Improved preparation process of indacaterol maleate

A preparation process and acid indene technology, applied in the field of pharmaceutical synthesis, can solve the problems of difficulty in purifying intermediate 4, long reaction time, low efficiency, etc., and achieve the effects of shortened reaction time, high yield and purity, and easy operation.

Active Publication Date: 2019-11-29
SHANGHAI INST OF PHARMA IND CO LTD +2
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  • Abstract
  • Description
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Problems solved by technology

[0010] The present invention aims at improving the preparation technology of the indacaterol maleate of above-mentioned route 1, especially wherein there are two problems: one is that the reaction time of the first step is long and the efficiency is not high, and the other is because the first step There are too many impurities obtained in the side reaction of the reaction, which makes the purification operation of intermediate 4 difficult

Method used

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  • Improved preparation process of indacaterol maleate
  • Improved preparation process of indacaterol maleate
  • Improved preparation process of indacaterol maleate

Examples

Experimental program
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Embodiment 15

[0026] Example 1.5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-phenylmethoxy-(1H)-quinone Preparation of lin-2-one p-methoxybenzoate

[0027]

[0028] Add 5.0 g of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine and 7 mL of dimethylmethylene sulfone, 7.0 g of 5‐(2R)‐2‐oxiranyl‐8‐benzyloxy‐2(1H)‐quinolinone was added to the solution, the resulting suspension was heated to 110 °C, and Stirring at this temperature for 7h, TLC showed that the reaction was complete. Cool the resulting brown solution to 60°C, add 80mL of ethanol, keep at 60°C, then add 4.4g of p-methoxybenzoic acid to dissolve completely, cool the solution to about 40°C, add seed crystals, and place in an ice bath to cool. 11.4 g of crude p-methoxybenzoate were isolated by filtration and recrystallized from ethanol to give 10.6 g of 5‐[(R)‐2‐(5,6‐diethyl‐indan‐2‐ylamino)‐1‐ The pure product of hydroxy‐ethyl]‐8‐phenylmethoxy‐(1H)‐quinolin‐2‐one p-methoxybenzoate is a white crystalline powder (yield 70.1%,...

Embodiment 25

[0029] Example 2.5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-phenylmethoxy-(1H)-quinone Preparation of lin-2-one p-toluate

[0030]

[0031] Add 5.0 g of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine and 7 mL of dimethylmethylene into a four-necked flask equipped with magnetic stirring, thermometer, addition funnel and reflux condenser sulfone, 7.0 g of 5‐(2R)‐2‐oxiranyl‐8‐benzyloxy‐2(1H)‐quinolinone was added to the solution, the resulting suspension was heated to 110 °C, and Stirring at this temperature for 7h, TLC showed that the reaction was complete. Cool the resulting brown solution to 60°C, add 80mL of ethanol, keep at 60°C, then add 3.9g p-toluic acid to dissolve completely, cool the solution to about 40°C, add seed crystals, and place in an ice bath to cool. 10.0 g of the crude p-toluate salt was isolated by filtration and recrystallized from ethanol to give 9.4 g of 5‐[(R)‐2‐(5,6‐diethyl‐indan‐2‐ylamino)‐1‐hydroxy‐ The pure product of ethyl]‐8‐phenylm...

Embodiment 35

[0032] Example 3.5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-phenylmethoxy-(1H)-quinone Preparation of lin‐2‐one p-nitrobenzoate

[0033]

[0034] Add 5.0 g of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine and 7 mL of dimethylmethylene into a four-necked flask equipped with magnetic stirring, thermometer, addition funnel and reflux condenser sulfone, 7.0 g of 5‐(2R)‐2‐oxiranyl‐8‐benzyloxy‐2(1H)‐quinolinone was added to the solution, the resulting suspension was heated to 110 °C, and Stirring at this temperature for 7h, TLC showed that the reaction was complete. Cool the resulting brown solution to 60°C, add 80mL of ethanol, keep at 60°C, then add 4.8g of p-nitrobenzoic acid to dissolve completely, cool the solution to about 40°C, add seed crystals, and place in an ice bath to cool. 11.2 g of crude p-methoxybenzoate were isolated by filtration and recrystallized from ethanol to give 9.8 g of 5‐[(R)‐2‐(5,6‐diethyl‐indan‐2‐ylamino)‐1‐ Hydroxy-ethyl]-8-phenylmethox...

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Abstract

The invention discloses an improved indacaterol maleate preparation technology. The technology comprises the following steps: 1, carrying out a ring opening reaction on a compound 2 and a compound 3 in a solvent to obtain a compound 4, carrying out salt formation on the compound 4 and an organic acid HA in a second solvent to obtain a compound 4.HA salt, and carrying out crystallization treatment to precipitate the compound 4.HA salt; and 2, carrying out catalytic hydrogenation debenzylation on the compound 4.HA salt in the presence of a catalyst, and carrying out salt formation on the compound 4.HA and maleic acid to obtain indacaterol maleate. The improved indacaterol maleate preparation technology greatly shortens the reaction time, and the obtained indacaterol maleate product has high yield and purity, so the integral technology has the advantages of simple operation and suitableness for industrialization.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an improved preparation process of bronchodilator drug-indacaterol maleate. Background technique [0002] Indacaterol Maleate (Indacaterol Maleate) is a bronchodilator drug developed by Swiss Novartis, which belongs to a new type of ultra-long-acting β2 receptor agonist. It was approved by the US FDA on July 1, 2011. Its product Named Arcapta. It is also the first and currently the only long-acting inhaled β2-agonist (LABA) approved by the US SFDA for maintenance treatment of stable adult patients with chronic obstructive pulmonary disease (COPD). As a new generation of LABA, the drug has the obvious advantages of once a day and rapid onset of action within 5 minutes, and is suitable for the maintenance treatment of stable COPD adult patients with airflow obstruction. [0003] The chemical name of indacaterol maleate is 5‐{(1R)‐2‐[(5,6‐diethyl‐2,3‐dihydro‐1H‐indan‐2‐yl)ammonia]‐1 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/26
Inventor 季宗德杨玉雷陈武莫利英朱雪焱袁哲东
Owner SHANGHAI INST OF PHARMA IND CO LTD
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