Purification method of clevidipine butyrate

Abstract

The invention provides a purification method of clevidipine butyrate, which is characterized by comprising the following steps: adding ethyl acetate into a clevidipine butyrate crude product, heating under reflux until the solution is clear, adding n-heptane in batches, heating under reflux until the solution is clear, carrying out programmed cooling for crystallization, and filtering to obtain the clevidipine butyrate refined product. The product purity is greater than or equal to 99.5%, the single impurity content is less than 0.05%, the chloromethyl butyrate content is less than 5 ppm. In the purification method, 3-5ml of ethyl acetate is added into every gram of clevidipine butyrate crude product; and in the n-heptane batch addition process, the addition amount of the n-heptane is 1-2 times of that of the ethyl acetate. The purification method is reasonable in raw material selection and purification steps, and ensures the product purity to achieve the quality requirements of active pharmaceutical ingredients. The maximum single impurity content is less than 0.05%, the gene toxic impurity chloromethyl n-butyrate content (GC) is less than 5 ppm, the yield is up to 85% or above, and the product is uniform white powder.

Description

technical field [0001] The invention belongs to the technical field of medicine, relates to hypertension pharmaceutical technology, in particular to a purification method of clevidipine butyrate. Background technique [0002] Clevidipine butyrate is an ultra-short-acting dihydropyridine calcium channel blocker, which is used to reduce blood pressure in patients who are not suitable for oral or oral treatment. Its chemical name is 4-(2,3-dichlorobenzyl )-methyl(1-butyryloxy)methyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. [0003] Clevidipine butyrate has a high degree of selectivity for blood vessels and myocardium, and is rapidly metabolized into inactive substances in the body. It has a strong activity of reducing pulse rate and has a dilating effect on systemic blood vessels and pulmonary blood vessels. This product was approved by the FDA in August 2008. The trade name is Cleviprex. It is mainly used for the blood pressure control of hospitalized patients, inc...

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Problems solved by technology

[0004] There are many published synthetic methods of clevidipine butyrate, such as the Chinese patent "Preparation method of 1,4-dihydropyridine derivatives" (patent application number: 200910061271.7), "A preparation method of clevidipine butyrate" (Patent application number: CN200910214376.1), New Manufacturing process (WO 00 / 31035), Short-acting Dihydropyridines (WO 95 / 12578), 1,4-Dihydropyridine derivatives (EP0106275A2), Process for Preparation of Clevidipine and its WO Intermediate ( 2012 / 069989), etc., all the preparation methods of the above-mentioned patents use chloromethyl butyrate, and the structure of chloromethyl butyrate is a potential genotoxic impurity, which should be required to be less than 5ppm in the quality standard of the raw material drug , while none of the purification methods mentioned the solution of this genotoxic impurity

Moreover, in most purification methods, multiple recrystallizations are often involved, which greatly reduces the yield of the product. The purification method using water will make the product slightly fluorescent yellow, and this raw material will make the product color when it is made into an emulsion. deepen

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