A continuous process for the synthesis of ethyl 2,3-dicyano-2-(pyridin-3- yl diazenyl)propionate

Abstract

The application discloses a continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, and belongs to the technical field of medicine intermediate preparation, which comprises the following steps: precooling 3-amino pyridine, strong acid and diazotization reagent in a pipeline, then pumping into a first mixer for mixing, and finally delivering into a first stage connecting reactor for reaction to obtain a 3-amino pyridine diazonium salt intermediate; precooling an ethyl alcohol solution of 2,3-dicyano propionic acid ethyl ester in a pipeline, then mixing with the 3-amino pyridine diazonium salt intermediate in a second mixer, and then delivering into a second stage connecting reactor for reaction to obtain a reaction product mixture; and separating and purifying the reaction product mixture to obtain a target product. The application can solve the problem of unstable process amplification caused by intermediate decomposition, and improve the production scale.

Description

TECHNICAL FIELD

[0001] The application relates to a continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) ethyl propionate and belongs to the technical field of preparation of medical intermediates. BACKGROUND

[0002] 2,3-dicyano-2-(pyridine-3-yl diazenyl) ethyl propionate is an important organic synthesis intermediate and is widely applied in the synthesis of medicines and pesticides, and a synthesis route is shown in the following. According to the literature, 3-aminopyridine is diazotized by using sodium nitrite and concentrated hydrochloric acid in a reaction kettle to obtain a 3-aminopyridine diazonium salt intermediate, and then the 3-aminopyridine diazonium salt intermediate is reacted with an ethyl alcohol solution of 2,3-dicyanoethyl propionate to obtain the final product. The method has the defects that the 3-aminopyridine diazonium salt intermediate is unstable and is easy to decompose, the safety risk is great, and the method cannot be used for large-scale production.

[0003] SUMMARY

[0004] The application aims to overcome the defects of the prior art and provide a continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) ethyl propionate, which can solve the problem that the process cannot be stably enlarged due to the decomposition of the intermediate and improve the production scale.

[0005] To solve the above technical problems, the technical scheme adopted by the application is as follows:

[0006] A continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) ethyl propionate comprises the following steps:

[0007] 3-aminopyridine, a strong acid and a diazotization reagent are pre-cooled in a pipeline, then are pumped into a first mixer for mixing and finally are delivered to a first-stage connecting reactor for reaction to obtain a 3-aminopyridine diazonium salt intermediate;

[0008] An ethyl alcohol solution of 2,3-dicyanoethyl propionate is pre-cooled in a pipeline, then is mixed with the 3-aminopyridine diazonium salt intermediate in a second mixer and then is delivered to a second-stage connecting reactor for reaction to obtain a reaction product mixture;

[0009] The reaction product mixture is separated and purified to obtain a target product.

[0010] The strong acid comprises concentrated hydrochloric acid, concentrated sulfuric acid or phosphoric acid, and the diazotization reagent comprises sodium nitrite or potassium nitrite.

[0011] The precooling temperature of the 3-aminopyridine, strong acid, diazotization reagent and organic solvent is -10~10℃, the precooling temperature of the ethyl 2,3-dicyanopropionate ethanol solution is -10~10℃, the reaction temperature of the first stage connecting reactor is -10~0℃, and the reaction temperature of the second stage connecting reactor is -20~20℃.

[0012] The first stage connecting reactor and the second stage connecting reactor comprise a pipe type reactor, a continuous stirring reactor or a microchannel reactor.

[0013] The molar ratio of the 3-aminopyridine, strong acid and diazotization reagent is 1: (1~2): (1~2).

[0014] The reaction residence time of the first stage connecting reactor is 18~30s, and the reaction residence time of the second stage connecting reactor is 18~30s.

[0015] The first mixer and the second mixer comprise a T-shaped tee joint or a Y-shaped tee joint.

[0016] The separation and purification comprises the following steps: firstly mixing the reaction product through organic solvent extraction, then washing with water, and finally directly concentrating and crystallizing.

[0017] The organic solvent is methyltetrahydrofuran, toluene, dichloromethane, ethyl acetate or methyl tert-butyl ether.

[0018] The water washing adopts pure water or salt water washing.

