Method for synthesising milrinone

A technology for synthesizing rice and compounds, which is applied in the direction of organic chemistry, can solve the problems of unfavorable industrial production, long reaction time, high price, etc., and achieve the effects of reducing the number of times of extraction, decompression and concentration, facilitating industrial production, and saving labor costs

Active Publication Date: 2013-09-11
NANJING KING FRIEND BIOCHEM PHARMA CO LTD
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

This type of method is such as reaction route I, and its first step can be realized through 2 paths, and the 1st path needs to use n-butyllithium, and well-known butyllithium is easy to produce exothermic reaction when encountering water and oxygen, and is flammable in air. , once it is heated and expanded, it will easily cause explosion, so it is difficult to operate, and the price is relatively expensive, which is not conducive to industrial production
The second path reacts with acetyl chloride at room temperature for 16 hours. Although the reaction conditions are relatively mild, the reaction time is too long
This method requires 3-step reactions to prepare milrinone, and it is impossible to achieve it through the "one-pot cooking" method, so the route is relatively long, and the last step reaction yield is only 34%, compared to 70% of other routes There is no competitive advantage in terms of yield

Method used

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  • Method for synthesising milrinone
  • Method for synthesising milrinone
  • Method for synthesising milrinone

Examples

Experimental program
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Embodiment 1

[0029] In a 100mL three-necked flask, add 7.95mL (81mmol) of 4-picoline, 30mL of dichloromethane and 20mg of anhydrous aluminum chloride, cool in an ice bath to 0°C, and dropwise add 11.7mL (165mmol) of acetyl chloride. Control the internal temperature below 10°C, raise the temperature to 25°C after the dropwise addition, and react for 2.5 hours. Under cooling in an ice bath, add 0.5 mol / L sodium hydroxide aqueous solution dropwise to the system to adjust the pH to 7-8, then add 19.5 mL saturated sodium bisulfite solution, and stir at room temperature for 2.5 hr. The combined organic layers were extracted with dichloromethane (50 mL×2), and dried over anhydrous sodium sulfate. After the solvent was recovered, 3.84 g of a fraction at 65-67°C / 2.7kPa was collected by vacuum distillation, which was unreacted 4-methylpyridine. The aqueous layer was adjusted to pH 13.25 with 6.25mol·L-1 sodium hydroxide solution, and reacted at room temperature for 2 hours. Add 24 mL of water, ext...

Embodiment 2

[0032] In a 1000mL three-necked flask, add 63.6mL (0.648mol) of 4-methylpyridine and 240mL of n-hexane, and add 66.9mL (0.972mol) of acetyl chloride dropwise under cooling in an ice bath, and control the internal temperature below 10°C during the dropwise addition , After the dropwise addition, the temperature was raised to 40° C. for reflux reaction, and the reaction was carried out for 3 hours. Add 6 mol·L dropwise to the system under cooling in an ice bath -1Adjust the pH to 7-8 with aqueous sodium hydroxide solution, then add 156 mL of saturated sodium bisulfite solution, and stir at room temperature for 2.5 hr. The combined organic layers were extracted with n-hexane (150 mL×2), and dried over anhydrous sodium sulfate. After recovering the solvent, 31.6 g of fractions at 65-67° C. / 2.7 kPa were collected by vacuum distillation, which was unreacted 4-picoline. The aqueous layer was adjusted to pH 13.08 with 6.25 mol·L-1 sodium hydroxide solution, and reacted at room tempe...

Embodiment 3

[0035] In a 2000mL three-necked flask, add 200mL (2.038mol) of 4-picoline, 800mL of cyclohexane and 1mL of copper trifluoromethanesulfonate, and add 361.3mL (5.092mol) of acetyl chloride dropwise under cooling in an ice bath. Control the internal temperature below 10°C, and raise the temperature to 30°C for 3.5 hours after the dropwise addition. Under cooling in an ice bath, 4 mol·L-1 sodium hydroxide aqueous solution was added dropwise to the system to adjust the pH to 7-8, then 491 mL of saturated sodium bisulfite solution was added, and stirred at room temperature for 2.5 hr. The combined organic layers were extracted with cyclohexane (400 mL×2), and dried over anhydrous sodium sulfate. After recovering the solvent, 93.95 g of fractions at 65-67°C / 2.7kPa were collected by vacuum distillation, which was unreacted 4-picoline. The aqueous layer was adjusted to pH 13.18 with 6.25 mol·L-1 sodium hydroxide solution, and reacted at room temperature for 2 hours. Add 600 mL of wat...

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Abstract

The invention discloses a method for synthesising milrinone. The method comprises the following steps of: mixing 4-methylpyridine with acetylchloride in a solvent at a temperature below 10 DEG C; heating to react with or without a catalyst, and then adjusting the pH value of the reaction solution to 7-8 by sodium hydroxide aqueous solution; then directly adding saturated sodium hydrogen sulfite aqueous solution, and reacting; adjusting the pH value of the water layer obtained by the reaction by sodium hydroxide, and reacting to obtain a compound in formula (III); mixing the compound in formula (III) with glacial acetic acid, acetic anhydride and triethyl orthoformate, and then reacting at 50-100 DEG C to obtain a compound in formula (IV); cyclizing the compound in formula (IV) with alpha-cyanoacetamide in an alkaline condition to obtain a compound in formula (V). The process is more moderate in reaction conditions, simpler and more convenient to operate, and capable of greatly shortening the original reaction time, reducing cost and increasing yield simultaneously; the process is a preparation method for milrinone which is suitable for industrialized production.

Description

technical field [0001] The invention relates to an improved method for the preparation of milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5carbonitrile), which belongs to the field of chemical industry and chemical medicine . Background technique [0002] Milrinone is the general name of 1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5carbonitrile, molecular formula: C 12 h 9 N 3 O, molecular weight: 211.22, its structural formula is: [0003] [0004] Milrinone was first successfully developed by Sterling Company of the United States. It was first approved by the FDA in the United States in 1987. It was officially launched in the United States in 1992, and was subsequently marketed in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries. [0005] This product is a phosphodiesterase inhibitor, a homologous drug of Amrinone, and its mechanism of action is the same as that of Amrinone. Oral and intravenous injection are effective, both ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/85
Inventor 唐咏群段艳冰
Owner NANJING KING FRIEND BIOCHEM PHARMA CO LTD
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