2,3-Dichloro-6-methoxyquinoxaline

6-Methoxy-1, 4-dihydro-quinoxaline-2, 3-dione (15.5 g, 1 mmol) was dissolved in 75 ml of phosphorus oxychloride, and the mixture was refluxed for 24 hours. The reaction was terminated by using water and methanol (1: 1 solution) at 0 to 5 ° C, and the resulting precipitate was filtered and dried under reduced pressure to obtain 17.2 g of the objective compound (93.1percent yield)A mixture of 6-methoxyquinoxaline-2, 3-diol (3.0 g, 1.562 mmol), freshly distilled phosphoryl chloride (8.7 mL, 9.37 mmol) and N, N-dimethylaniline (3.0 mL) were refluxed for 90 mm, then cooled and slowly poured into stirred ice-water. The obtained precipitate was filtered, washed with water, and dried in a vacuum and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed withbrine, dried over anhydrous Na, 504, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel (60-120) column chromatography using 2-5 percent EtOAc/Hexanes to afford a yellow solid(2.22 g, 62.2percent yield). ‘H NMR (500 MHz, DMSO-d6): (57.90 (d, 1H), 7.50 (d, 1H), 7.30 (s, 1H), 4.00 (s, 3H). LC-MS [mlz]: 229.1 [M+H], 99.77percent purity.General procedure: That 1 g O-phenylendiamine, 1.28 g oxalic acid and 3 g 200 - 300 mesh silica gel in the reaction bottle, adding 15 ml toluene, 110 C lower reaction 5 hours, the reaction is finished, by adding 8.4 ml phosphorus oxychloride and 5 ml DMF, 110 C continues reaction under 1 hour, the reaction is finished, adding 50 ml ice water quenching, adding 50 ml ethyl acetate, filtration, liquid, to continue to use the water layer is extracted with ethyl acetate, the combined ethyl acetate, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, reduced-pressure drying to obtain white solid, yield 92%Example 8: Preparation of 2, 3-Dichloro-6-methoxyguinoxaline (Compound 1 1): In a 22 L round bottomed flask equipped with a mechanical stirrer, thermocouple and condenser was added to 2, 3-dichloro-6-methoxyquinoxalone Compound 10 (3.8 kg). Charged slowly at room temperature was POC13 (5.92 L 99%). The grey slurry was heated to98 C for 20 hours. After 2-3 hours the slurry turned from grey to green, then to yellow and finally turned homogeneous red. As the slurry became homogenous in POC13, significant amounts of HCI off-gassing were produced. The dark red, homogenous solution was allowed to cool slowly to below 80 C. At this point, 19 L of acetonitrile (5.0 L/Kg) was charged which produced a dark brown slurry. The reaction was cooled to 10-15 C in an ice bath and reverse quenched into 45.6 L of cold water (12.0 L/Kg) in a 100 L cylindrical vessel. This exothermic quench was kept below 27 C. MeCN ( 4L) was used to aide in slurry transfer. The brownslurry was filtered and 5 L of water was used to wash the flask. The solids were washed with 1 cake volume of water (5 L). The pH of the filtrate was acidic. The solids were nextdisplacement washed with 2 cake volumes of 5% sodium bicarbonate (-20.00 L). The pH was between 8-9. A slurry wash was performed with 2 cake volumes of water (20 L total). The pH did not change. The solids were dried for 72 hours under reduced pressure and nitrogen flow togive tan product Compound 11 of 99.5% purity by HPLC assay with KF= 0.5 wt. % water.HPLC Conditions: Zorbax Eclipse Plus C 18 50 x 4.6 mm, 1.8 um, 1.5 mL/min, 210 nm, 25 C; Eluents: Water 0.1% H3P04 (A), Acetonitrile (B). 