[0019] The beneficial effects of the present application are as follows: the present application provides a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionate, firstly pumping raw materials into a first mixer for mixing, then delivering into a first stage connecting reactor for reaction to obtain a 3-aminopyridine diazonium salt intermediate, then pumping an ethyl 2,3-dicyanopropionate ethanol solution after precooling into a second mixer for mixing with the 3-aminopyridine diazonium salt intermediate, then delivering into a second stage connecting reactor for reaction, continuously adding raw materials and continuously producing products in the whole process, which can overcome the influence of heat transfer, mass transfer and other factors on the reaction in the process transfer process, solve the problem of unstable process amplification caused by intermediate decomposition, and improve the production scale. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 is a synthesis route diagram of the continuous synthesis method of ethyl 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionate according to the present application;

[0021] Figure 2is the HPLC spectrum of the 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester prepared by the embodiment of the present application.

[0022] Figure 3 is the nuclear magnetic spectrum of the 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester prepared by the embodiment of the present application. DETAILED DESCRIPTION

[0023] The present application is further described below in conjunction with the accompanying drawings, and the following examples are only used to more clearly illustrate the technical solutions of the present application, and cannot be used to limit the protection scope of the present application.

[0024] Example 1

[0025] The present application discloses a continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, comprising the following steps:

[0026] Step one, using a pipeline reactor to synthesize 3-aminopyridine diazonium salt intermediate (20 g scale). First, configure 20 g of compound 1 (3-aminopyridine) and 17 mL of concentrated hydrochloric acid solution for use, the concentration of the concentrated hydrochloric acid solution is 12.5 mol / L: compound 1 is added to the concentrated hydrochloric acid solution to obtain a concentrated hydrochloric acid solution of compound 1, which is then pre-cooled with 100 g of sodium nitrite aqueous solution (15w%) in a 1 / 16 inch tube, the molar ratio of 3-aminopyridine, strong acid and diazotization reagent is about 1:1:1. The pre-cooling temperature is -10~10℃, and then mixed in a T-shaped mixer. Among them, the flow rate of the concentrated hydrochloric acid solution of compound 1 is 0.5 mL / min, the flow rate of the sodium nitrite aqueous solution is 0.5 mL / min, the pre-cooling temperature is -10~10℃, and finally reacted in a 1 / 8 inch PFA pipeline, the reaction temperature is -10℃, the residence time is 18 s, and the residence time is 24 s to obtain 3-aminopyridine diazonium salt intermediate, while sampling and detecting the reaction at the outlet of the flow, and the detection results are shown in Table 1.

[0027] Step two, using a pipeline reactor to synthesize 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, specifically, compound a (2,3-dicyano propionic acid ethyl ester) is dissolved in ethanol for use; pre-cooled in a 1 / 16 inch PFA tube, the pre-cooling temperature is -10~10℃, then reacted with the above generated diazonium salt intermediate in a T-shaped mixer, wherein the flow rate of the diazonium salt intermediate is 0.5 mL / min, the flow rate of compound a is 0.6 mL / min, the reaction temperature is -20℃, and the residence time is 36 s, and then sample and detect the reaction at the outlet of the liquid, and the results are shown in Table 2.

[0028] Step three, the reaction product mixture was purified by separation to obtain the target product, specifically the reaction product mixture generated in step two was directly diluted with 2000 mL of water, then extracted with dichloromethane (2000 mL) for 3 times, separated, concentrated to a large amount of solid precipitated at 30-35℃, then filtered, dried to obtain the product with a purity of 98.6A%, and the yield was 88.5%.

[0029] Example 2

[0030] The application discloses a continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, comprising the following steps:

[0031] Step one, a pipeline reactor was used to synthesize the 3-aminopyridine diazonium salt intermediate (40 g in scale). First, 40 g of compound 1 (3-aminopyridine) and 34 mL of concentrated hydrochloric acid solution were prepared for use, the concentration of the concentrated hydrochloric acid solution was 12.5 mol / L: compound 1 was added to the concentrated hydrochloric acid solution to obtain a concentrated hydrochloric acid solution of compound 1, then the concentrated hydrochloric acid solution of compound 1 and 200 g of sodium nitrite aqueous solution (15 w%) were pre-cooled in 1 / 16 inch pipes respectively, the molar ratio of 3-aminopyridine, strong acid and diazotization reagent was about 1:1:1. The pre-cooling temperature was-10~10℃, then mixed in a T-shaped mixer. Among them, the flow rate of the concentrated hydrochloric acid solution of compound 1 was 0.8 mL / min, the flow rate of the sodium nitrite aqueous solution was 0.8 mL / min, the pre-cooling temperature was-10~10℃, finally reacted in a 1 / 8 inch PFA pipeline, the reaction temperature was-5℃, the residence time was 21 s, and the 3-aminopyridine diazonium salt intermediate was obtained, and the reaction was detected at the same time at the outlet of the flow. The detection results are shown in Table 1.

[0032] Step two, a pipeline reactor was used to synthesize 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, specifically, compound a (2,3-dicyano propionic acid ethyl ester) was dissolved in ethanol for use; pre-cooled in a 1 / 16 inch PFA pipe, the pre-cooling temperature was-10~10℃, then reacted with the above-mentioned diazonium salt intermediate in a T-shaped mixer, wherein the flow rate of the diazonium salt intermediate was 1.2 mL / min, the flow rate of compound a was 1.2 mL / min, the reaction temperature was-10℃, the residence time was 30 s, and then the reaction was detected by sampling at the outlet of the liquid. The results are shown in Table 2.

[0033] Step three, the reaction product mixture was purified to obtain the target product, specifically, the reaction product mixture generated in step two was directly diluted with 1200 mL of water, then extracted with dichloromethane (1200 mL) for 3 times, separated, concentrated to a large amount of solid precipitated at 30-35℃, then filtered, dried to obtain the product with a purity of 98.5A%, and the yield was 86.5%.

[0034] Example 3

[0035] The application discloses a continuous synthesis method of 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, comprising the following steps:

[0036] Step one, a pipeline reactor was used to synthesize the 3-aminopyridine diazonium salt intermediate (120 g scale). First, 120 g of compound 1 (3-aminopyridine) and 105 mL of concentrated hydrochloric acid solution were prepared for use, the concentration of the concentrated hydrochloric acid solution was 12.5 mol / L: compound 1 was added to the concentrated hydrochloric acid solution to obtain a concentrated hydrochloric acid solution of compound 1, then the three were pre-cooled in 1 / 16 inch pipes respectively, the molar ratio of 3-aminopyridine, strong acid and diazotization reagent was about 1:1:1. The pre-cooling temperature was -10~10℃, then mixed in a T-shaped mixer. Among them, the flow rate of the concentrated hydrochloric acid solution of compound 1 was 1.3 mL / min, the flow rate of the sodium nitrite aqueous solution was 1.3 mL / min, the pre-cooling temperature was -10~10℃, finally reacted in a 1 / 8 inch PFA pipe, the reaction temperature was -5℃, the residence time was 24 s, and the 3-aminopyridine diazonium salt intermediate was obtained. At the same time, the reaction was detected by sampling at the outlet, and the detection results are shown in Table 1.

[0037] Step two, a pipeline reactor was used to synthesize 2,3-dicyano-2-(pyridine-3-yl diazenyl) propionic acid ethyl ester, specifically, compound a (2,3-dicyano propionic acid ethyl ester) was dissolved in ethanol for use; pre-cooled in a 1 / 16 inch PFA pipe, the pre-cooling temperature was -10~10℃, then reacted with the above generated diazonium salt intermediate in a T-shaped mixer, wherein the flow rate of the diazonium salt intermediate was 3 mL / min, the flow rate of compound a was 3 mL / min, the reaction temperature was 10℃, the residence time was 20 s, and then the reaction was detected by sampling at the outlet, and the results are shown in Table 2.

[0038] Step three, the reaction product mixture is purified by separation to obtain the target product, specifically, the reaction product mixture generated in step two is directly diluted with 800 mL of water, then extracted with dichloromethane (800 mL) for 3 times, separated, concentrated to a large amount of solid precipitated at 30-35℃, then filtered, dried to obtain the product with a purity of 98.5A% and a yield of 86.5%.

[0039] Example 4

[0040] The application discloses a continuous synthesis method of 2,3-dicyano-2-(pyridine-3- yldiazenyl)propionic acid ethyl ester, comprising the following steps:

[0041] Step one, a pipeline reactor is used to synthesize a 3-aminopyridine diazonium salt intermediate (80 g in scale). First, 80 g of compound 1 (3-aminopyridine) and 68 mL of a concentrated hydrochloric acid solution are prepared for use, the concentration of the concentrated hydrochloric acid solution is 12.5 mol / L: compound 1 is added to the concentrated hydrochloric acid solution to obtain a compound 1 concentrated hydrochloric acid solution, then the compound 1 concentrated hydrochloric acid solution and 395 g of a sodium nitrite aqueous solution (15 w%) are pre-cooled in 1 / 16 inch pipes respectively, the molar ratio of the three, 3-aminopyridine, strong acid and diazotization reagent, is about 1:1:1. The pre-cooling temperature is -10~10℃, then the three are mixed in a T-shaped mixer. Among them, the flow rate of the compound 1 concentrated hydrochloric acid solution is 1.8 mL / min, the flow rate of the sodium nitrite aqueous solution is 1.8 mL / min, the pre-cooling temperature is -10~10℃, finally, the reaction is carried out in a 1 / 8 inch PFA pipeline, the reaction temperature is -5℃, and the residence time is 27 s, to obtain the 3-aminopyridine diazonium salt intermediate, and meanwhile, the reaction is detected by sampling at the outlet.

[0042] Step two, a pipeline reactor is used to synthesize 2,3-dicyano-2-(pyridine-3- yldiazenyl)propionic acid ethyl ester, specifically, compound a (2,3-dicyano propionic acid ethyl ester) is dissolved in ethanol for use; pre-cooling is carried out in a 1 / 16 inch PFA pipe, the pre-cooling temperature is -10~10℃, then the pre-cooled compound a is reacted with the diazonium salt intermediate generated above in a T-shaped mixer, wherein the flow rate of the diazonium salt intermediate is 6 mL / min, the flow rate of compound a is 6 mL / min, the reaction temperature is 10℃, and the residence time is 18 s, and then the reaction is detected by sampling at the outlet.

[0043] Step three, the reaction product mixture is purified by separation to obtain the target product, specifically, the reaction product mixture generated in step two is directly diluted with 800 mL of water, then extracted with dichloromethane (800 mL) for 3 times, separated, concentrated to a large amount of solid precipitated at 30-35℃, then filtered, dried to obtain the product with a purity of 98.5A% and a yield of 86.5%.

[0044] Example 5

[0045] A continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yl diazenyl) propanoate is disclosed, comprising the following steps:

[0046] Step one, using a pipeline reactor to synthesize the product 3-aminopyridine diazonium salt intermediate (200 g scale). First, configure 200 g of compound 1 (3-aminopyridine) and 170 mL of concentrated hydrochloric acid solution for use, the concentration of the concentrated hydrochloric acid solution is 12.5 mol / L: compound 1 is added to the concentrated hydrochloric acid solution to obtain a concentrated hydrochloric acid solution of compound 1, which is then pre-cooled with 980 g of sodium nitrite aqueous solution (15w%) in a 1 / 16 inch tube, the molar ratio of the three, 3-aminopyridine, strong acid and diazotization reagent, is about 1:1:1. The pre-cooling temperature is -10~10℃, and then mixed in a T-shaped mixer. Among them, the flow rate of the concentrated hydrochloric acid solution of compound 1 is 2.5 mL / min, the flow rate of the sodium nitrite aqueous solution is 2.5 mL / min, the pre-cooling temperature is -10~10℃, and finally reacted in a 1 / 8 inch PFA pipeline, the reaction temperature is 0℃, the residence time is 30s, and the 3-aminopyridine diazonium salt intermediate is obtained. At the same time, sample detection is carried out at the outlet of the flow, and the detection results are shown in Table 1.

[0047] Step two, using a pipeline reactor to synthesize ethyl 2,3-dicyano-2-(pyridin-3-yl diazenyl) propanoate, specifically, compound a (ethyl 2,3-dicyano propanoate) is dissolved in ethanol for use; pre-cooled in a 1 / 16 inch PFA tube, the pre-cooling temperature is -10~10℃, then reacted with the above generated diazonium salt intermediate in a T-shaped mixer, wherein the flow rate of the diazonium salt intermediate is 15 mL / min, the flow rate of compound a is 15 mL / min, the reaction temperature is 20℃, the residence time is 12s, and then the reaction is sampled and detected at the outlet of the liquid, and the results are shown in Table 2.

[0048] Step three, the reaction product mixture is separated and purified to obtain the target product, specifically the reaction product mixture generated in step two is directly diluted with 200 mL of water, then extracted with dichloromethane (200 mL) for 3 times, separated, concentrated to a large amount of solid precipitated at 30-35℃, then filtered and dried to obtain the product with a purity of 98.9A% and a yield of 86.5%.

[0049] Table 1. First stage reaction temperature and residence time for each example

[0050] Table 1. First stage reaction temperature and residence time for each example

[0051]

[0052] Table 2. Second stage reaction temperature and reaction time for each example

[0053]

[0054] Comparative Example

[0055] The comparative example uses the Batch method to synthesize the product 3-aminopyridine diazonium salt intermediate (20 g scale), which specifically involves adding 20 g of raw material 1 and 15 mL of concentrated hydrochloric acid and 60 mL of water to a reaction bottle, cooling to about -10°C, then adding 15 w% sodium nitrite aqueous solution to the reaction bottle, maintaining the temperature between -10 and 0°C, after the dropwise addition is complete, stirring below 0°C for 2-3 hours, and then sampling and detecting by liquid chromatography. The intermediate is 93.5 A%, and the raw material is not left over. Then the Batch method is used to synthesize the product 2,3-dicyano-2-(pyridin-3-yl diazenyl) propionic acid ethyl ester (20 g scale). Slowly add 15.6 g of compound a in ethanol solution to the above reaction bottle, maintain the temperature between 0 and 10°C, after the dropwise addition is complete, stir at 0°C for 3-5 hours, sample and detect by liquid chromatography, the product is 94.5 A%, and there is no intermediate left over. Dilute directly with 100 mL of water, then extract three times with dichloromethane (40 mL), separate the layers, concentrate to a large amount of solid precipitates at 30-35°C, then filter and dry to obtain the product with a purity of 98.7 A%, and a yield of 87.5%.

[0056] Comparing the examples of the present application with the comparative example, it can be seen that the purity and yield of the final product obtained by using the pipeline continuous synthesis method of the present application are basically the same as those of the existing method. Since the entire process is continuous synthesis, raw materials are continuously added during the process, and the product is continuously produced without interruption, the influence of heat transfer, mass transfer, etc. on the reaction during the process transfer process can be overcome, the problem of unstable process amplification caused by intermediate decomposition can be solved, and the production scale can be improved.

[0057] The above merely describes the preferred embodiments of the present application, and it should be pointed out that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A continuous synthesis method for ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate, characterized in that: Includes the following steps: 3-Aminopyridine, a strong acid, and a diazotizing agent are pre-cooled in a pipeline at a temperature of -10 to 10°C. The mixture is then pumped into a first mixer for mixing and finally fed into a first-stage connecting reactor for reaction at a temperature of -10 to 0°C to obtain a 3-aminopyridine diazonium salt intermediate. The strong acid includes one or more of concentrated hydrochloric acid, concentrated sulfuric acid, and phosphoric acid, and the diazotizing agent includes sodium nitrite or potassium nitrite. An ethanol solution of ethyl 2,3-dicyanopropionate was pre-cooled in a pipeline and then pumped into a second mixer with a 3-aminopyridine diazonium salt intermediate. The pre-cooling temperature of the ethanol solution of ethyl 2,3-dicyanopropionate was -10 to 10°C. The solution was then transported to a second-stage connecting reactor for reaction. The reaction temperature in the second-stage connecting reactor was -20 to 20°C, resulting in a mixture of reaction products. The target product was obtained by separating and purifying the reaction product mixture.

2. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 1, characterized in that: The first-stage connecting reactor and the second-stage connecting reactor include one of the following: a tubular reactor, a continuous stirred reactor, and a microchannel reactor.

3. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 1, characterized in that: The molar ratio of the 3-aminopyridine, the strong acid, and the diazotizing agent is 1:(1~2):(1~2).

4. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 1, characterized in that: The reaction residence time of the first stage connected reactor is 18-30 s, and the reaction residence time of the second stage connected reactor is 18-30 s.

5. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 1, characterized in that: The first mixer and the second mixer include a T-tee or a Y-tee.

6. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 1, characterized in that: The separation and purification process includes the following steps: first, the reaction products are mixed and extracted with an organic solvent, then washed with water, and finally concentrated and crystallized directly.

7. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 6, characterized in that: The organic solvent includes one or more of methyltetrahydrofuran, toluene, dichloromethane, ethyl acetate, and methyl tert-butyl ether.

8. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazetenyl)propionate according to claim 6, characterized in that: Use pure water or salt water for washing.

Images