Industrial preparation method of 4-methyl-5-ethyoxyl oxazole

Abstract

The invention provides an industrial preparation method of 4-methyl-5-ethyoxyl oxazole. The industrial preparation method of the 4-methyl-5-ethyoxyl oxazole comprises the following steps: (1) adding N-ethyoxyloxalyl alanine ethyl ester, bis(trichloromethyl)carbonate, chloroform and a catalyst at a certain ratio into a cyclization reaction kettle in sequence, wherein the catalyst is pyridine or acyl chloride, the components are dropwise added at the temperature of 0-20 DEG C for 5-10 hours and are subjected to cyclization reaction at the temperature of 30-60 DEG C, and heat is preserved for 2-4 hours; (2) washing the product of reaction with water after finishing the cyclization reaction, pumping the product into a saponification pot, reclaiming chloroform, dropwise adding a 20% alkali liquor, adjusting the pH value of the product to 14, preserving heat, and removing the generated ethanol; and (3) decarboxylating, neutralizing, distilling, and rectifying to obtain the 4-methyl-5-ethyoxyl oxazole. The industrial preparation method of the 4-methyl-5-ethyoxyl oxazole has the advantages of mild cyclization reaction condition and short cyclization reaction period. In addition, the cyclization reaction has no special requirement for equipment and consumes less energy, and 4-methyl-5-ethyoxyl oxazole is high in content, yield and purity.

Description

technical field

[0001] The invention relates to a preparation method of 4-methyl-5-ethoxy-oxazole, a key intermediate of vitamin B6. Background technique

[0002] 4-Methyl-5-ethoxyoxazole is one of the main intermediates for the synthesis of vitamin B6. At present, the oxazole production process mainly adopts N-ethoxyoxalylalanine ethyl ester / phosphoryl trichloride / triethylamine / toluene system, and the main process steps are: cyclization-extraction-saponification-acid analysis - Decarboxylation - Neutralization - Distillation.

[0003] Chinese application publication number CN 102321043A, the name of the invention is a preparation method of 4-methyl-5-ethoxy-oxazole of vitamin B6, which also uses N-ethoxyoxalylalanine ethyl ester / phosphorus oxychloride / Triethylamine / dimethylformamide as cyclodehydrating agent.

[0004] Chinese application publication number CN 103435568 A also uses N-ethoxyoxalyl-alpha-aminopropionic acid ethyl ester as raw material to carry out cyclizat...

Examples

example 1

[0033] Drop into 275kg (1.267kmol) N-ethoxyoxalylalanine ethyl ester successively in 3000 liters of reactors, 288kg (2.85kmol) triethylamine, catalyst acetyl chloride 2.9kg (37mol), above-mentioned solution is stirred and mixed, Control the dropping temperature below 20°C, then lower the temperature to below 5°C, add 150kg (0.507kmol) solid phosgene and 1206kg (10.136kmol) chloroform solution dropwise, and complete the dropwise addition in 6 hours. After the dropwise addition, keep the temperature at 40°C for 3 Hour. Add 500 liters of water, extract the aqueous layer twice with 200 liters of chloroform, then recover the organic solvent chloroform, add liquid caustic soda to adjust the pH to 14, keep the temperature at 60°C for 2 hours, and recover ethanol. Add aqueous hydrochloric acid to adjust the pH to 3 for acid analysis (acid analysis), heat to 60°C for decarboxylation for 2 hours, and react until no bubbles are generated, which is the end point. Cool down to room temper...

example 2

[0035] Drop into 275kg (1.267kmol) N-ethoxyoxalylalanine ethyl ester successively in 3000 liters of reactors, 288kg (2.85kmol) triethylamine, catalyzer pyridine 3.0kg (37mol), above-mentioned solution is stirred and mixed, control The dropping temperature is below 20°C, then the temperature is lowered to below 0°C, 150kg (0.507kmol) of solid phosgene and 1206kg (10.136kmol) of chloroform solution are added dropwise, and the dropwise addition is completed in 5 hours. After the dropwise addition, the temperature is kept at 30°C for 4 hours . Add 500 liters of water, extract the aqueous layer twice with 200 liters of chloroform, then recover the organic solvent chloroform, add liquid caustic soda to adjust the pH to 14, keep the temperature at 60°C for 2 hours, and recover ethanol. Add aqueous hydrochloric acid to adjust the pH to 3 for acid analysis (acid analysis), heat to 60°C for decarboxylation for 2 hours, and react until no bubbles are generated, which is the end point. A...

example 3

[0037] Drop into 285kg (1.313kmol) N-ethoxyoxalylalanine ethyl ester successively in 3000 liters of reactors, 531kg (5.252kmol) triethylamine, catalyst acetyl chloride 1.02kg (13mol), above-mentioned solution is stirred and mixed, Control the dropping temperature below 20°C, then lower the temperature to below 10°C, add 234kg (0.788kmol) of solid phosgene and 784kg (6.565kmol) of chloroform solution dropwise, and complete the dropwise addition in 10 hours. Hour. Add 500 liters of water, extract the aqueous layer twice with 200 liters of chloroform, then recover the organic solvent chloroform, add liquid caustic soda to adjust the pH to 14, keep the temperature at 60°C for 2 hours, and recover ethanol. Add aqueous hydrochloric acid to adjust the pH to 3 for acid analysis (acid analysis), heat to 60°C for decarboxylation for 2 hours, and react until no bubbles are generated, which is the end point. Add liquid caustic soda to adjust the pH to 12, and then obtain 127 kg of interm...

technical field

[0001] The invention relates to a preparation method of 4-methyl-5-ethoxy-oxazole, a key intermediate of vitamin B6. Background technique

[0002] 4-Methyl-5-ethoxyoxazole is one of the main intermediates for the synthesis of vitamin B6. At present, the oxazole production process mainly adopts N-ethoxyoxalylalanine ethyl ester / phosphoryl trichloride / triethylamine / toluene system, and the main process steps are: cyclization-extraction-saponification-acid analysis - Decarboxylation - Neutralization - Distillation.

[0003] Chinese application publication number CN 102321043A, the name of the invention is a preparation method of 4-methyl-5-ethoxy-oxazole of vitamin B6, which also uses N-ethoxyoxalylalanine ethyl ester / phosphorus oxychloride / Triethylamine / dimethylformamide as cyclodehydrating agent.

[0004] Chinese application publication number CN 103435568 A also uses N-ethoxyoxalyl-alpha-aminopropionic acid ethyl ester as raw material to carry out cyclizat...

Examples

example 1

[0033] Drop into 275kg (1.267kmol) N-ethoxyoxalylalanine ethyl ester successively in 3000 liters of reactors, 288kg (2.85kmol) triethylamine, catalyst acetyl chloride 2.9kg (37mol), above-mentioned solution is stirred and mixed, Control the dropping temperature below 20°C, then lower the temperature to below 5°C, add 150kg (0.507kmol) solid phosgene and 1206kg (10.136kmol) chloroform solution dropwise, and complete the dropwise addition in 6 hours. After the dropwise addition, keep the temperature at 40°C for 3 Hour. Add 500 liters of water, extract the aqueous layer twice with 200 liters of chloroform, then recover the organic solvent chloroform, add liquid caustic soda to adjust the pH to 14, keep the temperature at 60°C for 2 hours, and recover ethanol. Add aqueous hydrochloric acid to adjust the pH to 3 for acid analysis (acid analysis), heat to 60°C for decarboxylation for 2 hours, and react until no bubbles are generated, which is the end point. Cool down to room temper...

example 2

[0035] Drop into 275kg (1.267kmol) N-ethoxyoxalylalanine ethyl ester successively in 3000 liters of reactors, 288kg (2.85kmol) triethylamine, catalyzer pyridine 3.0kg (37mol), above-mentioned solution is stirred and mixed, control The dropping temperature is below 20°C, then the temperature is lowered to below 0°C, 150kg (0.507kmol) of solid phosgene and 1206kg (10.136kmol) of chloroform solution are added dropwise, and the dropwise addition is completed in 5 hours. After the dropwise addition, the temperature is kept at 30°C for 4 hours . Add 500 liters of water, extract the aqueous layer twice with 200 liters of chloroform, then recover the organic solvent chloroform, add liquid caustic soda to adjust the pH to 14, keep the temperature at 60°C for 2 hours, and recover ethanol. Add aqueous hydrochloric acid to adjust the pH to 3 for acid analysis (acid analysis), heat to 60°C for decarboxylation for 2 hours, and react until no bubbles are generated, which is the end point. A...

example 3

[0037] Drop into 285kg (1.313kmol) N-ethoxyoxalylalanine ethyl ester successively in 3000 liters of reactors, 531kg (5.252kmol) triethylamine, catalyst acetyl chloride 1.02kg (13mol), above-mentioned solution is stirred and mixed, Control the dropping temperature below 20°C, then lower the temperature to below 10°C, add 234kg (0.788kmol) of solid phosgene and 784kg (6.565kmol) of chloroform solution dropwise, and complete the dropwise addition in 10 hours. Hour. Add 500 liters of water, extract the aqueous layer twice with 200 liters of chloroform, then recover the organic solvent chloroform, add liquid caustic soda to adjust the pH to 14, keep the temperature at 60°C for 2 hours, and recover ethanol. Add aqueous hydrochloric acid to adjust the pH to 3 for acid analysis (acid analysis), heat to 60°C for decarboxylation for 2 hours, and react until no bubbles are generated, which is the end point. Add liquid caustic soda to adjust the pH to 12, and then obtain 127 kg of interm...

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