Preparation method of 4-vinylpyridine

Abstract

The preparation method of 4-vinylpyridine, S1, prepares 4-formylpyridine: 4-bromopyridine is dissolved in an organic solvent and cooled, a strong base is slowly added, and N, N-dimethylformamide is reacted under the action of the strong base to obtain 4-formylpyridine; S2, prepares 4-vinylpyridine: 4-formylpyridine is reacted with Teber's reagent in an organic solvent to obtain 4-vinylpyridine. The present invention has the advantages of simple equipment, short reaction time and high yield (65-80%); and has the prospect of industrial production.

Description

Technical Field

[0001] The invention relates to the field of preparation of pharmaceutical chemical raw materials, in particular to a method for preparing 4-vinylpyridine. Background Art

[0002] 4-vinylpyridine can be used as an intermediate in organic synthesis and a monomer for polymers, and is widely used in functional polymers, surfactants, antistatic agents, photosensitive resins, coatings, medicines, pesticides, etc. In particular, its corresponding polymers can be used as ion exchange resins, which have unique advantages in cation exchange and precious metal ion recovery.

[0003] The existing relevant preparation technologies all adopt the "one-step method", that is, using 4-methylpyridine as the raw material, and synthesizing 4-vinylpyridine through high temperature (400-500°C) and high pressure (1.5MPa). However, the major disadvantages of this scheme are the harsh preparation conditions and the easy occurrence of pipeline blockage during operation. At the same time, the monomer conversion rate of this scheme is low, and the impurity content of the prepared product is relatively large.

[0004] CN 106699641A discloses a process for preparing 4-hydroxyethylpyridine intermediate under normal pressure and low temperature (105-110°C) conditions using 4-methylpyridine as a raw material, and finally producing 4-vinylpyridine under alkaline and high temperature (180°C) conditions. However, this scheme has a major disadvantage, that is, the preparation of 4-hydroxyethylpyridine requires a long time (45-70h) and the conversion rate is low (40%-60%), which is obviously very unfavorable for the industrialization of the process.

[0005] The technical solution of CN 106008325A uses 4-hydroxyethylpyridine as a raw material, and successfully prepares 4-vinylpyridine under the action of specific catalysts such as calcium chloride and magnesium chloride. Although the yield reported is relatively high, the raw material 4-hydroxyethylpyridine used is an intermediate in the process of preparing 4-vinylpyridine from 4-methylpyridine, and it is very difficult to purify and obtain a product of high purity.

[0006] Therefore, developing new alternative synthetic routes for 4-vinylpyridine is an effective strategy to achieve its efficient and low-cost industrial production. Summary of the invention

[0007] The present invention aims to solve the existing problems and provide a method for preparing 4-vinylpyridine.

[0008] In order to achieve the above object, the technical solution adopted by the present invention comprises the following steps:

[0009] S1, preparing 4-formylpyridine: dissolving 4-bromopyridine in a dry organic solvent and cooling the solvent, slowly adding a strong base to the system, and reacting the solvent with N,N-dimethylformamide (DMF) under the action of the strong base to obtain 4-formylpyridine; restoring the reaction system to room temperature, stirring, and quenching with water after the reaction is complete, and extracting and separating;

[0010] S2, preparation of 4-vinylpyridine: the 4-aldehyde pyridine obtained in S1 is reacted with Tebbe's reagent in an organic solvent to obtain 4-vinylpyridine.

[0011] Preferably, in S1 and S2, the organic solvent is an aprotic solvent such as tetrahydrofuran, dioxane, diethyl ether, n-hexane or toluene, more preferably tetrahydrofuran.

[0012] Preferably, in S1, the strong base is one or a combination of methyl lithium, n-butyl lithium, lithium diisopropylamide (LDA), benzyl lithium, sodium hydride, potassium hydride, sodium amide, potassium amide, sodium bis(trimethylsilyl)amide (NaHMDS), and potassium bis(trimethylsilyl)amide (KHMDS).

[0013] Preferably, in S1, the molar ratio of 4-bromopyridine to the strong base is 1:1.5 to 1:5.0, more preferably 1:2 to 1:2.5. Preferably, in S1, the molar ratio of 4-bromopyridine to N,N-dimethylformamide (DMF) is 1:0.5 to 1:10.0, more preferably 1:1 to 1:3.0.

[0014] Preferably, in S1, the cooling temperature is -100°C to 0°C, more preferably -20°C to 0°C.

[0015] Preferably, in S1, the reaction time is 1-20 hours, more preferably 5-10 hours.

[0016] Preferably, in S2, the molar ratio of 4-formylpyridine to Teber's reagent is 1:0.5 to 1:10.0, more preferably 1:1 to 1:1.5.

[0017] Preferably, in S2, the reaction time is 0.5-10 hours, more preferably 0.5-1.5 hours.

[0018] Preferably, in S2, a crude product is obtained after the reaction is completed; the organic solvent is subsequently removed and the product is distilled under reduced pressure to obtain the final 4-vinylpyridine. The temperature of the distillation under reduced pressure is controlled at 30-150°C, more preferably 50-80°C. Compared with the prior art, the method of the present invention uses 4-bromopyridine as a raw material, reacts with N,N-dimethylformamide under the action of a strong base, and first obtains 4-aldehyde pyridine; and further reacts with Teber's reagent to obtain 4-vinylpyridine. The method has the advantages of simple equipment, short reaction time, and high yield (65-80%); and has the prospect of industrial production. DETAILED DESCRIPTION

[0019] The above scheme is further described below in conjunction with specific implementation examples. In the embodiment, the method of the present invention specifically includes the following steps:

[0020] S1: Preparation of 4-formylpyridine: Dissolve 4-bromopyridine in a dry organic solvent and cool it, slowly add a strong base to the system; after stirring at low temperature for a certain period of time, add dry N,N-dimethylformamide (DMF). Return the reaction system to room temperature, stir, and after the reaction is complete, add water to quench, and extract and separate.

[0021] S2: Preparation of 4-vinylpyridine: Dissolve the 4-formylpyridine obtained in S1 in an organic solvent, and slowly add the Teber reagent at room temperature; after the reaction is complete, remove the organic solvent and perform reduced pressure distillation to obtain the final 4-vinylpyridine.

[0022] The specific reaction equation is as follows:

[0023]

[0024] Embodiment 1:

[0025] Add 316g 4-bromopyridine and 1000mL dry tetrahydrofuran to a flask, cool to -60°C, and then dropwise add 1800mL n-butyl lithium solution (2.4mol / L in n-hexane) within 1 hour. Stir at -20°C for 2 hours, and then add 160.6g dry DMF. Return the reaction system to room temperature and continue stirring for 5 hours. Gas phase detection shows that 4-bromopyridine has reacted completely. Add 100g ammonium chloride aqueous solution to quench the reaction and separate the liquids.

[0026] 1100 mL of Turbo reagent (2.0 mol / L in THF) was slowly added to the obtained 4-formylpyridine tetrahydrofuran / n-hexane solution. After the addition was completed, the reaction was continued for 1 hour. 120 g of saturated ammonium chloride aqueous solution was added to quench the reaction. After static separation, a light yellow crude product was obtained. Vacuum distillation was performed at 60°C to obtain anhydrous clear liquid 4-vinylpyridine.

[0027] Based on 4-bromopyridine, the total yield of this embodiment is 68%. 80-100 ppm of p-diphenol should be added to the finished 4-ethylene and pyridine products as a polymerization inhibitor and stored at low temperature.

[0028] Embodiment 2:

[0029] Add 310g 4-bromopyridine and 1500mL dry tetrahydrofuran to the flask, cool to -0°C, and then dropwise add 1950mL KHMDS solution (2.0mol / L in THF) within 1 hour. After stirring at -0°C for 4 hours, add 155.2g dry DMF. After the reaction system returns to room temperature, continue stirring for 5 hours. Add 100g ammonium chloride aqueous solution to quench the reaction and separate the liquids.

[0030] Slowly add 1080 mL of Turbo reagent (2.0 mol / L THF) to the obtained 4-formylpyridine tetrahydrofuran solution, continue the reaction for 1 hour after the addition is complete, add 120 g of saturated ammonium chloride aqueous solution to quench the reaction, and after static separation, a light yellow crude product is obtained. Perform vacuum distillation at 60°C to obtain a clear liquid 4-vinylpyridine.

[0031] Based on 4-bromopyridine, the total yield of this embodiment is 80%.

[0032] Embodiment three:

[0033] 780 g of 4-bromopyridine and 1900 mL of dry tetrahydrofuran were added to the flask. After cooling to -20°C, 205 g of sodium hydride (60% in mineral oil) was added in batches over 1 hour. After stirring at -20°C for 2.5 hours, 365.2 g of dry DMF was added dropwise.

[0034] After the reaction system was returned to room temperature, stirring was continued for 5 hours. Filter, remove unreacted sodium hydride, and slowly drip 4200mL of Teber reagent (2.0mol / L in THF) in the above-mentioned 4-formylpyridine tetrahydrofuran filtrate, continue to react for 2 hours after dropwise addition, add 400g of saturated aqueous ammonium chloride solution to quench the reaction, and after static layering, obtain a light yellow crude product, and perform rectification under reduced pressure to obtain anhydrous clear liquid 4-vinylpyridine. Based on 4-bromopyridine, the total recovery of the present embodiment is 75%.

[0035] Embodiment 4:

[0036] Add 310 g of 4-bromopyridine and 2200 mL of dry toluene to a flask, cool to -10 ° C, add 733 g of NaHMDS solid in batches over 2 hours, continue stirring at -10 ° C for 5 hours, and then add 160.1 g of dry DMF. After the reaction system returns to room temperature, continue stirring for 4 hours. Add 120 g of saturated ammonium chloride aqueous solution to quench the reaction and separate the liquids.

[0037] 1100 mL of Turbo's reagent (2.0 mol / L inTol) was slowly added to the obtained 4-formylpyridine toluene solution. After the addition was completed, the reaction was continued for 1 hour. 120 g of saturated ammonium chloride aqueous solution was added to quench the reaction. After static separation, the crude product was obtained. Vacuum distillation was performed at 80°C to obtain clear liquid 4-vinylpyridine.

[0038] Based on 4-bromopyridine, the total yield of this embodiment is 72%.

[0039] Embodiment five:

[0040] 770 g of 4-bromopyridine and 1500 mL of dry dioxane were added to the reaction kettle. After cooling to -20°C, 210 g of sodium hydride (60% in mineral oil) was added in batches within 1 hour. After stirring at -20°C for 2.5 hours, 365.2 g of dry DMF was slowly added dropwise.

[0041] After the reaction system was restored to room temperature, stirring was continued for 5 hours. The unreacted sodium hydride was removed by filtration, and 4200 mL of Turbo reagent (2.0 mol / L in THF) was slowly added to the above 4-formylpyridine dioxane filtrate. After the addition was completed, the reaction was continued for 2 hours, and 400 g of saturated ammonium chloride aqueous solution was added to quench the reaction. After static stratification, a crude product was obtained, which was subjected to vacuum distillation to obtain anhydrous clear liquid 4-vinylpyridine.

[0042] Based on 4-bromopyridine, the total yield of this embodiment is 78%.

[0043] The novel 4-vinylpyridine preparation method provided by the present invention uses 4-bromopyridine as a raw material, reacts with N,N-dimethylformamide (DMF) under the action of a strong base to obtain 4-aldehyde pyridine; and further obtains the corresponding 4-vinylpyridine in the presence of Tebbe's reagent. The method requires a short time and has a high yield (65-80%), providing a novel path for the industrial production of 4-vinylpyridine.

Claims

1. A method for preparing 4-vinylpyridine, characterized in that: S1, preparing 4-formylpyridine: dissolving 4-bromopyridine in an organic solvent and cooling; slowly adding a strong base, and reacting with N,N-dimethylformamide under the action of the strong base to obtain 4-formylpyridine; Wherein, the strong base is one or a combination of n-butyl lithium, sodium hydride, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide; S2, preparation of 4-vinylpyridine: the 4-aldehyde pyridine obtained in S1 is reacted with Teber's reagent in an organic solvent to obtain 4-vinylpyridine.

2. The method according to claim 1, characterized in that: In S1 and S2, the organic solvent is an aprotic solvent: tetrahydrofuran, dioxane, diethyl ether, n-hexane or toluene.

3. The method according to claim 1 or 2, characterized in that: In S1, the molar ratio of 4-bromopyridine to the strong base is 1:1.5 to 1:5.0 or 1:2 to 1:2.

5.

4. The method according to claim 3, characterized in that: In S1, the molar ratio of 4-bromopyridine to N,N-dimethylformamide is 1:0.5 to 1:10.0 or 1:1 to 1:3.

0.

5. The method according to claim 1, characterized in that: In S1, the cooling temperature is -100°C to 0°C or -20°C to 0°C.

6. The method according to claim 1, characterized in that: In S1, the reaction time is 1-20 hours or 5-10 hours.

7. The method according to claim 1, characterized in that: In S2, the molar ratio of 4-formylpyridine to Teber's reagent is 1:0.5 to 1:10.0 or 1:1 to 1:1.

5.

8. The method according to claim 1, characterized in that: In S2, the reaction time is 0.5-10 hours or 0.5-1.5 hours.

9. The method according to claim 1, characterized in that: In S2, a crude product is obtained after the reaction is completed; the organic solvent is then removed and the product is distilled under reduced pressure to obtain the final 4-vinylpyridine; and / or the distillation temperature under reduced pressure is controlled at 30-150°C or 50-80°C.

Images