2-BROMO-6-MORPHOLINOPYRAZINE

In a pressure tube, argon was bubbled through a suspension of 3, 3-dimethyl-6-(2- methyl pyri m idin-5-y 1 )i ndol i n-2-onc (80 mg, 3 16 mu etaiotaomicron. Eq: 1, W02( ) 14/2( 12493 Al), 4-(6- bromopyrazin-2-yl)morpholine (116 mg, 474 mupiiotaomicron, Eq: 1.5) and potassium carbonate (87.3 mg, 632 mupiiotaomicron, Eq: 2) in acetonitrile (1.26 ml) for 5 minutes. Copper (I) iodide (6.02 mg, 31.6 mupiiotaomicron, Eq: 0.1) and N, N'-dimethylethylenediamine (5.57 mg, 6.8 mu, 63.2 mupiiotaomicron, Eq: 0.2) were added, again flushed with argon, and the tube was sealed and the reaction mixture was heated to 120 °C overnight. The crude material was diluted with dichloromethane and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the desired product as a white solid (115 mg, 87 ). MS (m/z) = 417.2 [M + H]+.19b) 1-CHLORO-4- (6-MORPHOLIN-4-VL-PVRAZIN-2-YL)-ISOQUINOLINE A solution of 4-BROMO-1-CHLORO-ISOQUINOLINE (400 mg, 1.65 MMOL) in THF (20 mL) is cooled TO-72°C. A solution of n-BuLi (2.5 M in hexanes) (0.80 mL, 2 MMOL) is added dropwise and the reaction temperature maintained AT-70 °C~-68°C FOR 30min. ZnBr2 (408 mg, 1.91 MMOL) is dissolved in THF (6 mL) and is transferred to above mixture slowly at-70 °C. The solution is stirred 40 min at-70 °C, then warmed to room temperature by removing the cooling bath. Pd (PPh3) 4 (190 mg, 0.164 MMOL) in 6ML THF and 4-(6-BROMO-PYRAZIN-2-YL)- morpholine (400 mg, 1.65 MMOL) in THF (4 mL) are added to the reaction mixture dropwise, then the solution is heated to 60 °C for 30 min and then kept at rt overnight. The reaction mixture is diluted with ethyl acetate, washed with sat. NH4CI . then brine, and dried over sodium sulfate. The solution is concentrated until white solid came out from solution. The solid is collected by filtration, washed with ether and dried under vacuum. 300 mg of 1- CHLORO-4- (6-MORPHOLIN-4-YL-PYRAZIN-2-YL)-ISOQUINOLINE IS obtained. Yield was 56percent. MS/ESI+, M+1 = 32719a) 4- (6-BROMO-PYRAZIN-2-YI)-MORPHOLINE PBr3 (11 g, 36.9 mmol, 5.5 eq) is added to 2, 6-dichloro-pyrazine (1.0 g, 6.7 mmol, 1 eq) at rt and heated to 150 °C for 24 h. This solution is dried in vacuum and the residue is dissolved in CH2CI2 (50 mL). The organics are washed with H20, brine and dried. Morpholine is added to this solution dropwise at 0 °C and warmed to rt in 5 h. The solution is washed with H20 and brine. Chromatography (SiO2, 10-60percent EtOAc-hexanes gradient elution) provides product 4-(6-BROMO-PYRAZIN-2-YL)-MORPHOLINE (0.5 g, 31 percent). MS/ESI, M+1 = 246.01, H NMR (400 MHz, CDCI3) 8 7.99 (s, 1 H), 7.95 (s, 1 H), 3.82 (t, J = 4.0 Hz, 4H), 3.58 (t, J = 4.0 Hz, 4H).

Molecular Weight:244.09
XLogP3:0.9
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:243.00072
Monoisotopic Mass:243.00072
Topological Polar Surface Area:38.2
Heavy Atom Count:13
Complexity:164
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes