Synthetic method for afatinib intermediate

A compound, fluorophenyl technology, applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of cumbersome processing, low yield and the like

Active Publication Date: 2016-02-10
CHIA TAI TIANQING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Yet the method for reduction with this type of reductant is not only loaded down with trivial details after the reaction, and productive rate

Method used

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  • Synthetic method for afatinib intermediate
  • Synthetic method for afatinib intermediate
  • Synthetic method for afatinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Synthesis of Example 1 (S)-4-(3-chloro-4-fluorophenyl)-7-[(tetrahydrofuran-3-yl)oxy]quinazoline-4,6-diamine

[0032]

[0033] Add (S)-N-(3-chloro-4-fluorophenyl)-6-nitro-7-[(tetrahydrofuran-3-yl)oxy]quinazolin-4-amine ( 50g, 0.124mol), add hydrosulfite (75g, 0.432mol), ethanol 250ml, water 100ml, heat up to 55°C for 1h, stop heating, cool down to room temperature, add 50% NaOH 60ml to adjust alkalinity under ice bath cooling, solid Precipitated, filtered, and dried to obtain 41.2 g of a light green solid, with a yield of 89% and a liquid phase purity of 98%.

[0034] 1 H-NMR (300Hz, DMSO-d6) δ: 9.39 (s, 1H, NH), 8.38 (s, 1H, ArH), 8.18-8.20 (m, 1H, ArH), 7.80-7.82 (m, 1H, ArH ), 7.36~7.41(m, 2H, ArH), 7.06(s, 1H, ArH), 5.38(s, 2H, NH 2 ), 5.23(s, 1H, 1 / 2CH 2 ), 3.89~4.03 (m, 3H, CH 2 ,1 / 2CH 2 ),3.76~3.83(m, 1H, 1 / 2CH 2 ),2.29~2.38(m,1H,1 / 2CH 2 ), 2.10~2.15(m, 1H, 1 / 2CH 2 ).

Embodiment 2

[0036] Add (S)-N-(3-chloro-4-fluorophenyl)-6-nitro-7-[(tetrahydrofuran-3-yl)oxy]quinazolin-4-amine ( 100.0g, 0.247mol), ethanol (1600ml), water (400ml) and glacial acetic acid (140ml), add reduced iron powder (55.0g, 0.99mol) after heating to reflux, and continue to reflux for 2 hours, and TLC detects that the reaction of the raw materials is complete ;Stop heating, lower the temperature to about 50°C (external temperature), filter the reaction solution through diatomaceous earth, and then filter the filtrate once through silica gel (100-200 mesh); spin the filtrate to dryness, and add 1L of dichloro Methane, after stirring evenly, suction filtration; spin dry the filtrate, add about 400ml ether to the residue, stir for 30min, suction filtration; filter cake is air-dried at 50°C, the yield is 70%, and the liquid phase purity is 97%.

Embodiment 3

[0038] Add (S)-N-(3-chloro-4-fluorophenyl)-6-nitro-7-[(tetrahydrofuran-3-yl)oxy]quinazolin-4-amine ( 5g, 0.012mol), ammonium chloride (0.89g, 0.0168mol), DMF50ml, then add Raney-Ni0.5g, hydrogenation reaction at room temperature for 2h, after the reaction is completed, diatomaceous earth filter, the reaction solution is poured into water, solid precipitates, filter , a light green solid was obtained with a liquid phase purity of 31.8%.

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Abstract

The invention relates to a synthetic method for an afatinib intermediate. The method comprises the step of: carrying out a reaction on (S)-N-(3-floro-4-fluorophenyl)-6-nitryl-7-[(tetrahydrofuran-3-yl)oxy]quinazoline-4-amine and sodium hydrosulfite. The method provided by the invention not only obtains a high yield, but also simplifies the post-treatment of reaction.

Description

technical field [0001] The present invention relates to the synthetic method of pharmaceutical intermediate, particularly a kind of synthetic method of afatinib intermediate. Background technique [0002] Afatinib, the chemical name is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2 -buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline has the structure. As aminoquinazoline derivatives, [0003] [0004] The compound has an irreversible dual inhibitory effect on EGFR / HER1, HER2 and HER4 receptor tyrosine kinases. It is mainly used for oral treatment of solid tumors, including non-small cell lung cancer (NSCLC), glioma, prostate cancer, colorectal cancer, breast cancer and head and neck cancer. [0005] (S)-4-(3-Chloro-4-fluorophenyl)-7-[(tetrahydrofuran-3-yl)oxy]quinazoline-4,6-diamine is a key intermediate in the synthesis of afatinib body, its structural formula is shown in Formula I. [0006] [0007] In the prior art, the method f...

Claims

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Application Information

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IPC IPC(8): C07D405/12
Inventor 甘宗捷陆平波张喜全
Owner CHIA TAI TIANQING PHARMA GRP CO LTD
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