Method for synthesizing dexmedetomidine hydrochloride

A technology of dexmedetomidine hydrochloride and a synthesis method, applied in the field of synthesis of dexmedetomidine hydrochloride, can solve problems such as difficult availability, low yield, lack of starting material supply, and achieves low cost and mild reaction conditions. Effect

Inactive Publication Date: 2019-04-12
CISEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But the supply of starting materials is lacking in this reaction route, is not easy to obtain
[0007] The second is to obtain 1-(2,3-dimethylphenyl)ethanol by reducing 2,3-dimethylacetophenone, and the chlorinated 1-(2,3-dimethylphenyl)-1 Ethyl chloride reacts with N-(trimethylsilane) imidazole to obtain medetomidine, and the route yield is lower

Method used

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  • Method for synthesizing dexmedetomidine hydrochloride
  • Method for synthesizing dexmedetomidine hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Preparation of N,N-Dimethylsulfonylimidazole (Compound Ⅰ)

[0030] Add 200.0ml (1.84mol) of N,N-dimethylsulfamoyl chloride, 147.0g (2.16mol) of imidazole and 280ml of triethylamine into 2.5L of anhydrous ether under stirring, and stir at room temperature for 16h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with 1.5 L of ether, and the filtrates were combined. The filtrate was dried with anhydrous Na2SO4, concentrated in vacuo to obtain a residue, and the residue was distilled to obtain a product: 305.1 g. b.p.110°C (0.4mmHg), standing to form colorless crystals. M.p. 42-44°C. Yield: 94.75%

[0031] Preparation of 1-N,N-dimethylsulfonyl-2-(tert-butyldimethylsilyl)-5-(2,3-dimethylbenzoyl)imidazole (compound Ⅱ)

[0032] Dissolve 300.0g (1.71mol) of compound I in dry 14.0L THF, lower the temperature to -78°C under the protection of argon, add dropwise 0.96L (1.92mol) 2.0M butyllithium n-hexane solution, after 0.5h, 306...

Embodiment 2

[0045] The pre-preparation steps were the same as in Example 1, and then weighed 40.0 g (0.169 mol) of crude dexmedetomidine hydrochloride, dissolved it in 200 ml of absolute ethanol at 50° C. with stirring, and filtered the obtained solution with a G4 sand core funnel once. Add 2L ether and 0.1g recrystallization of 3-epi-sabufabin into the filtrate dropwise under stirring. After dropping, place in freezer for 5 hours, filter the precipitated crystals with suction, and dry them in vacuum to obtain 31.0g white crystals with a yield of 77.4%. mp: 153-156°C.

Embodiment 3

[0047] The pre-preparation steps were the same as in Example 1, and then weighed 40.0 g (0.169 mol) of crude dexmedetomidine hydrochloride, dissolved it in 200 ml of absolute ethanol at 50° C. with stirring, and filtered the obtained solution with a G4 sand core funnel once. Add 2L ether and 0.1g recrystallization of sabubufabin dropwise to the filtrate under stirring, after dropping, place in freezer for 5 hours, filter the precipitated crystals with suction, and dry them in vacuum to obtain 38.7g white crystals with a yield of 96.8%. mp: 153-156°C.

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Abstract

The invention belongs to the technical field of drug preparation, and particularly relates to a method for synthesizing dexmedetomidine hydrochloride. The method for synthesizing dexmedetomidine hydrochloride comprises the steps that reaction of 2,3-dimethylbenzoyl chloride and 1-N,N-dimethyl sulfonyl-2-(tert-butyldimethylsily)-5-(2,3-dimethyl benzoyl) imidazole is adopted, reflux is carried out to remove a protecting group under the action of hydrochloric acid, intermediate 4(5)-(2,3-dimethyl benzoyl) imidazole is obtained, lastly, reduction is carried out to obtain medetomidine under the action of monomethylamine, dexmedetomidine is obtained through the resolution of medetomidine under the action of tartaric acid, and lastly, dexmedetomidine is salified with hydrochloric acid to obtain dexmedetomidine hydrochloride. Compared with the prior art, the method for synthesizing dexmedetomidine hydrochloride has the advantages that a synthetic route is shorter, the operation is easy, and astarting material is easy to obtain.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a synthesis method of dexmedetomidine hydrochloride. Background technique [0002] Dexmedetomidine Hydrochloride is a selective α2 adrenergic receptor antagonist developed by (Finland) Orion Pharma Company / (U.S.) Abott Company. Antisympathetic, analgesic and sedative effects. Its chemical name is (R)-4-[1-(2,3-dimethylphenyl))ethyl]-1H-imidazole hydrochloride, and its structural formula is as follows: [0003] [0004] Dexmedetomidine hydrochloride is a brand-new α2-adrenergic receptor agonist, which has anti-sympathetic, sedative and analgesic effects, which are 8 times that of clonidine. FDA approved it as a short-term (<24 hours) sedative and analgesic drug in intensive care, especially in the early postoperative period. It acts on two adrenergic receptors, inhibits the release of norepinephrine and stops the transmission of pain signals by ac...

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 王前英别粉霞龚若李中井姜瑞玲
Owner CISEN PHARMA
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