Efficient preparation method of tetracaine

Abstract

The invention discloses an efficient preparation method of tetracaine, which comprises the following steps: 1, reacting para aminobenzoic acid, 1-bromobutane and triethylamine, concentrating under reduced pressure, adding an organic solvent and water, performing hot extraction and liquid separation, cooling an organic phase to separate out a solid, adding an acidic aqueous solution, cooling to crystallize, filtering and drying to obtain 4-butyl aminobenzoic acid butyl ester; 2, 4-butylaminobenzoic acid butyl ester, water, alcohol and sodium hydroxide are subjected to a reaction; decompressing and concentrating to remove the solvent, adding water for dissolving, acidifying with hydrochloric acid to separate out a solid, filtering and drying to obtain 4-butylaminobenzoic acid; 3, 4-butylaminobenzoic acid, N, N-dimethylethanolamine, a condensing agent or a hydroxyl activating agent and a reaction organic solvent react; adding an alkaline aqueous solution for washing and liquid separation, carrying out vacuum concentration on an organic phase, adding a refining solvent into a concentrate, heating, adsorbing with activated carbon, cooling for crystallization, filtering and drying to obtain a tetracaine finished product; the reaction temperature can be reduced, and the energy consumption is low; and the obtained product has high purity and high yield.

Description

Technical Field

[0001] The present invention relates to a method for efficiently preparing tetracaine, belonging to the technical field of pharmaceutical chemical synthesis. Background Art

[0002] Tetracaine is a local anesthetic, chemically named 2-(dimethylamino)ethyl 4-(butylamino)benzoate, a white crystalline powder with the molecular formula C 15 H 24 N2O2, which is usually used to relieve the pain of the skin and mucous membranes. By blocking the conduction of nerve endings and reducing the transmission of pain signals, the effect of local anesthesia can be achieved.

[0003] As a long-acting local anesthetic, the existing synthesis processes of tetracaine have long-term technical bottlenecks:

[0004] 1) When introducing a butyl group onto the amino group, most methods use butyraldehyde reductive amination or nucleophilic substitution reaction with 1-bromobutane. When using butyraldehyde reductive amination, H2 and palladium-carbon reduction are required, resulting in high costs and certain safety risks; when using 1-bromobutane for nucleophilic substitution reaction, high temperatures (90 - 110 °C) are mostly used, and a large amount of disubstituted impurities and other impurities will be generated at high temperatures. At the same time, without a good refining method, a large amount of the product will be lost while removing impurities, leading to a decrease in the yield.

[0005] 2) When coupling N,N-dimethylethanolamine, most methods use transesterification or reflux dehydration under alkaline conditions. This reaction is a reversible reaction, and a large amount of raw materials will remain. To promote the reaction, high temperature conditions (110 °C - 150 °C) and a long reaction time are often required. At high temperatures, impurities such as dealkylated products and colored aniline compounds are easily generated in the reaction system, and subsequent complex refining operations are needed to meet the quality requirements. The energy consumption is high while the desired yield and purity cannot be obtained.

[0006] For example, in a method for preparing a high-purity tetracaine raw material drug with the publication number CN116444387A, p-aminobenzoic acid is used as the starting material, reacted with n-butyl bromide in an acid-binding agent to prepare p-butylaminobenzoic acid, then reacted with N,N-dimethylethanolamine under alkali catalysis, extracted with dichloromethane, and then prepared into tetracaine hydrochloride by salification with hydrochloric acid. Finally, it is dissociated with triethylamine in an organic solvent dichloromethane to obtain the tetracaine finished product. During the reaction process, high temperatures (90 - 100 °C) need to be controlled, the conditions are harsh, which is not conducive to large-scale production; the refining process uses salification and free removal of impurities, and the process is cumbersome; the yield of the first step is about 70%, and the total yield is about 50%, with a relatively low yield.

[0007] For example, a method for synthesizing tetracaine, published in CN116924924A, uses N-Boc-4-aminobenzoic acid as a raw material, which is reacted with n-butane bromide in a heat-insulated manner to produce N-Boc-N-butyl-4-aminobenzoic acid butyl ester. The Boc group of N-Boc-N-butyl-4-aminobenzoic acid butyl ester is then removed in the presence of a weak acid to produce N-butyl-4-aminobenzoic acid butyl ester. The N-butyl-4-aminobenzoic acid butyl ester is then reacted with N,N-dimethylethanolamine to produce tetracaine. This process uses N-Boc-4-aminobenzoic acid as the starting material, which is expensive and difficult to obtain. The subsequent removal of the Boc protection leads to low atom utilization, a cumbersome process, and is not conducive to scale-up production.

