Method for preparing high morphine hydrochloride

A technology of homomorpholine hydrochloride and compounds, applied in the direction of organic chemistry, etc., can solve the problems of unfavorable industrial scale-up production, few literature reports, and low total yield, and achieve high purity of target products, convenient purification, and simplified experimental operations Effect

Inactive Publication Date: 2012-01-18
陕西瑞科新材料股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Although homomorpholine hydrochloride has many uses in synthesis, there are very few reports on its synthesis
European patent EP1621537 mentions the method of utilizing rearrangement reaction to synthesize homomorpholine hydrochloride, but relatively expensive raw materials are needed, and the total yield is not high, which is not conducive to industrial scale-up production

Method used

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  • Method for preparing high morphine hydrochloride
  • Method for preparing high morphine hydrochloride
  • Method for preparing high morphine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] The synthesis of embodiment one N-benzyl ethanolamine III

[0039] Mix 2.3 kg of ethanolamine, 3.3 kg of benzaldehyde, and 10 kg of methanol in a reaction flask, then add 3.1 kg of sodium triacetate borohydride, heat up to 40°C, and react for 5 hours. The solvent benzaldehyde was removed under reduced pressure, and the obtained compound III was directly used in the next reaction without further purification.

Embodiment 2

[0040] The synthesis of embodiment two N-chloropropionyl-N-benzyl ethanolamine IV

[0041] The above crude compound III and 3 kg of triethylamine were dissolved in 15 liters of dichloromethane. Under ice bath, 5.1 kg of chloropropionyl chloride was slowly added dropwise, and reacted at room temperature for 6 hours after the drop was completed.

[0042] The reaction system was washed with 12 liters of water, the organic layer was dried over anhydrous sodium sulfate, and the organic solvent was removed to obtain 4.8 kg of compound IV. used directly in the next reaction.

Embodiment 3

[0043] The synthesis of embodiment three N-benzyl homomorpholin-2-ketones (V)

[0044] The above 4.8 kg of compound IV was dissolved in 40 liters of tetrahydrofuran. Under an ice bath, 1.5 kg of 50% sodium hydride was added in portions. Then react at room temperature for 2 hours.

[0045] Under ice-cooling, 25 liters of water was added to the reaction mixture to quench the reaction, and extracted three times with 5 liters of ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the organic solvent was removed to obtain 3.6 kg of compound V. used directly in the next reaction.

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Abstract

The invention discloses a method for preparing high morphine hydrochloride I. The method comprises the following steps of: taking ethanol amine as a starting material and generating N-benzyl ethanol amine III through a condensation reaction with phenyl aldehyde; reacting the obtained compound III with chlorpromazine chloride or bromidepropionyl bromide to generate homologous N-halogenated propionyl group-N-benzyl ethanol amine IV; generating a seven-membered ring intermediate body V through performing a ring closing reaction on the obtained compound IV; converting the obtained compound V under a reducing condition to a compound VI; and generating a target compound I from the obtained compound VI under a oxidation-reduction condition. The method provided by the invention has the advantagesof high overall yield, convenience for purifying the intermediate body, high purity of the target product and suitability for industrialized production and the like.

Description

technical field [0001] The invention relates to a method for synthesizing homomorpholine hydrochloride. Background technique [0002] Homomorpholine hydrochloride is a seven-membered ring-shaped small molecule compound containing two heteroatoms of nitrogen and oxygen in the molecule. It is a key fragment and raw material for the synthesis of many drug molecules. It is also widely used as an active structural module in the development of new drugs. middle. [0003] Although homomorpholine hydrochloride has many uses in synthesis, there are very few reports about its synthesis. European patent EP1621537 mentions the method of using rearrangement reaction to synthesize homomorpholine hydrochloride, but relatively expensive raw materials are needed, and the total yield is not high, which is not conducive to industrial scale-up production. Contents of the invention [0004] The object of the present invention is to overcome the defects of the above-mentioned prior art, and p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D267/10
Inventor 许华富蔡万煜
Owner 陕西瑞科新材料股份有限公司
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