Preparation method of dexmedetomidine and intermediate product thereof

A technology of dexmedetomidine and asana, which is applied in the field of preparation of dexmedetomidine and intermediates thereof, and can solve the problems of long synthesis process route, cumbersome processing technology, inconsistency with green chemistry and the like

Active Publication Date: 2016-12-07
JIANGSU HENGRUI MEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] The starting material 4-(1-triphenylmethyl)imidazole aldehyde used in the literature is prepared from fructose as the starting material. The raw material has good stability, high purity, is very easy to get in the market, and is low in price. It is similar to US20100048915 Compared with obvious advantages, but its synthetic process route is longer, and the heavy metal oxidant MnO is used in the process 2 , its treatment process is cumbersome, the production cost is relatively high, and it does not conform to the concept of green chemistry

Method used

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  • Preparation method of dexmedetomidine and intermediate product thereof
  • Preparation method of dexmedetomidine and intermediate product thereof
  • Preparation method of dexmedetomidine and intermediate product thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Preparation of 1-(1-bromoethyl)2,3-dimethylbenzene

[0058]

[0059] In a 5L three-necked flask, add 1L of tetrahydrofuran and 60g (2.5mol) of magnesium strips, heat to reflux, and add dropwise 750mL of a tetrahydrofuran solution of 463g (2.5mol) of 2,3-dimethylbromobenzene. After reflux for 1 hour, cool to room temperature, add dropwise acetaldehyde 180ml (3.2mol) / tetrahydrofuran 500mL solution, continue to reflux for 1 hour, remove tetrahydrofuran under reduced pressure, and slowly add ammonium chloride aqueous solution (125g ammonium chloride to 400ml water) and Ethyl acetate 1.5L. Stand to separate layers, dry the organic phase with anhydrous sodium sulfate, filter, distill off the solvent, and then distill under reduced pressure to collect fractions at 115-118°C / 300Pa. Dissolve 330 g of the distilled product in 1.5 L of dichloromethane, cool down to 0°C, add phosphorus tribromide (1188 g, 4.4 mol) in 1 L of dichloromethane solution dropwise, and stir at room te...

Embodiment 3

[0063] Example 3: Preparation of 4-[(2,3-dimethylphenyl)-ethyl]-1-(triphenylmethyl)imidazole

[0064]

[0065] Preparation of starting material 1: Weigh compound 1 (52.3g, 0.12mol), add 300ml tetrahydrofuran / water (2:1), mark A solution for future use;

[0066] Preparation of starting material 2: Weigh compound 2 (21.2g, 0.1mol), add 300ml tetrahydrofuran / water (2:1), then add 52.9g potassium phosphate, mark solution B for later use;

[0067] Prepare catalyst 0.5g PdCl 2 [dtbpf] tetrahydrofuran solution, add 10ml tetrahydrofuran mark C solution mark C solution;

[0068] Use a pump to inject solution A and solution B into the micromixer at a flow rate of 25ul / min, and at the same time add solution C to it at the same rate, and after mixing, enter the microtube reactor with a diameter of 0.5mm and a tube length of 1.5m for reaction. The oil temperature in the microtube reactor was 65°C, and it was detected by an HPLC detector. The solution containing the compound of formula I...

Embodiment 4

[0069] Example 4: Preparation of 4-[(2,3-dimethylphenyl)-ethyl]-1-(triphenylmethyl)imidazole

[0070]

[0071] Under argon atmosphere, add compound 1 (26.15g, 0.06mol), compound 2 (10.6g, 0.05mol) and 150mL tetrahydrofuran / water (2:1) to a 5L reaction flask, and then add 26.45g potassium phosphate , 0.25g PdCl 2 [dtbpf], after 2-3 times of argon replacement, microwave heating to 65°C, after 10 minutes, HPLC detected that the reaction was complete, filtered, concentrated under reduced pressure and evaporated to remove the solvent, and purified by column chromatography to obtain 19.74g, yield 95.1% .

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Abstract

The invention provides a preparation method of dexmedetomidine and an intermediate product thereof. Concretely, the method comprises the step of synthesizing a compound shown as a formula I by using SuzuKi coupling reaction. The invention also provides a method for continuously preparing the dexmedetomidine and the intermediate product thereof. The process has the advantages of short steps, high yield, operation simplicity, high purity and the like, and is suitable for industrial mass production.

Description

technical field [0001] The invention relates to a preparation method of dexmedetomidine and an intermediate thereof. Background technique [0002] Dexmedetomidine Hydrochloride Injection is an α2-adrenoceptor agonist jointly developed by Orion Pharma and Abott. It was first launched in the United States in March 2000 and in Japan in January 2004. This product is the dextroisomer of the α2-adrenoceptor agonist medetomidine. Compared with medetomidine, this product is more selective for central α2-adrenoceptor agonism and has a shorter half-life , the dosage is very small, and it is clinically suitable for the sedation of intubation and ventilator patients during intensive care treatment. [0003] Medetomidine, the chemical name is 5-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole, dexmedetomidine is its dextral isomer, which is decomposed by medetomidine The structures are obtained as follows: [0004] [0005] At present, the methods for preparing medetomidine are mainly d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58C07D233/62
CPCY02P20/55C07D233/58C07B2200/07C07D233/62
Inventor 侯宪山王俊琰廖晓军徐燕
Owner JIANGSU HENGRUI MEDICINE CO LTD
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