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The synthetic method of clevidipine butyrate

A technology of clevidipine butyrate and a synthetic method, which is applied in the chemical field, can solve problems such as inability to carry out industrial scale-up reactions, enzymatic hydrolysis reactions are not suitable for industrial production, and limit the size of reaction vessels, so as to achieve large-scale industrial production and low cost , the effect of simple steps

Active Publication Date: 2016-04-06
ARROMAX PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The ultrasonic conditions used in this method limit the size of the reaction vessel, making it impossible to carry out industrial scale-up reactions, and the enzymatic hydrolysis reaction is not suitable for industrial production

Method used

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  • The synthetic method of clevidipine butyrate
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  • The synthetic method of clevidipine butyrate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (a) Synthesis of Compound 3

[0038]

[0039] Compound 1 (2g, 13.4mmol) was dissolved in tetrahydrofuran (15ml), triethylamine (176mg) was added, compound 2 (2.1g, 24.8mmol) was added dropwise to the solution, and the dropwise addition was completed, heated to reflux at 60°C, and stirred overnight . Stop the reaction, add saturated citric acid (20ml) after the reaction solution is cooled, extract with dichloromethane, wash the organic layer with water, wash with saturated brine, and wash with anhydrous NaSO 4 After drying, compound 3 (2.2 g, 71% yield) was obtained by separation by column chromatography.

[0040] conduct 1 H-NMR nuclear magnetic resonance analysis result is as follows:

[0041] 1 H-NMR (CDCl 3 ,400MHz,δppm):4.81(s,2H,-CH 2 ),3.61(s,2H,-CH 2 ),2.28(s,3H,-CH 3 ).

[0042] (b) Synthesis of Compound 6

[0043]

[0044] Compound 4 (1.1g, 6.4mmol), Compound 3 (1.5g, 6.4mmol), Compound 5 (0.738g, 6.4mmol) were dissolved in ethanol (15ml), heate...

Embodiment 2

[0058]

[0059] Compound 6 (1g, 2.05mmol) was dissolved in tetrahydrofuran (10ml), under nitrogen protection, SmI was added 2 (5.8g, 14.3mmol), stirred at room temperature for 2h. The reaction solution was concentrated and evaporated to remove the solvent, added DMF to dissolve, filtered to remove insoluble matter, evaporated under reduced pressure to remove most of the DMF, added water, a large amount of solids were precipitated, filtered with suction, and the filter cake was rinsed with an eluent of PE:EA=20:1, Compound 7 (0.32 g, 44% yield) was obtained after oven drying.

Embodiment 3

[0061]

[0062] Compound 6 (1g, 2.05mmol) was dissolved in toluene (11ml), sodium (0.47g, 20.5mmol) was added, and stirred overnight at room temperature. The reaction solution was filtered, concentrated and evaporated to remove the solvent, added water, a large amount of solids were precipitated, filtered with suction, the filter cake was rinsed with PE:EA=20:1 eluent, and dried in an oven to obtain compound 7 (0.27g, 37% yield ).

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Abstract

The invention discloses a synthetic method of cleviprex. The method comprises the following steps: reacting a compound 1 with a compound 2 in the presence of tetrahydrofuran and triethylamine to generate a compound 3, dissolving the compound 3, a compound 4 and a compound 5 in ethanol, heating to 70 DEG C, reacting to generate a compound 6, performing zinc powder reduction hydrolysis reaction on the compound 6 under the acidic condition to generate a compound 7, and reacting the compound 7 with a compound 8 in the presence of NaHCO3 and DMF (dimethyl formamide) to obtain cleviprex. The invention further discloses the compound 6 which can be selectively subjected to zinc powder reduction hydrolysis reaction so as to achieve the purpose of producing cleviprex through single hydrolysis.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a synthesis method of small molecule chemical drugs. Background technique [0002] Clevidipine butyrate (clevidipinebutyrate), the chemical name is 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-oxobutoxy) methyl ester is the fourth generation dihydropyridine calcium channel blocker. It was developed by AstraZeneca as a short-term control drug for hypertension in the perioperative period. In 2002, Medicines obtained the authorization of the product from AstraZeneca, and in 2008, it was approved by the FDA for marketing under the trade name Cleviprex. This product is an intravenous injection emulsion, which is used for the treatment of high blood pressure that is not suitable for oral administration or oral administration is ineffective, and can also be used for the treatment of acute blood pressure elevation after surgery. Compared with many cu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 洪健许忻
Owner ARROMAX PHARMATECH
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