A method for the continuous synthesis of 3-nitro-4-fluoroaniline in a microchannel

Abstract

The application provides a method for continuously synthesizing 3-nitro-4-fluoroaniline in a microchannel, and belongs to the field of organic synthesis. The method uses 4-fluoroaniline as a raw material, and 3-nitro-4-fluoroaniline is prepared through a continuous flow process. The method has low energy consumption, is green and safe, and can automatically control the preparation of 3-nitro-4-fluoroaniline with high yield, and has good application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a method for continuously synthesizing 3-nitro-4-fluoroaniline in a microchannel. BACKGROUND

[0002] 3-nitro-4-fluoroaniline is an aromatic fluorine compound and an important raw material for synthesizing fluorine medicines. 3-nitro-4-fluoroaniline is also a raw material for special dyes and functional dyes, such as a raw material for synthesizing hair dyes and liquid crystal dyes, and has a wide range of uses.

[0003] Common synthesis methods of 3-nitro-4-fluoroaniline include using p-chloronitrobenzene as a raw material, using KF for fluorination, and synthesizing through steps of fluorination, reduction, acid dissolution, and nitration; or using 2-fluoro-3-nitrobenzoic acid as a starting raw material, generating 2-fluoro-3-nitrobenzoyl chloride through a nucleophilic substitution reaction with dichlorosulfoxide, and then reacting with 2-bromo-4-(perfluoroprop-2-yl)-2-(trifluoromethyl)aniline, in the presence of cyclopropylmethanal and p-fluorobenzoyl chloride, to generate the target product through a multi-step reaction.

[0004] However, these methods have the following problems: (1) high energy consumption, the synthesis process generates tar, greatly reducing the oxidation impurities; (2) the synthesis method generates a large amount of acid-containing wastewater, increasing the cost and difficulty of three-waste treatment; (3) the oxidizing agent used, such as chromium trioxide, has high toxicity and pollutes the environment; (4) the yield is low, the degree of automatic control is not high, and the labor cost is high; (5).

[0005] Therefore, it is urgent to develop a new green and efficient, safe method for improving the yield and purity of 3-nitro-4-fluoroaniline. SUMMARY

[0006] The present application aims to provide a method for continuously synthesizing 3-nitro-4-fluoroaniline in a microchannel.

[0007] The present application provides a method for continuously synthesizing 3-nitro-4-fluoroaniline in a microchannel, which is performed in a continuous flow reaction device. In the continuous flow reaction device, a raw material tank of 4-fluoroaniline and acid is connected to a metering pump one, a raw material tank of mixed acid is connected to a metering pump two, a raw material tank of water and sodium dithionite is connected to a metering pump three, the metering pump one is connected to a continuous flow pre-cooler one, the metering pump two is connected to a continuous flow pre-cooler two, and the metering pump three is connected to a continuous flow pre-cooler three; the continuous flow pre-cooler one and the continuous flow pre-cooler two are connected to a continuous flow mixer one, the continuous flow mixer one is connected to a continuous flow reactor one, the continuous flow reactor one and the continuous flow pre-cooler three are connected to a continuous flow mixer two, the continuous flow mixer two is connected to a continuous flow reactor two, and the continuous flow reactor two is connected to a post-treatment device; and the post-treatment device is connected to a product outlet.

[0008] The mixed acid is a mixture of nitric acid and acid;

[0009] The reaction route of the method is as follows:

[0010]

[0011] The method comprises the following steps: when the continuous flow pre-cooler one, the continuous flow pre-cooler two, the continuous flow mixer one, the continuous flow mixer two, the continuous flow reactor one and the continuous flow reactor two reach a circulation temperature, simultaneously opening the metering pump one and the metering pump two for 200s-300s, then opening the metering pump three for 250s-350s, and then quenching in the post-treater to obtain 3-nitro-4-fluoroaniline.

[0012] The reaction time of the metering pump one and the metering pump two comprises a preheating time and a residence time.

