A post-processing process for synthesizing procaine hydrochloride

Abstract

The present invention discloses a post-processing process for synthesizing procaine hydrochloride, comprising an esterification reaction, a reduction reaction, and a crystallization process. The reduction reaction comprises reducing a nitrocaine salt, performing filtration after precipitation, adding soda ash and xylene to the filtrate for extraction, collecting an organic phase, adding sodium hydrosulfite and dilute hydrochloric acid to the organic phase for back extraction, and collecting an aqueous phase to obtain a procaine hydrochloride solution. The crystallization process comprises concentrating the procaine hydrochloride solution, adding anhydrous ethanol for crystallization, and drying the crystals to obtain the finished procaine hydrochloride product. The present invention can reduce operational steps, shorten the production process time, and improve production efficiency and yield.

Description

Technical Field

[0001] The invention relates to a post-processing process for synthesizing procaine hydrochloride, and belongs to the technical field of medicine. Background Art

[0002] Procaine hydrochloride, whose chemical name is 4-aminobenzoic acid-2,2-diethylaminoethyl ester hydrochloride, has good local anesthetic effect and is a local anesthetic widely used in the medical field.

[0003] The existing process for synthesizing procaine hydrochloride includes esterification of p-nitrobenzoic acid and diethylaminoethanol, followed by dissolution in hydrochloric acid to obtain nitrocaine 4-nitrobenzoic acid-2,2-diethylaminoethyl ester hydrochloride, followed by reduction to obtain procaine 4-aminobenzoic acid-2,2-diethylaminoethyl ester, followed by salification to obtain crude procaine hydrochloride, and then refining to obtain finished procaine hydrochloride. The process involves multiple steps and is time-consuming. Furthermore, the reduction process requires cooling below room temperature for precipitation and transfer before the salification process, which is difficult and complex to operate and consumes energy. Furthermore, the salification and refining processes result in significant procaine hydrochloride product loss, resulting in a low yield of the finished procaine hydrochloride product. Summary of the Invention

[0004] In order to solve at least one problem existing in the above-mentioned prior art, the present invention provides a post-treatment process for synthesizing procaine hydrochloride, which can reduce the number of operating steps, shorten the production process time, and improve production efficiency and yield.

[0005] In order to achieve the above object, the present invention adopts the following technical scheme: a post-treatment process for synthesizing procaine hydrochloride, comprising three steps of esterification reaction, reduction reaction, and crystallization;

[0006] The reduction process comprises the following steps: the solution after nitrocaine is reduced to procaine is filtered after precipitation, the filtrate is mixed with soda ash and xylene to extract the organic phase, the organic phase is mixed with sodium hyposulfite and dilute hydrochloric acid to extract the aqueous phase, and thus the procaine hydrochloride solution is obtained;

[0007] Crystallization: Concentrate the procaine hydrochloride solution, then add anhydrous ethanol for crystallization and dry to obtain the finished procaine hydrochloride product.

[0008] Preferably, the specific steps of the post-treatment process for synthesizing procaine hydrochloride are as follows:

[0009] (1) Esterification reaction: p-nitrobenzoic acid and diethylaminoethanol are subjected to esterification reaction and adjusted with dilute hydrochloric acid to obtain nitrocaine hydrochloride solution;

[0010] (2) Reduction reaction: adjusting the pH of the nitrocaine hydrochloride solution of step (1) to 4-4.2, adding iron powder to carry out reduction reaction, filtering, reducing the pH of the filtrate to 7.8-8, precipitating, and then performing filter pressing. Adding soda ash and xylene to the filtrate for extraction, taking the organic phase, and then adding sodium sulfate and dilute hydrochloric acid to the organic phase for back extraction, taking the aqueous phase, and adjusting its pH to obtain a procaine hydrochloride solution;

[0011] (3) Crystallization: The procaine hydrochloride solution of step (2) is filtered through a microporous filter, the filtrate is concentrated, anhydrous ethanol is added while hot and mixed, cooled and crystallized, and the crystals are dried to obtain the finished procaine hydrochloride product.

