A preparation process of dimethocaine hydrochloride

Abstract

The present invention provides a preparation process of dimethocaine hydrochloride. The preparation process of dimethocaine hydrochloride of the present invention comprises the following steps: mixing 3-(diethylamino)-2,2-dimethylpropanol, dichloromethane and triethylamine, and protecting with inert gas; dropping a dichloromethane solution of p-nitrobenzoyl chloride, reacting at 25-30 °C for 8-16 h, and purifying to obtain intermediate EJK-101; (2) mixing intermediate EJK-101, water and concentrated hydrochloric acid to prepare an EJK-101 solution, stirring, adding water, iron powder, concentrated hydrochloric acid and an EJK-101 solution with a total volume of 30%-40%, heating to 58-62 °C and dropping the remaining EJK-101 solution, maintaining the reaction at 64-70 °C for 8-16 h, and purifying to obtain intermediate EJK-103; (3) mixing intermediate EJK-103 and ethyl acetate, stirring under ice bath, dropping a 1.0-1.5 mol / L hydrochloric acid ethyl acetate solution, continuing the reaction for 1-2 h after dropping, filtering by suction and drying to obtain the target product. Using the process of the present invention to prepare dimethocaine hydrochloride, the purity is high, the total impurity content is low, the impurity content is effectively reduced, and the drug safety is improved.

Description

Technical Field

[0001] The present invention relates to the field of drug preparation, and particularly to a preparation process of dimethocaine hydrochloride. Background Art

[0002] Dimethocaine (DMC), English name: Larocaine, Chinese name: 3 - diethylamino - 2,2 - dimethyl - 1 - propanol 4 - aminobenzoate, has the chemical formula C 16 H 26 N 2 O 2 and a molecular weight of 314.851. It was marketed as a local anesthetic in the 1930s and is used in dentistry, ophthalmology, etc. Dimethocaine hydrochloride (3 - (diethylamino) - 2,2 - dimethyl - 1 - propanol 4 - aminobenzoate hydrochloride) is a white crystalline powder with a solubility in water as high as 50%. Dimethocaine hydrochloride is commonly used as a local anesthetic and can also be used as a dopamine reuptake inhibitor (NDRIs), acting on the central nervous system.

[0003] The traditional preparation process of dimethocaine hydrochloride has high requirements for equipment, high material costs, and the purity of the prepared dimethocaine hydrochloride is poor with high impurity content, which is not conducive to improving drug safety. Therefore, it is urgent to develop a new preparation process of dimethocaine hydrochloride to solve the above problems. Summary of the Invention

[0004] In view of this, the present invention provides a preparation process of dimethocaine hydrochloride. By using the process of the present invention to prepare dimethocaine hydrochloride, the purity is high, the total impurity content is low, the impurity content is effectively reduced, and the drug safety is improved.

[0005] The technical solution of the present invention is realized as follows: A preparation process of dimethocaine hydrochloride, comprising the following steps:

[0006] (1) Preparation of intermediate EJK - 101

[0007] S1. Add intermediate EJK - 002, dichloromethane and triethylamine into a reaction vessel, and introduce an inert gas for protection; S2. Dropwise add a dichloromethane solution of p - nitrobenzoyl chloride at a temperature of 25 - 30 °C, react at a temperature of 25 - 30 °C for 8 - 16 h, and after purification, obtain intermediate EJK - 101; The intermediate EJK - 002 is 3 - (diethylamino) - 2,2 - dimethylpropanol.

[0008] (2) Preparation of intermediate EJK - 103

[0009] Mix the intermediate EJK-101, water and concentrated hydrochloric acid to prepare an EJK-101 solution with a pH value of 4-5; start stirring, and add water, iron powder, concentrated hydrochloric acid and 30%-40% of the total volume of the prepared EJK-101 solution respectively. Slowly heat up to 58-62 °C and then dropwise add the remaining EJK-101 solution. React at 64-70 °C for 8-16 h, and after purification, obtain the intermediate EJK-103;

[0010] (3) Preparation of 3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate hydrochloride

[0011] Add the intermediate EJK-103 and ethyl acetate into the reaction vessel, stir in an ice bath until EJK-103 dissolves, and slowly dropwise add a 1.0-1.5 mol / L hydrochloric acid ethyl acetate solution in an ice bath. After dropping into the mixed solution, the end point of the reaction is a pH value of 5-6 (that is, stop dropping the hydrochloric acid ethyl acetate solution when the pH value is 5-6). After dropping, continue to react for 1-2 h, filter by suction, and dry the suction filter cake to obtain the target product.

[0012] The optional concentrated hydrochloric acid mentioned above is 35-40 v / v% concentrated hydrochloric acid.

[0013] Further, in step (1), the molar ratio of EJK-002, p-nitrobenzoyl chloride, and triethylamine is 1:1.0-1.2:1.4-1.6;

[0014] In step (1) S1, the material ratio of EJK-002 to dichloromethane is 100-110 g:630-670 mL;

[0015] In step (1) S2, the material ratio of p-nitrobenzoyl chloride to dichloromethane is 130-140 g:580-620 mL.

[0016] Further, in step (1), the specific purification steps are as follows: monitor the end of the reaction by TLC, filter by suction to remove the solid triethylamine hydrochloride, wash the filter cake with dichloromethane, wash the organic phase with water, separate the liquid, concentrate the organic solvent under reduced pressure, and then add ethyl acetate and concentrate again; after dissolving the obtained solid in ethyl acetate, introduce hydrochloric acid gas dropwise at 0-5 °C. After the pH value reaches 1-3, continue to stir and react for 0.8-1.2 h, filter by suction to obtain a filter cake, wash the obtained filter cake with ethyl acetate, suction dry the filter cake, filter by suction, wash the obtained filter cake with ethyl acetate, suction dry, and dry the filter cake at 70-80 °C for 2-3 h to obtain the intermediate EJK-101.

[0017] Further, in step (2), the molar ratio of intermediate EJK-101 to iron powder is 1:5.0 - 5.2; the material ratio of EJK-101, water and concentrated hydrochloric acid in the EJK-101 solution is 150 - 160 g:680 - 720 mL:1.8 - 2.2 mL.

[0018] Further, in step (2), the specific purification steps are as follows: After the reaction is monitored by TLC and finished, filter while it is hot, wash the filter cake with hot water at 80 - 90 °C, extract the obtained aqueous phase with toluene, and separate the liquid; adjust the pH value of the aqueous phase to 10 - 11 with solid sodium carbonate, add ethyl acetate and stir until the material is dissolved clearly, filter, and rinse the filter residue with ethyl acetate; separate the obtained filtrate, extract the aqueous phase with ethyl acetate, combine the organic phases, wash the organic phase with water until the aqueous phase is neutral, and concentrate the obtained organic phase under reduced pressure to obtain intermediate EJK-103.

[0019] Further, in step (3), before adding the hydrochloric acid ethyl acetate solution, the material ratio of EJK-103 to ethyl acetate in the reaction vessel is 110 - 120 g:1000 - 1200 mL.

[0020] Further, in step (3), use ethyl acetate to wash during the filtration process; the drying temperature is 65 - 75 °C, and the drying time is 2 - 3 h.

[0021] Further, the preparation method of the intermediate EJK-002 includes the following steps: Add intermediate EJK-005 (3-(diethylamino)-2,2-dimethylpropanal), methanol and pure water into the reaction vessel according to the material ratio of 220 - 240 g:1000 - 1100 mL:330 - 350 mL, and start stirring; at 20 - 25 °C, slowly add NaBH 4 , the molar ratio of NaBH 4 to EJK-005 is 0.9 - 1.1:0.9 - 1.1, react at 25 - 40 °C for 1 - 2 h; monitor the reaction by TLC until it is finished; slowly add concentrated hydrochloric acid to the reaction system (the ratio of concentrated hydrochloric acid added to EJK-005 is 200 - 220 mL:220 - 240 g), adjust the pH value to 2 - 3, concentrate under reduced pressure, recover methanol, and extract the aqueous phase with ethyl acetate; then, adjust the pH value of the obtained aqueous phase to 10 - 11 with 10 - 30 wt% NaOH aqueous solution, extract with ethyl acetate, and dry the obtained ethyl acetate phase with anhydrous sodium sulfate; filter the obtained organic phase, concentrate under reduced pressure, and recover ethyl acetate to obtain intermediate EJK-002.

[0022] Further, the preparation method of the intermediate EJK-005 comprises the following steps: adding diethylamine and ethanol into a reaction vessel equipped with a condensation device, starting stirring, and purging with an inert gas for protection; dropping a formaldehyde solution (37%-40% wt) at 20-25°C, maintaining the reaction temperature at 25-40°C after the dropping is completed, stirring and reacting for 20-40 min, and then dropping isobutyraldehyde; stirring and reacting at 75-80°C for 9-10 h, monitoring the end of the reaction by TLC; concentrating under reduced pressure and recovering ethanol to obtain the intermediate EJK-005; furthermore, the molar ratio of diethylamine, formaldehyde, and isobutyraldehyde is 0.9-1.1:0.9-1.1:0.9-1.1; the feed ratio of diethylamine and ethanol is 200 g:1000-1100 mL.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] (1) When preparing dimethocaine hydrochloride by the process of the present invention, not only is the product yield high, but also the product purity is high, the total impurity content is low, and the maximum single impurity content is also low, greatly reducing the impurity content level and effectively improving the drug safety.

[0025] (2) When preparing the intermediate by the process of the present invention, the total impurity content is low, the number of impurity types is small, and the maximum single impurity content is low. New impurities are most likely to be avoided from being introduced during the preparation process, which is beneficial to the subsequent preparation of 3-(diethylamino)-2,2-dimethyl-1-propanol p-aminobenzoate hydrochloride and conducive to improving the quality of the target product dimethocaine hydrochloride.

[0026] (3) The preparation process of the present invention has low requirements for equipment, is easy to implement, the materials are easily available and the cost is low, the solvent can be recovered, it is environmentally friendly, and is conducive to large-scale production.

[0027] (4) On the premise of ensuring the product quality, the process of the present invention can fully recover the solvent, and the production cost can be reduced by about 60%. Description of the Drawings

[0028] Figure 1 Infrared spectrum of dimethocaine hydrochloride (EJK-102) prepared in Example 1.

[0029] Figure 2 Infrared spectrum of dimethocaine hydrochloride reference substance.

[0030] Figure 3 HPLC chart of dimethocaine hydrochloride prepared in Example 1. Detailed Embodiments

[0031] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0032] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0033] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can all be obtained from commercial channels.

[0034] The concentrated hydrochloric acid used in the embodiments of the present invention is commercially available concentrated hydrochloric acid, and the concentration of the concentrated hydrochloric acid is 37 v / v%.

[0035] Example 1

[0036] I. Process route:

[0037]

[0038] EJK-002: 3-(diethylamino)-2,2-dimethylpropanol

[0039] EJK-003: isobutyraldehyde

[0040] EJK-004: formaldehyde solution (37% content)

[0041] EJK-005: 3-(diethylamino)-2,2-dimethylpropanal

[0042] EJK-006: p-nitrobenzoyl chloride

[0043] EJK-101: 3-(diethylamino)-2,2-dimethyl-1-propyl p-nitrobenzoate

[0044] EJK-102: 3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate hydrochloride

[0045] EJK-103: 3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate

[0046] II. Process operation procedure

[0047] 1. Preparation of EJK-005 (3-(diethylamino)-2,2-dimethylpropanal)

