Preparation of gefitinib

A technology of gefitinib and compounds, applied in the field of preparation of 4--7-methoxy-6-quinazoline, which can solve the problems of many reaction by-products, difficult control of cyano hydrolysis, unavoidable by-products, etc. , to avoid excessive hydrolysis, shorten the synthesis route, and achieve the effect of mild reaction conditions

Active Publication Date: 2009-06-24
FUJIAN SOUTH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method has been improved and can be used for industrial production, the hydrolysis of the cyano group is difficult to control, and by-products of hydrolysis to acid are unavoidable.
[0012] Yuan Li et al. (Chinese Journal of Medicinal Chemistry, 2005, 15, 39) from Shenyang Pharmaceutical University used methyl 3-hydroxy-4-methoxybenzoate as a raw material. The route is basically similar to that of J.P. Gilday et al. The defect of many by-products

Method used

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  • Preparation of gefitinib
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  • Preparation of gefitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] ①Synthesis of Compound 1

[0042] Add 5L double-distilled toluene to a 10L four-neck bottle, add 1kg of isovanillin, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate under stirring, heat and reflux for 6 hours, cool to room temperature, filter, and use as filter cake The hot ethyl acetate was extracted to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain about 750g of the product.

[0043] ② Synthesis of Compound 2

[0044] Add compound 1 (1kg), 2kg of 3-morpholine-1-chloropropane, 3kg of potassium carbonate, 500g of tetrabutylammonium iodide and 5 liters of DMSO into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool , poured into 10 liters of ice wate...

Embodiment 2

[0056] ①Synthesis of Compound 1

[0057] Add 5L double-distilled toluene to a 10L four-neck bottle, add 1kg of isovanillin, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 4kg of anhydrous sodium sulfate under stirring, heat and reflux for 16 hours, cool to room temperature, filter, and use as filter cake The hot ethyl acetate was extracted to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain about 800g of product.

[0058] ② Synthesis of compound 2

[0059] Add compound 1 (1kg), 2kg of 3-morpholine-1-chloropropane, 3kg of potassium carbonate, 100g of tetrabutylammonium bromide and 5 liters of DMF into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool , poured into 10 liters of ice water, extra...

Embodiment 3

[0071] ①Synthesis of Compound 1

[0072] Add 5L double-distilled benzene into a 10L four-necked bottle, add 1kg of isovanillin, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate under stirring, heat and reflux for 10 hours, cool to room temperature, filter, and use as filter cake The hot ethyl acetate was extracted to TLC to detect no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product precipitated, added 2.5L petroleum ether, suction filtered, washed with a small amount of petroleum ether, and dried to obtain about 780g of the product.

[0073] ② Synthesis of compound 2

[0074] Add compound 1 (1kg), 3kg of 3-morpholine-1-chloropropane, 2kg of potassium carbonate, 250g of tetrabutylammonium bromide and 5 liters of DMSO into a 10-liter four-neck flask, heat to reflux, and after TLC detects that the reaction is complete, cool , poured into 10 liters of ic...

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Abstract

The invention discloses a preparation method of gefitinib. In the method, isovanillin is taken as a raw material and synthesized to obtain 7-methoxy-6-(3-morpholine-propoxy)quinazoline-4-one which is directly chloridized to obtain a product, the product is allowed to react with 3-chlorine-4-fluoroaniline to obtain gefitinib hydrochloride which neutralized off hydrochloric acid to obtain the gefitinib. The method has mild reaction condition and is applicable to industrialized production.

Description

Technical field: [0001] The present invention relates to the synthetic field of pharmaceutical compounds, in particular to a kind of 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline ( Gefitinib) preparation method. Background technique: [0002] 4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline (Gefitinib, Gefitinib, trade name: Iressa, Iressa) is a selective inhibitor of epidermal growth factor (EGFR) tyrosine kinase, and is currently clinically used for the treatment of non-small cell lung cancer. [0003] [0004] Gefitinib molecular structure [0005] The synthetic route of gefitinib is mainly reported by K.H. Gibson of Astra Zenica Co., Ltd. (WO9633980, CN96193526), ​​and its synthetic route is as follows: [0006] [0007] This route uses 6,7-dimethoxy-3,4-dihydroquinazolin-4-one as raw material, selectively removes the 6-position methyl group with methanesulfonic acid and L-methionine, protects by ace...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 沈鑫廖立新林复兴何晓杨继东詹华杏
Owner FUJIAN SOUTH PHARMA CO LTD
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