Preparation methods and applications of chloroprocaine hydrochloride and its intermediates

Abstract

This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing chloroprocaine hydrochloride and its intermediates, and their applications. The invention uses 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine as starting materials, and prepares nitrochlorocaine via sulfuric acid-catalyzed esterification. Nitrochlorocaine is then reduced with thiourea dioxide to obtain crude chloroprocaine. The crude chloroprocaine is then salted in hydrochloric acid and ethanol, crystallized, and dried to obtain the final product, chloroprocaine hydrochloride. This method features low cost, high product quality, high yield, simple process, high production capacity, environmental friendliness, and suitability for industrial production, thus possessing significant industrialization value.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for preparing chloroprocaine hydrochloride and its intermediates and their applications. Background Technology

[0002] Procaine hydrochloride is a short-acting benzoate local anesthetic. It primarily works by blocking sodium ion channels in nerve cells, inhibiting the generation and conduction of nerve impulses, thereby producing a local anesthetic effect. This drug has a rapid onset and moderate duration of action, making it suitable for short-duration surgeries or anesthetic needs requiring rapid sensory recovery.

[0003] In recent years, some existing technologies have reported synthetic routes for chloroprocaine hydrochloride. Details are as follows:

[0004] Option 1: Patent CN105968019A reports the following synthetic route:

[0005]

[0006] This patent describes a method for preparing nitrochlorocaine by refluxing 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine in xylene using p-toluenesulfonic acid, a supported liquid acid, and a weakly acidic metal salt as catalysts. The nitrochlorocaine is then reduced using iron powder, followed by post-treatment and crystallization to obtain chloroprocaine hydrochloride. This method uses iron powder to reduce nitrochlorocaine, which generates a large amount of iron sludge waste after reduction, resulting in high treatment costs and potential soil and water pollution.

[0007] Option 2: Patent CN119241383A reports the following synthetic route:

[0008]

[0009] This patent uses N,N-diethylethanolamine hydrochloride as a starting material, and prepares 2-diethylaminochloroethane hydrochloride through a chlorination reaction under thionyl chloride conditions. Then, it reacts with 2-chloro-4-nitrobenzoic acid to prepare nitrochlorocaine. Nitrochlorocaine is reduced using stannous chloride dihydrate, and after post-treatment and crystallization, chloroprocaine hydrochloride is obtained. This method uses stannous chloride to reduce the nitro group. After the reaction, the product and tin salt need to be separated through alkalization, extraction, and multiple water washing steps. During this process, a colloidal precipitate or emulsion layer is easily formed, making separation difficult and severely affecting the yield and purity. Simultaneously, it generates a large amount of tin-containing wastewater / residue, resulting in high environmental treatment costs and failing to conform to the trend of green chemistry.

[0010] Option 3: Xiong Haiwei et al. reported the following synthetic route:

[0011]

[0012] This method involves preparing 2-chloro-4-nitrobenzoic acid under thionyl chloride conditions to 2-chloro-4-nitrobenzoyl chloride, followed by esterification with N,N-diethylethanolamine to prepare nitrochlorocaine. Nitrochlorocaine is then hydrogenated using a Ni catalyst and hydrogen catalysis, followed by post-treatment and crystallization to obtain chloroprocaine hydrochloride. This method uses a Ni catalyst, which has relatively poor safety profile.

[0013] Option 4: Patent CN118108616A reports the following synthetic route:

[0014]

[0015] This patent describes the preparation of nitrochlorocaine using 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine on a PDVB-SO3H-SO3H solid acid catalyst, followed by catalytic hydrogenation using a novel supported platinum catalyst, Pt-T / AC. After post-treatment and crystallization, chloroprocaine hydrochloride is obtained. However, the catalyst used in this method is relatively expensive, resulting in no significant cost advantage in production.

[0016] Option 5: Patent CN119707723A reports the following synthetic route:

[0017]

[0018] This patent describes the preparation of 2-chloro-4-aminobenzoic acid via hydrogenation reduction of 2-chloro-4-nitrobenzoic acid in a ruthenium catalyst Ru / SNC system. The 2-chloro-4-aminobenzoic acid is then esterified with N,N-diethylethanolamine in a solid base catalyst K / r-G0 system. Post-treatment and crystallization yield chloroprocaine hydrochloride. The patent discloses the preparation methods for the ruthenium catalyst Ru / SNC and the solid base catalyst K / r-G0. However, the catalyst used in this method is relatively expensive, and the production cost advantage is not significant.

[0019] Schemes 1 and 2 use iron powder and stannous chloride to process waste, resulting in high environmental treatment costs. Schemes 3-5 introduce different heavy metal elements during the catalytic reduction of nitro groups. The reduction step is located in the later stage of the synthesis route (near the finished product). According to the ICH guidelines, the strict control standards for metal residues in the active pharmaceutical ingredient (which need to be controlled at the ppm level) mean that the crude products obtained by schemes 3-5 have a large amount of heavy metal residues. Therefore, multiple purifications are required to remove the heavy metal residues in order for the finished product to meet the ICH quality requirements. This not only increases the complexity of the process and the production cost, but also introduces the potential risk of incomplete removal of heavy metal impurities.

[0020] Therefore, it is necessary to develop a method for synthesizing chloroprocaine hydrochloride with low heavy metal residue, low environmental cost, and high green production efficiency. Summary of the Invention

[0021] To overcome the problems of high environmental costs and heavy metal residues in products associated with existing technologies, this invention proposes a method for preparing chloroprocaine hydrochloride and its intermediates, along with their applications. This invention uses 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine as starting materials to prepare nitrochlorocaine under sulfuric acid catalysis. The nitrochlorocaine is then further reduced using thiourea dioxide, followed by post-treatment and crystallization to obtain the final product, chloroprocaine hydrochloride. Compared to traditional processes, this method avoids the use of heavy metal catalysts and features inexpensive materials, fewer process steps, high product purity, high overall yield, good atom economy, lower emissions, and is more suitable for industrial production.

[0022] One objective of this invention is to provide a method for preparing chloroprocaine. This method combines sulfuric acid-catalyzed esterification and thiourea dioxide reduction to prepare chloroprocaine, which is environmentally friendly, highly efficient, and provides support for the subsequent preparation of chloroprocaine hydrochloride.

[0023] To achieve the above objectives, the present invention adopts the following technical solution:

[0024] The preparation method of chloroprocaine includes the following steps:

[0025] 1) Prepare a toluene solution of sulfuric acid under low temperature and nitrogen protection, add 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine, and obtain nitrochlorocaine by sulfuric acid-catalyzed esterification reaction;

[0026] 2) Add thiourea dioxide to the nitrochlorocaine obtained in step 1), adjust the pH of the reaction system to 7.5~8.5 with alkali, and obtain chloroprocaine through reduction reaction.

[0027] Preferably, in step 1), the molar ratio of 2-chloro-4-nitrobenzoic acid to N,N-diethylethanolamine is 1:0.9~1.1, more preferably 1:1.0.

[0028] Preferably, in step 1), the molar ratio of 2-chloro-4-nitrobenzoic acid to concentrated sulfuric acid is 1:0.1~0.6, more preferably 1.0:0.1.

[0029] Preferably, in step 1), the reaction solvent is any one or more of chlorobenzene, toluene, and xylene.

[0030] More preferably, in step 1), the reaction solvent is toluene.

[0031] Preferably, the ratio of 2-chloro-4-nitrobenzoic acid to solvent is 1 (g): 5~15 (mL), more preferably 1 (g): 10 (mL).

[0032] Preferably, in step 1), the reaction temperature is 101~115℃ and the reaction time is 10~20 hours.

[0033] More preferably, in step 1), the reaction temperature is 110°C and the reaction time is 15 hours.

[0034] Preferably, in step 1), the low temperature is -5 to -20°C, and more preferably -10°C.

[0035] As a preferred method, toluene is cooled to -10°C, purged with nitrogen three times, and then concentrated sulfuric acid is added dropwise to obtain a toluene solution of sulfuric acid.

[0036] Preferably, in step 1), a water separator is used to separate and remove the water generated during the reaction.

[0037] Preferably, step 1) further includes a post-processing step: the reaction solution obtained from the esterification reaction is extracted, separated, pH adjusted by adding alkali, crystallized, filtered, washed, and vacuum filtered to obtain wet nitrochlorocaine.

[0038] More preferably, the extraction solvent includes water and an aqueous solution of hydrochloric acid.

[0039] More preferably, the concentration of the hydrochloric acid aqueous solution is 1%.

[0040] More preferably, water is first added to the reaction system for extraction, and the aqueous phase ① is obtained by separation; the organic phase is extracted again with hydrochloric acid aqueous solution to obtain the aqueous phase ②, and the two aqueous phases are combined.

[0041] More preferably, an aqueous sodium hydroxide solution is added dropwise to the combined aqueous phase of the extraction to adjust the pH to 7.0-8.0, and a solid is precipitated.

[0042] More preferably, the crystallization includes: cooling to 0~5℃ and growing crystals for 3~5 hours; more preferably, growing crystals for 3 hours.

[0043] More preferably, the washing solvent is water.

[0044] Preferably, in step 2), the molar ratio of nitrochlorocaine to thiourea dioxide is 1:2.0~5.0, more preferably 1:2.0.

[0045] Preferably, in step 2), the alkali includes one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate.

[0046] More preferably, in step 2), the alkali is sodium hydroxide; more preferably, it is 20% sodium hydroxide.

[0047] Preferably, in step 2), the reaction solvent is any one or more of methanol, ethanol, and water.

[0048] Preferably, in step 2), the reaction solvent is ethanol.

[0049] Preferably, in step 2), the reaction conditions are room temperature reaction for 4-6 hours.

[0050] More preferably, in step 2), the reaction time is 5 hours.

[0051] Preferably, in step 2), after the reduction reaction is completed, the resulting reaction solution is filtered, washed, concentrated under reduced pressure, and crystallized to obtain crude chloroprocaine.

[0052] More preferably, the reaction byproducts urea and sodium sulfate are removed by filtration.

[0053] More preferably, the washing solvent is ethanol. Ethanol is used to wash away residual chloroprocaine from the filter cake.

[0054] More preferably, the vacuum concentration temperature is 30~60°C, more preferably 40°C.

[0055] More preferably, the crystallization includes: cooling to 0~5℃ and growing crystals for 3~5 hours; more preferably, growing crystals for 3 hours.

[0056] More preferably, after filtration and washing, the filtrates are combined, purified water is added and stirred evenly, the mixture is concentrated under reduced pressure until the flow stops, a large amount of solid is precipitated, the concentration is stopped, water is added, the mixture is cooled to grow crystals, filtered, the filter cake is washed with water, filtered and dried to obtain crude chloroprocaine.

[0057] The second objective of this invention is to provide a method for preparing chloroprocaine hydrochloride.

[0058] To achieve the above objectives, the present invention adopts the following technical solution:

[0059] The preparation method of chloroprocaine hydrochloride includes the following steps:

[0060] S1: Chloroprocaine is prepared using the aforementioned method for preparing chloroprocaine;

[0061] S2: The chloroprocaine obtained in S1 is salted and crystallized with hydrochloric acid to obtain chloroprocaine hydrochloride.

[0062] Preferably, in S2, the molar ratio of chloroprocaine to hydrochloric acid is 1:1.0~1.5, more preferably 1:1.1.

[0063] Preferably, in S2, the reaction solvent is ethanol, more preferably anhydrous ethanol.

[0064] Preferably, in S2, the crystallization temperature is 0~10℃ and the crystallization time is 2~5h; more preferably, the temperature is lowered to 5~10℃ and kept at that temperature for 3h.

[0065] As a preferred embodiment, S2 includes: mixing crude chloroprocaine, anhydrous ethanol, and activated carbon, dissolving, decolorizing, and filtering at 50°C, adding hydrochloric acid ethanol solution dropwise to the filtrate, and then cooling, crystallizing, filtering, washing, vacuum filtering, and drying to obtain the finished chloroprocaine hydrochloride product.

[0066] More preferably, the washing solvent is anhydrous ethanol.

[0067] More preferably, the concentration of the hydrochloric acid ethanol solution is 2~5 mol / L, more preferably 2.5 mol / L.

[0068] The beneficial effects of this invention are as follows:

[0069] 1. This invention provides a green synthesis method for chloroprocaine hydrochloride and its intermediates. Traditional processes often use heavy metal reducing agents such as iron powder and stannous chloride, which not only generate a large amount of highly polluting waste but also require additional purification steps due to heavy metal residues. This invention uses thiourea dioxide as a reducing agent, which avoids heavy metal pollution and, because the reducing agent itself is non-toxic and harmless, significantly reduces environmental treatment costs.

[0070] 2. The method of this invention achieves precise control over reaction conditions. On one hand, the esterification reaction is catalyzed by a concentrated sulfuric acid / toluene system, and the generated water is removed using a water separator, making the reaction more complete. On the other hand, the reduction stage uses thiourea dioxide and an alkaline solvent in synergy, which ensures reduction efficiency and avoids the purity problems caused by residual metal catalysts in traditional methods. In addition, the salt formation and crystallization stage is precisely controlled by a hydrochloric acid-ethanol system, ultimately obtaining a high-purity product with a purity of 99.97%.

[0071] 3. This method demonstrates significant advantages in industrial applications: 1) Low raw material costs, with toluene and thiourea dioxide being common chemicals; 2) Mild reaction conditions and minimal waste emissions, requiring no complex post-treatment, aligning with the trend of green chemistry; 3) High product purity and yield: the total molar yield of crude chloroprocaine reaches 92.5%, with a purity of 99.71%; the molar yield of finished chloroprocaine hydrochloride is 83.9%, with a purity of 99.97%. These improvements not only enhance production efficiency but also provide a reliable guarantee for the low-cost, large-scale manufacturing of drugs. Attached Figure Description

[0072] Figure 1 This is a schematic diagram of the synthetic reaction route for chloroprocaine hydrochloride.

[0073] Figure 2 The crude chloroprocaine hydrochloride solid prepared in Example 3 1 H-NMR spectrum;

[0074] Figure 3The crude chloroprocaine hydrochloride solid prepared in Example 3 13 C-NMR spectrum;

[0075] Figure 4 The HPLC chromatogram of crude chloroprocaine prepared in Example 3 is shown below.

[0076] Figure 5 The HPLC chromatogram of crude chloroprocaine prepared in Example 4 is shown below.

[0077] Figure 6 The image shows the HPLC chromatogram of the chloroprocaine product prepared in Example 4. Detailed Implementation

[0078] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0079] In this invention, more basic information about chloroprocaine hydrochloride is as follows:

[0080] The molecular formula of chloroprocaine hydrochloride is C 13 H 19 ClN2O2·HCl, with a molecular weight of 307.22 and CAS number 3858-89-7, has a structure based on the introduction of chlorine atoms as a modification of procaine, as shown in Formula VI.

[0081]

[0082] VI.

[0083] Chloroprocaine hydrochloride has approximately four times the anesthetic potency of procaine, while its toxicity is only half that of procaine, offering both high efficacy and safety. This drug has a rapid onset and moderate duration of action, with simultaneous and rapid recovery of motor and sensory functions after discontinuation. It can reduce the dosage of analgesics and related adverse reactions, and its overall safety is superior to traditional local anesthetics such as lidocaine, procaine, and tetracaine. Clinically, it is suitable for various scenarios including epidural anesthesia, local infiltration anesthesia in dentistry, ENT, and orthopedics, and peripheral nerve blocks. Due to its low lipid solubility, rapid metabolism, and near-non-transfer of the placenta, it has minimal impact on the fetus, making it particularly suitable for obstetric anesthesia. It can also be used in children and the elderly. No skin test is required, toxic reactions are minimal, analgesia and muscle relaxation are complete, and drug resistance is rare, making it an excellent local anesthetic choice that combines high efficacy, safety, and rapid recovery.

[0084] Information on key compounds in this invention is shown in Table 1.

[0085] Table 1. Compound Information Table

[0086]

[0087] In this embodiment of the invention, the chromatographic conditions for HPLC detection are shown in Tables 2-3.

[0088] Table 2. Chromatographic conditions

[0089]

[0090] Table 3. Gradient elution program table

[0091]

[0092] Example 1. Preparation method of chloroprocaine hydrochloride (investigation of the solvent tetrahydrofuran)

[0093] (1) Preparation of nitrochlorocaine

[0094] Add 100.0 g (0.496 mol, 1.0 eq) of 2-chloro-4-nitrobenzoic acid, 58.1 g (0.496 mol, 1.0 eq) of N,N-diethylethanolamine, 1000 ml of tetrahydrofuran, and 4.87 g (0.050 mol, 0.1 eq) of concentrated sulfuric acid to a three-necked flask. After the addition is complete, heat to 66 °C and react for 15 hours. A large amount of raw material remains and is discarded for further processing.

[0095] Example 2. Preparation method of chloroprocaine hydrochloride (investigation of reaction temperature at 66°C)

[0096] (1) Preparation of nitrochlorocaine

[0097] Add 100.0 g (0.496 mol, 1.0 eq) of 2-chloro-4-nitrobenzoic acid, 58.1 g (0.496 mol, 1.0 eq) of N,N-diethylethanolamine, 1000 ml of toluene, and 4.87 g (0.050 mol, 0.1 eq) of concentrated sulfuric acid to a three-necked flask. After the addition is complete, heat to 66 °C and react for 15 hours. A large amount of raw material remains and is discarded for further processing.

[0098] Example 3. Preparation method of chloroprocaine hydrochloride (investigation of reaction temperature at 110℃)

[0099] (1) Preparation of nitrochlorocaine

[0100] Add 100.0 g (0.496 mol, 1.0 eq) of 2-chloro-4-nitrobenzoic acid, 58.1 g (0.496 mol, 1.0 eq) of N,N-diethylethanolamine, 1000 ml of toluene, and 4.87 g (0.050 mol, 0.1 eq) of concentrated sulfuric acid to a three-necked flask. After the addition is complete, heat to 110 °C and react for 15 hours. During the reaction, use a water separator to remove the water generated in the reaction. Add 300 ml of water to the reaction system, extract and separate to obtain aqueous phase ①. Extract the organic phase again with 200 ml of 1% hydrochloric acid aqueous solution to obtain aqueous phase ②. Combine the two aqueous phases, add sodium hydroxide aqueous solution to adjust the pH to 7.0~8.0, and a large amount of solid precipitates. Cool to 0~5 °C and allow crystals to grow for 3 hours. Filter, wash the filter cake with 150 ml of water, and filter under vacuum to obtain wet nitrochlorocaine. The wet product is used directly in the next reaction.

[0101] (2) Preparation of chloroprocaine hydrochloride

[0102] Add the wet nitrochlorocaine from the previous step to a three-necked flask, along with 800 ml of ethanol. Add thiourea dioxide (59.6 g, 0.992 mol, 2.0 eq). Adjust the pH of the reaction system using 20% ​​sodium hydroxide to maintain a pH of 7.5–8.5. React at room temperature for 5 hours. Filter the reaction byproducts urea and sodium sulfate. Wash the filter cake with 200 ml of ethanol to remove residual chloroprocaine. Combine the two filtrates, add 500 ml of purified water, stir well, and concentrate under reduced pressure at 40°C until the flow stops. A large amount of solid precipitates. Stop the concentration, add 300 ml of water, cool to 0–5°C, and allow crystals to grow for 3 hours. Filter, wash the filter cake with 150 ml of water, filter again, and dry to obtain 123.9 g of pale yellow crude chloroprocaine solid. The total molar yield of the two steps is 92.2%, and the purity of the crude chloroprocaine is 98.53%.

[0103] Chloroprocaine crude 1 H-NMR spectrum as follows Figure 2 As shown, 13 C-NMR spectra as follows Figure 3 As shown; its HPLC detection results are shown in [the image / data]. Figure 4 The integration results are shown in Table 4.

[0104] Table 4. Figure 4 Integral Results Table

[0105]

[0106] Example 4. Preparation method of chloroprocaine hydrochloride (optimization of feeding method)

[0107] (1) Preparation of nitrochlorocaine

[0108] 1000 ml of toluene was added to a three-necked flask and cooled to -10 °C. After purging with nitrogen three times, concentrated sulfuric acid (4.87 g, 0.050 mol, 0.1 eq) was added dropwise, followed by 2-chloro-4-nitrobenzoic acid (100.0 g, 0.496 mol, 1.0 eq) and N,N-diethylethanolamine (58.1 g, 0.496 mol, 1.0 eq). After the addition of the materials was complete, the mixture was heated to 110 °C and reacted for 15 hours. During the reaction, a water separator was used to remove the water generated in the reaction. Add 300 ml of water to the reaction system, extract and separate to obtain aqueous phase ①, extract the organic phase again with 200 ml of 1% hydrochloric acid aqueous solution to obtain aqueous phase ②, combine the two aqueous phases, add sodium hydroxide aqueous solution to adjust the pH to 7.0~8.0, a large amount of solid precipitates out, cool to 0~5℃ to grow crystals for 3 hours, filter, wash the filter cake with 150 ml of water, filter under vacuum to obtain wet nitrochlorocaine, the wet product is directly used in the next reaction.

[0109] (2) Preparation of chloroprocaine hydrochloride

[0110] The wet nitrochlorocaine from the previous step was added to a three-necked flask along with 800 ml of ethanol. Thiourea dioxide (59.6 g, 0.992 mol, 2.0 eq) was then added. During the reaction, 20% sodium hydroxide was used to adjust the pH to maintain a reaction system pH of 7.5–8.5. The reaction was carried out at room temperature for 5 hours. The byproducts urea and sodium sulfate were filtered off. The filter cake was washed with 200 ml of ethanol to remove residual chloroprocaine. The two filtrates were combined, and 500 ml of purified water was added. After stirring thoroughly, the mixture was concentrated under reduced pressure at 40°C until the flow stopped, resulting in the precipitation of a large amount of solid. Concentration was stopped, and 300 ml of water was added. The mixture was cooled to 0–5°C and allowed to crystallize for 3 hours. After filtration, the filter cake was washed with 150 ml of water, filtered again, and dried to obtain 124.3 g of white crude chloroprocaine solid. The total molar yield of the two steps was 92.5%, and the purity of the crude chloroprocaine was 99.71%. HPLC results are shown below. Figure 5 The integration results are shown in Table 5.

[0111] In a three-necked flask, crude chloroprocaine solid (120.0 g, 0.443 mol, 1.0 eq), 600 ml anhydrous ethanol, and 5.0 g activated carbon were added. The solution was dissolved, decolorized, and filtered at 50 °C. A 2.5 mol / L hydrochloric acid-ethanol solution (195 ml, 0.488 mol, 1.1 eq) was added dropwise to the filtrate. After the addition was complete, the temperature was lowered to 5–10 °C, and the solution was kept at this temperature for 3 hours to allow crystals to form. The solution was then filtered, and the filter cake was washed with 150 ml of anhydrous ethanol. The solution was then filtered again and dried to obtain 114.3 g of chloroprocaine hydrochloride (white solid), with a molar yield of 83.9% and a purity of 99.97%. The HPLC results are shown below. Figure 6 The integration results are shown in Table 6.

[0112] Table 5. Figure 5 Integral Results Table

[0113]

[0114] Table 6. Figure 6 Integral Results Table

[0115]

[0116] The experimental results of Examples 1-4 are analyzed and discussed:

[0117] 1. In Example 1, because tetrahydrofuran is highly water-soluble, the water generated during the reaction cannot be removed in time, resulting in a large amount of raw materials remaining.

[0118] 2. Comparing Examples 2 and 3, the reaction was carried out in toluene solvent at 110°C. The water generated in the reaction evaporated with the toluene vapor and condensed into the water separator. The water was removed in the water separator and did not re-enter the reaction system. The reaction was relatively thorough. When the temperature was lowered to 66°C, there was no solvent reflux during the reaction process. The water could not be removed in time, and a large amount of raw materials remained.

[0119] 3. Comparing Examples 3 and 4, Example 3 may have problems such as oxidation and carbonization of the substrate by concentrated sulfuric acid, resulting in poor quality of crude chloroprocaine. Example 4 prepared a toluene solution of sulfuric acid under low temperature and nitrogen protection, and then added 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine to reduce the damage of concentrated sulfuric acid to the substrate. Compared with Example 3, Example 4 showed better purity and superior solid color and appearance of crude chloroprocaine.

[0120] Ultimately, Example 4 was selected for subsequent industrial production. This process produces high-quality products with low cost, high yield, simple procedures, high capacity, and is environmentally friendly, thus possessing significant industrialization value.

Claims

1. A method for preparing chloroprocaine, characterized in that, Includes the following steps: 1) Prepare a toluene solution of sulfuric acid under low temperature and nitrogen protection, add 2-chloro-4-nitrobenzoic acid and N,N-diethylethanolamine, and obtain nitrochlorocaine by sulfuric acid-catalyzed esterification reaction; 2) Add thiourea dioxide to the nitrochlorocaine obtained in step 1), adjust the pH of the reaction system to 7.5~8.5 with alkali, and obtain chloroprocaine through reduction reaction.

2. The preparation method according to claim 1, characterized in that, In step 1), the molar ratio of 2-chloro-4-nitrobenzoic acid to N,N-diethylethanolamine is 1:0.9~1.1; the molar ratio of 2-chloro-4-nitrobenzoic acid to concentrated sulfuric acid is 1:0.1~0.

6.

3. The preparation method according to claim 1, characterized in that, In step 1), the reaction solvent is any one or more of chlorobenzene, toluene, and xylene; the reaction temperature is 101~115℃, and the reaction time is 10~20 hours.

4. The preparation method according to claim 1, characterized in that, In step 1), the low temperature is -5 to -20°C.

5. The preparation method according to claim 1, characterized in that, In step 2), the molar ratio of nitrochlorocaine to thiourea dioxide is 1:2.0~5.

0.

6. The preparation method according to claim 1, characterized in that, In step 2), the alkali includes any one or more of sodium hydroxide, potassium hydroxide, and potassium carbonate.

7. The preparation method according to claim 1, characterized in that, In step 2), the reaction solvent is any one or more of methanol, ethanol, and water; the reaction conditions are room temperature reaction for 4-6 hours.

8. The preparation method according to claim 1, characterized in that, In step 2), after the reduction reaction is completed, the resulting reaction solution is filtered, washed, concentrated under reduced pressure, and crystallized to obtain crude chloroprocaine.

9. A method for preparing chloroprocaine hydrochloride, characterized in that, Includes the following steps: S1: Chloroprocaine is prepared using the preparation method described in any one of claims 1 to 8; S2: The chloroprocaine obtained in S1 is salted and crystallized with hydrochloric acid to obtain chloroprocaine hydrochloride.

10. The preparation method according to claim 9, characterized in that, In S2, the crystallization temperature is 0~10℃ and the crystallization time is 2~5h.

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