Full-continuous chemical synthesis method of diclofenac sodium

Abstract

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a full-continuous chemical synthesis method of diclofenac sodium. According to the method, aniline and chloroacetyl chloride are taken as starting raw materials, a fully continuous device consisting of a plurality of micro-mixers, micro-reactors, online solvent recovery equipment and the like which are sequentially communicated and are subjected to improved design is adopted, a high-purity (the purity is greater than 98.5%) diclofenac sodium product is synthesized through six-step chemical reaction and continuous operation, the recovery and reuse of the solvent are realized, and the method is suitable for industrial production. The problems of hydrochloride blockage and the like are solved, and three-waste discharge is obviously reduced. And through continuous synthesis, the production efficiency and the process control accuracy are greatly improved, and the stable product quality is ensured. In addition, the use amount of aluminum trichloride is reduced by more than 30%, the material loss caused by solvent switching is effectively reduced, and the production cost is reduced.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine and chemical industry, and particularly relates to a full-continuous chemical synthesis method of diclofenac sodium. BACKGROUND

[0002] Diclofenac sodium (molecular formula: C 14 H 10 Cl2NNaO2, CAS No.: 15307-79-6), chemical name: 2-[(2,6-dichlorophenyl) amino]-benzene acetic acid sodium, white crystal or crystalline powder. It is a strong non-steroidal anti-inflammatory drug (NSAIDs) belonging to benzene acetic acid derivatives, which mainly consists of benzene acetic acid group, secondary amino group and benzene ring with two adjacent chlorine groups. This kind of drug has good curative effect in treating pain, inflammation and fever, and is one of the important drugs in clinical treatment. So far, diclofenac sodium has been marketed in 120 countries around the world for 35 years, and occupies the important position of the 30th in the 200 most popular drugs in the world.

[0003] At present, the production of diclofenac sodium generally adopts an intermittent kettle reaction process, which has long reaction time, large energy consumption, many times of solvent switching, large amount of catalyst and produces a large amount of waste acid and waste salt. Patent CN 101701003 A describes a method using N,N-dimethyl-o-bromobenzene acetic amide as a starting material. In the method, N,N-dimethyl-o-bromobenzene acetic amide and 2,6-dichloroaniline are first subjected to condensation reaction to obtain N,N-dimethyl-2-(2,6-dichloroanilino) benzene acetic amide, and then subjected to hydrolysis reaction to obtain the product. The raw material N,N-dimethyl-o-bromobenzene acetic amide in the method is an intermediate, and there is no commercial product that can be purchased, self-made or customized at a high price, so it is difficult to realize industrialization, and has low practical value. Patent CN 103145574 B describes a method of obtaining a product through chlorination, acid catalysis, ring formation, alkaline hydrolysis and other steps using N-(2,6-dichlorophenyl) benzene acetic amide as a starting material. The raw material N-(2,6-dichlorophenyl) benzene acetic amide in the method is an intermediate, and there is no commercial product, so it is difficult to realize industrialization, and the chlorination process uses a chlorinating agent with high toxicity and strong corrosion, which causes serious environmental pollution. SUMMARY

[0004] The purpose of the present application is to provide a full-continuous chemical synthesis method of diclofenac sodium with high production efficiency, good product quality and less waste discharge.

[0005] The application provides a full-continuous chemical synthesis method of diclofenac sodium, which uses aniline and chloroacetyl chloride as starting materials, utilizes a micro-mixer, a micro-reactor and a self-designed solvent recovery system, and realizes high-purity diclofenac sodium product through six-step chemical reactions and continuous operation, and realizes the recycling of o-dichlorobenzene, solves the solid flow problem, significantly reduces the discharge of three wastes, realizes continuous synthesis, greatly improves the production efficiency and the accuracy of process control, and ensures the stable product quality.

[0006] The application provides a full-continuous chemical synthesis method of diclofenac sodium, which uses a full-continuous reaction device composed of a plurality of micro-mixers, micro-reactors, online solvent recovery and the like in sequence, and performs full-continuous chemical synthesis of diclofenac sodium.

