Method for synthesizing 4-amino-1-naphthol hydrochloride through continuous flow and application of 4-amino-1-naphthol hydrochloride

Abstract

The invention belongs to the technical field of organic chemical engineering and fine organic intermediate synthesis, and discloses a method for continuous flow synthesis of 4-amino-1-naphthol hydrochloride and application, and the method comprises the following steps: carrying out diazotization reaction on a nitrite solution, aniline and inorganic acid; then carrying out a coupling reaction with a coupling component 1-naphthol to generate an azo compound; carrying out reduction reaction on the azo compound solution and an alkaline solution of a reducing agent sodium hydrosulfite; and carrying out 4-amino-1-naphthol acidification with a hydrochloric acid solution flow to obtain the product 4-amino-1-naphthol hydrochloride. The continuous preparation of the 4-amino-1-naphthol hydrochloride is realized through four-step continuous flow, the process is simple, the reaction time is short, the dosage of a reaction reagent can be accurately controlled, and the preparation process is safe, controllable and environment-friendly; reaction liquid can be fully mixed in the microreactor, so that the reaction efficiency is improved, and the reactant conversion rate and the final product yield are relatively high.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical engineering and fine organic intermediate synthesis, in particular to a method for continuous flow synthesis of 4-amino-1-naphthol hydrochloride and its application. Background Art

[0002] 4-amino-1-naphthol hydrochloride is a potential pharmaceutical intermediate, and relevant studies have shown that its derivatives are of great significance for tumor treatment. For example, the clinical drug domamod, as a highly efficient and selective p38αMAPK inhibitor, can be synthesized with 4-amino-1-naphthol hydrochloride as the skeleton. The p38 MAPK signaling pathway plays a key role in a variety of physiological processes, including inflammatory response, cell cycle regulation, apoptosis, cell differentiation, developmental progression, aging, and tumor suppression, especially in regulating inflammatory response. With the development and application of downstream products, 4-amino-1-naphthol hydrochloride has a very large market prospect in the field of medicine and organic synthesis. The structural formula of 4-amino-1-naphthol hydrochloride is as follows:

[0003]

[0004] There are two traditional methods for synthesizing 4-amino-1-naphthol hydrochloride. Route 1: using p-nitronaphthalene as a raw material, hydroxylizing it to obtain 4-nitro-1-naphthol, then hydrogenating it through Pd catalysis to obtain 4-amino-1-naphthol, and then acidifying it to obtain 4-amino-1-naphthol hydrochloride. Route 2: using aniline and α-naphthol as starting materials, diazotizing aniline and then coupling it with α-naphthol to obtain an azo compound 4-(phenylazo)-1-naphthol, and then reducing the azo compound with a reducing agent to obtain 4-amino-1-naphthol, and then acidifying it to obtain 4-amino-1-naphthol hydrochloride.

[0005] In Chinese patent CN 102766103 A, 1-nitronaphthalene is used as the starting material, tert-butyl peroxide is added dropwise, and the reaction is carried out for 2 hours to obtain 4-nitro-1-naphthol. Under palladium catalysis, hydrogen is passed through the reaction for 10 hours to obtain 4-amino-1-naphthol, with a yield of about 83%. However, this reaction route takes a long time, a total of 12 hours, and a precious metal palladium catalyst is required. The tert-butyl peroxide reagent is also relatively dangerous.

[0006] Route 2 does not use precious metals, but the diazotization reaction is considered a high-risk chemical process. Diazo salts are unstable and easily decomposed. Using the traditional kettle method to implement this reaction is not only time-consuming, but also difficult to control the reaction parameters, prone to accidents such as material impact or even explosion, and poses a major safety hazard. Summary of the invention

[0007] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a method and application for synthesizing 4-amino-1-naphthol hydrochloride by continuous flow.

[0008] The technical solution adopted by the present invention to solve its technical problem is:

[0009] A method for continuous flow synthesis of 4-amino-1-naphthol hydrochloride comprises the following steps:

[0010] First, a series of solutions required for the reaction are prepared: a. Aniline and inorganic acid are dissolved in a water-ethanol solution in proportion to obtain solution A; b. Sodium nitrite is dissolved in a water-ethanol solution to obtain solution B; c. 1-naphthol is dissolved in a water-ethanol solution, and then the pH is adjusted with an inorganic alkali aqueous solution to obtain solution C; d. The required amount of sodium hydroxide is weighed and dissolved in water, and after mixing evenly, the reducing agent is weighed and dissolved in the solution to obtain solution D; e. The required amount of hydrochloric acid aqueous solution is prepared to obtain solution E; after all solutions are prepared, a continuous reaction is carried out;

[0011] The specific steps are as follows:

[0012] (1) First, solution A and solution B are respectively transported to a precooling module of a continuous flow reactor according to a set ratio, and after mixing, the raw materials flow into the reactor for diazotization reaction to obtain an aniline diazonium salt solution;

[0013] (2) the aniline diazonium salt solution is continuously mixed with solution C in a continuous flow reactor, and a coupling reaction is carried out at a set temperature to obtain an azo compound 4-(phenylazo)-1-naphthol;

[0014] (3) the azo compound solution is continuously mixed with solution D in a continuous flow reactor, and a reduction reaction is carried out at a set temperature to obtain an alkaline solution of 4-amino-1-naphthol;

[0015] (4) the alkaline solution of 4-amino-1-naphthol is mixed with solution E in a continuous flow reactor to carry out an acidification and salt-forming process of 4-amino-1-naphthol to obtain a 4-amino-1-naphthol hydrochloride solution;

[0016] (5) collecting the product solution obtained in step 4 at the outlet of the continuous flow reactor, performing reduced pressure distillation to remove ethanol and most of the water, cooling, standing, filtering, and vacuum drying to obtain 4-amino-1-naphthol hydrochloride.

[0017] Furthermore, the molar concentration of aniline in the solution A is 0.01-2 mol / L, the molar ratio of aniline to inorganic acid is 1:1-4, and the volume ratio of solvent water to ethanol is 1:0.2-9;

[0018] Alternatively, the molar concentration of sodium nitrite in the solution B is 0.01-2 mol / L, and the volume ratio of solvent water to ethanol is 1:0.2-9;

[0019] The molar concentration of the coupling component 1-naphthol in the solution C is 0.005-1 mol / L, the initial pH of the coupling component is 4-14, and the volume ratio of the solvent water to ethanol is 1:0.2-19;

[0020] Alternatively, the molar concentration of the reducing agent in the solution D is 0.005 to 1 mol / L, and the molar concentration of sodium hydroxide is 0.005 to 15 mol / L;

[0021] Alternatively, the molar concentration of hydrochloric acid in the solution E is 0.01-12 mol / L, the initial pH of the coupling component 1-naphthol is 4-14, and the volume ratio of solvent water to ethanol is 1:0.2-19.

[0022] Furthermore, in step a, the inorganic acid is selected from sulfuric acid or hydrochloric acid, preferably hydrochloric acid; in step c, the inorganic base is one or more of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; and in step d, the reducing agent is sodium dithionite.

[0023] Furthermore, in the diazotization reaction in step (1), the molar ratio of aniline to sodium nitrite is 1:1-1.5, the flow ratio of solution A to solution B is 1-9:1-9, the flow rate of solution A is 0.01 ml / min-100 ml / min, the temperature of the diazotization reaction is -20-35°C, and the residence time is 0.01-100 min;

[0024] Alternatively, in the coupling reaction in step (2), the molar ratio of 1-naphthol in solution C to aniline in solution A is 1:1-1.2, the flow ratio of solution C to diazonium salt solution is 1-9:1-9, the reaction temperature is -20-60°C, and the residence time is 0.01-100 min.

[0025] Furthermore, in the reduction reaction in step (3), the flow ratio of solution D to the azo compound solution is 1-9:1-9, the reduction reaction temperature is 15-75° C., the residence time is 1-100 min, and the molar ratio of 1-naphthol to the reducing agent is 1:1-10;

[0026] Alternatively, in the step (4), the flow ratio of solution E to the alkaline solution of 4-amino-1-naphthol in the acidification reaction is 1-9:1-9, and the residence time of the acidification reaction is 0.01-100 min.

[0027] Furthermore, the type of the continuous flow reactor described in steps (1) to (5) is a tubular reactor or a microchannel reactor, and the material is one or more of silicon carbide, Hastelloy, polymethyl methacrylate, polyethylene, polydimethylsiloxane, polyethylene terephthalate, glass, ceramic, aluminum, stainless steel, copper, glass or polytetrafluoroethylene.

[0028] Furthermore, the microchannel reactor consists of a micro mixer and a coil.

[0029] Furthermore, the micro mixer is one or more of a static mixer, a T-type micro mixer, a Y-type micro mixer, and a T-type three-way valve.

[0030] Furthermore, the inner diameter of the coil is 0.1 mm-20 cm, and the length of the coil is 1 cm-1200 m.

[0031] Application of the preparation method described above in the production of 4-amino-1-naphthol hydrochloride.

[0032] The advantages and positive effects achieved by the present invention are:

[0033] 1. The method of the present invention synthesizes 4-amino-1-naphthol hydrochloride in a continuous flow reactor, and the four-step reaction is carried out in a continuous flow manner, without the need for intermediate operations, thereby realizing continuous synthesis from raw materials to products and greatly improving efficiency. The operation process is carried out in a closed reaction tube, without the process of feeding and dropping, etc., the amount of online materials is small, and the contact between strong acids, strong bases, and toxic reagents and operators is reduced, thereby preventing them from causing damage to human health.

[0034] 2. In the method of the present invention, the diazotization reaction is carried out in a continuous flow, so that the reaction liquid can achieve high-speed collision in the microreactor, which greatly improves the mixing efficiency and shortens the reaction time; the continuous flow reactor has a high heat transfer coefficient and has better temperature control than the batch reactor; the unstable intermediate diazonium salt generated by the reaction can be immediately used in the next reaction, which effectively avoids the decomposition of the diazonium salt and reduces the occurrence of side reactions.

[0035] 3. In the method of the present invention, the coupling reaction is carried out in a continuous flow, so that the reaction solution can achieve high-speed collision in the microreactor, which greatly improves the mixing efficiency and shortens the reaction time; the rate and yield of the coupling reaction are greatly affected by the pH value of the system, and the continuous flow reactor can accurately control the pH of the reaction; compared with the batch reactor, the continuous flow reactor can accurately control the temperature of the coupling reaction and improve the yield of the azo compound.

[0036] 4. In the method of the present invention, the reduction reaction is carried out in a continuous flow, so that the reaction solution can achieve high-speed collision in the microreactor, which greatly improves the mixing efficiency and shortens the reaction time. Compared with the batch reactor, the continuous flow reactor can easily create an anaerobic environment without the need for nitrogen protection, thereby avoiding the loss of sodium dithionite. At the same time, the product 4-amino-1-naphthol obtained by the reduction reaction is easily oxidized and decomposed under alkaline conditions. Carrying out the reaction under continuous flow conditions can effectively avoid product deterioration.

[0037] 5. In the method of the present invention, the acidification reaction is carried out in a continuous flow, which can make the amount of hydrochloric acid used more accurate, avoid the waste of raw materials, and be more environmentally friendly.

[0038] 6. Compared with the long-term (3 to 6 hours) operation of preparing 4-amino-1-naphthol hydrochloride by an intermittent reactor, the continuous flow reaction time is only a few minutes (5 to 20 minutes), which greatly improves the efficiency of the reaction.

[0039] 7. The method of the present invention uses continuous flow technology to study a new process to prepare 4-amino-1-naphthol hydrochloride. The preparation method is simple, the raw materials are easily available, the safety performance is good, the environment is friendly, the reaction time is short, the process control is precise, the product yield is high, and it is easy to industrialize and apply, which overcomes the shortcomings of the traditional intermittent reactor synthesis method, which has complicated operation steps, great safety hazards, and low heat and mass transfer efficiency.

[0040] 8. The present invention realizes the continuous preparation of 4-amino-1-naphthol hydrochloride through 4-step continuous flow, has a simple process, short reaction time, can accurately control the amount of reaction reagents, the preparation process is safe, controllable, and environmentally friendly; the reaction solution can be fully mixed in the microreactor, the reaction efficiency is improved, and the reactant conversion rate and the final product yield are relatively high. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 A schematic diagram of a process flow for continuous flow synthesis of 4-amino-1-naphthol hydrochloride in the present invention;

[0042] Figure 2 The 600 MHz HNMR spectrum of the continuous flow synthesis of 4-amino-1-naphthol hydrochloride in the present invention. DETAILED DESCRIPTION

[0043] The present invention will be further described below in conjunction with the embodiments. The following embodiments are descriptive rather than restrictive, and the protection scope of the present invention cannot be limited by the following embodiments.

[0044] The various experimental operations involved in the specific embodiments are all routine techniques in the art. For parts not specially annotated in this document, ordinary technicians in the art can implement them by referring to various commonly used reference books, scientific and technological literature or related instructions, manuals, etc. before the filing date of this invention.

[0045] A method for continuous flow synthesis of 4-amino-1-naphthol hydrochloride comprises the following steps:

[0046] First, a series of solutions required for the reaction are prepared: a. Aniline and inorganic acid are dissolved in a water-ethanol solution in proportion to obtain solution A; b. Sodium nitrite is dissolved in a water-ethanol solution to obtain solution B; c. 1-naphthol is dissolved in a water-ethanol solution, and then the pH is adjusted with an inorganic alkali aqueous solution to obtain solution C; d. The required amount of sodium hydroxide is weighed and dissolved in water, and after mixing evenly, the reducing agent is weighed and dissolved in the solution to obtain solution D; e. The required amount of hydrochloric acid aqueous solution is prepared to obtain solution E; after all solutions are prepared, a continuous reaction is carried out;

[0047] The specific steps are as follows:

[0048] (1) First, solution A and solution B are respectively transported to a precooling module of a continuous flow reactor according to a set ratio, and after mixing, the raw materials flow into the reactor for diazotization reaction to obtain an aniline diazonium salt solution;

[0049] (2) the aniline diazonium salt solution is continuously mixed with solution C in a continuous flow reactor, and a coupling reaction is carried out at a set temperature to obtain an azo compound 4-(phenylazo)-1-naphthol;

[0050] (3) the azo compound solution is continuously mixed with solution D in a continuous flow reactor, and a reduction reaction is carried out at a set temperature to obtain an alkaline solution of 4-amino-1-naphthol;

[0051] (4) the alkaline solution of 4-amino-1-naphthol is mixed with solution E in a continuous flow reactor to carry out an acidification and salt-forming process of 4-amino-1-naphthol to obtain a 4-amino-1-naphthol hydrochloride solution;

[0052] (5) collecting the product solution obtained in step 4 at the outlet of the continuous flow reactor, performing reduced pressure distillation to remove ethanol and most of the water, cooling, standing, filtering, and vacuum drying to obtain 4-amino-1-naphthol hydrochloride.

[0053] Preferably, the molar concentration of aniline in the solution A is 0.01-2 mol / L, the molar ratio of aniline to inorganic acid is 1:1-4, and the volume ratio of solvent water to ethanol is 1:0.2-9;

[0054] Alternatively, the molar concentration of sodium nitrite in the solution B is 0.01-2 mol / L, and the volume ratio of solvent water to ethanol is 1:0.2-9;

[0055] The molar concentration of the coupling component 1-naphthol in the solution C is 0.005-1 mol / L, the initial pH of the coupling component is 4-14, and the volume ratio of the solvent water to ethanol is 1:0.2-19;

[0056] Alternatively, the molar concentration of the reducing agent in the solution D is 0.005 to 1 mol / L, and the molar concentration of sodium hydroxide is 0.005 to 15 mol / L;

[0057] Alternatively, the molar concentration of hydrochloric acid in the solution E is 0.01-12 mol / L, the initial pH of the coupling component 1-naphthol is 4-14, and the volume ratio of solvent water to ethanol is 1:0.2-19.

[0058] Preferably, the inorganic acid in step a is selected from sulfuric acid or hydrochloric acid, preferably hydrochloric acid; the inorganic base in step c is one or more of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; and the reducing agent in step d is sodium dithionite.

[0059] Preferably, in the diazotization reaction in step (1), the molar ratio of aniline to sodium nitrite is 1:1-1.5, the flow ratio of solution A to solution B is 1-9:1-9, the flow rate of solution A is 0.01 ml / min-100 ml / min, the temperature of the diazotization reaction is -20-35°C, and the residence time is 0.01-100 min;

[0060] Alternatively, in the coupling reaction in step (2), the molar ratio of 1-naphthol in solution C to aniline in solution A is 1:1-1.2, the flow ratio of solution C to diazonium salt solution is 1-9:1-9, the reaction temperature is -20-60°C, and the residence time is 0.01-100 min.

[0061] Preferably, in the reduction reaction in step (3), the flow ratio of solution D to the azo compound solution is 1-9:1-9, the reduction reaction temperature is 15-75° C., the residence time is 1-100 min, and the molar ratio of 1-naphthol to the reducing agent is 1:1-10;

[0062] Alternatively, in the step (4), the flow ratio of solution E to the alkaline solution of 4-amino-1-naphthol in the acidification reaction is 1-9:1-9, and the residence time of the acidification reaction is 0.01-100 min.

[0063] Preferably, the continuous flow reactor described in steps (1) to (5) is a tubular reactor or a microchannel reactor, and the material is one or more of silicon carbide, Hastelloy, polymethyl methacrylate, polyethylene, polydimethylsiloxane, polyethylene terephthalate, glass, ceramic, aluminum, stainless steel, copper, glass or polytetrafluoroethylene.

[0064] Preferably, the microchannel reactor consists of a micro mixer and a coil.

[0065] Preferably, the micro mixer is one or more of a static mixer, a T-type micro mixer, a Y-type micro mixer, and a T-type three-way valve.

[0066] Preferably, the inner diameter of the coil is 0.1 mm-20 cm, and the length is 1 cm-1200 m.

[0067] Application of the preparation method described above in the production of 4-amino-1-naphthol hydrochloride.

