Synthesis method of indacaterol and salt derivatives thereof and intermediate for the synthesis

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

Active Publication Date: 2019-08-16
SUZHOU ZHIYU BIOTECH CO LTD
View PDF8 Cites 0 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Synthesis method of indacaterol and salt derivatives thereof and intermediate for the synthesis
  • Synthesis method of indacaterol and salt derivatives thereof and intermediate for the synthesis
  • Synthesis method of indacaterol and salt derivatives thereof and intermediate for the synthesis

Examples

Experimental program
Comparison scheme
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 48.8 g (about 0.1 mol) of the formula IV compound prepared in Example 1 and 29 g (about 0.1 mol) of the formula V compound prepared in Example 2 in a 1000 ml three-necked flask, add 500 ml 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%.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of indacaterol and salt derivatives thereof and intermediate for the synthesis. The synthesis method of indacaterol comprises the following steps: carrying out amine alkylation and deprotection reaction, in a one-pot manner, on a compound shown as a general formula IV and a compound shownas a formula V serving as raw materials to obtain a compound shown as a formula I, wherein the reaction equation is shown as the specification; wherein R is a silane protecting group. According to the technical scheme provided by the invention, by carrying out Boc protection on the amino group, polyalkylation on the amino group is ingeniously avoided, so that under the condition that both the hydroxyl group and the amino group have proper protection, the alkylation reaction effectively avoids the generation of by-products; after the alkylation reaction, hydroxyl and amino deprotection can bedirectly carried out, so that the multi-step reaction is completed in one reactor; according to the method, the intermediate purification and separation process is omitted, the reaction yield is increased to the maximum extent, and the production cost is reduced.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Patent Type & Authority Applications(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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap