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Preparation method of 2-aminopyridine-4-methyl alcohol

A technology of aminopyridine and methanol, which is applied in the field of preparation of 2-aminopyridine-4-methanol, can solve the problems of difficult industrial production, low process yield, serious environmental pollution, etc., to avoid the generation of waste liquid and waste residue, shorten the Process flow and the effect of reducing production cost

Inactive Publication Date: 2014-03-26
ZHEJIANG UNIV +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This not only increases the cost of waste solid and waste liquid treatment, but also seriously pollutes the environment.
The yield of this process is low, and it is not easy for industrialized production
[0007] The acetyl group is removed simultaneously during the third step of the esterification reaction, and the overall reaction yield of this step can only reach about 34%, which is relatively low and is not suitable for industrial production.
In the fourth reduction reaction, it is necessary to use expensive lithium tetrahydrogen aluminum, which is costly and difficult to post-process.
There is no 2-aminopyridine-4-methanol preparation method suitable for industrialized production both at home and abroad at present,

Method used

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  • Preparation method of 2-aminopyridine-4-methyl alcohol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Preparation of methyl 2-chloroisonicotinate

[0026] Add methanol (316mL, 250g) and 2-chloroisonicotinic acid (50.0g, 0.32mol) into the four-neck flask, cool down to 0°C, add thionyl chloride (114.2g, 0.96mol) dropwise, and control the temperature at 0°C After the dropwise addition, raise the temperature to room temperature and stir for 30 minutes, raise the temperature and reflux for 4 hours, and conduct thin-layer chromatography analysis. After the reaction is completed, methanol is distilled off, dissolved in 200 mL of water, and sodium carbonate aqueous solution (10% by mass) is added dropwise to adjust the pH=8- 9. Extract with 300mL×2 ethyl acetate, wash the organic phase once with water, dry sodium sulfate, and concentrate to obtain colorless liquid methyl 2-chloroisonicotinate (51.3g, yield 93.5%).

[0027] (2) Preparation of 2-chloropyridine-4-methanol

[0028] Add tetrahydrofuran (289mL, 257.0g), methyl 2-chloroisonicotinate (51.4g, 0.30mol) and lithium c...

Embodiment 2

[0032] (1) Preparation of ethyl 2-chloroisonicotinate

[0033] Add ethanol (643mL, 500.0g), 2-chloroisonicotinic acid (50.0g, 0.32mol) into the four-neck flask, cool down to 3°C, add thionyl chloride (38.1g, 0.32mol) dropwise, and control the temperature for 3 ℃, after the dropwise addition, raise the temperature to room temperature and stir for 30min, raise the temperature and reflux for 5h, analyze by thin-layer chromatography, after the reaction is completed, distill off ethanol, add 200mL water to dissolve, add dropwise sodium carbonate aqueous solution (10% by mass) to adjust pH=8 -9, extracted with ethyl acetate 300mL×2, the organic phase was washed once with water, dried and concentrated to obtain colorless liquid ethyl 2-chloroisonicotinate (53.8g, yield 90.6%)

[0034] (2) Preparation of 2-chloropyridine-4-methanol

[0035] Add ethanol (606mL, 478.4g), ethyl 2-chloroisonicotinate (55.6g, 0.30mol), zinc chloride (26.6g, 0.20mol) to a four-neck flask, cool down to 5°C,...

Embodiment 3

[0039] (1) Preparation of isopropyl 2-chloroisonicotinate

[0040] Add isopropanol (954mL, 750.0g), 2-chloroisonicotinic acid (50.0g, 0.32mol) into the four-neck flask, cool down to 5°C, add thionyl chloride (57.1g, 0.48mol) dropwise, control The temperature is 5°C, the dropwise addition is completed, raised to room temperature and stirred for 30 minutes, heated to reflux for 6 hours, analyzed by thin-layer chromatography, after the reaction is completed, evaporate isopropanol, add 200mL of water to dissolve, add dropwise sodium carbonate aqueous solution (10% by mass) Adjust pH=8-9, extract with ethyl acetate 300mL×2, wash the organic phase once with water, dry sodium sulfate, concentrate to obtain colorless liquid isopropyl 2-chloroisonicotinate (62.6g, yield 98.0%)

[0041] (2) Preparation of 2-chloropyridine-4-methanol

[0042] Add methanol (211mL, 166.8g), isopropyl 2-chloroisonicotinate (59.8g, 0.30mol) and aluminum chloride (68g, 0.51mol) to a four-neck flask, cool dow...

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Abstract

The invention discloses a preparation method of 2-aminopyridine-4-methyl alcohol, which comprises the following steps: 2-chloropyridine-4-carboxylic acid is used as a raw material to be in esterification reaction with micromolecule alcohol so as to obtain 2-chloropyridine-4-carboxylic acid ester under the function of sulfoxide chloride; 2-chloropyridine-4-carboxylic acid ester is reduced to 2-chloropyridine-4-methyl alcohol under the function of a reducing agent; finally, 2-chloropyridine-4-methyl alcohol and ammonia water are in ammonolysis reaction so as to obtain 2-aminopyridine-4-methyl alcohol under the catalysis of a copper catalyst. With adoption of the preparation method, the process route is short, generation of large amount of waste liquid and waste residue is avoided, and pollution to the environment is reduced; in addition, the product yield is high, the copper-class catalyst in the ammonolysis reaction can be recycled, the production cost is reduced, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of 2-aminopyridine-4-methanol. Background technique [0002] 2-Aminopyridine-4-methanol is an important fine chemical intermediate, which is widely used in organic intermediates such as medicine and pesticides. At present, there is no public report on the method of synthesizing 2-aminopyridine-4-methanol in China. [0003] The more common production route used in enterprises is to obtain the product through amino protection of 2-amino-4-picoline, oxidation of methyl group, esterification of carboxylate, and reduction of ester. The production process is as follows: [0004] [0005] The first step of acylation and the second step of oxidation reaction can adopt the method disclosed in the patent document whose publication number is CN102249992A, wherein, in the first step of acylation reaction, the acylating reagent can adopt acetyl c...

Claims

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Application Information

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IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 张世界孙国庆张玲玲戴立言王晓钟陈英奇
Owner ZHEJIANG UNIV
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