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Preparation method for afatinib

A technology of afatinib and reaction, which is applied in the field of afatinib preparation, can solve the problems of large loss, difficult removal, and many impurities, and achieve the effect of low cost, less impurities, and reduced loss

Active Publication Date: 2017-12-19
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The chiral intermediate S-3-hydroxy-tetrahydrofuran is more expensive and will be lost in subsequent multi-step reactions;
[0009] The final product I produced by the Wittig-Horner-Emmons reaction carried out with intermediate 3 has more impurities and is difficult to remove

Method used

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  • Preparation method for afatinib
  • Preparation method for afatinib
  • Preparation method for afatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] first step:

[0039] Take 3.4g compound V, 153mg FeCl 3 , 50mL of a mixed solution of tert-butanol and acetone (the volume ratio of tert-butanol: acetone is 3:4) is put into a single-necked flask, electromagnetic stirring is started, the air is replaced by nitrogen 3 times, and the nitrogen is replaced by hydrogen 3 times, and the temperature and pressure are maintained for 4 hours. After completion, the catalyst was removed by suction filtration under reduced pressure, and the filtrate was rotary evaporated to dryness and dried to obtain intermediate IV with a yield of 99.6%.

[0040] The second step:

[0041] Take 2.0 g of diethyl phosphoacetic acid and 50 ml of tetrahydrofuran into a 250 ml three-necked flask, start stirring, slowly add 2.0 g of CDI, keep the reaction at 40°C for 1 hour, then add 3.0 g of Intermediate IV, continue the reaction for 1 hour, after the reaction is complete, a large amount of solids are deposited , Then add 50ml methyl tert-butyl ether, stir fo...

Embodiment 2

[0048] first step:

[0049] Take 3.4g of compound V, 102mg of 10% Pd / C, and 50mL of methyl tert-butyl ether into a single-necked flask, start electromagnetic stirring, replace air with nitrogen 3 times, replace nitrogen with hydrogen 3 times, keep the temperature and keep the pressure for 4 hours, the reaction is complete, reduce The catalyst was removed by suction filtration, the filtrate was evaporated to dryness and dried to obtain Intermediate IV with a yield of 99.1%.

[0050] The second step:

[0051] Take 2.0g of diethyl phosphoacetic acid and 50ml of methyl tert-butyl ether into a 250ml three-necked flask, start stirring, slowly add 4.5g of CDI, keep the reaction at 40°C for 1 hour, then add 3.0g of Intermediate IV, and continue the reaction for 1 hour. After completion, a large amount of solids were precipitated, and then 50 ml of methyl tert-butyl ether was added, and after stirring for 1 h, the intermediate III was obtained by suction filtration and drying. The yield was ...

Embodiment 3

[0058] first step:

[0059] Take 3.4g compound V, 170mg Fe(OH) 3 , 100mL acetone into a single-neck flask, start electromagnetic stirring, replace the air with nitrogen 3 times, replace the nitrogen with hydrogen 3 times, heat preservation and pressure reaction for 6h, after the reaction is completed, the catalyst is removed by vacuum filtration, the filtrate is evaporated to dryness, and the intermediate is dried. Ⅳ, the yield is 99.0%.

[0060] The second step:

[0061] Take 2.0g of diethyl phosphoacetic acid and 80ml of methanol into a 250ml three-necked flask, start stirring, slowly add 0.9g of DCC, keep the reaction at 40℃ for 1h, then add 3.0g of Intermediate IV, continue to keep the temperature for 1h, the reaction is complete, a large amount of precipitation For the solid, add 50ml of methanol, stir for 1h, filter with suction and dry to obtain Intermediate III with a yield of 96.2%.

[0062] third step:

[0063] Firstly, dimethylaminoacetaldehyde diethanol is deprotected to p...

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Abstract

The invention discloses a novel method for preparing afatinib. The method comprises the following steps: reducing N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine into N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine IV; then subjecting N-(3-chloro-4-fluorophenyl)-7-fluoro-6-amino-4-quinazolinamine IV and diethylphosphonoacetic acid to a condensation reaction so as to obtain a compound III; then subjecting the compound III and (dimethylamino)acetaldehyde diethyl acetal to a Wittig-Horner-Emmons reaction of so as to obtain a key intermediate II; and subjecting the key intermediate II and (S)-3-hydroxytetrahydrofuran to a substitution reaction so as to obtain a compound I. The method of the invention has high yield and high purity.

Description

Technical field [0001] The present invention is in the field of medicinal chemistry, and specifically relates to a method for preparing afatinib. Background technique [0002] Afatinib maleate is a multi-target oral small molecule drug developed by Boehringer Inheim, Germany. It is an epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine. Irreversible inhibitor of amino acid kinase. It is the second generation of highly effective dual irreversible tyrosine kinase inhibitor. The drug was approved by the US FDA on July 12, 2013. The trade name is Gilotrif. [0003] Afatinib maleate (I), chemical name 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1- Oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline dimaleate. [0004] [0005] The original Chinese patent CN1867564B of Boehringer Ingelheim Company reported the preparation method of afatinib: 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-fluoroquine Oxazoline (V) is th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 张贵民赵绪亮王秀娟
Owner SHANDONG NEWTIME PHARMA
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