Synthesis method of 4-hydroxyethyl pyridine compound

Abstract

The invention provides a synthetic method of a 4-hydroxyethylpyridine compound, which comprises the following step: by taking 4-methylpyridine and formaldehyde as raw materials, synthesizing a target product 4-hydroxyethylpyridine under the catalysis of Lewis acid. The reaction method has the advantages of cheap, easily available and recoverable starting raw materials, good one-way yield, high purity, high efficiency, simplicity and very high industrial application value.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing a 4-hydroxyethylpyridine compound. Background Technology

[0002] 4-Hydroxyethylpyridine is a high-value-added chemical product that can be used to synthesize 4-vinylpyridine and many other fine organic chemical intermediates. It has wide applications in polymer materials, surfactants, pharmaceuticals, pesticides and other fields. Therefore, it is of great significance to study synthesis methods with high yield and low waste.

[0003] The initial production process of 4-hydroxyethylpyridine mainly involved the reaction of 4-methylpyridine and formaldehyde under high temperature and pressure. However, under these conditions, the three hydrogens on the methyl group of 4-methylpyridine readily undergo addition reactions, forming di- and tri-addition products. These addition products may even undergo further dehydration to form unsaturated compounds. The extremely high temperature and pressure (British Patent GB901654) also pose significant challenges for industrial production. Later, the process was improved to allow the reaction of 4-methylpyridine and formaldehyde to occur under normal pressure, making the reaction conditions less demanding and increasing the feasibility of industrial production. According to the reaction mechanism, both acid and base catalysts can catalyze the reaction. Currently, base catalysts such as triethylamine (JP 2010270008 A) and triethanolamine (CN 106243016) are commonly used. These catalysts exhibit good selectivity, but the conversion rate of 4-methylpyridine is low, resulting in a relatively large amount of unreacted 4-methylpyridine and a small yield of the target product, 4-hydroxyethylpyridine, in each reaction. Unreacted 4-methylpyridine must be recovered, which increases energy consumption and reduces production efficiency in industrial applications. Here, we provide a method for synthesizing 4-hydroxyethylpyridine compounds using Lewis acid catalysis, which significantly improves the conversion rate of 4-methylpyridine and increases production efficiency. Summary of the Invention

[0004] The purpose of this invention is to provide a method for synthesizing 4-hydroxyethylpyridine compounds. This method provides a highly efficient catalyst, is simple to operate, uses readily available raw materials, and has high reactivity, which greatly improves production efficiency, reduces reaction costs, and has high industrial application value.

[0005] This invention provides a method for synthesizing 4-hydroxyethylpyridine compounds, the specific steps of which are as follows:

[0006] 4-Methylpyridine, formaldehyde, and water were added to a reaction flask in the specified proportions. Then, Lewis acid catalyst was added, and the temperature was raised to 100-150°C. The reaction was carried out for 1-24 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation, and the product 4-hydroxyethylpyridine was obtained by further vacuum distillation.

[0007]

[0008] Lewis acid is selected from one or more of AlCl3, MeAlCl2, FeCl3, FeCl2, CuCl2, Cu(OAc)2, ZnCl2, Zn(OTf)2, Zn(NTf2)2, Mg(OTf)2, BF3, SnCl4, and TiCl4, with ZnCl2 being preferred.

[0009] Formaldehyde is selected from paraformaldehyde, triformaldehyde, and formaldehyde aqueous solution, with triformaldehyde being preferred.

[0010] The molar ratio of 4-methylpyridine to formaldehyde is 0.1-20:1, preferably 0.5-10:1.

[0011] The molar ratio of formaldehyde to leucic acid catalyst is 10-1000:1, preferably 10-100:1. The mass ratio of 4-methylpyridine to water is 0.1-100:1, preferably 1-50:1. The catalytic reaction conditions are as follows:

[0012] The reaction temperature is 50℃-180℃, preferably 100℃-150℃.

[0013] The reaction time is 1-24 hours, preferably 5-15 hours.

[0014] The reaction method uses inexpensive, readily available, and recyclable starting materials, has a good single-pass yield, high purity, high efficiency, and is simple, making it highly valuable for industrial applications.

[0015] The present invention has the following advantages:

[0016] 1. The starting materials are readily available and easy to recycle.

[0017] 2. The reaction conditions are mild, resulting in high reactivity, high yield, and high efficiency.

[0018] 3. The catalyst is readily available, which greatly reduces the reaction cost, and the entire process is suitable for industrial production. Attached Figure Description

[0019] Figure 1 The 1H NMR spectrum of 4-hydroxyethylpyridine prepared in Example 1;

[0020] Figure 2 The carbon NMR spectrum of 4-hydroxyethylpyridine prepared in Example 1. Detailed Implementation

[0021] The following examples will further illustrate the present invention, but are not intended to limit the invention. Nuclear magnetic resonance (NMR) measurements were performed using a Bruker 400 NMR spectrometer, and gas chromatography was performed using an Agilent 7820A.

[0022] Example 1

[0023] 93 g (1 mol) of 4-methylpyridine, 12 g (0.4 mol) of paraformaldehyde, and 30 g of water were added to a reaction flask. Then, 5.3 g (0.04 mol) of AlCl3 was added, and the temperature was raised to 100 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 27.3 g (0.22 mol). Gas chromatography analysis showed that the purity was 98.2%.

[0024] 1 H NMR (400MHz, DMSO) δ8.46(dd,J=4.4,1.6Hz,2H),7.26(dd,J=4.4,1.6Hz,2H),4.78(t,J=5.2Hz,1H),3.67(td,J=6.6,5.2Hz,2H),2.75(t,J=6.7Hz,2H)..

[0025] 13 C NMR (400MHz, DMSO) δ149.7,149.2,125.0,61.4,38.5.

[0026] Example 2

[0027] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 10 g of water were added to a reaction flask. Then, 6.7 g (0.05 mol) of CuCl2 was added, and the temperature was raised to 110 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100 and 110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 29.8 g (0.24 mol). Gas chromatography analysis showed that the purity was 99.2%.

[0028] Example 3

[0029] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 10 g of water were added to a reaction flask, followed by 8.1 g (0.05 mol) of FeCl3. The temperature was raised to 110 °C, and the reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100 and 110 °C was collected. NMR analysis identified the product as 4-hydroxyethylpyridine, weighing 18.7 g (0.15 mol). Gas chromatography analysis showed a purity of 99.3%.

[0030] Example 4

[0031] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 10 g of water were added to a reaction flask, followed by 6.8 g (0.05 mol) of ZnCl2. The temperature was raised to 110 °C, and the reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100 and 110 °C was collected. NMR analysis identified the product as 4-hydroxyethylpyridine, weighing 25.6 g (0.20 mol). Gas chromatography analysis showed a purity of 99.1%.

[0032] Example 5

[0033] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 10 g of water were added to a reaction flask. Then, 6.8 g (0.05 mol) of ZnCl2 was added, and the temperature was raised to 120 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 30.5 g (0.25 mol). Gas chromatography analysis showed that the purity was 99.6%.

[0034] Example 6

[0035] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 15 g of water were added to a reaction flask, followed by 6.8 g (0.05 mol) of ZnCl2. The temperature was raised to 120 °C, and the reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 32.6 g (0.26 mol). Gas chromatography analysis showed that the purity was 99.5%.

[0036] Example 7

[0037] 93 g (1 mol) of 4-methylpyridine and 40.5 g (0.5 mol) of 37% formaldehyde aqueous solution were added to a reaction flask, followed by 6.8 g (0.05 mol) of ZnCl2. The temperature was raised to 120 °C, and the reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 20.7 g (0.17 mol). Gas chromatography analysis showed that the purity was 99.5%.

[0038] Example 8

[0039] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 15 g of water were added to a reaction flask. Then, 6.8 g (0.05 mol) of ZnCl2 was added, and the temperature was raised to 120 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 35.9 g (0.29 mol). Gas chromatography analysis showed that the purity was 99.2%.

[0040] Example 9

[0041] 93 g (1 mol) of 4-methylpyridine, 15 g (0.5 mol) of paraformaldehyde, and 5 g of water were added to a reaction flask. Then, 6.8 g (0.05 mol) of ZnCl2 was added, and the temperature was raised to 120 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 21.4 g (0.17 mol). Gas chromatography analysis showed that the purity was 99.3%.

[0042] Example 10

[0043] 93 g (1 mol) of 4-methylpyridine, 30 g (1 mol) of paraformaldehyde, and 30 g of water were added to a reaction flask. Then, 6.8 g (0.05 mol) of ZnCl2 was added, and the temperature was raised to 120 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 70.3 g (0.57 mol). Gas chromatography analysis showed that the purity was 99.2%.

[0044] Example 11

[0045] 93 g (1 mol) of 4-methylpyridine, 21 g (0.7 mol) of paraformaldehyde, and 20 g of water were added to a reaction flask. Then, 6.8 g (0.05 mol) of ZnCl2 was added, and the temperature was raised to 120 °C. The reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 50.2 g (0.41 mol). Gas chromatography analysis showed that the purity was 99.2%.

