2-chloro-6-fluoroaniline

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 20 g. of 2-chloro-6-fluorobenzoic acid, 100 ml. of chloroform and 50 ml. of concentrated sulfuric acid is added slowly 10.2 g. of sodium azide while the temperature is kept at 40°-55°. Stirring is continued for 2 hours at 40°-55° then the mixture is poured into 500 ml. of ice water containing 80 g. of sodium hydroxide. The mixture is extracted with ether and the other extracts are dried over magnesium sulfate. The dry extracts are then treated with hydrogen chloride, and the resultant product as the hydrochloride salt is collected by filtration yielding 12.6 g. of white solid which sublimes at 160°-170°. To a stirred mixture of 20 g is kept at 40°-55° the mixture is poured into 500 ml The mixture is extracted with ether the other extracts are dried over magnesium sulfate The dry extracts are then treated with hydrogen chloride the resultant product as the hydrochloride salt is collected by filtration yielding 12.6 g sublimes at 160°-170°

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2-chloro-6-fluoroaniline (0.183 g, 1.259 mmol) and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added LHMDS (1.0 M solution in THF; 1.259 ml, 1.259 mmol). The reaction was sealed and stirred 1 h at RT, then for 3 h at 70° C. The reaction was subsequently cooled to RT and stirred overnight. 1.5 mL DMSO and 10 drops TFA were added. The mixture was filtered and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA). The product-containing fractions were concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×), and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The material was dissolved in DCM/MeOH, adsorbed onto 0.75 g silica gel, and purified by silica gel chromatography using 0-50% 90/10 MeOH/DCM in DCM. The product-containing fractions were concentrated to separately afford 2-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.022 g, 0.054 mmol, 21% yield) as a light-yellow solid and 2-(2-((2-chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.0037 g, 9.14 μmol, 4% yield) as a yellow solid. 2-(2-((2-Chloro-6-fluorophenyl)amino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (7): 1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (1H, br. s), 9.34 (1H, s), 8.16 (1H, d, J=9.0 Hz), 8.01 (1H, dd, J=7.6, 1.6 Hz), 7.55-7.67 (2H, m), 7.41-7.54 (2H, m), 7.28 (1H, t, J=7.7 Hz), 7.13 (1H, d, J=9.0 Hz), 6.83-6.98 (2H, m), 3.32-3.44 (2H, m), 2.43 (2H, t, J=6.8 Hz). m/z (ESI, +ve) 406.9 (M+H)+. 2-(2-((2-Chloro-6-fluorophenyl)amino)quinolin-8-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (12): 1H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (1H, br. s), 10.68 (1H, d, J=6.1 Hz), 9.41 (1H, s), 8.11-8.26 (2H, m), 7.43-7.76 (4H, m), 7.34 (1H, t, J=7.7 Hz), 7.18-7.25 (1H, m), 7.14 (1H, d, J=9.0 Hz), 6.86-7.00 (1H, m), 5.91 (1H, d, J=6.8 Hz). m/z (ESI, +ve) 405.2 (M+H)+. The reaction was sealed for 3 h at 70° C The reaction was subsequently cooled to RT stirred overnight The mixture was filtered purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 10-80% ACN/H2O with 0.1% TFA) The product-containing fractions were concentrated in vacuo the residue was partitioned between saturated aq. NaHCO3 and DCM The aq. layer was extracted with DCM (3×) the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo The material was dissolved in DCM/MeOH purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-chloro-6-fluoroaniline (82 mg, 0.56 mmol) to provide 207 (101 mg, 69% yield) as a white solid. LC-MS (M+H=340, obsd.=340). The title compound was synthesized

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 2-chloro-6-fluoroaniline (82 mg, 0.56 mmol) to provide 207 (101 mg, 69% yield) as a white solid. LC-MS (M+H=340, obsd.=340). The title compound was synthesized

