Synthetic method of procaine hydrochloride

Abstract

The invention discloses a method for synthesizing procaine hydrochloride, which belongs to the technical field of chemical synthesis, and comprises the following steps: adding p-nitrobenzoic acid and diethylaminoethanol into a solvent, adding a catalyst, and carrying out esterification reaction to obtain 4-nitrobenzoic acid-2. 2-diethylaminoethyl ester; the preparation method comprises the following steps: adding 4-aminobenzoic acid-2. 2-diethylamino ethyl ester into a reaction kettle, carrying out hydrogenation reduction by adopting hydrogen to obtain 4-aminobenzoic acid-2. 2-diethylamino ethyl ester, and adding hydrochloric acid for acidification to obtain 4-aminobenzoic acid-2. 2-diethylamino ethyl ester According to the method, esterification, hydrogenation and hydrochloric acid acidification are carried out, xylene is used as a common solvent for esterification and hydrogenation reactions, the two-step reaction does not need to replace the solvent, and an intermediate 4-nitrobenzoic acid-2. 2-diethylamino ethyl ester does not need to be separated, so that the operation steps are saved, the solvent types are reduced, the yield is improved, and the method is suitable for industrial production. The method has remarkable economic value and environmental protection effect.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing procaine hydrochloride. Background Art

[0002] Procaine hydrochloride, namely 4-aminobenzoic acid-2.2-diethylaminoethyl ester hydrochloride, is a local anesthetic that acts on peripheral nerves to produce conduction blocking effects. It relies on concentration gradients to diffusely penetrate the nerve cell membrane, blocking the sodium ion channel on the inside, raising the excitation threshold of nerve cells, losing excitability and conductivity, and blocking information transmission, which has a good local anesthetic effect. The common synthesis method of procaine hydrochloride is: using p-nitrobenzoic acid as the starting material, esterification reaction, alkalization, acidification, dilution to adjust the pH value, and then adding iron powder for reduction, filtering, and then removing iron and alkalization to obtain procaine aminocaine, and then acidification and refining to obtain procaine hydrochloride.

[0003] Under the fierce market competition, the above-mentioned procaine hydrochloride synthesis process has at least the following disadvantages: the use of iron powder for reduction results in serious waste, waste gas and waste water, high environmental pressure and high disposal costs; the process is complicated and the production efficiency is not fully released; the yield is low and the product profit is not fully reflected. The above disadvantages have led to a decline in the market core competitiveness of using this process to synthesize procaine hydrochloride.

[0004] In order to solve the above-mentioned problem of "serious three wastes caused by iron powder reduction, high environmental pressure and high disposal cost", Chinese patent applications CN104341314A and CN115322111A both disclose a synthesis method using hydrogen instead of iron powder reduction. However, The method disclosed in patent application CN115322111A uses the intermediate diethylaminoethyl p-nitrobenzoate as a raw material for hydrogenation, and uses isopropanol as a solvent during the hydrogenation, so that the diethylaminoethyl p-nitrobenzoate needs to be separated from the first step of the reaction, which increases the separation and drying processes; and uses a different type of solvent from that used in the esterification reaction, which increases solvent consumption and additional solvent treatment; The method disclosed in patent application CN104341314A requires distillation of xylene after esterification, and then adding hydrochloric acid to prepare nitrocaine hydrochloride, which is then hydrogenated under acidic conditions. This patent distills the xylene solvent after esterification, and then adds hydrochloric acid and water to prepare nitrocaine hydrochloride, which is then hydrogenated under acidic conditions. This leads to high requirements for the hydrogenation reactor, which is prone to equipment corrosion, and there is a distillation process. There is room for improvement in equipment, energy consumption and efficiency. Summary of the invention

