The invention relates to 4, 4apos; process for the preparation of-dipyridyl

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a preparation method of 4, 4 '-dipyridyl, which is characterized by comprising the following steps: in a nitrogen or inert gas atmosphere, firstly dissolving metal sodium in 1, 3-dimethyl-2-imidazolinone, then adding pyridine for reaction, cooling the reaction liquid to 0-5 DEG C, adding deionized water, then adding N, N-dimethyl formamide, and reacting for 2-4 hours at the temperature of 0-5 DEG C to obtain the 4, 4'-dipyridyl. And introducing air to carry out oxidation reaction under the condition that N, N-dimethylformamide is added or N, N-dimethylformamide is not added, so as to obtain the 4, 4 '-dipyridyl. Pyridine is used as a raw material, the raw material is cheap and easy to obtain, and the production cost is low; green and safe 1, 3-dimethyl-2-imidazolinone is used as a reaction solvent, has the advantages of being low in toxicity, small in pollution, high in stability and the like, and meanwhile has good solubility on metal sodium, and the reaction activity of the sodium is remarkably improved. Meanwhile, N, N-dimethylformamide with high dielectric constant is used as an additive, so that the generation of the product is effectively promoted.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and relates to a preparation method of 4,4'-bipyridine. Background Art

[0002] 4,4′-Bipyridine is an important intermediate in organic synthesis and pharmaceutical chemistry, and is widely used in drug molecule synthesis, materials and basic chemistry research. 4,4′-Bipyridine is a key intermediate in the synthesis of the lethal herbicide paraquat; the nitrogen atoms at both ends can coordinate with metal atoms to obtain excellent bridging ligands, which play an important role in catalytic reactions; it can also be used as an indicator for detecting metal ions. 4,4′-Bipyridine has luminescent properties and can be used to prepare fluorescent materials.

[0003] At present, the preparation methods of 4,4′-bipyridine mainly include the following four methods:

[0004] ①4-halopyridine method: 4-chloropyridine or 4-bromopyridine is used as raw material, and NaH- t The BuONa-Ni(OAc)2-PPh3 catalyst is used to catalyze the synthesis of 4,4′-bipyridine. The yield of this method is good, but the raw material price is high, the production cost is high, and it is not suitable for industrial production.

[0005] ②Hot sodium method and low-temperature sodium method: The hot sodium method uses pyridine and metallic sodium as raw materials, reacts at a temperature of 95°C, and then oxidizes with air to obtain 4,4′-bipyridine. This method has low pyridine utilization and low product purity. It also generates highly toxic terpyridine, and has the disadvantages of easy ignition and explosion risks. The low-temperature sodium method was first invented by the British ICI company. This method uses pyridine as a raw material. Pyridine and sodium liquid ammonia solution react at -20 to -30°C, and then air is introduced for oxidation to obtain 4,4′-bipyridine. Compared with the hot sodium method, the low-temperature sodium method has a high pyridine utilization rate and a high purity product. However, this method uses volatile liquid ammonia as a solvent, and the reaction must be carried out at low temperatures. The reaction conditions are relatively harsh, and liquid ammonia is highly corrosive and toxic, which poses a huge safety hazard.

[0006] ③ p-Formaldehyde pyridine method: With aluminum silicate or phosphate as catalyst, p-Formaldehyde pyridine reacts with acetaldehyde and ammonia in a nitrogen stream at a temperature of 300-450°C to obtain 4,4′-bipyridine. This method uses formaldehyde pyridine as a raw material, which is relatively expensive and has high production costs.

[0007] ④ Coupling reaction: mainly palladium-catalyzed Suzuki coupling reaction of 4-chloropyridine and 4-boronic acid pyridine and copper-catalyzed photocatalytic coupling reaction of 4-boronic acid pyridine. These methods require the use of expensive metal catalysts, high production costs, and harsh reaction conditions, which limits their industrial production. Summary of the invention

[0008] The purpose of the present invention is to solve the technical problems existing in the existing synthesis methods in the above-mentioned background technology and to provide a method for preparing 4,4'-bipyridine.

