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A kind of preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid

A technology of phenylbutyric acid and p-amino group is applied in the field of preparation of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid, and can solve the problems of high cost of elimination, complicated post-treatment process, The problem of high cost of raw materials, to achieve the effect of safe and simple operation, novel process design, and environmentally friendly reaction conditions

Active Publication Date: 2016-05-11
ASTATECH CHENGDU BIOPHARM CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The disadvantage of the first route is that the yield of the second step reaction is very low, resulting in high cost of raw materials
In addition, a large amount of aluminum trichloride is used in the second step reaction, the post-treatment process is complicated and a large amount of industrial wastewater will be generated, and the cost of waste removal is very high
[0011] The disadvantage of the second route is that the second-step reaction requires highly toxic sodium cyanide, and highly toxic hydrogen cyanide gas is produced in the fourth-step reaction, all of which cause great difficulties for production control and environmental control, with huge potential risks

Method used

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  • A kind of preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid
  • A kind of preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid
  • A kind of preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid

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Experimental program
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Effect test

Embodiment 1

[0033] In the p-nitrobenzoic acid (I) of 500g, add the dichloromethane of 2.7kg, then successively add the propylidene malonate of 435g, the 4-N of 550g, N-dimethylaminopyridinium and 1.06kg of bicyclic Hexylcarbodiimide, the reaction temperature is 10°C, after 36 hours of reaction, filter out the insoluble solids, add 420 ml of 1N hydrochloric acid to the organic phase, stir well, and dry the separated organic phase with sodium sulfate for 5 hours , Sodium sulfate was filtered off, and it was suggested to evaporate the organic solvent to obtain 855kg of intermediate (II).

[0034] Add 2200g of DMF to 855g of intermediate (II), control the temperature of the mixture to 0°C in an ice-water bath, then add 200g of sodium ethylate to the mixture, then control the temperature of the reaction solution at -5°C, and add 460g of Methyl iodide was dropped in about 1 hour, and the reaction temperature was -5°C. After 13 hours of reaction, DMF was evaporated under reduced pressure, and th...

Embodiment 2

[0040] Add 3kg of dichloromethane in the p-nitrobenzoic acid (I) of 600g, then successively add 530kg of propylidene malonate, 520g of 4-N, N-dimethylaminopyridinamine and 1500g of dicyclohexyl carbon Diimine, the reaction temperature is 20°C, after reacting for 16 hours, filter out the insoluble solids, add 5 liters of 1N hydrochloric acid to the organic phase, stir well, dry the separated organic phase with sodium sulfate for 4 hours, filter Sodium sulfate was removed, and the organic solvent was suggested to be evaporated to obtain 1033g of intermediate (II).

[0041] Add 2.4kg of DMF to 1033g of intermediate (II), control the temperature of the mixed solution in an ice-water bath to 20°C, then add 290g of sodium ethylate to the mixed solution, then control the temperature of the reaction solution at 0°C, and add 540g of iodomethane, drop it in about 1 hour, and the reaction temperature is 5°C. After 10 hours of reaction, distill off DMF under reduced pressure, then add met...

Embodiment 3

[0047] In the p-nitrobenzoic acid (I) of 3kg, add the dichloromethane of 15kg, then successively add the propylidene malonate of 2.6kg, the 4-N of 3.1kg, N-dimethylaminopyridinamine and 7.4kg of dichloromethane Cyclohexylcarbodiimide, the reaction temperature is 28°C, after 32 hours of reaction, filter out the insoluble solids, add 25 liters of 1N hydrochloric acid to the organic phase, stir well, and dry the separated organic phase with sodium sulfate for 5 hours Finally, sodium sulfate was filtered off, and the organic solvent was suggested to be evaporated to obtain 5.15kg of intermediate (II).

[0048] Add 12kg of DMF to 5.15kg of intermediate (II), control the temperature of the mixed solution to 10°C in an ice-water bath, then add 1.44kg of sodium ethylate to the mixed solution, then control the temperature of the reaction solution at -5°C, drop Add 2.74kg of methyl iodide, drop it for about 1 hour, and the reaction temperature is 0°C. After 12 hours of reaction, distill...

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Abstract

The invention discloses a preparation method of a levosimendan key intermediate 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid, which comprises six reaction steps disclosed in the specification. The method has the advantages of novel technological design, accessible raw materials, environment-friendly reaction conditions, no need of virulent chemicals, high yield of each reaction step, high total yield and safe and simple operation, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of an intermediate of levosimendan, a medicine for enhancing myocardial contractility, and in particular to a preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid. Background technique [0002] Levosimendan is a calcium sensitizer drug for enhancing myocardial contractility developed by Orion, Finland, and is the first drug of this type to be marketed. First launched in Sweden in October 2000, it is used to treat various acute and refractory heart failure diseases. [0003] [0004] The mechanism of action of levosimendan is mainly by increasing the sensitivity of cardiac contractile proteins to calcium ions and opening the ATPase-sensitive potassium ion channels on the cell membrane, increasing the myocardial contractility while dilating peripheral blood vessels and coronary arteries, and reducing the anterior and posterior cardiac tension. The load can quickly improve the symptoms of pat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/42C07C227/04
Inventor 魏庚辉刘卫国罗建业郭鹏
Owner ASTATECH CHENGDU BIOPHARM CORP
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