[0048] Diethylamine (200.0 g, 2.73 mol, 1.0 eq) and ethanol (1000 mL) were added to a 2000 mL four-necked round-bottom flask equipped with a condensation device. Mechanical stirring was started, and an inert gas was passed for protection. Formaldehyde EJK-004 (222.0 g, 2.73 mol, 37% content, 1.0 eq) was added dropwise at 25 °C. The reaction temperature was maintained below 40 °C using an ice bath. After the addition was complete, the reaction temperature was maintained at 25 - 40 °C, and the reaction was stirred for 30 min. Then, isobutyraldehyde EJK-003 (197.0 g, 2.73 mol, 1.0 eq) was added dropwise. After the addition was complete, the reaction was stirred at 78 °C ± 2 °C for 9.5 - 10 h. The reaction was monitored by TLC. When no isobutyraldehyde was detected on the TLC, the reaction was completed. The reaction mixture was concentrated under reduced pressure at 40 °C for 5 h to recover ethanol, and a light yellow liquid product EJK-005 (378.4 g, purity 86.4%, yield 76%) was obtained.

[0049] 2. Preparation of EJK-002 (3-(diethylamino)-2,2-dimethylpropanol)

[0050] EJK-005 (230.0 g, 1.46 mol, 1.0 eq, purity 86.4%), methanol (1077 mL), and pure water (337 mL) were added to a 2000 mL four-necked reaction flask, and mechanical stirring was started. At 25 °C, NaBH 4 (54.5 g, 1.44 mol, 0.99 eq) was added slowly in small portions. The temperature was controlled at 25 - 40 °C using an ice bath. After the addition was complete, the reaction was carried out at 25 - 40 °C for 1 - 2 h. The reaction was monitored by TLC. When no starting material EJK-005 was detected in the reaction, the reaction was completed. Concentrated hydrochloric acid (about 210 mL) was slowly added to the reaction system to adjust the pH to 2 - 3. The reaction mixture was concentrated under reduced pressure at 45 °C to recover methanol. The aqueous phase was extracted once with ethyl acetate (350 mL). Then, the obtained aqueous phase was adjusted to pH = 10 - 11 with 20% aqueous NaOH solution and extracted three times with ethyl acetate (500 mL × 3). The obtained ethyl acetate phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure at 45 °C to recover ethyl acetate, and a colorless liquid product EJK-002 (175.0 g, purity 99.3%, yield 86.3%) was obtained.

[0051] 3. Preparation of EJK-101 (3-(diethylamino)-2,2-dimethyl-1-propyl p-nitrobenzoate)

[0052] Add EJK-002 (105.4 g, 0.66 mol, 1.0 eq, purity 99.3%), dichloromethane (650 mL) and triethylamine (97.5 g, 0.97 mol, 1.5 eq) into a 2 L three-neck reaction flask, and protect it by introducing an inert gas. Dropwise add a dichloromethane (600 mL) solution of p-nitrobenzoyl chloride EJK-006 (134.0 g, 0.72 mol, 1.1 eq) at 25 - 30 °C, and react at 25 - 30 °C for 8 - 12 h. Monitor the reaction by TLC. After the reaction is completed and there is no raw material EJK-002 left, filter off the solid triethylamine hydrochloride by suction. Wash the filter cake twice with dichloromethane (150 mL × 2). Wash the organic phase four times with water (350 - 500 mL × 4), separate the layers, concentrate the organic solvent under reduced pressure at 45 °C, then add ethyl acetate (250 mL) and concentrate again. Dissolve the obtained solid in ethyl acetate (1200 mL) in a 2 L three-neck flask, introduce hydrogen chloride gas dropwise at 0 - 5 °C. After the pH = 1 - 3, continue to stir and react for 1 h, filter by suction to obtain a filter cake. Wash the obtained filter cake twice with 250 mL of ethyl acetate each time, drain the filter cake, filter by suction to obtain a filter cake. Wash the obtained filter cake twice with 250 mL of ethyl acetate each time, drain, and dry the filter cake at 75 °C for 2 - 3 h to obtain a light yellow to white solid powder (192.0 g, purity 99.4%, yield 84.2%).

[0053] 4. Preparation of EJK-103 (3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate)

[0054] EJK-101 (156.0 g, 0.45 mol, 1.0 eq, purity 99.4%) was mixed with water (700 mL) and concentrated hydrochloric acid (2 mL) to prepare a mixed solution for later use. The pH of the mixed solution was 4 - 5. Stirring was started, and water (550 mL), iron powder (126.3 g, 2.26 mol, 5.0 eq), concentrated hydrochloric acid (12 mL) and 1 / 3 of the prepared EJK-101 solution were added to a 2 L three-necked reaction flask respectively. The temperature was slowly raised to 60 °C, and the remaining 2 / 3 of the EJK-101 solution was added dropwise. The reaction solution changed from gray to dark green, khaki to black. The reaction was maintained at 67 °C ± 3 °C for 8 - 12 h, and the reaction was monitored by TLC. There was no raw material EJK-101 on the TLC, the main spot was the product, and there were no other obvious impurity spots. The reaction ended. After the reaction ended, filtration was carried out while it was hot. The filter cake was washed several times with hot water (1500 mL) at 80 - 90 °C. The obtained aqueous phase was extracted once with toluene (200 mL), and the liquid was separated. The pH of the aqueous phase was adjusted to 10 - 11 with solid sodium carbonate, ethyl acetate (1000 mL) was added and stirred until the material was dissolved clearly, then filtered. The filter cake was rinsed several times with ethyl acetate (500 mL). The obtained filtrate was separated into phases. The aqueous phase was extracted twice with ethyl acetate (500 mL × 2). The organic phases were combined, and the organic phase was washed twice with 1000 mL of water until the aqueous phase was neutral. The obtained organic phase was concentrated under vacuum at 45 °C to obtain a light orange to white solid (115 g, purity 99.4%, yield 91.3%).

[0055] 5. Preparation of EJK-102 (3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate hydrochloride)

[0056] EJK-103 (115.0 g, 0.41 mol, purity 99.4%) and ethyl acetate (1100 mL) were added to a 2 L three-necked reaction flask. Stirring was carried out in an ice bath until EJK-103 was completely dissolved. A 1.0 mol / L hydrochloric acid ethyl acetate solution (about 450 mL, based on the reaction end point pH = 5 - 6) was slowly added dropwise in the ice bath. After the mixed solution was added dropwise, white solids began to precipitate. The more time passed, the more white solids precipitated. The reaction end point was between pH = 5 - 6. After the addition was complete, the reaction continued for 1 h, then filtered. The filter cake was washed twice with ethyl acetate (100 mL × 2). The dried filter cake after suction was broken up and dried at 70 °C for 2 - 3 h to obtain an off-white to white solid (127.0 g, purity 99.4%, yield 97.8%).

[0057] Table 1 Product inspection results

[0058]

[0059] In other embodiments,

[0060] In the preparation step of intermediate EJK-005, the molar ratio of diethylamine, formaldehyde, and isobutyraldehyde is 0.9 - 1.1:0.9 - 1.1:0.9 - 1.1; the feed ratio of diethylamine and ethanol is 200 g:1000 - 1100 mL;

[0061] In the preparation step of intermediate EJK-002, the molar ratio of EJK-005 and NaBH 4 is 0.9 - 1.1:0.9 - 1.1; the feed ratio of EJK-005, methanol, and pure water is 220 - 240 g:1000 - 1100 mL:330 - 350 mL; the feed ratio of EJK-005 and concentrated hydrochloric acid is 220 - 240 g:200 - 220 mL;

[0062] In the preparation step of intermediate EJK-101, the molar ratio of EJK-002, p-nitrobenzoyl chloride, and triethylamine is 1:1.0 - 1.2:1.4 - 1.6;

[0063] In the preparation step of intermediate EJK-103, the molar ratio of intermediate EJK-101 and iron powder is 1:5.0 - 5.2;

[0064] In the preparation step of product EJK-102, before dropping the hydrochloric acid ethyl acetate solution, the feed ratio of EJK-103 and ethyl acetate in the reaction flask is 110 - 120 g:1000 - 1200 mL; the concentration of the hydrochloric acid ethyl acetate solution is 1.0 - 1.5 mol / L;

[0065] Adjusting the amounts of reaction raw materials or reagents within the above ranges can achieve the purpose of the present invention.

