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Novel method for preparing 4-(3-chlorine-4-fluorophenylamino)-7-methoxyl-6-(3-morpholinepropoxy)quinazoline

The technology of morpholine propoxy and fluorophenyl amine group is applied in the field of preparation of 4--7-methoxy-6-quinazoline, and can solve the problems of purification of untargeted products, decreased yield, and easy raw material amidines. decomposition, etc.

Active Publication Date: 2011-07-13
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] 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
This route also did not carry out further purification to target product

Method used

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  • Novel method for preparing 4-(3-chlorine-4-fluorophenylamino)-7-methoxyl-6-(3-morpholinepropoxy)quinazoline
  • Novel method for preparing 4-(3-chlorine-4-fluorophenylamino)-7-methoxyl-6-(3-morpholinepropoxy)quinazoline
  • Novel method for preparing 4-(3-chlorine-4-fluorophenylamino)-7-methoxyl-6-(3-morpholinepropoxy)quinazoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Example 1: Synthesis of 3-morpholinopropyl chloride (II)

[0063] Dissolve 193 g of morpholine in 580 ml of toluene and raise the temperature to 85°C. 159 grams of 1-bromo-3-chloropropane was slowly dropped into the above mixture, and stirred at 85°C for 1 day.

[0064] Under an ice bath, 500 ml of 18% hydrochloric acid aqueous solution was slowly added dropwise to the reaction solution, and after thorough stirring, the water layer was separated. Also under an ice bath, slowly drop 250 ml of 50% sodium hydroxide aqueous solution into the water layer. The water layer was extracted 3 times with ethyl acetate, and then the water layer was removed. After the organic layer was dried over anhydrous sodium sulfate, the organic solvent was removed under reduced pressure to obtain 147 g of product with a yield of 90%.

Embodiment 2

[0065] Example 2 Synthesis of 2-hydroxy-3-methoxybenzonitrile (IV)

[0066] 150 grams of 3-hydroxy-4-methoxybenzaldehyde (III) and 205 grams of sodium formate were dissolved in 1.5 liters of formic acid. When the system was heated to 85°C, 97 g of hydroxylamine sulfate was slowly added to the above mixed solution within 6 hours, and then reacted for 6 hours.

[0067] After cooling to room temperature, 5 liters of saturated brine was added to the reaction system, and the solid was filtered out. After drying, 145 g of white solid was obtained with a yield of 99%.

Embodiment 3

[0068] Example 3 Synthesis of 3-(3-morpholinopropoxy)-4-methoxybenzonitrile (V)

[0069] 89 grams of 2-hydroxy-3-methoxybenzonitrile (IV), 108 grams of 3-morpholinopropyl chloride (II), and 141 grams of potassium carbonate were dissolved in 1 liter of DMF. After heating to 75°C, react for 4 hours.

[0070] 1.5 liters of water was added to the reaction mixture, and extraction was performed 3 times with 2 liters of ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the organic solvent was removed to obtain 165 g of viscous liquid with a yield of 99%.

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Abstract

The invention discloses a novel method for preparing 4-(3-chlorine-4-fluorophenylamino)-7-methoxyl-6-(3-morpholinepropoxy)quinazoline (gefitinib, I). The method comprises the following steps of: preparing an intermediate (VI), performing functional group transformation twice under a hydrogenation condition to generate 2-(N,N-dimethylformylimido)-4-methoxyl-5-(3-morpholinepropoxy)cyanophenyl (VIII), and performing ring closure rearrangement on the obtained (VIII) and 3-chlorine-4-fluoroaniline to generate the gefitinib (I). The method is short in steps and high in yield in each step, the intermediate is convenient to purify, a target product has high purity, and the method is suitable for industrial production.

Description

Technical field [0001] The invention relates to a preparation method of 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholinepropoxy)quinazoline (gefitinib, I) . 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 of epidermal growth factor receptor (EGFR) tyrosine kinase developed by Astra Zeneca, UK, with anti-proliferative activity Such as anti-tumor activity, currently clinically mainly used for the treatment of non-small cell lung cancer. It was first listed in Japan in 2002 and was approved by the US FDA in 2003. It was officially listed in China by the State Food and Drug Administration in 2005. It has now been approved for listing in more than 30 countries. The results of the study proved that gefitinib (I) can selectively block the epidermal growth factor ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 陈宇张春春竺伟甘立新马大为
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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