A kind of Afatinib intermediate and its synthetic method
A synthetic method, the technology of afatinib, which is applied in the field of afatinib intermediates and its synthesis, can solve the problems of large loss, difficult removal, and many impurities, and achieve the effects of low cost, less impurities, and reduced losses
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Embodiment 1
[0043] first step:
[0044] 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%.
[0045] Step two:
[0046] Take 2.0g of diethylphosphonoacetic acid and 50ml of tetrahydrofuran into a 250ml three-neck flask, start stirring, slowly add 2.0g of CDI, 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 solids are precipitated , and then added 50ml of methyl tert-butyl ether, stirred for 1 h, filtered with suction, and dried to...
Embodiment 2
[0053] first step:
[0054] 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%.
[0055] Step two:
[0056] 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%.
[0057] third ste...
Embodiment 3
[0063] first step:
[0064] 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%.
[0065] Step two:
[0066] 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%.
[0067] third step:
[0068] Firstly, dimethylaminoacetaldehyde diethyl acetal is deprotected to generate di...
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