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Preparation method for 3-amino-5-methylisoxazole

A technology of methylisoxazole and amino, which is applied in the field of preparation of 3-amino-5-methylisoxazole, which achieves the effects of convenient purchase, transportation and use, reduced labor protection, and low price

Active Publication Date: 2018-02-23
浦拉司科技(上海)有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the above methods, the use of highly toxic solvents chloroform or carbon tetrachloride is unavoidable. At the same time, there are either strong oxidation conditions or the separation of isomers. For the pharmaceutical field, the amount of single impurities needs to be strictly controlled. , especially isomers with very similar properties adversely affect

Method used

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  • Preparation method for 3-amino-5-methylisoxazole

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] The first step, in the 500mL reaction bottle, sodium hydride (12.0g, 0.3mol, 60%) was added in the acetonitrile (10.3g, 0.25mol) solution that was dissolved in 120mL tetrahydrofuran, then added ethyl acetate (26.4g, 0.3mol ), heated to reflux for 4 hours, down to room temperature, quenched with ice water, adjusted to pH 5-6 with 2N HCl, extracted with ethyl acetate, dried the organic layer over anhydrous sodium sulfate, concentrated the solvent to obtain 18.9 g of acetoacetonitrile, GC purity 96%, yield 91%.

[0026] In the second step, in a 1L reaction flask, dissolve the product acetoacetonitrile (18.9g, 0.23mol) obtained in the previous step in 600mL of methanol, add p-toluenesulfonylhydrazide (40.2g, 0.22mol), heat and reflux for 2 hours, and analyze the crystal, filtered to obtain 50.3 g of hydrazone as a white crystalline solid, with an HPLC purity of 99% and a yield of 88%.

[0027] The third step, in the 500mL reaction bottle, add hydroxylamine hydrochloride (1...

Embodiment 2

[0029] In the first step, in a 500mL reaction flask, sodium hydride (14g, 0.35mol, 60%) was added into a solution of acetonitrile (10.3g, 0.25mol) dissolved in 120mL of tetrahydrofuran, and then methyl acetate (25.9g, 0.35mol) was added , heated to reflux for 4 hours, lowered to room temperature, quenched with ice water, adjusted to pH 5-6 with 2N HCl, extracted with ethyl acetate, dried the organic layer over anhydrous sodium sulfate, concentrated the solvent to obtain 19.1 g of acetoacetonitrile, GC purity 96 %, yield 92%.

[0030] In the second step, in a 1L reaction flask, dissolve the product acetoacetonitrile (19.1g, 0.23mol) obtained in the previous step in 600mL ethanol, add p-toluenesulfonyl hydrazide (42.8g, 0.23mol), heat and reflux for 2 hours, and analyze the crystal, filtered to obtain 52.0 g of hydrazone as a white crystalline solid, with an HPLC purity of 99% and a yield of 90%.

[0031] The third step, in the 500mL reaction flask, add hydroxylamine hydrochlor...

Embodiment 3

[0033] In the first step, in a 500mL reaction flask, cool the solution system of diisopropylamine (35.4g, 0.35mol) in tetrahydrofuran (140mL) to below -30°C, and add dropwise a solution of n-butyllithium in n-hexane (140mL, 0.35mol, 2.5M), the dropwise addition was completed, stirred at room temperature for 30 minutes, cooled to -78°C, and acetonitrile (10.3g, 0.25mol) solution of ethyl acetate (30.8g, 0.35mol) was added dropwise, and the dropwise addition was completed. Stir at room temperature for 2 hours, quench with 2N HCl to adjust the pH value to 5-6 after the reaction, extract with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, and concentrate the solvent to obtain 18.1 g of acetoacetonitrile as a colorless oil, with a GC purity of 98% , yield 87%.

[0034] In the second step, in a 1L reaction flask, dissolve 18.1 g of acetoacetonitrile obtained in the previous step in 600 mL of methanol, add p-toluenesulfonyl hydrazide (40.5 g, 0.22 mol), heat to r...

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Abstract

The invention discloses a preparation method for 3-amino-5-methylisooxazole, belonging to the technical field of organic chemistry. The preparation method is completed through three steps: with an easily-available raw material namely ethyl acetate as a starting material, carrying out a reaction with acetonitrile in the presence of an alkali metal so as to form acetyl acetonitrile, then carrying out a reaction with p-toluenesulfonhydrazide so as to form hydrazone, and carrying out a ring closing reaction with hydroxylamine under an alkaline condition so as to obtain the 3-amino-5-methylisoxazole. According to the invention, raw materials in the reactions are common; chloroform or carbon tetrachloride in a traditional method are avoided; and analogous isomers of the 3-amino-5-methylisoxazoleare not detected in the reaction process.

Description

Technical field: [0001] The invention relates to a preparation method of 3-amino-5-methylisoxazole, belonging to the technical field of organic synthesis. Background technique: [0002] 3-Amino-5-methylisoxazole, English name 3-Amino-5-Methylisoxazole, white crystal, CAS: 1072-67-9. Soluble in alcohol and ether, volatile with water vapor. Pharmaceutical intermediates. Used in the production of sulfa drugs, especially the anti-infective drug sulfamethoxazole. Sumophen, a broad-spectrum antibiotic, belongs to the first-class antibacterial class. It is used for urinary tract infection, respiratory tract infection, skin suppurative infection, and tonsillitis; when used in combination with synergists, its antibacterial efficacy can be significantly enhanced and can be increased several times to dozens of times. It is clinically used for tonsillitis, acute bronchitis, lung infection, urinary tract infection, skin purulent infection, bacillary dysentery and typhoid fever, etc. ...

Claims

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Application Information

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IPC IPC(8): C07D261/14
CPCC07D261/14
Inventor 漆伟君肖海旺蔡伟兵
Owner 浦拉司科技(上海)有限责任公司
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