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Synthetic method of antineoplastic drug afatinib

An anti-tumor drug, afatinib technology, applied in the direction of anti-tumor drugs, drug combinations, organic chemistry, etc., can solve the problem of low total yield, achieve the effect of simplified process route, strong adaptability to conditions, and simple operation

Active Publication Date: 2018-11-27
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] This route is an improvement to the prior art, and the overall synthetic route is shortened to five-step reaction, but the overall yield is still not high

Method used

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  • Synthetic method of antineoplastic drug afatinib
  • Synthetic method of antineoplastic drug afatinib
  • Synthetic method of antineoplastic drug afatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Preparation of compound Ⅲ

[0034] Add 21.8g of compound II, 10.4g of formamidine acetate, 91.6g of tris(dibenzylideneacetone)dipalladium, 2-di-tert-butylphosphine-2',4',6'-triisopropyl Dimethoxy-3,6-dimethoxy-1,1′-biphenyl 96.94g, cesium carbonate 32.6g, n-butanol 2L, react at 85°C for 2h, TLC monitors that the reaction of the raw materials is complete, and naturally cools down to room temperature , filtered, and separated by column chromatography to obtain 16.4 g of compound III with a molar yield of 90% and an HPLC purity of 99.2%.

Embodiment 2

[0036] Preparation of compound Ⅲ

[0037] Add 21.8g of compound II, 11.5g of formamidine acetate, 374.7g of tris(dibenzylideneacetone)dipalladium, 2-di-tert-butylphosphine-2',4',6'-triisopropyl Base-3,6-dimethoxy-1,1′-biphenyl 290.8g, cesium carbonate 71.7g, methanol 2L, reacted at a temperature of 85°C for 2h, TLC monitored the reaction of the raw materials, naturally cooled to room temperature, filtered 17.1 g of compound III was obtained by column chromatography with a molar yield of 94% and a HPLC purity of 99.5%.

Embodiment 3

[0039] Preparation of compound Ⅲ

[0040] Add 21.8g of compound II, 11.5g of formamidine acetate, 374.7g of tris(dibenzylideneacetone)dipalladium, 2-(dicyclohexylphosphine)-3,6-dimethoxy-2' to the reaction flask , 322.1g of 4′,6′-triisopropyl-1,1′-biphenyl, 71.7g of cesium carbonate, 2L of n-butanol, and reacted for 2h at a temperature of 85°C. The raw materials were completely reacted by TLC, and naturally dropped to After filtration at room temperature, 16.2 g of compound III was obtained by column chromatography, with a molar yield of 88% and an HPLC purity of 98.5%.

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Abstract

The invention discloses a synthesis method of an anti-tumor medicine afatinib and belongs to the technical field of pharmaceutical chemistry. The method takes 2-nitryl-5-bromophenol as a raw material and obtains the afatinib through a five-step chemical reaction. The raw material of a synthesis route is easy to obtain, a process route is shortened, the operation is simple and the yield of products is high; and industrial production is easy to realize.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a method for synthesizing antitumor drug afatinib. Background technique [0002] Afatinib is a multi-target small molecule drug developed by Boehringer Ingelheim in Germany. It is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase, and it is also the first drug for lung cancer treatment after failure of epidermal growth factor receptor inhibitor therapy. Clinically, it can be used for the treatment of advanced non-small cell lung cancer, advanced breast cancer and intestinal cancer. The drug passed the US Food and Drug Administration (FDA) fast-track approval channel on February 15, 2008, and its trade name is Tovok. [0003] Afatinib (Afatinib, I), the chemical name is 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo Substituted-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)ox...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12A61P35/00
CPCC07D405/12
Inventor 李志滨李兆敏牛洪芬
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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