Preparation of optically-active pure ibutilide fumarate

A technology of ibutilide fumarate and ethyl, which is applied in the fields of sulfonamide preparation, cardiovascular system diseases, organic chemistry, etc., can solve the problems of relatively expensive price and high industrialization cost, and achieve good industrialized production prospects and operation Simple, high-yield effect

Inactive Publication Date: 2009-04-22
ZHEJIANG NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But this method is reducing agent with dipinyl boron chloride, and its price is more expensive, and industrialization cost is too high
Other synthetic methods are the synthesis of racemic ibutilide fumarate, which does not involve the synthesis of optically pure ibutilide fumarate

Method used

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  • Preparation of optically-active pure ibutilide fumarate
  • Preparation of optically-active pure ibutilide fumarate
  • Preparation of optically-active pure ibutilide fumarate

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Under nitrogen protection, at room temperature 25°C, dissolve 0.25mmol of CBS catalyst in 5mL of anhydrous THF, and then add 1.25mL of BH with a concentration of 2mol / L 3 · Me 2 S, after stirring for 10min, dissolve 2.5mmol N-ethyl-N-heptyl-4-oxo-4-(4-methanesulfonylaminophenyl)butanamide in 15mL anhydrous THF, and add dropwise to the above solution , stirred at room temperature 25° C. for 0.5 h, and followed the reaction by TLC. After the reaction was completed, cool in an ice bath, add MeOH and water in sequence to terminate the reaction, extract the aqueous phase with 60 mL of ethyl acetate, combine the ethyl acetate and the organic phase, and wash with water and saturated NaCl in sequence, followed by anhydrous NaCl 2 SO 4 After drying, the solvent (containing ethyl acetate and THF) was evaporated under reduced pressure. Carry out silica gel column chromatography separation with eluent (the volume ratio of methanol and dichloromethane is 1:25) to obtain white sol...

Embodiment 2

[0036] Under nitrogen protection, 0.125 mmol of CBS catalyst was dissolved in 10 mL of anhydrous CH 2 Cl 2 , then add 2.5 mL of BH with a concentration of 1 mol / L 3 THF, after stirring for 10min, cooled to -30°C, dissolved 2.5mmol N-ethyl-N-heptyl-4-oxo-4-(4-methanesulfonylaminophenyl)butyramide in 15mL of anhydrous CH 2 Cl 2 , was added dropwise to the above solution, stirred at -30°C for 1 h, and followed the reaction by TLC. After the reaction was completed, the temperature was raised to 0°C, MeOH was added sequentially, water was used to terminate the reaction, and 60mL CH 2 Cl 2 Extract the aqueous phase, CH 2 Cl 2 After combining with the organic phase, wash with water, saturated NaCl, anhydrous NaCl 2 SO 4 After drying, the solvent was evaporated under reduced pressure (CH 2 Cl 2 ). Silica gel column chromatography with eluent (volume ratio of methanol and dichloromethane is 1:25) to obtain a white solid: (S)-N-ethyl-N-heptyl-4-hydroxyl-4-(4 -(methylsulfona...

Embodiment 3

[0048] Under nitrogen protection, 0.25 mmol of CBS catalyst was dissolved in 10 mL of anhydrous PhCH 3 , then add 0.75mL concentration of 2mol / LBH 3 · Me 2 S, after stirring for 10min, heated to 45°C, dissolved 3.75mmol N-ethyl-N-heptyl-4-oxo-4-(4-methanesulfonylaminophenyl)butyramide in 15mL anhydrous PhCH 3 , was added dropwise to the reaction flask, stirred at 45°C for 1.5h, and followed by TLC. After the reaction was completed, MeOH was added sequentially, water was used to stop the reaction, and 60 mL of ethyl acetate was used for extraction. 2 SO 4 After drying, the solvent (containing ethyl acetate and PhCH 3 ). Silica gel column chromatography with eluent (volume ratio of methanol and dichloromethane is 1:25) to obtain white solid (S)-N-ethyl-N-heptyl-4-hydroxyl-4-(4- (Methylsulfonamide) phenyl) butyramide 0.675g. (S)-N-Ethyl-N-heptyl-4-hydroxy-4-(4-(methylsulfonamide)phenyl)butanamide: white solid, 45% yield, [ α ...

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Abstract

The invention provides a method for preparing optical rotation pure ibutilide fumarate. The method is characterized by comprising the following steps: N-ethyl-N-heptyl-4-oxo-4-(4-mesylamino phenyl) butyrylamide is subjected to asymmetric catalytic reduction by using CBS catalyst to obtain (S)-N-ethyl-N-heptyl-4-hydroxide radical-4-(4-(mesylamino)phenyl) butyrylamide; the (S)-N-ethyl-N-heptyl-4-hydroxide radical-4-(4-(mesylamino)phenyl) butyrylamide is reduced by LiAlH4 to be salified with fumaric acid to finally obtain the optical rotation pure ibutilide fumarate. The preparation method has the advantages of simple and convenient operation, mild reacting condition, good enantioselectivitiy, environment al friendliness, low cost and high yield.

Description

technical field [0001] The invention relates to the field of synthesis of optically active drugs, in particular to a preparation method of optically pure ibutilide fumarate. Background technique [0002] Ibutidine fumarate phenyl]methanesulfonamide, (E)-2-Butenedi oate(2:1)Salt, the structural formula is shown on the left. It is a new type of ion channel antagonist antiarrhythmic drug developed by Upjohn Company of the United States. It was first launched in the United States in 1996 under the trade name Convert, and it is also listed in 11 countries including Germany. The clinical use of its injection is mainly used for the conversion of atrial fibrillation and atrial flutter. Ibutilide fumarate is a new class III antiarrhythmic drug. Clinical studies have shown that the drug has significant curative effect and is highly selective. The average time to terminate arrhythmia is short, and 80% of patients can fully improve within 30 minutes after administration. A comprehe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/08C07C303/40A61P9/06
Inventor 牧初春李新生徐东成
Owner ZHEJIANG NORMAL UNIVERSITY
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