[0008] For example, in the paper "Improved Synthesis of Tetracaine Hydrochloride," Li Wenli et al. used ethyl p-aminobenzoate to prepare 4-butylaminobenzoic acid. N,N-dimethylethanolamine reacted with thionyl chloride to produce N,N-dimethylchloroethylamine hydrochloride. This reaction was then refluxed under alkaline conditions (116°C) for docking, post-processing, and salt formation to obtain tetracaine hydrochloride. This process used thionyl chloride, making scale-up unsuitable for both equipment and the environment. The docking reaction required high reaction temperatures, the post-processing salt formation step was lengthy, and the purified salt had a low purity (99.34%).

[0009] For example, the preparation method of tetracaine hydrochloride, disclosed in publication number CN109761835B, comprises a first step of reacting para-aminobenzoic acid with n-butyraldehyde, a second step of reacting the product of the first step with N,N-dimethylethanolamine, and a third step of salt formation to obtain tetracaine hydrochloride. The first step of this process uses palladium-catalyzed pressurized hydrogenation, which is costly and poses certain safety risks, making it unsuitable for scale-up production. The second step uses a reflux temperature (135°C ± 2°C), which is harsh and unfavorable for scale-up production. Summary of the Invention

[0010] In order to solve the above technical problems, the present invention provides an efficient preparation method of tetracaine, which has cheap and readily available raw materials and low cost; can reduce the reaction temperature of each step and has low energy consumption; and the obtained product has high purity and high yield.

[0011] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0012] An efficient preparation method of tetracaine comprises the following steps:

[0013] Step 1: reacting p-aminobenzoic acid, 1-bromobutane, and triethylamine; after concentrating under reduced pressure, adding an organic solvent and water, and hot extraction to obtain an organic phase; cooling the organic phase to precipitate a solid, adding an acidic aqueous solution, and continuing to cool and crystallize, filtering, and drying to obtain 4-butylaminobenzoic acid butyl ester;

[0014] Step 2: Butyl 4-butylaminobenzoate, water, alcohol and sodium hydroxide are reacted; the solvent is concentrated until no liquid flows out basically, water is added for dissolution, and the solid is precipitated by acidification with hydrochloric acid, filtered, and dried to obtain 4-butylaminobenzoic acid;

[0015] Step 3: 4-Butylaminobenzoic acid, N,N-dimethylethanolamine, a condensing agent or a hydroxyl activating agent and a reaction organic solvent are reacted; an alkaline aqueous solution is added for washing and liquid separation, the organic phase is concentrated under reduced pressure, a refining solvent is added to the concentrate, the temperature is raised, activated carbon is adsorbed, filtered, the temperature is lowered for crystallization, filtered, and dried to obtain the finished product of tetracaine.

[0016] A further improvement of the technical solution of the present invention lies in that: in the step one, the molar ratio of p-aminobenzoic acid, 1-bromobutane and triethylamine is 1:4-10:2-6, the reaction temperature is 65°C - 85°C, and the reaction time is 2h - 10h.

[0017] A further improvement of the technical solution of the present invention lies in that: the organic solvent added in the extraction process of the step one is n-heptane, hexane or petroleum ether, the mass ratio of the added amount to the mass of p-aminobenzoic acid is 2-6:1, and the extraction temperature is 40°C - 80°C.

[0018] A further improvement of the technical solution of the present invention lies in that: the acidic aqueous solution added in the process of cooling and crystallization in the step one is hydrochloric acid aqueous solution, sulfuric acid aqueous solution or phosphoric acid aqueous solution, the concentration is 0.01mol / L - 2mol / L, the dosage ratio to the mass of p-aminobenzoic acid is 1-5:1, and the temperature is further lowered to 0°C - 20°C for crystallization.

[0019] A further improvement of the technical solution of the present invention lies in that: the alcohol in the step two is methanol, ethanol or isopropanol, the molar volume ratio of butyl 4-butylaminobenzoate, water, alcohol and sodium hydroxide is 1mol:400ml - 1500ml:400ml - 1500ml:1.3mol - 3mol, the reaction temperature is 40°C - 80°C, and the reaction time is 2h - 10h.

[0020] A further improvement of the technical solution of the present invention lies in that: the volume of water added after concentration in the step two is in a mass ratio of 4mL - 15mL:1g to the mass of butyl 4-butylaminobenzoate; in the process of acidification with hydrochloric acid, concentrated hydrochloric acid is added dropwise to adjust the pH of the system < 4.

[0021] A further improvement of the technical solution of the present invention lies in that: the condensing agent in the step three is TBTU or CDI; the hydroxyl activating agent is TsCl or MsCl; the molar ratio of 4-butylaminobenzoic acid, N,N-dimethylethanolamine, the condensing agent or the hydroxyl activating agent is 1:0.9 - 3:0.9 - 3.

[0022] A further improvement of the technical solution of the present invention is that: in step 3, the organic solvent is dichloromethane, chloroform, ethyl acetate, isopropyl acetate or methyl isobutyl ketone, the volume to 4-butylaminobenzoic acid mass ratio is 4-15 ml: 1 g, the reaction temperature is 30-80 ° C, and the reaction time is 3h-16h.

[0023] A further improvement of the technical solution of the present invention is that: the alkaline aqueous solution in step three is an aqueous solution of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, with a concentration of 5%-15%, and the added volume to 4-butylaminobenzoic acid mass ratio is 4mL-10mL:1g.

[0024] A further improvement of the technical solution of the present invention is that: in the step 3, the refining solvent is n-heptane, hexane or petroleum ether, and the mass ratio of the refining solvent to 4-butylaminobenzoic acid is 5-10:1; the temperature is raised to 40°C-70°C; the amount of activated carbon added is 0.03-0.15:1 in the mass ratio of the activated carbon to 4-butylaminobenzoic acid, and the adsorption is carried out for 1-3 hours; the temperature is lowered to 0°C-20°C for crystallization.

[0025] Due to the adoption of the above technical solution, the technical advancements achieved by the present invention are:

[0026] The raw materials of the invention are cheap and readily available, and the cost is low; the reaction temperature of each step can be reduced, and the energy consumption is low; and the obtained product has high purity and high yield.

[0027] The reaction of p-aminobenzoic acid with 1-bromobutane adopts a reaction temperature of 65° C.-85° C., thereby ensuring complete reaction and significantly reducing the generation of disubstituted by-products, thereby improving the effective conversion rate. Post-treatment adopts organic solvent / acid water mixed crystallization, thereby effectively removing unsubstituted by-products and disubstituted by-product impurities on the amino group, and the obtained 4-butylaminobenzoic acid butyl ester has good purity and high yield.

[0028] The present invention adopts a method of adding a condensing agent or a hydroxyl activating agent to dock N,N-dimethylethanolamine, thereby achieving a full reaction at a relatively low temperature, avoiding the generation of excessive raw material residue during the esterification or transesterification reaction at a low temperature and the generation of impurities and color at a high temperature, which requires subsequent complex refining operations to meet quality requirements; post-processing only requires simple alkali washing and crystallization to meet quality requirements, with low energy consumption, low labor cost, small material loss, simple process operation, and suitability for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 It is a liquid chromatogram of the detection of the tetracaine finished product in Example 1 of the present invention. DETAILED DESCRIPTION

[0030] The present invention is described in further detail below in conjunction with the embodiments:

[0031] The present invention is a highly efficient method for preparing tetracaine, and the specific steps are as follows:

[0032] (1) Step 1

[0033] The molar ratio of p-aminobenzoic acid, 1-bromobutane and triethylamine is 1:4-10:2-6, and the reaction is carried out at 65°C-85°C for 2h-10h; after decompression concentration until almost no liquid flows out, an organic solvent and water are added, and hot extraction and separation are carried out at 40°C-80°C to obtain an organic phase, wherein the organic solvent is n-heptane, hexane or petroleum ether, and the mass ratio of the added organic solvent to the mass of p-aminobenzoic acid is 2-6:1; after the organic phase is cooled to precipitate a solid, a hydrochloric acid aqueous solution, a sulfuric acid aqueous solution or a phosphoric acid aqueous solution (acidic aqueous solution) with a concentration of 0.01-2mol / L is added, and the temperature is continuously lowered to 0°C-20°C for crystallization, and the mass ratio of the acidic aqueous solution to p-aminobenzoic acid is 1-5:1. The organic phase is filtered and dried to obtain 4-butylaminobenzoic acid butyl ester.