[0007] (a) dispersing aniline into a solvent, denoted as feed liquid A, dispersing chloroacetyl chloride into a solution, denoted as feed liquid B; the feed liquid A and the feed liquid B are first input into a micro-mixer 1 to be fully mixed, then are input into reaction kettles 1 and 2 to react, and 2-chloroacetanilide-containing reaction liquid is generated; the reaction liquid flows into a buffer tank 1 to obtain a solution of the product 2-chloroacetanilide, denoted as feed liquid C;

[0008] (b) pre-mixing 2,6-dichlorophenol and alkali in a solution as feed liquid D; the feed liquid C and the feed liquid D are fully mixed in a micro-mixer 2, then are input into a micro-reactor 1 to perform condensation reaction, and 2-(2,6-dichlorophenoxy)-N-phenylacetamide is generated, and the solution is denoted as feed liquid E and is input into the next step reaction;

[0009] (c) the feed liquid E and an alkali solution are input into a micro-mixer 3 to be mixed, then rearrangement reaction occurs in a micro-reactor 2, and an intermediate product 2,6-dichloro-N-phenylphenylamine is prepared; the reaction system is subjected to back pressure through a back pressure valve 1, and is subjected to online filtration to remove generated solid salts, and a solution of the 2,6-dichloro-N-phenylphenylamine is obtained, which is denoted as feed liquid F and flows into the next step reaction;

[0010] (d) solution concentration and solvent recovery: the feed liquid F is flowed into a solvent recovery device to perform solution concentration in the recovery device, the obtained solvent is recovered and reused through the way of reduced pressure distillation; after the concentration is completed, the concentrated liquid is denoted as feed liquid G and flows into the next step reaction;

[0011] (e) chloroacetyl chloride is dispersed in a solvent, denoted as feed liquid H; the feed liquid G and the feed liquid H are input into a micro-mixer 4 to be fully mixed, then are input into a micro-reactor 3 to react, the reaction system is subjected to back pressure through a back pressure valve 2, and 2,2',6'-trichloro-N-phenylacetanilide is generated; the reaction liquid is flowed into a reaction kettle 3 and a reaction kettle 4, and is denoted as feed liquid I;

[0012] (f) the mixture of the feed liquid I and aluminum chloride is pre-mixed in the reaction kettle 3, 4 at high temperature, the reaction kettle is heated by a circulating oil bath device, to form a complex; after the solution is clarified, it is fed into the micro-reactor 4 as feed liquid J to react to generate 1-(2, 6-dichlorophenyl)-1, 3-dihydro-2H-indol-2-one, the reaction system is back-pressured by the back-pressure valve 3; after the reaction liquid flows out, it is quenched by an acid to obtain a product 1-(2, 6-dichlorophenyl)-1, 3-dihydro-2H-indol-2-one solution, which is denoted as feed liquid K and is fed into the next step;

[0013] (g) the feed liquid K and a base solution are fully mixed in the micro-mixer 5, and then are fed into the micro-reactor 5 to perform a hydrolysis reaction to prepare a final product sodium diclofenac solution, the reaction system is back-pressured by the back-pressure valve 4; after the organic phase is removed by on-line liquid separation, the sodium diclofenac solution flows into a continuous crystallizer to wait for precipitation;

[0014] (h) the sodium diclofenac crude product precipitated from the above solution is subjected to decolorization, recrystallization, filtration and drying to prepare a sodium diclofenac product.

[0015] The purity of the sodium diclofenac product prepared by the method is greater than 98.5%.

[0016] Preferably, the aniline and the chloroacetyl chloride in steps (a) and (e) are dispersed into a solvent as a raw material liquid, and the solvent is selected from toluene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, dichloromethane, trichloromethane, cyclohexane, n-hexane and acetone.

[0017] Preferably, the base in steps (b), (c) and (g) is selected from sodium bicarbonate, sodium methoxide, potassium carbonate, sodium hydroxide, triethylamine, trimethylamine and N, N-diisopropyl ethylamine.

[0018] Preferably, the solvent for configuring the base solution in steps (b), (c) and (g) is selected from amyl alcohol, butanol, isobutyl alcohol, tert-butyl alcohol, propyl alcohol, isopropyl alcohol, ethanol, methanol, water, diethyl ether, acetone and butanone.

