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Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline

A technology of fluorophenylamine group and nitroquinazoline is applied in the field of preparing 4--7-methoxy-6-[3-propoxy]quinazoline, and can solve the problem of 3-hydroxy-4- Methyl methoxybenzoate is expensive, unsuitable for industrialized large-scale production, and has high production costs, which can reduce environmental pollution and production costs, simplify operations, and improve production efficiency.

Active Publication Date: 2009-11-04
CHONGQING WORLD HAORUI PHARM CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Though this method directly introduces 3-morpholine propoxy group at 3-position, has simplified reaction steps, has improved reaction yield, but used raw material 3-hydroxyl-4-methoxybenzoic acid methyl ester price ratio is expensive, Not easy to obtain, resulting in higher production costs, not suitable for large-scale industrial production

Method used

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  • Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline
  • Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline
  • Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline

Examples

Experimental program
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Effect test

Embodiment 1

[0053] Preparation of 4-methoxy-2-aminobenzoic acid (VIII). 113g of ammonium chloride, 2000ml of water, 280g of reduced iron powder, and 39ml of hydrochloric acid were sequentially added into a 5000ml reaction flask. Stir and heat up to 80-85°C, add 163g of 4-methoxy-2-nitrobenzoic acid in batches, pay attention to the feeding speed, keep the reaction for 3 hours after the feeding is completed. Cool to room temperature, adjust the pH to 12 with liquid alkali, keep stirring for 0.5 hours, filter, and wash the filter cake with hot water above 80°C until the filtrate is nearly colorless. The filtrate was cooled with ice water and the pH was adjusted down to 5-6, a large amount of white solid was precipitated, filtered and dried to obtain 127.2 g of 4-methoxy-2-aminobenzoic acid (VIII), the yield was 92.1%.

Embodiment 2

[0055] Preparation of 4-methoxy-5-nitro-2-aminobenzoic acid (VII). Add 162.1g of 4-methoxy-2-aminobenzoic acid and 1000ml of chloroform in sequence into a dry and clean 3000ml reaction flask, and stir evenly. Under ice water cooling, 136 g of 90% nitric acid was slowly added dropwise, and the dropping process was kept at 20-25°C. After the dropwise addition was completed, the reaction was maintained at 25-30°C for 3.0 hours. Add 500ml of water to dilute, adjust pH to about 7 with liquid caustic soda, distill off chloroform, filter and dry to obtain 176.5g of yellow product with a yield of 85.8%.

Embodiment 3

[0057] Preparation of 7-methoxy-6-nitroquinazolin-4(3H)-one (VI). Add 76.2g of 4-methoxy-5-nitro-2-aminobenzoic acid and 530.6g of formamide in sequence to a dry and clean 1000ml reaction flask, stir and raise the temperature to 135-140°C for 16 hours. After the reaction was completed, it was cooled to 5° C. with ice water, a large amount of solids were precipitated, filtered, washed with water, and dried to obtain 69.6 g of compound (VI) as brown-yellow crystals, with a yield of 92.6%.

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Abstract

The invention relates to a method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline (I). The method takes 4-methoxy-2-nitrobenzoic acid as initial material which is subjected to reduction and nitration to obtain 4-methoxy-5-nitryl-2-aminobenzoic acid, is then subjected to cyclization to obtain 7-methoxy-6-nitryl quinazoline-4(3H)-ketone, is again subjected to reduction and diazo reaction hydrolysis to obtain 7-methoxy-6-hydroxy quinazoline-4(3H)-ketone, after etherification reaction is carried out, phosphorus oxychloride is used for preparing 7-methoxy-6-[3-(4-morphjolinyl) propoxy]-4-chloroquinazoline, which is subjected to amination to obtain the compound in the formula (I). The initial material adopted by the preparation method is convenient and accessible, the cost is low, the process route is simple and reasonable, the three wastes produced in the process of preparation generates less pollution, therefore the preparation method can prepare final product with high quality and yield in mass production, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a method for preparing 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline. Background technique [0002] 4-(3-Chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyl)propoxy]quinazoline has the structure of formula (I): [0003] [0004] Hereinafter they are all referred to as compounds of formula (I). The compound of formula (1) is now called Iressa (trade name) and Gefitinib (common name), the code number is ZD1839, and the chemical abstract registration number is 1844-75-35-2, which is developed by Astra Zeneca Company against EGFR tyrosine Orally available small molecule inhibitors of acid kinases. In 2002, it was first marketed in Japan for the treatment of inoperable or recurrent non-small cell lung cancer. In May 2003, it was approved as a third-line monotherapy for advanced non-small cell lung cancer (NSCLC) in the United States and Australia. Target-specific small molecule tyrosi...

Claims

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Application Information

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IPC IPC(8): C07D239/94A61K31/5377A61P35/00
Inventor 林国跃颜伟伟陈晓朋舒坤
Owner CHONGQING WORLD HAORUI PHARM CHEM
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