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A kind of preparation method of high-purity milrinone

A technology of milrinone and sodium hydroxide, applied in the field of medicine, can solve the problems of relatively high reaction conditions, strict requirements on water for phenyllithium, unsuitable for industrial production, etc., and achieves high product purity, improved production environment, and hydrolysis. The effect of the process is simple and easy to operate

Active Publication Date: 2018-01-26
HUZHOU ZHANWANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

At present, there are many reports on the preparation methods of intermediate III, mainly the following three: 1, 4-picoline reacts with ethyl acetate under the catalysis of phenyllithium to obtain acylated 1-(4-pyridyl) - Acetone (III) (Zheng Xiaozhang et al., Chinese Journal of Pharmaceutical Industry, 1990, 21, 486), the phenyllithium used in this method has strict requirements on water, harsh reaction conditions, high production cost, and toxicity during the reaction process Larger risk of benzene, so not suitable for industrial production
2. The reaction of 4-picoline with acetyl chloride or acetic anhydride uses aluminum chloride as a catalyst and carbon disulfide as a solvent (Tian Zuguang et al., CN87102628). This method uses anhydrous aluminum chloride as a catalyst, and the conditions are relatively harsh; carbon disulfide is used as a catalyst. Solvents are more harmful to the human body
3. The reaction of 4-picoline with acetyl chloride is carried out under the catalysis of aluminum chloride, and the acylation reaction is carried out with chloroform as the solvent (Ippolito, Robert et al., US4681944). This method is greatly improved on the basis of the previous method 2, However, it still does not get rid of the fact that aluminum chloride is catalyzed, and the requirements for reaction conditions are relatively high
However, the milrinone produced by the prior art is generally darker in color, and needs to be repeatedly refined and decolorized to meet the requirements of the raw material drug for injection, and the cost is high; and in the decolorization process, impurities will be added and the purity will be reduced.
Moreover, the solubility of different crystal forms is also different, which has a great impact on the active ingredients of the preparation.

Method used

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  • A kind of preparation method of high-purity milrinone
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  • A kind of preparation method of high-purity milrinone

Examples

Experimental program
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Effect test

example 1

[0047] In a 1000mL three-necked flask, add 93.0g (1.0mol) of 4-picoline and 500mL of chloroform, place in an ice-water bath to control the temperature below 50°C, and add 80.0g (1.02mol) of acetyl chloride dropwise. Raise the temperature to 55°C for 2.5 hours. After the reaction is completed, add saturated sodium carbonate aqueous solution dropwise to the system under ice-cooling to adjust the pH to 5-7, then add 30.0g of 30wt% sodium hydroxide solution (sodium hydroxide 0.23mol), and stir at 30-50°C for 2.5hr. After the reaction was completed, the layers were separated, the water layer was removed, and dried over anhydrous sodium sulfate. After the solvent was recovered, the 100-105°C / 217kPa fraction was collected by distillation under reduced pressure, that is, 1-(4-pyridyl)-2-acetone, fraction 97.2g, HPLC: 98.4%, yield 72.08%.

[0048] Add 60.0 (0.44mol) g of 1-(4-pyridyl)-2-propanone into a 500mL round bottom flask, and mix 40.5g (0.44mol) triethyl orthoformate, 92.2g (0....

example 2

[0051] In a 5000mL three-necked flask, add 465.0g (5.0mol) of 4-methylpyridine and 3000mL of chloroform, place in an ice-water bath to control the temperature below 50°C, and add 588.8g (7.5mol) of acetyl chloride dropwise. Raise the temperature to 55°C for 3.5 hours. After the reaction is completed, add saturated sodium carbonate aqueous solution dropwise to the system under ice cooling to adjust the pH to 5-7, then add 160.0 g of 30% sodium hydroxide solution (sodium hydroxide 1.2 mol), and stir at 30-50°C for 2.5 hours. After the reaction was completed, the layers were separated, the water layer was removed, and dried over anhydrous sodium sulfate. After the solvent was recovered, the 100-105°C / 217kPa fraction was collected by distillation under reduced pressure, that is, 1-(4-pyridyl)-2-acetone, fraction 498.2g, HPLC: 98.2%, yield 73.8%.

[0052] Add 280.0g (2.07mol) of 1-(4-pyridyl)-2-propanone into a 3000mL round bottom flask, and mix 572.0g (6.21mol) of triethyl orthof...

example 3

[0055] In a 10000mL three-necked flask, add 930.0 g (10mol) of 4-picoline and 6500mL of chloroform, place in an ice-water bath to control the temperature below 50°C, and add 981.0 g (12.5mol) of acetyl chloride dropwise, and heat up after the dropwise addition React at 55°C for 3.0hr. After the reaction is completed, add saturated sodium carbonate aqueous solution dropwise to the system under ice cooling to adjust the pH to 5-7, then add 315.0 g of 30% sodium hydroxide solution (2.36 mol), and stir at 30-50°C for 3.0 hr. After the reaction was completed, the layers were separated, the water layer was removed, and dried over anhydrous sodium sulfate. After the solvent was recovered, the 100-105°C / 217kPa fraction was collected by distillation under reduced pressure, namely 1-(4-pyridyl)-2-acetone, fraction 996.0g, HPLC: 98.2%, yield 73.8%.

[0056] Add 600.0g (4.44mol) of 1-(4-pyridyl)-2-propanone into a 5000mL round bottom flask, and mix 817.0g (8.87mol) triethyl orthoformate,...

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Abstract

The invention discloses a preparation method for high-purity milrinone (shown as a formula (I), 1,6-dihydro-2-methyl-6-oxo-3,4-bipyridine-5-carbonitrile), and belongs to the field of chemical medicines. The method comprises: employing 4-methylpyridine as a raw material and acetylating with acetyl chloride, and hydrolyzing after the reaction is finished, so as to obtain a compound of a formula (III); mixing the compound of the formula (III) with glacial acetic acid, acetic anhydride and triethyl orthoformate, and reacting at 35 DEG C-45 DEG C, so as to obtain a compound of a formula (IV); performing cyclization on the compound of the formula (IV) and alpha-cyanoacetamide, so as to obtain a crude product of a compound of the formula (I); and refining the crude product of the formula (I) compound through an ethanol-water system, so as to obtain a high-purity refined product with the maximum interplanar spacing d of 8.39 + / - 0.02 Angstrom. The technology is relatively mild in reaction conditions and relatively simple in operation, and is capable of preparing the milrinone product with high purity and a single crystal form. The obtained milrinone crystal form is relatively excellent in solubility in normal saline or glucose, and is beneficial for improvement of the preparation quality.

Description

technical field [0001] The present invention relates to a preparation method of milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5-carbonitrile), specifically a The invention discloses a preparation method of high-purity single-crystal milrinone, which belongs to the technical field of medicine. Background technique [0002] Milrinone (milrinone, formula I), the chemical name is 1,6-dihydro-2-methyl-6-oxo-[3,4-bipyridine]-5-carbonitrile, and the molecular formula is C 12 h 9 N 3 O, with a molecular weight of 211.22, is a white or off-white crystalline powder, and its structural formula is: [0003] [0004] Milrinone was first developed by the American Sterling company as an anti-heart failure drug. It was first approved by the FDA in the United States in 1987 and officially launched in the United States in 1992. It was subsequently marketed in the United Kingdom, France, Germany, the Netherlands, Belgium and other countries. . [0005] Milrinone is a phosphodi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 敖玲玲张奔潘继成陈颖
Owner HUZHOU ZHANWANG PHARMA
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