Continuous synthesis method of ethyl 2, 3-dicyano-2-(pyridine-3-yl diazenyl) propionate

Abstract

The invention discloses a continuous synthesis method of ethyl 2, 3-dicyano-2-(pyridine-3-yl diazenyl) propionate, and belongs to the technical field of preparation of medical intermediates.The continuous synthesis method comprises the following steps that 3-aminopyridine, strong acid and a diazotization reagent are precooled in a pipeline and then pumped into a first mixer to be mixed; finally, conveying into a first-stage connection reactor for reaction to obtain a 3-aminopyridine diazonium salt intermediate; pre-cooling an ethanol solution of ethyl 2, 3-dicyanopropionate in a pipeline, pumping the pre-cooled ethanol solution and the 3-aminopyridine diazonium salt intermediate into a second mixer for mixing, and then conveying the mixture into a second-stage connection reactor for reaction to obtain a reaction product mixture; and separating and purifying the reaction product mixture to obtain a target product. The problem that the process cannot be stably amplified due to intermediate decomposition can be solved, and the production scale is increased.

Description

Technical Field

[0001] The invention relates to a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, belonging to the technical field of pharmaceutical intermediate preparation. Background Art

[0002] Ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate is an important organic synthesis intermediate, which is widely used in the synthesis of medicines and pesticides. Its synthesis route is shown below. According to literature reports, 3-aminopyridine is generally diazotized in a reactor using sodium nitrite and concentrated hydrochloric acid to obtain a 3-aminopyridine diazonium salt intermediate, and then the 3-aminopyridine diazonium salt intermediate is reacted with an ethanol solution of ethyl 2,3-dicyanopropionate to obtain the final product. The disadvantage of this method is that the 3-aminopyridine diazonium salt intermediate is unstable and easy to decompose, which has great safety risks, and is limited in scale-up production, and cannot be mass-produced.

[0003] Summary of the invention

[0004] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, which can solve the problem that the process cannot be stably scaled up due to the decomposition of the intermediate and improve the production scale.

[0005] In order to solve the above technical problems, the technical solution adopted by the present invention is:

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

[0007] 3-aminopyridine, a strong acid and a diazotizing agent are precooled in a pipeline, then pumped into a first mixer for mixing, and finally transported to a first-stage connection reactor for reaction to obtain a 3-aminopyridine diazonium salt intermediate;

[0008] The ethanol solution of ethyl 2,3-dicyanopropionate is precooled in a pipeline and then pumped into a second mixer for mixing with the 3-aminopyridine diazonium salt intermediate, and then transported to a second-stage connection reactor for reaction to obtain a reaction product mixture;

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

[0010] The strong acid includes concentrated hydrochloric acid, concentrated sulfuric acid or phosphoric acid, and the diazotizing agent includes sodium nitrite or potassium nitrite.

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

[0012] The first-stage connected reactor and the second-stage connected reactor include a pipeline reactor, a continuous stirring reactor or a microchannel reactor.

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

[0014] The reaction residence time of the first-stage connected reactor is 18 to 30 seconds, and the reaction residence time of the second-stage connected reactor is 18 to 30 seconds.

[0015] The first mixer and the second mixer include a T-type tee or a Y-type tee.

[0016] The separation and purification comprises the following steps: firstly, the reaction products are mixed and extracted by an organic solvent, then washed with water, and finally directly concentrated and crystallized.

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

[0018] Wash with pure water or salt water.

[0019] Beneficial effects of the invention: The invention provides a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, which comprises the following steps: firstly, the raw materials are pumped into a first mixer for mixing, and finally transported to a first-stage connecting reactor for reaction to obtain a 3-aminopyridine diazonium salt intermediate, and then the ethanol solution of ethyl 2,3-dicyanopropionate is pre-cooled and pumped into a second mixer with the 3-aminopyridine diazonium salt intermediate for mixing, and then transported to a second-stage connecting reactor for reaction. The whole process adopts continuous synthesis, and the raw materials are continuously added during the process, and the product is continuously produced and obtained, which can overcome the influence of heat transfer, mass transfer and the like on the reaction during the process transfer process, solve the problem that the process cannot be stably enlarged due to the decomposition of the intermediate, and improve the production scale. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 It is a synthetic route diagram of a continuous synthetic method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate of the present invention;

[0021] Figure 2is the HPLC spectrum of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate prepared in the embodiment of the present invention;

[0022] Figure 3 This is the nuclear magnetic spectrum of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate prepared in the embodiment of the present invention. DETAILED DESCRIPTION

[0023] The present invention will be further described below in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the protection scope of the present invention.

[0024] Example 1

[0025] The present invention discloses a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, comprising the following steps:

[0026] Step 1: Use a pipeline reactor to synthesize the product 3-aminopyridine diazonium salt intermediate (20 g scale). First, prepare 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: Add compound 1 to the concentrated hydrochloric acid solution to dilute the compound 1, and then pre-cool it with 100 g of sodium nitrite aqueous solution (15 w%) in a 1 / 16 inch tube. The molar ratio of 3-aminopyridine, strong acid and diazotizing agent is about 1:1:1. The pre-cooling temperature is -10~10°C, and then mix in a T-type mixer. The flow rate of the concentrated hydrochloric acid solution of compound 1 was 0.5 mL / min, the flow rate of the sodium nitrite aqueous solution was 0.5 mL / min, the precooling temperature was -10~10°C, and finally the reaction was carried out in a 1 / 8 inch PFA pipe. The reaction temperature was -10°C and the residence time was 18s. After the residence time was 24s to obtain the 3-aminopyridine diazonium salt intermediate, the reaction was sampled and tested at the outlet at the same time. The test results are shown in Table 1.

[0027] Step 2, using a pipeline reactor to synthesize ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, specifically, dissolving compound a (ethyl 2,3-dicyanopropionate) in ethanol for standby use; precooling in a 1 / 16 inch PFA tube, the precooling temperature is -10~10°C, and then reacting with the above-generated diazonium salt intermediate in a T-type 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°C, the residence time is 36s, and then sampling is taken at the liquid outlet to detect the reaction. The results are shown in Table 2.

[0028] Step 3, separating and purifying the reaction product mixture to obtain the target product. Specifically, the reaction product mixture generated in step 2 is directly diluted with 2000 mL of water, then extracted with dichloromethane (2000 mL) for 3 times, separated, concentrated until a large amount of solid precipitates at 30-35° C., then filtered and dried to obtain a product with a purity of 98.6A% and a yield of 88.5%.

[0029] Example 2

[0030] The present invention discloses a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, comprising the following steps:

[0031] Step 1: Use a pipeline reactor to synthesize the product 3-aminopyridine diazonium salt intermediate (40 g scale). First, prepare 40 g of compound 1 (3-aminopyridine) and 34 mL of concentrated hydrochloric acid solution for use. The concentration of the concentrated hydrochloric acid solution is 12.5 mol / L: Add compound 1 to the concentrated hydrochloric acid solution to dilute the compound 1 concentrated hydrochloric acid solution, and then pre-cool it with 200 g of sodium nitrite aqueous solution (15w%) in a 1 / 16 inch tube. The molar ratio of 3-aminopyridine, strong acid and diazotizing agent is about 1:1:1. The pre-cooling temperature is -10~10℃, and then mix in a T-type mixer. 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 precooling temperature was -10~10°C, and finally the reaction was carried out in a 1 / 8 inch PFA pipe, the reaction temperature was -5°C, the residence time was 21s, and after obtaining the 3-aminopyridine diazonium salt intermediate, the reaction was sampled and tested at the outlet at the same time. The test results are shown in Table 1.

[0032] Step 2, using a pipeline reactor to synthesize ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, specifically, dissolving compound a (ethyl 2,3-dicyanopropionate) in ethanol for standby use; precooling in a 1 / 16 inch PFA tube, the precooling temperature is -10~10°C, and then reacting with the above-generated diazonium salt intermediate in a T-type mixer, wherein the flow rate of the diazonium salt intermediate is 1.2 mL / min, the flow rate of compound a is 1.2 mL / min, the reaction temperature is -10°C, the residence time is 30s, and then sampling is taken at the liquid outlet to detect the reaction. The results are shown in Table 2.

[0033] Step 3, separating and purifying the reaction product mixture to obtain the target product. Specifically, the reaction product mixture generated in step 2 is directly diluted with 1200 mL of water, then extracted with dichloromethane (1200 mL) for 3 times, separated, concentrated until a large amount of solid precipitates at 30-35° C., then filtered and dried to obtain a product with a purity of 98.5A% and a yield of 86.5%.

[0034] Example 3

[0035] The present invention discloses a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, comprising the following steps:

[0036] Step 1: Use a pipeline reactor to synthesize the product 3-aminopyridine diazonium salt intermediate (120 g scale). First, prepare 120 g of compound 1 (3-aminopyridine) and 105 mL of concentrated hydrochloric acid solution for use. The concentration of the concentrated hydrochloric acid solution is 12.5 mol / L: Add compound 1 to the concentrated hydrochloric acid solution to dilute the compound 1 concentrated hydrochloric acid solution, and then pre-cool it with 590 g of sodium nitrite aqueous solution (15w%) in a 1 / 16 inch tube. The molar ratio of 3-aminopyridine, strong acid and diazotizing agent is about 1:1:1. The pre-cooling temperature is -10~10℃, and then mix in a T-type mixer. 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 precooling temperature was -10~10°C, and finally the reaction was carried out in a 1 / 8 inch PFA pipe. The reaction temperature was -5°C and the residence time was 24s. After the 3-aminopyridine diazonium salt intermediate was obtained, the reaction was sampled and tested at the outlet at the same time. The test results are shown in Table 1.

[0037] Step 2, using a pipeline reactor to synthesize ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, specifically, dissolving compound a (ethyl 2,3-dicyanopropionate) in ethanol for standby use; precooling in a 1 / 16 inch PFA tube, the precooling temperature is -10~10°C, and then reacting with the above-generated diazonium salt intermediate in a T-type mixer, wherein the flow rate of the diazonium salt intermediate is 3 mL / min, the flow rate of compound a is 3 mL / min, the reaction temperature is 10°C, the residence time is 20s, and then sampling is taken at the liquid outlet to detect the reaction. The results are shown in Table 2.

[0038] Step 3, separating and purifying the reaction product mixture to obtain the target product. Specifically, the reaction product mixture generated in step 2 is directly diluted with 800 mL of water, then extracted with dichloromethane (800 mL) for 3 times, separated, concentrated until a large amount of solid precipitates at 30-35° C., then filtered and dried to obtain a product with a purity of 98.5A% and a yield of 86.5%.

[0039] Example 4

[0040] The present invention discloses a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, comprising the following steps:

[0041] Step 1: Use a pipeline reactor to synthesize the product 3-aminopyridine diazonium salt intermediate (80 g scale). First, prepare 80 g of compound 1 (3-aminopyridine) and 68 mL of concentrated hydrochloric acid solution for use. The concentration of the concentrated hydrochloric acid solution is 12.5 mol / L: Add compound 1 to the concentrated hydrochloric acid solution to dilute the compound 1 concentrated hydrochloric acid solution, and then pre-cool it with 395 g of sodium nitrite aqueous solution (15w%) in a 1 / 16 inch tube. The molar ratio of 3-aminopyridine, strong acid and diazotizing agent is about 1:1:1. The pre-cooling temperature is -10~10℃, and then mix in a T-type mixer. The flow rate of the concentrated hydrochloric acid solution of compound 1 was 1.8 mL / min, the flow rate of the sodium nitrite aqueous solution was 1.8 mL / min, the precooling temperature was -10~10°C, and finally the reaction was carried out in a 1 / 8 inch PFA pipe. The reaction temperature was -5°C and the residence time was 27s. After the 3-aminopyridine diazonium salt intermediate was obtained, the reaction was sampled and tested at the outlet at the same time. The test results are shown in Table 1.

[0042] Step 2, using a pipeline reactor to synthesize ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, specifically, dissolving compound a (ethyl 2,3-dicyanopropionate) in ethanol for standby use; precooling in a 1 / 16 inch PFA tube, the precooling temperature is -10~10°C, and then reacting with the above-generated diazonium salt intermediate in a T-type 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°C, the residence time is 18s, and then sampling is taken at the liquid outlet to detect the reaction. The results are shown in Table 2.

[0043] Step 3, separating and purifying the reaction product mixture to obtain the target product. Specifically, the reaction product mixture generated in step 2 is directly diluted with 400 mL of water, then extracted with dichloromethane (400 mL) for 3 times, separated, concentrated until a large amount of solid precipitates at 30-35° C., then filtered and dried to obtain a product with a purity of 98.9A% and a yield of 89.9%.

[0044] Example 5

[0045] The present invention discloses a continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, comprising the following steps:

[0046] Step 1: Use a pipeline reactor to synthesize the product 3-aminopyridine diazonium salt intermediate (200 g scale). First, prepare 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: Add compound 1 to the concentrated hydrochloric acid solution to dilute the compound 1 concentrated hydrochloric acid solution, and then pre-cool it with 980 g of sodium nitrite aqueous solution (15w%) in a 1 / 16 inch tube. The molar ratio of 3-aminopyridine, strong acid and diazotizing agent is about 1:1:1. The pre-cooling temperature is -10~10℃, and then mix in a T-type mixer. The flow rate of the concentrated hydrochloric acid solution of compound 1 was 2.5 mL / min, the flow rate of the sodium nitrite aqueous solution was 2.5 mL / min, the precooling temperature was -10~10°C, and finally the reaction was carried out in a 1 / 8 inch PFA pipe, the reaction temperature was 0°C, the residence time was 30s, and after obtaining the 3-aminopyridine diazonium salt intermediate, sampling was performed at the outlet to detect the reaction. The test results are shown in Table 1.

