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A kind of preparation method of afatinib

Active Publication Date: 2020-08-28
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The price of chiral intermediate S-3-hydroxy-tetrahydrofuran is more expensive, and the loss is larger in the subsequent multi-step reaction;
[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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  • A kind of preparation method of afatinib
  • A kind of preparation method of afatinib
  • A kind of preparation method of afatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0038] first step:

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

[0040] Step two:

[0041]Take 2.0g of diethylphosphonoacetic acid and 50ml of tetrahydrofuran into a 250ml three-necked flask, start stirring, slowly add 2.0g of CDI, keep it warm at 40°C for 1 hour, then add 3.0g of intermediate IV, and keep warm for 1 hour. After the reaction is complete, a large amount of solids are precipitated , and then added 50ml of methyl tert-butyl ether, stirred for 1 h, filtered with suction, and ...

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 one-mouth bottle, start electromagnetic stirring, replace the air with nitrogen three times, replace the nitrogen with hydrogen three times, and keep the temperature and pressure for 4 hours. The catalyst was removed by pressure filtration, and the filtrate was rotary evaporated to dryness, and dried to obtain intermediate IV with a yield of 99.1%.

[0050] Step two:

[0051] Take 2.0g of diethylphosphonoacetic acid and 50ml of methyl tert-butyl ether into a 250ml three-necked bottle, start stirring, slowly add 4.5g of CDI, keep it at 40°C for 1 hour, then add 3.0g of intermediate IV, continue to keep it warm for 1 hour, and react After completion, a large amount of solids were precipitated, and then 50ml of methyl tert-butyl ether was added, stirred for 1 hour, filtered with suction, and dried to obtain intermediate III with a yield of 97.1%.

[0052] third ste...

Embodiment 3

[0058] first step:

[0059] Take 3.4g compound V, 170mgFe(OH) 3 , put 100mL of acetone into a single-necked bottle, start electromagnetic stirring, replace air with nitrogen 3 times, replace nitrogen with hydrogen 3 times, heat-preserve and pressurize for 6 hours, after the reaction is completed, remove the catalyst by vacuum filtration, and the filtrate is rotary evaporated to dryness, and dried to obtain the intermediate Ⅳ, the yield is 99.0%.

[0060] Step two:

[0061] Take 2.0g of diethylphosphonoacetic acid and 80ml of methanol into a 250ml three-neck flask, start stirring, slowly add 0.9g of DCC, keep it at 40°C for 1 hour, then add 3.0g of intermediate IV, keep it warm for 1 hour, after the reaction is complete, a large amount of solid, then add 50ml of methanol, stir for 1 hour, filter with suction, and dry to obtain Intermediate III with a yield of 96.2%.

[0062] third step:

[0063] Firstly, dimethylaminoacetaldehyde diethyl acetal is deprotected to generate di...

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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 invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of afatinib. Background technique [0002] Afatinib maleate is a multi-targeted oral small-molecule drug developed by Boehringer Inheim in Germany. It is an epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) receptor Irreversible inhibitor of amino acid kinases. It is a second-generation highly potent dual irreversible tyrosine kinase inhibitor. The drug was approved by the U.S. FDA on July 12, 2013. The trade name is Gilotrif. [0003] Afatinib maleate (I), 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 dimaleate. [0004] [0005] The original Chinese patent CN1867564B of Boehringer Ingelheim Company reported the preparation method of afatinib: the mother nucleus 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro...

Claims

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Application Information

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