Preparation method for high-purity milrinone

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...

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.

Images