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Preparation method of crystal form of gefitinib Form 1

A technology of gefitinib and crystal form, applied in the field of preparation of gefitinib Form 1 crystal form, can solve the problems of cumbersome operation, poor process stability, poor crystal form purity, etc., and achieve high yield and controllable increase Sexuality and stability, reducing the effect of finished products

Inactive Publication Date: 2015-01-14
CHENGDU SINO STRONG PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although, there are many preparation methods for gefitinib Form 1 crystalline forms reported in the literature, for example, CN101177415 announces that a gefitinib solvate is first prepared, and then Form 2, Form 3, and Form 5 crystals are removed by using solvent beating. Form 1 crystal form MeOH, DMSO or water to prepare the method of pure Form 1 crystal form; Subsequently, CN101973944, CN201310578929 etc. have reported the preparation method of the gefitinib of Form1 crystalline form successively, but these methods all have loaded down with trivial details operation, Problems such as poor process stability, poor crystal form purity, and inability to meet the purity of gefitinib

Method used

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  • Preparation method of crystal form of gefitinib Form 1
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  • Preparation method of crystal form of gefitinib Form 1

Examples

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Embodiment 1

[0025] Embodiment 1 Preparation of gefitinib crystal form I

[0026] Add 10.0g of crude gefitinib, 20g of N,N-dimethylformamide and 20g of ethyl acetate into the reaction flask, heat to 60~65°C under stirring, dissolve the solid completely, add activated carbon for decolorization, Filtrate while hot to remove activated carbon, add 40g of purified water dropwise to the mother liquor, naturally cool down to 15~25°C, stir and crystallize for 4 hours, filter, and dry the solid in vacuum (temperature 60~65°C, vacuum degree ≥0.08Mpa) to obtain 9.65g Gefitinib crystal form I, the yield is 96.5%, the chromatographic purity is 99.96%, the maximum single impurity is 0.02%, and the water content (Karl-Fischer method): 0.3%.

Embodiment 2

[0027] Embodiment 2 Preparation of gefitinib crystal form I

[0028] Add 10.0g of crude gefitinib, 20g of N,N-dimethylformamide and 20g of acetone in the reaction bottle, heat it to 55~60℃ under stirring to dissolve the solid completely, add activated carbon for decolorization, and Remove the activated carbon by filtration, add 40g of purified water dropwise to the mother liquor, naturally cool down to 15~25°C, stir and crystallize for 4 hours, filter, and dry the solid in vacuum (temperature 60~65°C, vacuum degree ≥ 0.08Mpa) to obtain 9.36g Jifei Tinib crystal form I, yield 93.6%, chromatographic purity 99.92%, maximum unmixed 0.04%, moisture (Karl Fischer method): 0.4%.

Embodiment 3

[0029] Example 3 Preparation of Gefitinib Form I

[0030] Add 10.0g of crude gefitinib, 20g of N,N-dimethylformamide and 20g of acetonitrile in the reaction flask, heat to 60~65°C under stirring to completely dissolve the solid, add activated carbon for decolorization, and heat Remove the activated carbon by filtration, add 40g of purified water dropwise to the mother liquor, naturally cool down to 15~25°C, stir and crystallize for 4 hours, filter, and dry the solid in vacuum (temperature 60~65°C, vacuum degree ≥ 0.08Mpa) to obtain 9.23g Jifei Crystal form I of Tini, the yield is 92.3%, the chromatographic purity is 99.95%, the maximum simplex is 0.03%, the water content (Karl Fischer method): 0.3%.

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Abstract

The invention discloses a preparation method of a crystal form of a gefitinib Form 1. The preparation method comprises the following steps: dissolving a crude gefitinib product in a single or mixed solvent through heating; keeping temperature till the crude gefitinib product is completely dissolved, and then adding water to a liquid; reducing the temperature; crystallizing; and carrying out post-processing to obtain the crystal form of the gefitinib Form 1. The preparation method disclosed by the invention prevents the problems of uncontrollable crystal form, complicated step and high cost in the preparation process of the crystal form of the gefitinib Form 1, enhances the operation controllability and stability, reduces the cost and is suitable for industrialized production; and the prepared crystal form of the gefitinib Form 1 can achieve high yield more than 90%, the chromatographic purity more than 99.8% basically and the maximal individual impurity less than 0.1% and meet the requirement on product quality.

Description

technical field [0001] The invention relates to a preparation method of Form 1 crystal form of gefitinib, which belongs to the field of preparation of pharmaceutical crystal forms. Background technique [0002] Gefitinib (English name: Gefitinib), chemical name N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine-4-propoxy)quinazole Lin-4-amine, whose structure is shown in formula I, is a selective epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor developed by AstraZeneca. The trade name of gefitinib is Iressa, which was first listed in Japan in July 2002 for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) who have previously received chemotherapy. In May 2003, it was approved by the FDA to go on the market in the United States, and in February 2005 it was approved by the SFDA to go on the market in China. [0003] The structure of the gefitinib compound: [0004] . [0005] So far, the crystal forms of gefiti...

Claims

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Application Information

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IPC IPC(8): C07D239/94
CPCC07D239/94C07B2200/13
Inventor 李佳张善军高建
Owner CHENGDU SINO STRONG PHARMA
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