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Preparing method of anticancer medicine

An anticancer drug, gefitinib technology, applied in the field of medicinal chemistry, can solve the problems of many by-products, low yield, many side reactions, etc., and achieve the effects of less three wastes, high yield, and reducing the generation of side reactions

Active Publication Date: 2014-10-01
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Abstract
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  • Claims
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AI Technical Summary

Problems solved by technology

Although this method uses simple 3,4-dimethoxybenzoic acid as the starting material, it has the following two shortcomings: (1) the method does not protect the hydroxyl group after demethylation, because the hydroxyl group is Active groups, resulting in many side reactions in steps such as reduction, cyclization, and chlorination, and the yield is low
(2) In the fourth step of the synthetic route, 2-amino-4-methoxy-5-hydroxybenzoic acid reacts directly with formamide to construct the parent ring of 4-carbonylquinazoline. This step has many by-products and low yield

Method used

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  • Preparing method of anticancer medicine
  • Preparing method of anticancer medicine
  • Preparing method of anticancer medicine

Examples

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example 1

[0039] The first step: 2-amino-4-methoxy-5-(3-morpholine propoxy) benzonitrile hydrochloride ( 3 ) preparation

[0040] Put 100.00 g of 4-methoxy-5-(3-morpholine propoxy)-2-nitrobenzonitrile into a reaction flask containing 300 ml of dioxane and 1000 ml of water, stir and heat to 70°C , then slowly add 325.20g of sodium hydrosulfite, keep warm for 6h, add 100mL of concentrated hydrochloric acid dropwise, after the addition is complete, the solution is clear. Cool the reaction solution to room temperature, add 120g of sodium hydroxide solution (30%), adjust the pH to strong alkalinity, extract with dichloromethane (1000ml×3), combine the dichloromethane phase, wash the dichloromethane phase with water, Then washed with saturated brine, anhydrous Na 2 SO 4 Drying, filtration, and concentration gave crude 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The above crude product was dissolved in 1000ml of absolute ethanol, and concentrated hydrochloric acid was added drop...

example 2

[0042] The first step: 2-amino-4-methoxy-5-(3-morpholine propoxy) benzonitrile hydrochloride ( 3 ) preparation

[0043] Put 100.00 g of 4-methoxy-5-(3-morpholine propoxy)-2-nitrobenzonitrile into a reaction flask filled with 1000 ml of dioxane and 300 ml of water, stir and heat to 50°C , and then slowly add 162.67g of sodium hydrosulfite, keep warm for 5h, add 100mL of concentrated hydrochloric acid dropwise, after the dropwise addition, the solution is clear. Cool the reaction solution to room temperature, add 120g of sodium hydroxide solution (40%), adjust the pH to strong alkalinity, extract with dichloromethane (800ml×3), combine the dichloromethane phase, wash the dichloromethane phase with water, Then washed with saturated brine, anhydrous Na 2 SO 4 Drying, filtration, and concentration gave crude 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The above crude product was dissolved in 700ml of absolute ethanol, and concentrated hydrochloric acid was added drop...

example 3

[0045] Step two: N '-(2-cyano-5-methoxy-4-(3-morpholinopropoxy)phenyl)- N , N -Dimethylformamide imine ( 4 ) preparation

[0046] the intermediate ( 3 ) 80.00g and N,N-dimethylformamide dimethyl acetal 169.00g were added to 1000ml toluene, heated to 100°C for 2h, and the reaction was stopped. Concentrate under reduced pressure to obtain a viscous liquid, add the obtained viscous liquid to 280ml of water, extract with dichloromethane (280ml×3), combine the dichloromethane phases, wash with water, wash with saturated brine, dry over anhydrous sodium sulfate, and filter , concentrated to obtain the crude product. Add 260ml of absolute ethanol to the above crude product, heat to reflux until the crude product is completely dissolved, cool to 10°C to crystallize, filter, and collect 66.30g of solid. Yield 78%.

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Abstract

The invention discloses a novel synthesis method of an anticancer medicine gefitinib. The preparing method includes subjecting 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile that is adopted as a raw material to reduction by sodium hydrosulfite, salifying with hydrochloric acid, reacting with N,N-dimethylformamide dimethyl acetal to obtain a condensation product, subjecting the condensation product and 3-chloro-4-fluoroaniline to cyclization to obtain the gefitinib. The initial raw material adopted by the preparing method is cheap and easily available. The synthesis route is simplified. The raw material utilization rate and the total yield are largely increased. Reaction intermediates are mostly purified by a recrystallization method or are directly used for a next reaction. The method has characteristics of high yield, less three-waste in reaction processes and low cost, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to anti-lung cancer drug 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (gefi Tini, Gefitinib) new preparation method. Background technique [0002] The present invention relates to the synthesis of antitumor drug epidermal growth factor receptor (EGFR) inhibitor gefitinib. The structure of gefitinib is as follows: [0003] [0004] Gefitinib (Gefitinib), the chemical name is 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, is Aspen An oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by Likang Company for the treatment of advanced non-small cell lung cancer (NSCLC). This product was first launched in Japan in July 2002, and was approved in the United States and Australia in May 2003 as a third-line monotherapy for advanced non-small cell lung cancer (NSCLC). It entered China in 2005 with t...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 陈矛朱少璇黄小光
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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