Potassium Carbonate → 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.33 g, 90.60 mmol) was combined with 6-fluoro-nicotinic acid methyl ester (16.9 g, 109 mmol) and K2CO3 (37.6 g, 272 mmol, 325 mesh) in a 500 mL N2-purged round bottom. Anhydrous dimethylformamide (115 mL) was added. The reaction was heated to 100° C. as a suspension. At 35 min another 3.00 g of 6-fluoro-nicotinic acid methyl ester was added. At 20 h, the reaction was placed in an ice bath and when the internal temperature was below room temperature sat. NH4Cl (500 mL) was added. This was stirred for a couple minutes in the bath and then the bath was removed and stirred at room temperature. Ethyl acetate (600 mL) and a small amount of water were added and the layers separated. The aqueous was extracted with ethyl acetate (150 mL) and the combined organics were washed with additional sat. NH4Cl (125 mL). The aqueous was back extracted with ethyl acetate (50 mL). The combined organics were dried over MgSO4. Purification was done by silica gel flash chromatography (ethyl acetate/heptane) to give impure 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester (38.07 g) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.85 (s, 2 H) 8.69 (d, J=1.6 Hz, 1 H) 8.55 (d, J=8.2 Hz, 2 H) 8.01 (dd, J=8.8, 2.1 Hz, 1 H) 7.74 (d, J=8.4 Hz, 2 H) 6.39 (d, J=8.8 Hz, 1 H) 5.01 (q, J=6.9 Hz, 1 H) 3.86 (s, 3 H) 1.85-1.98 (m, 1 H) 1.70-1.82 (m, 2 H) 1.05 (d, J=6.2 Hz, 3 H) 1.01 (d, J=6.0 Hz, 3 H); MS (M+1): 445.3.

Provenance & Evidence