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Indacaterol maleate intermediate, and preparation method and application thereof

A fumaric acid, solid technology, applied in the direction of organic chemistry, bulk chemical production, etc., can solve the problems of poor purification effect of enantiomer impurities, no purification effect, limited purification effect, etc., and achieves good removal effect, Good thermodynamic stability, good for storage

Active Publication Date: 2019-05-07
SICHUAN HAISCO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The data and experiments disclosed in the above documents show that these salt forms have certain effects on the purification of regioisomer impurities (formula IV-a) and disubstituted impurities (formula IV-b) in the compound of formula IV, but there are limited purification effects, Yield is lower etc. deficiencies; These salt types are to the purifying effect of enantiomer impurity (formula IV-c) in formula IV compound even worse, even if formula IV compound and chiral acid such as malic acid etc. salt crystallization, also No obvious purification effect on the enantiomer impurity (formula IV-c) was obtained
These studies show that the compound of formula Ⅳ purifies impurities therein, especially enantiomer impurities (formula Ⅳ-c), through salt-forming crystallization, and the effect is limited

Method used

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  • Indacaterol maleate intermediate, and preparation method and application thereof
  • Indacaterol maleate intermediate, and preparation method and application thereof
  • Indacaterol maleate intermediate, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1 -Hydroxyethyl]quinoline-2(1H)-one (the compound of formula IV)

[0062] Add about 1.21Kg of 5,6-diethyl-2,3-dihydro-1H-inden-2-ylamine (compound of formula II), 10.62Kg of tert-butanol, and 3.00Kg of dimethyl sulfoxide into the reactor. Add (R)-5-(2-oxiranyl)-8-benzyloxy-2(1H)-quinolinone (compound of formula Ⅲ) 1.36Kg under stirring, heat and reflux for 18 hours and then cool to 25 At °C, 15.25Kg of ethyl acetate and 27.24Kg of purified water were added, and after stirring, it was allowed to stand for liquid separation. The organic phase is washed 6 times with 15.93Kg of saturated brine each time, and concentrated under reduced pressure until no obvious fraction flows out, stop the concentration to obtain (R)-8-(benzyloxy)-5-[2-[(5,6 -Diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1-hydroxyethyl]quinoline-2(1H)-one (compound of formula IV), HPLC chemical purity: 63.6% (Among them, impurity for...

Embodiment 2

[0063] Example 2: (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1 -Hydroxyethyl]quinoline-2(1H)-one·0.75 fumarate (compound of formula VI) and preparation of its crystal form A

[0064] Add 160 g of anhydrous ethanol to the reaction flask, add 23 g (content 63.6%, 0.03 mol) of the compound of formula IV obtained above, stir and raise temperature and reflux to dissolve, then add 7.0 g (0.06 mol) of fumaric acid. After the addition, continue to reflux and stir to crystallize for about 2 hours. Cool down to 25°C. Filter and wash the filter cake with an appropriate amount of absolute ethanol. The obtained filter cake was added to the reaction flask, 120 g of absolute ethanol was added, and the temperature was raised to reflux for about 2 hours. Cool down to about 25°C. Filter and wash the filter cake with an appropriate amount of absolute ethanol. Then, it was put into a vacuum drying oven and dried under reduced pressure at 50-60°C to obtain 16.2g of the...

Embodiment 3

[0073] Example 3: (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-inden-2-yl)amino]-1 -Hydroxyethyl]quinoline-2(1H)-one·0.75 fumarate and its crystal form A (formula VI compound) preparation

[0074] Add 300 g of absolute ethanol to the reaction flask, add 23 g (content 63.6%, 0.03 mol) of the compound of formula IV obtained above, stir and raise the temperature to 40-50° C. to dissolve, then add 4.2 g (0.036 mol) of fumaric acid. After the addition, continue to stir for about 2 hours. Cool down to 0~5℃. Filter and wash the filter cake with an appropriate amount of absolute ethanol. Then it is put into a vacuum drying oven and dried under reduced pressure at 30-40°C to obtain the crystal form A of the compound of formula VI. HPLC chemical purity is 98.9%. (Among them, the impurity formula II compound is 0.1%, the impurity formula IV-a compound is 0.1%, the impurity formula IV-b compound is 0.3%, and the maximum single impurity is 0.3%), and the HPLC optical purity is 99.8...

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Abstract

The invention relates to a novel salt form of an indacaterol maleate intermediate namely (R)-8-(benzyloxy)-5-[2-[(5,6-diethyl-2,3-dihydro-1H-indene-2-yl)amino]-1-hydroxyethyl]quinoline-2(1H)-one and acrystal form thereof. The salt form and the crystal form thereof provided by the invention have good impurity removal effect and thermodynamic stability and simple and convenient preparation method,facilitate operation and storage, and are applicable to industrial application. The invention also relates to preparation methods for the salt form and the crystal form of the salt form, and an application of the salt form and the crystal form of the salt form in preparation of indacaterol maleate.

Description

Technical field [0001] The present invention relates to the field of organic chemistry and pharmacy, in particular to an intermediate of indacaterol maleate and a preparation method thereof, and the use of the intermediate in the preparation of indacaterol maleate. Background technique [0002] Indacaterol maleate, CAS number: 753498-25-8, chemical name: (R)-5-[2-(5,6-diethylinden-2-ylamino)-1 -Hydroxyethyl]-8-hydroxy-1H-quinolin-2-one maleate, the chemical structure is shown in formula I: [0003] [0004] Indacaterol maleate is a new type of ultra-long-acting β2 receptor agonist developed by Novartis for the treatment of chronic obstructive pulmonary disease (COPD). COPD is a disease characterized by irreversible airflow limitation. It has now become the fourth leading cause of death in patients, and the morbidity and mortality rates are still on the rise. Actively controlling patient symptoms and improving lung function have always been important goals of COPD treatment. Inda...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/26
CPCY02P20/55
Inventor 易仕旭何永耀高炳坤刘好江伟李彦霖吴雪兵王小平罗杰
Owner SICHUAN HAISCO PHARMA CO LTD
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