[0019] Preferably, the amount of the base in step (b) is 0.8-2.0 equivalents of the raw material; the amount of the base in step (c) is 1.0-3.0 equivalents of the raw material; the amount of the base in step (g) is 3.0-8.0 equivalents of the raw material; and the amount of the acid in step (f) is 1.0-5.0 equivalents of the product.

[0020] Preferably, the microreactor 1 in step (a), step (b), step (e), step (f) and step (g) has a reaction temperature of 90-200℃ and a reaction time of 15-60min; the microreactor 2 has a temperature of 100-300℃ and a reaction time of 15-75min, the microreactor 3 has a reaction temperature of 100-300℃ and a reaction time of 20-40min; the microreactor 4 has a reaction temperature of 90-190℃ and a reaction time of 10-30min; the reaction kettle 1 has a reaction temperature of 60-150℃ and a reaction time of 1-20min, the reaction kettle 2 has a reaction temperature of 60-150℃ and a reaction time of 5-50min; the reaction kettle 3 has a reaction temperature of 60-150℃ and a reaction time of 10-40min, and the reaction kettle 4 has a reaction temperature of 60-150℃ and a reaction time of 10-40min.

[0021] Preferably, the microreactor 2 in step (c) is a dynamic continuous stirring reactor, which is a horizontal or vertical multi-stage rotary stirring reactor with a heat exchange jacket, has a circular internal shape, an inner diameter of 10-500mm, and a length of 0.1-50m.

[0022] The reaction kettle 1 and the reaction kettle 2 in step (a) and step (f) have a diameter of 5-1000mm and a length-diameter ratio of 5:1-50:1; the reaction kettle 3 and the reaction kettle 4 have a diameter of 100-1000mm and a length-diameter ratio of 10:1-50:1.

[0023] The anti-corrosion glass column in the solvent recovery device in step (d) has a cylindrical internal shape, an inner diameter of 10-500mm, and a length of 0.1-50m.

[0024] Preferably, the pressure of the reduced pressure concentration in step (d) is 1-100mbar.

[0025] Preferably, the back pressure valve 1 in step (c) has a pressure of 0-10bar, the back pressure valve 2 in step (e) has a pressure of 1-20bar, the back pressure valve 3 in step (f) has a pressure of 1-20bar, and the back pressure valve 4 in step (g) has a pressure of 1-20bar.

[0026] Preferably, the solvent used in the recrystallization in step (h) is selected from water, methanol, ethanol, propanol, and isopropanol.

[0027] Compared with the prior art, the present application has the following technical advantages:

[0028] (1) Micro-mixer can greatly enhance the mass transfer effect of multi-phase system, improve the reaction rate while reducing the reactor volume, while the micro-channel reactor has excellent mass transfer, heat transfer and material continuous mixing enhancement performance, which can effectively shorten the reaction time, improve the reaction efficiency and the flux per unit volume of the reactor, and has higher reaction safety, while the three waste emissions and energy consumption are significantly reduced. From the traditional batch reaction kettle reaction of 10-40 hours to 1-5 hours can be completed.

[0029] (2) The present application realizes the stable full continuous industrial production from raw materials to diclofenac sodium, and the process is continuous and uninterrupted, with high automation degree, no external intervention in the middle, high space-time efficiency, greatly reducing the number of operating workers and labor intensity, and significantly reducing the production cost.

[0030] (3) The present application avoids the complicated operation, the danger of kettle temperature and material spraying in the traditional reaction kettle process, improves the production safety, and ensures the quality of diclofenac sodium product.

[0031] (4) The purity of the product is greater than 98.5%, and the total yield is greater than 60% based on diclofenac sodium.

[0032] (5) In addition, the present application also reduces the amount of aluminum chloride by more than 30%, effectively reduces the material loss caused by solvent switching, and reduces the production cost. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 It is a full continuous chemical synthesis process flow chart of diclofenac sodium.

[0034] Figure 2 It is a dynamic continuous stirring reactor diagram.

[0035] Label in the figure: 1-heat transfer fluid outlet, 2-heat transfer fluid interlayer, 3-coaxial multi-paddle stirring, 4-heat transfer fluid inlet, 5-motor, 6-bottom plate, 7-support frame, 8-reaction material outlet, 9-reaction material inlet. DETAILED DESCRIPTION

[0036] The present application will be further described below by combining the embodiments with the drawings.

[0037] Example 1

[0038] Aniline (0.1 kg / L, 1.0 eq) was dispersed into chlorobenzene, chloroacetyl chloride (1.1 eq) was dispersed into chlorobenzene, and the two streams were mixed thoroughly by passing through micromixer 1 and then acylation reaction was carried out in reactor 1, 2 at 100°C for 20 min to form 2-chloroacetanilide. Then 2,6-dichlorophenol and base solution were premixed, and then mixed thoroughly with the above reaction solution by passing through micromixer 2 and then fed into microreactor 1, where condensation reaction occurred at 100°C for 15 min to form 2-(2,6-dichlorophenoxy)-N-phenylacetamide. Then the reaction solution was mixed thoroughly with potassium carbonate solution (1.5 eq) by passing through micromixer 3, and then rearrangement reaction was carried out in microreactor 2 at 150°C for 20 min to form 2,6-dichloro-N-phenyl aniline. The reaction solution was fed into back pressure valve 1 (10 bar) to adjust the reaction pressure in microreactor 1 and 2, and then into a small buffer tank.

[0039] The reaction solution in buffer tank 2 was fed into a solvent recovery system by a plunger pump, and solvent was recovered under reduced pressure at 100°C and 50 mbar vacuum for 20 min. Then the concentrated solution was fed into a small buffer tank by a peristaltic pump.

[0040] The concentrated reaction solution was mixed with chloroacetyl chloride solution (1.5 eq) by passing through micromixer 4, and then acylation reaction occurred in microreactor 3 at 150°C for 60 min to form 2,2',6'-trichloro-N-phenylacetanilide. The reaction solution was fed into back pressure valve 2 (10 bar) to adjust the reaction pressure in microreactor 3. Then the reaction solution was fed into a reactor tank to carry out complexation with anhydrous aluminum chloride (2.5 eq) at high temperature (100°C). After the solution was clarified, the reaction solution was fed into microreactor 4 by a plunger pump, and Friedel-Crafts alkylation reaction occurred at 160°C for 20 min to form 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one. The reaction solution was fed into back pressure valve 3 (15 bar) to adjust the reaction pressure in microreactor 4.

[0041] The reaction solution from back pressure valve 3 was mixed with 10% hydrochloric acid solution by passing through micromixer 5, and then fed into a gravity separation column. The organic phase was fed into a small buffer tank by a peristaltic pump, and then mixed with 20% sodium hydroxide solution by passing through micromixer 6. The mixture was fed into microreactor 5, and hydrolysis reaction occurred at 90°C for 10 min to form sodium diclofenac.

[0042] After the reaction solution was separated by the gravity separation column, the aqueous phase was directly fed into a continuous crystallizer to crystallize at a reduced temperature to obtain sodium diclofenac solids. The sodium diclofenac solids were filtered and dried to obtain the finished product of sodium diclofenac with a purity of 99% and a total yield of 65% based on sodium diclofenac. The total reaction time was 165 min.

[0043] Example 2

[0044] Aniline (0.1 kg / L, 1.0 eq) was dispersed into chlorobenzene, chloroacetyl chloride (1.2 eq) was dispersed into chlorobenzene, and the two streams were mixed thoroughly by passing through micromixer 1 and then into reactor 1, 2, and acylation reaction was carried out at 100 °C for 20 min to form 2-chloroacetanilide. Then 2,6-dichlorophenol and base solution were premixed, and then mixed thoroughly with the above reaction solution by passing through micromixer 2 and then into microreactor 1, and condensation reaction was carried out at 100 °C for 15 min to form 2-(2,6-dichlorophenoxy)-N-phenylacetamide. Then the reaction solution was mixed thoroughly with sodium hydroxide solution (1.5 eq) by passing through micromixer 3, and then rearrangement reaction was carried out at 150 °C for 20 min in microreactor 2 to form 2,6-dichloro-N-phenyl aniline. The reaction solution was then passed into back pressure valve 1 (8 bar) to adjust the reaction pressure in microreactor 1 and 2, and then into a small buffer tank.