[0012] Preferably, in step (2), the amount of iron powder added is 75% to 95% of the initial weight of p-nitrobenzoic acid.

[0013] Preferably, in step (2), during extraction, the amount of soda ash added is at least 95.5%, preferably 95.5-96.5%, of the molar mass of the p-nitrobenzoic acid participating in the reaction. The molar mass of the p-nitrobenzoic acid participating in the reaction is equal to the initial molar mass of the p-nitrobenzoic acid plus the molar mass of the unreacted p-nitrobenzoic acid. A small amount of soda ash affects the collection of procaine during the reduction process, thereby affecting the product yield, and a large amount of soda ash increases the production cost.

[0014] Preferably, in step (2), during extraction, the amount of xylene added is 1.45 to 1.65 times the weight of the filtrate. A small amount of xylene affects the collection of procaine during the reduction process, thereby affecting the product yield. The amount of xylene used increases the production cost and operational difficulty of subsequent back extraction.

[0015] Preferably, in step (2), during back extraction, the molar mass of hydrochloric acid in the dilute hydrochloric acid is 99.2-99.5% of the molar mass of p-nitrobenzoic acid participating in the reaction, and the molar mass of p-nitrobenzoic acid participating in the reaction is equal to the initial molar mass of p-nitrobenzoic acid plus the molar mass of unreacted p-nitrobenzoic acid. If the molar mass of hydrochloric acid in the dilute hydrochloric acid is too small, the time for pH adjustment will be increased; if the molar mass of hydrochloric acid in the dilute hydrochloric acid is too large, pure water will be used for dilution, and a large amount of pure water will be used, which will extend the concentration time and energy consumption of the crystallization.

[0016] Preferably, in step (2), the pH of the aqueous phase after back extraction is adjusted to 3.8-4.5.

[0017] Preferably, in step (3), the filtrate is concentrated to a water content of 15-25%. Too low or too high a water content will affect the product yield.

[0018] Preferably, in step (3), the amount of anhydrous ethanol added is 20-25% of the total weight of the concentrated solution and the anhydrous ethanol mixture. If the amount of anhydrous ethanol is small, the product purity is slightly lower, which will also affect the output yield. If the amount of anhydrous ethanol is large, the product yield will be affected.

[0019] Preferably, in step (2), the pH of the nitrocaine hydrochloride solution in step (1) is adjusted to 4-4.2 with a 20% sodium hydroxide solution, and then iron powder is added for reduction reaction, filtered, and the iron powder is removed. The filtrate is first adjusted to pH 5 with dilute hydrochloric acid and then adjusted to pH 7.8-8 with a saturated sodium sulfate solution, precipitated for 2-3 hours, and then filtered, soda ash and xylene are added to the filtrate, the mixture is allowed to stand and decompose, the aqueous phase is removed, the organic phase is taken, and then sodium hydrosulfite and dilute hydrochloric acid are added to the organic phase to mix, back-extraction is performed, the organic phase is allowed to stand and decompose, the organic phase is removed, the aqueous phase is taken, and the pH is adjusted to 3.8-4.5, and procaine hydrochloride solution is obtained.

[0020] Preferably, in the esterification reaction of step (1), p-nitrobenzoic acid, diethylaminoethanol, solvent xylene and catalyst formic acid are mixed for esterification reaction, water, formic acid and xylene are removed, and dilute hydrochloric acid is used for adjustment to remove unreacted p-nitrobenzoic acid to obtain a nitrocaine hydrochloride solution.

[0021] Preferably, in the esterification reaction of step (1), p-nitrobenzoic acid, diethylaminoethanol, solvent xylene and catalyst formic acid are mixed and subjected to esterification reaction for 10 to 12 hours, and heated to remove water and formic acid, and then cooled and filtered, the filtrate is distilled to remove xylene, and the mixed distillation residue and filtered solid are adjusted with 4 to 10% dilute hydrochloric acid to remove unreacted p-nitrobenzoic acid, thereby obtaining a nitrocaine hydrochloride solution.

