Method for preparing gefitinib

A technology of gefitinib and methoxy, which is applied in the field of medicinal chemistry, can solve the problems of many by-products, low yield, and many side reactions, and achieve the effects of less waste, high yield, and less side reactions

Inactive Publication Date: 2011-04-27
SUN YAT SEN UNIV
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  • Abstract
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  • Claims
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Problems solved by technology

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 reductio

Method used

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  • Method for preparing gefitinib
  • Method for preparing gefitinib
  • Method for preparing gefitinib

Examples

Experimental program
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Example Embodiment

[0047] Example 1:

[0048] The first step: Preparation of 3,4-Dimethoxy-6-nitrobenzoic acid (3):

[0049] Put a 2L three-necked bottle in an ice bath and add 1100ml HNO to the bottle 3 (65%~68%), insert a thermometer and a mechanical stirring device, add 200g of 3,4-dimethoxybenzoic acid (2) in small batches under stirring, about 1h, after the addition, continue to stir for 15min, then vigorously Pour into a vessel containing 10L of cold water under stirring. After adding, continue to stir for 10 minutes, filter and suck dry, then beat with 5L of cold water for a few minutes, filter, and drain as much as possible. The crude product was dried in a vacuum drying oven at 50° C. for 48 hours to obtain 237 g of crude product. It was recrystallized with 95% ethanol to obtain 199 g of yellow solid with a yield of 80%.

[0050] Step 2: Preparation of 2-nitro-4-methoxy-5-hydroxybenzoic acid (4):

[0051] 199g of 3,4-dimethoxy-6-nitrobenzoic acid (3) was added to 1L of 20% NaOH solution, heat...

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Abstract

The invention discloses a novel preparation method for synthesizing gefitinib. 3,4-dimethoxybenzoic acid (2) is taken as a raw material, and the method comprises the following steps of: nitrifying, demethylating and methylating the 3,4-dimethoxybenzoic acid (2) to prepare an intermediate of 2-nitryl-4-methoxy-5-methyl-hydroxybenzoate (5); reacting the intermediate with 4-(3-bromopropyl) morpholine, and introducing an alkyl side chain to prepare an intermediate 6; reducing nitryl, and performing ring formation with methanamide to construct a quinoline matrix ring 8; halogenating 4-carbonyl by using the compound 8 under the action of thionyl chloride to generate an intermediate 9; and reacting with halogen substituted aromatic amine 3-chloro4-fluoroaniline to obtain the target product of gefitinib (1). In the method, the selected initial raw material is low in cost, the synthesizing route is simplified, and the raw material utilization rate and the total yield are greatly improved. The intermediates obtained in the reactions are mostly purified by a re-crystallization method, or directly subjected to the next reaction, so the yield is high, a few three wastes are generated in the reaction process, the cost is low and the method is favorable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to antitumor drug 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy] A new preparation method of quinazoline (gefitinib, Gefitinib). Background technique [0002] The present invention relates to the synthesis of antitumor drug epidermal growth factor receptor (EGFR) inhibitor gefitinib. The structure is as follows: [0003] [0004] Figure 1 Gefitinib structural formula [0005] 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 Asrazeneca 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 (NS...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 黎星术张爱琴黄玲
Owner SUN YAT SEN UNIV
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