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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: 2015-01-07
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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

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Experimental program
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Effect test

Embodiment 1

[0062] The synthesis of embodiment one 3-morpholine propyl chloride (II)

[0063] Dissolve 193 g of morpholine in 580 ml of toluene and heat up to 85°C. Slowly drop 159 g of 1-bromo-3-chloropropane into the above mixture, and stir 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 liquid, and after stirring well, the water layer was separated. Also under ice bath, 250 ml of 50% sodium hydroxide aqueous solution was slowly added dropwise to the water layer. The aqueous layer was extracted three times with ethyl acetate and the aqueous 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] The synthesis of embodiment two 2-hydroxyl-3-methoxybenzonitrile (IV)

[0066] 150 grams of 3-hydroxy-4-methoxybenzaldehyde (III), 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 mixture within 6 hours, followed by reaction for 6 hours.

[0067] After cooling to room temperature, 5 liters of saturated saline 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-morpholine propoxy)-4-methoxybenzonitrile (V)

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

[0070] 1.5 liters of water was added to the reaction mixture, which was extracted three 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 present invention relates to the preparation method of 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-morpholine propoxy)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-Morpholinopropoxy)quinazoline is the world's first oral small-molecule inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase developed by Astra Zeneca, UK, and 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 countries. The results of the study prove that gefitinib (I) can selectively block t...

Claims

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Application Information

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Patent Type & Authority Patents(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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