[0005] The purpose of the present invention is to provide a method for synthesizing procaine hydrochloride to solve the above problems.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows: a method for synthesizing procaine hydrochloride, comprising the following steps: (1) adding p-nitrobenzoic acid and diethylaminoethanol into a solvent, and adding a catalyst, and performing an esterification reaction to obtain 4-nitrobenzoic acid-2,2-diethylaminoethyl ester; (2) subjecting the 4-nitrobenzoic acid-2,2-diethylaminoethyl ester obtained in step (1) to hydrogen reduction using hydrogen to obtain 4-aminobenzoic acid-2,2-diethylaminoethyl ester; (3) adding hydrochloric acid to the 4-aminobenzoic acid-2,2-diethylaminoethyl ester obtained in step (2) for acidification to obtain 4-aminobenzoic acid-2,2-diethylaminoethyl ester hydrochloride, i.e., brucaine hydrochloride product.

[0007] As a preferred technical solution, in step (1), the catalyst is an acidic catalyst, more preferably one of p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, glacial acetic acid, phosphoric acid and sulfuric acid.

[0008] As a preferred technical solution, in step (1), the temperature of the esterification reaction is 130-150°C.

[0009] As a preferred technical solution, in step (1), after the esterification reaction is completed, the temperature is lowered to 0°C or below to precipitate excess p-nitrobenzoic acid, and the reaction mixture is filtered, and the filtrate is directly used in the reaction of step (2).

[0010] As a preferred technical solution, in step (2), during the hydrogenation reaction, the reaction temperature is 35-55°C and the reaction pressure is 0.15-0.25MPa.

[0011] As a preferred technical solution, in step (2), the hydrogenation reaction is carried out in a pressure reactor and palladium on carbon is added.

[0012] As a preferred technical solution, in step (2), after the reaction is completed, the temperature is lowered to 20°C or below, and then filtered with nitrogen. The filtrate is allowed to stand and then separated into layers, and the organic phase is used for the reaction in step (3).

[0013] As a preferred technical solution, in step (3), the organic phase obtained in step (2) is allowed to stand and separated into layers; the temperature of the organic phase is controlled to be below 40°C, hydrochloric acid solution is added dropwise to adjust the pH to 3-4.5; the mixture is stirred, allowed to stand, separated into layers, the water layer is heated to 70-80°C, sodium chloride is added, stirred, filtered while hot, the filtrate is cooled to 5-10°C, filtered, the filter cake is washed, filtered and dried to obtain the product.

[0014] Compared with the prior art, the advantages of the present invention are: (1) The present invention adds a catalyst, mild conditions, and a nitrogen atmosphere to effectively improve the utilization rate of diethylaminoethanol, so that the yield of the esterification step and the utilization rate of diethylaminoethanol in the esterification reaction are increased from 91% to 95%, and the purity of 4-nitrobenzoic acid-2,2-diethylaminoethyl ester is increased from 92% to 98%; (2) The present invention uses xylene as a common solvent for the esterification and hydrogenation reactions. The two-step reaction does not require the replacement of solvents, and there is no need to separate the intermediate 4-nitrobenzoic acid-2,2-diethylaminoethyl ester. The p-nitrobenzoic acid is recovered by simple filtration through a natural precipitation method. In contrast, in CN104341314A, xylene is evaporated after the esterification to obtain 4-nitrobenzoic acid-2,2-diethylaminoethyl ester. Nitrobenzoic acid-2.2-diethylaminoethyl ester, and then nitrocaine is added with dilute hydrochloric acid to prepare nitrocaine hydrochloride, and then hydrogenated; the present invention only needs to cool down to precipitate the p-nitrobenzoic acid remaining in the reaction process, which can be directly applied to the next batch reaction, and the filtrate is directly hydrogenated, which simplifies the operation steps compared with CN104341314A and improves the yield; relative to CN104341314A, the present application directly separates the unreacted p-nitrobenzoic acid by cooling and crystallizing after esterification, and then directly hydrogenates with a xylene solution without distillation, and the materials in the hydrogenation process are neutral, and the requirements for the hydrogenation reactor are low, and an ordinary stainless steel hydrogenation reactor can meet the requirements; (3) The present invention can reduce wastewater generation and significantly improve production efficiency; (4) The only by-product of the hydrogenation reaction of the present invention is water, the hydrogenation yield of the present invention is above 98%, and the purity of procaine hydrochloride is above 99.9%; (5) The present invention increases the total yield of procaine hydrochloride from esterification, hydrogenation to procaine hydrochloride from 70% to 93%. DETAILED DESCRIPTION

