3-METHOXYPYRAZINE-2-CARBOXYLICACID

2-Methoxy-3-methylpyrazine 1a (3.72 g, 30 mmol) was added slowly to a stirred mixture of HNO[0423] A solution of 3-amino-4-(4-(2, 4-difluorophenoxy)piperidin-l-yl)benzonitrile (50 mg, 0.152 mmol), 3~niethoxypyrazme-2-carboxyiie acid (46.8 mg, 0.304 mmol), HATU (115 mg, 0.304 mmol) and DIPEA (106 mu, , 0.607 mmol) in DMF (759 muEpsilon) was stirred on a hot plate at 80C overnight. The reaction mixture was filtered through a Millipore filter, diluted with DMF and MeOH, and purified by HPLC (Shimadzu) eluting with a gradient of ACN in water (basic mode) to give the title compound as a light brown solid (68.7 mg, 97%). .H NMR (400 MHz, CDCb) delta ppm 2.07 - 2.18 (m, 2 H), 2.19 - 2.28 (m, 2 H), 2.91 (ddd, J=l 1.68, 8.02, 3.28 Hz, 2 H), 3.26 (ddd, ./ 1 1.62. 7.58, 3.54 Hz, 2 H), 4.18 (s, 3 H), 4.37 - 4.45 (m, 1H), 6.78 ·· 6.86 (m, 1H), 6.90 (ddd, .7=11, 12, 8.34, 3.03 Hz, 1H), 7.03 (td, .7=9.09, 5, 56 Hz, 1H), 7.23 (d, .7=8, 34 Hz, 1H), 7.41 (dd, J=8.34, 2.02 Hz, 1H), 8.26 (d, J=2.27 Hz, 1H), 8.41 (d, J=2.53 Hz, 1H), 8.93 (d, ./ 1.77 Hz, 1H), 10.62 (s, 1H); ESI-MS m/z [M+H}+ 466.2.To a solution of amine salt E1.1 (0.868g, 3.39 mmol) and carboxylic acid 1a (0.475g, 3.08 mmol) in DCE (50 mL) at room temperature was sequentially added bromotripyrrolidinophosphonium hexafluorophosphate (1.80 g, 3.85 mmol), and DIEA (1.59g, 112.33 mmol). The reaction was then stirred at room temperature for 72 hours. Then CH2CI2 (100 mL) and water (100 mL) were added to the reaction, layers separated, and the organic phase washed with water (2 x 100 mL), dried over Na2S04, and concentrated in vacuoto afford a residue. The residue was purified by column chromatography using silica gel, eluting with 100% EtOAc, to afford the desired compound as an off white solid (0.690g, 69% yield). LC-MS: mass calc'd. for C17H15CI2N5O2 [M+H]+ 356.1 , found 356.0; tR= 0.688 min.2-Methoxy-3-methylpyrazine 1a (3.72 g, 30 mmol) was added slowly to a stirred mixture of HNO3 (5.5 ml, 100%) and H2SO4 (11 ml, 98%) at 30-35 C. The reaction mixture was heated at 45 C for 4 h. Afterwards, it was poured over ca. 50 g of crushed ice and extracted with EtOAc (3×50 ml). Combining the organic layers, washing with brine, drying (MgSO4), and removal ofsolvent afforded a mixture of products.The residue was subjected to column chromatography [eluting with hexane-EtOAc, 50:1' 5:1, Rf(2a) > Rf(3a) > Rf(4a) > Rf(5a)] to give pure products.4-(31) N-(3-((4aS, 5S, 7aS)-2-amino-5-(fluoromethyl)-4a, 5, 7, 7a-tetrahydro-4H-furo[3, 4-d][1, 3]thiazin-7a-yl)-4, 5-difluorophenyl)-5-methoxypyrazine-2-carboxamide (also called 4-(17))

Molecular Weight:154.12
XLogP3:-0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:154.03784206
Monoisotopic Mass:154.03784206
Topological Polar Surface Area:72.3
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes