A straightforward microwave method for rapid synthesis of N-1, C-6 functionalized 3,5-dichloro-2(1H)-pyrazinones.
A rapid and versatile one-pot, 2 x 10 min microwave protocol for the preparation of N-1 and C-6 decorated 3,5-dichloro-2(1H)-pyrazinones was developed. Comparable reaction sequences using classical conditions require about 1-2 days of heating. The alpha-aminonitrile was first generated in a Strecker reaction and thereafter cyclized under microwave heating. The microwave approach developed offers the possibility of efficiently generating and utilizing functionalized 3-amino-5-chloro-2(1H)-pyrazinone-N-1-carboxylic acids as beta-strand inducing core structures in a medicinal chemistry context. To illustrate the usefulness of the method, the synthesis of two novel 2(1H)-pyrazinone-containing Hepatitis C virus NS3 protease inhibitors is reported.
Gising
Johan
J
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Centre, Uppsala University, Box 574, SE-751 23, Uppsala, Sweden.
Ortqvist
Pernilla
P
Sandström
Anja
A
Larhed
Mats
M
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology; D008872:Microwaves; D015394:Molecular Structure; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D004791:Enzyme Inhibitors; D011719:Pyrazines; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases