Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

A kind of preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib

A technology of bosutinib and chloroquinoline, which is applied in the field of preparation of disubstituted 4-chloroquinoline-3-carbonitrile derivatives and bosutinib, and can solve problems such as high raw material prices, unfavorable industrialization, and large amount of three wastes

Active Publication Date: 2021-01-01
XINFA PHARMA
View PDF7 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0035] The raw material price of this method is high, the source of 3-cyano-6-acetylamino-7-ethoxy-4-chloroquinoline is limited, and the amount of three wastes in the production process is large, which is not conducive to industrialization

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
  • A kind of preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib
  • A kind of preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib
  • A kind of preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0087] Example 1: 4-[3-(4-methyl-1-piperazine)]propoxy-5-methoxy-2-nitrobenzoylacetonitrile (III 1 ) preparation

[0088] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser and dropping funnel, add 200 grams of tetrahydrofuran, 36.5 grams (0.1 mol) 4-[3-(4-methyl-1-piperazine)] Methyl propoxy-5-methoxy-2-nitrobenzoate, 6.0 g of acetonitrile, 17.5 g (0.13 mole) of potassium tert-butoxide, stirred at 55 to 60° C. for 3 hours. Cool to 20 to 25°C, use 20wt% ammonium chloride aqueous solution to acidify the pH value of the system to 4.0-4.5, add 200 grams of dichloromethane, separate layers, extract the water layer with dichloromethane 3 times, 50 grams each time, and combine the organic phases , Dichloromethane was reclaimed by distillation to obtain 33.7 grams of 4-[3-(4-methyl-1-piperazine)] propoxy-5-methoxy-2-nitrobenzoyl acetonitrile, and the yield was 89.5 %, the liquid phase purity is 99.4%.

Embodiment 2

[0089] Example 2: 4-[3-(4-methyl-1-piperazine)]propoxy-5-methoxy-2-nitrobenzoylacetonitrile (III 1 ) preparation

[0090] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser and dropping funnel, add 200 grams of tetrahydrofuran, 38.1 grams (0.1 mol) 4-[3-(4-methyl-1-piperazine)] Propoxy-5-methoxy-2-nitrobenzoic acid ethyl ester, 6.0 g of acetonitrile, 10.0 g (0.15 mol) of sodium ethoxide, stirred at 60 to 65° C. for 3 hours. Cool to 20 to 25°C, use 20wt% ammonium chloride aqueous solution to acidify the pH value of the system to 4.0-4.5, add 200 grams of dichloromethane, separate layers, extract the water layer with dichloromethane 3 times, 50 grams each time, and combine the organic phases , Dichloromethane was reclaimed by distillation to obtain 33.3 grams of 4-[3-(4-methyl-1-piperazine)]propoxy-5-methoxy-2-nitrobenzoyl acetonitrile, and the yield was 88.6 %, the liquid phase purity is 99.3%.

Embodiment 3

[0091] Embodiment 3: Formula IV 1 Compound preparation

[0092] In the 500 milliliters of four-neck flasks that are connected with stirring, thermometer, reflux condenser and 20wt% sodium hydroxide aqueous solution absorption device, add 150 grams of DMF, 37.5 grams (0.1 mole) 4-[3- (4-Methyl-1-piperazine)]propoxy-5-methoxy-2-nitrobenzoylacetonitrile (III 1 ), 45.0 grams (0.29 moles) of phosphorus oxychloride, stirred and reacted at 50 to 55° C. for 4 hours. Cool to 20 to 25°C, slowly pour the reaction liquid into 500 grams of water, adjust the pH of the system to 6.0-7.0 with 20 wt% aqueous sodium hydroxide solution, add 200 grams of dichloromethane, separate layers, and extract the water layer with dichloromethane 3 times, 50 grams each time, the organic phases were combined, and dichloromethane was reclaimed by distillation to obtain 35.3 grams of formula IV 1 Compound, the yield is 83.6%, and the liquid phase purity is 99.2%.

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 provides a preparation method of a disubstituted 4-chloroquinoline-3-carbonitrile derivative and a preparation method of bosutinib. The preparation method of the disubstituted 4-chloroquinoline-3-carbonitrile derivative comprises the following steps: disubstituted o-nitrobenzoate (II) used as a raw material and acetonitrile are condensed under the action of an alkali to obtain a compound of formula III; the compound of formula III and a chloroformylating reagent undergo a chloroformylating reaction to obtain a compound of formula IV1 or formula IV2; and the compound of formula IV1 undergoes catalytic hydrogenation cyclization in the presence of a hydrogenation catalyst to prepare 7-[3-(4-methyl-1-piperazinyl)propoxy]-6-methoxy-4-chloroquinoline-3-carbonitrile (Ia), or the compound of formula IV2 is subjected to catalytic hydrogenation cyclization and anhydride amidation to prepare 6-acetamido-7-ethoxy-4-chloroquinolin-3-carbonitrile (Ib). The compound of formula Ia or Ibis used to prepare bosutinib, neratinib or pelitinib. The method of the invention has the advantages of short process flow, simplicity in operation, easiness in realization, low cost, few three wastes, high yield, high purity, and easiness in industrial production.

Description

technical field [0001] The invention relates to a preparation method of a disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib, belonging to the field of pharmaceutical biochemical industry. Background technique [0002] Bosutinib, also known as Bosutinib, trade name Bosulif, English name Bosutinib, CAS No. 380843-75-4, chemical name: 4-[(2,4-dichloro-5-methoxy Phenyl) amino]-6-methoxyl group-7-[3-(4-methyl-1-piperazine) propoxyl group] quinoline-3-carbonitrile is produced by U.S. Wyeth Pharmaceuticals (Wyeth Pharmaceuticals) A potent protein kinase (Src / Abl) inhibitor developed, which can inhibit the autophosphorylation of Src protein in a variety of human tumor cells, and can also inhibit the phosphorylation process of Src and Abl substrates, published in September 2012 Approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with chronic myelogenous leukemia. In addition, the anticancer drug bosutinib can inhibit the...

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 Patents(China)
IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 戚聿新王宝昌郭德乾鞠立柱
Owner XINFA PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com