2-bromo-4-chloroaniline

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

Procedure: Heat a mixture of 2-bromo-4-chloro-phenylamine (8.24 g, 40 mmol), 3-nitrophenylboronic acid (10.0 g, 60 mmol), Pd(PPh3)4 (2.8 g) and Na2CO3 (17.0 g) in toluene (200.0 mL), EtOH (30.0 mL) and water (80.0 mL) to 80° C. (oil bath) with stirring overnight. Cool to room temperature, dilute the mixture with EtOAc, filter and concentrate. Dissolve the residue in EtOAc, wash with brine and dry over Na2SO4. Chromatograph the crude material on silica (gradient 25% EtOAc in hexane) to give 5.27 g of the desired product as a yellowish crystal. Heat filter concentrate Dissolve the residue in EtOAc wash with brine dry over Na2SO4

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

Procedure: Heat a mixture of 2-bromo-4-chloro-phenylamine (8.24 g, 40 mmol), 3-nitrophenylboronic acid (10.0 g, 60 mmol), Pd(PPh3)4 (2.8 g) and Na2CO3 (17.0 g) in toluene (200.0 mL), EtOH (30.0 mL) and water (80.0 mL) to 80° C. (oil bath) with stirring overnight. Cool to room temperature, dilute the mixture with EtOAc, filter and concentrate. Dissolve the residue in EtOAc, wash with brine and dry over Na2SO4. Chromatograph the crude material on silica (gradient 25% EtOAc in hexane) to give 5.27 g of the desired product as a yellowish crystal. Heat filter concentrate Dissolve the residue in EtOAc wash with brine dry over Na2SO4

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

Procedure: A solution of 2-bromo-4-chloroaniline (10.0 g, 48.4 mmol) and HBF4 in EtOH (60 mL) kept at 0° C. was treated with an aqueous solution (20 mL) of NaNO2 (3.34g, 48.4 mmol). After completion of the addition, diethyl ether (200 mL) was added to the mixture. The solid was collected by filtration, washed with water and dried under high vacuum affording the title compound (14.2 g, 96%) as white crystals. kept at 0° C. was added to the mixture The solid was collected by filtration washed with water dried under high vacuum

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

Procedure: A mixture of 0.25 g (1.10 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.27 g (1.3 mmol) of 2-bromo-4-chloroaniline, and 0.13 g (1.12 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol(97:3 to 90:10) to yield 0.10 g of 8-(2-bromo-4-chlorophenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as an yellow solid, mp 244-246° C. (shrinks at 200° C.). is heated at reflux temperature for 1 hour The solid is collected by filtration washed with water dried The solid is purified by silica gel chromatography

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

Procedure: A mixture of 0.25 g (1.10 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.27 g (1.3 mmol) of 2-bromo-4-chloroaniline, and 0.13 g (1.12 mmol) of pyridine hydrochloride in 7.0 mL of 2-ethoxyethanol is heated at reflux temperature for 1 hour, cooled to room temperature, poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography utilizing a gradient of methylene chloride/methanol(97:3 to 90:10) to yield 0.10 g of 8-(2-bromo-4-chlorophenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as an yellow solid, mp 244-246° C. (shrinks at 200° C.). is heated at reflux temperature for 1 hour The solid is collected by filtration washed with water dried The solid is purified by silica gel chromatography

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

Procedure: To a stirring solution of triphosgene (2.7 g, 9.0 mmol) in dichloromethane (100 mL) was added, dropwise via an addition funnel, a solution of 2-bromo-4-chloroaniline (5 g, 24.2 mmol) and N,N-diisopropylethylamine (6.9 g, 53.2 mmol) in dichloromethane (50 mL). After complete addition and an additional hour, a solution of N-Boc-piperazine (5 g, 26.6 mmol) in dichloromethane (50 mL) was added. After stirring overnight, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was separated and washed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate and finally with brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then dissolved in a minimal amount of chloroform and chromatographed over silica gel, eluting with 20% ethyl acetate in hexanes followed by 30% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo and the resulting solid was suspended in diethyl ether, sonicated and then filtered and dried in vacuo to give 7.2 g (71%) of a white powder. After complete addition the solvent was removed in vacuo the residue was partitioned between ethyl acetate and water The organic phase was separated washed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate and finally with brine dried with MgSO4 filtered concentrated in vacuo The residue was then dissolved in a minimal amount of chloroform chromatographed over silica gel eluting with 20% ethyl acetate in hexanes The product containing fractions concentrated in vacuo sonicated filtered dried in vacuo

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

Procedure: Made from 2-bromo-4-chloroaniline using the method for 7-bromo-5-(trifluoromethyl)-1H-indole. 1H-NMR (CDCl3, 400 MHz) δ 8.32 (bs, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.27 (t, J=3.0 Hz, 1H), 6.56 (dd, J=3.3, 2.3 Hz, 1H). LC/MS (HPLC method 4): tR=3.07 min, 229.95(MH)+.

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

Procedure: Made from 2-bromo-4-chloroaniline using the method for 7-bromo-5-(trifluoromethyl)-1H-indole. 1H-NMR (CDCl3, 400 MHz) δ 8.32 (bs, 1H), 7.55 (d, J=1.2 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.27 (t, J=3.0 Hz, 1H), 6.56 (dd, J=3.3, 2.3 Hz, 1H). LC/MS (HPLC method 4): tR=3.07 min, 229.95(MH)+.

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

Procedure: The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.

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

Procedure: The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.

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

Procedure: The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-bromo-4-chloroaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.

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

Procedure: Heat a mixture of 2-bromo-4-chloro-phenylamine (8.24 g, 40 mmol), 3-nitrophenylboronic acid (10.0 g, 60 mmol), Pd(PPh3)4 (2.8 g) and Na2CO3 (17.0 g) in toluene (200.0 mL), EtOH (30.0 mL) and water (80.0 mL) to 80° C. (oil bath) with stirring overnight. Cool to room temperature, dilute the mixture with EtOAc, filter and concentrate. Dissolve the residue in EtOAc, wash with brine and dry over Na2SO4. Chromatograph the crude material on silica (gradient 25% EtOAc in hexane) to give 5.27 g of the desired product as a yellowish crystal. Heat filter concentrate Dissolve the residue in EtOAc wash with brine dry over Na2SO4