Continuous flow synthesis method of 4, 6-diamino resorcinol salt

Abstract

The invention provides a continuous flow synthesis method of 4, 6-diamino resorcinol salt, and belongs to the technical field of chemical synthesis. According to the method, the 4, 6-diamino resorcinol salt is synthesized by automatic control through a continuous flow synthesis route of acetyl protection of phenolic hydroxyl group, nitration, nitro reduction and deacetylation-acidification, the whole reaction process is carried out in a closed environment, the reaction safety and the reaction efficiency are improved, and the method is suitable for industrial production. According to the present invention, the conditions such as the use amount of each reactant, the pumping speed, the reaction time, the reaction temperature and the like are controlled, such that the synthesized 4, 6-diamino resorcinol salt has high purity and high yield, the purity and the yield of the product can respectively achieve 99.9% and 85.0%, and the wide application prospect in the continuous fluidization industrial production is provided.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a continuous flow synthesis method for 4,6-diaminoresorcinol salt. Background Technology

[0002] 4,6-Diaminoresorcinol salts (such as 4,6-diaminoresorcinol hydrochloride) are core raw materials for the preparation of various high-performance materials and functional products. They can be used to synthesize high-performance polymer materials and nanomaterials such as poly(2,5-thiophene benzobisoxazole) resin and two-dimensional nanoporous Pd-COF materials. They are also important raw materials for the preparation of functional fabrics and other products.

[0003] Currently, several methods for synthesizing 4,6-diaminoresorcinol salts have been disclosed in existing technologies. One method uses trichlorobenzene as a starting material and prepares 4,6-diaminoresorcinol salts through continuous reaction steps such as nitration, hydrolysis, and reductive dechlorination. However, this synthetic route has significant technical defects, specifically poor process stability, easy occurrence of uncontrolled side reactions and uneven product distribution during the reaction process, and is accompanied by the discharge of a large amount of wastewater, waste gas, and waste residue, which puts great pressure on the ecological environment. Moreover, the reaction efficiency is low, making it difficult to improve the yield of the target product and failing to meet the economic requirements of large-scale industrial production. Another method uses resorcinol as a starting material and obtains 4,6-diaminoresorcinol salts through multi-step reactions such as sulfonation, nitration, desulfonation, and reduction. However, the insufficient selectivity of the sulfonation reaction easily leads to the generation of multiple sulfonation by-products, and the subsequent desulfonation step is also difficult to completely remove the sulfonated substituents, resulting in a decrease in the purity of the final product.

[0004] Therefore, existing methods for synthesizing 4,6-diaminoresorcinol salts generally suffer from poor process stability, large emissions of waste, low reaction efficiency and product yield, and insufficient product purity. These methods fail to simultaneously meet the economic, environmental, and product quality requirements of industrial production. Developing a stable, safe, and environmentally friendly method for synthesizing 4,6-diaminoresorcinol salts that can simultaneously guarantee high yield and high purity of the target product has significant industrial application value and practical significance. Summary of the Invention

[0005] The purpose of this invention is to provide a continuous flow synthesis method for 4,6-diaminoresorcinol salt.

[0006] This invention provides a continuous flow synthesis method for 4,6-diaminoresorcinol salt, the method being carried out in a continuous flow reactor and comprising the following steps: (1) Synthesis of intermediate 1: Resorcinol, acetylation reagent, and organic solvent are mixed to obtain mixture A. Mixture A is preheated in the first continuous flow preheater via metering pump A, and the acid-binding agent is preheated in the second continuous flow preheater via metering pump B. After preheating, mixture A and the acid-binding agent are simultaneously mixed in the first continuous flow mixer to obtain mixture B. Then, mixture B is reacted in the first continuous flow reactor to obtain reaction solution A. Reaction solution A is introduced into the second continuous flow mixer, and water is introduced into the second continuous flow mixer via metering pump C. Reaction solution A and water are mixed in the second continuous flow mixer to obtain mixture C. Then, mixture C is separated in the first continuous flow separator to collect organic phase 1, i.e., the organic solvent containing intermediate 1. The intermediate 1 is resorcinol diacetate. (2) Synthesis of intermediate 2: Organic phase 1 is preheated in continuous flow preheater 3 via metering pump D; the preheated organic phase 1 enters the third continuous flow mixer, while the acetylation reagent enters the third continuous flow mixer via metering pump E and the nitration reagent enters the third continuous flow mixer via metering pump F. The preheated organic phase 1, acetylation reagent, and nitration reagent are mixed in the third continuous flow mixer to obtain mixture D; mixture D enters the second continuous flow reactor to react and obtain reaction solution B; reaction solution B enters the fourth continuous flow mixer, while water enters the fourth continuous flow mixer via metering pump G. The reaction solution B and water are mixed in the fourth continuous flow mixer to obtain mixture D; then, mixture D enters the second continuous flow separator to separate and collect organic phase 2, i.e., the organic solvent containing intermediate 2; the intermediate 2 is 1,3-diacetoxy-4,6-dinitrobenzene; (3) Synthesis of intermediate 3: Organic phase 2 and reducing agent are respectively fed into the fifth continuous flow mixer through metering pump H and metering pump I, and then into the third continuous flow reactor. The third continuous flow reactor is filled with catalyst. Organic phase 2, reducing agent and catalyst react in the third continuous flow reactor to obtain reaction liquid C. Reaction liquid C enters the third continuous flow separator for separation and collection of organic phase 3, i.e. organic solvent containing intermediate 3; the intermediate 3 is 4,6-diaminoresorcinol. (4) Organic phase 3 enters the sixth continuous flow mixer through metering pump J. At the same time, water enters the sixth continuous flow mixer through metering pump K. Organic phase 3 and water are mixed in the sixth continuous flow mixer to obtain mixture E. Mixture E enters the fourth continuous flow separator for separation and collection of organic phase 4. Organic phase 4 enters the salting kettle. At the same time, salting reagent is introduced into the salting kettle. Organic phase 4 and salting reagent react in the salting kettle. After the reaction is completed, the mixture is filtered to obtain 4,6-diaminoresorcinol salt.

[0007] Furthermore, the reaction of the synthetic intermediate 3 is carried out in a fixed-bed reactor, which includes a fifth continuous flow mixer and a third continuous flow reactor. In step (1), the circulating temperature of the first continuous flow preheater, the second continuous flow preheater, the first continuous flow mixer, and the first continuous flow reactor is 50-70℃; the circulating temperature of the second continuous flow mixer is 10-30℃. In step (2), the circulating temperature of the continuous flow preheater 3, the third continuous flow mixer, and the second continuous flow reactor is 60-80℃; the circulating temperature of the fourth continuous flow mixer is 10-30℃. In step (3), the circulating temperature of the fifth continuous flow mixer and the third continuous flow reactor is -5 to -5℃; In step (4), the circulation temperature of the sixth continuous flow mixer is 10-30℃.

[0008] Further, in step (1), the circulation temperature of the first continuous flow preheater, the second continuous flow preheater, the first continuous flow mixer, and the first continuous flow reactor is 60°C; the circulation temperature of the second continuous flow mixer is 20°C. In step (2), the circulating temperature of the continuous flow preheater 3, the third continuous flow mixer, and the second continuous flow reactor is 70°C; the circulating temperature of the fourth continuous flow mixer is 20°C. In step (3), the circulation temperature of the fifth continuous flow mixer and the third continuous flow reactor is 0°C; In step (4), the circulation temperature of the sixth continuous flow mixer is 20°C.

[0009] Further, in step (1), the flow rate of metering pump A is 430-1310 ml / min, the flow rate of metering pump B is 230-700 ml / min, the flow rate of metering pump C is 80-250 ml / min, the running time of metering pump A and metering pump B is 2.5-7.5 min, and the running time of metering pump C is 1.5-4.5 min; In step (2), the flow rate of metering pump D is 380-580 ml / min, the flow rate of metering pump E is 175-270 ml / min, the flow rate of metering pump F is 85-135 ml / min, the flow rate of metering pump G is 100-135 ml / min, the running time of metering pump D, metering pump E and metering pump F is 8-12 min, and the running time of metering pump G is 1.5-4.5 min; In step (3), the flow rate of metering pump H is 425-1075 ml / min, the flow rate of metering pump I is 220-550 ml / min, and the running time of metering pump H and metering pump I is 10-25 min. In step (4), the flow rate of metering pump J is 400-420 ml / min, and the flow rate of metering pump K is 115-135 ml / min.

[0010] Further, in step (1), the flow rate of metering pump A is 434.1-1302.4 ml / min, the flow rate of metering pump B is 231.5-697.6 ml / min, the flow rate of metering pump C is 81.3-250.0 ml / min, the running time of metering pump A and metering pump B is 2.5-7.5 min, and the running time of metering pump C is 1.5-4.5 min; In step (2), the flow rate of metering pump D is 381.8-572.6 ml / min, the flow rate of metering pump E is 178.8-268.3 ml / min, the flow rate of metering pump F is 89.2-133.8 ml / min, the flow rate of metering pump G is 104.0-133.7 ml / min, the running time of metering pumps D, E and F is 8-12 min, and the running time of metering pump G is 1.5-4.5 min; In step (3), the flow rate of metering pump H is 428.2-1071.0 ml / min, the flow rate of metering pump I is 220.0-550.0 ml / min, and the running time of metering pump H and metering pump I is 10-25 min. In step (4), the flow rate of metering pump J is 400.0-420.0 ml / min, and the flow rate of metering pump K is 115.0-135.0 ml / min.

[0011] Further, in step (1), the flow rate of metering pump A is 430-820 ml / min, the flow rate of metering pump B is 230-440 ml / min, the flow rate of metering pump C is 80-160 ml / min, and the running time of metering pump A and metering pump B is 4.0-7.5 min. In step (3), the flow rate of metering pump H is 425-720 ml / min, the flow rate of metering pump I is 215-370 ml / min, and the running time of metering pump H and metering pump I is 15-25 min.

[0012] Further, in step (1), the flow rate of metering pump A is 434.1-814.0 ml / min, the flow rate of metering pump B is 231.5-436.0 ml / min, the flow rate of metering pump C is 81.3-156.0 ml / min, and the running time of metering pump A and metering pump B is 4.0-7.5 min. In step (3), the flow rate of metering pump H is 428.2-714.0 ml / min, the flow rate of metering pump I is 220.0-366.7 ml / min, and the running time of metering pump H and metering pump I is 15-25 min.

[0013] Further, in step (1), the flow rate of metering pump A is 650-655 ml / min, the flow rate of metering pump B is 345-350 ml / min, the flow rate of metering pump C is 120-130 ml / min, the running time of metering pump A and metering pump B is 4.5-5.5 min, and the running time of metering pump C is 2.5-3.5 min; In step (2), the flow rate of metering pump D is 455-460 ml / min, the flow rate of metering pump E is 210-220 ml / min, the flow rate of metering pump F is 105-110 ml / min, the flow rate of metering pump G is 120-130 ml / min, the running time of metering pump D, metering pump E and metering pump F is 8-12 min, and the running time of metering pump G is 2.5-3.5 min; In step (3), the flow rate of metering pump H is 530-540 ml / min, the flow rate of metering pump I is 270-280 ml / min, and the running time of metering pump H and metering pump I is 18-22 min. In step (4), the flow rate of metering pump J is 405-415 ml / min, and the flow rate of metering pump K is 120-130 ml / min.

[0014] Further, in step (1), the flow rate of metering pump A is 651.2 ml / min, the flow rate of metering pump B is 348.8 ml / min, the flow rate of metering pump C is 125.0 ml / min, the running time of metering pump A and metering pump B is 5 min, and the running time of metering pump C is 3 min. In step (2), the flow rate of metering pump D is 458.1 ml / min, the flow rate of metering pump E is 214.6 ml / min, the flow rate of metering pump F is 107.0 ml / min, the flow rate of metering pump G is 125.0 ml / min, the running time of metering pump D, metering pump E and metering pump F is 10 min, and the running time of metering pump G is 3 min. In step (3), the flow rate of metering pump H is 535.5 ml / min, the flow rate of metering pump I is 275.0 ml / min, and the running time of metering pump H and metering pump I is 20 min. In step (4), the flow rate of metering pump J is 410.7 ml / min and the flow rate of metering pump K is 125.0 ml / min.