[0022] Preferably, in step (1), the molar ratio of p-nitrobenzoic acid to diethylaminoethanol is 1:1 to 1.1:1.

[0023] Preferably, in step (1), the amount of formic acid as the catalyst added is 2-3% of the initial weight of p-nitrobenzoic acid; and the amount of xylene as the solvent added is 3.5-4.5 times the initial weight of p-nitrobenzoic acid.

[0024] Beneficial effects of the present invention:

[0025] 1. The post-treatment process for synthesizing procaine hydrochloride of the present invention comprises three steps: esterification, reduction, and crystallization. The salt-forming step is realized during the reduction step, and a separate salt-forming step is not required. This shortens the treatment process, shortens the production process time, and improves production efficiency.

[0026] 2. The post-treatment process of synthesizing procaine hydrochloride of the present invention adopts xylene extraction and dilute hydrochloric acid back extraction in the reduction process, thereby eliminating the need for cooling procaine below room temperature for precipitation, transfer, and subsequent salt formation, thereby shortening the reduction process and reducing energy consumption.

[0027] 3. Anhydrous ethanol is used in the crystallization process of the post-treatment process for synthesizing procaine hydrochloride of the present invention, thereby improving the product yield and purity and shortening the drying time.

[0028] 4. During the reduction process of the post-treatment process for synthesizing procaine hydrochloride of the present invention, the pH of the procaine hydrochloride solution is controlled at 3.8 to 4.5, which is beneficial to improving the yield of procaine hydrochloride. DETAILED DESCRIPTION

[0029] Below in conjunction with accompanying drawing, the technical scheme in the embodiment of the present invention is clearly and completely described, and described embodiment is only a part of embodiment of the present invention, rather than all embodiments. Based on the embodiment of the present invention, all other embodiments obtained by those of ordinary skill in the art without making creative work premise all fall within the scope of protection of the present invention. In the embodiment, those who do not indicate specific conditions, carry out according to normal conditions or the conditions recommended by the manufacturer. Reagents used or instruments, components that do not indicate manufacturers are conventional products that can be purchased commercially.

[0030] Example 1

[0031] A post-processing process for synthesizing procaine hydrochloride comprises the following steps:

[0032] (1) Esterification reaction: 240 kg of p-nitrobenzoic acid, 168 kg of diethylaminoethanol, 960 kg of xylene, and 7.2 kg of formic acid were placed in an esterification kettle and refluxed at 140°C to 145°C for 12 hours. Water and formic acid were then removed through a water separator, and the solid was cooled and filtered. The filtrate was placed in a liquid separation kettle for separation for 2 hours to remove the xylene. The remaining distillation residue and the filtered solid were placed in an acid adjustment kettle, and 678 kg of 8% dilute hydrochloric acid was added and stirred for 1 hour. Unreacted p-nitrobenzoic acid was precipitated, and 3 kg of p-nitrobenzoic acid was removed by filtration. The filtrate was recovered to obtain 1056 kg of nitrocaine hydrochloride solution.

[0033] (2) Reduction reaction: 1056 kg of the nitrocaine hydrochloride solution of step (1) is added to a reduction kettle, 20% sodium hydroxide solution is added to adjust the pH to 4-4.2, and then 190 kg of iron powder is added and reacted at a temperature of 100°C-105°C for 2 hours, and iron filings are removed by filtration. The iron filings are washed with water, and the washing liquid and the filtrate are mixed and added to a precipitation kettle, and dilute hydrochloric acid is first added to adjust the pH to 5, and then a saturated sodium sulfate solution is added to adjust the pH to 7.8-8. After precipitation for 3 hours, the sulfide iron mud is removed by filter pressing to obtain 1300 kg of filtrate, and 144 kg of soda ash and 2000 kg of xylene are added to mix and added. The mixture was placed in a separatory kettle and allowed to stand for 2 hours, the aqueous alkaline water was removed, the organic phase was extracted, and 5 kg of hydrosulfite and 513 kg of 10% dilute hydrochloric acid were added and mixed, and the mixture was placed in a separatory kettle and allowed to stand for stratification. The aqueous procaine hydrochloride solution was extracted, the organic phase was removed, and the pH of the procaine hydrochloride solution was adjusted to 3.8 with dilute sulfuric acid to obtain 763 kg of procaine hydrochloride solution with a pH of 3.8. After testing, the procaine content was 42.6%. The yield of procaine was calculated based on the p-nitrobenzoic acid involved in the reaction (i.e., the difference between the p-nitrobenzoic acid initially added and the unreacted p-nitrobenzoic acid).

