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Method for preparation of medetomidine with chloroacetone

A technology of reaction and compound, applied in the field of preparation of medetomidine, can solve the problems of relatively expensive use, high material consumption, long time consumption and the like

Inactive Publication Date: 2014-12-24
LONZA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Known processes for the preparation of compounds of formula (XX) generally use protecting groups, such as trityl (trityl) residues, which cause high material consumption and require protection / deprotection steps
Therefore, these syntheses are time consuming and expensive
In addition, more expensive and non-ready starting materials are used

Method used

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  • Method for preparation of medetomidine with chloroacetone
  • Method for preparation of medetomidine with chloroacetone
  • Method for preparation of medetomidine with chloroacetone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0241] Example 1: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), metal substitution with butyllithium in THF

[0242] To a solution of 1-bromo-2,3-dimethylbenzene (0.27ml, 2.0mmol) in THF (4.0ml) was added n-butyllithium (2.0ml of a 1.6M solution in hexane at -78°C , 3.2 mmol). The mixture was stirred at -78°C for 30 minutes, then a solution of chloroacetone (0.24ml, 3.0mmol) in toluene (0.42ml) was added dropwise over 20 minutes. The mixture was stirred at -78°C for 1 hour, then allowed to warm to room temperature. Analysis of a sample after 3 hours at room temperature showed the title epoxide to be the major reaction product. After stirring at room temperature for 3 days, the mixture was poured into water (20ml) and the product was extracted with ethyl acetate (1 x 10ml, 2 x 5ml). The combined extracts were washed with MgSO 4 Drying and concentration under reduced pressure afforded the title epoxide as an oil in quantitative yield.

[0243] 1 H NMR: 1...

Embodiment 2

[0245] Example 2: 2-(2,3-Dimethylphenyl)methyloxirane, compound of formula (XXII), metallized with magnesium in THF

[0246] To a suspension of magnesium (89 mg, 3.66 mmol) in THF (4.0 ml) was added NaH (81 mg, 60% in oil, 2.0 mmol), and after stirring at room temperature for 10 minutes, 1-bromo-2,3 - Dimethylbenzene (0.40ml, 2.96mmol). An exothermic reaction ensued and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then cooled to -20°C and a solution of chloroacetone (0.26ml, 3.3mmol) in toluene (0.63ml) was added dropwise over 10 minutes. The mixture was then stirred at room temperature for 2 hours. The samples were worked up by mixing with water, extracting with ethyl acetate, evaporating the ethyl acetate with a stream of nitrogen. use 1 H NMR analysis of the residue showed it to be a mixture of xylene and the title oxirane compound.

Embodiment 3

[0247] Example 3: 2-(2,3-Dimethylphenyl)propanal, compound of formula (XXI)

[0248] The 2-(2,3-dimethylphenyl)methyloxirane prepared according to Example 1, the compound of formula (XXII) (158mg, 0.97mmol) was dissolved in toluene (1.57mL), and at room temperature Join BF under 3 OEt 2 (0.006ml, 0.05mmol). After 2 hours at room temperature the sample was mixed with solid NaHCO 3 Mix, filter, concentrate under reduced pressure, use 1 H NMR analysis of the residue. The crude product consisted essentially of pure 2-(2,3-dimethylphenyl)propanal.

[0249] 1 H NMR: 1.40(d, J=7.1Hz, 3H), 2.25(s, 3H), 2.32(s, 3H), 3.89(qd, J=7.1, 1.0Hz, 1H), 6.89 to 6.92(m, 1H ), 7.12 (m, 2H), 9.67 (d, J=1.0Hz, 1H).

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Abstract

The invention discloses a method for the preparation of medetomidine starting from 1-bromo 2,3-dimethylbenzene and chloroacetone.

Description

technical field [0001] The invention discloses a method for preparing medetomidine starting from 1-bromo-2,3-dimethylbenzene and chloroacetone. Background technique [0002] Medetomidine is a compound of formula (XX), an alpha2 adrenergic agonist, currently used as a veterinary sedative and analgesic and is considered an anesthetic. [0003] [0004] Medetomidine is a 4-alkylimidazole. 4-Alkylimidazoles containing no other substituents at the nitrogen group are generally a mixture of two tautomers. For example, in the case of medetomidine, if medetomidine is dissolved or in a non-crystalline state, the two tautomeric forms (represented by the compound of formula (XX) and the compound of formula (XX-T)) are usually will change each other. Whether one of the tautomeric forms predominates or they exist in equal amounts depends on various factors such as pH, solvent or temperature. [0005] [0006] Herein, formula (XX) is used for medetomidine and is meant to include ...

Claims

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Application Information

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IPC IPC(8): C07D233/56A61K31/4164
CPCC07D233/58C07D263/16C07D233/56A61K31/4164
Inventor 弗洛伦斯奥·萨拉戈萨道尔沃德安娜·库勒撒史蒂芬·埃琳娜罗伯特·布约克兹比格纽·沃贝克里斯托弗·沃伊切霍夫斯基
Owner LONZA LTD
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