Method for preparing medetomidine

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

Active Publication Date: 2014-03-26
YICHANG HUMANWELL PHARMA +1
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  • Abstract
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  • Claims
  • Application Information

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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, eliminat

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  • Method for preparing medetomidine

Examples

Experimental program
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Example Embodiment

[0056] Example 14-Preparation of iodine-N,N-dimethyl-1H-imidazole-1-sulfonamide (Step 1)

[0057] Dissolve 4-iodo-imidazole (27g, 0.139mol) and N,N-dimethylchlorosulfonamide (21g, 0.146mol) in 100ml tetrahydrofuran, control the feeding temperature at 0~10℃ and add sodium hydroxide (8.4 g, 0.21mol); After feeding, warm to room temperature, after 12h reaction, add 50ml of water, 150ml of isopropyl acetate, separate the liquids, take the oil layer, concentrate to 100ml, add 100ml of n-hexane, heat to reflux for 0.5h, cool to separate Crystallized, filtered and dried to obtain 37.9 g of white solid, namely 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide, with a yield of 90.5%. 1 H-NMR(CDCl 3 , 400MHz): δ 7.84 (s, 1H), δ 7.48 (s, 1H), δ 2.94 (s, 6H).

Example Embodiment

[0058] Example 24-Preparation of iodine-N,N-dimethyl-1H-imidazole-1-sulfonamide (Step 1)

[0059] Dissolve 4-iodo-imidazole (27g, 0.139mol) and N,N-dimethylchlorosulfonamide (21g, 0.146mol) in 100ml acetonitrile, control the feeding temperature at 0~10℃, add potassium hydroxide (12g , 0.214mol); After feeding, warm to room temperature, after 15 hours of reaction, add 60ml of water, 200ml of isopropyl acetate, separate the liquids, take the oil layer, concentrate to 100ml, add 120ml of n-hexane, heat to reflux for 0.5h, cool and crystallize , Filtered and dried to obtain 37.8 g of white solid, which is 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide, with a yield of 90.3%.

Example Embodiment

[0060] Example 34-Preparation of iodine-N,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, control the feeding temperature at -5~5℃ and add sodium hydroxide ( 9.3g, 0.25mol); after the feeding is completed, the temperature is raised to 15°C, after 24h reaction, add 50ml of water, 150ml of isopropyl acetate, separate the layers, take the oil layer, concentrate to 100ml, add 100ml of n-hexane, and heat to reflux for 0.5h. After cooling and crystallization, filtration and drying, 37.4 g of white solid was obtained, 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 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 ...

Claims

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Application Information

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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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