-8 hours, the pH value is adjusted to 9-11 with a 5% sodium hydroxide solution, extraction, water washing, drying and concentration are performed to obtain the chloroprocaine hydrochloride intermediate III.

9. The method for synthesizing chloroprocaine hydrochloride according to claim 1, characterized in that: The chloroprocaine hydrochloride intermediate III in step S4 is dissolved in anhydrous ethanol, the mass ratio of chloroprocaine hydrochloride intermediate III to anhydrous ethanol is 1:5-20, and ethyl acetate hydrochloride solution is added dropwise at 0-20° C., the mass ratio of chloroprocaine hydrochloride intermediate III to ethyl acetate hydrochloride solution is 1:0.8-1.5, and the mixture is stirred for 2-4 hours to obtain crude chloroprocaine hydrochloride.

10. The method for synthesizing chloroprocaine hydrochloride according to claim 1, characterized in that: The refining method described in step S5 is as follows: 95% ethanol is added to the crude chloroprocaine hydrochloride, the mass ratio of the crude product to 95% ethanol is 1:5-20, refluxed at a temperature of 60-70°C until the crude chloroprocaine hydrochloride is completely dissolved, activated carbon and sodium dithionite are added, and the mass ratio of the crude product to activated carbon and sodium dithionite is 1:0.05-0.20:0.01-0.

10. Keep warm for 0.5-2h, and filter while hot. The filtrate is cooled to 0-20°C, kept warm and stirred for 1-4h, the obtained solid is washed with anhydrous ethanol, and dried to obtain the finished chloroprocaine hydrochloride.

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