4-CHLORO-6,7-DIMETHOXYQUINOLINE

Light brown powder

To a suspension of 6, 7-dimethoxyquinolin-4-ol (45 g, 0.22 mol) in toluene (100 mL) was added phosphoryl trichloride (60 mL, 0.66 mol, Tianjin FuChen Chem. Co. Ltd.). The reaction was heated to 115 °C for 1 hour and then cooled down to rt. The mixture was diluted with EtOAc (400 mL), and the pH of the solution was adjusted to 7-8 with 3 M NaOH aqueous solution. The resulted mixture was extracted with EtOAc (150 mL x 2). The combined organic phases were washed with brine (150 mL), dried over anhydrous NaA solution of 6 (50 g, 0.24 mol) in POCl3 (400 mL) was stirred at 100°C for 6 h. Most of the solvent was recovered under vacuum. The residue was added slowly to cooled water 500 mL and adjusted with 10percent K2CO3 to pH ~ 9, and stirred for another 1 h. The resulting solid was filtrated, washed with H2O (50 mL × 2), and dried at 55°C for 4 h to give 7 (41.8 g, 78percent) as a light brown solid; mp 130.2-131.4° C (Lit.13 130−131 C). 1H NMR (400 MHz, DMSO-d6): δ 3.96 (s, 3H), 3.97 (s, 3H), 7.35 (s, 1H), 7.44(s, 1H), 7.54 (d, J = 5.2 Hz, 1H), 8.61 (d, J = 5.2 Hz, 1H). MS (ESI): m/z =223.2 [M + H]+, 245.2 [M + Na]+.6, 7-Dimethoxyquinolin-4-ol (0.64g) was dissolved in net POCI3 (3 mL). The solution was heated to 125°C for 2 h. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was basified with sat. NaHC03 (aq) and then extracted with EtOAc. The organic layer was dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using 10No.20percent methanol/EtOAc to give 4-chloro-6, 7-dimethoxyquinoline (0.38 g, 55percent yield) ; To a mixture 6, 7-dimethoxyquinolin-4-ol (Intermediate A, Step 2, 245 mg, 1.2 mmol) in phosphorus oxychloride (10 ml_) was added DMF (0.1 ml_). The reaction was heated at reflux for 4 h, then cooled to rt and concentrated under reduced pressure. The residue was dissolved with ethyl acetate, and the organic solution was washed successively with NaHCψPreparation of 4-Chloro-6, 7-dimethoxy-quinoline[0059] A reactor was charged sequentially with 6, 7-dhnethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POClA reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heated to approximately 65 °C and phosphorus oxychloride (POCb, 50.0 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 80 °C. The reaction was deemed complete (approximately 9.0 hours) when less than 2 percent of the starting material remained (in process high-performance liquid chromotography [HPLC] analysis). The reaction mixture was cooled to approximately 10 °C and then quenched into a chilled solution of dichloromethane (DCM, 238.0 kg), 30percent ΝΗ, ΟΗ (135.0 kg), and ice (440.0 kg). The resulting mixture was warmed to approximately 14 °C, and phases were separated. The organic phase was washed with water (40.0 kg) and concentrated by vacuum distillation to remove the solvent (approximately 190.0 kg). Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and the mixture was cooled to approximately 10 °C, during which time the product crystallized out. The solids were recovered by centrifugation, washed with n heptane (20.0 kg), and dried at approximately 40 °C to afford the title compound (8.0 kg).[00119] A reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POClPreparation of 4-Chloro-6, 7-dimethoxy-quinoline [00114] A reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POClA reactor was charged sequentially with 6, 7-dimemoxy-quinoline-4— ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCI3, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent ΝΟΗ (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to - 20 to - 25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).A reactor was charged sequentially with 6, 7—dimethoxy—quinoline—4—ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCi3, 130.6 kg) was added. After the addition of POCi3, the temperature of the reaction mixture was raised to approximatey 77 °C. The reaction was deemed compiete (approximatey 13 hours) when less than 3percent of the starting materia remained, as measured by in-process bigh-performance liquid cbromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a cbilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resultmg mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyfio super-cel NF (Celite; 5.4 kg), and the futer bed was washed with DCM (118.9 kg). The combined organic phase was washed with brnie (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by yacuum distillation with the remoyal of solyent (approximately 95 L residual yolume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by yacuum distiliation with the remoyal of soiyent (approximateiy 90 L residual yolume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to —20 to —25 °C and heid for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a futer at approximately 25 °C under rtrogen to afford the title compound (35.6 kg).