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Method for preparing dexmedetomidine and hydrochloride thereof

A hydrochloride and catalyst technology, which is applied in the field of preparation of dexmedetomidine and its hydrochloride, can solve the problems of long time consumption, unfavorable production, waste of left-handed products, etc., and achieve high yield without chiral disassembly The effect of short synthesis route

Active Publication Date: 2019-06-21
SHANGHAI TIANCI INT PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This method adopts the method that medetomidine is formed into tartrate to carry out chiral resolution to obtain dexmedetomidine, including the steps of salt formation and resolution, which takes a long time and has low yield, and the resolution leads to the waste of levorotatory products, Increased cost, not conducive to production

Method used

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  • Method for preparing dexmedetomidine and hydrochloride thereof
  • Method for preparing dexmedetomidine and hydrochloride thereof
  • Method for preparing dexmedetomidine and hydrochloride thereof

Examples

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preparation example Construction

[0076] The preparation method of formula I compound

[0077] Provide a kind of preparation method of formula I compound, described method comprises steps:

[0078] (5) In the fifth solvent, in the presence of a catalyst and a hydrogen source, the compound of formula VIII undergoes a hydrogenation reduction reaction to obtain a compound of formula I,

[0079]

[0080] Wherein, the catalyst includes a carbon-carbon hydrogenation reduction catalyst and (R,S)-Duanphos.

[0081] In another preferred example, the total weight of the carbon-carbon hydrogenation reduction catalyst and (R,S)-Duanphos accounts for 50-100% of the total weight of the catalyst, preferably 80-100%, more preferably , 90-100%.

[0082] In another preference, the carbon-carbon hydrogenation reduction catalyst is selected from: Rh(COD) 2 BF 4 , palladium on carbon, sodium hydroxide palladium on carbon, platinum on carbon, palladium acetate, or combinations thereof.

[0083] In another preferred embodime...

Embodiment 1

[0110] Dissolve the compound of formula II (164.0 g, 0.67 mol) in THF (720 mL) and set aside;

[0111] Add magnesium chips (26g, 1.08mol) and THF (240mL) to a 2L three-necked reaction flask under nitrogen protection, add 1 grain of elemental iodine, add the tetrahydrofuran solution (10mL) of the compound of formula II at one time, and heat up to reflux (internal temperature = 70°C) , add dropwise the tetrahydrofuran solution of the remaining compound of formula II, keep reflux for 1.5h, and cool to room temperature for later use.

[0112]The compound of formula III (120g, 0.35mol,) was dissolved in tetrahydrofuran (1.2L), under nitrogen protection, cooled to -5°C, added dropwise the newly prepared Grignard reagent, controlled at -5-0°C, after the addition was completed, raised to room temperature After the reaction was completed, saturated ammonium chloride (700mL) was added dropwise, and DCM (2.5L) was added for extraction. The organic phase was washed with saturated brine (1...

Embodiment 2

[0114] Formula IV compound (50g, 0.11mol) was added in 1,4-dioxane (750mL), MnO 2 (100g, 1.15mol), heated to reflux, reacted for 3h, the reaction was complete, filtered while it was hot, and the filtrate was concentrated to dryness to obtain a white solid crude product, which was added to methanol (350mL) and beaten at room temperature (25°C) for 1-2h, filtered, and dried in vacuo to obtain White solid compound of formula V (45 g), yield: 90.0%. MS (ESI): [M+1] + = 443.20.

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Abstract

The invention provides a method for preparing dexmedetomidine and a hydrochloride thereof. Specifically, a composition of a carbon-carbon hydrogenation reduction catalyst and (R,S)-Duanphos is used asa catalyst for chiral catalytic reduction of a double bond, and the dexmedetomidine with an enantiomeric excess being 99.9% can be directly obtained. The preparation method provided by the inventionis short in synthetic route, and the product does not need chiral resolution and is high in yield.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of dexmedetomidine and hydrochloride thereof. Background technique [0002] Dexmedetomidine hydrochloride was jointly developed by Orion and Hospira, and was approved for marketing by the US Food and Drug Administration on December 17, 1998. Dexmedetomidine hydrochloride is an effective α2-adrenoceptor agonist, its affinity for α2-adrenoceptor is 8 times higher than that of clonidine, it is suitable for endotracheal intubation and mechanical ventilation in surgical patients undergoing general anesthesia calm at times. [0003] Medetomidine, its chemical name is 5-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, and dexmedetomidine is its active ingredient, and its structure is as follows: [0004] [0005] Document Synthetic Communications; vol.26; nb.8; (1996); p.1585-1593, the synthetic method of dexmedetomidine hydrochloride reported in paten...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58B01J31/22
CPCY02P20/584
Inventor 池王胄沙飞
Owner SHANGHAI TIANCI INT PHARMA
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