[0046] Example 12

[0047] 93 g (1 mol) of 4-methylpyridine, 21 g (0.7 mol) of paraformaldehyde, and 20 g of water were added to a reaction flask, followed by 1.4 g (0.01 mol) of ZnCl2. The temperature was raised to 120 °C, and the reaction was carried out for 12 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100 and 110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 49.4 g (0.40 mol). Gas chromatography analysis showed that the purity was 99.5%.

[0048] Example 13

[0049] 93 g (1 mol) of 4-methylpyridine, 21 g (0.7 mol) of paraformaldehyde, and 20 g of water were added to a reaction flask, followed by 1.4 g (0.01 mol) of ZnCl2. The temperature was raised to 120 °C, and the reaction was carried out for 24 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100 and 110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 52.9 g (0.43 mol). Gas chromatography analysis showed that the purity was 99.6%.

[0050] Example 14

[0051] 93 g (1 mol) of 4-methylpyridine, 21 g (0.7 mol) of paraformaldehyde, and 20 g of water were added to a reaction flask, followed by 1.4 g (0.01 mol) of ZnCl2. The temperature was raised to 120 °C, and the reaction was carried out for 15 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100 and 110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 52.1 g (0.42 mol). Gas chromatography analysis showed that the purity was 99.4%.

[0052] Example 15

[0053] 93 g (1 mol) of 4-methylpyridine, 21 g (0.7 mol) of paraformaldehyde, and 20 g of water were added to a reaction flask. Then, 2.6 g (0.01 mol) of SnCl4 was added, the temperature was raised to 120 °C, and the reaction was carried out for 15 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 23.7 g (0.19 mol). Gas chromatography analysis showed that the purity was 99.4%.

[0054] Example 16

[0055] 46.5 g (0.5 mol) of 4-methylpyridine, 30 g (1 mol) of paraformaldehyde, and 20 g of water were added to a reaction flask. Then, 1.4 g (0.01 mol) of ZnCl2 was added. The temperature was raised to 120 °C, and the reaction was carried out for 15 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation. Vacuum distillation was continued, and the fraction with a boiling range between 100-110 °C was collected. NMR analysis showed that the product was 4-hydroxyethylpyridine, weighing 16.0 g (0.13 mol). Gas chromatography analysis showed that the purity was 99.1%.

[0056] The above-described embodiments are merely examples of implementation methods of the present invention, but should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements are all within the scope of protection of the present invention.

Claims

1. A method for synthesizing 4-hydroxyethylpyridine, characterized in that: Using 4-methylpyridine and formaldehyde as raw materials, a reaction was carried out under Lewis acid catalysis, and the compound 4-hydroxyethylpyridine was obtained by vacuum distillation after the reaction was completed.

2. The synthesis method according to claim 1, characterized in that: The 4-hydroxyethylpyridine compound has the following structure:

3. The synthesis method according to claim 1, characterized in that, The reaction equation is shown below:

4. The synthesis method according to claim 1, characterized in that: Formaldehyde is selected from one or more of paraformaldehyde, triformaldehyde, and formaldehyde aqueous solution, with triformaldehyde being preferred.

5. The synthesis method according to claim 1, characterized in that: Lewis acid is selected from one or more of AlCl3, MeAlCl2, FeCl3, FeCl2, CuCl2, Cu(OAc)2, ZnCl2, Zn(OTf)2, Zn(NTf2)2, Mg(OTf)2, BF3, SnCl4, and TiCl4, with ZnCl2 being preferred.

6. The synthesis method according to claim 1, characterized in that: The molar ratio of 4-methylpyridine to formaldehyde is 0.1-20:1, preferably 0.5-10:1, and more preferably 0.5-8:1; The molar ratio of formaldehyde to leucic acid catalyst is 10-1000:1, preferably 10-500:1, and more preferably 10-100:1; The mass ratio of 4-methylpyridine to water is 0.1-100:1, preferably 1-80:1, and more preferably 1-50:

1.

7. The synthesis method according to claim 1, characterized in that: The reaction temperature is 50℃-180℃, preferably 100℃-170℃, and more preferably 100℃-150℃; The reaction time is 1-24 hours, preferably 5-15 hours, and more preferably 5-12 hours.

8. The synthesis method according to any one of claims 1-7, characterized in that: The method is as follows: 4-Methylpyridine, formaldehyde, and water were added to a reaction flask in a specific ratio. Then, Lewis acid catalyst was added, and the temperature was raised to 50°C-180°C. The reaction was carried out for 1-24 hours. After cooling, water and unreacted pyridine were removed by vacuum distillation, and the product 4-hydroxyethylpyridine was obtained by further vacuum distillation.

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