General scope of 1,4-diastereoselective additions to a 2(3H)-quinazolinone: practical preparation of HIV therapeutics.
The practical and highly diastereoselective syntheses of CF(3)-substituted dihydroquinazolinones via 1,4-additions of nucleophiles to chiral auxiliary substituted 2(3H)-quinazolinones is described. This methodology is applied to the syntheses of the NNRTIs (nonnucleoside reverse transcriptase inhibitors) DPC 961 (1) and DPC 083 (2), which are useful for the treatment of HIV (human immunodeficiency virus). The synthesis of DPC 961 (1) requires three steps, proceeds in >55% overall yield from the keto-aniline 9, and gives synthetic access to DPC 083 (2). In addition, the scope of the new diastereoselective 1,4-addition chemistry is investigated. The first preparation of DPC 961 (1) described in this paper is a derivatization fractional crystallization protocol.
Magnus
Nicholas A
NA
Chemical Process Research and Development Department, Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Deepwater, New Jersey 08023-0999, USA.
Confalone
Pat N
PN
Storace
Louis
L
Patel
Mona
M
Wood
Christopher C
CC
Davis
Wayne P
WP
Parsons
Rodney L
RL
D019380:Anti-HIV Agents / Q000032:analysis / Q000138:chemical synthesis*; D002384:Catalysis; D020650:Combinatorial Chemistry Techniques; D006678:HIV / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011799:Quinazolines / Q000032:analysis / Q000138:chemical synthesis*; D052999:Quinazolinones; D018894:Reverse Transcriptase Inhibitors / Q000032:analysis / Q000138:chemical synthesis*; D013055:Spectrophotometry, Infrared; D013237:Stereoisomerism
D019380:Anti-HIV Agents; C430648:DPC 083; C413505:DPC 961; D011799:Quinazolines; D052999:Quinazolinones; D018894:Reverse Transcriptase Inhibitors