Method for preparing medetomidine

Abstract

The invention discloses a method for preparing medetomidine. Medetomidine can be effectively prepared according to the method for preparing medetomidine, and by adopting a cheap 4-imidazole derivative and cheap 1-(2,3-dimethylphenyl)ethanone as raw materials, the medetomidine product is prepared only through three-step reactions. The method has simple process conditions, is easy to control, and is conducive to industrialized mass production; and the yield of medetomidine prepared by the method for preparing medetomidine can reach 76%, and the product purity can reach 99.5%.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular, the invention relates to a method for preparing medetomidine. Background technique [0002] Medetomidine (also known as medetomidine, see the compound shown in formula 1), chemical name 4-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole, is two The racemic mixture of equal proportions of optical isomers was jointly developed by Orion Pharma of Finland and Abott of the United States. It was first listed in the United States in March 2000 and listed in Japan in January 2004. Medetomidine is an α2-adrenergic receptor agonist, which plays an important medicinal role in the regulation of hypertension, bradycardia (lower heart rate), alertness and pain relief. The construct is also an anesthetic for the active ingredient. [0003] US4443466A discloses to use 2,3-dimethylbenzaldehyde as a starting material, through Grignard, chlorination, and reaction with titanium tetrachloride ...

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Problems solved by technology

[0005] US4544664A discloses the reaction of 4-imidazole formic acid methyl ester with 2,3-dimethylbenzenemagnesium bromide and methylmagnesium bromide, and then through reduction and catalytic hydrogenation to obtain medetomidine, the raw material 4 used in this method - Methyl imidazole carboxylate is expensive

[0006] J.Med Chem, 1994, 37 (9): 1328-1335 discloses that 4-imidazole methanol is used as a raw material to obtain medetomidine through oxidation, N protection, Grignard, oxidation, Grignard, dehydration, catalytic hydrogenation, This method is similar to the method disclosed in US4544664A, but also has the disadvantages of long route, repeated oxidation and Grignard reaction, and high cost

[0007] J.Med Chem, 1996,39(15): 3001-3013 discloses to use imidazole as raw material, react with iodine to obtain 2,4,5-triiodoimidazole, and then through N protection, Grignard, oxidation, Grignard dehydration, Catalytic hydrogenation to obtain medetomidine, this method also has the disadvantages of long route, repeated oxidation and Grignard reaction, and high cost

[0008] CN101235272A discloses to take 4-iodo-1-triphenylmethyl-1H-imidazole, 2,3-dimethylbenzaldehyde as starting material, through Grignard, oxidation, Grignard, elimination, alkalization, catalytic addition Hydrogen is used to obtain medetomidine. This method involves 7 steps of reaction, and the route is relatively long, including 2 Grignard reactions, which increases the process cost.

[0009] CN102753532A discloses using 2,3-dimethyl-benzoic acid as a starting material to obtain medetomidine through esterification, acylation, cyclization, catalytic hydrogenation, etc. The disadvantage of this method is that its process steps are long, involving 7 One-step reaction, two of which involve high-pressure catalytic hydrogenation reaction, resulting in complex synthesis process and high energy consumption. At the same time, the heavy metal lead, which is taboo in the field of medicine, is used in the process.

[0010] In summary, the existing technology for the preparation of medetomidine has difficult and expensive sources of raw materials, and requires the use of protecting groups and deprotecting groups, lengthy routes, harsh reaction conditions, difficult control, poor operability, and high requirements for production equipment , high pressure on safety and environmental protection, difficult product purification, low yield and other shortcomings, so it cannot meet the needs of industrial production

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