[0034] (2) Step 2

[0035] The molar volume ratio of butyl 4-butylaminobenzoate, water, alcohol and sodium hydroxide is 1 mol: 400 mL-1500 mL: 400 mL-1500 mL: 1.3 mol-3 mol, and the reaction is carried out at 40° C.-80° C. for 2 h-10 h; the solvent is concentrated under reduced pressure until almost no liquid flows out, water is added to dissolve the solution, and the mass ratio of water volume to butyl 4-butylaminobenzoate is 4 mL-15 mL: 1 g; concentrated hydrochloric acid is added dropwise to adjust the pH of the system to less than 4, and the solid is acidified to precipitate, which is filtered and dried to obtain 4-butylaminobenzoic acid.

[0036] (3) Step 3

[0037] 4-Butylaminobenzoic acid, N,N-dimethylethanolamine, a condensing agent or a hydroxyl activating agent and a reaction organic solvent are reacted at 30-80° C. for 3 h-16 h, wherein the condensing agent is TBTU or CDI; the hydroxyl activating agent is TsCl or MsCl; the molar ratio of 4-Butylaminobenzoic acid, N,N-dimethylethanolamine, and the condensing agent or hydroxyl activating agent is 1:0.9-3:0.9-3; the organic solvent is dichloromethane, chloroform, ethyl acetate, isopropyl acetate or methyl isobutyl ketone, and the volume ratio to the mass ratio of 4-Butylaminobenzoic acid is 4-15 m l:1g; adding a 5%-15% aqueous solution of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide at a volume to 4-butylaminobenzoic acid mass ratio of 4mL-10mL:1g, washing and separating the liquid, concentrating the organic phase under reduced pressure until substantially no liquid flows out, adding a refined solvent of n-heptane, hexane or petroleum ether to the concentrate, raising the temperature to 40°C-70°C, adding activated carbon at a mass ratio of 0.03-0.15:1 to 4-butylaminobenzoic acid, and adsorbing for 1-3 hours, filtering, cooling to 0°C-20°C for crystallization, filtering, and drying to obtain a tetracaine product.

[0038] The synthetic route is as follows:

[0039]

[0040] Example 1:

[0041] (1) Step 1

[0042] Add 600.0 g (5 eq) of 1-bromobutane, 120.0 g (1 eq) of p-aminobenzoic acid, and 265.6 g (3 eq) of triethylamine to the reactor. Start stirring and heat up to 80 °C for reaction for 3 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out. After concentration, add 480.0 g (4 M) of n-heptane and 360.0 g (3 M) of water, stir and wash at 50 °C, separate the liquid, and retain the organic phase. After the organic phase cools down and precipitates solids, add 180.0 g (1.5 M) of 0.05 mol / L hydrochloric acid aqueous solution, continue to cool down to 5 °C for crystallization, filter by suction, and dry to obtain 181.6 g of white solid butyl 4-butylaminobenzoate, with a yield of 83.2%.

[0043] (2) Step 2

[0044] Add 1080 mL (6 V) of water, 57.8 g (2 eq) of sodium hydroxide, 720 mL (4.0 V) of ethanol, and 180.0 g (1 eq) of butyl 4-butylaminobenzoate to the reactor. Heat up to 65 °C for reaction for 5 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out, add 1080 mL of water and stir to dissolve, dropwise add concentrated hydrochloric acid to adjust the pH of the system to < 4, filter by suction, and dry to obtain 138.1 g of white solid p-aminobenzoic acid, with a yield of 99.0%.