[0047] Step 2, using a pipeline reactor to synthesize ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, specifically, dissolving compound a (ethyl 2,3-dicyanopropionate) in ethanol for standby use; precooling in a 1 / 16 inch PFA tube, the precooling temperature is -10~10°C, and then reacting with the above-generated diazonium salt intermediate in a T-type 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°C, the residence time is 12s, and then sampling is taken at the liquid outlet to detect the reaction. The results are shown in Table 2.

[0048] Step 3, separating and purifying the reaction product mixture to obtain the target product. Specifically, the reaction product mixture generated in step 2 is directly diluted with 200 mL of water, then extracted with dichloromethane (200 mL) for 3 times, separated, concentrated until a large amount of solid precipitates at 30-35° C., then filtered and dried to obtain a product with a purity of 98.9A% and a yield of 86.5%.

[0049] In the table, compound I, compound II and compound III are 3-aminopyridine, 3-aminopyridine diazonium salt intermediate and ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, respectively, compound a is ethyl 2,3-dicyanopropionate, stage 1 represents the first stage connection reaction, and stage II represents the second stage connection reaction.

[0050] Table 1 Reaction temperature and residence time of the first stage of each example

[0051] Table 2 Reaction temperature and reaction time of the second stage of each embodiment

[0052] Comparative Example

[0053] This comparative example uses the Batch method to synthesize the product 3-aminopyridine diazonium salt intermediate (20 g scale), specifically, add 20 g of raw material 1 and 15 mL of concentrated hydrochloric acid and 60 mL of water to the reaction bottle, cool it to about -10 ° C, and then add 15w% sodium nitrite aqueous solution thereto, the temperature is kept between -10 and 0 ° C, after the addition is completed, keep stirring below 0 degrees for 2-3 hours, and take liquid phase detection of reaction sampling. The intermediate is 93.5A%, and there is no residual raw material. Then the Batch method is used to synthesize the product 2,3-dicyano-2-(pyridin-3-yldiazenyl) propionic acid ethyl ester (20 g scale). Slowly add 15.6g of compound a ethanol solution to the above reaction bottle, keep the temperature between 0-10 ° C, after the addition is completed, keep stirring at 0 degrees for 3-5 hours, and take liquid phase detection of reaction sampling. The product is 94.5A%, and there is no residual intermediate. After treatment, the product was directly diluted with 100 mL of water, then extracted with dichloromethane (40 mL) three times, separated, concentrated until a large amount of solid precipitated at 30-35°C, then filtered and dried to obtain a product with a purity of 98.7A% and a yield of 87.5%.

[0054] By comparing the embodiments of the present invention with the comparative examples, it can be seen that the purity and yield finally obtained by the pipeline continuous synthesis method of the present invention are basically the same as those of the existing method. Since the entire process adopts continuous synthesis, raw materials are continuously added during the process, and the product is produced continuously and uninterruptedly, it can overcome the influence of heat transfer, mass transfer, etc. on the reaction during the process transfer process, solve the problem that the process cannot be stably scaled up due to the decomposition of the intermediates, and improve the production scale.

[0055] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate, characterized in that: The following steps are involved: 3-aminopyridine, a strong acid and a diazotizing agent are precooled in a pipeline, then pumped into a first mixer for mixing, and finally transported to a first-stage connection reactor for reaction to obtain a 3-aminopyridine diazonium salt intermediate; The ethanol solution of ethyl 2,3-dicyanopropionate is precooled in a pipeline and then pumped into a second mixer for mixing with the 3-aminopyridine diazonium salt intermediate, and then transported to a second-stage connection reactor for reaction to obtain a reaction product mixture; The reaction product mixture is separated and purified to obtain the target product.

2. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate according to claim 1, characterized in that: 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.

3. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate according to claim 1, characterized in that: The precooling temperature of 3-aminopyridine, strong acid, diazotizing agent and organic solvent is -10~10°C, the precooling temperature of ethyl 2,3-dicyanopropionate ethanol solution is -10~10°C, the reaction temperature in the first stage connecting reactor is -10~0°C, and the reaction temperature in the second stage connecting reactor is -20~20°C.

4. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate according to claim 1, characterized in that: The first-stage connected reactor and the second-stage connected reactor include one of a pipeline reactor, a continuous stirring reactor, and a microchannel reactor.

5. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)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).

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

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

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

9. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate according to claim 8, characterized in that: The organic solvent includes one or more of methyltetrahydrofuran, toluene, dichloromethane, ethyl acetate, and methyl tert-butyl ether.

10. The continuous synthesis method of ethyl 2,3-dicyano-2-(pyridin-3-yldiazenyl)propionate according to claim 8, characterized in that: Wash with pure water or salt water.

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