[0068] Specifically, the relevant preparation and detection are as follows:

[0069] The main chemical reactions in the production process of the method of the present invention are as follows:

[0070] (1) Diazotization reaction:

[0071]

[0072] (2) Diazo coupling reaction:

[0073]

[0074] (3) Reduction reaction:

[0075]

[0076] (4) Acidification reaction:

[0077]

[0078] Specifically, the preparation is as follows:

[0079] Example 1

[0080] According to Figure 1 The process shown continuously prepares 4-amino-1-naphthol hydrochloride:

[0081] (1) Preparation of solution A: Weigh 0.93 g of aniline into a 100 mL beaker, add 3 g of concentrated hydrochloric acid (37 wt %, mass concentration, wt % indicated below means mass concentration), 20 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution A;

[0082] (2) Preparation of solution B: Take 0.731 g of sodium nitrite solid in a 100 mL beaker, add 20 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution B;

[0083] (3) Preparation of Solution C: 1.44 g of 1-naphthol solid was placed in a 200 mL beaker, 20 mL of ethanol was added, 20 mL of deionized water was added, 0.20 g of a 10 wt % aqueous sodium hydroxide solution was added, the volume was made up to 100 mL with ethanol, and the mixture was mixed to obtain Solution C;

[0084] (4) Preparation of solution D: 3.2 g of sodium hydroxide solid was placed in a 250 mL glass bottle, 100 mL of water was added, and the mixture was mixed well. 5.22 g of sodium dithionite was quickly weighed and poured into the solution, and the volume was adjusted to 200 mL with deionized water, and the solution was mixed well to obtain solution D. The solution was protected with inert gas.

[0085] (5) Preparation of Solution E: Dissolve 18 g of concentrated hydrochloric acid (37 wt%) in 200 mL of water, mix well, make up to 400 mL with deionized water, mix well, and prepare Solution E.

[0086] (6) Solution A and Solution B are respectively transported to a continuous flow reactor with an ice-water bath temperature of 0 to 5° C. at a rate of 0.5 mL / min, wherein the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the diazotization reaction is continued in the coil for 3 minutes to obtain an aniline diazonium salt solution;

[0087] (7) The aniline diazonium salt solution is continuously mixed with solution C at a volume flow rate ratio of 1:1 in a continuous flow reactor with an ice water bath temperature of 0 to 5° C. The delivery flow rate of solution C is set to 1 mL / min. The continuous flow reactor is mainly composed of a T-type tee and a coil. The two flows are quickly mixed in the T-type tee and the coupling reaction is continued in the coil for 1.5 minutes to obtain an azo compound 4-(phenylazo)-1-naphthol.

[0088] (8) the azo compound solution is continuously mixed with solution D at a volume flow rate ratio of 1:1 in a continuous flow reactor at a water bath temperature of 50° C., the delivery flow rate of solution D is set to 2 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the reduction reaction is continued in the coil for 12 minutes to obtain an alkaline solution of 4-amino-1-naphthol;

[0089] (9) the alkaline solution of 4-amino-1-naphthol is continuously mixed with solution E at a volume flow rate ratio of 1:1 in a continuous flow reactor at 25° C., the delivery flow rate of solution E is set to 4 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the acidification reaction is continued in the coil for 0.5 min to obtain a 4-amino-1-naphthol hydrochloride solution;

[0090] (10) The product solution obtained in step (9) is collected at the outlet of the continuous flow reactor, a small amount of sample is taken for liquid phase detection, and the remaining sample is subjected to reduced pressure distillation to remove ethanol and most of the water, cooled, allowed to stand, filtered, and vacuum dried to obtain 4-amino-1-naphthol hydrochloride, and a small amount of sample is taken for nuclear magnetic resonance detection. Figure 2 As shown, the NMR detection results confirmed that the obtained substance was 4-amino-1-naphthol hydrochloride, and the yield calculated by liquid chromatography was 87.2%.

[0091] Example 2

[0092] According to Figure 1 The process shown continuously prepares 4-amino-1-naphthol hydrochloride:

[0093] (1) Preparation of solution A: Weigh 0.93 g of aniline into a 100 mL beaker, add 3 g of concentrated hydrochloric acid (37 wt%), 15 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution A;

[0094] (2) Preparation of solution B: Take 0.718 g of sodium nitrite solid in a 100 mL beaker, add 15 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution B;

[0095] (3) Preparation of Solution C: 1.44 g of 1-naphthol solid was placed in a 200 mL beaker, 20 mL of ethanol was added, 30 mL of deionized water was added, 0.8 g of a 10 wt % aqueous sodium hydroxide solution was added, the volume was made up to 100 mL with ethanol, and the mixture was mixed to obtain Solution C;

[0096] (4) Preparation of solution D: 4 g of sodium hydroxide solid was placed in a 250 mL glass bottle, 100 mL of water was added, and the mixture was mixed well. 6.96 g of sodium dithionite was quickly weighed and poured into the mixture, and the volume was adjusted to 200 mL with deionized water. The mixture was mixed well to obtain solution D, and the mixture was protected with inert gas.

[0097] (5) Preparation of Solution E: Dissolve 20 g of concentrated hydrochloric acid (37 wt%) in 200 mL of water, mix well, make up to 400 mL with deionized water, mix well, and prepare Solution E.

[0098] (6) Solution A and Solution B are respectively transported to a continuous flow reactor with an ice-water bath temperature of 0 to 5° C. at a rate of 0.5 mL / min, wherein the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the diazotization reaction is continued in the coil for 6 minutes to obtain an aniline diazonium salt solution;

[0099] (7) The aniline diazonium salt solution is continuously mixed with solution C at a volume flow rate ratio of 1:1 in a continuous flow reactor with an ice water bath temperature of 0 to 5° C. The delivery flow rate of solution C is set to 1 mL / min. The continuous flow reactor is mainly composed of a T-type tee and a coil. The two flows are quickly mixed in the T-type tee and the coupling reaction is continued in the coil for 3 minutes to obtain an azo compound 4-(phenylazo)-1-naphthol.

[0100] (8) the azo compound solution is continuously mixed with solution D at a volume flow rate ratio of 1:1 in a continuous flow reactor at a water bath temperature of 45° C., the delivery flow rate of solution D is set to 2 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the reduction reaction is continued in the coil for 12 minutes to obtain an alkaline solution of 4-amino-1-naphthol;

[0101] (9) the alkaline solution of 4-amino-1-naphthol is continuously mixed with solution E at a volume flow rate ratio of 1:1 in a continuous flow reactor at 25° C., the delivery flow rate of solution E is set to 4 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the acidification reaction is continued in the coil for 0.5 min to obtain a 4-amino-1-naphthol hydrochloride solution;

[0102] (10) The product solution obtained in step (9) is collected at the outlet of the continuous flow reactor, and a small amount of sample is taken for liquid phase detection. The remaining sample is subjected to reduced pressure distillation to remove ethanol and most of the water, and the sample is cooled, allowed to stand, filtered, and vacuum dried to obtain 4-amino-1-naphthol hydrochloride. The yield calculated by liquid chromatography is 85.4%.

[0103] Example 3

[0104] According to Figure 1 The process shown continuously prepares 4-amino-1-naphthol hydrochloride:

[0105] (1) Preparation of solution A: weigh 0.93 g of aniline into a 100 mL beaker, add 3 g of concentrated hydrochloric acid (37 wt%), 25 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution A;

[0106] (2) Preparation of solution B: Take 0.745 g of sodium nitrite solid in a 100 mL beaker, add 25 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution B;

[0107] (3) Preparation of Solution C: 1.44 g of 1-naphthol solid was placed in a 200 mL beaker, 20 mL of ethanol, 20 mL of deionized water, 2.0 g of a 10 wt % aqueous sodium hydroxide solution, and the mixture was diluted to 100 mL with ethanol and mixed to obtain Solution C.

[0108] (4) Preparation of solution D: 4.8 g of sodium hydroxide solid was placed in a 250 mL glass bottle, 100 mL of water was added, and the mixture was mixed well. 6.96 g of sodium dithionite was quickly weighed and poured into the mixture, and the volume was adjusted to 200 mL with deionized water, and the mixture was mixed well to obtain solution D. The mixture was protected with inert gas.

[0109] (5) Preparation of Solution E: Dissolve 22 g of concentrated hydrochloric acid (37 wt%) in 200 mL of water, mix well, make up to 400 mL with deionized water, mix well, and prepare Solution E.

[0110] (6) Solution A and Solution B are respectively transported to a continuous flow reactor with an ice-water bath temperature of 0 to 5° C. at a rate of 0.5 mL / min, wherein the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the diazotization reaction is continued in the coil for 3 minutes to obtain an aniline diazonium salt solution;

[0111] (7) The aniline diazonium salt solution is continuously mixed with solution C at a volume flow rate ratio of 1:1 in a continuous flow reactor at a water bath temperature of 30° C. The delivery flow rate of solution C is set to 1 mL / min. The continuous flow reactor is mainly composed of a T-type tee and a coil. The two flows are quickly mixed in the T-type tee and the coupling reaction is continued in the coil for 3 minutes to obtain an azo compound 4-(phenylazo)-1-naphthol.

[0112] (8) the azo compound solution is continuously mixed with solution D at a volume flow rate ratio of 1:1 in a continuous flow reactor at a water bath temperature of 50° C., the delivery flow rate of solution D is set to 2 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the reduction reaction is continued in the coil for 8 minutes to obtain an alkaline solution of 4-amino-1-naphthol;

[0113] (9) the alkaline solution of 4-amino-1-naphthol is continuously mixed with solution E at a volume flow rate ratio of 1:1 in a continuous flow reactor at 25° C., the delivery flow rate of solution E is set to 4 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the acidification reaction is continued in the coil for 0.5 min to obtain a 4-amino-1-naphthol hydrochloride solution;

[0114] (10) The product solution obtained in step (9) is collected at the outlet of the continuous flow reactor, and a small amount of sample is taken for liquid phase detection. The remaining sample is subjected to reduced pressure distillation to remove ethanol and most of the water, and the sample is cooled, allowed to stand, filtered, and vacuum dried to obtain 4-amino-1-naphthol hydrochloride. The yield calculated by liquid chromatography is 84.5%.

[0115] Example 4

[0116] According to Figure 1 The process shown continuously prepares 4-amino-1-naphthol hydrochloride:

[0117] (1) Preparation of solution A: Weigh 0.465 g of aniline into a 100 mL beaker, add 3 g of concentrated hydrochloric acid (37 wt%), 30 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution A;

[0118] (2) Preparation of solution B: Take 0.36 g of sodium nitrite solid in a 100 mL beaker, add 30 mL of deionized water, dilute to 50 mL with ethanol, mix well, and prepare solution B;

[0119] (3) Preparation of Solution C: 1.44 g of 1-naphthol solid was placed in a 200 mL beaker, 20 mL of ethanol was added, 40 mL of deionized water was added, 0.4 g of a 10 wt % aqueous sodium hydroxide solution was added, the volume was made up to 100 mL with ethanol, and the mixture was mixed to obtain Solution C;

[0120] (4) Preparation of solution D: 2 g of sodium hydroxide solid was placed in a 250 mL glass bottle, 100 mL of water was added, and the mixture was mixed well. 2.61 g of sodium dithionite was quickly weighed and poured into the solution, and the volume was adjusted to 200 mL with deionized water. The solution was mixed well to obtain solution D, and the solution was protected with inert gas.

[0121] (5) Preparation of Solution E: Dissolve 10 g of concentrated hydrochloric acid (37 wt%) in 200 mL of water, mix well, make up to 400 mL with deionized water, mix well, and prepare Solution E.

[0122] (6) Solution A and Solution B are respectively transported to a continuous flow reactor with an ice-water bath temperature of 0 to 5° C. at a rate of 0.5 mL / min, wherein the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the diazotization reaction is continued in the coil for 6 minutes to obtain an aniline diazonium salt solution;

[0123] (7) The aniline diazonium salt solution is continuously mixed with solution C at a volume flow rate ratio of 1:1 in a continuous flow reactor with an ice water bath temperature of 0 to 5° C. The delivery flow rate of solution C is set to 1 mL / min. The continuous flow reactor is mainly composed of a T-type tee and a coil. The two flows are quickly mixed in the T-type tee and the coupling reaction is continued in the coil for 3 minutes to obtain an azo compound 4-(phenylazo)-1-naphthol.

[0124] (8) the azo compound solution is continuously mixed with solution D at a volume flow rate ratio of 1:1 in a continuous flow reactor at a water bath temperature of 46° C., the delivery flow rate of solution D is set to 2 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two flows are quickly mixed in the T-type tee and the reduction reaction is continued in the coil for 12 minutes to obtain an alkaline solution of 4-amino-1-naphthol;

[0125] (9) the alkaline solution of 4-amino-1-naphthol is continuously mixed with solution E at a volume flow rate ratio of 1:1 in a continuous flow reactor at 25° C., the delivery flow rate of solution E is set to 4 mL / min, and the continuous flow reactor is mainly composed of a T-type tee and a coil; the two streams are quickly mixed in the T-type tee and the acidification reaction is continued in the coil for 0.5 min to obtain a 4-amino-1-naphthol hydrochloride solution;

[0126] (10) The product solution obtained in step (9) is collected at the outlet of the continuous flow reactor, and a small amount of sample is taken for liquid phase detection. The remaining sample is subjected to reduced pressure distillation to remove ethanol and most of the water, and the sample is cooled, allowed to stand, filtered, and vacuum dried to obtain 4-amino-1-naphthol hydrochloride. The yield calculated by liquid chromatography is 79.1%.

[0127] Although the embodiments of the present invention are disclosed for illustrative purposes, those skilled in the art will appreciate that various substitutions, changes and modifications are possible without departing from the spirit and scope of the present invention and the appended claims. Therefore, the scope of the present invention is not limited to the contents disclosed in the embodiments.

Claims

1. A method for continuous flow synthesis of 4-amino-1-naphthol hydrochloride, characterized in that: The steps include: First, a series of solutions required for the reaction are prepared: a. Aniline and inorganic acid are dissolved in a water-ethanol solution in proportion to obtain solution A; b. Sodium nitrite is dissolved in a water-ethanol solution to obtain solution B; c. 1-naphthol is dissolved in a water-ethanol solution, and then the pH is adjusted with an inorganic alkali aqueous solution to obtain solution C; d. The required amount of sodium hydroxide is weighed and dissolved in water, and after mixing evenly, the reducing agent is weighed and dissolved in the solution to obtain solution D; e. The required amount of hydrochloric acid aqueous solution is prepared to obtain solution E; after all solutions are prepared, a continuous reaction is carried out; The specific steps are as follows: (1) First, solution A and solution B are respectively transported to a precooling module of a continuous flow reactor according to a set ratio, and after mixing, the raw materials flow into the reactor for diazotization reaction to obtain an aniline diazonium salt solution; (2) the aniline diazonium salt solution is continuously mixed with solution C in a continuous flow reactor, and a coupling reaction is carried out at a set temperature to obtain an azo compound 4-(phenylazo)-1-naphthol; (3) the azo compound solution is continuously mixed with solution D in a continuous flow reactor, and a reduction reaction is carried out at a set temperature to obtain an alkaline solution of 4-amino-1-naphthol; (4) the alkaline solution of 4-amino-1-naphthol is mixed with solution E in a continuous flow reactor to carry out an acidification and salt-forming process of 4-amino-1-naphthol to obtain a 4-amino-1-naphthol hydrochloride solution; (5) collecting the product solution obtained in step 4 at the outlet of the continuous flow reactor, performing reduced pressure distillation to remove ethanol and most of the water, cooling, standing, filtering, and vacuum drying to obtain 4-amino-1-naphthol hydrochloride.

2. The method according to claim 1, characterized in that: The molar concentration of aniline in the solution A is 0.01-2 mol / L, the molar ratio of aniline to inorganic acid is 1:1-4, and the volume ratio of solvent water to ethanol is 1:0.2-9; Alternatively, the molar concentration of sodium nitrite in the solution B is 0.01-2 mol / L, and the volume ratio of solvent water to ethanol is 1:0.2-9; The molar concentration of the coupling component 1-naphthol in the solution C is 0.005-1 mol / L, the initial pH of the coupling component is 4-14, and the volume ratio of the solvent water to ethanol is 1:0.2-19; Alternatively, the molar concentration of the reducing agent in the solution D is 0.005 to 1 mol / L, and the molar concentration of sodium hydroxide is 0.005 to 15 mol / L; Alternatively, the molar concentration of hydrochloric acid in the solution E is 0.01 to 12 mol / L.

3. The method according to claim 1, characterized in that: In step a, the inorganic acid is selected from sulfuric acid or hydrochloric acid; in step c, the inorganic base is one or more of sodium hydroxide and potassium hydroxide; and in step d, the reducing agent is sodium dithionite.

4. The method according to claim 1, characterized in that: In the diazotization reaction in step (1), the molar ratio of aniline to sodium nitrite is 1:1-1.5, the flow ratio of solution A to solution B is 1-9:1-9, the flow rate of solution A is 0.01 ml / min-100 ml / min, the temperature of the diazotization reaction is -20-35°C, and the residence time is 0.01-100 min; Alternatively, in the coupling reaction in step (2), the molar ratio of 1-naphthol in solution C to aniline in solution A is 1:1-1.2, the flow ratio of solution C to diazonium salt solution is 1-9:1-9, the reaction temperature is -20-60°C, and the residence time is 0.01-100 min.

5. The method according to claim 1, characterized in that: In the step (3), the flow ratio of solution D to the azo compound solution in the reduction reaction is 1-9:1-9, the reduction reaction temperature is 15-75° C., the residence time is 1-100 min, and the molar ratio of 1-naphthol to the reducing agent is 1:1-10; Alternatively, in the step (4), the flow ratio of solution E to the alkaline solution of 4-amino-1-naphthol in the acidification reaction is 1-9:1-9, and the residence time of the acidification reaction is 0.01-100 min.

6. The method according to claim 1, characterized in that: The type of the continuous flow reactor described in steps (1) to (5) is a tubular reactor or a microchannel reactor, and the material is one or more of silicon carbide, Hastelloy, polymethyl methacrylate, polyethylene, polydimethylsiloxane, polyethylene terephthalate, glass, ceramic, aluminum, stainless steel, copper, glass or polytetrafluoroethylene.

7. The method according to claim 6, characterized in that: The microchannel reactor consists of a micro mixer and a coil.

8. The preparation method according to claim 7, characterized in that: The micro mixer is one or more of a static mixer, a T-type micro mixer, a Y-type micro mixer, and a T-type three-way valve.

9. The method according to claim 7 or 8, characterized in that: The inner diameter of the coil is 0.1 mm-20 cm, and the length of the coil is 1 cm-1200 m.

10. Use of the preparation method according to any one of claims 1 to 9 in the production of 4-amino-1-naphthol hydrochloride.

Images