Preparation method of 3, 6-bis (3-pyridyl)-1, 2, 4, 5-tetraazabenzene

Abstract

The invention discloses a preparation method of 3, 6-bis (3-pyridyl)-1, 2, 4, 5-tetraazabenzene, which comprises the following steps: 1, dropwise adding a mercaptan catalyst into hydrazine hydrate, adding 3-cyanopyridine, adding ethanol for dissolving, keeping reflux stirring, and enabling a reaction system to gradually become brown turbid liquid; filtering and washing with water to obtain a brown yellow viscous solid; 2, dissolving the solid in an acidic aqueous solution, then adding a nitrite solid, generating reddish brown gas, and enabling a reaction system to become purple; and 3, firstly adding a first organic solvent for extraction, then adding an inorganic alkali solid, releasing gas and heat, adjusting the pH to be alkaline, performing liquid separation, washing with organic phase saturated salt, drying, filtering and performing rotary evaporation to obtain a crude product, and pulping with a second organic solvent to obtain a purple crystal pure product. The method has the advantages of simple preparation process route, mild reaction, easiness in control, low purification difficulty, few byproducts, high yield and high purity.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of tetrazine material synthesis, in particular to a preparation method of 3,6-bis(3-pyridyl)-1,2,4,5-tetrazine. BACKGROUND

[0002] Since Hantzsch and Lehmann first reported 1,2,4,5-tetrazine in 1900, 1,2,4,5-tetrazine and its 3,6-disubstituted derivatives have attracted extensive attention due to their unique skeleton and chemical / physical properties and special application potential in the fields of industry, agriculture and medicine.

[0003] At present, there are mainly two methods for synthesizing 3,6-bis(3-pyridyl)-1,2,4,5-tetrazine. The first preparation method is to use zinc trifluoromethanesulfonate as a catalyst, 3-cyanopyridine and hydrazine hydrate as raw materials, and to stir under reflux. The main disadvantage of this method is low yield and long reaction time.

[0004] The second preparation method (CN 112111090 A) is to use sulfur as an additive, 3-cyanopyridine and hydrazine hydrate as raw materials, and to stir under reflux. The main disadvantage of this method is that sulfur is a controlled product, the yield is low, and the reaction time is long. SUMMARY

[0005] The purpose of the application is to provide a preparation method of 3,6-bis(3-pyridyl)-1,2,4,5-tetrazine, which is easy to obtain raw materials, simple in preparation process, high in yield and suitable for industrial production.

[0006] To achieve the above purpose, the technical scheme adopted by the application is a preparation method of 3,6-bis(3-pyridyl)-1,2,4,5-tetrazine, which comprises the following steps: I. Thiol catalyst is added dropwise into hydrazine hydrate, 3-cyanopyridine is put in, ethanol is added for dissolution, and reflux stirring is kept, and the reaction system gradually changes into a brown turbid liquid; hot filtration is directly carried out, water washing is carried out, and a brown-yellow viscous solid is obtained; the molar ratio of 3-cyanopyridine to hydrazine hydrate is 1: (1.5-2); II. The brown-yellow viscous solid is dissolved in an acidic aqueous solution, then nitrite solid is added, red-brown gas is generated, and the reaction system turns purple; III. First, a first organic solvent for extraction is added, then inorganic alkali solid is added, gas and heat are released, the pH is adjusted to be alkaline, liquid-liquid separation is carried out, the organic phase is washed with saturated brine, drying is carried out, filtration is carried out, rotary evaporation is carried out, a crude product is obtained, and the second organic solvent is used for pulping to obtain a purple crystal pure product.

[0007] The above reaction formula is as follows: .

[0008] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the thiol catalyst in the first step is selected from one of 3-mercaptopropionic acid, mercaptoacetic acid, L-cysteine.

[0009] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the molar ratio of 3-cyanopyridine to the thiol catalyst in the first step is 1:(0.1-0.2).

[0010] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the mass ratio of 3-cyanopyridine to ethanol in the first step is 1:(3-5).

[0011] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the stirring time in the first step is 3-5 hours.

[0012] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the acid aqueous solution in the second step is selected from one of hydrochloric acid, formic acid, acetic acid, and the molar amount of the acid is 4-7 times the molar amount of 3-cyanopyridine.

[0013] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the nitrite salt in the second step is selected from one of sodium nitrite and potassium nitrite, and the molar amount of the nitrite salt is 3-5 times the molar amount of 3-cyanopyridine.

[0014] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the inorganic base in the third step is selected from one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate, and the pH value is adjusted to 9-10 by adding the inorganic base.

[0015] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the hydrazine hydrate is 50% hydrazine hydrate.

[0016] Further, the aforementioned method for preparing 3,6-di(3-pyridyl)-1,2,4,5-tetrazine, wherein the first organic solvent in the third step is dichloromethane, and the second organic solvent is a mixture of n-hexane and chloroform, and the volume ratio of n-hexane to chloroform is 8:1.

[0017] The advantages of the present application are: 1. The process route is very simple, the reaction conditions are mild, easy to control, the purification difficulty is low, the by-product is less, the yield is high, and the purity is high. 2. The reaction time is greatly shortened, the raw materials can be directly purchased, and the production cost is greatly reduced. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The nuclear magnetic hydrogen spectrum of the product in Example 1.

[0019] Figure 2 The nuclear magnetic carbon spectrum of the product in Example 1. DETAILED DESCRIPTION

[0020] The preparation method of the 3,6-di(3-pyridyl)-1,2,4,5-tetrazabenzene described in the present application will be described in detail below through specific examples.

[0021] Example 1: 1. 10 g of 3-mercapto propionic acid (0.1 e.q.) is added dropwise into 144 g of 50% hydrazine hydrate (1.5 e.q.), 100 g of 3-cyanopyridine is added, 300 g of ethanol is added for dissolution, and stirring is maintained under reflux for 3 h. The reaction system gradually turns into a brown turbid liquid. Hot filtration is directly performed, and water washing is performed to obtain a brown-yellow sticky solid.

[0022] 2. The brown-yellow sticky solid is dissolved in 1751 g of 10 wt% HCl (5 e.q.) solution, and 198 g of sodium nitrite solid (3 e.q.) is added in batches. Red-brown gas nitrogen dioxide is generated, and the reaction system turns purple.

[0023] 3. 1000 g of dichloromethane is added, sodium bicarbonate solid is added in batches, gas and heat are released, the pH value is adjusted to 9, liquid-liquid separation is performed, the organic phase is washed with saturated brine, anhydrous sodium sulfate is dried, filtration is performed, rotary evaporation is performed, and the crude product is obtained. The purple crystal pure product 96 g (yield: 85%, purity: 99.3%) is obtained by slurry treatment with a mixed solvent (the volume ratio of n-hexane to chloroform is 8:1). The product nuclear magnetic hydrogen spectrum is shown in Figure 1 , and the nuclear magnetic carbon spectrum is shown in Figure 2 .

[0024] Example 2: 1. 17.6 g of 2-mercapto acetic acid (0.2 e.q.) is added dropwise into 192 g of 50% hydrazine hydrate (2 e.q.), 100 g of 3-cyanopyridine is added, 500 g of ethanol is added for dissolution, and stirring is maintained under reflux for 5 h. The reaction system gradually turns into a brown turbid liquid. Hot filtration is directly performed, and water washing is performed to obtain a brown-yellow sticky solid.

[0025] II. Dissolve the brownish yellow sticky solid in 1403 g of aqueous acetic acid, where acetic acid 403 g (7 e.q.), add 408 g of solid sodium nitrite (5 e.q.) in portions, red brown gas nitrogen is generated, the reaction system turns purple.

[0026] III. Add 1000 g of dichloromethane, add sodium bicarbonate solid in portions, gas and heat are released, adjust the pH to 10, separate the liquid, the organic phase is washed with saturated brine, dry with anhydrous sodium sulfate, filter, rotary evaporate, get the crude product, mix the solvent (volume ratio of n-hexane and chloroform is 8:1) to slurry to get the purple crystal pure product 88 g (yield: 78%, purity: 99.1%).

[0027] Example 3: I. Add 11 g of L-cysteine (0.1 e.q.) dropwise into 144 g of 50% hydrazine hydrate (1.5 e.q.), add 100 g of 3-cyanopyridine, dissolve with 300 g of ethanol, keep stirring under reflux for 3 h, the reaction system gradually turns into brownish turbid liquid. Filter directly while hot, wash with water, get brownish yellow sticky solid.

[0028] Dissolve the brownish yellow sticky solid in 1175 g of aqueous formic acid, where formic acid 175 g (4 e.q.), add 198 g of solid sodium nitrite (3 e.q.) in portions, red brown gas nitrogen is generated, the reaction system turns purple.

[0029] III. Add 1000 g of dichloromethane, add sodium bicarbonate solid in portions, gas and heat are released, adjust the pH to 9, separate the liquid, the organic phase is washed with saturated brine, dry with anhydrous sodium sulfate, filter, rotary evaporate, get the crude product, mix the solvent (volume ratio of n-hexane and chloroform is 8:1) to slurry to get the purple crystal pure product 91 g (yield: 80%, purity: 99.3%).

[0030] Example 4: I. Add 15 g of 3-mercaptopropionic acid (0.15 e.q.) dropwise into 163 g of 50% hydrazine hydrate (1.7 e.q.), add 100 g of 3-cyanopyridine, dissolve with 300 g of ethanol, keep stirring under reflux for 3 h, the reaction system gradually turns into brownish turbid liquid. Filter directly while hot, wash with water, get brownish yellow sticky solid.

[0031] II. Dissolve the brownish yellow sticky solid in 1751 g of 10 wt% HCl (5 e.q.) solution, add 198 g of solid sodium nitrite (3 e.q.) in portions, red brown gas nitrogen is generated, the reaction system turns purple.

[0032] III. Add 1000g dichloromethane, add sodium carbonate solid in batches, gas and heat are released, adjust the pH value to 9, separate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, rotary evaporation, get the crude product, mixed solvent (volume ratio of n-hexane and chloroform is 8:1) slurry to get purple crystal pure product 92g (yield: 81%, purity: 99.3%).

[0033] Example 5: I, 12g of 3-mercaptopropionic acid (0.12 e.q.) was added dropwise into 144g of 50% hydrazine hydrate (1.5 e.q.), 100g of 3-cyanopyridine was added, dissolved in 400g of ethanol, stirred at reflux for 3h, the reaction system gradually changed into brown turbid liquid. Hot direct filtration, water washing, get brown yellow sticky solid.

[0034] The brown yellow sticky solid was dissolved in 1751g of 10 wt% HCl (5 e.q.) solution, 198g of sodium nitrite solid (3 e.q.) was added in batches, red brown gas nitrogen was generated, and the reaction system turned purple.

[0035] III. Add 1000g dichloromethane, add sodium carbonate solid in batches, gas and heat are released, adjust the pH value to 9, separate, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, rotary evaporation, get the crude product, mixed solvent (volume ratio of n-hexane and chloroform is 8:1) slurry to get purple crystal pure product 92g (yield: 81%, purity: 99.3%).

[0036] Comparative Example 1: 12g of 3-mercaptopropionic acid (0.12 e.q.) was added dropwise into 1440g of 50% hydrazine hydrate (1.5 e.q.), 100g of 3-cyanopyridine was added, dissolved in 400g of ethanol, stirred at reflux for 48h, the reaction system gradually changed into brown liquid. Only LC detection has product signal.

[0037] From Comparative Example 1: Too much hydrazine hydrate can greatly reduce the yield of the product.

[0038] Comparative Example 2: 100g of 3-cyanopyridine was added dropwise into 144g of 50% hydrazine hydrate (1.5 e.q.) and dissolved in 400g of ethanol, stirred at reflux for 48h, the reaction system gradually changed into brown liquid. Only LC detection has product signal.

[0039] From Comparative Example 2: Without catalyst, the reaction time is long, the yield is low, and the reaction is seriously affected.

[0040] The advantages of the present application are: 1. The process route is very simple, the reaction conditions are mild, easy to control, the purification difficulty is low, the by-product is less, the yield is high, and the purity is high. 2. The reaction time is greatly shortened, the raw materials can be directly purchased, and the production cost is greatly reduced.

Claims

1. A process for the preparation of 3,6-bis(3-pyridyl)-1,2,4,5-tetrazine comprising the steps of: I. drop mercaptan catalyst into hydrazine hydrate, put 3-cyanopyridine, add ethanol to dissolve, keep refluxing and stirring, the reaction system gradually turns into brown turbid liquid; filter directly while hot, wash with water, get brown-yellow sticky solid; the molar ratio of 3-cyanopyridine to hydrazine hydrate is 1: (1.5-2); II. dissolve the brown-yellow sticky solid in acidic aqueous solution, then add nitrite solid, red-brown gas is generated, the reaction system turns purple; III. first add the first organic solvent for extraction, then add inorganic base solid, gas and heat are released, adjust pH to alkaline, separate, wash the organic phase with saturated brine, dry, filter, rotary evaporate, get crude product, the second organic solvent is used to slurry the purple crystal product.

2. The method of claim 1, wherein the 3,6-di(3-pyridyl)-1,2,4,5-tetrazine is prepared by the method comprising: The mercaptan catalyst in the first step is selected from one of 3-mercaptopropionic acid, mercaptoacetic acid and L-cysteine. ​ 3. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: The molar ratio of 3-cyanopyridine to mercaptan catalyst in the first step is 1: (0.1-0.2).

4. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: The mass ratio of 3-cyanopyridine to ethanol in the first step is 1: (3-5).

5. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: The refluxing and stirring time in the first step is 3-5h.

6. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: The acidic aqueous solution in the second step is selected from one of hydrochloric acid aqueous solution, formic acid aqueous solution and acetic acid aqueous solution, wherein the molar amount of acid is 4-7 times of the molar amount of 3-cyanopyridine.

7. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: The nitrite in the second step is selected from one of sodium nitrite and potassium nitrite; the molar amount of nitrite is 3-5 times of the molar amount of 3-cyanopyridine.

8. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: The inorganic base used in the third step is selected from one of sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate; the inorganic base is added to adjust pH to 9-10.

9. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 1, characterized in that: Hydrazine hydrate is 50% hydrazine hydrate.

10. The method for preparing 3,6-bis(3-pyridyl)-1,2,4,5-tetraazabenzene according to claim 2, characterized in that: In the third step, the first organic solvent is dichloromethane, the second organic solvent is a mixed solvent of n-hexane and chloroform, and the volume ratio of n-hexane to chloroform is 8:1.

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