Lapatinib intermediate crystal form and preparation method thereof

A technology of lapatinib and patiniamine, applied in the chemical field, can solve problems such as ineffective progress of intermediates, obstacles to lapatinib research, cumbersome removal steps, etc., to achieve removal of impurities and suitable for industrialization The effect of stable production and reaction

Active Publication Date: 2014-08-13
QILU PHARMA HAINAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The above-mentioned compounds are all present in the preparation process of lapatinib, but they have not received sufficient attention, and the research as an intermediate has not been carried out effectively, and there are partial reactions in the subsequent reaction of lapatinib amine The problem of compound decomposition; at the same time, there are relatively many impurities in the process of preparing lapatinib, and the removal steps are cumbersome, which has actually hindered the further research of lapatinib

Method used

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  • Lapatinib intermediate crystal form and preparation method thereof
  • Lapatinib intermediate crystal form and preparation method thereof
  • Lapatinib intermediate crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Preparation of lapatinib amine crystal form

[0029] Add 100g of lapatinib crude product (solid) into 1L of tetrahydrofuran, heat to reflux to dissolve, filter with suction, cool the filtrate to 2-6°C for crystallization for 5 hours, filter with suction, wash the filter cake with 100ml of tetrahydrofuran to obtain a yellow solid , and dried at room temperature for 8-10 hours to obtain 83 g of lapatinib amine crystal form, with a yield of 83%.

[0030] Powder X-ray diffraction determination of lapatinib amine crystal form:

[0031] Carry out powder X-ray diffraction measurement to the lapatinib amine that embodiment 1 obtains, measurement result is as table 1 and figure 1 shown.

[0032] Table 1

[0033]

[0034] Experimental study on the stability of lapatinib amine crystal form:

[0035] About 2 g of the crystal form of lapatinia amine obtained in Example 1 was put into a sample bottle, and stored at 2-6°C and 20-25°C. The purity of the original sample was take...

Embodiment 2

[0040] Preparation of lapatinib amine crystal form

[0041] Add 100g of lapatinib crude product (solid) into 1L of tetrahydrofuran, heat to reflux to dissolve, filter with suction, add 1L of ethanol to the filtrate, cool down to 2-6°C to crystallize for 5h, filter with suction, and filter the cake with 100ml of ethanol After washing, a yellow solid was obtained, which was dried at room temperature for 8-10 hours to obtain 89 g of lapatinib amine crystal form, with a yield of 89%. According to the XRD data, the obtained crystal form is the lapatinib amine crystal form described in the present invention.

Embodiment 3

[0043] Preparation of lapatinib amine crystal form

[0044] Add 50 g of lapatinib crude product (oil) into 0.6 L of ethyl acetate, heat to reflux to dissolve, filter with suction, add 1 L of ethanol to the filtrate, cool down to 2-6°C for crystallization for 5 hours, filter with suction, filter The cake was washed with 50 ml of ethyl acetate to obtain a yellow solid, which was dried at room temperature for 7-8 hours to obtain 40 g of the crystal form of lapatinib with a yield of 80%. According to the XRD data, the obtained crystal form is the lapatinib amine crystal form described in the present invention.

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Abstract

The invention relates to a crystal form of a key intermediate compound I of a tyrosine kinase inhibitor lapatinib (a lapatinib imine crystal form for short) and a lapatinib imine p-toluenesulfonate crystal form (a crystal form of a compound II for short), and a preparation method for the crystal forms. The crystal shape of a lapatinib imine crystal is determined through powder X-ray diffraction detection; and the crystal shape of a lapatinib imine p-toluenesulfonate crystal is determined through powder X-ray diffraction detection. The two crystal forms have the advantages that: lapatinib imine can be separated from reaction liquid and purified, the crystal forms have positive significance for improving the quality of lapatinib, and the preparation process is simple and suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of chemistry, and relates to a crystal form and a preparation method of a key intermediate of the tyrosine kinase inhibitor lapatinib, specifically, the present invention relates to a crystal form of lapatinib amine, lapatinib Crystal form of imine p-toluenesulfonate, and preparation method thereof. Background technique [0002] Lapatinib is the world's first marketed oral tyrosine kinase inhibitor (TKI) drug for human epidermal growth factor receptor 2 (HER2) positive breast cancer developed by GlaxoSmithKline. [0003] Compound I is the key intermediate of lapatinib, referred to as lapatinib amine, and its structural formula is as follows: [0004] [0005] Compound II is lapatinib p-toluenesulfonate, and its structural formula is as follows: [0006] [0007] The above-mentioned compounds are all present in the preparation process of lapatinib, but they have not received sufficient attention, and the resear...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/04
Inventor 王晶翼冷传新林栋范传文张进王丙忠罗宝鹏
Owner QILU PHARMA HAINAN
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