Process for preparing medetomidine

A temperature control and compound technology, applied in the direction of organic chemistry, can solve the problems of long route, high production equipment requirements, high cost, etc., and achieve the effect of simple process conditions, efficient preparation, and easy control

Active Publication Date: 2015-11-25
YICHANG HUMANWELL PHARMA +1
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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.MedChem, 1994,37 (9): 1328-1335 discloses to use 4-imidazole methanol as a raw material, through oxidation, N protection, Grignard, oxidation, Grignard, dehydration, catalytic hydrogenation to obtain medetomidine, the The 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.MedChem, 1996, 39 (15): 3001-3013 discloses using imidazole as a raw material, reacting with iodine to obtain 2,4,5-triiodoimidazole, and then N protection, Grignard, oxidation, Grignard dehydration, catalysis 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

Method used

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Experimental program
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Embodiment 14

[0056] Embodiment 14-Iodo-N, the preparation of N-dimethyl-1H-imidazole-1-sulfonamide (step 1)

[0057] 4-iodo-imidazole (27g, 0.139mol) and N, N-dimethyl chlorosulfonamide (21g, 0.146mol) were dissolved in 100ml tetrahydrofuran, and sodium hydroxide (8.4 g, 0.21mol); after feeding, warm to room temperature, react for 12h, add water 50ml, isopropyl acetate 150ml, separate liquid, take oil layer, concentrate to 100ml, add n-hexane 100ml, heat to reflux for 0.5h, cool and analyze crystal, filtered, and dried to obtain 37.9 g of a white solid, namely 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide, with a yield of 90.5%. 1 H-NMR (CDCl 3 , 400MHz): δ7.84(s, 1H), δ7.48(s, 1H), δ2.94(s, 6H).

Embodiment 24

[0058] Example 24-Iodo-N, the preparation of N-dimethyl-1H-imidazole-1-sulfonamide (step 1)

[0059] Dissolve 4-iodo-imidazole (27g, 0.139mol) and N, N-dimethyl chlorosulfonamide (21g, 0.146mol) in 100ml of acetonitrile, and add potassium hydroxide (12g , 0.214mol); after the feeding was completed, it was raised to room temperature, and after 15 hours of reaction, 60ml of water and 200ml of isopropyl acetate were added for liquid separation, and the oil layer was taken, concentrated to 100ml, added with 120ml of n-hexane, heated to reflux for 0.5h, cooled and crystallized , filtered, and dried to obtain 37.8 g of a white solid, namely 4-iodo-N, N-dimethyl-1H-imidazole-1-sulfonamide, with a yield of 90.3%.

Embodiment 34

[0060] Example 34-Iodo-N, the preparation of N-dimethyl-1H-imidazole-1-sulfonamide (step 1)

[0061] Dissolve 4-iodo-imidazole (27g, 0.139mol) and N,N-dimethylchlorosulfonamide (20g, 0.139mol) in 100ml tetrahydrofuran, and add sodium hydroxide ( 9.3g, 0.25mol); after feeding, raise to 15°C, react for 24h, add 50ml of water, 150ml of isopropyl acetate, separate liquid, take oil layer, concentrate to 100ml, add 100ml of n-hexane, heat and reflux for 0.5h, Cooling and crystallization, filtration, and drying yielded 37.4 g of a white solid, namely 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide, with a yield of 89.4%.

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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 OrionPharma Company of Finland and Abott Company 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...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D233/58
CPCC07D233/58
Inventor 许勇李莉娥王学海李杰乐洋江曦冯权武杨仲文肖强田华杨菁
Owner YICHANG HUMANWELL PHARMA
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