[0015] Further, in step (1), the molar ratio of resorcinol, acetylation reagent, and acid-binding agent is (5-15):(15-25):(15-25); the molar ratio of resorcinol to organic solvent is (5-15):(20-45). In step (2), the molar ratio of organic phase 1, acetylation reagent, and nitration reagent is (5-15):(15-25):(15-25); In step (3), the molar ratio of organic phase 2, reducing agent and catalyst is (5-15):(30-40):(1-2.5); In step (4), the molar ratio of resorcinol to salt-forming reagent is (5-15):(20-35).

[0016] Further, in step (1), the molar amounts of resorcinol, acetylation reagent, and acid-binding agent are (8-12):(17-22):(18-22), respectively; the molar ratio of resorcinol to organic solvent is (8-12):(35-40). In step (2), the molar amounts of organic phase 1, acetylation reagent, and nitration reagent are (8-12):(16-20):(18-22), respectively; In step (3), the molar amounts of organic phase 2, reducing agent and catalyst are (8-12) : (34-38) : (1.5-2); In step (4), the molar ratio of resorcinol to salt-forming reagent is (8-12):(25-30).

[0017] Further, the acetylation reagent is selected from one or a mixture of two of acetic anhydride and acetyl chloride; the organic solvent includes dichloromethane or dichloroethane; the acid-binding agent includes triethylamine, tributylamine, or diisopropylethylamine; the nitrating reagent includes nitric acid nitrating reagents, nitric acid-anhydride complex nitrating reagents, nitrogen oxide nitrating reagents, alkyl nitrate ester nitrating reagents, or nitronium salt nitrating reagents; the reducing agent includes hydrazine hydrate or hydrogen; the catalyst includes nickel, γ-Fe2O3 / C, or palladium on carbon; and the salt-forming reagent includes inorganic acid or organic acid.

[0018] Preferably, the catalyst is a self-made active iron catalyst, which is safer and more economical, and is prepared by the following method: ferric chloride hexahydrate and sodium hydroxide in a mass ratio of (2-4):(1-2) are respectively prepared into aqueous solutions with a mass fraction of 3-8%. The ferric chloride aqueous solution is rapidly added dropwise to the sodium hydroxide aqueous solution, stirred for 0.5-1.5 hours, allowed to stand, filtered, washed with water, dried, and the solid dispersed. Then, it is dried at 120-160℃ for 2-5 hours, and cooled to obtain the active iron catalyst.

[0019] Further, the nitric acid nitrating reagents include fuming nitric acid, dilute nitric acid, concentrated nitric acid, sodium nitrate-concentrated nitric acid composite reagent, potassium nitrate-concentrated nitric acid composite reagent, ammonium nitrate-concentrated nitric acid composite reagent, nitric acid-concentrated sulfuric acid composite reagent, or nitric acid-concentrated hydrochloric acid composite reagent; the nitric acid-anhydride composite nitrating reagents include nitric acid-acetic anhydride composite reagent, fuming nitric acid-acetic anhydride composite reagent, nitric acid-propionic anhydride composite reagent, fuming nitric acid-propionic anhydride composite reagent, nitric acid-trifluoroacetic anhydride composite reagent, nitric acid-phthalic anhydride composite reagent, or nitric acid-fluorosulfonic acid composite reagent; the nitrogen oxide nitrating reagents The reagents include nitrogen dioxide-nitrogen tetroxide composite reagents, nitrogen trioxide, or nitrogen pentoxide; the alkyl nitrate nitrating reagents include methyl nitrate, ethyl nitrate, n-pentyl nitrate, neopentyl nitrate, tert-butyl nitrate, or isoamyl nitrate; the nitonium salt nitrating reagents include nitonium tetrafluoroborate, nitonium hexafluorophosphate, nitonium hexafluoroarsenate, or nitonium trifluoromethanesulfonate; the inorganic acids include at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, carbonic acid, and sodium dihydrogen phosphate; and the organic acids include at least one of acetic acid, propionic acid, citric acid, maleic acid, aromatic carboxylic acids, alkyl sulfonic acids, and aromatic sulfonic acids.

[0020] This invention employs continuous flow technology with automated control to synthesize 4,6-diaminoresorcinol salt, making both nitration and reduction steps safer. Simultaneously, a strategy of protecting the phenolic hydroxyl group with acetyl groups before nitration is adopted to avoid phenol oxidation during nitration, inhibiting the formation of nitrated isomers. Unprotected phenol is directly nitrated, with isomers accounting for 10-20%. Utilizing this protection-before-nitration strategy, combined with continuous flow and timely quenching to terminate the reaction without backmixing, excessive reaction is effectively suppressed, keeping the nitrated isomer content below 2%, significantly improving nitration selectivity. The catalyst in the reaction of reducing nitro to amino is packed in a fixed-bed reactor and continuously kept in a closed system, which is more conducive to maintaining its activity; the reduction of nitro and deacetylation are combined, shortening the route, simplifying the operation, and improving the yield; moreover, the solvent used in the method of this invention is singular and can be recycled, with only a small amount of wastewater, making it green and environmentally friendly.

[0021] As is well known to those skilled in the art, reactions carried out in continuous flow reactors have the advantages of high efficiency and time saving. Moreover, the entire process is carried out in a closed system, overcoming the problems of separate feeding, separation, and low yield in traditional batch reactors, thus simplifying the process. However, obtaining high-yield and high-purity target products using continuous flow reactors requires creative effort.

[0022] Experiments have demonstrated that this invention, by controlling reaction conditions such as the amount of reactants, pumping rate, reaction time, and reaction temperature, achieves both high purity and high yield of the synthesized 4,6-diaminoresorcinol salt. Specifically, the purity of the synthesized 4,6-diaminoresorcinol hydrochloride can reach up to 99.9%, and the yield can reach up to 85.0%. This method is efficient, safe, and environmentally friendly, and the synthesized 4,6-diaminoresorcinol salt exhibits high purity and high yield, showing broad application prospects in continuous fluidized bed industrial production.

[0023] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0024] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0025] Figure 1 This is a flow chart of the continuous flow synthesis process for 4,6-diaminoresorcinol hydrochloride.

[0026] Figure 2 This is a route diagram for the synthesis of 4,6-diaminoresorcinol hydrochloride.

[0027] Figure 3 It is the 4,6-diaminoresorcinol hydrochloride of Example 1. 1 H NMR spectrum.

[0028] Figure 4 It is the 4,6-diaminoresorcinol hydrochloride of Example 1. 1 ¹H NMR (DMSO-d6) image.

[0029] Figure 5 This is a flow chart of a fixed-bed reactor for the synthesis of intermediate 3 (4,6-diaminoresorcinol), corresponding to... Figure 1 The portion within the Chinese frame. Detailed Implementation

[0030] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0031] In a specific embodiment, the continuous flow synthesis process for synthesizing 4,6-diaminoresorcinol hydrochloride is as follows: Figure 1 As shown, the reaction route is as follows Figure 2 As shown.

[0032] Example 1: Synthesis and Characterization of 4,6-Diaminoresorcinol Hydrochloride Synthesis of 1,4,6-diaminoresorcinol hydrochloride 4,6-Diaminoresorcinol hydrochloride was synthesized using the following method: (1) Synthetic intermediate 1 (resorcinol diacetate): Setting up the first continuous flow preheater ( Figure 1 Continuous flow preheater 1), second continuous flow preheater ( Figure 1 Continuous flow preheater 2), first continuous flow mixer ( Figure 1 Continuous flow mixer 1), First continuous flow reactor ( Figure 1 The circulating temperature of the continuous flow reactor 1 was set to 60℃, reaching a stable state; the second continuous flow mixer ( Figure 1 The circulating temperature of the continuous flow mixer 2) is 20℃, reaching a stable state; 1000g resorcinol (9.08mol), 1946.7g acetic anhydride (19.07mol), and 3000g dichloroethane (30.3mol) were mixed to obtain mixture A. Mixture A was preheated in the first continuous flow preheater via metering pump A. 2021.4g triethylamine (20.00mol) was preheated in the second continuous flow preheater via metering pump B. The preheated mixture A and triethylamine were then mixed in the first continuous flow mixer to obtain mixture B. Mixture B was then reacted in the first continuous flow reactor to obtain reaction solution A. Reaction solution A was then introduced into the second continuous flow mixer. Simultaneously, 1000g water was introduced into the second continuous flow mixer via metering pump C. Reaction solution A and water were mixed in the second continuous flow mixer to obtain mixture C. Finally, mixture C was introduced into the first continuous flow separator. Figure 1 Separate the liquid in the continuous flow separator 1) and collect organic phase 1, which is a dichloroethane solution containing intermediate 1; In this scenario, metering pumps A and B are turned on simultaneously, with the flow rate of metering pump A set to 651.2 ml / min and the flow rate of metering pump B set to 348.8 ml / min, both for a running time of 5 min; the flow rate of metering pump C is set to 125.0 ml / min, and the running time is set to 3 min. (2) Synthetic intermediate 2 (1,3-diacetoxy-4,6-dinitrophenyl): Set up a third continuous flow preheater ( Figure 1 Continuous flow preheater 3), third continuous flow mixer ( Figure 1 Continuous flow mixer 3), second continuous flow reactor ( Figure 1 The circulating temperature of the continuous flow reactor 2) is set at 70℃, reaching a stable state; the fourth continuous flow mixer ( Figure 1The continuous flow mixer 4) has a circulation temperature of 20℃, reaching a stable state; 4764g of organic phase 1 (9.08mol) was preheated in continuous flow preheater 3 via metering pump D. The preheated organic phase 1 then entered the third continuous flow mixer. Simultaneously, 1854.0g of acetic anhydride (18.16mol) and 1284.1g of fuming nitric acid (19.98mol) were introduced into the third continuous flow mixer via metering pump E and metering pump F, respectively. The preheated organic phase 1, acetic anhydride, and fuming nitric acid were mixed in the third continuous flow mixer to obtain mixture D. Mixture D was then introduced into the second continuous flow reactor to react, yielding reaction solution B. Reaction solution B entered the fourth continuous flow mixer. Simultaneously, 1000g of water was introduced into the fourth continuous flow mixer via metering pump G. Reaction solution B and water were mixed in the fourth continuous flow mixer to obtain mixture D. Finally, mixture D entered the second continuous flow separator. Figure 1 Separate the liquid in the continuous flow separator 2) and collect the organic phase 2, which is a dichloroethane solution containing intermediate 2; In this scenario, metering pumps D, E, and F are simultaneously activated, with the flow rates of metering pump D set to 458.1 ml / min, E to 214.6 ml / min, and F to 107.0 ml / min, all for a duration of 10 minutes. Metering pump G is set to a flow rate of 125.0 ml / min for a duration of 3 minutes. (3) Synthetic intermediate 3 (4,6-diaminoresorcinol): The reaction for synthesizing intermediate 3 is carried out in a fixed-bed reactor, such as... Figure 5 As shown, the fixed-bed reactor includes a fifth continuous flow mixer ( Figure 1 and Figure 5 The continuous flow mixer 5 and the third continuous flow reactor ( Figure 1 and Figure 5 Continuous flow reactor 3); The fifth continuous flow mixer and the third continuous flow reactor were set to a circulating temperature of 0°C to reach a steady state. 5580g of organic phase 2 (9.08mol) and 2272.8g of 80% hydrazine hydrate solution (36.32mol) were respectively fed into the fifth continuous flow mixer via metering pump H and metering pump I, and then into the third continuous flow reactor. The third continuous flow reactor was packed with 100g (1.7mol) of active iron catalyst to form a catalyst bed. Organic phase 2, 80% hydrazine hydrate, and active iron catalyst reacted in the third continuous flow reactor to obtain reaction solution C. Reaction solution C entered the third continuous flow separator. Figure 1 The liquid is separated in the continuous flow separator 3) and the organic phase 3 is collected. The organic phase 3 is a dichloroethane solution of intermediate 3. In this scenario, metering pump H and metering pump I are turned on simultaneously, with the flow rate of metering pump H set to 535.5 ml / min and the flow rate of metering pump I set to 275.0 ml / min, and the running time for both pumps is 20 min. (4) Synthesis of 4,6-diaminoresorcinol hydrochloride: Set the sixth continuous flow mixer ( Figure 1 The continuous flow mixer (6) reaches a stable state with a circulating temperature of 20℃. 4271g of organic phase 3 (9.08mol) enters the sixth continuous flow mixer via metering pump J. Simultaneously, 1000g of water enters the sixth continuous flow mixer via metering pump K. Organic phase 3 and water are mixed in the sixth continuous flow mixer to obtain mixture E. Mixture E then enters the fourth continuous flow separator. Figure 1 The organic phase 4 is collected by separating the liquid in the continuous flow separator 4. The organic phase 4 enters the salting vessel. At the same time, 994.3g of hydrogen chloride (27.24mol) is introduced into the salting vessel. The organic phase 4 and hydrogen chloride react in the salting vessel. After the reaction is completed, the precipitated solid is filtered under nitrogen protection. The filter cake is dried under reduced pressure to obtain 4,6-diaminoresorcinol hydrochloride. In this process, metering pumps J and K are turned on simultaneously, with the flow rate of metering pump J set to 410.7 ml / min and the flow rate of metering pump K set to 125.0 ml / min.

