Hydrochloric Acid → Pyrido(3,2-d)pyrimidine

Beteiligte Stoffe

Reaktionsschritte

In another embodiment, Scheme 7B provides the preparation of 2,4,7-trisubstituted pyrido-pyrimidine compounds which are encompassed by formula (I), where X is N, Y and Z are CH, and R1, R3, and R6 are H. Specifically, 2-cyano-3-nitro-5-bromopyridine [CC1] is converted to the corresponding amide [DD1] using Raney Nickel and H2. Desirably, the reaction is performed in the presence of ethanol for about 14-20 h. Amide [DD1] is then converted to the corresponding acid [EE1] using NaOH (5 eq) and H2O at about 110° C. for about 5 h, followed by work-up using dil. HCl. Acid [EE1] is cyclized using urea (10 eq) at about 200° C. for about 3 h to form pyrido-pyrimidine intermediate [FF1]. Intermediate [FF1] is reacted with POCl3 and DIPEA at about 130° C. for about 10 h. The 4-position of the pyrido-pyrimidine is then substituted using morpholine in CH2Cl2 at a temperature of about 0° C. for about 30 min to form compound [HH1]. Compound [HH1] is then coupled with R2 using R2B(OR)2, PdCl2(PPh3)2 (0.05 eq), Na2CO3 (1.5 eq), DMF, and H2O at about 90° C. for about 2-3 h to form compound [JJ1]. The title compound is then formed by reacting compound [JJ1] with PdCl2(PPh3)2 (0.05 eq), Cs2CO3 (2 eq), DMF, and H2O at a temperature of about 90° C. for about 2-3 h. Alternatively, the title compound may be formed by reacting intermediate [JJ1] with PdCl2(PPh3)2 (0.05 eq) and Cs2CO3 (2 eq) in toluene, ethanol, and H2O at a temperature of about 90° C. for about 2-3 h.

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