Yongjun Mao

Design, synthesis and biological evaluation of novel pyrimidine, 3-cyanopyridine and m-amino-N-phenylbenzamide based monocyclic EGFR tyrosine kinase inhibitors.

36 new compounds with the typical skeleton of 4-anilino-5-vinyl/ethynyl pyrimidine, 4-anilino-3-cyano-5-vinyl/ethynyl/phenyl pyridine, and m-amino-N-phenylbenzamide, are designed, synthesized and selectively tested on EGFR, ErbB-2 kinases, and A-549, HL60 cells growth inhibition. Results from the bioactivity and chemical structures yield preliminary structure-activity relationships (SARs). The most potent 5-ethynylpyrimidine derivative 20a has an IC50 value of 45 nM to EGFR kinase. Several compounds of other series also show IC50 values <1 μM for EGFR and <5 μM for A-549 and HL60 cells growth inhibition.

SYNTHESIS OF N-(3-CYANO-7-ETHOXY-1,4-DIHYDRO-4-OXOQUINOLIN-6-YL)ACETAMIDE

New route for the preparation of N-(3-cyano-7-ethoxy-1,4dihydro-4-oxoquinolin-6-yl)acetamide (1), a key intermediate for the synthesis of selective EGFR kinase inhibitors, was described. 4(1H)-Quinolones are a series of important intermediates for the synthesis of anticancer, antimalarial, antidiabetic, antiviral agents and reversible (H/K) ATPase inhibitors. N-(3-Cyano-7-ethoxy-1,4dihydro-4-oxoquinolin-6-yl)acetamide (1, Figure 1) was a key intermediate for either EKB-569 (2) or neratinib (3) , both of which were developed as dual irreversible inhibitors of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (EGFR-2) protein tyrosine kinases. In the previous reports, 1 was prepared using 2-amino-5-nitrophenol (4) as starting material. 5 was synthesized by acelytion, ethylation and reduction of 4 (Scheme 1), and then reacted with ethyl (E)-2-cyano-3-ethoxypropenoate to furnish 6. In the following thermal cyclization, the reaction mixture was heated at 260 °C for 20 h to give 1 with 35% yield.

NOVEL AND PRACTICAL SYNTHESIS OF CANDESARTAN CILEXETIL

A novel and convergent synthetic route of candesartan cilexetil (API of Atacand), an effective angiotensin II receptor blocker, is described. Cleavage of the N-Boc and N-trityl protective group are implemented simultaneously and formation of the benzimidazole ring is conducted at the last step of this route, which gives candesartan cilexetil in 55% yield over six steps with 99.1% purity (HPLC).