[0033] The active iron catalyst was prepared by the following method: 266.4 g of sodium hydroxide was dissolved in deionized water to prepare a 5% sodium hydroxide aqueous solution. Then, 600 g of ferric chloride hexahydrate was dissolved in deionized water to prepare a 5% aqueous solution and quickly added dropwise to the sodium hydroxide solution. The mixture was stirred for 1 hour, allowed to stand, the supernatant was poured off, the lower solid was filtered and washed with deionized water, most of the water was dried at 45°C, the solid was dispersed and then dried at 140°C for 3 hours. After cooling, 700 g of active iron catalyst (Fe2O3) was obtained.

[0034] Characterization of 2,4,6-diaminoresorcinol hydrochloride like Figure 3 As shown, 1 H NMR (D2O, 400MHz): δ (ppm) 7.13 (1H,s), 6.48 (1H,s).

[0035] like Figure 4 As shown, 1 H NMR (DMSO-d6, 400MHz): δ (ppm) 10.99 (2H,s), 9.79 (6H,s), 7.43 (1H,s), 6.87 (1H,s).

[0036] This demonstrates the successful synthesis of 4,6-diaminoresorcinol hydrochloride in this embodiment.

[0037] Example 2: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the dichloroethane used in step (1) is replaced with dichloromethane.

[0038] Example 3: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the dichloroethane used in step (1) is 2000g.

[0039] Example 4: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the dichloroethane used in step (1) is 4000g.

[0040] Example 5: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (1), the flow rate of metering pump A is set to 1302.4 ml / min, the flow rate of metering pump B is set to 697.6 ml / min, and the running time is 2.5 min; the flow rate of metering pump C is set to 250.0 ml / min.

[0041] Example 6: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (1), the flow rate of metering pump A is set to 814.0 ml / min, the flow rate of metering pump B is set to 436.0 ml / min, and the running time is 4 min; the flow rate of metering pump C is set to 156.0 ml / min.

[0042] Example 7: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (1), the flow rate of metering pump A is set to 434.1 ml / min, the flow rate of metering pump B is set to 232.5 ml / min, and the running time is 7.5 min; the flow rate of metering pump C is set to 81.3 ml / min.

[0043] Example 8: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of acetic anhydride in step (1) is 2039.3g (19.98mol).

[0044] Example 9: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of acetic anhydride in step (1) is 1854 g (18.16 mol).

[0045] Example 10: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (1), the circulation temperature of the first continuous flow preheater, the second continuous flow preheater, the first continuous flow mixer, and the first continuous flow reactor is set to 50°C.

[0046] Example 11: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (1), the circulation temperature of the first continuous flow preheater, the second continuous flow preheater, the first continuous flow mixer, and the first continuous flow reactor is set to 70°C.

[0047] Example 12: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of fuming nitric acid in step (2) is 1167.4 g (18.16 mol).

[0048] Example 13: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of fuming nitric acid in step (2) is 1400.9g (21.65mol).

[0049] Example 14: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (2), acetic anhydride is replaced with 1780.0g of sulfuric acid (18.16mol).

[0050] Example 15: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of acetic anhydride in step (2) is 927.0 g (9.08 mol).

[0051] Example 16: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the metering pump E is not turned on in step (2), and only the preheated organic phase 1 and fuming nitric acid are mixed in the third continuous flow mixer.

[0052] Example 17: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (2), the circulation temperature of the second continuous flow preheater, the third continuous flow mixer, and the second continuous flow reactor is set to 60°C.

[0053] Example 18: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (2), the circulation temperature of the second continuous flow preheater, the third continuous flow mixer, and the second continuous flow reactor is set to 80°C.

[0054] Example 19: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (2), the flow rate of metering pump D is set to 572.6 ml / min, the flow rate of metering pump E is set to 268.3 ml / min, the flow rate of metering pump F is set to 133.8 ml / min, and the running time is 8 min for all of them; the flow rate of metering pump G is set to 133.7 ml / min.

[0055] Example 20: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (2), the flow rate of metering pump D is set to 381.8 ml / min, the flow rate of metering pump E is set to 178.8 ml / min, the flow rate of metering pump F is set to 89.2 ml / min, and the running time is 12 min; the flow rate of metering pump G is set to 104.0 ml / min.

[0056] Example 21: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of the 80% hydrazine hydrate solution in step (3) is 1704.6 g (27.24 mol).

[0057] Example 22: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that the mass of the 80% hydrazine hydrate solution in step (3) is 2841.4g (45.40mol).

[0058] Example 23: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (3), the circulation temperature of the fifth continuous flow mixer and the third continuous flow reactor is set to -5°C.

[0059] Example 24: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (3), the circulation temperature of the fifth continuous flow mixer and the third continuous flow reactor is set to 5°C.

[0060] Example 25: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (3), the flow rate of metering pump H is set to 1071.0 ml / min, the flow rate of metering pump I is set to 550.0 ml / min, and the running time is 10 min.

[0061] Example 26: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (3), the flow rate of metering pump H is set to 714.0 ml / min, the flow rate of metering pump I is set to 366.7 ml / min, and the running time is 15 min.

[0062] Example 27: Synthesis of 4,6-diaminoresorcinol hydrochloride Referring to Example 1, the only difference is that in step (3), the flow rate of metering pump H is set to 428.2 ml / min, the flow rate of metering pump I is set to 220.0 ml / min, and the running time is 25 min.

[0063] The following experimental examples demonstrate the beneficial effects of the present invention.

[0064] Experimental Example 1: Determination of the purity and yield of 4,6-diaminoresorcinol hydrochloride 1. Detection Method The purity of the 4,6-diaminoresorcinol hydrochloride synthesized in Examples 1-27 was determined by high performance liquid chromatography (HPLC).

[0065] Yield calculation: Theoretical yield of 4,6-diaminoresorcinol hydrochloride: 9.08 mol 213.06 g / mol = 1934.58 g, yield = actual yield of 4,6-diaminoresorcinol hydrochloride / theoretical yield.

[0066] 2. Experimental Results As shown in Table 1, the purity of Example 1 of the present invention is as high as 99.9%, and the yield is as high as 85.0%. Compared with Example 1, the yield of Example 2, which uses dichloromethane as the organic solvent, is reduced to 80.6%. This shows that a higher product yield can be achieved by selecting a suitable organic solvent.

[0067] Compared to Example 1, Example 3 used less dichloroethane in intermediate 1, which did not affect the yield, but there was a risk of solid precipitation during the reaction, which could easily clog the continuous flow equipment and make the reaction unstable. Example 4 used more dichloroethane in intermediate 1, resulting in greater product loss during the reaction and a slight decrease in yield. Example 5 used a metering pump with a fast flow rate and short running time for intermediate 1, leading to a significant decrease in yield to only 65.7%. Example 7 used a metering pump with a slow flow rate and long running time for intermediate 1, which did not significantly improve the yield and also reduced production capacity. Example 10 used a low reaction temperature for intermediate 1, resulting in a significant decrease in yield to 75.0%. Example 11 used a high reaction temperature for intermediate 1, resulting in a slight decrease in yield.

[0068] Example 12 shows that the amount of fuming nitric acid used in the synthesis of intermediate 2 was small, resulting in a significantly reduced yield of 79.7%. Example 13 shows that the amount of intermediate 2 used was large, which failed to improve the yield and wasted production capacity. Example 14 shows that the combination of sulfuric acid and fuming nitric acid was used in the synthesis of intermediate 2, resulting in a decrease in both purity and yield. Example 15 shows that the amount of acetic anhydride used in the synthesis of intermediate 2 was small, resulting in a significantly reduced yield, with a purity of only 98.4% and a yield of only 70.6%. Example 16 shows that acetic anhydride was not used in the synthesis of intermediate 2, resulting in a significant decrease in both purity and yield, with a purity of only 98.7% and a yield of only 55.8%. Example 17 shows that the reaction temperature was low in the synthesis of intermediate 2, resulting in a significant decrease in both purity and yield, with a purity of only 98.5% and a yield of only 78.5%. Example 18 shows that the reaction temperature was high in the synthesis of intermediate 2, resulting in a slight decrease in yield.

[0069] In Example 21, the amount of hydrazine hydrate used in the synthesis of intermediate 3 was small, resulting in a significant decrease in both purity and yield, with purity and yield of only 97.8% and 70.5%, respectively. In Example 22, the amount of hydrazine hydrate used in the synthesis of intermediate 3 was large, but the yield did not improve. In Example 23, the reaction temperature was low, resulting in a slight decrease in yield. In Example 24, the reaction temperature was high, resulting in a slight decrease in yield. In Examples 25 and 26, the metering pump flow rate was high and the running time was short, leading to a significant decrease in purity and yield. The purity and yield of Example 25 were only 95.1% and 60.3%, respectively, and the purity and yield of Example 26 were only 98.6% and 75.6%, respectively.

[0070] The above experimental results demonstrate that, in the synthesis of intermediates 1, 2, and 3, it is necessary to control the amount of each reactant, the reaction temperature, and the flow rate and running time of each metering pump to simultaneously achieve high purity, high yield, and high production capacity. Specifically, in the reaction for synthesizing intermediate 1, the preferred organic solvent is dichloroethane; the flow rate of metering pump A is 651.2 ml / min, the flow rate of metering pump B is 348.8 ml / min, and the flow rate of metering pump C is 125.0 ml / min; the running time of metering pumps A and B is 5 min each; the amount of acetic anhydride is 18.16 mol, and the reaction temperature is 60℃. In the reaction for synthesizing intermediate 2, the preferred nitrating agent is a combination of 19.98 mol fuming nitric acid and 18.16 mol acetic anhydride; the flow rate of metering pump D is 458.1 ml / min, and the flow rate of metering pump E is 214.6 ml / min. In the reaction of intermediate 3, the flow rate of metering pump F was 107.0 ml / min, the flow rate of metering pump G was 125.0 ml / min, and the running time of metering pumps D, E, and F was 10 min each; the reaction temperature was 70 °C; in the reaction of synthesizing intermediate 3, the preferred amounts of hydrazine hydrate were 36.32 mol; the flow rate of metering pump H was 535.5 ml / min, the flow rate of metering pump I was 275.0 ml / min, and the running time of metering pumps H and I was 20 min each; the reaction temperature was 0 °C; the purity of the finally synthesized 4,6-diaminoresorcinol hydrochloride reached 99.9%, and the yield was as high as 85%.

[0071] Meanwhile, in the reaction for synthesizing intermediate 1, the organic solvent was dichloroethane; the flow rate of metering pump A was 434.1-814.0 ml / min, the flow rate of metering pump B was 231.5-436.0 ml / min, and the flow rate of metering pump C was 81.3-156.0 ml / min; the running time of metering pumps A and B was 4.0-7.5 min, and the running time of metering pump C was 1.5-4.5 min; the amount of acetic anhydride used was 18.16-19.98 mol, and the reaction temperature was 50-70℃. In the reaction for synthesizing intermediate 2, the nitrating agent was a combination of 18.16-21.65 mol of fuming nitric acid and 9.08-18.16 mol of acetic anhydride; the flow rate of metering pump D was 381.8-572.6 ml / min, and the flow rate of metering pump E was 178.8-268.3 ml / min. The flow rate of metering pump F was 89.2-133.8 ml / min, the flow rate of metering pump G was 104.0-133.7 ml / min, the running time of metering pumps D, E, and F was 8-12 min, and the running time of metering pump G was 1.5-4.5 min; the reaction temperature was 60-80℃; in the reaction for synthesizing intermediate 3, the amount of hydrazine hydrate was 27.24-45.40 mol, the flow rate of metering pump H was 428.2-714.0 ml / min, the flow rate of metering pump I was 220.0-366.7 ml / min, and the running time of metering pumps H and I was 15-25 min; the reaction temperature was -5℃ to -5℃; the purity of the finally synthesized 4,6-diaminoresorcinol hydrochloride could reach over 97%, and the yield could reach over 70%.

