A kind of one-step synthesis method of pharmaceutical grade metadoxine

Abstract

The invention discloses a one-step synthesis method of medicinal metadoxine. The method comprises the steps that vitamin B6 is adopted as a starting raw material and directly reacts with L-pyroglutamic acid after alkali dissociation to obtain metadoxine through one-step synthesis. The proper solvent, the reaction raw material ratio and the proper reaction temperature are adopted, the medicinal metadoxine with the stable crystal form, the good flowability and high purity can be produced industrially without recrystallization or purification, the preparation steps are simplified, operation is easy, the solvent usage amount is decreased, and the production cost is saved. The medicinal metadoxine can be used for treating acute and chronic alcoholism and alcoholic liver diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a one-step synthesis method of pharmaceutical grade metadoxine. Background technique [0002] The chemical name of metadoxine is: pyridoxine L-2-pyrrolidone-5-carboxylate (1:1), and the molecular formula is: C 8 h 11 NO 3 ·C 5 h 7 NO 3 , Molecular weight: 298.29. Metadoxine alias: vitamin B6 pyroglutamate, its structure is: [0003] [0004] As a drug that accelerates the metabolism of alcohol in the body and improves liver dysfunction, the emergence of metadoxine has brought good news to the majority of patients with liver diseases. In December 2013, Metadoxin was rated as one of the top ten blockbuster drugs in 2013 at the "Eleventh China Pharmaceutical Marketing Forum" in December 2013. It can increase the activity of human aldehyde dehydrogenase and accelerate Eliminate ethanol and acetaldehyde in plasma and urine, thus playing a greater protective ro...

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Problems solved by technology

The method for preparing metadoxine needs to be purified by ion exchange chromatography, and the eluent needs to be evaporated under high temperature and reduced pressure, which not only consumes high energy, but also easily causes product decomposition, which is very unfavorable for industrial production.

Guo Xuefei and others reported a two-step synthesis method for the preparation of metadoxine in "Chemical Intermediates" 2006, 4, 19, first using vitamin B6 hydrogen chloride salt and sodium hydroxide to prepare vitamin B6 base, and then reacting with L-burnt gluten amino acid reaction to prepare metadoxine finished product, the method for preparing metadoxine will produce a large amount of sodium chloride in the process of preparing vitamin B6 base, because sodium chloride has similar solubility to the product, it is difficult to produce metadoxine in the system removal, thus affecting the progress of the salt-forming reaction

In addition, in this method, the two raw materials of vitamin B6 base and L-pyroglutamic acid need to be ground and sieved, and they need to be fully mixed in a solvent-free state, which is time-consuming and labor-intensive in industrial production, and the operation is inconvenient, so it is difficult to industrialize

Both patent application WO9419324A and patent application CN101092394A have reported the method of using vitamin B6 base and L-pyroglutamic acid to prepare metadoxine finished product under the condition of isopropanol as solvent, although this method can achieve the preparation of metadoxine finished product However, due to the existence of multiple electron-donating groups in the vitamin B6 base, it is easily oxidized and unstable, so it is difficult to carry out quality control on it, and then the quality of the finished product of metadoxine cannot be guaranteed, and it is difficult to achieve medicinal use. level

In addition, because vitamin B6 base is more expensive than vitamin B6, and because its structure is unstable, it will greatly increase production costs such as special storage conditions, thereby limiting the industrialization of this method

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