[0034] (3) Crystallization: 763 kg of the procaine hydrochloride solution prepared in step (1) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 308 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 115 kg of anhydrous ethanol was added and mixed, cooled to below 10° C. for crystallization for 7 h, and placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 350 kg of procaine hydrochloride product with a purity of 99.4%. The yield was 90.1% calculated based on the p-nitrobenzoic acid involved in the reaction.

[0035] Example 2

[0036] A post-processing process for synthesizing procaine hydrochloride comprises the following steps:

[0037] (1) Esterification reaction: 180 kg of p-nitrobenzoic acid, 126 kg of diethylaminoethanol, 630 kg of xylene, and 4.5 kg of formic acid were placed in an esterification kettle and refluxed at 140°C to 145°C for 11 hours. Water and formic acid were then removed through a water separator. The solid was cooled and filtered. The filtrate was placed in a liquid separation kettle for separation for 2 hours to remove the xylene. The residual liquid and the filtered solid were placed in an acid adjustment kettle, and 508 kg of 8% dilute hydrochloric acid was added and stirred for 1 hour. The mixture was filtered to remove 2.5 kg of p-nitrobenzoic acid to obtain a filtrate, i.e., 790 kg of nitrocaine hydrochloride solution.

[0038] (2) Reduction reaction: 790 kg of the nitrocaine hydrochloride solution of step (1) was added to a reduction kettle, 20% sodium hydroxide solution was added to adjust the pH to 4-4.2, and then 144 kg of iron powder was added and reacted at a temperature of 100°C-105°C for 2 hours. The iron filings were filtered to remove the iron filings, and the iron filings were washed with water. The washing liquid and the filtrate were mixed and added to a precipitation kettle, and dilute hydrochloric acid was first added to adjust the pH to 5, and then a saturated sodium sulfate solution was added to adjust the pH to 7.8-8. After precipitation for 2 hours, the iron sulfide mud was removed by pressure filtration to obtain 960 kg of filtrate, and 108 kg of soda ash was added. and 1395kg of xylene, put it into a separatory kettle and let it stand for 2h, remove the aqueous alkaline water, extract the organic phase and add 3.5kg of hydrosulfite and 383kg of 10% dilute hydrochloric acid, put it into a separatory kettle and let it stand for stratification, extract the aqueous procaine hydrochloride solution, remove the organic phase, adjust the pH of the procaine hydrochloride solution to 4.2 with dilute sulfuric acid, and obtain 594kg of procaine hydrochloride solution with a pH of 4.2. After testing, the procaine content was 41%, and the yield of procaine was 97% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0039] (3) Crystallization: 594 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 235 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 105 kg of anhydrous ethanol was added and mixed, cooled to below 10° C. for crystallization for 7 h, and placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 265 kg of procaine hydrochloride product with a purity of 99.7%. The yield was 91.5% based on the p-nitrobenzoic acid involved in the reaction.

[0040] Example 3

[0041] A post-processing process for synthesizing procaine hydrochloride comprises the following steps:

[0042] (1) Esterification reaction: 120 kg of p-nitrobenzoic acid, 84 kg of diethylaminoethanol, 540 kg of xylene, and 2.4 kg of formic acid were placed in an esterification kettle and refluxed at 140°C to 145°C for 10 hours. Water and formic acid were then removed through a water separator, and the solid was cooled and precipitated. The filtrate was filtered and placed in a liquid separation kettle for 2 hours to remove the xylene. The residual liquid and the filtered solid were placed in an acid adjustment kettle, and 338 kg of 8% dilute hydrochloric acid was added and stirred for 1 hour. The mixture was filtered to remove 2 kg of p-nitrobenzoic acid to obtain a filtrate, i.e., 528 kg of nitrocaine hydrochloride solution.

