Continuous flow synthesis process of 3-aminopyridine

Abstract

The invention discloses a continuous flow synthesis process of 3-aminopyridine. The invention specifically provides a preparation method of 3-aminopyridine, which comprises the following steps: carrying out a rearrangement reaction on an aqueous solution of 3-cyanopyridine, liquid caustic soda and an aqueous solution of sodium hypochlorite to generate isocyanate, and continuing a degradation reaction to generate 3-aminopyridine, the rearrangement reaction is carried out in a CSTR (continuous stirred-tank reactor). The preparation method provided by the invention is safe, efficient, simple to operate, suitable for process amplification and high in product yield.

Description

Technical Field

[0001] The invention relates to a continuous flow synthesis process of 3-aminopyridine. Background Art

[0002] 3-Aminopyridine is an important pharmaceutical and pesticide intermediate, and its downstream product 2,3-dichloropyridine is an important intermediate for the insecticide chlorfenapyr.

[0003] There are three main synthesis methods: (1) using 3-bromopyridine as the raw material, copper sulfate as the catalyst, and heating the reaction in concentrated ammonia water to produce it; (2) using 3-cyanopyridine as the raw material, hydrolyzing it to produce nicotinamide, and then producing it through the Hofmann degradation reaction. The steps are relatively more complicated; (3) using 3-cyanopyridine as the raw material, using sodium hypochlorite solution under alkaline conditions to prepare 3-aminopyridine in one pot. The reaction process is simpler, but a large amount of heat and gas will be released instantly during the heating degradation operation, which poses a great safety risk.

[0004] At present, the main public patents for the synthesis of 3-aminopyridine are as follows:

[0005] Chinese patent CN107963990 A discloses a one-step method for preparing 3-aminopyridine. The method adopts a one-step method to prepare 3-aminopyridine. The method reduces the reaction steps and also saves energy and equipment. However, both operations involve removing the heat exchange medium for natural temperature rise. The operation is only suitable for laboratory use and is not suitable for industrial production, which poses a great safety risk.

[0006] Chinese patent CN113149896 A discloses a method for preparing 3-aminopyridine. The method adopts a pipeline reactor to solve the problem of too fast temperature rise in the degradation stage and too high production risk. However, the raw material is still prepared by a 3-cyanopyridine autoclave process, and the product yield is not mentioned.

[0007] Chinese patent CN114436953 A discloses a synthesis process of 3-aminopyridine. This method uses nicotinamide as a raw material and adopts a traditional kettle production process, which cannot solve the problem of process safety risks. At the same time, the nicotinamide raw material needs to be prepared by 3-cyanopyridine, which increases the operation steps and production costs. Summary of the invention

[0008] The problem to be solved by the present invention is to provide a continuous flow synthesis process of 3-aminopyridine in order to overcome the deficiencies of the prior art. The process method provided by the present invention is safe, efficient, simple to operate, suitable for process amplification, and has a high product yield.

[0009] The present invention solves the above technical problems through the following technical solutions.

[0010] The invention provides a preparation method of 3-aminopyridine, which comprises the following steps: an aqueous solution of 3-cyanopyridine, liquid alkali and an aqueous solution of sodium hypochlorite are subjected to rearrangement reaction to generate isocyanate, and then a degradation reaction is further performed to generate 3-aminopyridine; the rearrangement reaction is performed in a CSTR reactor.

[0011] In some embodiments of the present invention, the CSTR reactor comprises two or more reactors connected in series or in parallel; preferably, each reactor of the CSTR reactor can realize feeding, mixing, heat exchange and reaction; for example, the CSTR reactor is composed of 4 or 5 reactors connected in series.

[0012] In some embodiments of the present invention, the residence time of the rearrangement reaction in the CSTR reactor is 30 to 120 min, preferably 50 to 100 min, for example, 51 min, 59 min, 66 min, 69 min, 70 min, 72 min, 76 min, 80 min, 81 min or 94 min.

[0013] In some embodiments of the present invention, the reaction temperature of the CSTR reactor is 10-40°C, preferably 20-40°C, such as 20°C, 25°C, 30°C, 35°C or 40°C.

[0014] In some embodiments of the present invention, the system pressure of the degradation reaction is 1-5 bar, for example, 1 bar, 2 bar, 3 bar, 4 bar or 5 bar.

[0015] In some embodiments of the present invention, the degradation reaction may be carried out in a microchannel reactor or a tubular reactor.

[0016] In some embodiments of the present invention, the temperature of the degradation reaction is 70-100°C, preferably 75-95°C, such as 75°C, 85°C, 90°C or 95°C.

[0017] In some embodiments of the present invention, the degradation reaction further includes cooling after the reaction is completed; the cooling can be carried out in a microchannel reactor or a tubular reactor; preferably, the cooling temperature is 10~30℃, preferably 20~30℃, for example 20℃ or 25℃.

[0018] In some embodiments of the present invention, the residence time of the degradation reaction is 1 to 20 min, preferably 5 to 10 min, for example 5 min or 6 min.

[0019] In some embodiments of the present invention, the cooling residence time is 1 to 5 min, preferably 1 to 3 min, for example 1 min or 2 min.

[0020] In some embodiments of the present invention, the mass concentration of the aqueous solution of 3-cyanopyridine may be 10-40%, preferably 10-30%, for example 15%, 20% or 25%.

[0021] In some embodiments of the present invention, the mass concentration of the liquid caustic soda may be 10-40%, preferably 15-30%, for example 20%, 25% or 30%.

[0022] In some embodiments of the present invention, the aqueous solution of sodium hypochlorite may have an effective chlorine content of 10-15%, preferably 10-14%, such as 11%, 12% or 13%.

[0023] In some embodiments of the present invention, the molar ratio of the sodium hypochlorite to the 3-cyanopyridine is (1.0-1.2):1, preferably (1.05-1.15):1, for example 1.06:1, 1.12:1, 1.08:1, 1.19:1, 1.15:1 or 1.07:1.

[0024] In some embodiments of the present invention, the molar ratio of sodium hydroxide in the liquid alkali to the 3-cyanopyridine is (1.5-2.5):1, for example, 1.74:1, 1.88:1, 2.17:1, 1.63:1, 1.95:1 or 1.67:1.

[0025] In some embodiments of the present invention, the flow rate of the aqueous solution of 3-cyanopyridine may be 10 to 50 g / min, preferably 10 g / min, 30 g / min or 50 g / min.

[0026] In some embodiments of the present invention, the flow rate of the liquid caustic soda may be 4 to 40 g / min, preferably 4 g / min, 5 g / min, 8 g / min, 13 g / min, 15 g / min, 25 g / min, 30 g / min or 40 g / min.

[0027] In some embodiments of the present invention, the flow rate of the aqueous solution of sodium hypochlorite may be 5 to 80 g / min, preferably 9.5 g / min, 10 g / min, 14 g / min, 16 g / min, 29 g / min, 45 g / min, 50 g / min, 53 g / min, 70 g / min or 80 g / min.

[0028] In some embodiments of the present invention, the preparation method comprises the following steps:

[0029] (1) Using a constant flow pump to transport the 3-cyanopyridine aqueous solution, the sodium hypochlorite aqueous solution and the liquid alkali solution to the CSTR reactor respectively;

[0030] (2) The isocyanate aqueous solution at the CSTR outlet enters the transfer kettle;

[0031] (3) Turn on the degradation pipeline heat exchanger and set the degradation reaction temperature and the cooling section temperature;

[0032] (4) Turn on the isocyanate aqueous solution constant flow pump to feed the degradation pipeline. The outlet of the pipeline is 3-aminopyridine solution.

[0033] (5) The crude 3-aminopyridine solution is extracted with chloroform and distilled to obtain 3-aminopyridine.

[0034] In some embodiments of the present invention, the residence time can be determined according to conventional techniques in the art, based on the number of CSTR reactors and / or the flow rate of the reaction materials.

[0035] In some embodiments of the present invention, the preparation method comprises the following steps:

[0036] Step 1, start the CSTR heat exchanger, set the heat exchanger to 20°C, and set the 3-cyanopyridine aqueous solution constant flow pump to 60°C;

[0037] Step 2, prepare 15-25% 3-cyanopyridine aqueous solution (keep warm at 60°C) and 20-30% liquid alkali in a preparation kettle;

[0038] Step 3, start the constant flow pump of 3-cyanopyridine aqueous solution, set the flow rate to 10-50 g / min; start the constant flow pump of sodium hypochlorite aqueous solution, the available chlorine in the sodium hypochlorite aqueous solution is 11-12%, and the flow rate is set to 9.5-80 g / min; start the liquid alkali constant flow pump, set the flow rate to 4-40 g / min; after the reaction materials are mixed, they are sequentially passed through the CSTR reactors connected in series for rearrangement reaction;

[0039] Step 4, the isocyanate aqueous solution at the outlet of the CSTR enters the transfer kettle;

[0040] Step 5, start the degradation pipeline heat exchanger, set the degradation reaction temperature to 75~95°C, and the cooling section to 20~25°C;

[0041] Step 6, start the isocyanate aqueous solution constant flow pump to feed into the degradation pipeline, and the pipeline outlet is 3-aminopyridine solution.

[0042] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0043] The reagents and raw materials used in the present invention are commercially available.

[0044] The positive improvement effect of the present invention is that the synthesis process provided by the present invention has one or more of the following advantages:

[0045] (1) The present invention adopts a continuous flow process, and successfully solves the problem of rapid heat release in the existing process by dividing the functional single temperature zones, setting and optimizing the temperature and, as well as coupling with the heat transfer and mass transfer advantages of the continuous flow, so that the materials can be transported to the continuous flow reactor for reaction at one time, and can run smoothly, and the reaction time is greatly shortened;

[0046] (2) The present invention creatively reduces the generation of impurities in the reaction system, improves the selectivity of 3-aminopyridine, greatly shortens the reaction time, and has fewer operating steps, simple operation, and high stability;

[0047] (3) The present invention can effectively avoid the generation of hot spots in the exothermic reaction, greatly improving the safety of the process;

[0048] (4) The present invention utilizes the plug flow characteristics of continuous flow to greatly reduce the occurrence of backmixing, resulting in fewer side reactions, fewer impurities in the crude product, high yield, and simple post-processing;

[0049] (5) The present invention greatly shortens the high temperature time of the reaction process, greatly reduces energy consumption, and saves costs;

[0050] (6) There is no scale-up effect, that is, the process can still complete the reaction in a relatively short time on an industrial scale, and the product content and yield are basically the same as those on a laboratory scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 Schematic diagram of the 3-aminopyridine synthesis process apparatus of Example 1. DETAILED DESCRIPTION

[0052] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0053] CSTR Reactor

[0054] Model: JR-S500GG

[0055] Capacity: 500mL (effective liquid holding volume 300mL); or, 5000mL (effective liquid holding volume 3000mL).

[0056] Example 1 (Device schematic diagram as shown Figure 1 ):

[0057] a. Turn on the CSTR heat exchanger, set the heat exchanger to 20°C, and set the 15% 3-cyanopyridine aqueous solution constant flow pump to 60°C;

[0058] b. Prepare in a preparation kettle: 15% 3-cyanopyridine aqueous solution (60°C insulation), liquid alkali (25% sodium hydroxide aqueous solution);

[0059] c. Turn on the constant flow pump of 15% 3-cyanopyridine aqueous solution, set the flow rate to 10g / min, turn on the constant flow pump of sodium hypochlorite aqueous solution, set the flow rate to 9.50g / min, turn on the liquid alkali (25% sodium hydroxide aqueous solution) constant flow pump, set the flow rate to 4.00g / min; after the reaction materials are mixed, they are sequentially passed through five series-connected CSTR reactors (single reactor volume is 500mL, normal pressure) for rearrangement reaction;

[0060] d. The rearrangement reaction (isocyanate aqueous solution) liquid at the CSTR outlet enters the transfer kettle.

[0061] e. Turn on the degradation pipeline heat exchanger, set the degradation reaction temperature to 90°C, and the cooling section to 25°C;

[0062] f. Turn on the constant flow pump of the isocyanate aqueous solution and feed it into the degradation pipeline. The outlet of the pipeline is the 3-aminopyridine solution. The crude 3-aminopyridine solution is extracted with chloroform and distilled to obtain 3-aminopyridine. HPLC is used to detect the raw material residue and product purity, and the product yield is determined using an HPLC external standard.

[0063] HPLC analysis method:

[0064]

[0065] Using the same preparation process as above, the experimental conditions and results of Examples 1-10 are shown in Table 1:

[0066] Table 1

[0067] .

[0069] The experimental results of Comparative Examples 1-4 are shown in Table 2:

[0070] Table 2

[0071] .

[0073] Comparative Example 5:

[0074] Flask inspection: Add 30g of 15% 3-cyanopyridine aqueous solution and 13g of 25% liquid alkali into a flask, raise the temperature to 80-90°C, and add 29g of 12% sodium hypochlorite aqueous solution dropwise while controlling the temperature. HPLC detection shows that no product is generated, and the main product is hydrolyzed nicotinic acid.

Claims

1. A method for preparing 3-aminopyridine, characterized in that: The method comprises the following steps: an aqueous solution of 3-cyanopyridine, liquid alkali and an aqueous solution of sodium hypochlorite are subjected to rearrangement reaction to generate isocyanate, and then further subjected to degradation reaction to generate 3-aminopyridine; The rearrangement reaction is carried out in a CSTR reactor.

2. The preparation method according to claim 1, characterized in that It meets one or more of the following conditions: (1) The residence time of the rearrangement reaction in the CSTR reactor is 30 to 120 minutes; (2) The reaction temperature of the CSTR reactor is 10-40°C; (3) The degradation reaction is carried out in a microchannel reactor or a tubular reactor; (4) The temperature of the degradation reaction is 70-100°C; (5) The residence time of the degradation reaction is 1 to 20 minutes; (6) The degradation reaction also includes cooling after the reaction is completed.

3. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The residence time of the rearrangement reaction in the CSTR reactor is 50 to 100 minutes; (2) The reaction temperature of the CSTR reactor is 20-40°C; (3) The temperature of the degradation reaction is 75-95°C; (4) The system pressure of the degradation reaction is 1~5 bar; (5) The residence time of the degradation reaction is 5 to 10 minutes.

4. The preparation method according to claim 3, characterized in that: It meets one or more of the following conditions: (1) The residence time of the rearrangement reaction in the CSTR reactor is 51 min, 59 min, 66 min, 69 min, 70 min, 72 min, 76 min, 80 min, 81 min or 94 min; (2) The reaction temperature of the CSTR reactor is 20°C, 25°C, 30°C, 35°C or 40°C; (3) The temperature of the degradation reaction is 75°C, 85°C, 90°C or 95°C; (4) The system pressure of the degradation reaction is 1 bar, 2 bar, 3 bar, 4 bar or 5 bar; (5) The residence time of the degradation reaction is 5 min or 6 min.

5. The preparation method according to claim 1, characterized in that: It meets one or more of the following conditions: (1) The mass concentration of the aqueous solution of 3-cyanopyridine is 10-40%; (2) The mass concentration of the liquid caustic soda is 10-40%; (3) The aqueous solution of sodium hypochlorite has an effective chlorine content of 10-15%; (4) The molar ratio of the sodium hypochlorite to the 3-cyanopyridine is (1.0-1.2):1; (5) The molar ratio of sodium hydroxide in the liquid alkali to 3-cyanopyridine is (1.5-2.5):1; (6) The flow rate of the aqueous solution of 3-cyanopyridine is 10 to 50 g / min; (7) The flow rate of the liquid caustic soda is 4-40 g / min; (8) The flow rate of the aqueous solution of sodium hypochlorite is 5 to 80 g / min.

6. The preparation method according to claim 5, characterized in that: It meets one or more of the following conditions: (1) The mass concentration of the aqueous solution of 3-cyanopyridine is 10-30%; (2) The mass concentration of the liquid caustic soda is 15-30%; (3) The aqueous solution of sodium hypochlorite has an effective chlorine content of 10-14%; (4) The molar ratio of the sodium hypochlorite to the 3-cyanopyridine is (1.05-1.15):1; (5) The flow rate of the aqueous solution of 3-cyanopyridine is 10 g / min, 30 g / min or 50 g / min; (6) The flow rate of the liquid caustic soda is 4 g / min, 5 g / min, 8 g / min, 13 g / min, 15 g / min, 25 g / min, 30 g / min or 40 g / min; (7) The flow rate of the aqueous solution of sodium hypochlorite is 9.5 g / min, 10 g / min, 14 g / min, 16 g / min, 29 g / min, 45 g / min, 50 g / min, 53 g / min, 70 g / min or 80 g / min.

7. The preparation method according to claim 5, characterized in that: It meets one or more of the following conditions: (1) The mass concentration of the aqueous solution of 3-cyanopyridine is 15%, 20% or 25%; (2) The mass concentration of the liquid caustic soda is 20%, 25% or 30%; (3) The aqueous solution of sodium hypochlorite has an effective chlorine content of 11%, 12% or 13%; (4) The molar ratio of the sodium hypochlorite to the 3-cyanopyridine is 1.06:1, 1.12:1, 1.08:1, 1.19:1, 1.15:1 or 1.07:1; (5) The molar ratio of sodium hydroxide in the liquid alkali to 3-cyanopyridine is 1.74:1, 1.88:1, 2.17:1, 1.63:1, 1.95:1 or 1.67:

1.

8. The preparation method according to claim 2, characterized in that: It meets one or more of the following conditions: (1) The cooling is carried out in a microchannel reactor or a tubular reactor; (2) The cooling temperature is 10-30°C; (3) The cooling residence time is 1 to 5 minutes.

9. The preparation method according to claim 2, characterized in that: The cooling temperature is 20-30°C, for example 20°C or 25°C; And / or, the cooling residence time is 1 to 3 minutes, for example, 1 minute or 2 minutes.

10. The preparation method according to any one of claims 1 to 9, characterized in that: It includes the following steps: (1) Using a constant flow pump to transport the 3-cyanopyridine aqueous solution, the sodium hypochlorite aqueous solution and the liquid alkali solution to the CSTR reactor respectively; (2) The isocyanate aqueous solution at the CSTR outlet enters the transfer kettle; (3) Turn on the degradation pipeline heat exchanger and set the degradation reaction temperature and the cooling section temperature; (4) Turn on the isocyanate aqueous solution constant flow pump to feed the degradation pipeline, and the pipeline outlet is 3-aminopyridine solution; (5) The crude 3-aminopyridine solution is extracted with chloroform and distilled to obtain 3-aminopyridine; Preferably, the preparation method comprises the following steps: Step 1, start the CSTR heat exchanger, set the heat exchanger to 20°C, and set the 3-cyanopyridine aqueous solution constant flow pump to 60°C; Step 2, prepare in a preparation kettle: 15-25% 3-cyanopyridine aqueous solution (60°C insulation), 20-30% liquid caustic soda; Step 3, start the constant flow pump of 3-cyanopyridine aqueous solution, set the flow rate to 10-50 g / min; start the constant flow pump of sodium hypochlorite aqueous solution, the available chlorine in the sodium hypochlorite aqueous solution is 11-12%, set the flow rate to 9.5-80 g / min, start the liquid alkali constant flow pump, set the flow rate to 4-40 g / min; after mixing the reaction materials, sequentially pass through the series-connected CSTR reactors for rearrangement reaction; Step 4, the isocyanate aqueous solution at the outlet of the CSTR enters the transfer kettle; Step 5, start the degradation pipeline heat exchanger, set the degradation reaction temperature to 75~95°C, and the cooling section to 20~25°C; Step 6, start the isocyanate aqueous solution constant flow pump to feed into the degradation pipeline, and the pipeline outlet is 3-aminopyridine solution.

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