4-bromo-2-chloroaniline

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: A mixture of 4-bromo-2-chloro-phenylamine (6 g, 29.06 mmol), [CAS 38762-41-3], 1,4-cyclohexanedione monoethyleneketal [CAS 4746-97-8], (6.908 g, 43.59 mmol), and sodium triacetoxy-borohydride (9.239 g, 43.59 mmol) in DCE (100 ml) and acetic acid (0.2 ml) was stirred at r.t. for 2 days. The mixture was then filtered through a pad of diatomaceous earth and washed with DCM. The filtrate was washed with NaHCO3 (aqueous sat. solution), sodium chloride (aqueous sat. solution), dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/AcOEt 4:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D38 (8.57 g, 85%). The mixture was then filtered through a pad of diatomaceous earth washed with DCM The filtrate was washed with NaHCO3 (aqueous sat. solution), sodium chloride (aqueous sat. solution) dried (MgSO4) concentrated in vacuo

Conditions: temp:68.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-chloroaniline (C.A.S. 38762-41-3), (1 g, 4.843 mmol) in AcOH (19 ml) and MeOH (10 mL) was added [(1-ethoxycyclopropyl)oxy]-trimethylsilane (1.199 ml, 5.57 mmol) dropwise at r.t. The reaction mixture was then refluxed at 67-69° C. for 3 h. under a N2 atmosphere. The mixture was then concentrated in vacuo to obtain a crude oil. Into a 200 mL four-necked flask fitted with a reflux condenser, a mechanical stirrer and a thermometer were added NaBH4 (0.366 g, 9.687 mmol) and anhydrous THF (10 mL). After cooling to 5° C., BF3.Et2O complex (1.228 ml, 9.687 mmol) was added dropwise and the mixture stirred under a N2 atmosphere at 5° C. for 1 h. The crude oil dissolved in THF (5 mL), was added dropwise at 5-10° C. over 20 min. After stirring at r.t. for 5 h, at reflux for 2 h. and then removing THF by distillation, the mixture was cooled to r.t. and poured into water. The resulting mixture was extracted with Et2O. The Et2O layer was washed with water and dried (Na2SO4) followed by the removal of Et2O in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; Heptane/AcOEt 99:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D34 (0.390 g, 32.6%). The mixture was then concentrated in vacuo to obtain a crude oil Into a 200 mL four-necked flask fitted with a reflux condenser, a mechanical stirrer After cooling to 5° C. BF3.Et2O complex (1.228 ml, 9.687 mmol) was added dropwise was added dropwise at 5-10° C. over 20 min After stirring at r.t. for 5 h at reflux for 2 h. removing THF by distillation the mixture was cooled to r.t. poured into water The resulting mixture was extracted with Et2O The Et2O layer was washed with water dried (Na2SO4) followed by the removal of Et2O in vacuo

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

Procedure: A mixture of 4-bromo-2-chloro-phenylamine (4 g, 19.37 mmol), tetrahydro-4H-pyran-4-one (2.69 ml, 29.05 mmol), oven-dried molecular sieves 4 Å (2 g) and sodium triacetoxyborohydride (6.12 g, 29.05 mmol) in DCE (100 ml) was stirred at r.t. for 72 h. The mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was then washed with DCM. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried (Na2SO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 5%). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D32 as a brown oil (4.83 g, 86%). The mixture was filtered through a pad of diatomaceous earth The diatomaceous earth pad was then washed with DCM The combined filtrates were washed with NaHCO3 (aqueous saturated solution) dried (Na2SO4) concentrated in vacuo The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 5%) The desired fractions were collected concentrated in vacuo

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

Procedure: A mixture of 4-bromo-2-chloro-phenylamine (4 g, 19.37 mmol), tetrahydro-4H-pyran-4-one (2.69 ml, 29.05 mmol), oven-dried molecular sieves 4 Å (2 g) and sodium triacetoxyborohydride (6.12 g, 29.05 mmol) in DCE (100 ml) was stirred at r.t. for 72 h. The mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was then washed with DCM. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried (Na2SO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 5%). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D32 as a brown oil (4.83 g, 86%). The mixture was filtered through a pad of diatomaceous earth The diatomaceous earth pad was then washed with DCM The combined filtrates were washed with NaHCO3 (aqueous saturated solution) dried (Na2SO4) concentrated in vacuo The crude product thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 5%) The desired fractions were collected concentrated in vacuo

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

Procedure: The title compound is prepared from 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid by the procedure described in step e for Example 5, using 4-bromo-2-chloroaniline instead of 2-fluoro-4-iodoaniline. The title compound is used for the next reaction without further purification.

