Method for preparing 3-nitrile pyridine and method for preparing 3-pyridine formamidine
Through a new method of preparing 3-nitrile pyridine and 3-pyridine carboxamidine, the problems of low atomic utilization and environmental pollution in the prior art have been solved, and a high yield and environmentally friendly preparation of 3-pyridine carboxamidine is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202510573946.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-05-06
- Publication Date
- 2025-07-04
AI Technical Summary
The prior art has problems of low atomic utilization, complicated reaction steps and environmental pollution when preparing 3-pyridine carboxamide, especially the hydroxyamide oxime method and the orthoformate method, which have difficulty in separating intermediates and harmful gas emissions.
3-nitrile pyridine is prepared by reacting 3-iodopyridine with potassium peroxide as ligand, potassium carbonate as base, and palladium acetate as catalyst, and NaH is used as catalyst to add it to ammonia to form 3-pyridine carboxamidine.
The yield of 3-nitrile pyridine and the total yield of 3-pyridine carboxamidine are improved, and the process is simple, environmentally friendly and easy to be used in industrial use.
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Abstract
Description
Technical Field
[0001] The present invention relates to the field of chemical synthesis, and particularly provides a method for preparing 3-cyanopyridine and a method for preparing 3-pyridinecarboximidamide. Background Art
[0002] 3-Pyridinecarboximidamide, a colorless crystalline solid, is soluble in water and some organic solvents such as ethanol and methanol, and is commonly used as a catalyst, ligand or intermediate in organic synthesis.
[0003] The prior art generally uses the hydroxylamine oxime method and the orthoformate method for preparation. Among them, the hydroxylamine oxime method requires multiple steps of reaction, involving the separation and purification of intermediates, resulting in low atom utilization rate and increasing the consumption of time and resources; the orthoformate method will generate harmful gases (such as SO2), posing a threat to the environment and operation safety. Summary of the Invention
[0004] The present invention aims at the above-mentioned deficiencies of the prior art and provides a method for preparing 3-cyanopyridine.
[0005] A further technical task of the present invention is to provide a method for preparing 3-pyridinecarboximidamide that is green, environmentally friendly and easy to industrialize.
[0006] The technical solution adopted by the present invention to solve its technical problems is: for the method for preparing 3-cyanopyridine, the feature is that using tert-butyl perbenzoate as a ligand and potassium carbonate as a base, under the action of palladium acetate, 3-iodopyridine undergoes a cyanation reaction with potassium ferrocyanide to generate 3-cyanopyridine, and the reaction formula is as follows:
[0007]
[0008] Preferably, the method for preparing 3-cyanopyridine includes the following steps:
[0009] Add 1 mol of 3-iodopyridine, 0.3 - 0.8 mol% of palladium acetate, 1 - 3 mol of potassium carbonate and 0.2 - 0.5 mol of potassium ferrocyanide into 500 - 800 mL of N,N-dimethylformamide, stir to dissolve, then add 0.5 - 1 mol of tert-butyl perbenzoate, heat up to 130 - 150 °C and react for 6 - 8 h. After the reaction is completed, obtain the 3-cyanopyridine product through purification.
[0010] Preferably, after the reaction is completed, add 1% dilute hydrochloric acid to the reaction system to adjust the pH = 6 - 7, separate the phases, add 100 - 200 mL of ethyl acetate to extract the aqueous phase three times, combine the organic phases, concentrate the organic phases under reduced pressure to dryness, and obtain the white solid 3-cyanopyridine product by distilling the obtained crude product.
[0011] A method for preparing 3-pyridinecarboximidamide, characterized by comprising: 3-cyanopyridine undergoes an addition reaction with an ammonia source in the presence of NaH to form 3-pyridinecarboximidamide, and the reaction formula is as follows:
[0012]
[0013] Preferably, the method for preparing 3-pyridinecarboximidamide is as follows: Add 3-cyanopyridine to a tetrahydrofuran solution of NaH, stir at a temperature below 0 °C (preferably 0 - 10 °C) for 20 - 45 min, then raise the temperature to room temperature, continuously stir for 8 - 12 h, slowly add the ammonia source, raise the temperature to the reflux state, react for 2 - 3 h. After the reaction is completed, cool the temperature to below 5 °C, add water to quench the reaction, and obtain the 3-pyridinecarboximidamide product through purification.
[0014] Preferably, after adding water to quench the reaction, extract the reaction solution with ethyl acetate, adjust the pH = 6 - 7, wash the organic phase with saturated NaCl solution, then dry the organic phase with anhydrous Na2SO4, evaporate the organic phase to dryness, and obtain the 3-pyridinecarboximidamide product through column chromatography. Preferably, the column chromatography uses an ethyl acetate / petroleum ether system.
[0015] Preferably, in the tetrahydrofuran solution of NaH, the concentration of NaH is 0.6 - 3 mol / L.
[0016] Preferably, the molar ratio of NaH, ammonia source to 3-cyanopyridine is (0.1 - 0.3):(0.5 - 1):0.5.
[0017] Preferably, the ammonia source is NH4Cl or NH3·H2O.
[0018] Preferably, the 3-cyanopyridine is prepared by the method for preparing 3-cyanopyridine of the present invention.
[0019] Compared with the prior art, the method for preparing 3-pyridinecarboximidamide of the present invention has the following outstanding beneficial effects:
[0020] (1) Using 3-cyanopyridine as a raw material, preparing 3-pyridinecarboximidamide in the presence of NaH, with high yield, simple process, mild reaction conditions, and being easy to be popularized and applied industrially;
[0021] (2) Using 3-iodopyridine as a raw material to prepare 3-cyanopyridine, which has a higher yield, and thus improves the total yield of 3-pyridinecarboximidamide. Detailed Embodiments
[0022] The present invention will be further described below with reference to specific embodiments, but it is not intended to limit the present invention.
[0023] Unless otherwise specified, the weighing parts of each raw material in the following embodiments are all volume ratios.
[0024] Example 1
[0025] S1. Prepare 3-cyanopyridine
[0026]
[0027] Add 1 mol of 3-iodopyridine, 0.5% mol of palladium acetate, 1.5 mol of potassium carbonate, and 0.3 mol of potassium ferrocyanide to 600 mL of N,N-dimethylformamide, stir to dissolve, then add 0.7 mol of tert-butyl peroxybenzoate, heat up to 140 °C and react for 8 h. After the reaction is completed, add 1% dilute hydrochloric acid to the system to adjust the pH = 7, separate the phases, add 130 mL of ethyl acetate to extract the aqueous phase three times, combine the organic phases, concentrate the organic phases under reduced pressure to dryness, and obtain 91.62 g of 3-cyanopyridine white solid product by distillation of the crude product, with a yield of 88%.
[0028] S2. Prepare 3-pyridinecarboximidamide
[0029]
[0030] Add 0.2 mol of NaH to 100 mL of tetrahydrofuran and start stirring, add 0.5 mol of 3-cyanopyridine, cool down to -5 °C, stir for 30 min, then naturally warm up to room temperature and continue stirring for 10 h. Then, slowly add 0.7 mol of NH4Cl, heat up to the reflux state, and react for 2.5 h. After the reaction is completed, cool down to below 5 °C, add water to quench the reaction, extract the reaction solution with ethyl acetate (100 mL × 3), adjust the pH = 6 - 7 with 10% citric acid, wash the organic phase with saturated NaCl solution, dry the organic phase with anhydrous Na2SO4, evaporate the organic phase to dryness, and obtain 87.22 g of 3-pyridinecarboximidamide product by column chromatography (ethyl acetate / petroleum ether system), with a yield of 72%. 1 H NMR(500MHz,CDCl3)δ: 8.8(d,J = 2.4Hz,1H),8.6(dt,J = 4.8,1.5Hz,1H),7.7(dt,J = 8.2,2.1Hz,1H),7.2(dd,J = 7.8,4.7Hz,1H),5.7(s,3H).
[0031] Example 2:
[0032] Add 0.1 mol of NaH to 100 mL of tetrahydrofuran, start stirring, add 0.5 mol of 3-cyanopyridine (prepared by the method in step S1 of Example 1), cool down to -5 °C, stir for 30 min, then naturally warm up to room temperature and continue stirring for 10 hours. Then, slowly add 1 mol of NH4Cl, heat up to the reflux state, react for 2.5 h. After the reaction is completed, cool down to below 5 °C, add water to quench the reaction, extract the reaction solution with ethyl acetate, adjust the pH to 6 - 7 with citric acid, wash the organic phase with saturated NaCl solution, dry the organic phase with anhydrous Na2SO4, evaporate the organic phase to dryness, and obtain 85.4 g of 3-pyridinecarboximidamide product by column chromatography (ethyl acetate / petroleum ether system), with a yield of 70.5%.
[0033] Example 3:
[0034] Add 0.3 mol of NaH to 100 mL of tetrahydrofuran, start stirring, add 0.5 mol of 3-cyanopyridine (prepared by the method in step S1 of Example 1), cool down to -5 °C, stir for 30 min, then naturally warm up to room temperature and continue stirring for 10 hours. Then, slowly add 0.5 mol of NH4Cl, heat up to the reflux state, react for 2.5 h. After the reaction is completed, cool down to below 5 °C, add water to quench the reaction, extract the reaction solution with ethyl acetate, adjust the pH to 6 - 7 with citric acid, wash the organic phase with saturated NaCl solution, dry the organic phase with anhydrous Na2SO4, evaporate the organic phase to dryness, and obtain 73.89 g of 3-pyridinecarboximidamide product by column chromatography (ethyl acetate / petroleum ether system), with a yield of 61%.
[0035] Example 4:
[0036] Add 0.2 mol of NaOH to 100 mL of tetrahydrofuran, start stirring, add 0.5 mol of 3-cyanopyridine (prepared by the method in step S1 of Example 1), cool down to -5 °C, stir for 30 min, then naturally warm up to room temperature and continue stirring for 10 hours. Then, slowly add 0.7 mol of NH4Cl, heat up to the reflux state, react for 2.5 h. After the reaction is completed, cool down to below 5 °C, add water to quench the reaction, extract the reaction solution with ethyl acetate, adjust the pH to 6 - 7 with citric acid, wash the organic phase with saturated NaCl solution, dry the organic phase with anhydrous Na2SO4, evaporate the organic phase to dryness, and obtain 78.98 g of 3-pyridinecarboximidamide product by column chromatography (ethyl acetate / petroleum ether system), with a yield of 65.2%.
[0037] Example 5:
[0038] 0.2 mol of KOH was added to 100 mL of tetrahydrofuran and stirring was started. 0.5 mol of 3-cyanopyridine (prepared by the method of step S1 in Example 1) was added. The temperature was lowered to -5 °C. After stirring for 30 min, the temperature was naturally raised to room temperature and stirring was continued for 10 hours. Then, 0.7 mol of NH4Cl was slowly added, and the temperature was raised to the reflux state. The reaction was carried out for 2.5 h. After the reaction was completed, the temperature was lowered to below 5 °C, and water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the pH was adjusted to 6-7 with citric acid. The organic phase was washed with saturated NaCl solution, and the organic phase was dried over anhydrous Na2SO4. The organic phase was evaporated to dryness, and 82.92 g of 3-pyridinecarboximidamide product was obtained by column chromatography (ethyl acetate / petroleum ether system), and the yield was 68.45%.
