Tetrahydrofuran → N2-Cyclopropylpyrazine-2,3-diamine

Temperature

45 °C

To a 250 mL round bottomed flask was added 2-amino-3-chloropyrazine (2.2204 g, 17.14 mmol, Synthetech, Inc.) and BrettPhos precatalyst (0.411 g, 0.514 mmol, Sigma-Aldrich Chemical Company, Inc.), and the reaction mixture were placed under vacuum. The round bottomed flask was flushed with argon. This process was repeated 3 times. Cyclopropylamine (1.803 ml, 25.7 mmol, Fluka Chemie GmbH) was added followed by a dropwise addition of lithium bis(trimethylsilyl)amide, 1.0 m solution in tetrahydrofuran (42.8 ml, 42.8 mmol, Sigma-Aldrich Chemical Company, Inc.). The reaction mixture was then heated to 45° C. for 2 h. The reaction mixture was then diluted with saturated NH4Cl and extracted with CH2Cl2. The organic extract was washed with water, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage SNAP HP-silica gel column (50 g), eluting with a gradient of 10% to 60% Acetone in DCM, to provide the title compound (0.7993 g, 5.32 mmol, 31.1% yield). LCMS showed product peak at 0.629 min (m+1=151.1) with purity at 80-90%. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.31-0.38 (m, 2 H) 0.59-0.66 (m, 2 H) 2.64 (tq, J=6.85, 3.52 Hz, 1 H) 5.79 (s, 2 H) 6.25 (d, J=2.15 Hz, 1 H) 7.08 (d, J=3.13 Hz, 1 H) 7.20 (d, J=3.13 Hz, 1 H).

1. customThe round bottomed flask was flushed with argon
2. extractionextracted with CH2Cl2
3. extractionThe organic extract
4. washwas washed with water, saturated NaCl
5. dry with materialdried over MgSO4
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customchromatographed through a Biotage SNAP HP-silica gel column (50 g)
9. washeluting with a gradient of 10% to 60% Acetone in DCM

ORD record

ord-e3f1a11114cf495d908a182ef61a3855

Source dataset

uspto-grants-2015_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09174992B2