[0066] Comparative Research Example 1

[0067] The main difference from Example 1 is that dichloromethane was replaced with an equal volume of chloroform and triethylamine was replaced with an equal molar amount of diethylamine during the preparation process of intermediate EJK-101.

[0068] The specific treatment is as follows: Add intermediate EJK-002, chloroform, and diethylamine to a 2 L three-necked reaction flask and protect it with an inert gas; dropwise add a chloroform solution of p-nitrobenzoyl chloride EJK-006 at 25 - 30 °C and react at 25 - 30 °C for 8 - 12 h. Other operations are the same as in Example 1. The purity of the reaction raw material intermediate EJK-002 is the same as in Example 1.

[0069] Table 2 Comparison of the purity, total impurities, and yield of intermediate EJK-101

[0070] This example Example 1 Purity of intermediate EJK-101 (HPLC) 87.1％ 99.4％ Total impurity content of intermediate EJK-101 (HPLC) 12.9％ 0.6％ Yield of intermediate EJK-101 67.84％ 84.2％

[0071] The results showed that the purity of the intermediate EJK-101 prepared in this example was 87.1% and the yield was 67.84%. Compared with Example 1 (purity 99.4%, yield 84.2%), its purity and yield decreased significantly. The total impurity content was 12.9%, the types of impurities increased significantly, and the impurity content level also increased significantly, which was 21.5 times that of Example 1, and was very unfavorable for the improvement of the quality of the subsequent target product.

[0072] Comparative Research Example 2

[0073] The difference from Example 1 was that iron powder was replaced by an equimolar amount of zinc powder in the preparation process of the intermediate EJK-103.

[0074] The specific treatment was as follows: EJK-101, water and concentrated hydrochloric acid were mixed to prepare a mixed solution for standby, and the pH of the mixed solution was 4-5. Start stirring, and add water, zinc powder, concentrated hydrochloric acid and 1 / 3 of the solution of standby EJK-101 into a 2L three-neck reaction flask respectively. Slowly heat up to 60 °C and dropwise add the remaining 2 / 3 of the EJK-101 solution. Other operations were the same as those in Example 1. The purity of the reaction raw material intermediate EJK-101 was the same as that in Example 1.

[0075] Table 3 Comparison of the purity, total impurities and yield of the intermediate EJK-103

[0076] This example Example 1 Purity of intermediate EJK-103 (HPLC) 89.7％ 99.0％ Total impurity content of intermediate EJK-103 (HPLC) 10.3％ 1.0％ Yield of intermediate EJK-103 82.6％ 91.3％

[0077] The results showed that the purity of the intermediate EJK-103 prepared in this example was 89.7%. The purity of the product EJK-103 in this example decreased significantly compared with Example 1 (99.0%). The total impurity content of the intermediate EJK-103 was 10.3% (about 10 times that of Example 1), the types of impurities increased significantly, and the impurity content level also increased significantly. The introduction of new impurities was not conducive to the preparation of 3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate hydrochloride subsequently and was not conducive to the improvement of the quality of the target product.

[0078] Comparative Research Example 3

[0079] The difference from Example 1 was that ethyl acetate was replaced by an equal volume of acetone in the preparation step of EJK-102 (3-(diethylamino)-2,2-dimethyl-1-propyl p-aminobenzoate hydrochloride).

