Formal synthesis of angiogenesis inhibitor NM-3.
We report the formal synthesis of angiogenesis inhibitor NM-3 (1) in six steps from either of the 2,4-dimethoxyhalobenzenes 13a,b or 3,5-dimethoxychlorobenzene (13c). The first key reaction is the regiospecific alkylation/rearrangement between the aryne derived from 13a-c with sodium diethylmalonate in THF to produce diester 11, which after hydrolysis and cyclization affords homophthalic anhydride 3. The second is the reaction of anhydride 3 with either ethyl 2-methylmalonate (28a), in the presence of 1,1'-carbonyldiimidazole, or ethyl-2-methylmalonyl chloride (28b) under basic conditions to afford key isocoumarin 27. The conversion of 27 constitutes a formal synthesis of NM-3.
Bauta
William E
WE
Department of Process Chemistry, Ilex Oncology, Inc., 14785 Omicron Drive, Suite 201, San Antonio, Texas 78245, USA. wbauta@ilexonc.com
Lovett
Dennis P
DP
Cantrell
William R
WR
Burke
Brian D
BD
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis*; D003374:Coumarins / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D049934:Isocoumarins; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008968:Molecular Conformation
D020533:Angiogenesis Inhibitors; D003374:Coumarins; D007202:Indicators and Reagents; D049934:Isocoumarins; C453300:isocoumarin NM-3