6-Chloropyrazine-2-carboxylic acid

6-((3aR, 6aS)-hexahydropyrrolo[3, 4-c]pyrrol-2(1H)-yl)-N-m-tolylpyrazine-2-carboxamide; Example 15A; 6-chloropyrazine-2-carboxylic Acid; The product from Example 1E (1.78 g, 10.3 mmol) was dissolved in EtOH (25 mL). 1M NaOH (25 mL) was added, and the reaction stirred at ambient temperature for 2 h. The reaction mixture was acidified to pH3 with 1M HCl (aq). The mixture was then diluted with water (150 mL) and extracted with EtOAc (4.x.100 mL). The organic extracts were combined, washed with brine (100 mL), dried over NaThis compound was prepared following a literature procedure.33 Toa solution of Na2WO4·2H2O (0.025 equiv., 0.24 mmol) in H2O (0.05 M)was added aq·H2O2 (30percent, 1.1 equiv., 1 mL) at RT, followed by theaddition of H2SO4 (1 M) to make pH=2, then pyrazine-2-carboxylicacid 52 (1.0 equiv., 8 mmol) was added, and the resulting suspensionwas stirred at 80 °C for 2 h. After completion monitored by TLC, themixture was settled at RT until the precipitate was obtained, filteredand washed by H2O and dried under reduced pressure to get white solidcompound 3-carboxypyrazine 1-oxide without further purification. Asolution of 3-carboxypyrazine 1-oxide (1.0 equiv., 7 mmol) in POCl3(3 mL) in sealed tube was heated to 120 °C and stirred for 2 h. Aftercompletion monitored by TLC, the reaction mixture was cooled to RTand poured to ice water (20 mL), neutralised with sat. Na2CO3 (aq.) andextracted with ethyl acetate (3×20 mL). The combined organic layerswere dried over MgSO4 and concentrated in vacuo. The crude productwas recrystallised from ethanol, filtered and washed by hexane, dried toget the product 53 as a white solid (880 mg, 70percent). m.p. 158–160 °C; Rf(hexane/ethyl acetate 1:1): 0.25; 1H NMR (500 MHz, d6-DMSO): δ 9.13(1H, s), 9.00 (1H, s); 13C NMR (125 MHz, d6-DMSO): δ 163.8, 148.0, 147.8, 143.7, 143.3. The spectroscopic data matched that reported inthe literature.A mixture of Compound 3A (220 mg, 1.39 mmol; prepared as described in Sato, N. J. Heterocyc. Chem. 1994, 31, 1177), DPPA (575 mg, 2.09 mmol) and triethylamine (0. [39] [ML, ] 2. 80 mmol) in [T-BUOH] (3 mL) and toluene (2 mL) was heated at [65 C] for 1.5 h, then at [85 C] for 2 h. After concentration, the mixture was purified by flash chromatography (EtOAc/hexane) to give Compound 3B (180 mg, 57%) as a white [SOLID. 1H NMR] (300 MHz, CDC13) 8 [9. 19 (S, ] 1H), 8.26 (s, 1H), 7.17 (brs, 1H), 1.54 (s, 9H). A mixture of Compound 3B (160 mg, 0.697 mmol), [(3-BROMOPROPOXY)-TERT-] butyldimethylsilane (220 mg, 0.870 mmol) and [CS2CO3] (340 mg, 1.04 mmol) in dry DMF (2 mL) was stirred at [60 C] for 2.5 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane) to provide Compound 3C (262 mg, 94%) as clear [OIL. LH NMR (300 MHZ, CDC13) 6 9.] 01 (s, 1H), 8.20 (s, 1H), 4.00 (t, J= 7.4 Hz, 2H), 3. 68 (t, J= [6.] 2 Hz, 2H), 1.87 [(M, ] 2H), 1.54 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H). A mixture of Compound 3C (123 mg, 0.306 mmol), bis [(TRIMETHYLTIN)] (200 mg, 0.611 mmol), tetrakis (triphenylphosphine) palladium (35 mg, 0.030 mmol), LiCl (40 mg, 0.94 mmol) and 2, 6-di-tert-butyl-4-methylphenol (3 mg, 0.014 mmol) in anhydrous 1, 4- dioxane (2 [ML)] was refluxed for 4 h under nitrogen. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel (EtOAc/hexane) to give Compound 3D (154 mg, 95%) as clear [OIL. 1H NMR] (300 MHz, CDC13) 8 8.79 (s, 1H), 8.21 (s, [1H), ] 4.01 (t, J= 7.2 Hz, 2H), 3.67 (t, J= 6.0 Hz, 2H), 1.90 [(M, ] 2H), 1.53 (s, 9H), 0. 87 (s, 9H), 0.36 (s, 9H), 0.02 (s, 6H); MS (ES) m/z : 531 (M+H). A mixture of Compound 3D (73 mg, 0.14 [MMOL), ] Compound 1C (52 mg, 0.15 mmol), dichlorobis (triphenylphosphine) palladium (15 mg, 0.021 mmol) and LiCl (18 mg, 0.42 mmol) in anhydrous toluene (3 mL) was stirred at [100 C] overnight under nitrogen. The mixture was cooled, concentrated under vacuum and purified by flash chromatography (EtOAc/hexane) to give the coupled product as yellow oil. TFA (1 mL) was added and the mixture was stirred at [20 C] for 4 h. After it was concentrated, saturated NH40H solution and water were added until the mixture turned basic. After the precipitated solid was collected through filtration, it was washed with water and [ET20] and dried under vacuum to provide Compound 3 (1.5 mg, 47%) as a yellow solid. [H NMR] (300 MHz, DMSO-d6) [6] 10.59 (s, 1H), 8.91 (s, 1H), 8.63 (s, 1H), 8.20 (brs, 1H), 8.12 (s, 1H), 7.80 (brs, 1H), 7.39 (t, J= 8.2 Hz, 1H), 7.34 (brs, 1H), 7.13 [(D, ] [J=] 7.8 Hz, 1H), 4.60 [(M, ] 1H), 3.50 [(M, ] 2H), 3.32 [(M, ] 2H), 1.76 (t, J= 6.4 Hz, [2H) ;] MS (ES) m/z: 358 [(M+H.]4-Phenoxyaniline (0.185 g, 1.0 mmol), The preparation method is: 0.185 g (ie 1.0 mmol) of 4-phenoxyaniline, 0.158 g (ie 1.0 mmol) of 2-Phenoxyaniline (0.185 g, 1.0 mmol), The preparation method is:0.185 g (ie 1.0 mmol) of 2-phenoxyaniline, 0.158 g (ie 1.0 mmol) of This compound was prepared following a literature procedure.33 Toa solution of Na2WO4·2H2O (0.025 equiv., 0.24 mmol) in H2O (0.05 M)was added aq·H2O2 (30%, 1.1 equiv., 1 mL) at RT, followed by theaddition of H2SO4 (1 M) to make pH=2, then pyrazine-2-carboxylicacid 52 (1.0 equiv., 8 mmol) was added, and the resulting suspensionwas stirred at 80 C for 2 h. After completion monitored by TLC, themixture was settled at RT until the precipitate was obtained, filteredand washed by H2O and dried under reduced pressure to get white solidcompound 3-carboxypyrazine 1-oxide without further purification. Asolution of 3-carboxypyrazine 1-oxide (1.0 equiv., 7 mmol) in POCl3(3 mL) in sealed tube was heated to 120 C and stirred for 2 h. Aftercompletion monitored by TLC, the reaction mixture was cooled to RTand poured to ice water (20 mL), neutralised with sat. Na2CO3 (aq.) andextracted with ethyl acetate (3×20 mL). The combined organic layerswere dried over MgSO4 and concentrated in vacuo. The crude productwas recrystallised from ethanol, filtered and washed by hexane, dried toget the product 53 as a white solid (880 mg, 70%). m.p. 158-160 C; Rf(hexane/ethyl acetate 1:1): 0.25; 1H NMR (500 MHz, d6-DMSO): delta 9.13(1H, s), 9.00 (1H, s); 13C NMR (125 MHz, d6-DMSO): delta 163.8, 148.0, 147.8, 143.7, 143.3. The spectroscopic data matched that reported inthe literature.

Molecular Weight:158.54
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:157.9883050
Monoisotopic Mass:157.9883050
Topological Polar Surface Area:63.1
Heavy Atom Count:10
Complexity:142
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes