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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 difficult control of cyano hydrolysis, many reaction by-products, unavoidable by-products, etc. , to avoid excessive hydrolysis, mild reaction conditions, and shorten the synthesis route

Active Publication Date: 2011-06-08
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
  • Preparation of gefitinib
  • Preparation of gefitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] ① Synthesis of compound 1

[0042] Add 5L of re-distilled toluene into a 10L four-neck flask, add 1kg of raw material isvanillin, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate with stirring, heat to reflux for 6 hours, cool to room temperature, filter, and filter cake Hot ethyl acetate is hot extracted until TLC detects no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product precipitates, added 2.5L petroleum ether, filtered with suction, washed with a small amount of petroleum ether, and dried to obtain about 750g product.

[0043] ② Synthesis of compound 2

[0044] Compound 1 (1kg), 2kg of 3-morpholine-1-chloropropane, 3kg of potassium carbonate, 500g of tetrabutylammonium iodide and 5 liters of DMSO were added to a 10-liter four-necked flask, heated to reflux, TLC detected the reaction was complete, and cooled , Poured into 10 liters of ice water, ...

Embodiment 2

[0056] ① Synthesis of compound 1

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

[0058] ② Synthesis of compound 2

[0059] Compound 1 (1kg), 2kg of 3-morpholine-1-chloropropane, 3kg of potassium carbonate, 100g of tetrabutylammonium bromide and 5 liters of DMF were added to a 10-liter four-necked flask, heated to reflux, and TLC detected that the reaction was complete, then cooled , Poured into 10 lit...

Embodiment 3

[0071] ① Synthesis of compound 1

[0072] Add 5L of re-distilled benzene to a 10L four-necked flask, add 1kg of raw material isvanillin, 500g of hydroxylamine hydrochloride, 160g of p-toluenesulfonic acid and 5kg of anhydrous magnesium sulfate while stirring, heat to reflux for 10 hours, cool to room temperature, filter, and filter cake Hot ethyl acetate is hot extracted until TLC detects no product, combined, washed with water, washed with saturated brine, dried, concentrated until a large amount of product precipitates, added 2.5L petroleum ether, filtered with suction, washed with a small amount of petroleum ether, and dried to obtain about 780g product.

[0073] ② Synthesis of compound 2

[0074] Compound 1 (1kg), 3kg of 3-morpholine-1-chloropropane, 2kg of potassium carbonate, 250g of tetrabutylammonium bromide and 5 liters of DMSO were added to a 10-liter four-necked flask, heated to reflux, TLC detected the reaction was complete, and cooled , Poured into 10 liters of ice wate...

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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 field of synthesis of pharmaceutical compounds, in particular to a 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline ( Gefitinib) preparation method. Background technique: [0002] 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (Gefitinib, trade name: Iressa, Iressa) is a selective inhibitor of epidermal growth factor (EGFR) tyrosine kinase, currently clinically mainly 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 (WO9633980, CN96193526) of Astrazenica Co., Ltd. The synthetic route is as follows: [0006] [0007] This route uses 6,7-dimethoxy-3,4-dihydroquinazolin-4-one as the raw material, uses methanesulfonic acid and L-methionine to selectively remove the 6-position methyl group, acetylation protection, and then Chlorinated, amina...

Claims

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Application Information

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Patent Type & Authority Patents(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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