[0045] (3) Step 3

[0046] Add 135.0 g (1.0 eq) of p-aminobenzoic acid, 81.0 g (1.3 eq) of N,N-dimethylethanolamine, 1.35 L (10 V) of dichloromethane to the reactor, add 269.2 g (1.2 eq) of TBTU, and heat up to 35 °C for reaction for 6 h. After the reaction is completed, add 800 mL of 5% sodium carbonate aqueous solution for washing, separate the liquid and retain the organic phase. Concentrate the organic phase under reduced pressure until almost no liquid flows out. Add 1080.0 g of n-heptane to the concentrate, heat up to 50 °C, add 10.0 g of activated carbon for adsorption for 2 h, filter while hot, cool the filtrate to 5 °C for crystallization, filter, and dry to obtain 157.5 g of white crystalline solid tetracaine finished product, with a yield of 85.3%.

[0047] The total yield of the three steps is 70.3%; the related substances of the above tetracaine finished product are determined by high performance liquid chromatography, and the liquid chromatogram is as Figure 1 , and the purity is 99.945%.

[0048] Example 2:

[0049] (1) Step 1

[0050] Add 699.4 g (7 eq) of 1-bromobutane, 100.0 g (1 eq) of 4-aminobenzoic acid, and 184.5 g (2.5 eq) of triethylamine to the reactor. Start stirring and heat up to 70 °C for reaction for 8 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out. After concentration, add hexane (6 M) and 300.0 g (3 M) of water, stir and wash at 65 °C, separate the liquid, and retain the organic phase. After the organic phase cools down and precipitates solids, add 300.0 g (3 M) of 0.01 mol / L sulfuric acid aqueous solution, continue to cool down to 5 °C for crystallization, filter by suction, and dry to obtain 148.4 g of white solid butyl 4-butylaminobenzoate, with a yield of 81.6%.

[0051] (2) Step 2

[0052] Add 1168 mL (8 V) of water, 70.3 g (3 eq) of sodium hydroxide, 876 mL (6.0 V) of ethanol, and 146.0 g (1 eq) of butyl 4-butylaminobenzoate to the reactor. Heat up to 75 °C for reaction for 3 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out, add 2190 mL of water and stir to dissolve, dropwise add concentrated hydrochloric acid to adjust the pH of the system < 4, filter by suction, and dry to obtain 111.6 g of white solid 4-butylaminobenzoic acid, with a yield of 98.6%.

[0053] (3) Step 3

[0054] Add 110.0 g (1.0 eq) of 4-butylaminobenzoic acid, 152.2 g (3 eq) of N,N-dimethylethanolamine, and 880 mL (8 V) of methyl isobutyl ketone to the reactor. Add 108.5 g (1.0 eq) of TsCl in batches, heat up to 60 °C for reaction for 8 h. After the reaction is completed, add 550 mL of 15% potassium carbonate aqueous solution for washing, separate the liquid and retain the organic phase. Concentrate the organic phase under reduced pressure until almost no liquid flows out. Add 770.0 g (7 M) of n-heptane to the concentrate, heat up to 40 °C, add 11.0 g of activated carbon for adsorption for 2 h, filter while hot, cool the filtrate to 5 °C for crystallization, filter, and dry to obtain 132.7 g of white crystalline solid tetracaine finished product, with a yield of 88.2%.

[0055] The total yield of the three steps is 71.0%; the related substances of the above tetracaine finished product are determined by high performance liquid chromatography, and the purity is 99.976%.

[0056] Example 3:

[0057] (1) Step 1

[0058] Add 699.4 g (10 eq) of 1-bromobutane, 70.0 g (1 eq) of p-aminobenzoic acid, and 309.9 g (6 eq) of triethylamine to the reactor. Start stirring and heat up to 65 °C for reaction for 10 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out. After concentration, add 420.0 g (6 M) of petroleum ether and 210.0 g (3 M) of water, stir and wash at 60 °C, separate the liquid, and retain the organic phase. After the organic phase cools down and precipitates solids, add 140.0 g (2 M) of 0.05 mol / L hydrochloric acid aqueous solution, continue to cool down to 5 °C for crystallization, filter by suction, and dry to obtain 100.7 g of white solid butyl 4-butylaminobenzoate, with a yield of 79.1%.

[0059] (2) Step 2

[0060] Add 600 mL (6 V) of water, 48.1 g (3 eq) of sodium hydroxide, 500 mL (5 V) of ethanol, and 100.0 g (1 eq) of butyl 4-butylaminobenzoate to the reactor. Heat up to 50 °C for reaction for 8 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out, add 1000 mL of water and stir to dissolve, add concentrated hydrochloric acid dropwise to adjust the pH of the system < 4, filter by suction, and dry to obtain 77.2 g of white solid 4-butylaminobenzoic acid, with a yield of 99.6%.

