Environment-friendly preparation method of substituted oxazole compound

A compound, the technology of oxazole, which is applied in the field of environmentally friendly preparation of oxazole compounds, can solve the problems of large amount of waste water, high product cost, unfavorable environmental protection, etc.

Active Publication Date: 2020-10-20
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The preparation process of this method is cumbersome, high energy consumption, need to use dehydrating agent such as phosphorus oxychloride to close ring, large amount of waste water, high waste salt content, poor atom economy, not conducive to environmental protection, high product cost

Method used

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  • Environment-friendly preparation method of substituted oxazole compound
  • Environment-friendly preparation method of substituted oxazole compound
  • Environment-friendly preparation method of substituted oxazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: 4-methyl-5-ethoxy-2-ethoxycarbonyl oxazole (Ⅰ 1 ) preparation

[0055] To a 250 ml flask was added 100 g of chloroform, 33.3 g (0.1 mol) of triphenylphosphine dichloride and 21.7 g (0.1 mol) of N-ethoxyoxalyl-α-alanine ethyl ester, 20-25 At ℃, add 20.2 grams (0.2 moles) of triethylamine dropwise within 2 hours, then react at 35-40℃ for 1 hour, check that the reaction of raw materials is complete, add 30 grams of water, separate layers, and extract the obtained water layer twice with chloroform (Using 30 grams in total), the organic phases are combined, and the organic phase atmospheric distillation reclaims chloroform, and then underpressure distillation obtains 18.8 grams of 4-methyl-5-ethoxyl-2-ethoxycarbonyloxazole, yield 94.4 %, GC purity 99.9%; the main component of the residue after vacuum distillation is triphenylphosphine oxide, which can be used repeatedly as a dehydrating agent.

[0056] The NMR data of the resulting product are as follows:

[00...

Embodiment 2

[0059] Example 2: 4-methyl-5-ethoxy-2-ethoxycarbonyl oxazole (Ⅰ 1 ) preparation

[0060] In 500 milliliters of four-necked flasks, add 100 grams of toluene, 3.4 grams (0.01 moles) triphenylphosphine dichloride, 21.7 grams (0.1 moles) N-ethoxy oxalyl-α-alanine ethyl ester, 20.8 grams ( 0.206 moles) of triethylamine, dropwise add a solution of 9.9 grams (0.1 moles) of phosgene and 50 grams of toluene between 25-30°C, dropwise addition is completed in 2 hours, then react at 65-70°C for 1 hour, and detect that the reaction of raw materials is complete. Add 30 grams of water, separate layers, and the gained water layer is extracted twice with toluene (using 30 grams in total), the organic phases are combined, and the organic phase is distilled under normal pressure to reclaim toluene, and then distilled under reduced pressure to obtain 4-methyl-5-ethoxy - 18.9 g of 2-ethoxycarbonyloxazole, yield 94.9%, GC purity 99.9%; the main component of the residue after vacuum distillation is...

Embodiment 3

[0061] Example 3: 4-methyl-5-ethoxy-2-ethoxycarbonyl oxazole (Ⅰ 1 ) preparation

[0062] Add 100 g of toluene, 27.8 g (0.1 mole) of triphenylphosphine oxide, 21.7 g (0.1 mole) of N-ethoxyoxalyl-α-alanine ethyl ester into a 500 ml four-neck flask, at 20-25°C , add dropwise a solution of 100 grams of toluene and 9.9 grams (0.033 moles) of triphosgene to the above-mentioned 500 milliliter four-necked flask within 2 hours, and dropwise add 24.3 grams (0.24 moles) of triethylamine at the same time. 1 hour, detection raw material reaction is complete, adds 30 grams of water, layering, gained water layer is extracted twice with toluene (uses 30 grams altogether), merges organic phase, organic phase normal pressure distillation reclaims toluene, then underpressure distillation obtains 4- Methyl-5-ethoxy-2-ethoxycarbonyloxazole 19.1 g, yield 96%, GC purity 99.9%; the main component of the residue after vacuum distillation is triphenylphosphine oxide, which can be used repeatedly as a ...

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Abstract

The invention provides an environment-friendly preparation method of a substituted oxazole compound. According to the method, N-substituted formyl-alpha-substituted glycine ester is used as an initialraw material, a cyclization reaction is performed under the action of a dehydrating agent (trisubstituted aryl phosphine dichloride, a combination of trisubstituted aryl phosphine dichloride and an acyl chloride reagent, or a combination of trisubstituted aryl phosphine oxide and an acyl chloride reagent) and organic amine to obtain the substituted oxazole compound, and the obtained substituted oxazole compound can be further saponified and de-carboxylated to obtain a medical intermediate 4-substituent-5-substituent oxy-oxazole. In the reaction process, the byproduct (trisubstituted aryl phosphine oxide) can be repeatedly used, the cost is reduced; dehydrating agents (phosphorus oxychloride and phosphorus pentoxide), which are high in price and generate a large amount of wastewater, are not used; a high-temperature cyclization reaction is not needed, the process is simple, operation is easy and convenient, no phosphorus-containing wastewater is discharged in the technological process,and the preparation method is environmentally friendly, low in cost, high in atom economy, high in target product yield and purity, and suitable for industrial application.

Description

technical field [0001] The invention relates to an environment-friendly preparation method of a substituted oxazole compound, which belongs to the technical field of pharmaceutical biochemical industry. Background technique [0002] Oxazole compounds are a class of important intermediates for the preparation of bioactive substances, for example, 4-methyl-5-alkoxy oxazole is an important intermediate for the synthesis of vitamin B6. Vitamin B6 is one of the essential vitamins, which plays a key role in the growth of animals and humans, and is therefore widely used in the fields of medicine, food, feed additives and cosmetics industries. [0003] At present, the preparation of oxazole compound 4-methyl-5-alkoxy oxazole (taking 4-methyl-5-ethoxy oxazole as an example) mainly contains the following two methods: [0004] 1. Formyl cyclization method [0005] The literature "J.Am.Chem.Soc.2007,129,4440-4455" and the literature "European Journal of Medicinal Chemistry 62(2013) 48...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/42
CPCC07D263/42Y02P20/10
Inventor 周立山王成威刘宁宁戚聿新
Owner XINFA PHARMA
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