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The synthetic method of indacaterol intermediate and indacaterol

A synthetic method and intermediate technology, applied in the field of drug synthesis, can solve the problems of high impurity content, high production cost, and low product yield, and achieve the effects of simple operation, low cost, and avoidance of by-products

Active Publication Date: 2016-08-24
SHANGHAI VIWIT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Therefore, the reported preparation method has more types of impurities and higher impurity content, which increases the difficulty of product separation and purification, the yield of the product is low, and the production cost is high, which pushes up the sales price of the preparation product from the cost level. financial burden on patients

Method used

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  • The synthetic method of indacaterol intermediate and indacaterol
  • The synthetic method of indacaterol intermediate and indacaterol
  • The synthetic method of indacaterol intermediate and indacaterol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] 1.N-benzyl-5,6-diethyl-2,3-dihydro-1H-inden-2-amine (formula II compound) synthesis

[0047]Under nitrogen protection, add 6.00g 5,6-diethyl-2,3-dihydro-1H-indene-2-amine (compound of formula I), 60.00ml methanol and 4.50g benzaldehyde, oil The bath was warmed to 65°C for 4 hours. Then slowly lower the temperature to -25°C, add 4.80g of sodium borohydride in batches, keep the internal temperature below 25°C, after the addition is complete, slowly raise the temperature to room temperature, and react overnight. Most of the methanol was removed by rotary evaporation, 50.00ml of water was added dropwise to the residue, and then 50.00ml of ethyl acetate was added for separation. The aqueous phase was back-extracted three times with 20.00ml of ethyl acetate, and the organic phases were combined. Dry over anhydrous sodium sulfate, filter, and concentrate to remove most of the solvent. 50ml of HCl / MeOH (wt=32%) was slowly added dropwise to the obtained solid-liquid mixture. A...

Embodiment 2

[0059] 1.N-benzyl-5,6-diethyl-2,3-dihydro-1H-inden-2-amine (formula II compound) synthesis

[0060] Under nitrogen protection, add 6.00 g of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (compound of formula I ), 60.00ml ethanol and 2.00g benzaldehyde, 1.00g NaBH 3 CN, the temperature of the oil bath was raised to 80°C for 4 hours. Rotary evaporation to remove most of the ethanol, drop 50.00ml of water into the residue, then add 50.00ml of ethyl acetate to separate the liquid, back extract the aqueous phase with 20.00ml of ethyl acetate for 3 times, combine the organic phases, and wash with anhydrous sulfuric acid Dry over sodium, filter, and concentrate to remove most of the solvent. To the obtained solid-liquid mixture, 50.00 ml of HCl / MeOH (wt=32%) was slowly added dropwise. After dropping, the mixture was stirred for 1 hour and then filtered to obtain a white solid (dry weight 5.50 g, yield 91%, purity 99%).

[0061] 1 H NMR (400MHz, CD 3 OD): δ7.61-7.45(m, 5H), 7.10(s, 2...

Embodiment 3

[0072] 1.N-benzyl-5,6-diethyl-2,3-dihydro-1H-inden-2-amine (formula II compound) synthesis

[0073] Under nitrogen protection, add 6.00 g of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine (compound of formula I) to the reaction flask at -25°C (cooling with dry ice-acetone bath) , 60.00ml THF and 6.70g benzaldehyde, 34.00g NaBH (OAc) 3 , the temperature of the oil bath was raised to 80° C. for 4 hours. Most of the THF was removed by rotary evaporation, 50.00 ml of water was added dropwise to the residue, and then 50.00 ml of ethyl acetate was added for separation. The aqueous phase was back-extracted 3 times with 20.00ml of ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the solvent, and slowly added dropwise 50.00ml of HCl / MeOH (wt =32%), dropwise, and filtered after stirring for 1 hour to obtain a white solid (dry weight 5.50 g, yield 91%, purity 99%).

[0074] 1 H NMR (400MHz, CD 3 OD): δ7.61-7.45(...

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Abstract

Disclosed is an intermediate for synthesizing indacaterol, having a structure represented by formula IV. Also disclosed are a method for synthesizing the indacaterol intermediate and a method for synthesizing indacaterol by using the intermediate. During synthesis of indacaterol, the intermediate of formula IV is reduced to obtain a chiral or racemic compound, which is then debenzylated to obtain indacaterol or a raceme thereof. By using the compound of formula IV as an intermediate for synthesizing indacaterol, the present invention provides a new route for synthesizing indacaterol, and avoids various byproducts produced in the process of synthesizing indacaterol using conventional methods.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an intermediate of indacaterol, a preparation method of the intermediate, and a method for synthesizing indacaterol by using the intermediate. Background technique [0002] The chemical name of Indacaterol Maleate is: 5-{(1R)-2-[(5,6-diethyl-2,3-dihydro-1H-indan-2-yl ) ammonia] -1-hydroxyethyl}-8-hydroxyl-1H-quinolin-2-one maleate, its structural formula is as follows: [0003] [0004] Indacaterol maleate is a new type of ultra-long-acting β2-receptor agonist developed by Novartis, Switzerland. It was approved by the US FDA on July 1, 2011, and its trade name is Arcapta. The finished product is an inhalation powder hard capsule, which is used for the treatment of patients with chronic bronchial obstructive disease (COPD) airflow obstruction, including chronic bronchitis or emphysema, but not for the treatment of acutely exacerbated chronic bronchial obstructive disease and ast...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/26
CPCC07D215/26
Inventor 魏彦君周海周建华王葱葱王成于向达
Owner SHANGHAI VIWIT PHARMA CO LTD
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