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Method for preparing dexmedetomidine hydroch

A technology for dexmedetomidine hydrochloride and racemic beauty, which is applied in the field of pharmaceutical preparation, can solve the problems of unspecified chemical purity of split substances, inability to obtain purity, high dexmedetomidine and the like, and achieves the advantages of being beneficial to industrial production, The effect of relatively low cost and short synthetic route

Active Publication Date: 2015-12-23
CISEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The dexmedetomidine yield that adopts this scheme to finally obtain can reach 44%, but can't obtain the higher dexmedetomidine of purity
[0007] Scheme 3: Patent CN200910093379.4 discloses a method for splitting the left-handed and right-handed enantiomers of medetomidine, using S-(+)-phosphoric acid-hydrogen-1,1′-linked-2,2′ -Naphthyl ester, D-(+)-dibenzoyl tartaric acid are dextrorotatory resolving agents, L-(-)-dibenzoyl tartaric acid, R-(-)-phosphoric acid-hydrogen-1,1′-linked -2,2'-Naphthyl ester is a left-handed resolving agent to obtain the left-handed and right-handed enantiomers of medetomidine respectively. The method mentioned is cumbersome to operate and cannot guarantee a higher product yield
[0008] Scheme 4: Patent 201410332901.0 discloses an industrial resolution method of medetomidine, which uses L-(-)-camphorsulfonic acid as a chiral reagent and C1-C5 alcohol as a chiral auxiliary agent for the resolution of racemization Body medetomidine, its resolution yield can reach more than 40%, and the optical purity of resolution material can reach more than 99.5% simultaneously, and technological operation is comparatively simple, but refining process uses second class solvent dichloromethane, the obtained The chemical purity of the resolved material is also not stated

Method used

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  • Method for preparing dexmedetomidine hydroch
  • Method for preparing dexmedetomidine hydroch
  • Method for preparing dexmedetomidine hydroch

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Preparation of dexmedetomidine: Add 50 g of racemic medetomidine and 18.4 g of S-(+)-mandelic acid into a 500 mL three-necked flask, add 200 mL of methanol and stir for 2 h under heating at 70°C; add 150 mL of diethyl ether Cool and stand for 24 hours to crystallize, filter; add 52.8 g of L-(-)-dibenzoyl tartaric acid to the mother liquor, stir and crystallize for 24 hours, filter to obtain dexmedetomidine, ee% 99.54%.

[0018] The preparation of dexmedetomidine hydrochloride: join dexmedetomidine (36g, 180mmol) and 100mL absolute ethanol in the 1000mL reaction flask, add the 1LHCl / diethyl ether saturated solution that has configured in the system, this moment pH Value is 3, stirred and crystallized, filtered, and the filter cake was recrystallized through ethanol:ether (20ml:200ml), and vacuum-dried to obtain dexmedetomidine hydrochloride (38.0g, yield 90.0%), mp156.0~156.9°C, (Literature value: mp156.5~157.5°C); purity: 99.8%; ee%: 100%.

Embodiment 2

[0020] The preparation of dexmedetomidine: add 50g of racemic medetomidine, 18.4g of S-(+)-mandelic acid and 0.2g of pyracline B into a 500mL three-necked flask, add 200mL of methanol and heat at 70°C Stir under the conditions for 2h; add 150mL ether, cool and stand for 24h to crystallize, filter; add 52.8 grams of L-(-)-dibenzoyl tartaric acid to the mother liquor, stir and crystallize for 24 hours, filter to obtain dexmedetomidine, ee %99.94%.

[0021] The preparation of dexmedetomidine hydrochloride: join dexmedetomidine (36g, 180mmol) and 100mL absolute ethanol in the 1000mL reaction flask, add the 1LHCl / diethyl ether saturated solution that has configured in the system, this moment pH Value is 3, stirred and crystallized, filtered, and the filter cake was recrystallized through ethanol:ether (20ml:200ml), vacuum-dried to obtain dexmedetomidine hydrochloride (38.9g, yield 92.2%), mp156.1~156.9 ℃, (Literature value: mp156.5~157.5°C); purity: 99.9%; ee%: 100%.

[0022] con...

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Abstract

The invention relates to a method for preparing dexmedetomidine hydroch. The method particularly includes the following steps that 1, dispinner medetomidine is dissolved in methyl alcohol and mixed with a right-handed resolving agent according to the molar ratio of 1:0.4-0.6, stirring is conducted for 2-3 hours at the heating temperature of 60-80 DEG C, diethyl ether is added, cooling, still standing, crystallization and filtering are conducted, a mother solution and a left-handed resolving agent are mixed according to the molar ratio of 1:0.4-0.6, stirring and crystallization are conducted for 24 hours, and dexmedetomidine is obtained after filtering is completed; 2, obtained dexmedetomidine is placed in HCl / diethyl ether, and the end product dexmedetomidine hydroch is formed. Compared with the prior art, dexmedetomidine hydroch is prepared at low cost; the synthetic route is short, dexmedetomidine hydroch with high purity can be prepared, isomers are not detected, quality meets the newest standard of the pharmacopeia, and industrial production is facilitated. Adopted raw materials are low in cost, reaction conditions are moderate, and the method can be applied to actual production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a method for preparing dexmedetomidine hydrochloride. Background technique [0002] The chemical name of dexmedetomidine hydrochloride is 4-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole hydrochloride, which is a new type of 2 - Adrenoceptor agonist with anti-sympathetic sedative and analgesic effects, with α2 / α1 selectivity as high as 45,000. Dexmedetomidine hydrochloride was first launched in the United States in March 2000 (trade name Precedex), and was subsequently approved for marketing in many countries. At present, many domestic pharmaceutical companies are imitating it, and it has entered the clinical trial stage. Dexmedetomidine hydrochloride has the following structure: [0003] [0004] There are many synthetic methods of dexmedetomidine hydrochloride, and the racemic medetomidine can be industrially produced, and the resolution scheme of...

Claims

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Application Information

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IPC IPC(8): C07D233/58C07B57/00
CPCC07B57/00C07B2200/13C07D233/58
Inventor 孙守飞卢秀莲杜振新何作鹏孙品李中井
Owner CISEN PHARMA
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