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

Procedure: LiHMDS (261 mL of a 1 M solution in hexanes) was added dropwise over 30 minutes to a solution of 4-bromo-2-chlorophenylamine (35.0 g, 172 mmol) in THF (80 mL) at −78° C. After 1 hour, 4,6-dichloronicotinic acid (23) (15.7 g, 81.7 mmol) was added dropwise over 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred 16 hours. The reaction mixture was quenched with water, diluted with EtOAc and acidified with 1 N HCl. The resulting precipitate was isolated by filtration and washed with EtOAc. The solids were twice concentrated from toluene, triturated with CH2Cl2 and collected by filtration. The solids were further concentrated from toluene (3×) followed by drying in vacuo to give the desired product (24) containing a small amount of water (36.0 g). The reaction mixture was quenched with water diluted with EtOAc The resulting precipitate was isolated by filtration washed with EtOAc The solids were twice concentrated from toluene triturated with CH2Cl2 collected by filtration The solids were further concentrated from toluene (3×) by drying in vacuo

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

Procedure: LiHMDS (261 mL of a 1 M solution in hexanes) was added dropwise over 30 minutes to a solution of 4-bromo-2-chlorophenylamine (35.0 g, 172 mmol) in THF (80 mL) at −78° C. After 1 hour, 4,6-dichloronicotinic acid (23) (15.7 g, 81.7 mmol) was added dropwise over 30 minutes. The reaction mixture was slowly warmed to room temperature and stirred 16 hours. The reaction mixture was quenched with water, diluted with EtOAc and acidified with 1 N HCl. The resulting precipitate was isolated by filtration and washed with EtOAc. The solids were twice concentrated from toluene, triturated with CH2Cl2 and collected by filtration. The solids were further concentrated from toluene (3×) followed by drying in vacuo to give the desired product (24) containing a small amount of water (36.0 g). The reaction mixture was quenched with water diluted with EtOAc The resulting precipitate was isolated by filtration washed with EtOAc The solids were twice concentrated from toluene triturated with CH2Cl2 collected by filtration The solids were further concentrated from toluene (3×) by drying in vacuo

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-bromo-2-chloro-phenylamine (4.2 g, 20 mmol), in dioxane (80 mL) was added triethylamine (10 mL, 72 mmol). The pale yellow solution was sparged with nitrogen. During the nitrogen sparge, 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.5 mL, 59 mmol) was added dropwise over 10 minutes. After 20 minutes the nitrogen sparge was discontinued and dichloro[1,1′-bis(diphenylphosphino)ferrocene)palladium (II) dichloromethane adduct (603 mg, 0.74 mmol) was added. The reaction was then heated to 100° C. in a temperature controlled heating mantle. After stirring for 20 hours at 100° C., HPLC analysis of the reaction showed clean conversion to a product. The reaction was allowed to cool to ambient temperature and diluted with Et2O (250 mL) and H2O (100 mL). The resulting brown biphasic suspension was filtered to remove some solids that had formed. The layers were separated, and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, then filtered and concentrated under reduced pressure to afford a brown oil, which partially solidified after standing at ambient temperature. This crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane on silica. The product peak was collected to afford 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (2.6 g, 50% yield) as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 7.69 (1H, d, J=1.3 Hz), 7.49 (1H, dd, J=8.1, 1.3 Hz), 6.72 (1H, d, J=8.1 Hz), 4.25 (2H, br s), 1.31 (12H, s). The pale yellow solution was sparged with nitrogen During the nitrogen sparge After 20 minutes the nitrogen sparge controlled heating mantle to cool to ambient temperature The resulting brown biphasic suspension was filtered to remove some solids that had formed The layers were separated the aqueous layer was extracted with Et2O (3×50 mL) The combined organic layers were washed with brine (100 mL) dried over Na2SO4 filtered concentrated under reduced pressure to afford a brown oil, which after standing at ambient temperature This crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 20% ethyl acetate/hexane on silica The product peak was collected

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

Procedure: 3,3-Dimethylbutanoyl chloride (717 mg, 0.74 mL, 5.32 mmol) was added to a solution of 4-Bromo-2-chloro-phenylamine (1.0 g, 4.84 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.04 g, 72% yield). the precipitate formed collected