[0009] To achieve the above object, the present invention provides the following technical solutions:

[0010] A preparation method of 4,4'-bipyridine comprises: using pyridine as a raw material, sodium metal as a catalyst, and 1,3-dimethyl-2-imidazolidinone as a reaction solvent, dissolving the sodium metal in 1,3-dimethyl-2-imidazolidinone under a nitrogen or inert gas atmosphere, adding pyridine for reaction, cooling the reaction solution to 0-5°C, adding deionized water, and introducing air for oxidation reaction with or without adding N,N-dimethylformamide to obtain 4,4'-bipyridine.

[0011] The molar ratio of metallic sodium to pyridine is 1:1 to 1:5, preferably 1:2 to 1:4, more preferably 1:2 to 1:3, and most preferably 1:2.

[0012] The mass ratio of pyridine to 1,3-dimethyl-2-imidazolidinone is 1:2 to 1:8, preferably 1:2 to 1:4.

[0013] Specifically, the mass ratio of pyridine to 1,3-dimethyl-2-imidazolidinone can be 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, or 1:8.

[0014] The mass ratio of the deionized water to pyridine is 1:1.5 to 1:5, preferably 1:2 to 1:5, and most preferably 1:3 to 1:3.5.

[0015] The mass ratio of N,N-dimethylformamide to 1,3-dimethyl-2-imidazolidinone is 1:2 to 1:5, preferably 1:2 to 1:3.

[0016] The reaction temperature is 20-60°C, preferably 30-50°C, more preferably 30-40°C, further preferably 35-40°C, and most preferably 40°C; the reaction time is 12-48h, preferably 20-30h.

[0017] Preferably, the reaction solution is cooled to 0°C.

[0018] The temperature of the oxidation reaction is 20-25° C., and the time of the oxidation reaction is 10-12 hours.

[0019] As a further preferred technical solution of the preparation method of 4,4′-bipyridine of the present invention, the method comprises: first mixing metallic sodium and 1,3-dimethyl-2-imidazolidinone under a nitrogen or inert gas atmosphere, adding pyridine to react after the sodium is completely dissolved, cooling the reaction solution to 0-5° C., adding deionized water and N,N-dimethylformamide; and introducing air to carry out an oxidation reaction to obtain 4,4′-bipyridine.

[0020] As a further preferred technical scheme of the preparation method of 4,4′-bipyridine of the present invention, it also includes: after the reaction is completed, water is added to quench the reaction, and ethyl acetate is used for extraction, and the organic phase is taken, the organic phase is concentrated to remove the solvent, and silica gel column chromatography is performed, and the eluent is petroleum ether:ethyl acetate=4:1V / V, and 4,4′-bipyridine is separated and purified.

[0021] Compared with the prior art, the present invention has the following advantages:

[0022] (1) The present invention uses pyridine as raw material, which is cheap and easy to obtain, and the production cost is low.

[0023] (2) The present invention uses green and safe 1,3-dimethyl-2-imidazolidinone as a reaction solvent, which has the advantages of low toxicity, low pollution and high stability. At the same time, it has good solubility in metallic sodium and significantly improves the reaction activity of sodium. At the same time, N,N-dimethylformamide with a high dielectric constant is used as an additive to effectively promote the formation of the product. The yield of 4,4′-bipyridine in the present invention can generally reach more than 80%, and can reach more than 95% at most.

[0024] (3) The reaction conditions of the present invention are mild, the process is simple, and the operation is easy, thus having good industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 4,4′-bipyridine.

[0026] Figure 2 This is the carbon NMR spectrum of 4,4′-bipyridine. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is further described in detail below in conjunction with specific implementation methods.

[0028] The room temperature of the present invention refers to 20-25°C.

[0029] Example 1

[0030] In a pre-dried 250mL three-necked flask, add 47.4g of 1,3-dimethyl-2-imidazolidinone, add 2.3g of metallic sodium under a nitrogen atmosphere, start stirring (speed is 800rpm), after the sodium is completely dissolved, add 15.8g of pyridine, stir and react at a temperature of 40℃ (speed is 600rpm) for 30h. After the reaction is completed, the reaction solution is cooled to 0℃ in an ice water bath, and then 50g of deionized water is slowly added at 0℃, followed by 23.7g of N,N-dimethylformamide; after the addition of N,N-dimethylformamide is completed, air is introduced, and the product is stirred at room temperature (rotation speed is 600 rpm) for 12 hours for oxidation reaction. After the reaction is completed, the product is extracted with ethyl acetate 5 times to take the organic phase; the organic phase is concentrated to remove the solvent, and then subjected to silica gel column chromatography (200 mesh silica gel) with an eluent of petroleum ether:ethyl acetate = 4:1 V / V, and 4,4′-bipyridine 7.57 g (purity 98%) is separated and purified, with a yield (based on sodium, the same below) of 97.0% and a selectivity of 98.0%.

