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Process for preparing lapatinib synthetic intermediate

A technology of lapatinib and preparation process, which is applied in the field of preparation of lapatinib synthetic intermediates, can solve the problems of large environmental pollution and difficult post-processing, and achieve the effects of reducing pollution, simple operation, and high yield

Inactive Publication Date: 2009-11-11
NANJING MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Wherein, the synthesis of 4-chloro-6-iodoquinazoline adopts 4-hydroxyl 6-iodoquinazoline as raw material, and reacts with excess thionyl chloride or phosphorus oxychloride, and the post-processing is difficult and the environmental pollution is large

Method used

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  • Process for preparing lapatinib synthetic intermediate
  • Process for preparing lapatinib synthetic intermediate
  • Process for preparing lapatinib synthetic intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] The preparation of embodiment 1N-(3-chloro-4-(3-fluorobenzyloxy) phenyl)-6-iodoquinazolin-4-amine (1)

[0015] Add 5-iodo-2-aminobenzonitrile (18.4g, 75mmol), DMF-DMA (N,N-dimethylformamide dimethyl acetal, 40ml) into a 100ml eggplant-shaped bottle, heat to reflux at 90-100°C After 1h, excess DMF-DMA was distilled off under reduced pressure, glacial acetic acid (100ml), 3-chloro-4-(3-fluorobenzyloxy)aniline (15g, 59.5mmol) were added and heated to reflux for 1h, cooled to room temperature, poured Pour into ice water (500ml), filter with suction, wash the filter cake with ice water (about 500ml), wash with methanol (1L), and vacuum dry to obtain 124.8g of light yellow solid, yield 82.4%.

[0016] 1 H NMR (DMSO-d6, 300Hz): 5.26(s, 2H); 7.18(m, 1H); 7.34-7.26(m, 3H); 7.47(m, 1H); 7.56(d, J=8.7Hz, 1H ); 7.75(d, J=8.8Hz, 1H); 8.03(s, 1H); 8.11(d, J=8.6Hz, 1H); 8.61(s, 1H); 8.95(s, 1H); 9.84(s ,1H); 13 C NMR (DMSO-d6, 300MHz): 162.2 (d, J=970Hz), 156.3, 154.7, 149.7, 148....

Embodiment 2

[0017] The preparation of embodiment 2N-(3-chloro-4-(3-fluorobenzyloxy) phenyl)-6-iodoquinazolin-4-amine (1)

[0018] Mix 5-iodo-2-aminobenzonitrile and DMF-DMA, the molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is 1:1-5, heat and reflux at 90-100°C for 1h, 0.1MPa / 70-80°C under reduced pressure distillation for 30 minutes to remove excess DMF-DMA, add glacial acetic acid, 3-chloro-4-(3-fluorobenzyloxy)aniline, based on the mass of 5-iodo-2-aminobenzonitrile, The feeding amount of the glacial acetic acid is 1-40ml / g, and the molar ratio of 3-chloro-4-(3-fluorobenzyloxy)aniline and 5-iodo-2-aminobenzonitrile is 1: 1-3, Heat to reflux at 90-100°C for 1h, cool to room temperature, pour into ice water, filter with suction, wash the filter cake with ice water, then methanol, and dry in vacuo to obtain light yellow solid N-(3-chloro-4-(3 -fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine.

[0019] The molar ratio of 5-iodo-2-aminobenzonitrile and DMF-DMA is preferably 1:2-3...

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Abstract

The invention relates to a process for preparing a lapatinib synthetic intermediate, which is characterized by comprising the following process steps: mixing 5-iodo-2-aminobenzonitrile and DMF-DMA; heating and refluxing the mixture at a temperature of between 90 and 100 DEG C for 1 to 2 hours, and performing reduced pressure distillation at a pressure of 0.1 MPa and at a temperature of between 70 and 80 DEG C for 10 to 30 minutes to remove excessive DMF-DMA; adding glacial acetic acid and 3-chloro-4-(3-fluorophenyl-methoxy) aniline; heating and refluxing the mixture at a temperature of between 90 and 100 DEG C for 1 hour, cooling the mixture to the room temperature, and pouring the mixture to ice water; performing vacuum filtration, and washing a filter cake with the ice water and then with methanol; and performing vacuum drying on the filter cake to obtain a faint yellow solid N-(3-chloro-4-(3-fluorophenylmethoxy)phenyl)-6-iodoquinazoline-4-amine. The route avoids the use of thionyl chloride or phosphorus oxychloride and reduces pollutions to the environment; besides, the process has high yield and simple operation and is suitable for industrial production.

Description

1. Technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and in particular relates to a preparation process of a synthetic intermediate of lapatinib. 2. Background technology [0002] Lapatinib [0003] [0004] The chemical name is N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylamino)methyl)furan-2- Base) quinazolin-4-amine bis(4-methylbenzenesulfonate) monohydrate, a new type of tyrosine kinase inhibitor developed by GlaxoSmithKline, for the treatment of HER-2 overexpression For patients with advanced or metastatic breast cancer, it was approved for marketing by the US FDA in March 2007. N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (1) is a key intermediate for the synthesis of lapatinib, and its CAS accession number is 231278-20-9. The preparation process currently used is: 5-iodo-2-aminobenzoic acid is used as the starting material, and 4-hydroxy-6-iodoquinazoline is obtained by cy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/94
Inventor 李飞王武伟季兴许贯虹殷晓佳孙旭
Owner NANJING MEDICAL UNIV
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