Preparation method of atipamezole

A technology of atipamezole and compounds, which is applied in the field of preparation of atipamezole, can solve the problems of harsh reaction conditions, inability to withstand high-pressure hydrochloric acid reaction, and high requirements for reaction equipment, so as to achieve high selectivity and avoid the formation of impurities , good product yield and purity

Pending Publication Date: 2021-01-15
HUNAN NORCHEM PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are very few suppliers of the starting material 2-acetylindanone for this route. We can consider using indanone and imidazole to synthesize it ourselves, which requires two-step reactions
[0013] The fourth route uses nitrosomethane, chlorine and hydrazine hydrate for reduction, the reaction conditions are harsh, and there is a certain degree of danger
And it requires high reaction equipment
[0014] The fifth process route is most suitable for industrial production, but the last step of reduction reported in the literature also uses hydrochloric acid as a solvent for catalytic hydrogenation. Conventional autoclaves are made of stainless steel and cannot withstand the high-pressure reaction involving hydrochloric acid.

Method used

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  • Preparation method of atipamezole
  • Preparation method of atipamezole
  • Preparation method of atipamezole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1 prepares compound 2

[0032] In a cold water bath at 0-5°C, take 7g of compound 1 and add 105ml of absolute ethanol (15V / W), stir, add 2.8g of sodium borohydride, react for 24 hours, spot the plate to monitor the reaction, and take acetone when compound 1 disappears 30ml was added dropwise to the reaction mixture to terminate the reaction. The solvent was removed under reduced pressure, 200 ml of dichloromethane was added, stirred for 2 hours, filtered, and the solvent was removed under reduced pressure to obtain 5.92 g of crude compound 2, yield: 84.57%.

Embodiment 2

[0033] Embodiment 2 prepares atipamezole

[0034] Take 5.4g of compound 2 and add it to 20ml of acetonitrile, then add 10ml of dichloromethane, cool down to -20~-10°C, add 20ml of iodotrimethylsilane to react, TLC detects that the reaction is complete, add 2M sodium thiosulfate to terminate the reaction, Stand still to separate the liquids, wash the organic phase once with saturated saline, concentrate the organic phase to remove the solvent, add 50ml of 2M hydrochloric acid, react at 100°C for 1-1.5 hours, remove the protecting group, filter, adjust the pH of the aqueous phase with 40% sodium hydroxide >10, filtered to obtain 2.3g of light yellow solid. Yield 92%.

Embodiment 3

[0035] Embodiment 3 prepares atipamezole hydrochloride

[0036] Take 4 grams of atipamezole, add two equivalents of ethanol hydrochloride (6M) dropwise in a cold water bath at 5°C, and stir for 30 minutes after the addition; remove the solvent under reduced pressure; then add 3-5 (v / w) anhydrous Slurry with ethanol for 3 hours at a temperature of 25-30°C and filter. The filter cake was dried under reduced pressure at 60°C for 24 hours to obtain atipamezole hydrochloride: 3.81 g, yield 95.25%.

[0037] High-performance liquid chromatography detection: the content is greater than 99%, and the single impurity content is less than 0.1%.

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Abstract

The invention belongs to the technical field of veterinary drug preparation methods, and particularly relates to a preparation method of atipamezole. The method comprises the following steps: carryingout two-step reduction on a compound 1 to prepare atipamezole, wherein the reaction route is shown in Figure 6, in the second step, a compound 2 is dispersed in an organic solvent, a reducing agent trimethyliodosilane is added, the reaction is performed to obtain the atipamezole, the reaction conditions of the preparation method are mild, the weight yield can reach 74% or above, and the purity is99% or above.

Description

technical field [0001] The invention belongs to the technical field of preparation methods of veterinary medicines, and in particular relates to a preparation method of atipamezole. Background technique [0002] Atipamezole hydrochloride, chemical name: 4-(2-ethyl-2-indane) imidazole hydrochloride, trade name: Antisedan, developed by the U.S. Orion-Farmos company. Atipamezole hydrochloride is a synthetic alpha2 adrenergic receptor antagonist used to reverse the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. It reverses its action by competitively binding to α2-adrenoceptor sedatives. Atipamezole is highly specific for α2-adrenergic receptors. The incidence of side effects is low. Atipamezole is primarily used in veterinary medicine and is now licensed for intramuscular intravenous administration in dogs and cats. Its characteristics are: the onset is very fast, usually within 3-5 minutes, and the maximum blood sugar concentration is reached i...

Claims

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Application Information

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IPC IPC(8): C07D233/58
CPCC07D233/58Y02P20/55
Inventor 靳志忠邓伟曾春玲刘喜荣
Owner HUNAN NORCHEM PHARMACEUTICAL CO LTD
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