Erlotinib-hydrate crystal form I preparation method

A technology of monohydrate and erlotinib hydrochloride, which is applied in the field of preparation of erlotinib monohydrate crystal form I, can solve the problems of unsuitability for industrial scale production, cumbersome preparation methods, and easy generation of mixed crystals. Easy to recycle and reuse, strong operability and good stability

Active Publication Date: 2015-04-22
QILU PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the preparation method disclosed in this patent document is relatively cumbersome, prone to mixed crystals, low production efficiency, and uses volatile low-boiling solvents ethanol and acetone, which is not suitable for industrial scale production

Method used

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  • Erlotinib-hydrate crystal form I preparation method
  • Erlotinib-hydrate crystal form I preparation method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Preparation of erlotinib monohydrate crystal form I

[0030] Erlotinib hydrochloride 6.0g (14mmol), add 30ml of n-butanol, add 1.0mol / L potassium hydroxide aqueous solution 15ml, heat to 80 ℃ under stirring, the solid dissolves completely, let stand and separate, discard the water phase, Separate the organic phase while it is hot, and naturally cool the organic phase to room temperature while stirring, continue to stir for 1 hour, filter with suction, and dry the filter cake at 50-60°C to obtain the white crystal of erlotinib monohydrate crystal form I Sexual solid 5.21g, yield 86.8%, HPLC purity is 99.7%, measure the X-PRD that obtains and figure 1 Basically the same.

Embodiment 2

[0031] Embodiment 2: Preparation of erlotinib monohydrate crystal form I

[0032] Add 6.0g of erlotinib hydrochloride, add 36ml of n-butanol, add 14ml of 2.0mol / L sodium hydroxide aqueous solution, heat to 85°C under stirring, until the solid is completely dissolved, let stand to separate layers, discard the water phase, and Separate the organic phase, and naturally cool the organic phase to room temperature while stirring, continue to stir for 1 hour, filter with suction, and dry the filter cake at 40-50°C to obtain erlotinib monohydrate crystal form I as a white crystalline solid 5.14g, yield 85.7%, HPLC purity 99.8%.

Embodiment 3

[0033] Embodiment 3: Preparation of erlotinib monohydrate crystal form I

[0034] Add 6.0g of erlotinib hydrochloride, add 48ml of n-butanol, add 1.0mol / L potassium carbonate aqueous solution 15ml, heat under stirring until the temperature reaches 70°C, the solid is completely dissolved, let stand to separate layers, discard the water phase, and The organic phase is separated by heat, and the organic phase is naturally cooled to room temperature under stirring. After continuing to stir for 2 hours, it is filtered with suction, and the filter cake is dried at 50-60°C to obtain the white crystalline form of erlotinib monohydrate The solid was 5.03g, the yield was 83.8%, and the HPLC purity was 99.9%.

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Abstract

The invention relates to an erlotinib-hydrate crystal form I preparation method. The erlotinib-hydrate crystal form I preparation method comprises the following steps of: naturally cooling an n-butyl alcohol thermal solution containing erlotinib, and reducing temperature and devitrifying to obtain the erlotinib-hydrate crystal form I. The erlotinib-hydrate crystal form I preparation method is safe and simple, has strong operability and is easy for industrial production; an obtained product has the advantages of single crystal form, high purity and good stability; and the method can be used as an erlotinib purification method for preparing high-purity erlotinib hydrochloride.

Description

technical field [0001] The invention relates to a preparation method of erlotinib monohydrate crystal form I, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Erlotinib (Erlotinib), the chemical name is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, which has the formula I Chemical structure, is a human epidermal growth factor receptor tyrosine kinase domain selective inhibitor. [0003] [0004] Studies in erlotinib-sensitive non-small cell lung cancer suggest that activation of anti-apoptotic pathways is primarily responsible for mutations in the epidermal growth factor receptor tyrosine kinase domain gene. In 2004, Erlotinib was first launched in the United States in the form of hydrochloride, mainly for the treatment of locally advanced or metastatic non-small cell lung cancer and pancreatic cancer. [0005] Patent document WO1996030347 first reported the compound erlotinib, and at the same time d...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 李燕高永宏吴兆春张明会
Owner QILU PHARMA CO LTD
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