[0043] (2) Reduction reaction: 528 kg of the nitrocaine hydrochloride solution of step (1) was added to a reduction kettle, 20% sodium hydroxide solution was added to adjust the pH to 4-4.2, and then 110 kg of iron powder was added and reacted at a temperature of 100°C-105°C for 2 h. Iron filings were removed by filtration, and the iron filings were washed with water. The washing liquid and the filtrate were mixed and added to a precipitation kettle, and dilute hydrochloric acid was added to adjust the pH to 5, and then a saturated sodium sulfate solution was added to adjust the pH to 7.8-8. After precipitation for 3 h, the sulfide iron mud was removed by filter pressing to obtain 670 kg of filtrate, and 72 kg of soda ash and 1 100kg of xylene was mixed and placed in a separatory kettle and allowed to stand for 2h. The aqueous alkaline water was removed, the organic phase was extracted and 2.6kg of hydrosulfite and 255kg of 10% dilute hydrochloric acid were added and mixed, and the aqueous phase of procaine hydrochloride solution was extracted. The organic phase was removed and the pH of the procaine hydrochloride solution was adjusted to 4.5 with dilute sulfuric acid to obtain 391kg of procaine hydrochloride solution with a pH of 4.5. After testing, the procaine content was 41.5%. The yield of procaine was 97.2% calculated based on the p-nitrobenzoic acid involved in the reaction.

[0044] (3) Crystallization: 391 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporator, and the filtrate was placed in a concentration kettle for concentration, 173 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 72 kg of anhydrous ethanol was added and mixed. The solution was cooled to below 10° C. and crystallized for 7 h. The solution was placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 174 kg of procaine hydrochloride product with a purity of 99.7%. The yield was 90.3% based on the p-nitrobenzoic acid involved in the reaction.

[0045] Comparative Example 1

[0046] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 1.5 kg of p-nitrobenzoic acid is precipitated; in step (2), 670 kg of press filtrate is obtained, 72 kg and 1100 kg of soda ash are added, and 391 kg of procaine hydrochloride solution with a pH of 4.2 is obtained; after testing, the procaine content is 41.6%, and the yield of procaine is 97.1% calculated based on the p-nitrobenzoic acid participating in the reaction;

[0047] (3) Crystallization: 391 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 165 kg of water was removed, and the concentrate was placed in a crystallization kettle while hot and 56 kg of anhydrous ethanol was added and mixed. The mixture was cooled to below 10° C. and crystallized for 7 h. The mixture was placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 173 kg of procaine hydrochloride product with a purity of 98.7%. The yield was 89.4% based on the p-nitrobenzoic acid involved in the reaction.

[0048] Comparative Example 2

[0049] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 2 kg of p-nitrobenzoic acid is precipitated; in step (2), 668 kg of press filtrate is obtained, 72 kg and 1100 kg of soda ash are added, and 389 kg of procaine hydrochloride solution with a pH of 4 is obtained; after testing, the procaine content is 41.7%, and the yield of procaine is 97.2% calculated based on the p-nitrobenzoic acid participating in the reaction;

[0050] (3) Crystallization: 389 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 161 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 77 kg of anhydrous ethanol was added and mixed. The solution was cooled to below 10° C. and crystallized for 7 h. The solution was placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 169 kg of procaine hydrochloride product with a purity of 99.7%. The yield was 87.8% based on the p-nitrobenzoic acid involved in the reaction.

[0051] Comparative Example 3

[0052] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 2 kg of p-nitrobenzoic acid is precipitated; in step (2), 672 kg of press filtrate is obtained, 71 kg and 1105 kg of soda ash are added, and 390 kg of procaine hydrochloride solution with a pH of 4.5 is obtained; after testing, the procaine content is 41.1%, and the yield of procaine is 96.1% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0053] (3) Crystallization: 390 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 174 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 65 kg of anhydrous ethanol was added and mixed, cooled to below 10° C. for crystallization for 7 h, and placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 172 kg of procaine hydrochloride product with a purity of 99.6%. The yield was 89.3% calculated based on the p-nitrobenzoic acid involved in the reaction.

[0054] Comparative Example 4

[0055] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 2 kg of p-nitrobenzoic acid is precipitated; in step (2), 670 kg of press filtrate is obtained, 72 kg and 960 kg of soda ash are added, and 392 kg of procaine hydrochloride solution with a pH of 3.9 is obtained; after testing, the procaine content is 41%, and the yield of procaine is 96.3% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0056] (3) Crystallization: 392 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 165 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 70 kg of anhydrous ethanol was added and mixed. The solution was cooled to below 10° C. and crystallized for 7 h. The solution was placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 173 kg of procaine hydrochloride product with a purity of 99.6%. The yield was 89.8% based on the p-nitrobenzoic acid involved in the reaction.

[0057] Comparative Example 5

[0058] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 2 kg of p-nitrobenzoic acid is precipitated; in step (2), 670 kg of press filtrate is obtained, 72 kg and 1100 kg of soda ash and 2 kg of sodium hydrosulfite are added to obtain 390 kg of procaine hydrochloride solution with a pH of 3.8; after testing, the procaine content is 41.4%, and the yield of procaine is 96.8% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0059] (3) Crystallization: 390 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 172 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 65 kg of anhydrous ethanol was added and mixed, cooled to below 10° C. for crystallization for 7 h, and placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 170 kg of procaine hydrochloride product with a purity of 99.6%. The yield was 88.3% based on the p-nitrobenzoic acid involved in the reaction.

[0060] Comparative Example 6

[0061] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 2 kg of p-nitrobenzoic acid is precipitated; in step (2), 670 kg of press filtrate is obtained, 72 kg and 1100 kg of soda ash and 254 kg of 10% dilute hydrochloric acid are added and mixed, and the pH of the aqueous procaine hydrochloride solution is adjusted to 3.2 with dilute sulfuric acid to obtain 390 kg of procaine hydrochloride solution with a pH of 3.2; after testing, the procaine content is 41.6%, and the yield of procaine is 97.2% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0062] (3) Crystallization: 390 kg of the procaine hydrochloride solution in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 170 kg of water was removed, and the concentrate was placed in a crystallization kettle while hot and 66 kg of anhydrous ethanol was added and mixed, cooled to below 10° C. and crystallized for 7 h, and placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 166 kg of procaine hydrochloride product with a purity of 99%. The yield was 86.2% calculated based on the p-nitrobenzoic acid involved in the reaction.

[0063] Comparative Example 7

[0064] A post-treatment process for synthesizing procaine hydrochloride is partially the same as that of Example 3, except that: in step (1), 2 kg of p-nitrobenzoic acid is precipitated; in step (2), 670 kg of press filtrate is obtained, 72 kg and 1100 kg of soda ash and 254 kg of 10% dilute hydrochloric acid are added and mixed, and the pH of the aqueous procaine hydrochloride solution is adjusted to 5.1 with dilute sulfuric acid to obtain 396 kg of procaine hydrochloride solution with a pH of 5.1; after testing, the procaine content is 40.9%, and the yield of procaine is 97.1% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0065] (3) Crystallization: 396 kg of the procaine hydrochloride solution prepared in step (2) was filtered through a microporous filter, and the filtrate was placed in a concentration kettle for concentration, 176 kg of water was removed, and the concentrated solution was placed in a crystallization kettle while hot and 66 kg of anhydrous ethanol was added and mixed, cooled to below 10° C. for crystallization for 7 h, and placed in a centrifuge for centrifugation for 1 h, the mother liquor was removed, and the separated solid was dried for 6 h to obtain 164 kg of procaine hydrochloride product with a purity of 99.1%. The yield was 85.15% calculated based on the p-nitrobenzoic acid involved in the reaction.

[0066] Comparative Example 8

[0067] The existing process for synthesizing procaine hydrochloride has the following specific steps:

[0068] Step 1, esterification reaction: 120 kg of p-nitrobenzoic acid, 84 kg of diethylaminoethanol, 412 kg of xylene, and 3.4 kg of formic acid are placed in an esterification kettle, and refluxed at a temperature of 140°C to 145°C for 10 hours. Water and formic acid are then removed through a water separator, and the mixture is cooled to 10°C to precipitate a solid. The solid is filtered, and the filtrate is placed in a liquid separation kettle for separation for 2 hours to remove xylene. The remaining distillation residue and the filtered solid are placed in an acid adjustment kettle, and 652 kg of 4% dilute hydrochloric acid is added and stirred for 1 hour. The mixture is filtered to remove 2 kg of p-nitrobenzoic acid to obtain a filtrate, i.e., 840 kg of nitrocaine hydrochloride solution;

[0069] Step 2, reduction reaction: 840 kg of the nitrocaine hydrochloride solution in step 1 is added to a reduction kettle, 20% sodium hydroxide solution is added to adjust the pH to 4-4.2, and then 132 kg of iron powder is added and reacted at a temperature of 100°C to 105°C for 2 hours, iron filings are filtered to remove, the iron filings are washed with water, the washing liquid and the filtrate are mixed and put into a precipitation kettle, dilute hydrochloric acid is first added to adjust the pH to 5, and then a saturated sodium sulfate solution is added to adjust the pH to 7.8-8. After precipitation for 2 hours, sulfide iron mud is filtered to remove, the sulfide iron mud is washed with water, the washing liquid and the filtrate are mixed and put into a crystallization kettle, and then 10% sodium carbonate solution is added to adjust the pH to 9-9.5, and the solution is cooled to below 10°C and alkali precipitation is carried out for 3 hours. Solid is precipitated, purified water is added to mix, and the solution is put into a centrifuge for centrifugation for 1.5 hours to remove the alkaline water to obtain 162 kg of solid, i.e., procaine. The yield of procaine is 97.1% calculated based on the p-nitrobenzoic acid involved in the reaction;

[0070] Step 3, salt formation: 162 kg of procaine in step 2 was added into a dissolution kettle, dilute hydrochloric acid was added to dissolve and the pH was adjusted to 5.5, heated to 50-55 ° C, and then 2.4 kg of hydrosulfite was added and dissolved into salt for 1 hour. The mixture was filtered while hot, and the filtrate was continued to be heated to 70-75 ° C and concentrated for 2 hours. The concentrated solution was put into a crystallization kettle, and sodium chloride was added to saturation. It was cooled to below 10 ° C and crystallized for 8 hours. It was put into a centrifuge and centrifuged for 1 hour. The crude mother liquor was removed and the separated solid was dried for 10 hours to obtain 151 kg of crude procaine hydrochloride;

[0071] Step 4, refining: 151 kg of the crude procaine acid product of step 3 was put into a dissolution kettle, and purified water was added, the temperature was maintained at 70 ° C, the solid was completely dissolved, filtered while hot, and the filtrate was put into a crystallization kettle and cooled to below 10 ° C for crystallization for 8 hours, and then centrifuged in a centrifuge for 1 hour, the refined mother liquor was removed, and the separated solid was dried for 10 hours to obtain 116 kg of procaine hydrochloride product with a purity of 99.1%. The yield of procaine hydrochloride was 60.2% calculated based on the p-nitrobenzoic acid involved in the reaction.

