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Preparation method of gefitinib

A technology for gefitinib and compounds, applied in the field of pharmaceutical preparation, can solve the problems of low purity and yield of formamidine intermediates, affecting the purity and yield of gefitinib, and difficult separation and purification of products, and achieves a purification method. Simple, mild reaction conditions

Active Publication Date: 2014-02-12
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Abstract
  • Description
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Problems solved by technology

[0007] Although this method can be industrialized, in step I, (1) is reduced to (2) while also generating a by-product of nitrile group reduction. Because the product is not easy to separate and purify, the formamidine intermediate generated in step II (3) The purity and yield are not high, which affects the purity and yield of gefitinib

Method used

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  • Preparation method of gefitinib

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preparation example Construction

[0030] The invention provides a preparation method of gefitinib: use 4-methoxy-5-(3-morpholine propoxy)-2-nitrobenzonitrile as raw material, and obtain an intermediate through reduction and salt formation 3 reacted directly with N,N-dimethylformamide dimethyl acetal to obtain 5,5 rearranged with 3-chloro-4-fluoroaniline to obtain gefitinib. The synthetic route is as follows:

[0031]

Embodiment 1

[0033] (1) Synthesis of compound 2

[0034] Put 30g of 4-methoxy-5-(3-morpholinopropoxy)-2-nitrobenzonitrile into 400mL of tap water, stir, heat to 50°C, then slowly add 45g of hydrosulfite, keep warm for reaction After 2 hours, the solution was not clear at this time, and the temperature was raised to 70°C, and 151 mL of concentrated hydrochloric acid was added dropwise. After the addition was complete, the solution was clear, and TLC (thin layer chromatography) showed that the reaction of the raw materials was complete. Filter the reaction solution while it is hot (filter out a small amount of insoluble suspended solids), cool the filtrate to room temperature, adjust the pH to 10 with 50% NaOH solution, then extract 500 mL x 3 times with dichloromethane, combine the dichloromethane phases, Washed with water, washed with saturated brine, anhydrous Na 2 SO 4 Drying, rotary evaporation of dichloromethane, and vacuum drying gave 24 g of crude compound 2, with a yield of 88% an...

Embodiment 2

[0043] (1) Synthesis of compound 2

[0044] Put 1500g of compound 1 into a reaction kettle containing 15L of dioxane and 15L of water, stir, heat to 50°C, then slowly add 2440g of sodium hydrosulfite, and keep it warm for 2 hours. At this time, the solution is not clear, and then heated to 70 ℃, add 1500mL of concentrated hydrochloric acid dropwise, after the addition is complete, the solution is clear, and TLC shows that the reaction of the raw materials is complete. Cool the reaction solution to room temperature, add about 1200g of a saturated solution of sodium hydroxide, adjust the pH to 10, then extract 20L x 3 times with dichloromethane, combine the dichloromethane phases, wash with water, wash with saturated saline, and anhydrous Na 2 SO 4 Drying and rotary evaporation of dichloromethane gave 1251 g of the crude product of compound 2 (directly used in the next step of salt formation reaction), with a yield of 92%.

[0045] (2) Synthesis of compound 3

[0046] Dissolv...

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Abstract

The invention discloses a preparation method of gefitinib. The preparation method takes 4-methoxyl-5-(3-morpholine propoxyl)-2-nitrobenzonitrile as a raw material, then subjecting the raw material to treatments of reduction and salt forming reactions so as to obtain an intermediate 2-amino-4-methoxyl-5-(3-morpholine propoxyl) benzonitrile hydrochloride, then directly subjecting the intermediate to react with N,N-dimethyl formamide dimethyl acetal so as to obtain N'-(2-cyano-5-methoxyl-4-(3-morpholinyl propoxyl)benzyl)-N,N-dimethyl formamidine, and finally subjecting the formamidine intermediate to carry out rearrangement reactions with 3-chloro-4-fluoroaniline so as to obtain the gefitinib. The preparation method has the advantages of mild reaction conditions, convenient intermediate purification method, and suitability for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of epidermal growth factor (EGFR) inhibitor gefitinib, an anti-non-small cell lung cancer drug. technical background [0002] Gefitinib is an epidermal growth factor EGFR tyrosine kinase small molecule inhibitor anticancer drug developed by Astra Zeneca. It was first launched in Japan in 2002 for the treatment of inoperable or metastatic and recurrent non-small cell lung cancer. It was approved in the United States and Australia in 2003 as a third-line monotherapy for advanced non-small cell lung cancer. Gefitinib is the first small molecule protein tyrosine kinase inhibitor targeted anticancer drug for the treatment of solid tumors. Approved by the State Food and Drug Administration (SFDA) on February 25, 2005, it was officially launched in China (trade name: Iressa), for the treatment of locally advanced or metastatic non-small ce...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCC07D239/94
Inventor 丁克李伟华陆小云
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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