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Preparation method of gefitinib intermediate

A technology of gefitinib and intermediates, applied in the direction of organic chemistry, etc., can solve the problems of many by-products and low reaction yield, and achieve the effects of less by-products, less destructive parent ring, and increased substitution yield

Inactive Publication Date: 2016-06-22
田静
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] The object of the present invention is to overcome the defects such as low reaction yield and many by-products in the preparation method of the above-mentioned existing gefitinib intermediate, and provide a kind of preparation method of the gefitinib intermediate

Method used

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  • Preparation method of gefitinib intermediate
  • Preparation method of gefitinib intermediate
  • Preparation method of gefitinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] A kind of preparation method of gefitinib intermediate, this preparation method comprises the following steps:

[0032] 1) Under nitrogen protection, 14g of D301 macroporous weakly basic styrene-based anion exchange resin, 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (23.4g , 100mol), sulfuryl chloride (20.3g, 150mmol) in 100ml of acetonitrile for contact reaction, the temperature of the contact reaction is 65 ° C, quenched with ice water after the reaction, extracted with dichloromethane, concentrated under reduced pressure to obtain 6-acetoxy 24.3 g of 4-chloro-7-methoxyquinazoline, yield 96.3%, purity 98.81%.

[0033] 2) AuCl (4.2g, 18mmol), 6-acetoxy-4-chloro-7-methoxyquinazoline (12.6g, 50mmol), 3-chloro-4-fluoroaniline (12.3g, 85mmol ) in 50ml of methanol at 65°C for substitution reaction, after the reaction was completed, filtered, the filtrate was concentrated, and washed with petroleum ether to obtain 16.9g of gefitinib intermediate, with a yield of 93.4% a...

Embodiment 2

[0035] A kind of preparation method of gefitinib intermediate, this preparation method comprises the following steps:

[0036] 1) Under nitrogen protection, D301 macroporous weakly basic styrene-based anion exchange resin (15.2g), 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (23.4g, 100mol), sulfonyl chloride (21.6g, 160mmol) carry out contact reaction in 120ml acetonitrile, the temperature of contact reaction is 70 ℃, ice water is quenched after reaction finishes, dichloromethane extracts, concentrates under reduced pressure, obtains 6 -Acetoxy-4-chloro-7-methoxyquinazoline 24.2g, yield 95.63%, purity 98.10%,.

[0037] 2) AuCl (3.5g, 15mmol), 6-acetoxy-4-chloro-7-methoxyquinazoline (12.6g, 50mmol), 3-chloro-4-fluoroaniline (10.9g, 75mmol ) in 50ml of methanol at 60°C for a substitution reaction, after the reaction was completed, filtered, the filtrate was concentrated, and washed with petroleum ether to obtain 16.4g of the gefitinib intermediate, with a yield of 90.7% and...

Embodiment 3

[0039] A kind of preparation method of gefitinib intermediate, this preparation method comprises the following steps:

[0040] 1) Under nitrogen protection, D301 macroporous weakly basic styrene-based anion exchange resin (14.5g), 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (23.4g, 100mol), sulfonyl chloride (18.9g, 140mmol) carry out contact reaction in 90ml acetonitrile, the temperature of contact reaction is 75 ℃, ice water is quenched after reaction finishes, dichloromethane extracts, concentrates under reduced pressure, obtains 6 -Acetoxy-4-chloro-7-methoxyquinazoline 24.1 g, yield 95.47%, purity 96.95%,.

[0041]2) AuCl (4.7g, 20mmol), 6-acetoxy-4-chloro-7-methoxyquinazoline (12.6g, 50mmol), 3-chloro-4-fluoroaniline (14.6g, 100mmol ) in 30ml of methanol at 65°C for substitution reaction, after the reaction was completed, filtered, the filtrate was concentrated, and washed with petroleum ether to obtain 16.8g of gefitinib intermediate, with a yield of 92.7% and a pur...

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Abstract

The invention discloses a preparation method of a gefitinib intermediate. The preparation method comprises steps as follows: 1) in the presence of anion exchange resin, 6-acetoxyl-7-methoxy-3,4-dihydroquinazoline-4-ketone and sulfonyl chloride are subjected to a contact reaction in acetonitrile, after the reaction ends, ice water quenching, dichloromethane extraction and concentration under the reduced pressure are performed, and 6-acetoxyl-4-chloro-7-methoxyquinazoline is obtained, wherein the temperature for the contact reaction ranges from 65 DEG C to 75 DEG C; 2) in the presence of AuCl, 6-acetoxyl-4-chloro-7-methoxyquinazoline obtained in the step 1) and 3-chloro-4-fluoroaniline are subjected to a substitution reaction at the temperature of 55-65 DEG C, and the gefitinib intermediate is obtained. By means of the method, the product yield can be greatly increased, the conditions are mild, and few by-products are produced.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of a gefitinib intermediate. Background technique [0002] Gefitinib, English name Gefitinib, is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by AstraZeneca, which was launched in Japan in 2002 for the treatment of advanced non-small cell lung cancer ( NSCLC). It was launched in China under the trade name Iressa in 2005 for the treatment of locally advanced or metastatic non-small cell lung cancer who have previously received chemotherapy. [0003] The chemical name of gefitinib is 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, and the specific structure is as follows: [0004] [0005] At present, there are many studies on the preparation of gefitinib. CN1182421A discloses a preparation method of gefitinib. The specific synthetic route is as follows: [0006] ...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D239/86
CPCC07D239/86C07D239/94Y02P20/55
Inventor 何宝红
Owner 田静
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