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Preparation method of vernakalant hydrochloride

A technology of venakaran hydrochloride and solvent, which is applied in the field of chemical synthesis, can solve the problems of long synthesis route, heavy metal residue, difficulty in industrial scale up, etc., and achieves the effect of facilitating development and reducing production cost.

Inactive Publication Date: 2021-03-09
BEIJING MEDISAN TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] Chinese patent CN104610121 reports the following route, which successfully solves the problem of heavy metal residues, but its synthetic route is relatively long. In the cyclization process, acid chloride is used as the cyclizing agent, and acid gas escapes. During the reduction process, the batch is enlarged and quenched A large amount of hydrogen is released during the process, making industrial scale-up difficult

Method used

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  • Preparation method of vernakalant hydrochloride
  • Preparation method of vernakalant hydrochloride
  • Preparation method of vernakalant hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride (Venakalant hydrochloride ) preparation

[0038] In a single-necked bottle, add (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamine (14.0g, 50mmol), 200ml of acetonitrile, electromagnetically stir until completely dissolved, add anhydrous Potassium carbonate (8.3g, 60mmol), add R-1,2 epoxybromobutane (7.6g, 50mmol) dropwise, heat up to reflux, control the system temperature at 70-80°C, and keep the reaction time for 6 hours, filter, and filter out inorganic Salt, add 5M hydrochloric acid / methanol solution (100ml) to the organic phase and stir for 1 hour until the salt is completely formed. The organic phase is evaporated to remove the solvent under reduced pressure to obtain the crude product of vernakalant as a light-colored viscous substance, which is separated by adding isopropyl ether and beating , and filtered to obtain 13.41 g of (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cycloh...

Embodiment 2

[0040] Example 2 (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride (Venakalant hydrochloride ) preparation

[0041] In a single-necked bottle, add (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamine (14.0g, 50mmol), 200ml of acetonitrile, electromagnetically stir until completely dissolved, add anhydrous Potassium carbonate (8.3g, 60mmol), add R-1,2 epichlorobutane (5.3g, 50mmol) dropwise, heat up to reflux, control the system temperature at 70-80°C, reaction time 6h, filter, filter out inorganic salts , add 5M hydrochloric acid / methanol solution (100ml) to the organic phase and stir for 1h until the salt is completely formed. The organic phase is evaporated to remove the solvent under reduced pressure to obtain the crude product of vernakalant as a light-colored viscous substance, which is recrystallized by adding isopropyl acetate. , and filtered to obtain 14.41 g of (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride as ...

Embodiment 3

[0043]Example 3 (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylpyrrol-3-ol hydrochloride (Venakalant hydrochloride ) preparation

[0044] In a single-necked bottle, add (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexylamine (14.0g, 50mmol), 200ml tetrahydrofuran, stir until completely dissolved, add DBU ( 9.1g, 60mmol), add (R)-4-methylbenzenesulfonyloxy-1,2-epoxybutane (12.1g, 50mmol) dropwise, slowly raise the temperature to reflux, control the system temperature at 60-70°C, The reaction time is 6h, after the reaction is complete, add 200ml of purified water, extract 2 times with ethyl acetate 200ml, add 5M hydrochloric acid / methanol solution (100ml) to the organic phase and stir for 1h until the salt is completely formed, evaporate the solvent under reduced pressure to obtain Wiener The crude product of Kalan is a light-colored viscous substance, which is recrystallized by adding isopropyl acetate, and filtered to obtain (R)-1-((1R,2R)-2-(3,4-dimethoxyphenethoxy Base) cy...

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Abstract

The invention discloses a preparation method of vernakalant hydrochloride. The preparation method comprises the following steps: (1) adding a substrate (1R, 2R)- 2- (3, 4-dimethoxyphenethoxy) cyclohexylamine into a solvent; (2) adding an alkaline reagent, and controlling the temperature of the system; (3) adding an epoxy compound, controlling the temperature of the system, and raising the temperature to carry out cyclization reaction for a period of time; and (4) filtering to obtain a vernakalant solution, adding a hydrochloric acid solution to salify, concentrating under reduced pressure, andadding a crystallization solvent to crystallize, thereby obtaining the vernakalant hydrochloride. According to the invention, a chiral epoxy compound is adopted for cyclization reaction, the characteristics of high yield, short reaction time, simplicity and convenience in operation, mild conditions, convenience in post-treatment, easiness in industrial production and the like are realized, the use of heavy metals is avoided, and the development of injection medicines is facilitated.

Description

technical field [0001] The invention relates to a preparation method of a compound, in particular to a new preparation method of vernakalant hydrochloride, which belongs to the field of chemical synthesis. Background technique [0002] Vernakalant is a novel atrial-selective class III antiarrhythmic drug. Jointly developed by Cardionme Pharma Pharmaceutical Company of Canada and Astellas Pharma Pharmaceutical Company of the United States, the mechanism of action is to selectively block the sodium and potassium (IKur) ion channels of the atria during the onset of atrial fibrillation, and inhibiting the IKur current can prolong the action potential duration of the atria , reduce the risk of arrhythmia. Judging from the existing data, it shows good efficacy and safety in converting newly-occurring atrial fibrillation, and its curative effect is better than that of amiodarone. It is clinically used for the treatment of atrial fibrillation. [0003] WO2004099137 and WO200501863...

Claims

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Application Information

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IPC IPC(8): C07D207/12C07B53/00
CPCC07D207/12C07B53/00C07B2200/07
Inventor 刘荣宁瑞勃向松喻海陈帅
Owner BEIJING MEDISAN TECH
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