Preparation method of ABT-737 key intermediate and preparation method of ABT-737
A technology of ABT-737 and intermediates, applied in the field of drug synthesis, can solve the problems of difficult large-scale synthesis, poor stability of intermediates, and low yield of products, so as to avoid the use of toxic and harmful reagents, easy operation, and flexible synthetic routes Effect
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[0057] The present invention provides a kind of preparation method of ABT-737 key intermediate, comprises the following steps:
[0058] (1) Esterifying a compound having a structure shown in formula I with an activator to obtain an active ester; performing a reduction reaction with the active ester and a first reducing agent to obtain a compound having a structure shown in formula II;
[0059]
[0060] (2) The compound having the structure shown in formula II, vulcanizing agent and organic phosphine are carried out vulcanization reaction, obtain the compound having the structure shown in formula III; Described vulcanizing agent comprises thiophenol metal salt and diphenyl disulfide one or more of them;
[0061]
[0062] In formulas I to III, R is an alkyl group or a cycloalkyl group, and the number of C atoms in the alkyl group is preferably no more than 8, more preferably 1 to 6, and specifically preferably methyl, ethyl or iso Butyl; the number of carbon atoms of the ...
Embodiment 1
[0128] to have the formula I (R is -CH 3 ) The compound of the structure shown in ) is a starting material, and the specific synthesis steps are as follows:
[0129] 1) has the formula II (R is -CH 3 ) Preparation of structural compounds shown in
[0130] Add 81.7g (0.33mol) of the compound with the structure shown in formula I and 1600mL of ethyl acetate into the three-neck flask to dissolve, after nitrogen replacement, lower the system to below 0°C, and add 41.8g of N-hydroxysuccinimide in the open (0.363mol), then dropwise add dicyclohexylcarbodiimide ethyl acetate solution (75g (0.363mol) dicyclohexylcarbodiimide dissolved in 250mL ethyl acetate), keep the temperature at -5~0℃ , the system was turbid, reacted at room temperature for 24h, and TLC confirmed that the raw materials disappeared (dichloromethane: methanol: acetic acid = 4ml: 0.2ml: 0.1ml); the resulting product material liquid was filtered with diatomaceous earth, and the filtrate was washed with 800mL saturat...
Embodiment 2
[0146] to have the formula I (R is -CH 3 ) The compound of the structure shown in ) is a starting material, and the specific synthesis steps are as follows:
[0147] 1) have the preparation of structure compound shown in formula II
[0148] In the there-necked flask, add 35g (0.121mol) of the compound having the structure shown in formula I and 700mL of ethyl acetate to dissolve, under nitrogen protection, lower to about 0°C, then add 15.3g (0.133mol) of N-hydroxysuccinimide, Start to add dropwise a solution of 27.4 g (0.133 mol) of dicyclohexylcarbodiimide dissolved in 140 mL of ethyl acetate, control the temperature at -5 to 0 ° C, remove the ice bath, and react at room temperature for 24 h. After TLC confirms that the raw materials disappear, the obtained The product feed liquid was filtered with diatomaceous earth, the filter cake was washed with ethyl acetate, 300 mL of saturated aqueous sodium carbonate was added to the filtrate for washing, 200 mL of ethyl acetate was ...
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