[0080] The specific treatment was as follows: EJK-103 and acetone were added into a 2L three-neck reaction flask, and stirred in an ice bath until EJK-103 was completely dissolved. A dry 1.0 mol / L hydrochloric acid acetone solution was slowly added dropwise in the ice bath. Other operations were the same as those in Example 1. The purity of the reaction raw material intermediate EJK-103 was the same as that in Example 1.

[0081] Table 4 Comparison of the purity, total impurities and yield of the product EJK-102

[0082] This example Example 1 Purity of EJK-102 (HPLC) 91.5％ 99.4％ Total impurity content of EJK-102 (HPLC) 8.5％ 0.6％ Largest single impurity (HPLC) 2.4％ 0.4％ Yield of EJK-102 87.3％ 97.8％

[0083] The results show that the purity of the product prepared in this example is 91.5% and the yield is 87.3%. Compared with the product of Example 1 (purity 99.4%, yield 97.8%), both the purity and yield of the product in this example are significantly reduced. The total impurity content of the product in this example is 8.5%. Not only does the variety of impurities increase, but the impurity content also increases significantly. The total impurities are about 14 times that of Example 1, and the maximum single impurity is 6 times that of Example 1.

[0084] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A process for preparing dimethocaine hydrochloride, characterized in that: The following steps are involved: (1) Preparation of intermediate EJK-101 S1, adding intermediate EJK-002, dichloromethane and triethylamine into a reaction vessel, and introducing inert gas protection; S2, add a dichloromethane solution of p-nitrobenzoyl chloride dropwise at 25-30°C, react at 25-30°C for 8-16h, and purify to obtain the intermediate EJK-101; The intermediate EJK-002 is 3-(diethylamino)-2,2-dimethylpropanol; (2) Preparation of intermediate EJK-103 The intermediate EJK-101, water and concentrated hydrochloric acid are mixed to obtain an EJK-101 solution, the pH value of which is 4-5; stirring is started, and water, iron powder, concentrated hydrochloric acid and 30%-40% of the total volume of the EJK-101 solution are added respectively, and the remaining EJK-101 solution is added dropwise when the temperature rises to 58-62°C, and the reaction is carried out at 64-70°C for 8-16h, and the intermediate EJK-103 is obtained after purification; (3) Add the intermediate EJK-103 and ethyl acetate into a reaction vessel, stir under ice bath until EJK-103 is dissolved, add 1.0-1.5 mol / L hydrochloric acid ethyl acetate solution dropwise, stop adding when the pH value is 5-6, continue the reaction for 1-2 hours after the addition is completed, filter with suction, and dry the filter cake to obtain the target product; The intermediate EJK-101 is 3-(diethylamino)-2,2-dimethyl-1-propanol p-nitrobenzoate; The intermediate EJK-103 is 3-(diethylamino)-2,2-dimethyl-1-propanol p-aminobenzoate.

2. The process for preparing dimethocaine hydrochloride according to claim 1, characterized in that: In step (1), the molar ratio of EJK-002, p-nitrobenzoyl chloride, and triethylamine is 1: 1.0-1.2: 1.4-1.6; In step (1) S1, the ratio of EJK-002 to dichloromethane is 100-110 g: 630-670 mL; In step (1) S2, the solid-liquid ratio of p-nitrobenzoyl chloride to dichloromethane is 130-140 g: 580-620 mL.

3. The process for preparing dimethocaine hydrochloride according to claim 1 or 2, characterized in that: In step (1), the specific steps of purification are as follows: after the reaction is completed by monitoring by TLC, solid triethylamine hydrochloride is removed by suction, the filter cake is washed with dichloromethane, the organic phase is washed with water, the liquids are separated, the organic phase is concentrated under reduced pressure, and then ethyl acetate is added and concentrated again; After the obtained solid is dissolved in ethyl acetate, hydrochloric acid gas is added dropwise at 0-5°C. When the pH value reaches 1-3, the reaction is continued with stirring for 0.8-1.2h, and filtered to obtain a filter cake. The obtained filter cake is washed with ethyl acetate, the filter cake is dried, filtered, the obtained filter cake is washed with ethyl acetate, dried, and dried at 70-80°C for 2-3h to obtain the intermediate EJK-101.

4. The process for preparing dimethocaine hydrochloride according to claim 1, characterized in that: In step (2), the molar ratio of the intermediate EJK-101 to the iron powder is 1: 5.0-5.2; the material-liquid ratio of EJK-101, water and concentrated hydrochloric acid in the EJK-101 solution is 150-160 g: 680-720 mL: 1.8-2.2 mL.

5. The process for preparing dimethocaine hydrochloride according to claim 1 or 4, characterized in that: In step (2), the specific purification steps are as follows: filtering while hot after the reaction is completed as monitored by TLC, washing the filter cake with hot water at 80-90° C., extracting the obtained aqueous phase with toluene, and separating the liquids; adjusting the pH value of the aqueous phase to 10-11 with solid sodium carbonate, adding ethyl acetate and stirring to dissolve the material, filtering with suction, rinsing the filter cake with ethyl acetate; separating the obtained filtrate, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing the organic phases with water until the aqueous phase is neutral, and concentrating the obtained organic phase under reduced pressure to obtain the intermediate EJK-103.

6. The process for preparing dimethocaine hydrochloride according to claim 1, characterized in that: Step (3), before the hydrochloric acid ethyl acetate solution is added dropwise, the material-liquid ratio of EJK-103 to ethyl acetate in the reaction container is 110-120 g: 1000-1200 mL.

7. The process for preparing dimethocaine hydrochloride according to claim 1 or 6, characterized in that: In step (3), ethyl acetate is used for washing during the filtration process; the drying temperature is 65-75° C. and the drying time is 2-3 hours.

8. The process for preparing dimethocaine hydrochloride according to claim 1, characterized in that: The preparation method of the intermediate EJK-002 comprises the following steps: adding the intermediate EJK-005, methanol and pure water into a reaction container at a material-liquid ratio of 220-240 g: 1000-1100 mL: 330-350 mL, and starting stirring; adding NaBH4 at 20-25° C., wherein the molar ratio of NaBH4 to EJK-005 is 0.9-1.1: 0.9-1.1, and reacting at 25-40° C. for 1-2 hours; monitoring the reaction by TLC until the reaction is complete; adding concentrated hydrochloric acid to the reaction system, adjusting the pH value to 2-3, concentrating under reduced pressure, recovering methanol, and extracting the aqueous phase with ethyl acetate; then, adjusting the pH value of the obtained aqueous phase to 10-11 with a 10-30wt% NaOH aqueous solution, extracting with ethyl acetate, and drying the obtained ethyl acetate phase with anhydrous sodium sulfate; concentrating the obtained organic phase after suction filtration under reduced pressure, recovering ethyl acetate, and obtaining the intermediate EJK-002; The intermediate EJK-005 is 3-(diethylamino)-2,2-dimethylpropanal.

9. The process for preparing dimethocaine hydrochloride according to claim 8, characterized in that: The preparation method of the intermediate EJK-005 comprises the following steps: adding diethylamine and ethanol into a reaction container with a condensing device, starting stirring, and passing inert gas protection; adding formaldehyde solution dropwise at 20-25° C., stirring and reacting at 25-40° C. for 20-40 min, and then adding isobutyraldehyde dropwise; stirring and reacting at 75-80° C. for 9-10 h, and monitoring the completion of the reaction by TLC; and concentrating under reduced pressure to recover ethanol to obtain the intermediate EJK-005.

10. The process for preparing dimethocaine hydrochloride according to claim 9, characterized in that: The molar ratio of diethylamine, formaldehyde and isobutyraldehyde is 0.9-1.1: 0.9-1.1: 0.9-1.1; The solid-liquid ratio of the diethylamine and ethanol is 200g:1000-1100mL.

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