Preparation process of milrinone

A technology of milrinone and intermediates, applied in the field of drug synthesis, can solve the problems of low operation safety, difficult operation, harsh reaction conditions, etc., and achieve the effects of shortening the process route, easy control of the feeding amount, and simple operation.

Pending Publication Date: 2021-10-12
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] 一种方法是采用“直线式”合成路线(如US4469871A,US4413127A,EP0095152,US4313951A,J.Med.Chem.,1986,29,635-640,CN103288725B,CN104387320B,CN1253439C,CN106243032A,CN105777626A,CN104526975A,CN101143844A等): With 4-picoline as the starting material, 1-(4-pyridyl)-2-propanone is prepared. This step reaction can be realized through two paths. The first path is to use n-butyllithium or phenyllithium It reacts with ethyl acetate under certain conditions, but the reaction conditions are harsh, and the requirements for water are strict. It is easy to produce exothermic reaction when it encounters water and oxygen, and it is easy to burn in the air. Once it is heated, it will easily cause explosion. More expensive, and there is a risk of generating toxic benzene during the reaction, so it is not suitable for industrial production
The second path is to react with acetyl chloride at room temperature for 16 hour

Method used

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  • Preparation process of milrinone
  • Preparation process of milrinone
  • Preparation process of milrinone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] Example 1 Preparation of 1-(1-acetylpyridine-4(1H)-ylidene)-2-propanone

[0081] Add 4-picoline (93.08g, 1.0mol) into dichloromethane (200ml), and add acetyl chloride (172.72g, 2.2mol) at a temperature of 15-20°C. After 1 hour, the reaction is complete; temperature control is 10-15° C., adding purified water (400 ml), adding sodium hydroxide solution (about 7.5 mol / ml) while stirring to adjust the pH value of the reaction solution to 13-14, separating the liquids, and collecting the organic phase. Extract the aqueous phase with dichloromethane (100ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, control the temperature of the filtrate at 50-60°C and distill under reduced pressure until no fraction flows out, and continue to heat up the concentrated solution at 70-80°C to concentrate under reduced pressure , to obtain viscous liquid (recovery 4-picoline 55.85g, recovery rate 60%); add ethyl acetate (45ml) to viscous liquid, add acetic anhydri...

Embodiment 2

[0082] Example 2 Preparation of 1-(1-acetylpyridine-4(1H)-ylidene)-2-propanone

[0083] Add 4-methylpyridine (93.12g, 1.0mol) into dichloromethane (150ml), and add acetyl chloride (94.24g, 1.2mol) at a temperature of 20-25°C. After the addition is complete, control the temperature at 20-30°C to react 6 After 1 hour, the reaction is complete; temperature control is 0~10 DEG C, add purified water (400ml), while stirring, add sodium hydroxide solution (about 7.5mol / ml) to adjust the pH value of the reaction solution to 13~14, separate the liquid, collect the organic phase, Extract the aqueous phase with dichloromethane (100ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, control the temperature of the filtrate at 50-60°C and distill under reduced pressure until no fraction flows out, and continue to heat up the concentrated solution at 70-80°C to concentrate under reduced pressure , to obtain viscous liquid (recovery 4-picoline 57.73g, recovery rate 6...

Embodiment 3

[0084] Example 3 Preparation of 1-(1-acetylpyridin-4(1H)-ylidene)-2-propanone

[0085] Add 4-methylpyridine (93.07g, 1.0mol) into dichloromethane (300ml), add acetyl chloride (235.54g, 3mol) under temperature control at 20-25°C, and react for 5 hours under temperature control at 20-30°C , the reaction is complete; add purified water (500ml) at 15-20°C with temperature control, add sodium hydroxide solution (about 7.5mol / ml) while stirring, adjust the pH value of the reaction solution to 13-14, separate the liquids, collect the organic phase, water Extract with dichloromethane (150ml×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, control the temperature of the filtrate at 50-60°C and distill under reduced pressure until no fraction flows out, continue to heat up the concentrated solution at 70-80°C and concentrate under reduced pressure. A viscous liquid was obtained (54.91 g of 4-picoline was recovered, the recovery rate was 59%); ethyl acetate (50 ...

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Abstract

The invention discloses a preparation method of milrinone, and belongs to the technical field of drug synthesis. According to the method, 1-(4-pyridyl)-2-acetone is used as a raw material and is subjected to a heating reaction with alpha-(substituted methylene) cyanoacetamide under an alkaline condition, and milrinone is obtained. The method for preparing milrinone is simple and convenient to operate, high in safety, high in yield and suitable for industrial large-scale production. The appearance and the purity of the obtained milrinone finished product both reach the standard.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of milrinone. Background technique [0002] Milrinone, also known as cyanopyridone, its CAS number is: 78415-72-2, is 1,6-dihydro-2-methyl-6-oxo-[3,4'-linked The general name of pyridine]-5-carbonitrile was first successfully developed by Sterling Company of the United States. It was first approved by the FDA in the United States in 1987 and officially listed in the United States in 1992. It was subsequently sold in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries. It is marketed in Brazil and other countries, and its lactate is used clinically. It is mainly suitable for the treatment of refractory heart failure and heart failure patients with digitalis poisoning. Recent studies have shown that milrinone can also be used for low cardiac output after extracorporeal circulation in cardiac surgery. Syndrome, r...

Claims

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Application Information

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IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 鲍广龙张乃华
Owner LUNAN PHARMA GROUP CORPORATION
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