[0072] Table 1. Purity and yield of 4,6-diaminoresorcinol hydrochloride synthesized in Examples 1-27 In summary, this invention successfully synthesized 4,6-diaminoresorcinol hydrochloride using continuous flow technology and automated control. The strategy of protecting the phenolic hydroxyl group with an acetyl group before nitration avoids phenol oxidation during nitration. Simultaneously, by appropriately increasing steric hindrance and controlling the continuous flow reaction process, the formation of nitrated isomers is suppressed, improving nitration selectivity. The catalyst in the nitro-to-amino group reduction reaction remains in a closed system, further enhancing its activity. Furthermore, combining the reduction of the nitro group and the deacetylation shortens the route, simplifies the operation, and increases the yield, achieving both high purity and high yield of the synthesized 4,6-diaminoresorcinol salt. In Example 1, the purity reached as high as 99.9%, and the yield reached as high as 85.0%. This invention's method is efficient and safe, and the synthesized 4,6-diaminoresorcinol salt exhibits high purity and high yield, showing broad application prospects in continuous flow industrial production.

[0073] The nitrated isomer is 1,3-diacetoxy-2,6-dinitrobenzene, and its structural formula is as follows: .

Claims

1. A continuous flow process for the synthesis of a 4,6-diaminoresorcinol salt, characterized in that, The method is performed in a continuous flow reactor, comprising the following steps: (1) synthesis of intermediate 1: mixed liquid A is obtained by mixing resorcinol, acetylating agent and organic solvent, mixed liquid A is preheated by metering pump A in the first continuous flow preheater, acid binding agent is preheated by metering pump B in the second continuous flow preheater; the preheated mixed liquid A and the acid binding agent are mixed in the first continuous flow mixer to obtain mixed liquid B; then, mixed liquid B is reacted in the first continuous flow reactor to obtain reaction liquid A; reaction liquid A enters the second continuous flow mixer, at the same time, water enters the second continuous flow mixer through metering pump C, and reaction liquid A and water are mixed in the second continuous flow mixer to obtain mixed liquid C; then, mixed liquid C is separated in the first continuous flow liquid separator, and organic phase 1, i.e. organic solvent containing intermediate 1, is collected; the intermediate 1 is resorcinol diacetate; (2) synthesis of intermediate 2: organic phase 1 enters the third continuous flow preheater through metering pump D; the preheated organic phase 1 enters the third continuous flow mixer, acetylating agent enters the third continuous flow mixer through metering pump E, and nitration agent enters the third continuous flow mixer through metering pump F; the preheated organic phase 1, acetylating agent and nitration agent are mixed in the third continuous flow mixer to obtain mixed liquid D; mixed liquid D is reacted in the second continuous flow reactor to obtain reaction liquid B; reaction liquid B enters the fourth continuous flow mixer, at the same time, water enters the fourth continuous flow mixer through metering pump G, and reaction liquid B and water are mixed in the fourth continuous flow mixer to obtain mixed liquid D; then, mixed liquid D is separated in the second continuous flow liquid separator, and organic phase 2, i.e. organic solvent containing intermediate 2, is collected; the intermediate 2 is 1,3-diacetoxy-4,6-dinitrobenzene; (3) synthesis of intermediate 3: organic phase 2 enters the fifth continuous flow mixer through metering pump H, and then enters the third continuous flow reactor, at the same time, reducing agent enters the third continuous flow reactor through metering pump I, the third continuous flow reactor is provided with a catalyst, and organic phase 2, reducing agent and catalyst are reacted in the third continuous flow reactor to obtain reaction liquid C; reaction liquid C is separated in the third continuous flow liquid separator, and organic phase 3, i.e. organic solvent containing intermediate 3, is collected; the intermediate 3 is 4,6-diaminoresorcinol; (4) organic phase 3 enters the sixth continuous flow mixer through metering pump J, at the same time, water enters the sixth continuous flow mixer through metering pump K, and organic phase 3 and water are mixed in the sixth continuous flow mixer to obtain mixed liquid E; mixed liquid E is separated in the fourth continuous flow liquid separator, and organic phase 4 is collected; organic phase 4 enters the salt formation kettle, at the same time, salt forming agent is introduced into the salt formation kettle, and organic phase 4 and salt forming agent are reacted in the salt formation kettle; after the reaction is completed, filtration is performed to obtain 4,6-diaminoresorcinol salt.

2. The continuous flow synthesis method according to claim 1, wherein: the reaction for synthesizing intermediate 3 is performed in a fixed bed reaction device, and the fixed bed reaction device comprises a fifth continuous flow mixer and a third continuous flow reactor. ​ In step (1), the circulating temperature of the first continuous flow preheater, the second continuous flow preheater, the first continuous flow mixer, and the first continuous flow reactor is 50-70℃; the circulating temperature of the second continuous flow mixer is 10-30℃; In step (2), the circulating temperature of the third continuous flow preheater, the third continuous flow mixer, and the second continuous flow reactor is 60-80℃; the circulating temperature of the fourth continuous flow mixer is 10-30℃; In step (3), the circulating temperature of the fifth continuous flow mixer and the third continuous flow reactor is -5-5℃; In step (4), the circulating temperature of the sixth continuous flow mixer is 10-30℃.

3. The continuous flow synthesis method according to claim 2, wherein: In step (1), the circulating temperature of the first continuous flow preheater, the second continuous flow preheater, the first continuous flow mixer, and the first continuous flow reactor is 60℃; the circulating temperature of the second continuous flow mixer is 20℃; In step (2), the circulating temperature of the third continuous flow preheater, the third continuous flow mixer, and the second continuous flow reactor is 70℃; the circulating temperature of the fourth continuous flow mixer is 20℃; In step (3), the circulating temperature of the fifth continuous flow mixer and the third continuous flow reactor is 0℃; In step (4), the circulating temperature of the sixth continuous flow mixer is 20℃.

4. The continuous flow synthesis method according to claim 1, wherein: In step (1), the flow rate of the metering pump A is 430-1310 ml / min, the flow rate of the metering pump B is 230-700 ml / min, the flow rate of the metering pump C is 80-250 ml / min, the operation time of the metering pump A and the metering pump B is 2.5-7.5 min, and the operation time of the metering pump C is 1.5-4.5 min; In step (2), the flow rate of the metering pump D is 380-580 ml / min, the flow rate of the metering pump E is 175-270 ml / min, the flow rate of the metering pump F is 85-135 ml / min, the flow rate of the metering pump G is 100-135 ml / min, the operation time of the metering pump D, the metering pump E, and the metering pump F is 8-12 min, and the operation time of the metering pump G is 1.5-4.5 min; In step (3), the flow rate of the metering pump H is 425-1075 ml / min, the flow rate of the metering pump I is 220-550 ml / min, and the operation time of the metering pump H and the metering pump I is 10-25 min; In step (4), the flow rate of the metering pump J is 400-420 ml / min, and the flow rate of the metering pump K is 115-135 ml / min.

5. The continuous flow synthesis method according to claim 4, wherein: In step (1), the flow rate of the metering pump A is 430-820 ml / min, the flow rate of the metering pump B is 230-440 ml / min, and the flow rate of the metering pump C is 80-160 ml / min; the operating time of the metering pump A and the metering pump B is 4.0-7.5 min; In step (3), the flow rate of the metering pump H is 425-720 ml / min, the flow rate of the metering pump I is 215-370 ml / min, and the operating time of the metering pump H and the metering pump I is 15-25 min.

6. The continuous flow synthesis method according to claim 5, wherein: In step (1), the flow rate of the metering pump A is 650-655 ml / min, the flow rate of the metering pump B is 345-350 ml / min, and the flow rate of the metering pump C is 120-130 ml / min; the operating time of the metering pump A and the metering pump B is 4.5-5.5 min, and the operating time of the metering pump C is 2.5-3.5 min; In step (2), the flow rate of the metering pump D is 455-460 ml / min, the flow rate of the metering pump E is 210-220 ml / min, the flow rate of the metering pump F is 105-110 ml / min, and the flow rate of the metering pump G is 120-130 ml / min; the operating time of the metering pump D, the metering pump E and the metering pump F is 8-12 min, and the operating time of the metering pump G is 2.5-3.5 min; In step (3), the flow rate of the metering pump H is 530-540 ml / min, the flow rate of the metering pump I is 270-280 ml / min, and the operating time of the metering pump H and the metering pump I is 18-22 min; In step (4), the flow rate of the metering pump J is 405-415 ml / min, and the flow rate of the metering pump K is 120-130 ml / min.

7. The continuous flow synthesis method according to claim 1, wherein: In step (1), the molar ratio of the resorcinol, the acetylating agent and the acid-binding agent is (5-15) : (15-25) : (15-25); and the molar ratio of the resorcinol and the organic solvent is (5-15) : (20-45); In step (2), the molar ratio of the organic phase 1, the acetylating agent and the nitration agent is (5-15) : (15-25) : (15-25); In step (3), the molar ratio of the organic phase 2, the reducing agent and the catalyst is (5-15) : (30-40) : (1-2.5); In step (4), the molar ratio of the resorcinol and the salt-forming agent is (5-15) : (20-35).

8. The continuous flow synthesis method according to claim 7, wherein: In step (1), the molar amount of the resorcinol, the acetylating agent and the acid-binding agent is (8-12) : (17-22) : (18-22) respectively; and the molar ratio of the resorcinol and the organic solvent is (8-12) : (35-40). In step (2), the molar ratio of organic phase 1, acetylating agent and nitrating agent is (8-12):(16-20):(18-22). In step (3), the molar ratio of organic phase 2, reducing agent and catalyst is (8-12):(34-38):(1.5-2). In step (4), the molar ratio of resorcinol and salt forming agent is (8-12):(25-30).

9. The continuous flow synthesis process according to any one of claims 1 to 8, wherein: The acetylating agent is selected from acetic anhydride, acetyl chloride or a mixture of the two; the organic solvent includes dichloromethane or dichloroethane; the acid binding agent includes triethylamine, tributylamine or diisopropyl ethylamine; the nitrating agent includes nitric acid nitrating agent, nitric acid-acetic anhydride complex nitrating agent, nitrogen oxide nitrating agent, alkyl nitrate nitrating agent or nitrosonium salt nitrating agent; the reducing agent includes hydrazine hydrate or hydrogen; the catalyst includes nickel, γ-Fe2O3 / C or palladium-carbon; and the salt forming agent includes inorganic acid or organic acid.

10. The continuous flow synthesis process of claim 9, wherein: The nitric acid nitrating agent includes fuming nitric acid, dilute nitric acid, concentrated nitric acid, sodium nitrate-concentrated nitric acid complex reagent, potassium nitrate-concentrated nitric acid complex reagent, ammonium nitrate-concentrated nitric acid complex reagent, nitric acid-concentrated sulfuric acid complex reagent or nitric acid-concentrated hydrochloric acid complex reagent; the nitric acid-acetic anhydride complex nitrating agent includes nitric acid-acetic anhydride complex reagent, fuming nitric acid-acetic anhydride complex reagent, nitric acid-propionic anhydride complex reagent, fuming nitric acid-propionic anhydride complex reagent, nitric acid-trifluoroacetic anhydride complex reagent, nitric acid-phthalic anhydride complex reagent or nitric acid-fluorosulfonic anhydride complex reagent; the nitrogen oxide nitrating agent includes nitrogen dioxide-dinitrogen tetroxide complex reagent, dinitrogen trioxide or dinitrogen pentoxide; the alkyl nitrate nitrating agent includes methyl nitrate, ethyl nitrate, n-pentyl nitrate, neopentyl nitrate, t-butyl nitrate or isoamyl nitrate; the nitrosonium salt nitrating agent includes nitrosonium tetrafluoroborate, nitrosonium hexafluorophosphate, nitrosonium hexafluoroarsenate or nitrosonium triflate; the inorganic acid includes at least one of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, carbonic acid and sodium dihydrogen phosphate; and the organic acid includes at least one of acetic acid, propionic acid, citric acid, maleic acid, aromatic carboxylic acid, alkyl sulfonic acid and aromatic sulfonic acid.

Images