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Preparation method of high-purity gefitinib

A technology of gefitinib and fluoroaniline, applied in the field of preparation of gefitinib, can solve problems such as long reaction time and many impurities, and achieve the effects of simple operation, improved yield and reduced difficulty

Active Publication Date: 2015-05-13
QILU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0023] Aiming at the deficiencies in the prior art, the present invention provides a preparation method of high-purity gefitinib, which mainly solves the problems of long reaction time and many impurities in large-scale production. The preparation method of the present invention is simple to operate, easy to refine, and the yield High, high product purity, suitable for industrial production

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  • Preparation method of high-purity gefitinib

Examples

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Effect test

Embodiment 1

[0048] Preparation of gefitinib crude product: 40kg compound II 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-alcohol was added to 400L of N,N-dimethylformamide , add 35kg potassium carbonate (d(0.5) is 49μm), 4kg anhydrous magnesium sulfate, 25kg N-(3-chloropropyl)morpholine successively under stirring, react at 70°C, TLC detects that the reaction is complete after 5h, and cools down to room temperature After that, 2000L of purified water was added, centrifuged, and dried to obtain 47.6 kg of crude gefitinib, with a yield of 85.1% and a purity of 98.95%.

[0049] Refining of gefitinib: 47.6 kg of gefitinib obtained was added to 900 L of ethanol, refluxed for dissolution, cooled to -5 to 5° C., centrifuged, and dried to obtain 43.4 kg of gefitinib with a yield of 91.2%. The purity is 99.93%, and the largest single hetero compound IV is 0.04%.

Embodiment 2

[0051] Preparation of crude gefitinib: Add 40 g of 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol (compound II) to 400 ml of N,N-dimethylformaldehyde Add 40g of potassium carbonate (d(0.5) is 39μm), 10g of anhydrous sodium sulfate, and 25g of N-(3-chloropropyl)morpholine successively under stirring, and react at 85°C. After 4 hours, TLC detects that the reaction is complete. After reaching room temperature, 2L of purified water was added, suction filtered, and dried to obtain 48.2 g of crude gefitinib, with a yield of 86.2% and a purity of 98.87%.

[0052] Refining of Gefitinib: 48.2 g of Gefitinib obtained was added to 900 ml of ethanol, dissolved under reflux, cooled to -5 to 5° C., centrifuged, and dried to obtain 44.1 g of Gefitinib, with a yield of 91.5%. The purity is 99.92%, and the largest single hetero compound IV is 0.04%.

Embodiment 3

[0054] Preparation of crude gefitinib: Add 40 g of 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol (compound II) to 500 ml of N,N-dimethylformaldehyde Add 30g of potassium carbonate (d(0.5) is 39μm), 3g of anhydrous sodium sulfate, and 24g of N-(3-chloropropyl)morpholine successively under stirring, and react at 120°C. After 4 hours, TLC detects that the reaction is complete. After reaching room temperature, 2.5 L of purified water was added, suction filtered, and dried to obtain 47.3 g of crude gefitinib, with a yield of 84.6% and a purity of 99.02%.

[0055] Refining of Gefitinib: 47.3 g of Gefitinib obtained was added to 900 ml of ethanol, dissolved under reflux, cooled to -5 to 5° C., centrifuged, and dried to obtain 43.1 g of Gefitinib with a yield of 91.1%. The purity is 99.93%, and the largest single hetero compound IV is 0.05%.

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Abstract

The invention provides a preparation method of high-purity gefitinib. The preparation method includes the steps of adding 4-(3-chlorine-4-fluoroaniline)-7-methoxy-quinazoline-6-alcoholic compound II into N, N-dimethylformamide, then adding potassium carbonate with particle size d (0.5) less than or equal to 50microns, anhydrous sodium sulfate or anhydrous magnesium sulfate, and N-(3-chloropropyl) morpholine, heating to perform reaction, conduct aftertreatment to obtain the gefitini through postprocessing. According to the preparation method, the problems that the reaction time is long and more impurities exist during large-scale production are solved by controlling particle size of the potassium carbonate and adding the anhydrous sodium sulfate or the anhydrous magnesium sulfate; the preparation method has the advantages of simplicity in operation, easiness in refining, high yield and high product purity; and high-purity gefitinib is suitable for industrial production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular to a preparation method of gefitinib. Background technique [0002] Gefitinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by AstraZeneca, which is suitable for the treatment of locally advanced or metastatic non-small cell tumors who have previously received chemotherapy or are not suitable for chemotherapy. Cell lung cancer (NSCLC), which is the first small molecule protein tyrosine kinase inhibitor targeted anticancer drug for the treatment of solid tumors. The chemical name is N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine propoxy)quinazolin-4-amine, and the structure is as shown in formula I: [0003] [0004] The preparation method of gefitinib in the prior art mainly contains following several kinds: [0005] Method-: The patent CN1182421A applied by Zenica Co., Ltd. of the United Kingdom discl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 冷传新李燕林栋范传文倪刚张少宁
Owner QILU PHARMA CO LTD
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