Preparation method of dexmedetomidine

A dexmedetomidine and group technology, which is applied in the field of organic chemical synthesis, can solve the problems of poor atom economy, high three-waste emission and high cost, and achieves the effects of reducing environmental protection pressure, avoiding the generation of process impurities, and reducing pressure.

Active Publication Date: 2018-04-06
RAFFLES PHAMRMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, the current synthesis method of optically pure dexmedetomidine mainly relies on splitting, with low yield and poor atom economy, resulting in high cost and high discharge of three wastes

Method used

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  • Preparation method of dexmedetomidine
  • Preparation method of dexmedetomidine
  • Preparation method of dexmedetomidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] step 1:

[0036] (2,3-dDimethylphenyl)(1H-imidazol-4-yl)methanol

[0037]

[0038] Add 60 g of (2,3-dimethylphenyl)(1H-imidazol-4-yl)methanone into a 1000 mL four-neck flask, add 300 mL of methanol, and add 34.53 g sodium borohydride, temperature control below 0 ℃, there is gas generation and exotherm, after adding sodium borohydride for 20 minutes, sampling TLC shows that the reaction is complete, carry out post-treatment: control temperature below 10 ℃, add 100 mL ice water to quench, Add another 1200 mL of ice water, stir in an ice ethanol bath (0 °C) for 30 min to precipitate a light yellow solid, filter with suction, discard the filtrate, add 200 mL of water to rinse the filter cake, filter with suction, discard the filtrate, and add the filter cake to vacuum Put it in a vacuum drying oven in a drying oven, drying conditions: temperature 60 °C, vacuum -0.09 MPa, time 10 h, and a yellow solid was obtained after drying.

[0039] Step 2:

[0040]

[0041] Tak...

Embodiment 2

[0054] Step 4:

[0055]

[0056] The residue obtained in the previous step was dissolved in 2000 ml of toluene, and then 2 g of a phase transfer catalyst (structure shown below) was added. Then 20 g of 1,5,7-triazidebicyclo(4.4.0)dec-5-ene were added. Subsequently, 15 g of iodomethane was added and stirred at room temperature for 12 hours. After the reaction was completed, 1000 ml of water was added for liquid separation. The organic phase was desolvated and recrystallized from 700 ml of ethyl acetate. The optical purity of the obtained product was 99.7%.

[0057] The phase transfer catalyst structure is:

[0058]

Embodiment 3

[0060] Step 4:

[0061]

[0062] The residue obtained in the previous step was dissolved in 2000 ml of toluene, and then 3 g of a phase transfer catalyst (structure shown below) was added. Then 20 g of 1,5,7-triazidebicyclo(4.4.0)dec-5-ene were added. Subsequently, 15 g of iodomethane was added and stirred at room temperature for 12 hours. After the reaction was completed, 1000 ml of water was added for liquid separation. The organic phase was desolvated and recrystallized from 700 ml of ethyl acetate. The optical purity of the obtained product was 99.0%.

[0063] The phase transfer catalyst structure is:

[0064]

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Abstract

The invention discloses a preparation method of dexmedetomidine, which includes the steps of: performing a methylation reaction to 5-(2,3-dimethylphenyl)-1-triphenylmethyl-1H-imidazole and MeI under effect of a phase transfer catalyst; removing a triphenylmethyl protective group with concentrated hydrochloric acid to obtain the dexmedetomidine. The method reduces synthesis cost and avoids rigorousreaction conditions. The method employs simple reaction conditions and can produce dexmedetomidine at high chemical and optical purities. The method has excellent processability, is beneficial to industrial production, can reduce environment stress, is simple in synthesis route and can avoid generation of some technical impurities, thus reducing work load of purifying a final product.

Description

technical field [0001] The present invention relates to the field of organic chemical synthesis, more specifically, to a preparation method of dexmedetomidine. Background technique [0002] Dexmedetomidine is an α2-adrenoceptor agonist indicated for sedation during tracheal intubation and mechanical ventilation in surgical patients undergoing general anesthesia. In recent years, dexmedetomidine has been widely used in clinical anesthesia. [0003] [0004] At present, there are two main routes for the synthesis of this drug. [0005] Synthetic route one: [0006] [0007] Synthetic route two: [0008] [0009] It can be seen that both routes synthesize the racemic product medetomidine first, and then resolve it with L-tartaric acid to obtain optically pure dexmedetomidine. The yield of the resolution process is generally 20-30%. [0010] To sum up, the current synthesis method of optically pure dexmedetomidine mainly relies on resolution, with low yield and poo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58
CPCC07D233/58Y02P20/55
Inventor 叶伟平费安杰周章涛尹志媛郭陆川黄萍谢阳银
Owner RAFFLES PHAMRMATECH CO LTD
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