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Gefitinib glycol solvate and its preparation method and use

A technology of gefitinib glycol and solvate, which is applied in the field of gefitinib ethylene glycol solvate and its crystalline form to prepare high-purity gefitinib Form 1 crystal form, which can solve the problems of unfavorable industrial production, inability to It is better applicable to the problems of industrial production and high boiling point, and achieves the effects of easy industrial preparation, good controllability and simple operation.

Active Publication Date: 2016-06-15
QILU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Patent documents CN1182421A and WO2006090413A1 disclose that 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol is added to N,N-dimethylformamide (DMF), and then Add potassium carbonate, N-(3-chloropropyl) morpholine, heat the reaction for 3h, after the reaction finishes, filter, the filtrate is evaporated to dryness, obtain Gefitinib Form1 crystal form through column chromatography and toluene recrystallization; But this method In the post-treatment process, N,N-dimethylformamide needs to be evaporated to dryness, and column chromatography is required before crystallization can be carried out, and DMF has a high boiling point, so evaporation to dryness and subsequent column chromatography steps are not conducive to industrial production
[0005] CN101177415A, CN101973944A, CN103896862A, CN103360326A disclose the method for preparing Form1 crystal form with gefitinib solid crude product, but these methods are limited to the follow-up purification of gefitinib crude product, and the quality after its purification depends on the crude product adopted quality, and not directly crystallized from the gefitinib reaction system
Therefore, there are still limitations and cannot be better adapted to the needs of industrialized production

Method used

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  • Gefitinib glycol solvate and its preparation method and use
  • Gefitinib glycol solvate and its preparation method and use
  • Gefitinib glycol solvate and its preparation method and use

Examples

Experimental program
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Embodiment 1

[0048] The preparation of embodiment 1 gefitinib glycol solvate

[0049] Add 40kg of 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol into 100kg of N,N-dimethylformamide, then add 40kg of potassium carbonate, N- (3-Chloropropyl)morpholine 25kg; react at 80-100°C for 4h, filter to remove insoluble inorganic salts; add ethylene glycol 1000kg to the filtrate, centrifuge and dry to obtain 60.9kg of gefitinib glycolate , yield 85.2%, purity 99.65%, ethylene glycol mass content 20.2%,; after determination, its X-RPD is as figure 1 As shown, its DSC spectrum is as figure 2 As shown, its TGA spectrum is as image 3 shown.

Embodiment 2

[0050] The preparation of embodiment 2 gefitinib glycol solvates

[0051] Add 40g of 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol to 100g of N,N-dimethylformamide, then add 40g of potassium carbonate, N- (3-Chloropropyl)morpholine 25g; react at 80-90°C for 6h, filter to remove insoluble inorganic salts; add ethylene glycol 300g to the filtrate, filter with suction, and dry to obtain gefitinib glycolate 56.9 g, yield 79.6%, purity 99.55%, ethylene glycol content 21.1%; after determination, its X-RPD collection of patterns and figure 1 Basically the same, its DSC spectrum and figure 2 Basically the same.

Embodiment 3

[0052] The preparation of embodiment 3 gefitinib glycol solvates

[0053] Add 40g of 4-(3-chloro-4-fluoroaniline)-7-methoxyquinazolin-6-ol to 100g of N,N-dimethylformamide, then add 40g of potassium carbonate, N- (3-Chloropropyl)morpholine 25g; react at 70-80°C for 8h, filter to remove insoluble inorganic salts; add ethylene glycol 2000g to the filtrate, filter, and dry to obtain 61.4g of gefitinib glycolate , yield 85.9%, purity 99.57%, ethylene glycol content 21.3%; after determination, its X-RPD pattern and figure 1 Basically the same, its DSC spectrum and figure 2 Basically the same.

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Abstract

The invention belongs to the technical field of medicinal chemistry and in particular relates to a gefitinib ethylene glycol solvate, a preparation method of the solvate, and a method for preparing a high-purity gefitinib Form 1 crystal form by adopting the gefitinib ethylene glycol solvate. The gefitinib ethylene glycol solvate is simple in large-scale preparation, easy to operate, high in stability and high in purity and can be used for preparing the high-purity gefitinib Form 1 crystal form.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to a gefitinib ethylene glycol solvate and its crystal form, and specifically discloses its preparation method and its use for preparing high-purity gefitinib Form1 crystal form . Background technique [0002] Gefitinib (Gefitinib), the chemical name is N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholine propoxy)quinazolin-4-amine, With the chemical structure shown in formula I, it is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor developed by AstraZeneca, which is suitable for the treatment of locally advanced patients who have previously received chemotherapy or are not suitable for chemotherapy Or metastatic non-small cell lung cancer (NSCLC), it is the first small molecule protein tyrosine kinase inhibitor targeted anticancer drug for the treatment of solid tumors. [0003] [0004] The pharmaceutical crystal form of g...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
CPCC07B2200/13C07D239/94
Inventor 林栋冷传新范传文蔡文亮
Owner QILU PHARMA CO LTD
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