Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine

A technology for medetomidine and enantiomers, which is applied in the field of drug synthesis and can solve the problems of complicated operation and difficult to meet the requirements of optical purity and the like

Inactive Publication Date: 2010-03-17
北京华禧联合科技发展有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such methods are cumbersome to operate, and in many cases it is difficult to meet the requirements of optical purity
Other domestic and foreign literatures have not reported the method for separating the enantiomers of medetomidine

Method used

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  • Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine
  • Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine
  • Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Preparation of L-(-)-Medetomidine(base)·S-(+)-BNP

[0016] (±)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole 20.0g, S-(+)-phosphoric acid-hydrogen-1,1'-linked-2, Add 17.6g of 2'-naphthyl ester into a 250ml three-necked flask, add 50ml of methanol and stir for 1 hour, add 150ml of anhydrous ether, and place it at 5-8°C for 48 hours to precipitate crystals (if no crystals precipitate during the period, you can add a little levorotatory seed crystal ). After filtration, 15.8 g of (A) was obtained as a white crystalline solid, and the mother liquor (B) was used for later use. A was recrystallized once with anhydrous methanol / ether to obtain L-(-)-Medetomidine (base) S-(+)-BNP 14.7g, mp 181-183℃, [α] D 20 +174.9° (c, 1 g / 100 ml water).

[0017] Preparation of L-(-)-Medetomidine(base)·HCl

[0018] Add 14.7g of L-(-)-Medetomidine (base)·S-(+)-BNP, 120ml of water, and 120ml of ether into a 500ml three-neck flask, add sodium bicarbonate under stirring until the pH value is 1...

Embodiment 2

[0022] D-(+)-Medetomidine (base) R-(-)BNP

[0023] Evaporate the solvent from the mother liquor B obtained after filtering A in Example 1, then add 150ml of anhydrous diethyl ether, place it at 3-8°C for 48 hours, then suck it up, evaporate the filtrate to dryness under normal pressure, dissolve the residue in 110ml of diethyl ether, and wash with 1N hydrochloric acid Extract (70ml×3). The extract was neutralized to strong alkalinity with 20% sodium hydroxide solution, and extracted with ether (75ml×3). The extract was dried with anhydrous sodium sulfate for 5 hours, and then the ether was distilled off. The residue was dissolved in 65 ml of absolute anhydrous methanol, and 11.8 g of R-(-)-phosphate-hydrogen-1,1'-bi-2,2'-naphthyl ester [R-(-)BNP] was added. Stand at 3-8°C for 72 hours to precipitate crystals, filter to obtain white crystalline solid D-(+)-Medetomidine (base)·R-(-)BNP 15.0g, mp 183-184°C, [α] D 20 -173.5°(c, 1g / 100ml water)

[0024] D-(+)-Medetomidine (base...

Embodiment 3

[0029] Preparation of L-(-)-Medetomidine(base)·D-(+)-DBTA

[0030] (±)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole 20.0g, D-(+)-dibenzoyl tartaric acid [D-(+)-DBTA ] 17.9g into a 250ml three-neck flask, add 60ml of methanol and stir for 30 minutes, add 150ml of anhydrous ether, and place at 5-10°C for 48 hours to precipitate crystals (if no crystals precipitate during the period, a little L-isomer seed can be added). The obtained white crystalline solid 21.6g (C) was filtered, and the mother liquor (D) was used for later use. C was recrystallized once with absolute ethanol / ether to obtain L-(-)-Medetomidine (base)·(+)-DBTA 18.7g, mp 220-223℃, [α] D 20 +86.6° (c, 1 g / 100 ml water).

[0031] The corresponding hydrochloride L-(-)-Medetomidine (base) HCl 9.3g can be prepared according to the method in Example 1, mp155-157°C, [α] D 20 -52.9° (c, 1 g / 100 ml water). And free base L-(-)-Medetomidine (base) 6.2g. mp148-150°C, [α] D 20 -74.8°(c, 1g / 100ml methanol)

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Abstract

The invention discloses a method for obtaining levorotatory enantiomer and dexiotropic enantiomer by separation from medetomidine (chemical name: 4-(1-(2,3-dimethylphenyl)-ethyl)-1H-imidazole) of racemate, which comprises the steps of reacting medetomidine racemate with optically active acid so that medetomidine racemate can be converted into salts of diastereoisomer, and then separating the saltsof the diastereoisomer by using a half-dose resolution method so as to obtain single enantiomer with particular optical purity.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a novel chiral resolution process and method of racemic medetomidine. Background technique [0002] (±)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole, Chinese name Medetomidine, English name Medetomidine, has the following structure and is considered to be selective and Potent α2-receptor agonist. [0003] [0004] (-)-(S)-4-[1-(2,3-Dimethylphenyl)ethyl]-1H-imidazole, the left-handed enantiomer of medetomidine derivatives (L-(-) Medetomidine) having the following structure has been found to be an inverse agonist of adrenergic α2-receptors (WO9715302). [0005] [0006] Such compounds are therefore believed to prevent and treat diseases associated with overexpression or hypersensitization of adrenergic α2-receptors. Coffman et al. reported that such compounds can be used to treat Raynaud's phenomenon (J. Vasc. Med. Biol, 3, 100). Orthostatic hypoten...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/58C07B57/00
Inventor 周泽建王玉莉毕华
Owner 北京华禧联合科技发展有限公司
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