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2-(2,3-Dimethylphenyl)malonate diester, its preparation method and use

A technology of malonic acid diester and dimethylbenzoic acid is applied in the field of preparation of dexmedetomidine hydrochloride intermediate 1-ethanol, which can solve the problems of inconvenient operation, harsh reaction conditions, inflammability and explosion, etc. The effect of simple operation, mild conditions, and easy large-scale production

Active Publication Date: 2015-09-09
SHANGHAI SYNFARM PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In the first step of this method, LiAlH 4 Reduction and the final step of Grignard reaction with Grignard reagent methylmagnesium iodide all require strict anhydrous conditions, and the reagents are expensive, flammable and explosive, and unfriendly in operation, making the synthesis of 1-(2,3-dimethyl The cost of base phenyl) ethanol (I) increases, and active manganese dioxide needs to be prepared and used immediately, which is not environmentally friendly
[0006] Therefore, in the above-mentioned synthetic 1-(2,3-dimethylphenyl)ethanol (I) process, the main technical problems are as mentioned above, the reaction conditions are harsh, the cost of additional reagents is expensive, the operation is inconvenient, etc., and it is not suitable for industrial production.

Method used

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  • 2-(2,3-Dimethylphenyl)malonate diester, its preparation method and use
  • 2-(2,3-Dimethylphenyl)malonate diester, its preparation method and use
  • 2-(2,3-Dimethylphenyl)malonate diester, its preparation method and use

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Embodiment 1

[0020] Dissolve II (8.25g) in 80mL of dichloromethane, add 8.90g of thionyl chloride, drop a few drops of DMF to initiate the reaction, stir at room temperature overnight, evaporate the solvent to obtain acid chloride III; 11.71g of diethyl malonate , 14.73g of triethylamine and 3.50g of anhydrous magnesium chloride were put into 70mL of ethyl acetate and stirred at room temperature for 45 minutes. After cooling slightly to 10°C, the above-prepared acid chloride III was slowly added dropwise to the system. Stir for 50 minutes to end the reaction, wash with 10% dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine successively, dry the organic layer through anhydrous magnesium sulfate, and obtain 18.60 g of the crude product of V after removing the solvent; in order to obtain the analysis of V With the sample, 3.40g of it was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20:1) to obtain 2.81g of pure V, which was a c...

Embodiment 2

[0022] Dissolve II (8.25g) in 80mL of dichloromethane, add 10.20g of thionyl chloride, drop a few drops of DMF to initiate the reaction, stir at room temperature overnight, evaporate the solvent to obtain acid chloride III; add 9.64g of dimethyl malonate , 14.73g of triethylamine and 3.50g of anhydrous magnesium chloride were put into 70mL of ethyl acetate and stirred at room temperature for 45 minutes. After cooling slightly to 10°C, the above-prepared acid chloride III was slowly added dropwise to the system. Stir for 50 minutes to end the reaction, wash with 10% dilute hydrochloric acid, saturated sodium bicarbonate, and saturated brine successively, dry the organic layer through anhydrous magnesium sulfate, and obtain 15.46 g of the crude product of V after removing the solvent; in order to obtain the analysis of V With the sample, 3.0 g of it was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 20: 1) to obtain 2.63 g of pure V, which ...

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Abstract

The invention discloses a type of 2-(2,3-dimethyl phenyl) diester malonate, a preparation method thereof, and an application thereof in an intermediate 1-(2,3-dimethyl phenyl) ethanol used for synthesizing dexmedetomidine hydrochloride. According to the invention, 2,3-dimethylbenzoic acid is adopted as an initial raw material. The initial raw material is chlorized into 2,3-dimethylbenzoyl chloride. 2,3-dimethylbenzoyl chloride is subject to a reaction with diester malonate under the existences of triethanolamine and magnesium chloride anhydrous, such that 2-(2,3-dimethyl phenyl) diester malonate is obtained. 2-(2,3-dimethyl phenyl) diester malonate is hydrolyzed with sulfuric acid, such that 1-(2,3-dimethyl phenyl)ethanone is obtained. 1-(2,3-dimethyl phenyl)ethanone is then reduced by a reducing agent, such that 1-(2,3-dimethyl phenyl)ethanol is obtained. The operation of the method is simple and convenient; the raw materials of the method are cheap and are easy to obtain; the reaction conditions are mild; and the purity of the finished products is high. With the method provided by the invention, special separating and purifying are not required. The method is suitable to be applied in large-scale productions.

Description

technical field [0001] The present invention relates to a kind of preparation method of medicine intermediate, especially a kind of synthetic dexmedetomidine hydrochloride intermediate 1-(2,3-dimethyl that is suitable for starting intubation during intensive care treatment and sedation of ventilator patients The preparation method of phenyl) ethanol. Background technique [0002] Dexmedetomidine hydrochloride (English name: dexmedetomidine hydrochloride; chemical name: (R)-4-[1-(2,3-dimethylphenyl) ethyl]-1H-imidazole monohydrochloride) is highly effective , Highly selective α2 adrenergic receptor agonist, has dose-dependent sedative, analgesic, anxiolytic, sympathetic inhibition, etc., with few and mild side effects, and was approved for use in intensive care units in the United States in 1999 (ICU) adult sedation and analgesia, and has been successfully applied in many clinical practices such as neurosurgery, preoperative medication, general anesthesia adjuvant, postopera...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C69/738C07C67/343C07C33/20C07C29/143
Inventor 邱友春袁培斋郑美葭蔡继东
Owner SHANGHAI SYNFARM PHARMA TECH