Synthesis of 4-hydroxy-, 4-chloro-, 4-amino- and 4-substituted aminoisoxazolo [5.4-d] pyrimidines

Iminopropadienones from Dioxanediones, Isoxazolopyrimidinones, Pyridopyrimidinones, and Pyridopyrimidinium Olates

“…The Meldrum's acid precursor 5 was synthesized by reaction of 5-(bismethylthiomethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione with 2,6-difluoroaniline, and 5 ‘ was formed by further substitution of the SMe group by dimethylamine. Compound 6 was obtained from 2,6-difluorobenzaldehyde by adaptation of a standard procedure . A 1:1 mixture of olates 7a and 7b was obtained by reaction of 8 (generated by preparative FVT of either 5 or 6 ) with 2-(methylamino)pyridine (Scheme 1).…”

“…A stream of gaseous dimethylamine was bubbled via a pipet through the stirred solution at such a slow rate that the gas just absorbed; the solution was then either heated at 50 °C for 24 h in a closed round-bottom flask or heated in a minireactor at 90 °C under high pressure (1000 psi) for 6 h. ( CAUTION : The heating in a closed system or under pressure should be carried out in an apparatus equipped with a proper safety valve.) The resulting solution was concentrated by evaporating some of the solvent to precipitate white crystals, which were collected by filtration and recrystallized from hot THF to give 6.9 g (yield 70%) in the first case and 8.8 g (yield 90%) in the second case as colorless crystals: mp 186−188 °C; 1 H NMR (400 MHz, CDCl 3 ) δ = 1.67 (s, 6 H), 2.89 (s, 6 H), 6.96 (t, J = 8.4 Hz, 2H), 7.17−7.22 (m, 1H) 9.23 (s, br, 1 H, NH); 13 C NMR (100 Hz,CDCl 3 ) δ 26.2, 41.4, 76.2, 102.3, 112.1, 116.7, 127.7, 157.3 (dd, J CF = 252 Hz), 164.3, 165.2. Anal.…”

Isoxazolopyrimidines as Novel ΔF508-CFTR Correctors

“…24 Hydroximoyl chlorides are well-established nitrile oxide precursors (via dehydrochlorination) that readily participate in 1,3-diploar cycloadditions. Adapting a protocol reported by Rajagopalan and Talaty, 25 hydroximoyl chloride 3 was dissolved in ethanol and added dropwise to an ethanol suspension of (2-amino-1-cyano-2-oxoethyl)sodium to produce 5-amino-3-arylisoxazole-4-carboxamide 4 (35–89% yield). Next, carboxamide 4 and triethyl orthoformate were dissolved in acetic anhydride, and the solution was refluxed for 2.5 hours to give 3-isoxazolo[5,4- d ]pyrimidin-4(5 H )-one 5 in 48–75% yield.…”

“…26 The chlorination of 5a to 6a was also attempted with excess phosphorous oxychloride as described by Rajagopalan and Talaty. 25 However, after washing with water, only starting material 5a was recovered suggesting that, under acidic conditions, water displaces the chloride to reverse the transformation (e.g., 6a → 5a ). We also found that treating chloropyrimidine 6a with 2,3-dimethylaniline under reflux in methanol for 24 hours in the presence of K 2 CO 3 failed to deliver isoxazolopyrimidine 7 (4-chloro- → 4-hydroxypyrimidine occurred instead).…”

“…Fortunately, target molecules 7-26 were obtained by refluxing an isopropanol solution of 6 with the appropriate aniline (2 equiv) in the presence of a catalytic amount of HCl gas. 27 Twenty isoxazolo [5,4-d]pyrimidine analogues (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were synthesized using the method outlined in Scheme 1 by varying R 1 (four inputs) and R 2 (five inputs). DF508-CFTR corrector data for six active compounds are summarized in Table 1.…”