[0031] 1 H NMR (300MHz, DMSO-d6) δ8.72 (dd, J=4.2, J=1.8Hz, 4H), 7.82 (dd, J=4.5, 1.5Hz, 4H); 13 C NMR(75MHz,DMSO-d6)δ150.6,144.3,121.3.

[0032] Example 2

[0033] In a pre-dried 250mL three-necked flask, 47.4g of 1,3-dimethyl-2-imidazolidinone was added. Under a nitrogen atmosphere, 2.3g of metallic sodium was added, and stirring (speed was 800rpm) was started. After the sodium was completely dissolved, 15.8g of pyridine was added, and the reaction was stirred at a temperature of 50°C (speed was 600rpm) for 30h. After the reaction was completed, the reaction solution was cooled to 0°C in an ice water bath, and then 50g of deionized water was slowly added at 0°C, followed by 23.7g of N,N-dimethylformamide. After the addition of N,N-dimethylformamide was completed, air was introduced, and the oxidation reaction was carried out by stirring at room temperature (speed was 600rpm) for 12h. After the reaction was completed, the reaction solution was sampled, and liquid chromatography was used for quantitative analysis to calculate the yield and selectivity of the product. The results are shown in Table 1.

[0034] Example 3

[0035] In a pre-dried 250mL three-necked flask, 47.4g of 1,3-dimethyl-2-imidazolidinone was added. Under a nitrogen atmosphere, 2.3g of metallic sodium was added, and stirring (speed was 800rpm) was started. After the sodium was completely dissolved, 15.8g of pyridine was added, and the reaction was stirred at a temperature of 30°C (speed was 600rpm) for 30h. After the reaction was completed, the reaction solution was cooled to 0°C in an ice water bath, and then 50g of deionized water was slowly added at 0°C, followed by 23.7g of N,N-dimethylformamide. After the addition of N,N-dimethylformamide was completed, air was introduced, and the oxidation reaction was carried out by stirring at room temperature (speed was 600rpm) for 12h. After the reaction was completed, the reaction solution was sampled, and liquid chromatography was used for quantitative analysis to calculate the yield and selectivity of the product. The results are shown in Table 1.

[0036] Table 1: Effect of reaction temperature on the reaction

[0037] Temperature(℃) Yield (%) Selectivity (%) Example 3 30 84.3 95.0 Example 1 40 97.0 98.0 Example 2 50 78.0 75.4

[0038] As shown in Table 1, when the reaction temperature is 40°C, the yield and selectivity of the product 4,4′-bipyridine are good; when the reaction temperature is 30°C, the yield of the product decreases, and the selectivity of the product does not change much; when the reaction temperature is 50°C, the yield and selectivity of the product will decrease, indicating that when the temperature is too high, the by-products generated by the reaction will increase. Therefore, the optimal reaction temperature is 40°C.

[0039] Example 4

[0040] In a pre-dried 500mL three-necked flask, 71.1g of 1,3-dimethyl-2-imidazolidinone was added. Under a nitrogen atmosphere, 2.3g of metallic sodium was added, and stirring (speed was 800rpm) was started. After the sodium was completely dissolved, 23.7g of pyridine was added, and the reaction was stirred at a temperature of 40°C (speed was 600rpm) for 30h. After the reaction was completed, the reaction solution was cooled to 0°C in an ice water bath, and then 50g of deionized water was slowly added at 0°C, followed by 35.6g of N,N-dimethylformamide. After the addition of N,N-dimethylformamide was completed, air was introduced, and the oxidation reaction was carried out by stirring at room temperature (speed was 600rpm) for 12h. After the reaction was completed, the reaction solution was sampled, and liquid chromatography was used for quantitative analysis to calculate the yield and selectivity of the product. The results are shown in Table 2.

[0041] Example 5

[0042] In a pre-dried 500mL three-necked flask, 94.8g of 1,3-dimethyl-2-imidazolidinone was added, and 2.3g of metallic sodium was added under a nitrogen atmosphere. The stirring speed was turned on (the speed was 800rpm). After the sodium was completely dissolved, 31.6g of pyridine was added, and the reaction was stirred at a temperature of 40°C (the speed was 600rpm) for 30h. After the reaction was completed, the reaction solution was cooled to 0°C in an ice water bath, and then 50g of deionized water was slowly added at 0°C, followed by 47.4g of N,N-dimethylformamide. After the addition of N,N-dimethylformamide was completed, air was introduced, and the oxidation reaction was carried out by stirring at room temperature (the speed was 600rpm) for 12h. After the reaction was completed, the reaction solution was sampled, and the liquid chromatography quantitative analysis was performed to calculate the yield and selectivity of the product. The results are shown in Table 2.

[0043] Table 2: Effect of the molar ratio of sodium metal to pyridine on the reaction

[0044]

[0045]

[0046] As shown in Table 2, when the reaction molar ratio of sodium to pyridine is 1:2, the yield and selectivity are the best. When the reaction molar ratio of sodium to pyridine is 1:3 or 1:4, the yield and selectivity of the product will decrease. This is because the amount of pyridine far exceeds the amount of metallic sodium required for the reaction, which will lead to the formation of other by-products.

[0047] Example 6

[0048] In a pre-dried 250mL three-necked flask, 47.4g of 1,3-dimethyl-2-imidazolidinone was added. Under a nitrogen atmosphere, 2.3g of metallic sodium was added and stirring was started (speed was 800rpm). After the sodium was completely dissolved, 15.8g of pyridine was added and stirred at 40°C (speed was 600rpm) for 30h. After the reaction was completed, the reaction solution was cooled to 0°C in an ice water bath, and then 50g of deionized water was slowly added at 0°C. After the addition of N,N-dimethylformamide was completed, air was introduced and the oxidation reaction was carried out by stirring at room temperature (speed was 600rpm) for 12h. After the reaction was completed, the reaction solution was sampled and quantitatively analyzed by liquid chromatography to calculate the yield and selectivity of the product. The results are shown in Table 3.

[0049] Table 3: Effect of additives on the reaction

[0050] additive Yield (%) Selectivity (%) Example 6 none 85.0 88.0 Example 1 N,N-Dimethylformamide 97.0 98.0

[0051] As shown in Table 3, when N,N-dimethylformamide is added in the oxidation stage of the reaction, the selectivity and yield of 4,4′-bipyridine are significantly improved. It is speculated that N,N-dimethylformamide is a diluent with a high dielectric constant and can effectively promote the formation of 4,4′-bipyridine during the oxidation process.

[0052] Comparative Example 1

[0053] In a pre-dried 250mL three-necked flask, 47.4g of hexamethylphosphoric acid triamide was added, and 2.3g of metallic sodium was added under a nitrogen atmosphere. Stirring was started (speed was 800rpm). After the sodium was completely dissolved, 15.8g of pyridine was added, and the mixture was stirred at a temperature of 40°C (speed was 600rpm) for 30h. After the reaction was completed, the reaction solution was cooled to 0°C in an ice water bath, and then 50g of deionized water was slowly added at 0°C, followed by 23.7g of N,N-dimethylformamide. After the addition of N,N-dimethylformamide was completed, air was introduced, and the mixture was stirred at room temperature (speed was 600rpm) for 12h for oxidation reaction. After the reaction was completed, the reaction solution was sampled, and liquid chromatography was used for quantitative analysis to calculate the yield and selectivity of the product. The results are shown in Table 4.

[0054] Table 4: Effect of solvent on reaction

[0055] Solvents Yield (%) Selectivity (%) Example 1 1,3-Dimethyl-2-imidazolidinone 97.0 98.0 Comparative Example 1 Hexamethylphosphoric acid triamide 45.0 62.3

[0056] It can be seen from Table 4 that when hexamethylphosphoric acid triamide is used as the reaction solvent, the selectivity and yield of 4,4′-bipyridine are relatively low. The results show that 1,3-dimethyl-2-imidazolidinone, as a non-proton strong polar solvent, has excellent solubility for metallic sodium and improves the reaction activity of sodium.

