吡唑并[3,4-d]嘧啶类mtorpi3k抑制剂的合成研究-synthesis of pyrazolo [ 3,4 - d ] pyrimidine mt orpi 3k inhibitor.docx

A b s tra c tA b st r a c tT h e m am m alian targ et o f rap am y cin (m T O R ), a central regu lato r of gro w th , su rv iv al, and m etabo lism , is a validated target for can cer therap y . H erein , w e rep ort the d esign and syn thesis o f a series o f l//-p yrazo lo [3 ,4 -{i]p y rim id in es as p oten t an d selectiv e in h ib itors o f the m am m alian targ et o f rap am y cin (m T O R ). M o dificatio n b y th e 4 -u reid op h en y l and 6-am in o su b stitu ent is p rov ed to b e cap ab le o f im p ro v in g th e in h ib itio n , selectiv ity an d stab ility .In th is th esis,w e firstly describ ed the synthesis o f 1//-pyrazo lo [3,4 -^ p yrim id ine analo gs b y the p arallel synthetic m eth o d s. F irstly , the startin g m aterial of b arbitu ric acid w as form ylated by V ilsm eier-H aack reaction , then chlorid ed ， and cyclized w ith (tetrah y dro -2//-p yran -4 -y l)h y drazin e; w h ich w a s synth esized b y red uctive am in ation of dih ydro -2//-p yran -4(3//)-on e an d ^ r/-butyl h ydrazin ecarboxylate and dep rotection , to g ive the key interm ed iate of 4 ,6 -d ich loro -1-(tetrahydro -2//-py ran -4-y l)-1//-p yrazolo [3,4 -(/]pyrim id ine 3 . A t the sam e tim e, w e synth esized th e analogs o f arom atic pin aco lato b o ron 4 b y co up lin g o f bro m o arom atics w ith b is(p in aco lato )d ib oro n . F in ally , w e su ccessfu lly accom p lish ed the sy nth esis of th e target com p o u n d s b y seq u en tial S u zuk i cro ss-cou p lin g an d n ucleop h ilic sub stitu tion reactio n w ith a series o f am in es. A ll of th einvolved interm ediates and targetcom pounds w ere characterized by LC -M S ，N M R ，13CN M R ， N O E .K eyw ord s: P I3K ; m T O R ; Suzuki cro ss-coup ling ; V ilsm eier-H aackform ylation ;4 ,6 -D ich lo ro -l-(tetrah yd ro -p y ran -4 -y l)-l//-py raz o lo [3 ,4 -^ p yrim id in eC la ss if ic a tio n C o d e ： 0 6 24复旦大学工程硕士论文第 一 章前 言1.1 抗 癌 药 物 的 概 述早 在 距 今 约 3 50 0