[0039] Example 6:
[0040] 0.2 mol of NaH was added to 100 mL of tetrahydrofuran and stirring was started. 0.5 mol of 3-cyanopyridine (prepared by the method of step S1 in Example 1) was added. The temperature was lowered to -5 °C. After stirring for 30 min, the temperature was naturally raised to room temperature and stirring was continued for 10 hours. Then, 0.7 mol of NH3·H2O was slowly added, and the temperature was raised to the reflux state. The reaction was carried out for 2.5 h. After the reaction was completed, the temperature was lowered to below 5 °C, and water was added to quench the reaction. The reaction solution was extracted with ethyl acetate, and the pH was adjusted to 6-7 with citric acid. The organic phase was washed with saturated NaCl solution, and the organic phase was dried over anhydrous Na2SO4. The organic phase was evaporated to dryness, and 85.56 g of 3-pyridinecarboximidamide product was obtained by column chromatography (ethyl acetate / petroleum ether system), and the yield was 70.6%.
[0041] The above examples are only the optimal cases selected from all conditions for comparison and do not represent all. All research and exploration carried out on the basis of parallel changes of all data and conditions in the present invention are within the scope of protection.
Claims
1. A method for preparing 3-cyanopyridine, characterized in that: Using tert-butyl perbenzoate as a ligand and potassium carbonate as a base, in the presence of palladium acetate, 3-iodopyridine undergoes a cyanation reaction with potassium ferrocyanide to form 3-cyanopyridine.
2. The method for preparing 3-cyanopyridine according to claim 1, characterized in that: 1 mol of 3-iodopyridine, 0.3 - 0.8 mol% of palladium acetate, 1 - 3 mol of potassium carbonate and 0.2 - 0.5 mol of potassium ferrocyanide are added to 500 - 800 mL of N,N-dimethylformamide, stirred and dissolved, then 0.5 - 1 mol of tert-butyl perbenzoate is added, the temperature is raised to 130 - 150 °C and the reaction is carried out for 6 - 8 h. After the reaction is completed, the 3-cyanopyridine product is obtained through purification.
3. The preparation method of 3-cyanopyridine according to claim 2, characterized in that: After the reaction is completed, 1% dilute hydrochloric acid is added to the reaction system to adjust the pH to 6 - 7, the phases are separated, 100 - 200 mL of ethyl acetate is added to extract the aqueous phase three times, the organic phases are combined, the organic phase is concentrated under reduced pressure to dryness, and the obtained crude product is distilled to obtain the white solid 3-cyanopyridine product.
4. A method for preparing 3-pyridinecarboximidamide, characterized in that, Including: 3-cyanopyridine undergoes an addition reaction with an ammonia source in the presence of NaH to form 3-pyridinecarboximidamide.
5. The method for preparing 3-pyridinecarboximidamide according to claim 4, characterized in that: 3-cyanopyridine is added to a tetrahydrofuran solution of NaH, stirred at a temperature below 0 °C for 20 - 45 min, then the temperature is raised to room temperature and stirring is continued for 8 - 12 h. The ammonia source is slowly added, the temperature is raised to the reflux state, and the reaction is carried out for 2 - 3 h. After the reaction is completed, the temperature is lowered to below 5 °C, water is added to quench the reaction, and the 3-pyridinecarboximidamide product is obtained through purification.
6. The method for preparing 3-pyridinecarboximidamide according to claim 5, wherein: After quenching the reaction with water, the reaction solution is extracted with ethyl acetate, the pH is adjusted to 6 - 7, the organic phase is washed with saturated NaCl solution, then the organic phase is dried with anhydrous Na2SO4, the organic phase is evaporated to dryness, and the 3-pyridinecarboximidamide product is obtained through column chromatography.
7. The method for preparing 3-pyridinecarboximidamide according to claim 5 or 6, characterized in that: In the tetrahydrofuran solution of NaH, the concentration of NaH is 0.006 - 0.03 mol / L.
8. The method for preparing 3-pyridinecarboximidamide according to claim 7, wherein: The molar ratio of NaH, ammonia source to 3-cyanopyridine is (0.1 - 0.3):(0.5 - 1):0.
5.
9. The method for preparing 3-pyridinecarboximidamide according to claim 8, wherein: The ammonia source is NH4Cl or NH3·H2O.
10. The method for preparing 3-pyridinecarboximidamide according to claim 4, characterized in that, The 3-cyanopyridine is prepared by the method described in claim 1 or 2.