[00264] A reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C and phosphonas oxychioride (POd3, 130.6 kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-2 5 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NP (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase wasconcentrated by vacuum distillation with the removal of solvent (approximateLy 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound. (35.6 kg).Fool 13] A reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POC13, 130.6 kg) was added. After the addition of POCI3, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLCJ analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged, and the temperature of the mixture was adjusted to -20 to -25 °C and held for 2.5 hours resulting in solid precipitate, which was then filtered, washed with n-heptane (92.0 kg), and dried on a filter at approximately 25 °C under nitrogen to afford the title compound (35.6 kg).A reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POCl10096] A reactor was charged sequentially with 6, 7- dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60° C. and phosphorus oxychloride (POC13, 130.6kg) was added. After the addition of POC13, the temperature of the reaction mixture was raised to approximately 77° C. The reaction was deemed complete (approximately 13 hours) when <3percent of the starting material remained (in-process high-performance liquid chromatography [HPLC] analysis). The reaction mixture was cooled to approximately 2-7° C. and then quenched into a chilled solution of dichioromethane (DCM, 482.8 kg), 26percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20-25° C., and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cd NF (Celite; 5.4 kg) and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated and the organic phase was concentrated by vacuum distillation with the removal of solvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by vacuum distillation with the removal of solvent (approximately 90 L residual volume). Methyl t-butyl ether (MTBE, 226.0 kg) was then charged and the temperature of the mixture was adjusted to —20 to —25° C. and held for 2.5 hours resulting in solid precipitate which was then filtered and washed with n-heptane (92.0 kg), and dried on a filter at approximately 25° C. under nitrogen to afford the title compound. (35.6 kg).The 6, 7-dimethoxy-quinolin-4-ol (47.0 kg) and acetonitrile (318.8 kg) are sequentially added into the reactor. The resulting mixture is heated to about 60 °C, and add phosphorus acyl chlorine (POClPreparation of 4-Chloro-6, 7-dimethoxy-quinoline 1.65 kg (13.9 mol) of thionyl chloride was added dropwise to a solution containing 2.2 kg (10.72 mol)4-hydroxy-6, 7-dimethoxyquinoline in 5.3 L (57 mol) solution of N, N-dimethylacetamide was added and heated to 100 to 120 ° C for 4 to 7 hours (when HPLC Indicating that the feed is less than 3percent unreacted as the reaction is complete). After the reaction was cooled to room temperature, was added 2.2L of ice water, with 30percent sodium hydroxide solution to PH = 7 ~ 8, and a temperature controlled at 25 . And after completion, stirring was continued for 1 hour, sufficiently precipitate solid particles, was filtered; the cake was washed twice with 1L of water, and dried at 60 ~ 70 , to give a yellowish white powder of 4-chloro-6, 7-dimethoxy-quinoline 1775.9 g, molar yield 74.2percentA reactor was charged sequentially with 6, 7-dimethoxyquinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by [00841 A reactor was charged sequentially with 6, 7—dimethoxy—quinoline—4—oI (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxychloride (POd3, 130.6 kg) was added. After the addition of P0db, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH4OH (251.3 kg), and water (900 L). The resulting mixture was warmed to approximately 20 to 25 °C, and phases were separated. The organic phase was filtered through a bed of AW hyflo super-cel NF (Celite; 5.4 kg), and the filter bed was washed with DCM (118.9 kg). The combined organic phase was washed with brine (282.9 kg) and mixed with water (120 L). The phases were separated, and the organic phase was concentrated by vacuum distillation with the removaL of soLvent (approximately 95 L residual volume). DCM (686.5 kg) was charged to the reactor containing organic phase and concentrated by[00166] A reactor was charged sequentially with 6, 7-dimethoxy-quinoline-4-ol (47.0 kg) and acetonitrile (318.8 kg). The resulting mixture was heated to approximately 60 °C, and phosphorus oxy chloride (POCb, 130.6 kg) was added. After the addition of POCb, the temperature of the reaction mixture was raised to approximately 77 °C. The reaction was deemed complete (approximately 13 hours) when less than 3percent of the starting material remained, as measured by in-process high-performance liquid chromatography [HPLC] analysis. The reaction mixture was cooled to approximately 2 to 7 °C and then quenched into a chilled solution of dichloromethane (DCM, 482.8 kg), 26 percent NH(4) A mixture of 1 (1.0 g, 4.9 mmol) and POCl3 (0.68 mL, 7.3mmol) was heated at 130 °C (bath) for 1 h. The resulting liquid was allowed to cool and was stirred with CH2Cl2 (10 mL) and aqueous NH3 (25percent; 10 mL). The organic layer was washed with H2O (10 mL), dried over MgSO4 and the solvent removed. The residue was dissolved in a mixture of t-BuOMe (5 mL) and CH2Cl2 (2 mL) at 50 °C (bath), and the solution was kept at –30 °C overnight. The resulting crystals were collected and dried (0.65 g, 60percent); mp. 132–133 °C (lit.15, 19 130–131 °C); IR (neat): 1470, 1221, 1139, 1006, 853 cm–1; 1H NMR (300 MHz, CDCl3) δ 4.02 (s, 3H), 4.03 (s, 3H), 7.33 (d, J = 4.9 Hz, 1H), 7.36 (s, 1H), 7.42 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 56.4, 56.5, 101.9, 108.1, 119.8, 122.3, 140.9, 146.1, 147.4, 151.0, 153.4; HRMS (FAB) m/z 224.0434 (calcd 224.0473 for C11H11NO2Cl, [M+H]+).Step 2:

Molecular Weight:223.65
XLogP3:2.8
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:223.0400063
Monoisotopic Mass:223.0400063
Topological Polar Surface Area:31.4
Heavy Atom Count:15
Complexity:215
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes