Preparation method for high-purity milrinone

A milrinone, high-purity technology, applied in the field of medicine, can solve the problems of strict requirements on water for phenyllithium, relatively high reaction conditions, and the influence of active ingredients in preparations, and achieves improved production environment, high product purity, and solubility. better results

Active Publication Date: 2015-03-04
HUZHOU ZHANWANG PHARMA
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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...

Method used

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  • Preparation method for high-purity milrinone
  • Preparation method for high-purity milrinone
  • Preparation method for high-purity milrinone

Examples

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example 1

[0050] In a 1000mL three-necked flask, add 93.0g (1.0mol) of 4-methylpyridine and 500mL of chloroform, place in an ice water bath and control the temperature below 50℃, add 80.0g (1.02mol) of acetyl chloride dropwise, after the addition is complete The temperature was raised to 55°C for 2.5hr. After the reaction is completed, a saturated aqueous sodium carbonate solution is added dropwise to the system under ice cooling to adjust the pH to 5-7, and then 30.0g 30wt% sodium hydroxide solution (0.23mol sodium hydroxide) is added, and the reaction is stirred at 30-50°C for 2.5hr. After the reaction is completed, separate the layers, remove the water layer, dry with anhydrous sodium sulfate, recover the solvent, and collect the 100-105°C / 217kPa fraction, namely 1-(4-pyridyl)-2-acetone, by distillation under reduced pressure, the fraction 97.2g, HPLC: 98.4%, the yield is 72.08%.

[0051] Add 60.0 (0.44mol) g of 1-(4-pyridyl)-2-acetone into a 500mL round-bottomed flask, mix 40.5g (...

example 2

[0054] In a 5000mL three-necked flask, add 465.0g (5.0mol) of 4-methylpyridine and 3000mL of chloroform, place it in an ice water bath to control the temperature below 50℃ and add 588.8g (7.5mol) of acetyl chloride dropwise, after the addition is complete The temperature was raised to 55°C for 3.5hr. After the reaction is completed, a saturated aqueous sodium carbonate solution is added dropwise to the system under ice cooling to adjust the pH to 5-7, and then 160.0g 30% sodium hydroxide solution (1.2mol sodium hydroxide) is added, and the reaction is stirred at 30-50°C for 2.5hr. After the reaction is complete, separate the layers, remove the water layer, dry with anhydrous sodium sulfate, recover the solvent and distill under reduced pressure to collect 100-105°C / 217kPa fraction, namely 1-(4-pyridyl)-2-acetone, fraction 498.2g, HPLC: 98.2%, yield 73.8%.

[0055] Add 280.0g (2.07mol) of 1-(4-pyridyl)-2-acetone into a 3000mL round-bottomed flask, mix 572.0g (6.21mol) of triethyl...

example 3

[0058] In a 10000mL three-necked flask, add 930.0 g (10mol) of 4-methylpyridine and 6500mL of chloroform, place in an ice water bath and control the temperature below 50℃. Add 981.0 g (12.5mol) of acetyl chloride dropwise. React at 55°C for 3.0hr. After the reaction is completed, add saturated sodium carbonate aqueous solution to the system under ice-bath cooling to adjust the pH to 5-7, then add 315.0g 30% sodium hydroxide solution (2.36mol), stir and react at 30-50℃ for 3.0hr. After the reaction is complete, separate the layers, remove the water layer, dry with anhydrous sodium sulfate, recover the solvent and distill under reduced pressure to collect the 100-105°C / 217kPa fraction, namely 1-(4-pyridyl)-2-acetone, fraction 996.0g, HPLC: 98.2%, yield 73.8%.

[0059] Add 600.0g (4.44mol) of 1-(4-pyridyl)-2-acetone into a 5000mL round-bottomed flask, mix 817.0g (8.87mol) of triethyl orthoformate, 1133.0g (11.10mol) of acetic anhydride and 1201.0 (20.00 mol) glacial acetic acid wa...

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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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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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