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Preparation method of 4-(3-chloro-4-fluorophenyl amido)-7-methoxy-6-(3-morpholine propoxy) quinazoline

A technology of methoxybenzoic acid and morpholine, which is applied in the field of preparation of 4--7-methoxy-6-quinazoline, and can solve the problems of many side reactions, low yield, and decreased yield

Active Publication Date: 2015-12-16
上海天慈中商药业有限公司
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Problems solved by technology

[0013] However, this method also has defects: as the last step of the rearrangement process needs to be carried out at a very high temperature for a long time, at this high temperature, the raw amidine is easily decomposed and the yield decreases
Though this method is with simple 3,4-dimethoxybenzoic acid as starting material, there are following two weak points: (1) this method does not protect hydroxyl after demethylation, because hydroxyl is Active groups, resulting in many side reactions in steps such as reduction, cyclization, and chlorination, and the yield is low
(2) The fourth step reaction of this synthetic route, 2-amino-4-methoxy-5-hydroxybenzoic acid directly reacts with formamide to construct the 4-carbonylquinoline parent ring, and this step has many by-products and low yield

Method used

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  • Preparation method of 4-(3-chloro-4-fluorophenyl amido)-7-methoxy-6-(3-morpholine propoxy) quinazoline

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preparation example Construction

[0089] Preparation of Gefitinib

[0090] The present invention provides a kind of preparation method of gefitinib, specifically, described preparation method prepares a kind of compound shown in following formula IV as intermediate:

[0091]

[0092] Described formula IV compound can be prepared by the following method:

[0093]

[0094] (3) In an inert solvent, in the presence of a catalyst, the compound of formula III is reacted with ammonium formate oxime to obtain the compound of formula IV.

[0095] In another preference, in the step (3), the catalyst is selected from the group consisting of trimethylaluminum, tri-n-propylaluminum, trioctylaluminum, triisobutylaluminum, triethylaluminum , tetrabutyl titanate, aluminum sulfate, trimethylaluminum silane; preferably trimethylaluminum.

[0096] In the step (3), all the other conditions can be determined according to actual needs, such as the scale of the reaction, the selected specific catalyst and other factors. Pref...

Embodiment 1

[0158] (1) Synthesis of 3-hydroxyl-4-methoxybenzoic acid methyl ester (II)

[0159] 3-Hydroxy-4-methoxybenzaldehyde (10g, 65.7mmol) was dissolved in formic acid (9.1g, 197.1mmol), the solution was lowered to 0°C, and 35% hydrogen peroxide (22.3g, 230mmol) was slowly added dropwise as above The solution was kept at 4°C for overnight reaction. After the reaction, the solid matter was filtered, washed with ice water, and dried to obtain a solid matter. The solid was dissolved in methanol (50ml), and concentrated sulfuric acid (98%, 3.2ml, 59.1mmol) was slowly added dropwise, heated to reflux, and the solvent was removed to obtain a crude product, which was recrystallized from 10% methanol aqueous solution to obtain 3-hydroxy-4-methanol Methyl oxybenzoate (II) (9.6 g), 80% yield.

[0160](2) Synthesis of methyl 4-methoxy-5-[3-(4-morpholinyl)propoxy]benzoate (III)

[0161] 3-Hydroxy-4-methoxybenzoic acid methyl ester (II) (15g, 82.3mmol), anhydrous sodium carbonate (23.2g, 167.9...

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Abstract

The invention provides a preparation method of 4-(3-chloro-4-fluorophenyl amido)-7-methoxy-6-(3-morpholine propoxy) quinazoline. Specifically, according to the method, 3-hydroxy-4-methoxybenzaldehyde (isovanillin) serves as raw materials, and the target product (I) is synthesized through the steps of oxidation, esterification, amidation, cyclization and the like. The method has the advantages of being short in synthetic route, low in cost, environmentally friendly, short in reaction step, easy to operate, high in yield and product purity and the like, and therefore the preparation method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, specifically, the present invention relates to 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)quinazoline ( Gefitinib I) preparation method. Background technique [0002] Gefitinib (I), the English name is Gefitinib; the trade name is Iressa, Iressa; the chemical name is 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-( 3-morpholine propoxy) quinazoline is the world's first oral small-molecule inhibitor for epidermal growth factor receptor (EGFR) tyrosine kinase developed by AstraZeneca, a British company. It has anti-proliferative activity such as Anti-tumor activity, currently clinically mainly used for the treatment of non-small cell lung cancer. It was first launched in Japan in 2002, approved by the US FDA in 2003, officially launched in China with the approval of the State Food and Drug Administration in 2005, and has now been approved for marketing in more than 30 coun...

Claims

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Application Information

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IPC IPC(8): C07D295/088C07D239/94C07D239/88
CPCC07D239/88C07D239/94C07D295/088
Inventor 李新涓子李健之马西来池王胄孙黎刘海胡旭华郑肖利翟志军李建勋
Owner 上海天慈中商药业有限公司
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