6-Bromo-1-chloroisoquinoline

Yellow solid

Step 2: N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POClN-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POClN-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POClN-Oxide 6-Bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL) And POCl 3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45 ° C. for 2 hours. After cooling the reaction to RT, DCM and excess POCl 3 were removed under vacuum. The crude was redissolved in 100 ml of DCM and washed with saturated Na 2 CO 3, water and brine. The separated organic layer was dried over Na 2 SO 4 and concentrated to give a brown solid. The crude was purified by flash column using 2percent MeOH in DCM to afford the pale yellow solid 6-bromo-1-chloroisoquinoline (1.27 g, ~65percent yield)General procedure: To a stirred solution of the appropriate azine N-oxides in anhydrous CH[0189] N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POClN-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 ml_), POCI: 1 -(2, 6-dimethylphenyl)-3-[(E)-[3-[4-(trifluoromethoxy)phenyl]imidazo[2, 1 -a]isoquin- olin-8-yl]methyleneamino]thiourea (C-1 ). Step 1 : 6-bromo-1 -chloro-isoquinoline A stirred solution of 6-bromo-2H-isoquinolin-1-one (1.0 g, 4.5 mmol) and POC was heated at at 100°C for 4 h. The reaction mixture was then allowed to cool to r.t.then concentrated to dryness. The crude compound was titrurated with an aqueous solution of NaHCC>3 and the resultant solid was isolated by filtration and dried under vacuum to afford 6-bromo-1-chloro-isoquino- line (1 .05 g), which was used directly in the next step without further purification.LC/MS (method 3): Rt : 3.01 min; MS: m / z = 244.Step 2: N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POCl3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45C for 2 hours. After cooling down the reaction to RT, DCM and excessive POCl3 were removed under the vacuum. The crude was re-dissolved into lOOmL DCM and was washed by saturated Na2C03, water and brine. The separated organic layer was dried over Na2S04, and concentrated to give brown solid. The crude was purified by flash column using 2% MeOH in DCM to get the pale yellow solid 6-bromo-l-chloroisoquinoline (1.27g, yield ~65%), MS m z 242.0 (M + 1).N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POCl3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45C for 2 hours. After cooling down the reaction to RT, DCM and excessive POCl3 were removed under the vacuum. The crude was re- dissolved into 100mL DCM and was washed by saturated Na2CO3, water and brine. The separated organic layer was dried over Na2SO4, and concentrated to give brown solid. The crude was purified by flash column using 2% MeOH in DCM to get the pale yellow solid 6-bromo-1-chloroisoquinoline (1.27g, yield -65%). MS m/z 242.0 (M + 1).N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POCl3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45 C. for 2 hours. After cooling down the reaction to RT, DCM and excessive POCl3 were removed under the vacuum. The crude was re-dissolved into 100 mL DCM and was washed by saturated Na2CO3, water and brine. The separated organic layer was dried over Na2SO4, and concentrated to give brown solid. The crude was purified by flash column using 2% MeOH in DCM to get the pale yellow solid 6-bromo-1-chloroisoquinoline (1.27 g, yield ~65%). MS m/z 242.0 (M+1).N-Oxide 6-Bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL) And POCl 3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45 C. for 2 hours. After cooling the reaction to RT, DCM and excess POCl 3 were removed under vacuum. The crude was redissolved in 100 ml of DCM and washed with saturated Na 2 CO 3, water and brine. The separated organic layer was dried over Na 2 SO 4 and concentrated to give a brown solid. The crude was purified by flash column using 2% MeOH in DCM to afford the pale yellow solid 6-bromo-1-chloroisoquinoline (1.27 g, ~65% yield)General procedure: To a stirred solution of the appropriate azine N-oxides in anhydrous CH2Cl2 (0.1M) at 0 C is added POCl3 (1.2 equiv) followed by dropwise addition of DMF (0.5 equiv) under argon. The resulting reaction mixture was warmed to 25 C and stirred for several hours until the reaction is complete as indicated by TLC. Saturated aqueous sodium carbonate solution is added to the reaction mixture slowly to adjust the pH to 7~8. The resulting mixture is separated and the aqueous phase is extracted with CH2Cl2 thoroughly. The organic phase is combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude product, which is purified by flash column chromatography using PE/EA (80:1) as eluent.53.0 g (236, . mmol) of 6-bromo-isoquinoline 2-oxide (4) were heated in 400 ml of POCI3 under reflux conditions in two portions. After 4 h, the reaction was cooled to room temperature and poured carefully on ice with mechanical stirring. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated, which gave 42.8 g of the title compound, which was used without further purification. Rt = 1.64 min (Method C). Detected mass: 242.1/244.2 (M+H+).6-Bromo-1 -chloro-isoquinoline (5) [0189] N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL), POCl3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45C for 2 hours. After cooling down the reaction to RT, DCM and excessive POCI3 were removed under the vacuum. The crude was re- dissolved into lOOmL DCM and was washed by saturated Na2C03, water and brine. The separated organic layer was dried over Na2S04, and concentrated to give brown solid. The crude was purified by flash column using 2% MeOH in DCM to get the pale yellow solid 6-bromo- 1 -chloroisoquinoline (1.27g, yield -65%). MS m/z 242.0 (M + 1).Step S1 obtained 6-bromo-isoquinoline nitrogen oxide was added portionwise to phosphorus oxychloride in 450ml, was added after the temperature was raised to 70 , the reaction 30min, TLC displayed after completion of the reaction, the reaction mixture was poured all 3kg into crushed ice, the precipitated solid was large, subjected to suction filtration, and washed three times each with at least 500ml of water, after washing, the aqueous phase was extracted 3 times with each direct 2L of ethyl acetate, the ethyl acetate phases, each wash with saturated aqueous sodium carbonate 3L 3 times to wash until neutral, and then washed with 2L of saturated brine once, dried over anhydrous sodium sulfate and then an appropriate amount, to give a crude aqueous phase, the organic phase direct rotary evaporation to give the crude organic phase and the combined aqueous phase and an organic phase the crude product the crude product through a column of 400g silica gel 100-200 mesh, eluent petroleum ether and ethyl acetate mixture selected, wherein the volume ratio of petroleum ether: ethyl acetate = 20: 1 to give the product of step S2 bromo-1-chloro isoquinoline.The N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 mL) and POCI3 (1.12 mL, 1.5 eq) was added dropwise at RT.The reaction was heated to 45 C for 2 hours.After the reaction cooled to RT, DCM and excess POCl3 were removed under vacuum. The crude product was redissolved in 100 mL of DCM and washed with saturated Na2CO3, water and brine. The separated organic layer was dried over Na 2 SO 4 and then concentrated to give a brown solid. Purification by flash column chromatographyThe crude product was purified in 2% methanol in DCM to give a pale yellow solid6-Bromo-1-chloroisoquinoline (1.27 g, yield ~ 65%).N-oxide 6-bromoisoquinoline (1.82 g, 8.12 mmol) was dissolved in dry DCM (80 ml_), POCI3 (1.12 ml, 1.5 eq) was added dropwise at RT. The reaction was heated to 45C for 2 hours. After cooling down the reaction to RT, DCM and excessive POCI3 were removed under the vacuum. The crude was re-dissolved into 100ml_ DCM and was washed by saturated Na2C03, water and brine. The separated organic layer was dried over Na2S04, and concentrated to give brown solid. The crude was purified by flash column using 2% MeOH in DCM to get the pale yellow solid 6-bromo-1-chloroisoquinoline (1.27g, yield ~65%). MS m/z 242.0 (M + 1).A mixture of (2S, 3R)-2-amino-A/, 3-di-tert-butoxy-butanamide (2 g, 8.1 mmol), 6-bromo-1- chloroisoquinoline (1 .97 g, 8.1 mmol) and K2C03 (2.47 g, 17.8 mmol) in DMSO (6 mL) was heated at 100 C for 3 days. The reaction mixture was then allowed to attain room temperature and partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was separated and extracted with brine (5 x 100 mL), dried over Na2S04, concentrated under reduce pressure and purified by column chromatography on silica gel (petroleum ether / ethyl acetate) to provide the desired compound.C. C. : 1 -(2, 6-dimethylphenyl)-3-[(E)-[3-[4-(trifluoromethoxy)phenyl]imidazo[2, 1 -a]isoquin- olin-8-yl]methyleneamino]thiourea (C-1 ). Step 1 : 6-bromo-1 -chloro-isoquinoline A stirred solution of 6-bromo-2H-isoquinolin-1-one (1.0 g, 4.5 mmol) and POC was heated at at 100C for 4 h. The reaction mixture was then allowed to cool to r.t.then concentrated to dryness. The crude compound was titrurated with an aqueous solution of NaHCC>3 and the resultant solid was isolated by filtration and dried under vacuum to afford 6-bromo-1-chloro-isoquino- line (1 .05 g), which was used directly in the next step without further purification.LC/MS (method 3): Rt : 3.01 min; MS: m / z = 244.

Molecular Weight:242.50
XLogP3:3.8
Hydrogen Bond Acceptor Count:1
Exact Mass:240.92939
Monoisotopic Mass:240.92939
Topological Polar Surface Area:12.9
Heavy Atom Count:12
Complexity:165
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes