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Preparation method of indacaterol and salt thereof

A technology for indacaterol salts and compounds, which is applied in the direction of carboxylate preparation, carboxylate preparation, organic compound preparation, etc., can solve the problems of high cost, low yield, low purity, etc., and achieve low cost and high yield. High rate, high quality effect

Active Publication Date: 2020-10-23
SHANGHAI ANOVENT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is to provide a new method for overcoming the defects of high cost, low yield and low purity of the preparation method of indacaterol and its salt or its intermediate (formula II) in the prior art. The preparation method of indacaterol and its salt or its intermediate (formula II)

Method used

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  • Preparation method of indacaterol and salt thereof
  • Preparation method of indacaterol and salt thereof
  • Preparation method of indacaterol and salt thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Add 2-amino-5,6-diethylindane (22.7g) and n-butanol 600ml into a 2L reaction flask, stir to dissolve, then add 8-phenylmethoxy-5-(R) -Oxiranyl-1H-quinolin-2-one (29.3 g, S isomer content 0.5%), heated to 110° C., stirred for 4 hours, TLC detected that the reaction was complete. Under reduced pressure, the reaction solution was concentrated to obtain a crude brown oily product, which was added with 800ml of ethanol and stirred to dissolve, and 200ml of ethanol solution of m-chlorobenzoic acid (31.3g) was added, stirred and dissolved at 80°C, cooled to 30°C, and stirred for 6 hours, filtered, washed twice with a small amount of ethanol, and dried at 60°C for 8 hours to obtain off-white solid product (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1 -Hydroxy-ethyl]-8-benzyloxy-2-ketone m-chlorobenzoate (47.9g), the yield is 75.1%, the HPLC purity is 99.8% (area normalized method), and the single impurity content is less than 0.05 %, S isomer content is 0.06%. HPLC impurity analys...

Embodiment 2

[0056] Add 2-amino-5,6-diethylindane (27.2g) and n-butanol 600ml into a 2L reaction flask, stir to dissolve, then add 8-phenylmethoxy-5-(R) to the solution -Oxiranyl-1H-quinolin-2-one (29.3g, S isomer content 0.5%), heated to 80°C, stirred for 8 hours, TLC detected that the reaction was complete. Under reduced pressure, the reaction solution was concentrated to obtain a crude brown oil, which was added with 400 ml of tetrahydrofuran and stirred to dissolve, then added with 200 ml of tetrahydrofuran solution of m-chlorobenzoic acid (78.2 g), stirred and dissolved at 50°C, cooled to 30°C, and stirred for 6 hours, filtered, washed twice with a small amount of tetrahydrofuran, and dried at 60°C for 8 hours to obtain an off-white solid product (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1 -Hydroxy-ethyl]-8-benzyloxy-2-ketone m-chlorobenzoate (46.3g), the yield is 72.5%, the HPLC purity is 99.8% (area normalized method), and the single impurity content is less than 0.05 %, S isomer cont...

Embodiment 3

[0058] Add 2-amino-5,6-diethylindane (20.8g) and n-butanol 600ml into a 2L reaction flask, stir to dissolve, then add 8-phenylmethoxy-5-(R) -Oxiranyl-1H-quinolin-2-one (29.3 g, S isomer content 0.5%), heated to 120° C., stirred for 6 hours, TLC detected that the reaction was complete. Under reduced pressure, the reaction solution was concentrated to obtain a crude brown oily product, which was added with 800ml of isopropanol and stirred to dissolve, then added with 200ml of isopropanol solution of m-chlorobenzoic acid (15.7g), stirred and dissolved at 80°C, and cooled to 30°C. ℃, stirred for 6 hours, filtered, washed twice with a small amount of isopropanol, and dried at 60°C for 8 hours to obtain the off-white solid product (R)-5-[2-(5,6-diethyl-indane-2 -ylamino)-1-hydroxyl-ethyl]-8-benzyloxy-2-ketone m-chlorobenzoate (48.2g), yield 75.5%, HPLC purity 99.7% (area normalization method) , the single hetero content is less than 0.05%, and the S isomer content is 0.08%.

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Abstract

The invention relates to a preparation method of indacaterol and a salt thereof. The preparation method comprises the following steps: in a solvent, reacting a mixture containing a compound as shown in a formula I with m-chlorobenzoic acid to obtain a compound as shown in a formula II-1; and subjecting the obtained compound as shown in the formula II-1 to reacting and conversion to obtain indacaterol and the salt thereof. The preparation method of indacaterol and the salt thereof has the advantages of higher yield, high purity, easiness in refining, simple and convenient operation and suitability for industrialization.

Description

technical field [0001] The present invention specifically relates to the preparation method of indacaterol and its salt. Background technique [0002] long-acting beta 2 - The adrenergic agonist drug Indacaterol Maleate, which has the chemical name (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1 -Hydroxyethyl]-8-hydroxy-1H-quinolin-2-one maleate, molecular formula: C 24 h 28 N 2 o 3 ·C 4 h 4 o 4 , Molecular weight: 508.56, developed by Novartis, the indication is the maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD), the structural formula is as follows: [0003] [0004] The synthesis process of indacaterol maleate is disclosed in the prior art, such as patents WO2000 / 075114, WO2004 / 076422, CN201410682500 and WO2016 / 161956 disclose the use of 8-phenylmethoxy-5-(R) epoxy Ethyl-1H-quinolin-2-one and 2-amino-5,6-diethylindane are used as raw materials to prepare indacaterol maleate through ring-opening substitution, debenzylation an...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/26C07C51/41C07C51/43C07C63/70
CPCC07B2200/07C07C51/412C07C51/43C07C63/70C07D215/26Y02P20/55
Inventor 黄才古孙辉聂秋朋
Owner SHANGHAI ANOVENT PHARMA CO LTD
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