[0045] The reaction solution in buffer tank 2 was outputted into a solvent recovery system by a plunger pump, and the solvent was recovered under reduced pressure at 100 °C and a vacuum degree of 50 mbar for 20 min. Then the concentrated solution was outputted into a small buffer tank by a peristaltic pump.

[0046] The concentrated reaction solution was mixed thoroughly with chloroacetyl chloride solution (1.3 eq) by passing through micromixer 4 and then into microreactor 3, and acylation reaction was carried out at 150 °C for 80 min to form 2,2',6'-trichloro-N-phenylacetanilide. The reaction solution was then passed into back pressure valve 2 (10 bar) to adjust the reaction pressure in microreactor 3. The reaction solution was then passed into a reactor tank and complexed with anhydrous aluminum chloride (2.0 eq) at high temperature (100 °C). After the solution was clarified, the reaction solution was inputted into microreactor 4, and Friedel-Crafts alkylation reaction was carried out at 180 °C for 20 min to form 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one. The reaction solution was then passed into back pressure valve 3 (10 bar) to adjust the reaction pressure in microreactor 4.

[0047] The reaction solution from back pressure valve 3 was mixed thoroughly with 10% hydrochloric acid solution by passing through micromixer 5 and then into a gravity separation column. The organic phase was then inputted into a small buffer tank by a peristaltic pump, and then mixed thoroughly with 20% sodium hydroxide solution by passing through micromixer 6 and then into microreactor 5. Hydrolysis reaction was carried out at 100 °C for 10 min to form diclofenac sodium.

[0048] The reaction solution is separated by a gravity separation column, and the water phase is directly transported to a continuous crystallizer for cooling crystallization to obtain sodium diclofenac solid. After filtration and drying, the sodium diclofenac product is obtained, with a purity of 99.2% and a total yield of 62% based on sodium diclofenac, and the total reaction time is 185 min.

[0049] Example 3

[0050] Aniline (0.1 kg / L, 1.0 eq) is dispersed in chlorobenzene, chloroacetyl chloride (1.2 eq) is dispersed in chlorobenzene, and the two streams are mixed by a pump through a micro-mixer 1, and then the mixture is acylated in a reaction kettle 1, 2 at 120°C for 20 min to generate 2-chloroacetanilide. Then 2,6-dichlorophenol and a base solution are premixed, and then mixed with the reaction solution of the previous step by a micro-mixer 2, and then the mixture is introduced into a micro-reactor 1 at 110°C for 15 min to generate 2-(2,6-dichlorophenoxy)-N-phenylacetamide by condensation reaction. Then the reaction solution is mixed with a potassium hydroxide solution (1.2 eq) by a micro-mixer 3, and then the mixture is rearranged in a micro-reactor 2 at 120°C for 20 min to generate 2,6-dichloro-N-phenylphenylamine. The reaction solution flows into a back pressure valve 1 (10 bar) to adjust the reaction pressure in the micro-reactors 1 and 2, and then flows into a small buffer tank.

[0051] The reaction solution in the buffer tank 2 is output by a plunger pump into a solvent recovery system, and the solvent is recovered under reduced pressure at 100°C and a vacuum degree of 50 mbar for 30 min. Then the concentrated solution is output by a peristaltic pump into a small buffer tank.

[0052] The concentrated reaction solution is mixed with a chloroacetyl chloride solution (1.2 eq) by a pump in a micro-mixer 4, and then the mixture is introduced into a micro-reactor 3 at 170°C for 50 min to generate 2,2',6'-trichloro-N-phenylacetanilide by acylation. The reaction solution flows into a back pressure valve 2 (15 bar) to adjust the pressure in the micro-reactor 3. Then the reaction solution flows into a reaction tank and is complexed with anhydrous aluminum chloride (2.0 eq) at high temperature (120°C). After the solution is clarified, the reaction solution is input into a micro-reactor 4 by a plunger pump, and then Friedel-Crafts alkylation occurs at 200°C for 20 min to generate 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one. The reaction solution enters a back pressure valve 3 (15 bar) to control and adjust the reaction pressure in the micro-reactor 4.