90% A 0 mm, 5% A 5 mm, 5% A 6 mm.Compound 10 1.55 mm (sometimes two peaks)Compound 11 4.55 mm An analytical sample was obtained by silica gel chromatography and as acolorless foam: 'HNMR (CDC13, 400 MHz) 60.50 (q, 1H, J 6.3 Hz), 1.04 (br s, 1111), 1.20 (br s, 3H), 1.45 (br s, 13 H), 1.72 (m, 2H), 2.40 (m, 1H), 2.63 (m, IH), 2.93 9m, 2H), 3.68-3.94(m, 9H), 4.15 (br m, 1H), 4.46 and 4.60 (t, due to rotamers, 1H, J 7.8 Hz), 5.27 (br m, IH), 5.78 (br rn, 1H), 7.18 (m, 1H), 7.20 (m, 111), 7.85 (m, 1H); '3C NMR (CDC13, 100 MHz) 6 11.9, 18.5, 26.6, 27.0, 28.1, 28.3, 28.4, 29.1, 30.9, 32.9, 34.1, 35.7, 36.6, 49.4, 52.1, 52.2, 52.4, 55.1, 55.7, 57.7, 58.2, 62.3, 73.5, 74.1, 80.7, 106.0, 118.8, 128.5, 133.7, 141.1. 148.2, 153.9, 154.5, 155.3, 157.1, 160.4, 173.2, 173.3, 174.4.In a 22 L round bottomed flask equipped with a mechanical stirrer, thermocouple and condenser was added to 2, 3-dichloro-6-methoxyquinoxalone Compound 10 (3.8 kg). Charged slowly at room temperature was POCl3 (5.92 L at 99%). The grey slurry was heated to 98 C for 20 hours. After 2-3 hours the slurry turned from grey to green, then to yellow and finally turned homogeneous red. As the slurry became homogenous in POCl3, significant amounts of HCl off-gassing were produced. The dark red, homogenous solution was allowed to cool slowly to below 80 C. At this point, 19 L of acetonitrile (5.0 L/Kg) was charged which produced a dark brown slurry. The reaction was cooled to 10-15 C in an ice bath and reverse quenched into 45.6 L of cold water (12.0 L/Kg) in a 100 L cylindrical vessel. This exothermic quench was kept below 27 C. MeCN (- 4L) was used to aide in slurry transfer. The brown slurry was filtered and 5 L of water was used to wash the flask. The solids were washed with 1 cake volume of water (?5 L). The pH of the filtrate was acidic. The solids were next displacement washed with 2 cake volumes of 5% sodium bicarbonate (-20.00 L). The pH was between 8-9. A slurry wash was performed with 2 cake volumes of water (20 L total). The pH did not change. The solids were dried for 72 hours under reduced pressure and nitrogen flow to give tan product Compound 1 1 of 99.5% purity by HPLC assay with KF= 0.5 wt. % water. HPLC Conditions: Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 urn, 1.5 mL/min, 210 nm, 25 C; Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 min, 5% A 5 min, 5% A 6 min. Compound 10 1.55 min (sometimes two peaks) Compound 1 1 4.55 min [0180] An analytical sample was obtained by silica gel chromatography and as a colorless foam: 'H NMR (CDCl3, 400 MHz) delta 0.50 (q, 1H, J = 6.3 Hz), 1.04 (br s, 1 1 H), 1.20 (br s, 3H), 1.45 (br s, 13 H), 1.72 (m, 2H), 2.40 (m, 1H), 2.63 (m, I H), 2.93 9m, 2H), 3.68-3.94 (m, 9H), 4.15 (br m, 1 H), 4.46 and 4.60 (t, due to rotamers, 1H, J = 7.8 Hz), 5.27 (br m, 1H), 5.78 (br m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H); 13C NMR (CDCl3, 100 MHz) delta 11.9, 18.5, 26.6, 27.0, 28.1, 28.3, 28.4, 29.1, 30.9, 32.9, 34.1, 35.7, 36.6, 49.4, 52.1, 52.2, 52.4, 55.1, 55.7, 57.7, 58.2, 62.3, 73.5, 74.1, 80.7, 106.0, 118.8, 128.5, 133.7, 141.1, 148.2, 153.9, 154.5, 155.3, 157.1, 160.4, 173.2, 173.3, 174.4.Step 3: Preparation of Intermediate C1 : In a dry flask under a dry N2 atmosphere was placed 41 .0 g (213 mmol) of C1 -2, 200 mL of POCI3, and 41 mL tri-n-propylamine (41 mL, 217 mmol). The exothermic reaction mixture was then allowed to stir at rt for 1 h and thereafter was refluxed overnight. The mixture was cooled again to rt and poured slowly over ice/water. The resulting aqueous mixture was stirred at rt for 20 min, then filtered. The recovered precipitate was washed with water and dissolved in chloroform. The chloroform solution was filtered to remove insoluble material and the filtrate was successively washed with water, saturated sodium bicarbonate solution and brine. Concentration of the washed solution in vacuo was followed by recrystallization of the residue from ethanol. The product was purified via silica gel chromatography to produce Intermediate C1. 