A kind of synthetic method and synthetic intermediate of indacaterol and its salt derivatives

A synthesis method and technology of derivatives, applied in the field of synthesis methods of indacaterol and its salt derivatives and intermediates for synthesis, can solve the problems of many by-products, difficult purification, low yield, etc., and avoid by-products , Improve the reaction yield and reduce the production cost

Active Publication Date: 2022-03-08
SUZHOU ZHIYU BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The invention provides a synthesis method of indacaterol and its salt derivatives and an intermediate for synthesis, which are used to solve the problems of many by-products, low yield and difficult purification in the synthesis of indacaterol

Method used

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  • A kind of synthetic method and synthetic intermediate of indacaterol and its salt derivatives
  • A kind of synthetic method and synthetic intermediate of indacaterol and its salt derivatives
  • A kind of synthetic method and synthetic intermediate of indacaterol and its salt derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0031] 8-benzyloxy-5-((R)-2-bromo-1-(tert-butyldimethylsilyl)oxy-ethyl)-1H-quinolin-2-one (compound of formula IV) synthesis

[0032] Add 50g of the compound of formula III and 600ml of dichloromethane into a 1000mL three-necked flask, stir and dissolve at room temperature, add 17g of triethylamine after dissolving, cool in an ice bath to 0°C, and add dropwise tert-butyldimethylsilyl chloride 24.8 g, after the addition is complete, return to room temperature and react for 2 to 4 hours. After the reaction, cool to 0°C, slowly add 1N HCl solution dropwise, separate layers, extract the aqueous phase with 200ml of dichloromethane, combine the organic phases, dry, and concentrate to obtain 78g of the target compound, with a yield of 99.3%.

Embodiment 2

[0034] Synthesis of 2-tert-butoxycarbonyl-amino-(5,6-diethyl)indan (compound of formula V)

[0035] Add 40g of the compound of formula II and 600ml of dichloromethane into a 1000ml three-neck flask, stir at room temperature, cool in an ice bath to 0-5°C, add 37.6g of triethylamine under stirring, and slowly dropwise add 39.4g of di-tert-butyl carbonate , about 0.5 hours after dropping, stirred and reacted at 0-5°C for 4 hours, poured the reaction solution into 500ml of ice water for layering, extracted the aqueous phase with 200ml of dichloromethane, combined the organic phases, dried and concentrated to obtain compound 49.1 of formula V g, yield 96%. h 1 NMR (300MHz, CD 3 OD)ppm: 7.20(s,2H), 4.15(t,1H), 2.90-3.15(m,4H), 2.83(q,4H), 1.41(s,9H), 1.28(t,6H); MS: 290.4 (M+).

Embodiment 3

[0037] (R)-5-[2-(5,6-Diethylindan-2-ylamino)-1-hydroxyethyl]-8-benzyloxy-1H-quinolin-2-one hydrochloride Synthesis of salt (compound hydrochloride of formula I)

[0038] Add 48.8g (about 0.1mol) of the formula IV compound prepared in Example 1 and 29g (about 0.1mol) of the formula V compound prepared in Example 2 in a 1000ml three-necked flask, add 500ml DMF, and cool to -5 ~ in an ice-salt bath Under stirring at 0°C, slowly add 12.3 g of potassium tert-butoxide, keeping the temperature below 0°C. Slowly return the temperature to normal temperature after the addition, and after stirring for 4 hours, pour the reaction solution into 1000ml of ice water, extract twice with 300ml of ethyl acetate, combine the organic phases and concentrate to dryness, add 500mL of absolute ethanol, and add 40mL of concentrated hydrochloric acid , stirred at room temperature for 2 hours, and suction filtered to obtain 45.67 g of compound hydrochloride of formula I, with a yield of 88%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of indacaterol and its salt derivatives and an intermediate for synthesis. The synthesis method of indacaterol, which uses the compound of general formula IV and compound of formula V as raw materials to obtain the compound of formula I through amine alkylation and deprotection one-pot reaction, the reaction equation is as follows: wherein, R is a silyl protecting group . The technical solution provided by the present invention cleverly avoids polyalkylation on the amino group through Boc protection of the amino group. Under the condition that both the hydroxyl group and the amino group are properly protected, the alkylation reaction effectively avoids the generation of by-products, and After the alkylation reaction, the deprotection of hydroxyl group and amino group can be carried out directly, and the multi-step reaction can be completed in one reactor, which saves the process of intermediate purification and separation, and also improves the reaction yield to the greatest extent and reduces the production cost.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of indacaterol and its salt derivatives and an intermediate for synthesis. Background technique [0002] Indacaterol (Indacaterol), chemical name (R)-5-[2-(5,6-diethyldihydroinden-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H- Quinolin-2-one, the molecular formula is C 24 h 28 N 2 o 3 , structural formula I is as follows: [0003] [0004] Indacaterol is a long-acting β2-adrenoceptor agonist. Indacaterol acts as a bronchodilator locally in the lung after inhalation, and is suitable for maintenance treatment of adult patients with chronic obstructive pulmonary disease (COPD). [0005] Indacaterol is composed of 5,6-diethyl-2,3-dihydro-1H-inden-2-amine hydrochloride (compound of formula II) and [0006] R-8-(benzyl chloride)-5-(2-bromo-1-hydroxyethyl)quinolinone (compound of formula III) obtained by alkylation of amine. The specific sy...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/26C07C269/04C07C271/24
CPCC07D215/26C07C269/04C07C271/24C07C2602/08Y02P20/55
Inventor 肖海英马义成
Owner SUZHOU ZHIYU BIOTECH CO LTD
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