Preparation process of anti-infective drug nifuratel

Abstract

The invention belongs to the technical field of drug synthesis and in particular relates to a preparation process of an anti-infective drug nifuratel. The preparation process comprises the following steps: taking iodomethane, sodium sulfide and chlorocyclopropane as initial raw materials to obtain epoxy propyl methyl sulfide, carrying out ring-opening reaction with hydrazine hydrate to obtain 3-methylmercapto-2-hydroxyl-propylhydrazine, carrying out a ring-closure reaction to obtain N-amino-5-methylthiomethyl-2-oxazolidinone, hydrolyzing 5-nitro furfural diacetate in the presence of trifluoroacetic acid to obtain 5-nitro-2-furancarboxaldehyde, and performing condensation with N-amino-5-methylthiomethyl-2-oxazolidinone, thereby obtaining the nifuratel. Safe and cheap reagents are selected in the process route, and environment hazards are reduced. Meanwhile, the operating difficulty and reaction after-treatment burdens are reduced, the production safety is ensured, the process is a simple, green and economic process route for preparing the nifuratel, and the obtained product is high in yield, excellent in purity and suitable for large-scale industrial production of the nifuratel.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation process of an anti-infective drug nifuratel. Background technique [0002] Nifuratel is a drug mainly used for gynecological infections developed by Italy Puli Chemical Company, chemical name: 5-[(methylthio)methyl]-3-{[(5-nitro-2-furan )methylene]amino}-2-oxazolidinone, which is a broad-spectrum antibiotic, especially for common pathogens of gynecological infections such as Gram-positive and negative bacteria, trichomonas, mold, chlamydia and mycoplasma, etc. It has a strong killing effect and has a good curative effect on the treatment of common gynecological vaginal infections caused by trichomonas, Candida albicans, and bacteria. It is now on the market in my country and many other countries with dosage forms such as tablets, capsules, and suppositories. [0003] The chemical structure of Nifuratel is as follows: [0004] [0005] The pu...

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Problems solved by technology

[0013] Route one and route two are basically similar, and the main difference is that when preparing 3-methylthio-2-hydroxypropylhydrazine, methyl mercaptan and sodium methyl mercaptide are used respectively, and the preparation process of the intermediate oxazolidinone The sodium methoxide / methanol system is used, and metal sodium is used in feeding, which has great potential safety hazards, and it is very easy to cause combustion and explosion, and strict feeding and production operations are required; the separation process of intermediates is mostly high vacuum distillation. The requirements for equipment are high, the operation is difficult, and the yield is low. Due to the foul smell of methyl mercaptan and sodium methyl mercaptide used, it is easy to cause damage to the environment and has a greater pressure on environmental protection.

[0014] Compared with route 1 and route 2, route 3 has the biggest advantage in that compound 3 is prepared under the conditions of dimethyl sulfate and thiourea, which avoids the stench produced during the use of sodium methyl mercaptide and methyl mercaptan, but Li Zhi The route reported by Wan et al. is long and the yield is low, while the patent CN100516063C utilizes sodium hydride for cyclization to prepare compound 5

Though route three has certain advancement than previous two routes, there is still certain shortcoming: (1) the toxicity of dimethyl sulfate is bigger, causes the operation difficulty of technique to become larger; (2) in cyclization reaction although Sodium metal is not used, but the danger of sodium hydride is also very high, and it is very easy to spontaneously ignite and explode; (3) The separation process of compound 4 and compound 5 requires vacuum distillation, which requires high equipment

Because 5-nitrofurfural is easy to change color when exposed to light, and the aldehyde group is unstable, it will cause faster discoloration under heating conditions, more side reactions, easy to generate polymers, and poor product quality. At the same time, the yield of 5-nitrofurfural Reduce, cause the yield of nifuratel to reduce, and the color of product deepens, has influenced the quality of nifuratel

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