Preparation method for indacaterol maleate

A technology of acid addition salts and compounds, applied in the field of drug synthesis, can solve problems such as multiple secondary substitutions and positional isomer impurities

Active Publication Date: 2018-07-06
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The above-mentioned synthesis method will generate more secondary sub

Method used

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  • Preparation method for indacaterol maleate
  • Preparation method for indacaterol maleate
  • Preparation method for indacaterol maleate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] The preparation of embodiment 1 compound IIA

[0064]

[0065] Prepare NaOH aqueous solution ①: Add 32g of sodium hydroxide to 1000ml of purified water, stir to dissolve, and set aside for later use. Prepare NaOH aqueous solution ②: add 16g of sodium hydroxide to 1000ml of purified water, stir to dissolve, and set aside for later use. Add 90 g of compound IIA hydrochloride, 50 ml of methanol and NaOH aqueous solution ① into the reaction flask, stir for 30 minutes, extract with 1600 ml of dichloromethane in two equal parts, combine the organic phases; wash once with NaOH aqueous solution ②, and use 2000 ml of purified water to Wash twice; the organic phase was stirred and dried with anhydrous sodium sulfate for 1 h; the desiccant was filtered off, and the filtrate was evaporated to dryness.

Embodiment 2

[0066] The preparation of embodiment 2 indacaterol intermediate II hydrobromide

[0067]

[0068] Add the residue compound IIA, 125g of compound IIB-1 and 1300ml of n-butanol solution obtained in Example 1 to dryness into a 5L reaction flask, stir evenly, heat to 100-110°C, and start TLC detection for 3 hours until compound IIA reacts Turn off the heat when complete. Evaporate to dryness at 50-60°C under reduced pressure, transfer to a 3L reaction flask, add 1000ml ethyl acetate, heat to 70-78°C, reflux and beat for 1.5h; filter with suction, dry the filter cake at 50°C under reduced pressure for 5h to obtain 174.4g The hydrobromide of formula II is a dark brown solid powder with a yield of 93% and a liquid phase purity of 97.82%. Its element analysis data is: C 31 h 33 BrN 2 o 3 Found (theoretical) %: C 66.25 (66.31), H 5.93 (5.92), O 8.56 (8.55), N 4.99 (4.99), Br 14.22 (14.23).

Embodiment 3

[0069] The preparation of embodiment 3 indacaterol intermediate III-2

[0070]

[0071] Add indacaterol intermediate II-1 and tetrahydrofuran into the reaction flask, stir evenly, under nitrogen protection, and ice-water bath to lower the reaction temperature to 0-3°C, add (R)-2-methyl-CBS-oxazole boron Alkanes, and then dropwise added tetrahydrofuran borane solution, about 30min dropwise. Continue to keep the reaction internal temperature at 0-3°C for 6-8 hours until the reaction is complete as monitored by TLC. The reaction was quenched by adding methanol solution dropwise, the reaction liquid was evaporated under pressure to remove the solvent, slurried with 1M dilute hydrochloric acid for 3 hours, and filtered to obtain an off-white solid. Air-dried at 60°C for 6 hours to obtain 7.5 g of the hydrobromide salt of formula III (formula III-1) as an off-white solid with a liquid phase purity of 97.86%.

[0072] Add the hydrobromide salt of indacaterol intermediate III (fo...

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Abstract

The invention specifically relates to a preparation method for indacaterol maleate, belonging to the field of drug synthesis. The preparation method is simple and short in steps, easy to operate, safe, friendly to environment and fee of an alkaline solution; after a heating reaction, a coupled product in the step 1) can be obtained, and the amount of produced regioisomers, dimers and other by-products is small; the yield of the product indacaterol maleate is high, as high as 93%, and the HPLC purity of the product indacaterol maleate is more than 97.8%; post-treatment is simple, and industrialproduction of indacaterol maleate is facilitated; and the product indacaterol maleate is high in optical purity.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of indacaterol maleate. Background technique [0002] Indacaterol Maleate (Indacaterol Maleate) is a new long-acting β2-adrenoceptor agonist (LABA). receptor selectivity. The product is a bronchodilator drug developed by Novartis, Switzerland, which was approved by the US FDA on July 1, 2011. Its trade name is Arcapta, and it is suitable for 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-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy- Quinolin-2 (1H)-ketone maleate, its structural formula is as shown in formula I: [0004] [0005] V...

Claims

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Application Information

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IPC IPC(8): C07D215/26
CPCC07D215/26Y02P20/55
Inventor 王小宁刘飞邹云飞
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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