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Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline

A fluoroanilino, methoxyl technology, applied in the field of pharmaceutical preparation, can solve the problems of not getting rid of high-risk, high-polluting halogenated reagents, low total yield, long reaction steps, etc., and achieves cost reduction, total yield improvement, Effects of short synthesis steps

Inactive Publication Date: 2009-04-08
浙江精进药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route has been pilot tested, it still does not get rid of the use of highly dangerous and highly polluting halogenated reagents, such as thionyl chloride, phosphorus oxychloride, etc.
And the reaction steps are long, the total yield is low

Method used

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  • Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline
  • Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline
  • Synthesis method of 4-(3-chlorine-4-fluorobenzene amino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] Embodiment 1, a kind of synthetic method of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy]quinoline, followed by Do the following steps:

[0039] 1), the preparation of 3-hydroxyl-4-methoxybenzonitrile (structural formula is 2):

[0040] Stir 3-hydroxy-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formate (89.4g, 1.31mol) and formic acid (480ml), mix and heat to 80°C, add hydroxylamine sulfate (114.8g, 0.70mol ), hydroxylamine sulfate was equally divided into six parts, and one part was added every 30 minutes; after the addition was completed, it was heated and stirred at 80°C for 5 hours.

[0041]The mixture obtained by the reaction was cooled to room temperature, 250ml of saturated saline solution was added, stirred, filtered, the separated precipitate was separated, washed with water, and dried to obtain an off-white solid, which was 3-hydroxy-4-methoxybenzonitrile (79.0g , yield 80%). 1 H NMR (DMSO-d 6 , 300MHz): 3.83(s, 3H), 7.00-7.13(m,...

Embodiment 2

[0056] Embodiment 2, a kind of synthetic method of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxyl]quinoline, sequentially Do the following steps:

[0057] 1), the preparation of 3-hydroxyl-4-methoxybenzonitrile (structural formula is 2):

[0058] Stir 3-hydroxy-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formate (135.1g, 1.98mol) and formic acid (600ml), mix and heat to 85°C, add hydroxylamine sulfate (162.4g, 0.99mol ), hydroxylamine sulfate was divided into six equal portions, and each portion was added every 30 minutes; after the addition was completed, it was heated and stirred at 85°C for 6 hours.

[0059] The resulting mixture was treated in the same manner as in Example 1 to obtain a white solid (86.5 g, yield 88%).

[0060] 2), the preparation of 4-methoxy-3-[3-(4-morpholinyl) propoxy]benzonitrile (structural formula is 3):

[0061] 3-Hydroxy-4-methoxybenzocyanide (80.0g, 0.54mol), sodium carbonate (138.9g, 1.35mol), sodium iodide (4.5g, 0....

Embodiment 3

[0073] Embodiment 3, a kind of synthetic method of 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy]quinoline, sequentially Do the following steps:

[0074] 1), the preparation of 3-hydroxyl-4-methoxybenzonitrile (structural formula is 2):

[0075] Stir 3-hydroxy-4-methoxybenzaldehyde (100.0g, 0.66mol), sodium formate (130.0g, 1.91mol) and formic acid (600ml), mix and heat to 90°C, add hydroxylamine sulfate (162.4g, 0.99mol ), hydroxylamine sulfate was equally divided into six parts, and the parts were added every 30 minutes; after the addition was completed, it was heated and stirred at 90°C for 5 hours.

[0076] The resulting mixture was treated in the same manner as in Example 1 to obtain a white solid (84.6 g, yield 86%).

[0077] 2), the preparation of 4-methoxy-3-[3-(4-morpholinyl) propoxy]benzonitrile (structural formula is 3):

[0078] 3-Hydroxy-4-methoxybenzocyanide (80.0g, 0.54mol), lithium carbonate (90.4g, 1.35mol), sodium iodide (4.5g, 0.030m...

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Abstract

The invention discloses a method for synthesizing 4-(3-chloro-4-fluorophenylamino)-7-methoxy -6-[3-(4-morpholinyl)-propoxy] quinoline. The method comprises the following steps: 1) 3-hydroxide radical-4-methoxybenzaldehyde is used as a raw material to prepare 3-hydroxide radical-4-methoxy-benzonitrile; 2) the 3-hydroxide radical-4-methoxy-benzonitrile and 3- chloropropy morpholinehydrochloride are heated to have reflux reaction to obtain 4- methoxy-3-[3-(4- morpholinyl) propoxy] benzonitrile; 3) the 4- methoxy-3-[3-(4-morpholinyl) propoxy] benzonitrile is subjected to nitration to obtain 2- nitryl-4- methoxy -5-[3-(4-morpholinyl) propoxy] benzonitrile; 4) the 2- nitryl-4- methoxy -5-[3-(4-morpholinyl) propoxy] benzonitrile is subjected to reduction to obtain 2-amido-4- methoxy-5-[3-(4-morpholinyl) propoxy] benzonitrile; and 5) the 2-amido-4- methoxy-5-[3-(4-morpholinyl) propoxy] benzonitrile and an azomethine intermediate of 3-chloro-4-fluoroaniline have rearrangement reaction to obtain 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy] quinoline. The method has characteristics of environmental protection and high production rate.

Description

technical field [0001] The present invention relates to 4-(3-chloro-4-fluoroanilino)-7-methoxy-6-[3-(4-morpholinyl)-propoxy]quinoline (gefitinib, Gefitinib) The preparation method belongs to the technical field of medicine preparation. Background technique [0002] Gefitinib (Gefitinib) is a new type of anti-tumor drug developed by Astra Zeneca. It is an oral small molecule inhibitor against EGFR protein tyrosine kinase. It was first launched in Japan in 2002 for the treatment of inoperable tumors. Or metastatic and recurrent non-small cell lung cancer, it 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 is the first small molecule protein tyrosine for the treatment of solid tumors Kinase inhibitors target anticancer drugs. Approved by the State Food and Drug Administration (SFDA) on February 25, 2005, it was officially launched in China (trade name: Gefitinib), for locally advanced ...

Claims

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Application Information

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IPC IPC(8): C07D239/94
Inventor 张华赵金浩王晖
Owner 浙江精进药业有限公司
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