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Preparation method of tyrosine enzyme inhibitor Foretinib

A tyrosinase and inhibitor technology, which is applied in the field of preparation of the compound Foretinib, can solve the problems of harsh reaction conditions, long reaction routes, and large environmental pollution, and achieves mild reaction conditions, avoiding column chromatography, and high product purity. Effect

Active Publication Date: 2016-01-06
JIANGSU ZHONGBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] In summary, there are following defects in the process of preparing Foretinib: raw and auxiliary materials are expensive, such as using expensive palladium reagent; long, many by-products are difficult to purify, etc.; or the reaction conditions are harsh and the environment is polluted, such as using potassium tert-butoxide and ferric acid (ammonium) reduction in the reaction

Method used

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  • Preparation method of tyrosine enzyme inhibitor Foretinib
  • Preparation method of tyrosine enzyme inhibitor Foretinib
  • Preparation method of tyrosine enzyme inhibitor Foretinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Synthesis of Compound 4

[0046] Add 372.4g (2.0mol) diethyl 1,1-cyclopropyldicarboxylate to a 5L reaction flask, add 1400mL ethanol, cool the system to 10°C in an ice-salt bath, then slowly add 62.4g (2.6mol) hydrogen dropwise A solution made of lithium oxide and 480mL of water was dropped, and kept at 35°C for 48 hours to stop the reaction. Evaporate the solvent under reduced pressure, add 1400mL water to the system, adjust the pH to about 4 with 5%-10% dilute hydrochloric acid after cooling down to 10°C, extract the system with 3X1000mL ethyl acetate, combine the organic layers, dry the organic layers, and filter , and the solvent was distilled off to obtain 311 g of a pale yellow oil. Put the product directly into a 5L reaction bottle, add 1500mL tetrahydrofuran, cool the system to 0°C, add 300g (2.4mol) oxalyl chloride and 5gDMF dropwise to the system, after the drop, react below 15°C for 3-5h and then detect the raw materials by TLC The response is complete. Th...

Embodiment 2

[0058] Synthesis of Compound 4

[0059] Add 372.4g (2.0mol) diethyl 1,1-cyclopropyldicarboxylate to a 5L reaction flask, add 1200mL isopropanol, cool the system to 10°C in an ice-salt bath, and slowly add 80.0g (2.0mol) ) sodium hydroxide and 453mL of water, after dropping, keep warm at 35°C for 30h and then stop the reaction. Evaporate the solvent under reduced pressure, add 1000mL water to the system, adjust the pH to about 4 with 5%-10% dilute hydrochloric acid after cooling down to 10°C, extract the system with 3X1000mL ethyl acetate, combine the organic layers, dry the organic layers, and filter , and the solvent was distilled off to obtain 315.7 g of a pale yellow oil. Put the product directly into a 5L reaction flask, add 1500mL tetrahydrofuran, cool the system down to 0°C, add 295.6g (2.4mol) thionyl chloride and 5gDMF dropwise into the system, after the drop is complete, react at a temperature below 15°C for 3-5h TLC detects that the reaction of raw materials is com...

Embodiment 3

[0067] Synthesis of Compound 4

[0068] Add 372.4g (2.0mol) diethyl 1,1-cyclopropyldicarboxylate to a 5L reaction flask, add 800mL 1,4-dioxane, cool the system to 10°C in an ice-salt bath, and slowly add 112.0 g (2.0mol) of potassium hydroxide and 500mL of water, after dropping, keep warm at 30°C for 24h and then stop the reaction. Add 800mL of water to the system, lower the temperature to 10°C, adjust the pH to about 4 with 5%-10% dilute hydrochloric acid, extract the system with 3X800mL ethyl acetate, combine the organic layers, dry the organic layers, filter, and evaporate the solvent to obtain 314.4g Pale yellow oil. Put the product directly into a 5L reaction flask, add 1500mL tetrahydrofuran, cool the system down to 0°C, add 295.6g (2.4mol) thionyl chloride and 5gDMF dropwise into the system, after the drop is complete, react at a temperature below 15°C for 3-5h TLC detects that the reaction of raw materials is complete. The temperature of the system was lowered to 0°...

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Abstract

The present invention provides a preparation method of a tyrosine enzyme inhibitor Foretinib. The method is as below: subjecting 1,1-cyclopropyl dicarboxylic acid diethyl ester to selective hydrolysis; amidating with p-fluoro aniline to obtain a compound shown in a formula 4; hydrolyzing and amidating with 4-amino-2-fluorophenol to obtain a compound shown in a formula 6; conducting substitution on 4-chloro-6-methoxy-7-quinolinol and N-(3-chloropropyl) morpholine to obtain a compound shown in formula 8; conducting substitution on the compound in formula 6 and compound shown in the formula 8 to obtain a target product N-[3-fluoro-4-({6-(methyl oxy)-7-[(3-morpholine-4-yl phenyl)-oxy] quinoline-4-yl}oxy)phenyl]-N'-(4-fluorophenyl) cyclopropane-1,1-dicarboamide crude product. The crude product is re-crystallized in an ethanol / acetone solution to obtain a high purity product with an overall yield of 44-55%. The method has the advantages of easy and feasible process, easily available raw materials, high overall yield and good product quality, and is applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of a compound Foretinib which can be used to regulate protein kinase activity. Background technique [0002] Foretinib is a new type of dual tyrosine kinase inhibitor that acts on the kinases c-Met and VEGFR / KDR developed by Exelixis of France, and the subsequent research and development rights have been transferred to GlaxoSmithKline. Foretinib is an ATP-competitive MET inhibitor. It is an oral small-molecule tyrosine kinase inhibitor targeting Met, RON, Axl, and VEGFR. It binds to the ATP pocket of MET and VEGFR-2 with high affinity and competitively inhibits their activity. Preclinical studies have shown that Foretinib inhibits tumor growth mediated by HGF and VEGF receptors by directly affecting cell proliferation, inhibiting tumor cell invasion and angiogenesis, and can also inhibit the anchorage-independent growth of tumor cel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22
CPCC07D215/22
Inventor 赵光荣黄双李维思史书晨韩武
Owner JIANGSU ZHONGBANG PHARMA
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