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluoroaniline (0.48 g) and 2-chlorobenzimidazole (0.5 g) were mixed in a flask and then kept at 170° C. for 30 min. After cooling, the residue was dissolved out of the flask at boiling heat using 1 N HCl and 10% ethanol. The material dissolved out was then stirred at RT for 30 min, then the insoluble material was filtered off with suction and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was adjusted to pH 10 with potassium carbonate solution, extracted three times with EA, and then the combined phases were dried, filtered, and concentrated. The residue was taken up using HCl/water and freeze-dried. 27 mg of the title compound were obtained. After cooling the residue was dissolved out of the flask at boiling heat The material dissolved out the insoluble material was filtered off with suction the filtrate was evaporated The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA) extracted three times with EA the combined phases were dried filtered concentrated freeze-dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-6-fluoroaniline (0.48 g) and 2-chlorobenzimidazole (0.5 g) were mixed in a flask and then kept at 170° C. for 30 min. After cooling, the residue was dissolved out of the flask at boiling heat using 1 N HCl and 10% ethanol. The material dissolved out was then stirred at RT for 30 min, then the insoluble material was filtered off with suction and the filtrate was evaporated. The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA). The clean fractions were combined, the acetonitrile was stripped off, the residue was adjusted to pH 10 with potassium carbonate solution, extracted three times with EA, and then the combined phases were dried, filtered, and concentrated. The residue was taken up using HCl/water and freeze-dried. 27 mg of the title compound were obtained. After cooling the residue was dissolved out of the flask at boiling heat The material dissolved out the insoluble material was filtered off with suction the filtrate was evaporated The residue was purified by means of preparative HPLC on RP-18 using acetonitrile/water (0.05% TFA) extracted three times with EA the combined phases were dried filtered concentrated freeze-dried

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-6-fluoroaniline (4.00 g, 27.5 mmol), 4-bromotoluene (4.70 g, 27.5 mmol), sodium tert-butylate (4.75 g, 49.4 mmol), and toluene (55 mL) is stirred at 25° C. under nitrogen for 30 minutes. To this mixture, a solution of palladium-bis-(dibenzylidenacetone) (15.8 mg, 55 mmol) and tri-tert-butylphosphine (1) (8.3 mg, 0.04 mmol) in toluene (5 mL) is added and the resulting suspension is stirred at 110° C. for 14 hours. The mixture is then cooled to 30° C. Water (30 ml), concentrated hydrochloric acid (10 ml), charcoal and cellite (1 g each) are added and stirring is continued for 1 hour. The mixture is filtered and the filtrate is separated into its phases. The organic phase is washed three times with water (10 mL) and concentrated in vacuo to give 6.5 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used directly in the next step (Step 1.2). Alternatively, it can be distilled in vacuo by Kugelrohr. the resulting suspension is stirred at 110° C. for 14 hours The mixture is then cooled to 30° C stirring is continued for 1 hour The mixture is filtered the filtrate is separated into its phases The organic phase is washed three times with water (10 mL) concentrated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-chloro-6-fluoroaniline (4.00 g, 27.5 mmol), 4-bromotoluene (4.70 g, 27.5 mmol), sodium tert-butylate (4.75 g, 49.4 mmol), and toluene (55 mL) is stirred at 25° C. under nitrogen for 30 minutes. To this mixture, a solution of palladium-bis-(dibenzylidenacetone) (15.8 mg, 55 mmol) and tri-tert-butylphosphine (1) (8.3 mg, 0.04 mmol) in toluene (5 mL) is added and the resulting suspension is stirred at 110° C. for 14 hours. The mixture is then cooled to 30° C. Water (30 ml), concentrated hydrochloric acid (10 ml), charcoal and cellite (1 g each) are added and stirring is continued for 1 hour. The mixture is filtered and the filtrate is separated into its phases. The organic phase is washed three times with water (10 mL) and concentrated in vacuo to give 6.5 g of crude (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The product can be used directly in the next step (Step 1.2). Alternatively, it can be distilled in vacuo by Kugelrohr. the resulting suspension is stirred at 110° C. for 14 hours The mixture is then cooled to 30° C stirring is continued for 1 hour The mixture is filtered the filtrate is separated into its phases The organic phase is washed three times with water (10 mL) concentrated in vacuo