[0053] The reaction solution flowed out from the back pressure valve 3 is mixed with 10% hydrochloric acid solution in the micro-mixer 5 by pump, and then enters the gravity separation column. Subsequently, the organic phase is input into a small buffer tank by a peristaltic pump, and then is output by a plunger pump and mixed with 20% sodium hydroxide solution in the micro-mixer 6. The mixture enters the micro-reactor 5, and a hydrolysis reaction occurs at 80°C for 30 min to generate diclofenac sodium.

[0054] After the reaction solution is separated by the gravity separation column, the water phase is directly transported to the continuous crystallizer for cooling crystallization to obtain diclofenac sodium solid. After filtration and drying, the diclofenac sodium product is obtained, with a purity of 98.7% and a total yield of 63% based on diclofenac sodium. The total reaction time is 185 min.

[0055] It should be noted that although the above embodiments have been described in the present text, the patent protection scope of the present application is not limited thereby. Therefore, based on the innovative idea of the present application, changes and modifications to the embodiments described in the present text, or equivalent structures or equivalent process transformations made using the content of the present application specification and drawings, direct or indirect application of the above technical solutions to other related technical fields, are all included in the protection scope of the claims of the present application.

Claims

1. A fully continuous chemical synthesis process of Diclofenac sodium characterized in that, The full continuous reaction device is composed of a plurality of sequentially connected micro-mixers, micro-reactors, online solvent recovery and other devices, and is used for full continuous chemical synthesis of diclofenac sodium; the specific steps are as follows: (a) dispersing aniline into a solvent, denoted as feed liquid A, dispersing chloroacetyl chloride into a solution, denoted as feed liquid B; feed liquid A and feed liquid B are first input into a first micro-mixer for fully mixing, and then are input into a first reaction kettle and a second reaction kettle for reaction, to generate a reaction liquid containing 2-chloroacetanilide; the reaction liquid is flowed into a first buffer tank to obtain a solution of product 2-chloroacetanilide, denoted as feed liquid C; (b) pre-mixing 2,6-dichlorophenol and alkali in a solution as feed liquid D; fully mixing feed liquid C and feed liquid D in a second micro-mixer, and then inputting into a first micro-reactor for condensation reaction, to generate 2-(2,6-dichlorophenoxy)-N-phenylacetamide, denoted as feed liquid E, which is input into the next step reaction; (c) inputting feed liquid E and alkali solution into a third micro-mixer for mixing, and then inputting into a second micro-reactor for rearrangement reaction, to prepare intermediate product 2,6-dichloro-N-phenylphenylamine; the reaction system is back-pressured by a first back pressure valve, and is filtered online to remove generated solid salts, to obtain a solution of 2,6-dichloro-N-phenylphenylamine, denoted as feed liquid F, which is flowed into the next step reaction; (d) solution concentration and solvent recovery: flowing the above-mentioned feed liquid F into a solvent recovery device, and performing solution concentration in the recovery device; by means of reduced pressure distillation, the obtained solvent is recovered and reused; after the concentration is completed, the concentrated liquid is denoted as feed liquid G, which is flowed into the next step reaction; (e) dispersing chloroacetyl chloride into a solvent, denoted as feed liquid H; inputting feed liquid G and feed liquid H into a micro-mixer 4 for fully mixing, and then inputting into a micro-reactor 3 for reaction; the reaction system is back-pressured by a back pressure valve 2, to generate 2,2',6'-trichloro-N-phenylacetanilide; the reaction liquid is flowed into a reaction kettle 3 and a reaction kettle 4, denoted as feed liquid I; (f) pre-mixing feed liquid I and aluminum trichloride in the reaction kettle 3 and 4, heating the reaction kettle by a circulating oil bath device to form a complex; after the solution is clarified, it is denoted as feed liquid J and is input into a micro-reactor 4 for reaction, to generate 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one; the reaction system is back-pressured by a back pressure valve 3; after the reaction liquid is flowed out, it is quenched by acid to obtain a product 1-(2,6-dichlorophenyl)-1,3-dihydro-2H-indol-2-one solution, denoted as feed liquid K, which is input into the next step reaction; (g) fully mixing feed liquid K and alkali solution in a fifth micro-mixer, and then inputting into a fifth micro-reactor 5 for hydrolysis reaction, to prepare a final product diclofenac sodium solution; the reaction system is back-pressured by a fourth back pressure valve; after the organic phase is removed by online liquid separation, the diclofenac sodium solution is flowed into a continuous crystallizer to wait for precipitation; (h) performing decolorization, recrystallization, filtration and drying on the crude diclofenac sodium precipitated from the above-mentioned solution, to prepare a diclofenac sodium product.

2. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 1, wherein, The aniline, chloroacetyl chloride in step (a) and step (e) are dispersed into solvent as raw material solution, the solvent is selected from toluene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, dichloromethane, trichloromethane, cyclohexane, n-hexane, acetone.

3. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 1, wherein, The base in step (b), step (c) and step (g) is selected from the group consisting of sodium bicarbonate, sodium methoxide, potassium carbonate, sodium hydroxide, triethylamine, trimethylamine, N,N - diisopropylethylamine.

4. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein, The solvent for configuring the base solution in step (b), step (c) and step (g) is selected from amyl alcohol, butanol, isobutyl alcohol, tert-butyl alcohol, propyl alcohol, isopropyl alcohol, ethanol, methanol, water, diethyl ether, acetone, butanone, methyl isobutyl ketone.

5. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein The amount of the base in step (b) is 0.8-2.0 equivalent of raw material; the amount of the base in step (c) is 1.0-3.0 equivalent of raw material; the amount of the base in step (g) is 3.0-8.0 equivalent of raw material; the amount of the acid in step (f) is 1.0-5.0 equivalent of product.

6. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein, The reaction temperature of the micro-reactor 1 is 90-200 o C, and the reaction time is 15-60 min; the reaction temperature of the micro-reactor 2 is 100-300 o C, and the reaction time is 15-75 min; the reaction temperature of the micro-reactor 3 is 100-300 o C, and the reaction time is 20-40 min; the reaction temperature of the micro-reactor 4 is 90-190 o C, and the reaction time is 10-30 min; the reaction temperature of the micro-reactor 4 is 90-190 o C, and the reaction time is 10-30 min; the reaction temperature of the reaction kettle 1 is 60-150 o C, and the reaction time is 1-20 min; the reaction temperature of the reaction kettle 2 is 60-150 o C, and the reaction time is 5-50 min; the reaction temperature of the reaction kettle 3 is 60-150 o C, and the reaction time is 10-40 min; the reaction temperature of the reaction kettle 4 is 60-150 o C, and the reaction time is 10-40 min.

7. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein, The microreactor 2 is a dynamic continuous stirring reactor, which is horizontal or vertical multi-stage rotary stirring reactor with heat exchange jacket, the inside is circular, the inner diameter is 10-500 mm, the length is 0.1-50 m; the diameter of the reactor 1 and the reactor 2 is 5-1000 mm, the length-diameter ratio is 5:1-50:1; the diameter of the reactor 3 and the reactor 4 is 100-1000 mm, the length-diameter ratio is 10:1-50:

1.

8. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein, The anticorrosive glass column in the solvent recovery device in step (d) is cylindrical in the inside, the inner diameter is 10-500 mm, the length is 0.1-50 m; The pressure of the vacuum concentration in step (d) is 1-100 mbar.

9. The process for the fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein, The pressure of the back pressure valve 1 in step (c) is 0-10 bar; the pressure of the back pressure valve 2 in step (e) is 1-20 bar; the pressure of the back pressure valve 3 in step (f) is 1-20 bar; the pressure of the back pressure valve 4 in step (g) is 1-20 bar.

10. The method of fully continuous chemical synthesis of diclofenac sodium as claimed in claim 3, wherein, The solvent used in recrystallization in step (h) is selected from water, methanol, ethanol, propanol, isopropanol.

Images