1H-NMR (DMSO-c/6, 400 MHz): delta 7.99 (d, J = 9.2 Hz, 1 H), 7.59 (dd, J = 9.2, 2.8 Hz, 1 H), 7.50 (d, J = 2.8 Hz, 1 H), 3.96 (s, 1 H).In a 22 L round bottomed flask equipped with a mechanical stirrer, thermocouple and condenser was added to 2, 3-dichloro-6-methoxyquinoxalone Compound 10 (3.8 kg). Charged slowly at room temperature was POCl3 (5.92 L 99%). The grey slurry was heated to 98 C. for 20 hours. After 2-3 hours the slurry turned from grey to green, then to yellow and finally turned homogeneous red. As the slurry became homogenous in POCl3, significant amounts of HCl off-gassing were produced. The dark red, homogenous solution was allowed to cool slowly to below 80 C. At this point, 0.19 L of acetonitrile (5.0 L/Kg) was charged which produced a dark brown slurry. The reaction was cooled to 10-15 C. in an ice bath and reverse quenched into 45.6 L of cold water (12.0 L/Kg) in a 100 L cylindrical vessel. This exothermic quench was kept below 27 C. MeCN (4 L) was used to aide in slurry transfer. The brown slurry was filtered and 5 L of water was used to wash the flask. The solids were washed with 1 cake volume of water (5 L). The pH of the filtrate was acidic. The solids were next displacement washed with 2 cake volumes of 5% sodium bicarbonate (20.00 L). The pH was between 8-9. A slurry wash was performed with 2 cake volumes of water (20 L total). The pH did not change. The solids were dried for 72 hours under reduced pressure and nitrogen flow to give tan product Compound 11 of 99.5% purity by HPLC assay with KF=0.5 wt. % water. (0213) HPLC Conditions: Zorbax Eclipse Plus C18 50×4.6 mm, 1.8 um, 1.5 mL/min, 210 nm, 25 C.; Eluents: Water 0.1% H3PO4 (A), Acetonitrile (B). 90% A 0 min, 5% A 5 min, 5% A 6 min. An analytical sample was obtained by silica gel chromatography and as a colorless foam: 1H NMR (CDCl3, 400 MHz) delta 0.50 (q, 1H, J=6.3 Hz), 1.04 (br s, 11 H), 1.20 (br s, 3H), 1.45 (br s, 13 H), 1.72 (m, 2H), 2.40 (m, 1H), 2.63 (m, 1H), 2.93 9m, 2H), 3.68-3.94 (m, 9H), 4.15 (br m, 1H), 4.46 and 4.60 (t, due to rotamers, 1H, J=7.8 Hz), 5.27 (br m, 1H), 5.78 (br m, 1H), 7.18 (m, 1H), 7.20 (m, 1H), 7.85 (m, 1H); 13C NMR (CDCl3, 100 MHz) delta 11.9, 18.5, 26.6, 27.0, 28.1, 28.3, 28.4, 29.1, 30.9, 32.9, 34.1, 35.7, 36.6, 49.4, 52.1, 52.2, 52.4, 55.1, 55.7, 57.7, 58.2, 62.3, 73.5, 74.1, 80.7, 106.0, 118.8, 128.5, 133.7, 141.1, 148.2, 153.9, 154.5, 155.3, 157.1, 160.4, 173.2, 173.3, 174.4.A mixture of 6-methoxyquinoxaline-2, 3-diol (3.0 g, 1.562 mmol), freshly distilled phosphoryl chloride (8.7 mL, 9.37 mmol) and N, N-dimethylaniline (3.0 mL) were refluxed for 90 mm, then cooled and slowly poured into stirred ice-water. The obtained precipitate was filtered, washed with water, and dried in a vacuum and extracted with EtOAc (3 X 50 mL). The combined organic layers were washed withbrine, dried over anhydrous Na, 504, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel (60-120) column chromatography using 2-5 % EtOAc/Hexanes to afford a yellow solid(2.22 g, 62.2% yield). 'H NMR (500 MHz, DMSO-d6): (57.90 (d, 1H), 7.50 (d, 1H), 7.30 (s, 1H), 4.00 (s, 3H). LC-MS [mlz]: 229.1 [M+H], 99.77% purity.

Molecular Weight:229.06
XLogP3:3.1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:227.9857182
Monoisotopic Mass:227.9857182
Topological Polar Surface Area:35
Heavy Atom Count:14
Complexity:205
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes