Preparation method of ethyl bromodifluoroacetate

A technology of ethyl difluorobromoacetate and difluorobromoacetonitrile, which is applied in the field of preparation of ethyl difluorobromoacetate, can solve the problems of poor selectivity, easy hydrolysis, damage, etc., and achieve the effect of reducing requirements

Active Publication Date: 2017-02-15
河北正朗制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] (1) 1,1-difluoro-1-bromo-halogenated ethane is used as raw material, basically under the action of oxidant and toxic mercury salt (such as mercuric oxide, mercuric chloride, etc.) to catalyze difluorobromoacetyl Halogen (acyl fluoride, acid chloride and acid bromide, etc.), the oxidant used in this process is either fuming sulfuric acid, which has a harsh operating environment and great pollution; or uses peroxide, oxygen or ozone, or in a high-pressure system, but chooses Poor performance, extremely low yield, and extremely high cost;
[0016] (2) In this process, the intermediate difluorobromoacetyl halide

Method used

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  • Preparation method of ethyl bromodifluoroacetate
  • Preparation method of ethyl bromodifluoroacetate
  • Preparation method of ethyl bromodifluoroacetate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of difluorobromoacetonitrile from difluorodibromomethane

[0041]

[0042]Add 90 g of cuprous cyanide powder to 500 ml of 1:1 (volume ratio) N,N-dimethylformamide (DMF) / ethylene glycol dimethyl ether (DME) mixed solvent, and add 1 g of catalyst Dibenzo-18-crown-6, slowly add a molar amount of difluorodibromomethane dissolved in DMF / DME (volume ratio 1:1) mixed solution, and start monitoring after half an hour of reaction at 20°C , monitored by GC (column: PEG-20M) until the conversion was 80%.

[0043] The temperature was slowly raised to 50°C to evaporate the difluorobromoacetonitrile, and then the difluorobromoacetonitrile was collected at a low temperature through a cold well below 0°C.

[0044] Carbon NMR spectrum: 13 CNMR: σ C 115.5ppm, σ C 98.6ppm.

Embodiment 2

[0046] Add 90 g of cuprous cyanide powder to 500 ml of 1:2 (volume ratio) N,N-dimethylformamide (DMF) / ethylene glycol dimethyl ether (DME) mixed solvent, and add 2 g of catalyst Dibenzo-18-crown-6 was slowly added dropwise to a mixed solution of difluorodibromomethane dissolved in DMF / DME (volume ratio 1:2). Column: PEG-20M) The reaction was stopped when the conversion rate was 85%. Slowly raise the temperature to 50°C to evaporate the difluorobromoacetonitrile, and then pass through a cold well below 0°C to collect the difluorobromoacetonitrile at a low temperature.

[0047] Carbon NMR spectrum: 13 CNMR: σ C 115.5ppm, σ C 98.4ppm.

Embodiment 3

[0049] Add 90 g of cuprous cyanide powder to 500 ml of 1:3 (volume ratio) N,N-dimethylformamide (DMF) / ethylene glycol dimethyl ether (DME) mixed solvent, and add 3 g of catalyst Dibenzo-18-crown-6 was slowly added dropwise to the mixed solution of difluorodibromomethane DMF / DME, and the reaction was carried out at 20°C for half an hour, and the conversion rate was measured by GC (chromatographic column: PEG-20M). up to 90%. Slowly raise the temperature to 50°C to evaporate the difluorobromoacetonitrile, and then collect the difluorobromoacetonitrile at a low temperature through a cold well below 0°C.

[0050] Carbon NMR spectrum: 13 CNMR: σ C 115.4ppm,σ C 98.6ppm.

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Abstract

The invention belongs to the field of organic synthesis and discloses a preparation method of ethyl bromodifluoroacetate. Difluorobromoacetonitrile is taken as a raw material, and prepared through a one-pot method and subjected to alcoholysis and esterification in ethanol aqueous solution to obtain ethyl bromodifluoroacetate. According to the method provided by the invention, difluorobromoacetonitrile is taken as the raw material and then bromodifluoroacetic acid is subjected to the alcoholysis and esterification after directly hydrolyzed, without generating a toxic bromodifluoroacetyl halide intermediate, and the use of fuming sulfuric acid as an oxidant and bad in operating environments and maximum in pollution, or peroxide or ozone, or oxygen in a high pressure system to result in poor selectivity and very low yield is avoided. Furthermore, the existence of by-products with extremely strong hydrogen halide corrosion of hydrogen fluoride and the like which both have extremely large corrosion to metal and glass-lined materials is avoided in the process, so that the requirements for production reaction equipment are lowered, and the preparation of ethyl bromodifluoroacetate can be carried out in the ordinary glass-lined reaction device.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of ethyl difluorobromoacetate. Background technique [0002] Ethyl difluorobromoacetate compound is an intermediate for the synthesis of drugs and high-energy materials. It has been disclosed that the compound is prepared by reacting ethanol with difluorobromoacetyl halide to prepare ethyl difluorobromoacetate, and its chemical reaction formula is as follows: [0003] [0004] Wherein, X can be F, Cl or Br, and difluorobromoacetyl halide can be prepared according to various process methods to prepare difluorobromoacetyl halide (acid chloride, acid bromide and acid fluoride). [0005] In numerous published documents and patents, various process methods are listed in detail, but the fundamental core technology is the preparation technology of difluorobromoacetyl halide, which is basically based on 1,1-difluoro-1-bromo-halogenated Ethane is used...

Claims

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Application Information

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IPC IPC(8): C07C67/00C07C67/08C07C69/63C07C51/08C07C53/18C07C253/14C07C255/10
CPCC07C51/08C07C67/00C07C67/08C07C253/14C07C69/63C07C53/18C07C255/10
Inventor 谢素琼候利民刘金城
Owner 河北正朗制药有限公司
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