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Preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid

A technology of phenylbutyric acid and p-amino, which is applied in the field of preparation of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid, can solve the problem of complex post-treatment process, high waste removal cost, High cost of raw materials and other issues, to achieve the effect of novel process design, safe and simple operation, and environmentally friendly reaction conditions

Active Publication Date: 2015-04-08
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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  • Preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid
  • Preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid
  • Preparation method of 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 500g of p-nitrobenzoic acid (I) was added with 2.7kg of dichloromethane, and then 435g of propylmalonate, 550g of N,N-lutidine and 1.06kg of dicyclohexyl carbon two were added successively Imine, the reaction temperature is 10℃, after 36 hours of reaction, filter out the insoluble solids, add 420 ml of 1N hydrochloric acid to the organic phase, stir thoroughly, and dry the separated organic phase with sodium sulfate for 5 hours, then filter out Sodium sulfate, it is recommended to distill off the organic solvent to obtain 855kg of intermediate (II).

[0034] Add 2200g of DMF to 855g of intermediate (II), control the temperature of the mixed solution to 0°C with an ice-water bath, then add 200g of sodium ethoxide to the mixed solution, then control the temperature of the reaction solution at -5°C, and add 460g dropwise The reaction temperature is -5℃. After 13 hours of reaction, the DMF is distilled off under reduced pressure, and then methyl tert-butyl ether is added; the ...

Embodiment 2

[0040] Add 3kg of dichloromethane to 600g of p-nitrobenzoic acid (I), then add 530kg of propylmalonate, 520g of N,N-lutidine and 1500g of dicyclohexylcarbodiimide. , The reaction temperature is 20 ℃, after 16 hours of reaction, filter out the insoluble solids, add 5 liters of 1N hydrochloric acid to the organic phase, after fully stirring, the separated organic phase is dried with sodium sulfate for 4 hours, then the sodium sulfate is filtered out It is recommended to distill off the organic solvent to obtain 1033g of intermediate (II).

[0041] Add 2.4kg of DMF to 1033g of intermediate (II), control the temperature of the mixed solution with an ice-water bath to 20°C, then add 290g of sodium ethoxide to the mixed solution, control the temperature of the reaction solution at 0°C, and add 540g dropwise The reaction temperature is 5℃. After 10 hours of reaction, the DMF is distilled off under reduced pressure, and then methyl tert-butyl ether is added; the temperature of the soluti...

Embodiment 3

[0047] Add 15 kg of dichloromethane to 3 kg of p-nitrobenzoic acid (I), then add 2.6 kg of propyl malonate, 3.1 kg of N,N-lutidine and 7.4 kg of dicyclohexyl carbon. Diimine, the reaction temperature is 28 ℃, after 32 hours of reaction, filter out the insoluble solids, add 25 liters of 1N hydrochloric acid to the organic phase, after fully stirring, the separated organic phase is dried with sodium sulfate for 5 hours, then filtered After sodium sulfate is removed, it is recommended to distill off the organic solvent to obtain 5.15 kg of intermediate (II).

[0048] Add 12kg of DMF to 5.15kg of intermediate (II), control the temperature of the mixed solution to 10℃ in an ice-water bath, then add 1.44kg of sodium ethoxide to the mixed solution, and then control the temperature of the reaction solution at -5℃. Add 2.74kg of methyl iodide and drip it in about 1 hour. The reaction temperature is 0°C. After 12 hours of reaction, the DMF is evaporated under reduced pressure, and then met...

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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 for preparing an intermediate of levosimendan, a medicine for enhancing myocardial contractility, in particular to a preparation method for 3-methyl-4-oxo-4-(p-amino)phenylbutyric acid. Background technique [0002] Levosimendan is a calcium sensitizer developed by Orion, Finland, to enhance myocardial contractility. It is the first drug of this type to be marketed. It was first launched in Sweden in October 2000 for the treatment of various acute and intractable heart failure. [0003] [0004] The mechanism of action of Levosimendan is mainly by increasing the sensitivity of cardiac contractile protein to calcium ions and opening the ATPase-sensitive potassium ion channel on the cell membrane, increasing the contractility of the myocardium while dilating peripheral blood vessels and coronary arteries, reducing the front and back of the heart Load, quickly improve the symptoms of patients with acute heart failur...

Claims

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Application Information

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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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