[0061] (3) Step 3

[0062] Add 70.0 g (1.0 eq) of 4-butylaminobenzoic acid, 64.6 g (2 eq) of N,N-dimethylethanolamine, and 700 mL (10 V) of ethyl acetate to the reactor. Add 88.1 g (1.5 eq) of CDI in batches, heat up to 70 °C for reaction for 16 h. After the reaction is completed, add 700 mL of 5% sodium carbonate aqueous solution for washing, separate the liquid, and retain the organic phase. Concentrate the organic phase under reduced pressure until almost no liquid flows out. Add 945.0 g (6 M) of n-heptane to the concentrate, heat up to 60 °C, add 10.0 g of activated carbon for adsorption for 2 h, filter while hot, cool the filtrate to 5 °C for crystallization, filter, and dry to obtain 81.1 g of white crystalline solid tetracaine product, with a yield of 84.7%.

[0063] The total yield of the three steps is 66.7%; the related substances of the above tetracaine product are determined by high performance liquid chromatography, and the purity is 99.921%.

[0064] Example 4:

[0065] (1) Step 1

[0066] Add 524.5 g (5 eq) of 1-bromobutane, 105.0 g (1 eq) of p-aminobenzoic acid, and 306.9 g (4 eq) of triethylamine to the reactor. Start stirring and heat up to 80 °C for reaction for 6 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out. After concentration, add 420.0 g (4 M) of n-heptane and 315.0 g (3 M) of water, stir and wash at 50 °C, separate the liquid, and retain the organic phase. After the solid precipitates out when the organic phase cools down, add 157.5 g (1.5 M) of 1 mol / L hydrochloric acid aqueous solution, continue to cool down to 15 °C for crystallization, filter by suction, and dry to obtain 156.4 g of white solid butyl 4-butylaminobenzoate, with a yield of 81.9%.

[0067] (2) Step two

[0068] Add 1500 mL (10 V) of water, 72.2 g (3 eq) of sodium hydroxide, 1500 mL (10 V) of ethanol, and 150.0 g (1 eq) of butyl 4-butylaminobenzoate to the reactor. Heat up to 65 °C for reaction for 4 h. After the reaction is completed, concentrate under reduced pressure until almost no liquid flows out, add 1500 mL (10 V) of water and stir to dissolve, dropwise add concentrated hydrochloric acid to adjust the pH of the system to < 4, filter by suction, and dry to obtain 114.6 g of white solid p-aminobenzoic acid, with a yield of 98.6%.

[0069] (3) Step three

[0070] Add 110.0 g (1 eq) of p-aminobenzoic acid, 101.5 g (2.0 eq) of N,N-dimethylethanolamine, 1.1 L (10 V) of dichloromethane to the reactor, add 365.5 g (2.0 eq) of TBTU, heat up to 30 °C for reaction for 7 h. After the reaction is completed, add 880 mL (8 V) of 10% sodium carbonate aqueous solution for washing, separate the liquid and retain the organic phase. Concentrate the organic phase under reduced pressure until almost no liquid flows out. Add 770.0 g (7 M) of n-heptane to the concentrate, heat up to 70 °C, add 11.0 g (0.1 M) of activated carbon for adsorption for 1 h, filter while it is hot, cool the filtrate to 10 °C for crystallization, filter, and dry to obtain 127.5 g of white crystalline solid tetracaine finished product, with a yield of 84.7%.

[0071] The total yield of the three steps is 68.4%; the related substances of the above tetracaine finished product are determined by high performance liquid chromatography, and the purity is 99.952%.

[0072] Example 5:

[0073] Add 239.8 g (6 eq) of 1-bromobutane, 40.0 g (1 eq) of 4-aminobenzoic acid, and 118.1 g (4 eq) of triethylamine to the reactor. Start stirring and heat up to 70 °C for reaction for 10 h. After the reaction is completed, concentrate under reduced pressure until basically no liquid flows out. After concentration, add 240.0 g (6 M) of n-heptane and 120.0 g (3 M) of water, stir and wash at 70 °C, separate the liquid, and retain the organic phase. After the organic phase cools down and precipitates solids, add 120.0 g (3 M) of 0.05 mol / L hydrochloric acid aqueous solution, continue to cool down to 0 °C for crystallization, filter by suction, and dry to obtain 61.2 g of white solid butyl 4-butylaminobenzoate, with a yield of 84.2%.

