Preparation method of medicine intermediate di-cyclopropyl methylamine

A technology of dicyclopropylmethylamine and dicyclopropyl ketone, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of low total reaction yield, difficult operation of the reaction, long reaction route, etc., and achieve safe process operation and short reaction steps Less, the effect of improving the total yield

Inactive Publication Date: 2012-02-15
HEFEI UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The traditional synthesis method has a long reaction route and involves the application of metal sodium in the reaction process, so there are disadvantages such as difficult operation of the reaction, great safety hazards, and low total reaction yield (the traditional total yield is about 25%).

Method used

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  • Preparation method of medicine intermediate di-cyclopropyl methylamine
  • Preparation method of medicine intermediate di-cyclopropyl methylamine
  • Preparation method of medicine intermediate di-cyclopropyl methylamine

Examples

Experimental program
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Embodiment 1

[0020] Weigh 55g of dicyclopropyl ketone and add it to a 500mL three-neck flask connected with a condensation and water separation device, add 62g of ammonium formate under slow stirring, slowly raise the temperature to an oil bath temperature of 170°C, and continuously separate water during the reaction process and remove the upper layer Return the organic phase to the three-necked flask to continue the reflux reaction. After 5 hours of reflux reaction, the reflux temperature in the reaction bottle reaches 160-170°C and no longer rises. Reflux at this temperature for 10 hours. After the reaction, cool to room temperature and wash the reaction mixture with water. 3 times, the amount of water for washing is 30mL each time, the organic phase is separated, and 10% hydrochloric acid is added to adjust the pH value to 4-5, and then washed three times with dichloromethane, the amount of dichloromethane for washing is 40mL each time, after washing Adjust the pH value to 10 with 10% so...

Embodiment 2

[0025] Weigh 110g of dicyclopropyl ketone into a 500mL three-neck flask connected with a condensation and water separation device, and add 184g of ammonium formate while stirring slowly. Slowly heat up to the temperature of the oil bath at 170°C. During the reaction process, water is continuously separated and the upper organic phase is returned to the three-necked flask to continue the reflux reaction. After 5 hours of reflux reaction, the reflux temperature in the reaction bottle reaches 160-170°C and no longer rises. Reflux at temperature for 10 hours. Cool to room temperature after the reaction, wash the reaction mixture 3 times with water, the amount of water used for washing is 40mL each time, separate the organic phase, add 10% hydrochloric acid to adjust the pH value to 4-5, wash with dichloromethane three times, and wash The amount of dichloromethane used is 60mL each time, and the aqueous solution after washing is adjusted to a pH value of 10 with 10% sodium hydroxid...

Embodiment 3

[0030] Weigh 220g of dicyclopropyl ketone into a 1000mL three-neck flask connected with a condensation and water separation device, and add 244g of ammonium formate under slow stirring. Slowly heat up to the temperature of the oil bath at 170°C. During the reaction process, water is continuously separated and the upper organic phase is returned to the three-necked flask to continue the reflux reaction. After 5 hours of reflux reaction, the reflux temperature in the reaction bottle reaches 160-170°C and no longer rises. Reflux at temperature for 10 hours. Cool to room temperature after the reaction, wash the reaction mixture 3 times with water, the amount of water used for washing is 80mL each time, separate the organic phase, add 10% hydrochloric acid to adjust the pH value to 4-5, wash with dichloromethane three times, wash The amount of dichloromethane used is 120mL each time, and the pH value of the washed aqueous solution is adjusted to 10 with 10% sodium hydroxide solutio...

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Abstract

The invention discloses a preparation method of a medicine intermediate di-cyclopropyl methylamine. The method comprises the following steps: based on di-cyclopropyl ketone as a raw material and ammonium formate as a reducing agent, stirring and reacting under refluxing for 10-12 hours at the temperature of 165-170 DEG C and normal pressure; after completing the reaction, cooling to room temperature; subsequently washing with water, regulating the pH value to 4-5, washing with dichloromethane, regulating the pH value to 10, extracting with dichloromethane and drying to obtain a di-cyclopropyl methylamine crude product; distilling the di-cyclopropyl methylamine crude product at reduced pressure of 100mmHg, and collecting a fraction of 110-120 DEG C. The method disclosed by the invention has less step, a target compound is directly obtained from di-cyclopropyl ketone with one-step reaction, and the total yield is greatly improved; and compared with the original process, by using the method disclosed by the invention, the use of metal sodium is avoided, so that process operation is safer and operation method is simpler.

Description

1. Technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of a pharmaceutical intermediate dicyclopropylmethylamine. 2. Background technology [0002] Dicyclopropylmethylamine is an important intermediate of antihypertensive drug rilmenidine, which is widely used in the synthesis of medicine. The synthetic method of traditional production dicyclopropylmethylamine is to generate oximide by the reaction of dicyclopropyl ketone and hydroxylamine, and then obtain dicyclopropylmethylamine through reduction of metal sodium or other reducing agent to obtain dicyclopropylmethylamine. The reaction process is as follows: [0003] [0004] The traditional synthetic method has a long reaction route and involves the application of metal sodium in the reaction process, so there are disadvantages such as difficult operation of the reaction, great safety hazards, and low total reaction yield (the tradit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/17C07C209/22
Inventor 王磊陈国祥随露
Owner HEFEI UNIV OF TECH
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