反応 #40535

反応方程式

NaOH

2-methyl-2-thiopseudourea

ethyl chloroformate

1-(2,3-diamino-5-pyridin-3-yl-phenyl)-propan-1-one

→

title compound

(7-Propionyl-5-pyridin-3-yl-1H-benzoimidazol-2-yl)-carbamic acid ethyl ester

溶媒

water

AcOH

water

water

EtOAc

反応条件

後処理

1. 1
   workup.ADDITIONwas subsequently added to the reaction mixture
2. 2
   温度cooled to ambient temperature
3. 3
   その他The phases were separated
4. 4
   抽出the aqueous layer extracted with EtOAc (3×)
5. 5
   洗浄The combined organic extracts were washed with brine
6. 6
   乾燥dried (MgSO4)
7. 7
   ろ過filtered
8. 8
   濃縮the filtrate concentrated in vacuo
9. 9
   その他purified by preparative HPLC

実験手順

To a mixture of 2-methyl-2-thiopseudourea (109 mg, 0.39 mmol) and ethyl chloroformate (75 μL, 0.78 mmol) in water (2 mL) at 5° C. was added over 40 minutes a 6N aqueous NaOH solution until pH stabilized to 8. The pH was then adjusted to 5 with glacial AcOH. A suspension of 1-(2,3-diamino-5-pyridin-3-yl-phenyl)-propan-1-one (0.30 mmol) in water (5 mL) was subsequently added to the reaction mixture. The reaction was heated at 90° C. for 18 hours, cooled to ambient temperature, and diluted with water (10 mL) and EtOAc (20 mL). The phases were separated and the aqueous layer extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. The crude residue was taken up in DMSO, purified by preparative HPLC, and by flash column chromatography (SiO2; CH2Cl2:MeOH, 1:0 to 19:1). The residue was then converted to the bis-HCl salt to afford the title compound as an off white solid (5.0 mg): HPLC (10 to 90% CH3CN, 8 min.): Rt=3.90 minutes; 1H NMR (CD3OD, 500 MHz) δ 9.39 (d, 1H), 9.07 (d, 1H), 8.93 (d, 1H), 8.48 (d, 1H), 8.28 (d, 1H), 8.25 (dd, 1H), 4.46 (q, 2H), 3.35 (q, 2H), 1.43 (t, 3H), 1.29 (t, 3H); MS (ES+) m/z (M++1) 339.1.

出典