Acetonitrile--water (1/1) → 6-(1,4-Dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine-4-carbonitrile

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Reaction Conditions

Reaction Steps

4-Chloro-6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine (described in Example 1, Step 1) (27.1 mg, 0.0800 mmol) was stirred in N,N-dimethylformamide (1.3 mL). Zinc cyanide (23 mg, 0.20 mmol) was adde, followed by tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0096 mmol). The solution was flushed with nitrogen (subsurface). The vial was sealed, and the solution was heated at 140° C. for 10 minutes in a microwave reactor. LCMS showed no remaining starting material and showed a new peak that did not ionize. The product was isolated by preparative LC using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column; 62% CH3CN—H2O (0.1% TFA), 0.5 min, 4.5 min gradient to 82%; 60 mL/min; detector set at 254 nm; retention time=3.8 min. The solvent was removed by rotary evaporation to give 21 mg. 1H NMR (400 MHz, acetone-d6): δ 7.78 (s, 1H); 5.41 (m, 1H, OCH); 3.94 (s, 4H, OCH2); 1.9-2.1 (m, 4H); 1.83 (m, 2H); 1.67 (m, 2H). 13C NMR (100 MHz, acetone-d6): δ 171.6 (s, OC); 142.1 (s, C—N); 117.8 (s, CH); 115.8 (s, CN); 108.2 (s, O2C); 76.1 (s, OCH); 65.0 (s, OCH2); 31.7 (s, CH2); 28.6 (s, CH2); two quartets were not resolved due to insufficient number of scans. The compound of Example 54 was then obtained by following the steps described for Example 45.

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