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Method for preparing dexmedetomidine and intermediate thereof

A compound and selected technology, applied in organic chemical methods, bulk chemical production, organic chemistry, etc., can solve problems such as multi-industrial impurities, synthetic process inconsistencies, unfavorable purification process development, etc., to avoid process impurities and ensure quality , the effect of convenient operation

Active Publication Date: 2016-08-24
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] At the same time, its synthesis process does not conform to the concept of green chemistry, and produces more industrial impurities, especially more specific process impurities, which is not conducive to the development of subsequent purification processes. The specific structure is as follows

Method used

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  • Method for preparing dexmedetomidine and intermediate thereof
  • Method for preparing dexmedetomidine and intermediate thereof
  • Method for preparing dexmedetomidine and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation of 1-(2,3-dimethylphenyl)-1-(1H-imidazol-4-yl)ethanol

[0045] Refer to "Laboratory Chemicals Purification Handbook (Original Work Fifth Edition)" to process the solvent tetrahydrofuran used in the reaction, and add an appropriate amount of water, and use the AKF-1 moisture meter to measure its moisture content to be 0.13%.

[0046]

[0047] In a 500ml reaction flask, the temperature was lower than 50°C, magnesium (5.5g, 224mmol) was added to tetrahydrofuran (140ml), and iodine (10mg) was stirred. Cool down to room temperature, add dropwise a solution of 2,3-dimethylbromobenzene (40.2g, 217mmol) in tetrahydrofuran (120ml, the water content is 0.13% as measured by AKF-1 moisture meter), and stir the mixture at 20-25°C for 1.5h . Heat to reflux for an additional hour, then cool to room temperature. A solution of 1-(1H-imidazol-4-yl)ethanone (19.8g, 180mmol) in tetrahydrofuran (50ml) was added dropwise at 20°C, and stirring was continued at room...

Embodiment 2

[0051] Example 2: Preparation of 1-(triphenylmethyl)-1-(1H-imidazol-4-yl)ethanone

[0052]

[0053] In a 2000ml reaction flask, put 41.3g (282mol) of imidazole-4-ethanone hydrochloride (2), 380ml of DMF, 114ml of triethylamine, under the protection of nitrogen, add triphenylchloromethane dropwise at an internal temperature below 15°C 91.2g (327mmol) was dissolved in 570ml of N,N-dimethylformamide (DMF), and the solution was added in about 1 hour, and the reaction was continued for 1 hour. Cool to below 5°C, filter and drain. Take it out, stir evenly in 1140ml of water, filter, and wash the filter cake with water (200ml). After drying, 88.4 g of solids were obtained, with a yield of 89.0%. (TLC detection, developer: chloroform: methanol: ammoniacal liquor=50:5:1), MS (m / z), 353.3 (MH + ).

Embodiment 3

[0054] Example 3: Preparation of 4-[(2,3-dimethylphenyl)-1-hydroxyethyl]-1-(triphenylmethyl)imidazole

[0055] Refer to "Laboratory Chemicals Purification Handbook (Original Work Fifth Edition)" to process the solvent tetrahydrofuran used in the reaction, and add an appropriate amount of water, and use the AKF-1 moisture meter to measure its moisture content to be 0.09%.

[0056]

[0057] In a 2000ml reaction flask, a solution of 2,3-dimethylbromobenzene (46g, 248mmol) in tetrahydrofuran (800ml, its moisture content measured by AKF-1 moisture meter is 0.09%) was added dropwise to magnesium (6g, 0.25 mmol), an appropriate amount of iodine in tetrahydrofuran (200ml) solution, after the addition, heated to reflux for 1 hour, then cooled to room temperature. The above-prepared solution was added dropwise to a solution of 1-(triphenylmethyl)imidazolone 4 (70 g, 199 mmol) in THF (800 ml) at 20°C. After the addition was complete, the mixture was warmed to room temperature and sti...

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Abstract

The invention provides a method for preparing dexmedetomidine and an intermediate thereof. Specifically speaking, the method comprises the steps that a compound shown as a formula II (please see the formula in the description) reacts with metal magnesium to prepare a metal magnesium Grignard reagent, and then the metal magnesium Grignard reagent reacts with a compound shown as a formula III (please see the formula in the description). The process has the advantages of being few in step, high in yield, easy to operate, high in product purity and the like and is quite suitable for large-scale industrialized production.

Description

technical field [0001] The invention relates to a preparation method of dexmedetomidine and an intermediate thereof. Background technique [0002] Alpha-2 adrenergic receptor agonists are used clinically to treat hypertension and drug and ethanol withdrawal symptoms. These drugs can produce anti-anxiety, sedative, anti-sympathetic and other effects, and can meet different needs during surgery, so they are widely used in clinical anesthesia. Dexmedetomidine, one of the α-2 receptor agonists, has a chemical name of (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, structure As follows: [0003] [0004] Dexmedetomidine is split from medetomidine, and its hydrochloride is dexmedetomidine hydrochloride, which is an α-2 adrenergic receptor agonist jointly developed by OrionPharma / Abott. It was released in March 2000 Listed in the United States, in January 2004 in Japan. Dexmedetomidine has anti-sympathetic, sedative and analgesic effects. This product is more selective for...

Claims

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Application Information

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IPC IPC(8): C07D233/64C07D233/58
CPCY02P20/55C07D233/64C07B2200/07C07D233/58
Inventor 侯宪山王治安徐燕陈永江
Owner JIANGSU HENGRUI MEDICINE CO LTD
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