[0013] The circulation temperatures of the continuous flow pre-cooler one, the continuous flow pre-cooler two, the continuous flow mixer one and the continuous flow reactor one are consistent; and the circulation temperatures of the continuous flow pre-cooler three, the continuous flow mixer two and the continuous flow reactor two are consistent.

[0014] Further, the acid is an inorganic acid; the molar ratio of the 4-fluoroaniline to the mixed acid is 1:1.05-2.0; and the mixed acid is a mixture of nitric acid and sulfuric acid in a mass ratio of 1:0.5-1.5.

[0015] Further, the inorganic acid is sulfuric acid; the molar ratio of the 4-fluoroaniline to the mixed acid is 1:1.05-2.0; and the mixed acid is a mixture of nitric acid and sulfuric acid in a mass ratio of 1:1.05.

[0016] Further, the circulation temperatures of the continuous flow pre-cooler one, the continuous flow pre-cooler two, the continuous flow mixer one and the continuous flow reactor one are 0-15℃; and the circulation temperatures of the continuous flow pre-cooler three, the continuous flow mixer two and the continuous flow reactor two are-5-0℃.

[0017] Further, the circulation temperatures of the continuous flow pre-cooler one, the continuous flow pre-cooler two, the continuous flow mixer one and the continuous flow reactor one are 10℃; and the circulation temperatures of the continuous flow pre-cooler three, the continuous flow mixer two and the continuous flow reactor two are 0℃.

[0018] Further, the mass ratio of the water to the sodium hydrosulfite is 100-300:1.

[0019] Further, the mass ratio of the water to the sodium hydrosulfite is 200:1.

[0020] Further, after the quenching, the following purification steps are further included: adjusting the pH of the reaction solution, filtering, and drying to obtain 3-nitro-4-fluoroaniline.

[0021] Furthermore, the flow rate of metering pump one is set to 47.0~200.0 ml / min; the flow rate of metering pump two is set to 6.9~35.0 ml / min; the flow rate of metering pump three is set to 118.0~487.0 ml / min; the residence time of metering pump one and metering pump two is 4~7 min; and the reaction time of metering pump three is 4~6 min.

[0022] Furthermore, the flow rate of metering pump one is set to 200 ml / min; the flow rate of metering pump two is set to 35 ml / min; the flow rate of metering pump three is set to 487 ml / min; the residence time of metering pump one and metering pump two is 3 min; and the reaction time of metering pump three is 5 min.

[0023] This invention uses 4-fluoroaniline as raw material to prepare 3-nitro-4-fluoroaniline through a continuous flow process. This method has low energy consumption, is green and safe, and can produce high yields of 3-nitro-4-fluoroaniline through automated control, showing good application prospects.

[0024] 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.

[0025] 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

[0026] Figure 1 This is a process flow diagram. Detailed Implementation

[0027] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0028] according to Figure 1 The process flow shown illustrates the following synthetic route for the preparation of 3-nitro-4-fluoroaniline:

[0029]

[0030] Example 1

[0031] 1) Prepare a mixed solution of 4-fluoroaniline (550g, 4.95mol) and sulfuric acid (3300g, 6w), and connect it to metering pump one; prepare a mixed acid solution (334g nitric acid + 334g sulfuric acid, 1.05eq), and connect it to metering pump two; prepare an aqueous solution of sodium hydrosulfite (5500g water + 27.5g sodium hydrosulfite), and connect it to metering pump three.

[0032] 2) Set the continuous flow pre-cooler 1, continuous flow pre-cooler 2, continuous flow mixer 1, continuous flow reactor 1, the cycle temperature is 10℃, reach the steady state; Set the continuous flow pre-cooler 3, continuous flow mixer 2, continuous flow reactor 2, the cycle temperature is set to -5℃.

[0033] 3) Set the flow rate of metering pump 1 to 200ml / min, set the flow rate of metering pump 2 to 35ml / min, set the flow rate of metering pump 3 to 487ml / min.

[0034] 4) Start metering pump 1 and metering pump 2 at the same time, run for 240s (60s is pre-cooling time, the rest is residence time), then start metering pump 3, run for 300s after starting metering pump 3, quench in post-treatment, adjust pH to 7 with ammonia water, filter, dry the product, get 714.73g product, HPLC purity 99.6%, yield: 92.5%. Orange yellow crystalline powder, melting point: 97.1-97.4. Structural characterization data: MS: 157.11, HNMR (300MHz, DMSO) δ (ppm): 5.63 (s, 2H, -NH2), 6.89-7.01 (m, 1H, Ar-H), 7.18-7.23 (m, 2H, Ar-H)

[0035] The following is the preparation of the control sample by comparing the control example.

[0036] Control Example 1

[0037] According to the preparation method of Reference Example 1, according to the screening conditions in Table 1, replace 1.05eq nitric acid + sulfuric acid (1:1) with 1.5eq nitric acid, set the flow rate of metering pump 1 to 50ml / min, set the flow rate of metering pump 2 to 7ml / min, set the residence time in the running time of metering pump 1 and metering pump 2 to 6min, set the cycle temperature of continuous flow pre-cooler 1, 2, continuous mixer 1, continuous reactor 1 to 5℃, prepare the product with purity of 99% and yield of 52%. Light brown solid, melting point: 97.1-98℃.

[0038] Control Example 2

[0039] Reference Example 1, the product was prepared with purity of 99.2% and yield of 70% following the screening conditions of Table 1 by replacing 1.05 eq nitric acid + sulfuric acid (1 : 1) with 2.0 eq nitric acid, setting the flow rate of metering pump one at 48 ml / min, setting the flow rate of metering pump two at 9 ml / min, setting the residence time in the run time of metering pump one and metering pump two at 6 min, setting the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, continuous reactor one at 5 °C. Light brown solid, melting point: 96-98 °C.

[0040] Comparative Example 3

[0041] Reference Example 1, the product was prepared with purity of 99.4% and yield of 91.5% following the screening conditions of Table 1 by setting the flow rate of metering pump one at 48.5 ml / min, setting the flow rate of metering pump two at 8.5 ml / min, setting the residence time in the run time of metering pump one and metering pump two at 6 min, setting the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, continuous reactor one at 5 °C.

[0042] Comparative Example 4

[0043] Reference Example 1, the product was prepared with purity of 99.4% and yield of 91.2% following the screening conditions of Table 1 by replacing 1.05 eq nitric acid + sulfuric acid (1 : 1) with 1.2 eq nitric acid + sulfuric acid (1 : 1), setting the flow rate of metering pump one at 47.5 ml / min, setting the flow rate of metering pump two at 9.5 ml / min, setting the residence time in the run time of metering pump one and metering pump two at 6 min, setting the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, continuous reactor one at 5 °C. Orange yellow solid, melting point: 96.9-97.6 °C.

[0044] Comparative Example 5

[0045] Reference Example 1, the product was prepared with purity of 99.1% and yield of 85.4% following the screening conditions of Table 1 by replacing 1.05 eq nitric acid + sulfuric acid (1 : 1) with 1.05 eq nitric acid + sulfuric acid (1 : 0.5), setting the flow rate of metering pump one at 50.5 ml / min, setting the flow rate of metering pump two at 6.9 ml / min, setting the residence time in the run time of metering pump one and metering pump two at 6 min, setting the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, continuous reactor one at 5 °C. Light brown solid, melting point: 96.2-97.3 °C.

[0046] Comparative Example 6

[0047] Following the preparation method of Example 1 and according to the screening conditions in Table 1, 1.05 eq nitric acid + sulfuric acid (1:1) was replaced with 1.05 eq nitric acid + sulfuric acid (1:1.5). The flow rate of metering pump one was set to 47 ml / min, and the flow rate of metering pump two was set to 10 ml / min. The residence time of metering pumps one and two was set to 6 min. The circulation temperature of continuous flow precoolers one and two, continuous mixer one, and continuous reactor one was set to 5°C. A product with a purity of 99.3% and a yield of 90% was obtained. It is an orange-yellow solid with a melting point of 97-97.8°C.

[0048] Compare with Example 7

[0049] Following the preparation method of Example 1 and the screening conditions in Table 1, the flow rate of metering pump one was set to 48.5 ml / min, the flow rate of metering pump two was set to 8.5 ml / min, the residence time of metering pumps one and two was set to 2 min, and the circulation temperature of continuous flow precoolers one and two, continuous mixer one, and continuous reactor one was set to 5°C. A product with a purity of 99% and a yield of 88% was obtained. It is an orange-yellow solid with a melting point of 96.9-97.7°C.

[0050] Compare with Example 8

[0051] Following the preparation method of Example 1 and according to the screening conditions in Table 1, the flow rate of metering pump one was set to 48.5 ml / min, the flow rate of metering pump two was set to 8.5 ml / min, the residence time of metering pumps one and two was set to 3 min, and the circulation temperature of continuous flow precoolers one and two, continuous mixer one, and continuous reactor one was set to 5°C. A product with a purity of 99.6% and a yield of 92.3% was obtained. It is an orange-yellow solid with a melting point of 97.1-97.8°C.

[0052] Compare with Example 9

[0053] Following the preparation method of Example 1 and the screening conditions in Table 1, the flow rate of metering pump one was set to 48.5 ml / min, the flow rate of metering pump two was set to 8.5 ml / min, the residence time of metering pumps one and two was set to 4 min, and the circulation temperature of continuous flow precoolers one and two, continuous mixer one, and continuous reactor one was set to 5°C. A product with a purity of 99.2% and a yield of 91% was obtained. It is an orange-yellow solid with a melting point of 96.5-97.8°C.

[0054] Compare with Example 10

[0055] The product was prepared in accordance with the preparation method of Reference Example 1, under the screening conditions of Table 1, by setting the flow rate of metering pump one at 48.5 ml / min, the flow rate of metering pump two at 8.5 ml / min, the residence time of the operating time of metering pump one and metering pump two at 6 min, and the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, and continuous reactor one at 5°C. The product was obtained in a purity of 99.3% and a yield of 90%. Yellow solid, melting point: 97.2-98°C.

[0056] Comparative Example 11

[0057] The product was prepared in accordance with the preparation method of Reference Example 1, under the screening conditions of Table 1, by setting the flow rate of metering pump one at 48.5 ml / min, the flow rate of metering pump two at 8.5 ml / min, the residence time of the operating time of metering pump one and metering pump two at 6 min, and the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, and continuous reactor one at 5°C. The product was obtained in a purity of 99.3% and a yield of 90%. Yellow solid, melting point: 97.2-98°C.

[0058] Comparative Example 12

[0059] The product was prepared in accordance with the preparation method of Reference Example 1, under the screening conditions of Table 1, by setting the flow rate of metering pump one at 48.5 ml / min, the flow rate of metering pump two at 8.5 ml / min, the residence time of the operating time of metering pump one and metering pump two at 6 min, and the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, and continuous reactor one at 5°C. The product was obtained in a purity of 99.3% and a yield of 90%. Yellow solid, melting point: 97.2-98°C.

[0060] Comparative Example 13

[0061] The product was prepared in accordance with the preparation method of Reference Example 1, under the screening conditions of Table 1, by setting the flow rate of metering pump one at 48.5 ml / min, the flow rate of metering pump two at 8.5 ml / min, the residence time of the operating time of metering pump one and metering pump two at 6 min, and the circulation temperature of continuous flow pre-cooler one, two, continuous mixer one, and continuous reactor one at 5°C. The product was obtained in a purity of 99.3% and a yield of 90%. Yellow solid, melting point: 97.2-98°C.

[0062] Comparative Example 14

[0063] Reference Example 1 was prepared according to the preparation method of Reference Example 1, except that the flow rate of metering pump one was set to 100 ml / min, the flow rate of metering pump two was set to 17.5 ml / min, the residence time of the operating time of metering pump one and metering pump two was set to 3 min, and the circulating temperature of continuous flow pre-cooler one, continuous flow pre-cooler two, continuous flow mixer one, and continuous flow reactor one was set to 15°C. The product was prepared in a purity of 99.3% and a yield of 90%. Yellow solid, melting point: 96.9-96.9°C.

[0064] Comparative Example 15

[0065] 1) A mixture solution of 4-fluoroaniline (550 g, 4.95 mol) and sulfuric acid (3300 g, 6 w) was prepared and connected to metering pump one. A mixed acid solution (334 g of nitric acid + 334 g of sulfuric acid, 1.05 eq) was prepared and connected to metering pump two. Water (5500 g, 10 w) was added to the reactor, and the temperature was lowered to 0°C in advance.

[0066] 2) The circulating temperature of continuous flow pre-cooler one, continuous flow pre-cooler two, continuous flow mixer one, and continuous flow reactor one was set to 10°C, and the system was brought to a stable state.

[0067] 3) The flow rate of metering pump one was set to 200 ml / min, and the flow rate of metering pump two was set to 35 ml / min.

[0068] 4) Metering pump one and metering pump two were started at the same time, and after 240 s, the reaction was directly quenched in the reactor. The pH was adjusted to 7 with sodium hydroxide, and the product was filtered and dried. 602.7 g of product was obtained, with a purity of 99.1% by HPLC and a yield of 78%. Light brown solid, melting point: 96.4-97.8°C.

[0069] Comparative Example 16

[0070] Reference Example 1 was prepared according to the preparation method of Reference Example 1, except that the water and sodium bisulfite in metering pump three were replaced with the same mass of water. The product was prepared in a purity of 99.3% and a yield of 85%. Light brown solid, melting point: 96.7-98.1°C.

[0071] The beneficial effects of the present application are demonstrated by the following experimental examples.

[0072] Experimental Example 1, Screening of Experimental Conditions of the Present Invention

[0073] 1. Experimental Method

[0074] According to the preparation method of Reference Example 1, except that the flow rate of metering pump one was set to 100 ml / min, the flow rate of metering pump two was set to 17.5 ml / min, the residence time of the operating time of metering pump one and metering pump two was set to 3 min, and the circulating temperature of continuous flow pre-cooler one, continuous flow pre-cooler two, continuous flow mixer one, and continuous flow reactor one was set to 15°C. The product was prepared in a purity of 99.3% and a yield of 90%. Yellow solid, melting point: 96.9-96.9°C. Figure 1The process flow chart shown is used to prepare 3-nitro-4-fluoroaniline, and comparative examples 1, control examples 1-16 are screened in terms of nitration reagent and amount, reaction time (residence time of the mixture of metering pump one and metering pump two in the reactor), reaction temperature (circulating temperature of continuous flow pre-cooler one, continuous flow pre-cooler two, continuous flow mixer one, and continuous flow reactor one), and quenching mode.

[0075] 2. Experimental results

[0076] Table 1 is the screening result of nitration reagent and amount, reaction time, and reaction temperature:

[0077] Table 1

[0078]

[0079] Table 2 is the screening result of quenching mode:

[0080] Table 2

[0081]

[0082] In the screening of nitration reagent and amount (control examples 1-6), the results show that 1.05 eq of nitric acid + sulfuric acid (1:1) is the best nitration reagent and amount; in the screening of reaction time (control examples 7-10), the results show that the reaction time of 2 min is the best reaction time; in the screening of reaction temperature (control examples 11-14), the results show that the reaction temperature of 5℃ is the best reaction temperature; in the screening of quenching mode (control examples 15, 16, and example 1), the results show that using water and sodium hydrosulfite is the best quenching mode under continuous flow process.

[0083] In summary, the present application provides a method for continuously synthesizing 3-nitro-4-fluoroaniline in a microchannel. The present application uses 4-fluoroaniline as a raw material to prepare 3-nitro-4-fluoroaniline through continuous flow process. The method has low energy consumption, is green and safe, and can produce high yield of 3-nitro-4-fluoroaniline through automatic control, and has good application prospect.

Claims

1. A method for continuous microchannel synthesis of 3-nitro-4-fluoroaniline, characterized in that, The method is carried out in a continuous flow reactor. In the continuous flow reactor, the raw material storage tanks for 4-fluoroaniline and sulfuric acid are connected to metering pump one, the raw material storage tank for mixed acid is connected to metering pump two, and the raw material storage tanks for water and sodium hydrosulfite are connected to metering pump three. Metering pump one is connected to continuous flow precooler one, metering pump two is connected to continuous flow precooler two, and metering pump three is connected to continuous flow precooler three. Continuous flow precooler one and continuous flow precooler two are connected to continuous flow mixer one, continuous flow mixer one is connected to continuous flow reactor one, continuous flow reactor one and continuous flow precooler three are connected to continuous flow mixer two, continuous flow mixer two is connected to continuous flow reactor two, continuous flow reactor two is connected to post-processor, and post-processor is connected to product outlet. The mixed acid is a mixture of nitric acid and sulfuric acid; The reaction route of the method is as follows: The method includes the following steps: when the continuous flow precooler one, continuous flow precooler two, continuous flow mixer one, continuous flow mixer two, continuous flow reactor one, and continuous flow reactor two reach the circulation temperature, metering pump one and metering pump two are simultaneously turned on for 200s~300s, then metering pump three is turned on for 250s~350s, and then quenched by a post-processor to obtain 3-nitro-4-fluoroaniline; The reaction time of metering pumps one and two includes preheating time and residence time; Among them, the circulating temperatures of continuous flow precooler one, continuous flow precooler two, continuous flow mixer one and continuous reactor one are the same; the circulating temperatures of continuous flow precooler three, continuous flow mixer two and continuous flow reactor two are the same. The mass ratio of water to sodium hydrosulfite is 100~300:

1.

2. The method according to claim 1, characterized in that, The molar ratio of 4-fluoroaniline to the mixed acid is 1:1.05~2.0; the mixed acid is a mixture of nitric acid and sulfuric acid in a mass ratio of 1:0.5~1.

5.

3. The method according to claim 2, characterized in that, The molar ratio of 4-fluoroaniline to the mixed acid is 1:1.05~2.0; the mixed acid is a mixture of nitric acid and sulfuric acid in a mass ratio of 1:1.

05.

4. The method according to claim 1, characterized in that, The circulating temperature of the first continuous flow precooler, the second continuous flow precooler, the first continuous flow mixer, and the first continuous reactor is 0~15℃; the circulating temperature of the third continuous flow precooler, the second continuous flow mixer, and the second continuous flow reactor is -5~0℃.

5. The method according to claim 4, characterized in that, The circulating temperature of the first continuous flow precooler, the second continuous flow precooler, the first continuous flow mixer, and the first continuous flow reactor is 10°C; the circulating temperature of the third continuous flow precooler, the second continuous flow mixer, and the second continuous flow reactor is 0°C.

6. The method according to claim 1, characterized in that, The mass ratio of water to sodium hydrosulfite is 200:

1.

7. The method according to claim 1, characterized in that, The quenching process also includes the following purification steps: adjusting the pH of the reaction solution, filtering, and drying to obtain 3-nitro-4-fluoroaniline.

8. The method according to claim 1, characterized in that, The flow rate of metering pump one is set to 47.0~200.0 ml / min; the flow rate of metering pump two is set to 6.9~35.0 ml / min; the flow rate of metering pump three is set to 118.0~487.0 ml / min; the residence time of metering pump one and metering pump two is 4~7 min; and the reaction time of metering pump three is 4~6 min.

9. The method according to claim 1, characterized in that, The flow rate of metering pump one is set to 200 ml / min; the flow rate of metering pump two is set to 35 ml / min; the flow rate of metering pump three is set to 487 ml / min; the residence time of metering pump one and metering pump two is 3 min; and the reaction time of metering pump three is 5 min.

Images