Methyl2,4-Dichloropyrimidine-5-carboxylate

Synthesis

Methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) were slowly added to a solution of 2,4-dichloropyrimidine-5-carbocarbonyl chloride (500 mg, 2.38 mmol) in methylene chloride (30 mL) at 0 °C. The reaction mixture was stirred continuously at 0 °C for 1 hour. After completion of the reaction, the solvent was removed by rotary evaporator. The obtained residue (461 mg, 94% yield) was dissolved in isopropanol (20 mL), followed by dropwise addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) and diisopropylethylamine (461.4 mg, 3.57 mmol). The reaction mixture was continued to be stirred at 0 °C for 90 min. Next, n-butylamine (208.8 mg, 2.86 mmol) and diisopropylethylamine (461.4 mg, 3.57 mmol) were added and the mixture was stirred at room temperature for 3 hours. At the end of the reaction, the reaction was quenched by the addition of water. The reaction mixture was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by an ISCO automated fast chromatography system to afford methyl 2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, three-step overall yield 89%).1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H) 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J=9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J=7.2Hz, 3H); 13C NMR (101MHz, CDCl3) δ 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+.

References

[1] Patent: WO2013/177168, 2013, A1. Location in patent: Page/Page column 34; 35
[2] Patent: WO2014/85225, 2014, A1. Location in patent: Page/Page column 18; 19; 28; 29
[3] Patent: WO2015/157127, 2015, A1. Location in patent: Page/Page column 167
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 16, p. 4857 - 4859
[5] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 16, p. 4642 - 4646