[0074] (2) Step two

[0075] Add 600 mL (10 V) of water, 28.9 g (3 eq) of sodium hydroxide, 600 mL (10 V) of ethanol, and 60.0 g (1 eq) of butyl 4-butylaminobenzoate to the reactor. Heat up to 65 °C for reaction for 6 h. After the reaction is completed, concentrate under reduced pressure until basically no liquid flows out, add 480 mL (8 V) of water and stir to dissolve, dropwise add concentrated hydrochloric acid to adjust the pH of the system < 4, filter by suction, and dry to obtain 46.2 g of white solid 4-aminobenzoic acid, with a yield of 99.3%.

[0076] (3) Step three

[0077] Add 41.0 g (1 eq) of 4-aminobenzoic acid, 56.7 g (3 eq) of N,N-dimethylethanolamine, 410 mL (10 V) of dichloromethane to the reactor, add 143.05 g (2.1 eq) of TBTU, heat up to 35 °C for reaction for 3 h. After the reaction is completed, add 410 mL (10 V) of 10% potassium carbonate aqueous solution for washing, separate the liquid and retain the organic phase. Concentrate the organic phase under reduced pressure until basically no liquid flows out. Add 287.0 g (7 M) of n-heptane to the concentrate, heat up to 50 °C, add 1.23 g (0.03 M) of activated carbon for adsorption for 3 h, filter while it is hot, cool the filtrate to 0 °C for crystallization, filter, and dry to obtain 48.9 g of white crystalline solid tetracaine finished product, with a yield of 87.2%.

[0078] The total yield of the three steps is 72.9%; the related substances of the above-mentioned tetracaine finished product are determined by high performance liquid chromatography, and the purity is 99.893%.

[0079] Comparative example 1:

[0080] The difference between this comparative example and Example 1 is that the reaction temperature in Step 1 is higher, that is: after adding 1-bromobutane, 4-aminobenzoic acid, and triethylamine to the reactor, heat up to 100 °C for reaction for 3 h; the remaining steps remain unchanged.

[0081] In Step 1, 141.2 g of white solid butyl 4-butylaminobenzoate was obtained, with a yield of 64.7%.

[0082] The remaining steps (including Step 2 and Step 3) remained unchanged, and the final test results were not much different from those in Step 1.

[0083] Comparative Example 2:

[0084] The difference between this comparative example and Example 1 was that the reaction temperature in Step 1 was lower, that is, after adding 1-bromobutane, p-aminobenzoic acid and triethylamine into the reactor, the temperature was raised to 50 °C and reacted for 3 h; the remaining steps remained unchanged.

[0085] In Step 1, 78.8 g of white solid butyl 4-butylaminobenzoate was obtained, with a yield of 36.1%.

[0086] The remaining steps (including Step 2 and Step 3) remained unchanged, and the final test results were not much different from those in Step 1.

[0087] Comparative Example 3:

[0088] The difference between this comparative example and Example 1 was that in Step 1, organic solvent / acid water mixed crystallization was not used, and direct cooling crystallization was carried out, that is, the organic phase was cooled to 5 °C for crystallization, filtered by suction, and dried; the remaining steps (including Step 1, Step 2 and Step 3) remained unchanged.

[0089] In Step 1, 185.0 g of white solid butyl 4-butylaminobenzoate was obtained, with a yield of 84.8%;

[0090] In Step 2, 137.5 g of brown-yellow solid 4-butylaminobenzoic acid was obtained, with a yield of 98.6%;

[0091] In Step 3, 154.0 g of yellow solid tetracaine finished product was obtained, with a yield of 83.4%, and the color was poor, making it difficult to meet the requirements of the bulk drug.

Claims

1. A highly efficient preparation method of tetracaine, characterized in that It includes the following steps: Step 1: React p-aminobenzoic acid, 1-bromobutane and triethylamine; after concentration under reduced pressure, add an organic solvent and water, perform thermal extraction and liquid separation to obtain an organic phase; after the organic phase cools and precipitates solids, add an acidic aqueous solution and continue to cool and crystallize, filter, and dry to obtain butyl 4-butylaminobenzoate; Step 2: React butyl 4-butylaminobenzoate, water, alcohol and sodium hydroxide; concentrate the solvent until there is basically no liquid flowing out, add water to dissolve, acidify with hydrochloric acid to precipitate solids, filter, and dry to obtain 4-butylaminobenzoic acid; Step 3: React 4-butylaminobenzoic acid, N,N-dimethylethanolamine, a condensing agent or a hydroxyl activating agent and a reaction organic solvent; add an alkaline aqueous solution for washing and liquid separation, concentrate the organic phase under reduced pressure, add a refining solvent to the concentrate, raise the temperature, adsorb with activated carbon, filter, cool and crystallize, filter, and dry to obtain the finished product of tetracaine.

2. The highly efficient preparation method of tetracaine according to claim 1, characterized in that: In Step 1, the molar ratio of p-aminobenzoic acid, 1-bromobutane and triethylamine is 1:4-10:2-6, the reaction temperature is 65°C-85°C, and the reaction time is 2h-10h.

3. The highly efficient preparation method of tetracaine according to claim 1, wherein: In the extraction process of Step 1, the organic solvent added is n-heptane, hexane or petroleum ether, and the mass ratio of the added amount to the mass of p-aminobenzoic acid is 2-6:1, and the extraction temperature is 40°C-80°C.

4. The highly efficient preparation method of tetracaine according to claim 1, characterized in that: In the process of cooling and crystallizing in Step 1, the acidic aqueous solution added is hydrochloric acid aqueous solution, sulfuric acid aqueous solution or phosphoric acid aqueous solution, with a concentration of 0.01mol / L-2mol / L, and the dosage ratio to the mass of p-aminobenzoic acid is 1-5:1, and continue to cool to 0°C-20°C for crystallization.

5. The highly efficient preparation method of tetracaine according to claim 1, characterized in that: In Step 2, the alcohol is methanol, ethanol or isopropyl alcohol, and the molar volume ratio of butyl 4-butylaminobenzoate, water, alcohol and sodium hydroxide is 1mol:400ml-1500ml:400ml-1500ml:1.3mol-3mol, the reaction temperature is 40°C-80°C, and the reaction time is 2h-10h.

6. The highly efficient preparation method of tetracaine according to claim 1, characterized in that: In Step 2, the volume of water added after concentration is in a ratio of 4mL-15mL:1g to the mass of butyl 4-butylaminobenzoate; in the process of acidification with hydrochloric acid, concentrated hydrochloric acid is added dropwise to adjust the pH of the system to <4.

7. The high-efficient preparation method of tetracaine according to claim 1, wherein: In Step 3, the condensing agent is TBTU or CDI; the hydroxyl activating agent is TsCl or MsCl; the molar ratio of 4-butylaminobenzoic acid, N,N-dimethylethanolamine, the condensing agent or the hydroxyl activating agent is 1:0.9-3:0.9-3.

8. The highly efficient preparation method of tetracaine according to claim 1, characterized in that: In Step 3, the organic solvent is dichloromethane, chloroform, ethyl acetate, isopropyl acetate or methyl isobutyl ketone, and the volume ratio to the mass of 4-butylaminobenzoic acid is 4-15ml:1g, the reaction temperature is 30-80°C, and the reaction time is 3h-16h.

9. The highly efficient preparation method of tetracaine according to claim 1, wherein: In Step 3, the alkaline aqueous solution is an aqueous solution of sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide, with a concentration of 5%-15%, and the added volume ratio to the mass of 4-butylaminobenzoic acid is 4mL-10mL:1g.

10. The highly efficient preparation method of tetracaine according to claim 1, wherein: In the third step, the refining solvent is n-heptane, hexane or petroleum ether, and the mass ratio to 4-butylaminobenzoic acid is 5-10:1; the temperature is raised to 40°C - 70°C; the addition amount of activated carbon is 0.03-0.15:1 in mass ratio to 4-butylaminobenzoic acid, and adsorption is carried out for 1-3 h; the temperature is lowered to 0°C - 20°C for crystallization.

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