[0015] The present invention will be further described below in conjunction with embodiments. Example

[0016] A method for synthesizing procaine hydrochloride comprises the following steps: (1) Esterification reaction: Take p-nitrobenzoic acid (114 g), xylene (720 g), catalyst (benzenesulfonic acid) (1 g), and diethylaminoethanol (76 g), stir, heat to 147°C and reflux for 15 hours, cool to 0°C, filter, dry the filter cake (recover p-nitrobenzoic acid) and 7.2 g; set the filtrate aside; (2) Hydrogenation reaction: add the filtrate of step (1) and catalyst (5wt% palladium carbon, 3% platinum carbon 0.6g dry basis) to a magnetically driven high-pressure reactor, check the air tightness, replace with nitrogen three times if no abnormality is found, and then replace with hydrogen three times; raise the temperature to 40°C, pressurize the hydrogen to 0.2MPa, and react for 3 hours; after the reaction is completed, replace with nitrogen three times, cool to 20°C, filter the material liquid with nitrogen, let the filtrate stand for 10 minutes, and separate; the organic phase is set aside; (3) Hydrochloric acid treatment: the phase obtained in step (2) was added dropwise with 5 wt % aqueous hydrochloric acid solution at a temperature below 40° C., and the pH value was adjusted to 3-4.5; the mixture was stirred for 0.5 hour, allowed to stand for 0.5 hour, and separated into layers. The water layer was heated to 80° C., sodium chloride (34 g) was added, stirred for 5 minutes, and filtered while hot. The filtrate was cooled to 5° C., filtered, and the filter cake was washed with a small amount of 95 wt % ethanol and filtered. The filter cake was dried in a forced air oven at 50° C. for 8 hours to obtain 161.2 g of procaine hydrochloride with a total yield of 91.12% and a purity of 99.95%. Example

[0017] (1) Esterification reaction: Take p-nitrobenzoic acid (114 g), xylene (720 g), catalyst (benzenesulfonic acid) (1 g), and diethylaminoethanol (76 g), stir, heat to 140°C and reflux for 18 hours, cool to 0°C, filter, dry 6.8 g of the filter cake (recovered p-nitrobenzoic acid), and set aside for use; (2) Hydrogenation reaction: add the filtrate of step (1) and catalyst (5wt% palladium carbon, 3% platinum carbon 0.6g dry basis) to a magnetically driven high-pressure reactor, check the air tightness, replace with nitrogen three times if no abnormality is found, and then replace with hydrogen three times; raise the temperature to 40°C, pressurize the hydrogen to 0.2MPa, and react for 3 hours; after the reaction is completed, replace with nitrogen three times, cool to 20°C, filter the material liquid with nitrogen, let the filtrate stand for 10 minutes, and separate; the organic phase is set aside; (3) Hydrochloric acid treatment: the organic phase obtained in step (2) was added dropwise with a 5 wt % aqueous hydrochloric acid solution at a temperature below 40° C., and the pH value was adjusted to 3-4.5; the mixture was stirred for 0.5 hour, allowed to stand for 0.5 hour, and separated into layers. The aqueous layer was heated to 80° C., sodium chloride (34 g) was added, stirred for 5 minutes, and filtered while hot. The filtrate was cooled to 5° C., filtered, and the filter cake was washed with a small amount of 95 wt % ethanol and filtered. The filter cake was dried in a forced air oven at 50° C. for 8 hours to obtain 164.6 g of procaine hydrochloride with a total yield of 93.05% and a purity of 99.92%. Example

[0018] (1) Esterification reaction: Take p-nitrobenzoic acid (114 g), xylene (720 g), catalyst (benzenesulfonic acid) (1 g), and diethylaminoethanol (76 g), stir, heat to 150°C and reflux for 18 hours, cool to 0°C, filter, dry 6.9 g of the filter cake (recovered p-nitrobenzoic acid), and set aside for use; (2) Hydrogenation reaction: add the filtrate of step (1) and catalyst (5wt% palladium carbon, 3% platinum carbon 0.6g dry basis) to a magnetically driven high-pressure reactor, check the air tightness, replace with nitrogen three times if no abnormality is found, and then replace with hydrogen three times; raise the temperature to 40°C, pressurize the hydrogen to 0.2MPa, and react for 3 hours; after the reaction is completed, replace with nitrogen three times, cool to 20°C, filter the material liquid with nitrogen, let the filtrate stand for 10 minutes, and separate; the organic phase is set aside; (3) Hydrochloric acid treatment: the organic phase obtained in step (2) was added dropwise with a 5 wt % aqueous hydrochloric acid solution at a temperature below 40° C., and the pH value was adjusted to 3-4.5; the mixture was stirred for 0.5 hour, allowed to stand for 0.5 hour, and separated into layers. The aqueous layer was heated to 80° C., sodium chloride (34 g) was added, stirred for 5 minutes, and filtered while hot. The filtrate was cooled to 5° C., filtered, and the filter cake was washed with a small amount of 95 wt % ethanol and filtered. The filter cake was dried in a forced air oven at 50° C. for 8 hours to obtain 164.3 g of procaine hydrochloride with a total yield of 92.88% and a purity of 99.98%.

[0019] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing procaine hydrochloride, characterized in that: The steps include: (1) adding p-nitrobenzoic acid and diethylaminoethanol into a solvent, and adding a catalyst, and subjecting the mixture to an esterification reaction to obtain 4-nitrobenzoic acid-2,2-diethylaminoethyl ester; (2) subjecting the 4-nitrobenzoic acid-2,2-diethylaminoethyl ester obtained in step (1) to hydrogen reduction using hydrogen to obtain 4-aminobenzoic acid-2,2-diethylaminoethyl ester; (3) adding hydrochloric acid to the 4-aminobenzoic acid-2,2-diethylaminoethyl ester obtained in step (2) for acidification to obtain 4-aminobenzoic acid-2,2-diethylaminoethyl ester hydrochloride, i.e., brucaine hydrochloride product.

2. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (1), the catalyst is an acidic catalyst.

3. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (1), the temperature of the esterification reaction is 130-150°C.

4. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (1), after the esterification reaction is completed, the temperature is lowered to 0°C or below to precipitate the excess p-nitrobenzoic acid, and the reaction mixture is filtered, and the filtrate is directly used in the reaction of step (2).

5. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (2), during the hydrogenation reaction, the reaction temperature is 35-55° C. and the reaction pressure is 0.15-0.25 MPa.

6. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (2), the hydrogenation reaction is carried out in a pressure reactor and palladium on carbon is added.

7. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (2), after the reaction is completed, the temperature is lowered to 20° C. or below, and then filtered with nitrogen. The filtrate is allowed to stand and then separated into layers. The organic phase is used for the reaction in step (3).

8. A method for synthesizing procaine hydrochloride according to claim 1, characterized in that: In step (3), the organic phase obtained in step (2) is allowed to stand and separated into layers; the temperature of the organic phase is controlled to be below 40° C., hydrochloric acid solution is added dropwise to adjust the pH value to 3-4.5; the mixture is stirred, allowed to stand, separated into layers, the water layer is heated to 70-80° C., sodium chloride is added, stirred, filtered while hot, the filtrate is cooled to 5-10° C., filtered, the filter cake is washed, filtered, and dried to obtain the product.