Synthesis method of beta-aminopyridine

Abstract

The invention relates to the technical field of preparation of beta-aminopyridine, in particular to a synthesis method of beta-aminopyridine, which comprises the following steps: weighing 3-chloropyridine, a catalyst, K2CO3 and K4Fe (CN) 6, adding into an organic solvent, sequentially adding KI and TABP, extracting a water phase, combining the organic phases, concentrating under reduced pressure to be dry, and distilling to obtain white solid nicotinonitrile; the preparation method comprises the following steps: adding an organic solvent into nicotinamide, stirring, dissolving and clarifying, sequentially adding NaOH and NH3.H2O, extracting a water phase, combining organic phases, concentrating under reduced pressure to be dry, and recrystallizing to obtain white solid nicotinamide; adding water into nicotinamide, stirring and dissolving, cooling to below 5 DEG C, slowly dropwise adding NaClO, extracting reaction liquid, and performing reduced pressure distillation to dryness to obtain a crude product; and recrystallizing and purifying to obtain faint yellow beta-aminopyridine. According to the method for synthesizing the beta-aminopyridine by adopting the steps, different products are obtained by independently controlling the reaction of each step, and the yield and the purity of the beta-aminopyridine are high.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of beta-aminopyridine, in particular to a method for synthesizing beta-aminopyridine. Background Art

[0002] As a multifunctional compound, β-aminopyridine is widely used as a catalyst, ligand and intermediate in organic synthesis reactions; it can also be applied to coatings, plastics, dyes, polymers and other fields. Common synthesis methods include aminolysis, reduction, photochemical reduction, catalytic hydrogenation and direct amination, but in the preparation process, impure raw materials will lead to reduced product purity and more side reactions, and more side reactions will lead to low product yields. Summary of the invention

[0003] The invention aims to provide a method for synthesizing beta-aminopyridine, which has high beta-aminopyridine yield and purity, independently controls each step of the reaction, and has high operability.

[0004] To achieve the above object, the present invention provides a method for synthesizing β-aminopyridine, comprising the following steps:

[0005] S1. Weigh 3-chloropyridine, catalyst, K2CO3 and K4Fe(CN)6 into DMF, stir until the solution is clear, then add KI and TABP in sequence. After the heating reaction is completed, adjust the pH and separate the phases. Add ethyl acetate to extract the aqueous phase and combine the organic phases. Concentrate to dryness under reduced pressure and distill to obtain white solid nicotinonitrile.

[0006] S2, add DMSO to the nicotinamide obtained in S1, stir to dissolve, add NaOH and NH3·H2O in sequence, heat to react, adjust the pH and then separate the phases, extract the aqueous phase with CH2Cl2 and combine the organic phases, concentrate to dryness under reduced pressure, and recrystallize to obtain white solid nicotinamide;

[0007] S3, take nicotinamide in S2, add water, stir and dissolve, cool to below 5°C, slowly add NaClO dropwise, stir for 20-40min, heat the reaction until the end, adjust the pH, add dichloromethane to extract the reaction solution, and evaporate to dryness by reduced pressure distillation to obtain a crude product;

[0008] S4. Recrystallize and purify the crude product in S3 to obtain light yellow β-aminopyridine.

[0009] Preferably, in S1, the molar ratio of 3-chloropyridine to K4Fe(CN)6 is 1:0.2-0.5.

[0010] Preferably, in S1, the heating reaction is to raise the temperature to 130-150° C. for 8-12 hours, and adjust the pH to 7.

[0011] Preferably, in S1, the catalyst is palladium acetate.

[0012] Preferably, in S2, the molar ratio of nicotinonitrile, NaOH and NH3·H2O is 1:1-2:2.5-6.

[0013] Preferably, in S2, the heating reaction is to raise the temperature to 80-100° C. for 6-10 hours, and adjust the pH to 6.

[0014] Preferably, in S2, 1.5-3 times the volume of diethyl ether is added during recrystallization.

[0015] Preferably, in S3, the molar ratio of nicotinamide to NaClO is 1:1-1.5.

[0016] Preferably, in S3, the heating reaction is to raise the temperature to 50-80° C., react for 2-3 hours, and adjust the pH to 6-7.

[0017] Preferably, in S4, 1.5-2 times the volume of petroleum ether of the crude product is added during recrystallization.

[0018] Preferably, the organic solvent includes one or more of dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethanol, acetone and tetrahydrofuran.

[0019] Therefore, the present invention adopts a method for synthesizing β-aminopyridine using the above steps, the β-aminopyridine has high yield and purity, each step of the reaction is independently controlled to obtain different products, the operability is high, the generation of side reaction products is reduced, and the method has economic adaptability.

[0020] The technical solution of the present invention is further described in detail below through embodiments. DETAILED DESCRIPTION

[0021] The present invention is further described below in conjunction with embodiments. Unless otherwise defined, the technical terms or scientific terms used in the present invention should be the common meanings understood by people with ordinary skills in the field to which the present invention belongs. The above-mentioned features or features mentioned in the specific examples mentioned in the present invention can be combined arbitrarily, and these specific embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0022] Example 1

[0023] A method for synthesizing β-aminopyridine comprises the following steps:

[0024] S1, 3-chloropyridine undergoes nitrilation reaction under the action of catalyst to synthesize nicotinonitrile (3-nitrile pyridine)

[0025] Weigh 113.5g 3-chloropyridine, 1.8g catalyst palladium acetate, 414.6g K2CO3 and 164.5g K4Fe(CN)6 into 600mL DMF and stir until the solution is clear. Then add 99.6g KI and 194.22g tert-butyl perbenzoate TABP (as a ligand) in sequence, heat to 150°C and react for 8-12h. After the reaction is completed, adjust the pH to 7 with 1% dilute hydrochloric acid and separate the phases. Add 150mL ethyl acetate to extract the aqueous phase three times. Combine the organic phases and concentrate under reduced pressure to dryness. Distill to obtain white solid nicotinonitrile with a yield of 82.2%.

[0026]

[0027] S2, nicotinonitrile undergoes a one-step hydrolysis reaction to generate nicotinamide

[0028] To 0.5 mol of nicotinonitrile obtained in S1, add DMSO and stir to dissolve, then add 36 g of NaOH and 61.25 g of NH3·H2O in sequence, and heat to 100°C for reaction for 6-10 h. After the reaction, adjust the pH to 6 with citric acid and separate the phases. Extract the aqueous phase three times with 100 mL of CH2Cl2, combine the organic phases, and concentrate to dryness under reduced pressure. Add 1.5-3 times the volume of ether to recrystallize to obtain white solid nicotinamide with a yield of 78%.

[0029] Hydrogen spectrum of niacinamide: 1 HNMR (300MHz, DMSO-d6): δ: 9 (s, 1H), 8.73 (d, J = 6Hz), 8.2 (d, J = 6Hz), 8.15 (s, 1H), 7.6 (s, 1H), 7.50 (dd, J = 3.6Hz, 1H).

[0030]

[0031] S3, nicotinamide finally undergoes Hofmann degradation reaction to generate β-aminopyridine

[0032] Take 1 mol of nicotinamide in S2, add 200-300 mL of water, stir and dissolve, cool to below 5°C, slowly drop 89.3 g of 9.53% NaClO, stir for 20-40 min, heat to 50-80°C, react for 2-3 h, adjust the pH to 6-7 with 20-30% NaOH after the reaction, add 100-150 mL of dichloromethane to extract the reaction solution 2-3 times, and evaporate to dryness under reduced pressure to obtain a crude product.

[0033]

[0034] The crude products in S4 and S3 were added to 1.5-2 times the volume of petroleum ether for recrystallization and purified to obtain light yellow β-aminopyridine with a yield of 87.1%.

[0035] Hydrogen spectrum of β-aminopyridine: 1 H NMR (CDCl3, 400MHz): δ: 8.04 (d, 1H, J = 4Hz), 7.95 (d, 1H, J = 4Hz), 6.93-7.02 (m, 2H), 3.86 (s, 2H).

[0036] Example 2

[0037] A method for synthesizing β-aminopyridine comprises the following steps:

[0038] S1. Weigh 1 mol 3-chloropyridine, 0.003 mol catalyst palladium acetate, 1 mol K2CO3 and 0.2 mol K4Fe(CN)6, add them into 800 mL DMF, stir until the solution is clear, then add 0.3 mol KI and 0.5 mol TABP in sequence, heat to 150°C and react for 8-12 h. After the reaction, adjust the pH to 7 with 1% dilute hydrochloric acid, separate the phases, add 100-200 mL ethyl acetate to extract the aqueous phase three times, combine the organic phases, concentrate under reduced pressure to dryness, and distill to obtain white solid nicotinonitrile.

[0039] S2. Add DMSO to 0.5 mol of nicotinonitrile obtained in S1 and stir to dissolve. Add 0.5 mol NaOH and 1.25 mol NH3·H2O in sequence. Heat to 100°C and react for 6-10 h. After the reaction, adjust the pH to 6 with citric acid and separate the phases. Extract the aqueous phase three times with 50-100 mL CH2Cl2. Combine the organic phases and concentrate to dryness under reduced pressure. Add 1.5-3 times the volume of ether and recrystallize to obtain white solid nicotinamide.