[0057] Example 7

[0058] In a pre-dried 250mL three-necked flask, add 47.4g of 1,3-dimethyl-2-imidazolidinone, add 2.3g of metallic sodium under a nitrogen atmosphere, start stirring (speed is 800rpm), after the sodium is completely dissolved, add 15.8g of pyridine, stir and react at a temperature of 40℃ (speed is 600rpm) for 30h. After the reaction is completed, the reaction solution is cooled to 0℃ in an ice water bath, and then 50g of deionized water is slowly added at 0℃, followed by 15.8g of N,N-dimethylformamide; after the addition of N,N-dimethylformamide is completed, air is introduced, and the mixture is stirred at room temperature (rotation speed is 600 rpm) for 12 hours for oxidation reaction. After the reaction is completed, the mixture is extracted with ethyl acetate for 5 times, and the organic phase is taken; the organic phase is concentrated, the solvent is removed, and then silica gel column chromatography (200 mesh silica gel) is performed, and the eluent is petroleum ether:ethyl acetate=4:1V / V, and 4,4′-bipyridine 7.43 g (purity 98%) is separated and purified, with a yield of 95.2% and a selectivity of 97.20%.

[0059] The above describes the optional embodiments of the present invention to teach those skilled in the art how to implement and reproduce the present invention. The raw materials and equipment used in the present invention, unless otherwise specified, are all commonly used raw materials and equipment in the art; the methods used in the present invention, unless otherwise specified, are all conventional methods in the art. In order to teach the scheme of the present invention, some conventional technical aspects have been simplified and omitted. Those skilled in the art should understand that variations arising from this aspect are all within the scope of protection of the present invention.

Claims

1. A method for preparing 4,4'-bipyridine, characterized in that: include: With pyridine as a raw material, sodium metal as a catalyst and 1,3-dimethyl-2-imidazolidinone as a reaction solvent, in a nitrogen or inert gas atmosphere, sodium metal is first dissolved in 1,3-dimethyl-2-imidazolidinone, and then pyridine is added for reaction, the reaction liquid is cooled to 0-5°C, deionized water is added, and air is introduced for oxidation reaction with or without adding N,N-dimethylformamide to obtain 4,4'-bipyridine.

2. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: The molar ratio of the metallic sodium to the pyridine is 1:1 to 1:

5.

3. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: The molar ratio of the metallic sodium to the pyridine is 1:2 to 1:4, preferably 1:2 to 1:

3.

4. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: The mass ratio of pyridine to 1,3-dimethyl-2-imidazolidinone is 1:2 to 1:

8.

5. The method for preparing 4,4'-bipyridine according to claim 4, characterized in that: The mass ratio of pyridine to 1,3-dimethyl-2-imidazolidinone is 1:2 to 1:

4.

6. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: The mass ratio of the N,N-dimethylformamide to 1,3-dimethyl-2-imidazolidinone is 1:2 to 1:

5.

7. The method for preparing 4,4'-bipyridine according to claim 6, characterized in that: The mass ratio of the N,N-dimethylformamide to 1,3-dimethyl-2-imidazolidinone is 1:2 to 1:

3.

8. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: The reaction temperature is 20-60°C, preferably 30-50°C, more preferably 30-40°C, and most preferably 40°C; the reaction time is 12-48h, preferably 20-30h; the oxidation reaction temperature is 20-25°C, and the oxidation reaction time is 10-12h.

9. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: include: In a nitrogen or inert gas atmosphere, metallic sodium and 1,3-dimethyl-2-imidazolidinone are first mixed, and after the sodium is completely dissolved, pyridine is added to react, the reaction solution is cooled to 0-5°C, deionized water and N,N-dimethylformamide are added, and air is introduced to carry out an oxidation reaction to obtain 4,4'-bipyridine.

10. The method for preparing 4,4'-bipyridine according to claim 1, characterized in that: Also includes: After the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was collected, concentrated to remove the solvent, and subjected to silica gel column chromatography. The eluent was petroleum ether:ethyl acetate = 4:1 V / V. 4,4'-bipyridine was separated and purified.

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