[0072] In summary, the post-treatment process for synthesizing procaine hydrochloride of the present invention adopts a filter press method to produce iron sulfide mud precipitation after reduction treatment, and simultaneously uses soda ash and xylene to extract procaine, and then uses dilute hydrochloric acid and sodium hydrosulfite for back extraction, and controls the pH value of the back extraction process to be 3.8-4.5, thereby avoiding the need for cooling below room temperature for precipitation and transfer before performing a salt formation process in the existing reduction treatment process, shortening the operating procedures of the reduction process, and eliminating the need for a separate salt formation process, shortening the operating steps and time, reducing energy consumption, and improving production efficiency and yield, with the yield being greater than 90%. At the same time, dehydration and addition of anhydrous ethanol during the crystallization process further improve the yield and purity of the product, and at the same time helping to shorten the drying time.

[0073] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the present invention can be embodied in other specific forms without departing from the spirit and essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

[0074] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A post-processing process for synthesizing procaine hydrochloride, characterized in that: The process includes three steps: esterification reaction, reduction reaction and crystallization; The reduction process comprises the following steps: the solution after nitrocaine is reduced to procaine is filtered after precipitation, the filtrate is mixed with soda ash and xylene to extract the organic phase, the organic phase is mixed with sodium hyposulfite and dilute hydrochloric acid to extract the aqueous phase, and thus the procaine hydrochloride solution is obtained; Crystallization: Concentrate the procaine hydrochloride solution, then add anhydrous ethanol for crystallization and dry to obtain the finished procaine hydrochloride product; During the reduction process: take the aqueous phase and adjust its pH; adjust the pH of the aqueous phase after back extraction to 3.8~4.

5.

2. A post-processing process for synthesizing procaine hydrochloride according to claim 1, characterized in that, The specific steps of the post-processing process are as follows: (1) Esterification reaction: p-nitrobenzoic acid and diethylaminoethanol are subjected to esterification reaction and adjusted with dilute hydrochloric acid to obtain nitrocaine hydrochloride solution; (2) Reduction reaction: adjust the pH of the nitrocaine hydrochloride solution of step (1) to 4-4.2, add iron powder to carry out reduction reaction, filter, adjust the pH of the filtrate to 5 first, and then use saturated sodium sulfate solution to adjust the pH to 7.8-8, precipitate, and then filter press, add soda ash and xylene to the filtrate for extraction, take the organic phase, and then add sodium hydroxide and dilute hydrochloric acid to the organic phase for back extraction, take the aqueous phase, adjust its pH, and obtain the procaine hydrochloride solution; (3) Crystallization: The procaine hydrochloride solution of step (2) is filtered through a microporous filter, the filtrate is concentrated, anhydrous ethanol is added while hot, and the mixture is cooled to crystallize. The crystals are dried to obtain the finished product of procaine hydrochloride.

3. A post-processing process for synthesizing procaine hydrochloride according to claim 2, characterized in that, In step (2), during the extraction, the amount of soda ash added is at least 95.5% of the molar mass of the p-nitrobenzoic acid participating in the reaction.

4. A post-processing process for synthesizing procaine hydrochloride according to claim 2 or 3, characterized in that, In step (2), during the extraction, the amount of soda ash added is 95.5-96.5% of the molar mass of p-nitrobenzoic acid participating in the reaction.

5. A post-processing process for synthesizing procaine hydrochloride according to claim 2, characterized in that, In step (2), during extraction, the amount of xylene added is 1.45 to 1.65 times the weight of the filtrate.

6. A post-processing process for synthesizing procaine hydrochloride according to claim 2, characterized in that, In step (2), during the back extraction, the molar mass of hydrochloric acid in the dilute hydrochloric acid is 99.2-99.5% of the molar mass of p-nitrobenzoic acid participating in the reaction.

7. A post-treatment process for synthesizing procaine hydrochloride according to claim 2, characterized in that: In step (3), the filtrate is concentrated to a water content of 15-25%.

8. A post-treatment process for synthesizing procaine hydrochloride according to claim 2, characterized in that: In step (3), the amount of anhydrous ethanol added is 20-25% of the total weight of the mixture of the concentrated solution and anhydrous ethanol.

9. A post-treatment process for synthesizing procaine hydrochloride according to claim 2, characterized in that: In step (2), the amount of iron powder added is 75% to 95% of the initial weight of p-nitrobenzoic acid.