[0040] S3, take 1 mol of nicotinamide in S2, add 200-300 mL of water, stir and dissolve, cool to below 5°C, slowly add 1 mol of 9.53% NaClO, stir for 20-40 min, heat to 50-80°C, react for 2-3 h, adjust the pH to 6-7 with 20-30% NaOH after the reaction, add 100-150 mL of dichloromethane to extract the reaction solution 2-3 times, evaporate to dryness under reduced pressure to obtain a crude product.

[0041] The crude products in S4 and S3 are added to 1.5-2 times the volume of petroleum ether for recrystallization and purified to obtain light yellow β-aminopyridine.

[0042] Example 3

[0043] A method for synthesizing β-aminopyridine comprises the following steps:

[0044] S1. Weigh 1 mol 3-chloropyridine, 0.008 mol catalyst palladium acetate, 2 mol K2CO3 and 0.5 mol K4Fe(CN)6, add them into 500 mL DMF, stir until the solution is clear, then add 0.6 mol KI and 1 mol TABP in sequence, heat to 150°C and react for 8-12 h. After the reaction, adjust the pH to 7 with 1% dilute hydrochloric acid, separate the phases, add 100-200 mL ethyl acetate to extract the aqueous phase three times, combine the organic phases, concentrate under reduced pressure to dryness, and distill to obtain white solid nicotinonitrile.

[0045] S2. Add DMSO to 0.5 mol of nicotinonitrile obtained in S1 and stir to dissolve. Add 1 mol NaOH and 3 mol NH3·H2O in sequence. Heat to 100°C and react for 6-10 h. After the reaction, adjust the pH to 6 with citric acid and separate the phases. Extract the aqueous phase three times with 50-100 mL CH2Cl2. Combine the organic phases and concentrate to dryness under reduced pressure. Add 1.5-3 times the volume of ether and recrystallize to obtain white solid nicotinamide.

[0046] S3, take 1 mol of nicotinamide in S2, add 200-300 mL of water, stir and dissolve, cool to below 5°C, slowly add 1.5 mol of 9.53% NaClO, stir for 20-40 min, heat to 50-80°C, react for 2-3 h, adjust the pH to 6-7 with 20-30% NaOH after the reaction, add 100-150 mL of dichloromethane to extract the reaction solution 2-3 times, and evaporate to dryness under reduced pressure to obtain a crude product.

[0047] The crude products in S4 and S3 are added to 1.5-2 times the volume of petroleum ether for recrystallization and purified to obtain light yellow β-aminopyridine.

[0048] Therefore, the present invention adopts a method for synthesizing β-aminopyridine using the above steps, the β-aminopyridine has high yield and purity, each step of the reaction is independently controlled to obtain different products, the operability is high, the generation of side reaction products is reduced, and the method has economic adaptability.

[0049] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing β-aminopyridine, characterized in that: The following steps are included: S1. Weigh 3-chloropyridine, catalyst, K2CO3 and K4Fe(CN)6 into an organic solvent, stir until the solution is clear, then add KI and TABP in sequence, after the heating reaction is completed, adjust the pH and separate the phases, add ethyl acetate to extract the aqueous phase, combine the organic phases, concentrate to dryness under reduced pressure, and distill to obtain white solid nicotinonitrile; S2, adding an organic solvent to the nicotinamide obtained in S1, stirring to dissolve, adding NaOH and NH3·H2O in sequence, heating to react, adjusting the pH, separating the phases, extracting the aqueous phase with CH2Cl2, combining the organic phases, concentrating to dryness under reduced pressure, and recrystallizing to obtain white solid nicotinamide; S3, take nicotinamide in S2, add water, stir and dissolve, cool to below 5°C, slowly add NaClO dropwise, stir for 20-40min, heat the reaction until the end, adjust the pH, add dichloromethane to extract the reaction solution, and evaporate to dryness by reduced pressure distillation to obtain a crude product; S4. Recrystallize and purify the crude product in S3 to obtain light yellow β-aminopyridine.

2. A method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S1, the molar ratio of 3-chloropyridine to K4Fe(CN)6 is 1:0.2-0.

5.

3. A method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S1, the heating reaction is to raise the temperature to 130-150° C. for 8-12 hours, and adjust the pH to 7.

4. A method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S1, the catalyst is palladium acetate.

5. A method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S2, the molar ratio of nicotinonitrile, NaOH and NH3·H2O is 1:1-2:2.5-6.

6. The method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S2, the heating reaction is to raise the temperature to 80-100°C for 6-10h, and adjust the pH to 6.

7. The method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S2, 1.5-3 volumes of ether are added during recrystallization.

8. The method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S3, the molar ratio of nicotinamide to NaClO is 1:1-1.

5.

9. The method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S3, the heating reaction is to raise the temperature to 50-80°C, react for 2-3 hours, and adjust the pH to 6-7.

10. The method for synthesizing β-aminopyridine according to claim 1, characterized in that: In S4, 1.5-2 times the volume of petroleum ether of the crude product is added during recrystallization.

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