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Method for preparing milrinone

A milrinone and pyridyl-based technology, which is applied in the field of preparation of milrinone, can solve the problems of safety hazards, harsh conditions, and instability in personal health, and achieve easy industrial promotion, mild reaction conditions, and no safety hazards Effect

Inactive Publication Date: 2017-05-10
HUZHOU HENGYUAN BIOCHEM TECH
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

[0021] Comprehensive analysis of the above synthesis routes, the existing milrinone initial raw material 1-(4-pyridyl)-acetone synthesis route has high cost, harsh conditions, and potential safety hazards to human health; using 1-(4-pyridyl)-acetone In the route of synthesizing milrinone, N,N-dimethylformamide dimethyl acetal is more expensive and unstable than triethyl orthoformate, and has high requirements for use and storage, and Soxhlet extraction is used in the process The extraction and recrystallization of the device is cumbersome; the last step uses cyanoacetamide as the cyclizing agent and uses sodium methoxide as the catalyst. Sodium methoxide is highly corrosive and sensitive to water, which is not conducive to storage and equipment maintenance

Method used

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  • Method for preparing milrinone

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preparation example Construction

[0045] The invention provides a kind of preparation method of milrinone, comprises the following steps:

[0046] (1) Preparation of 1-(4-pyridyl)-acetone

[0047] a. First mix 4-picoline and maleic anhydride in the solvent, then add the catalyst, keep the temperature at 30-45°C, keep stirring, and slowly add propanol to react for 30-60 minutes;

[0048] b. Evaporate the reactant obtained in step a, then extract with acetone, and finally dry and filter with anhydrous copper sulfate to obtain 1-(4-pyridyl)-acetone;

[0049] (2) Preparation of 1-ethoxy-2-(4-pyridyl) vinyl methyl ketone

[0050] a. Add triethyl orthoformate, maleic anhydride and maleic acid to the 1-(4-pyridyl)-acetone prepared in step (1), maintain the temperature at 20-45° C., and react for 1-3 hours;

[0051] b. Evaporate the reactant obtained in step a to remove maleic anhydride and maleic acid to obtain 1-ethoxy-2-(4-pyridyl)vinyl methyl ketone;

[0052] (3) Preparation of Milrinone

[0053] a. Add ethano...

Embodiment 1

[0081] 1, the preparation of 1-(4-pyridyl)-acetone

[0082] In a three-necked flask, add 1mol 4-picoline, 2mol maleic anhydride and 500ml n-hexane and mix well, add 3ml sulfuric acid dropwise, keep the temperature at 35-40°C in an ice-water bath, keep stirring, and slowly add 500ml propane Alcohol, react for 30 minutes; when the temperature is 55-65°C, evaporate the above reactant for 60 minutes to remove excess propanol, then add 300ml acetone for extraction, extract three times, evaporate to remove excess acetone, and finally use anhydrous copper sulfate Dry and filter to obtain 1-(4-pyridyl)-acetone.

[0083] 2. Preparation of 1-ethoxy-2-(4-pyridyl) vinyl methyl ketone

[0084] Add 1 mol of 1-(4-pyridyl)-acetone, 2 mol of triethyl orthoformate, 2.5 mol of maleic anhydride and 3 mol of maleic acid into a three-necked flask, stir, and maintain the temperature at 30-40°C in an ice-water bath. Reaction for 1.5h; at a temperature of 50-60°C, evaporate the above reactant for 1....

Embodiment 2

[0088] 1, the preparation of 1-(4-pyridyl)-acetone

[0089] In a three-necked flask, add 1mol 4-picoline, 3mol maleic anhydride and 500ml n-hexane and mix well, add 5ml sulfuric acid dropwise, keep the temperature at 35-40°C in an ice-water bath, keep stirring, and slowly add 500ml propane Alcohol, react for 40 minutes; when the temperature is 55-65°C, evaporate the above reactant for 50 minutes to remove excess propanol, then add 300ml acetone for extraction, extract three times, evaporate to remove excess acetone, and finally use anhydrous copper sulfate Dry and filter to obtain 1-(4-pyridyl)-acetone.

[0090] 2. Preparation of 1-ethoxy-2-(4-pyridyl) vinyl methyl ketone

[0091] Add 1 mol of 1-(4-pyridyl)-acetone, 2.2 mol of triethyl orthoformate, 2.5 mol of maleic anhydride and 3 mol of maleic acid into a three-necked flask, stir, and maintain the temperature at 30-40°C in an ice-water bath , reacted for 2h; when the temperature was 50-60°C, evaporate the above reactant f...

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Abstract

The invention discloses a method for preparing milrinone. The method comprises the following steps: (1) mixing 4-methyl pyridine and maleic anhydride in a solvent, adding a catalyst, maintaining the temperature to be 30-45 DEG C, continuously stirring, slowly adding propyl alcohol, reacting for 30-60 minutes, and finally evaporating and extracting so as to obtain 1-(4-pyridyl)-acetone; (2) adding triethyl orthoformate, maleic anhydride and maleic acid into a product prepared in the step (1), maintaining the temperature to be 20-45 DEG C, reacting for 1-3 hours, and evaporating so as to obtain 1-ethyoxyl-2-(4-pyridyl) vinyl methyl ketone; and (3) adding ethanol, acetone and propane dinitrile into the product prepared in the step (2), maintaining the temperature to be 40-65 DEG C, reacting for 1-5 hours so as to obtain crude milrinone, and purifying, thereby obtaining the pure milrinone. According to the method for preparing milrinone provided by the invention, reaction conditions are mild, the yield is high, the cost is low, the operation is easy and convenient and industrialized popularization and application are convenient.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to a preparation method of milrinone. Background technique [0002] Milrinone is the general name of l,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5carbonitrile, molecular formula: C 12 h 9 N 3 O. Milrinone is a phosphodiesterase inhibitor. As a non-catecholamine, non-digital positive inotrope, it is suitable for the treatment of refractory heart failure and heart failure patients who have already suffered from digitalis poisoning. It has played an increasingly important role in the treatment of congestive heart failure and peripheral vasodilation. In the United States and other countries, intravenous injection of milrinone has been widely used to improve the heart function of patients with heart failure. [0003] Milrinone is the homologous drug of amrinone. Its mechanism of action is the same as that of amrinone, but its potency is stronger than that of amrinone. It is...

Claims

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Application Information

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IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 马维恒包建辉谢何青俞彬
Owner HUZHOU HENGYUAN BIOCHEM TECH
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