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Preparation method of indacaterol intermediate M

A technology for intermediates and compounds, applied in the field of preparation of indacaterol intermediate M, can solve problems such as long reaction steps and low yield, and achieve the effects of short steps, high product quality and low process cost

Inactive Publication Date: 2020-01-07
TIANJIN PHARMA GROUP CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This route uses ethylbenzene as a raw material, which is actually a combination of the two methods of route 1 and route 2. Although the use of expensive palladium carbon catalysts is avoided, the reaction steps are long and the yield is low

Method used

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  • Preparation method of indacaterol intermediate M
  • Preparation method of indacaterol intermediate M
  • Preparation method of indacaterol intermediate M

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] The preparation of embodiment 1 formula I compound

[0034]

Embodiment 1-1

[0036] Under nitrogen protection, add 36g of n-butyraldehyde (0.5mol), 6.7g of copper chloride, 5g of triethylamine and 4g of pyridine into a 1L reaction flask, add 500mL of methanol, adjust the temperature at about 25°C, and stir the reaction. After the reaction was detected by TLC, the insolubles were removed by filtration, the filtrate was concentrated to remove methanol, and 400 mL of dichloromethane was added to dissolve the residue, treated with 400 mL of 1N hydrochloric acid aqueous solution, separated, the organic phase was washed with saturated brine, and the organic phase was separated with After drying with anhydrous sodium sulfate and concentrating, 60 g of oily product was obtained, the HPLC content was 83%, and the yield was 85%.

Embodiment 1-2

[0038] Under nitrogen protection, add 36g of n-butyraldehyde, 33g of copper bromide, 10g of triethylamine and 9g of pyridine into a 1L reaction flask, add 750mL of ethanol, heat to about 35°C, and stir to react. After the reaction was detected by TLC, the insolubles were removed by filtration, the filtrate was concentrated to remove ethanol, and 400 mL of dichloromethane was added to dissolve the residue, treated with 400 mL of 1N hydrochloric acid aqueous solution, separated, the organic phase was washed with saturated brine, and the organic phase was separated and washed with After drying over anhydrous sodium sulfate and concentrating, 62 g of an oily product was obtained, the HPLC content was 85%, and the yield was 87%.

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Abstract

The invention provides a preparation method of indacaterol intermediate M: 5, 6-diethyl-2, 3-dihydro-1H-indene-2-amine. The preparation method comprises the following steps: by using n-butyraldehyde as an initiator, condensing to obtain a dialdehyde intermediate I, carrying out enolization on the dialdehyde intermediate I to obtain an intermediate II, carrying out D-A reaction on the intermediateII and 3-cyclopentene amine to obtain an intermediate III, and dehydrating to directly obtain a target product. According to the technical scheme, the process is simple, the steps are short, aftertreatment is easy and convenient, and dangerous catalytic hydrogenation is avoided; reaction raw materials are cheap and easily available, and the method is green and energy-saving; the reaction yield ishigh, the product quality is high, and the process cost is low.

Description

technical field [0001] The present invention relates to a synthesis process of a key intermediate of a raw material drug, in particular to a synthesis process and method of indacaterol intermediate M5,6-diethyl-2,3-dihydro-1H-indene-2-amine . Background technique [0002] Indacaterol (Indacaterol, chemical name: (R)-5-[2-(5,6-diethyldihydroinden-2-ylamino)-1-hydroxyethyl]-8-hydroxyl-1H- Quinolin-2-one), which belongs to the class of long-acting inhaled β2 receptor agonists (LABA), is suitable for the maintenance treatment of adults with chronic obstructive pulmonary disease (COPD). Indacaterol has a 5-minute onset of action and a 24-hour duration. This product is produced by Swiss Novartis Pharmaceuticals, and has been listed in more than 70 countries and regions around the world since 2009; in June 2012, it was approved by the State Food and Drug Administration for listing in China, with the trade name Angrun It is the first LABA single preparation approved for the trea...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/68C07C211/42C07C213/00C07C215/44C07C45/72C07C47/12
CPCC07C209/68C07C213/00C07C45/72C07C2602/08
Inventor 张成飞李强张静丁丽
Owner TIANJIN PHARMA GROUP CORP