2-Amino-5-bromobenzaldehyde

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

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

Procedure: In a manner similar to that described previously (Example 1), 2-amino-5-bromobenzaldehyde was sequentially reacted with 7-(4-fluorophenyl)-7-oxoheptanoic acid and TFAA-tBuOH. The resulting ester 5B was converted to 5C (Pd(OAc)2, dcpp-2(HBF)4, K2CO3, 5 atm CO, H2O-DMF, 100° C. overnight), coupled with (R)-1-(4-chlorophenyl)ethanamine (HATU, DIPEA) and deprotected with TFA to provide the title compound, 6-[[[1(R)-(4-chlorophenyl)ethyl]amino]carbonyl]-2-(4-fluorophenyl)-3-quinolinepentanoic acid, 5. LCMS (M+H)=505.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7-Oxo-7-phenylheptanoic acid (5.00 g, 22.7 mmol) and 2-amino-5-bromobenzaldehyde (5.45 g, 27.2 mmol) were dissolved in a solution of methanol (100 mL) and 2 M NaOH (30 mL). The reaction mixture was heated to 110° C. in an oil bath and refluxed overnight. The reaction was concentrated, acidified with 10% aq. HCl to pH 1 and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 8.97 g, LCMS (M+H)=384). refluxed overnight The reaction was concentrated diluted with DCM The biphasic solution was separated the aqueous layer was extracted with DCM (3×) The combined organic phase was dried over anhydrous sodium sulfate concentrated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7-Oxo-7-phenylheptanoic acid (5.00 g, 22.7 mmol) and 2-amino-5-bromobenzaldehyde (5.45 g, 27.2 mmol) were dissolved in a solution of methanol (100 mL) and 2 M NaOH (30 mL). The reaction mixture was heated to 110° C. in an oil bath and refluxed overnight. The reaction was concentrated, acidified with 10% aq. HCl to pH 1 and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 8.97 g, LCMS (M+H)=384). refluxed overnight The reaction was concentrated diluted with DCM The biphasic solution was separated the aqueous layer was extracted with DCM (3×) The combined organic phase was dried over anhydrous sodium sulfate concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To acetic acid anhydride (34.8 ml) was added formic acid (17.0 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (200 ml). In THF (100 ml) was dissolved 2-amino-5-bromobenzaldehyde (16.40 g), and the mixture was added dropwise to the previously prepared solution of formic acid anhydride in THF at 0° C. The mixture was stirred at 0° C. for 2 hours, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and filtered to give 4-bromo-2-formylphenylformamide (15.24 g, 82%). cooled The mixture was stirred at 0° C. for 2 hours the solvent was evaporated under reduced pressure The residue was washed with hexane filtered

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To acetic acid anhydride (34.8 ml) was added formic acid (17.0 ml) at 0° C., and the mixture was stirred at 60° C. for 2 hours, cooled and diluted with THF (200 ml). In THF (100 ml) was dissolved 2-amino-5-bromobenzaldehyde (16.40 g), and the mixture was added dropwise to the previously prepared solution of formic acid anhydride in THF at 0° C. The mixture was stirred at 0° C. for 2 hours, and the solvent was evaporated under reduced pressure. The residue was washed with hexane and filtered to give 4-bromo-2-formylphenylformamide (15.24 g, 82%). cooled The mixture was stirred at 0° C. for 2 hours the solvent was evaporated under reduced pressure The residue was washed with hexane filtered

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

Procedure: To acetone (300 ml) were added (2-amino-5-bromophenyl)methanol (23.32 g) and active manganese dioxide (58.5 g), and the mixture was stirred at room temperature for 17.5 hours and filtered. The solvent was evaporated under reduced pressure to give 2-amino-5-bromobenzaldehyde (16.41 g, 71%). filtered The solvent was evaporated under reduced pressure

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

Procedure: To a vial charged with 2-amino-5-bromobenzaldehyde (commercially available from Matrix Scientific, Columbia, S.C.) (0.500 g, 2.500 mmol) were added THF (4.17 mL), toluene (4.17 mL), TEA (0.871 mL, 6.25 mmol) and phthalic anhydride (0.849 mL, 8.75 mmol). The mixture was heated at 100° C. overnight. LC-MS indicated that the product was present as a component of a complex mixture. The resulting mixture was passed through a 10 g SCX-2 column with much solid sticking to the top of the column and some product eluting through indicating a solubility issue in MeOH. The solid and filtrate were dissolved in DCM:MeOH and the crude residue was adsorbed onto silica gel with drying under reduced pressure. The adsorbed material was purified with a 50 g SNAP column ramping EtOAc in heptane from 0-45%, then isocratic at 45% to elute 5-bromo-2-(1,3-dioxoisoindolin-2-yl)benzaldehyde (0.290 g, 0.878 mmol, 35.1% yield) as a yellow solid. m/z (ESI) 330.0/332.0 (M+H)+. some product eluting The solid and filtrate were dissolved in DCM with drying under reduced pressure The adsorbed material was purified with a 50 g SNAP column

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-5-bromobenzaldehyde (29) (6 g, 30.0 mmol) and urea (30) (27 g, 450.0 mmol) was heated to 180° C. and stirred for 5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, and the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. 6-bromoquinazolin-2-ol (31)(6 g, 89%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 224. found: 225, 227 [M+H]+. The reaction mixture was cooled to room temperature the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-5-bromobenzaldehyde (29) (6 g, 30.0 mmol) and urea (30) (27 g, 450.0 mmol) was heated to 180° C. and stirred for 5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, and the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. 6-bromoquinazolin-2-ol (31)(6 g, 89%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 224. found: 225, 227 [M+H]+. The reaction mixture was cooled to room temperature the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture

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

Procedure: A mixture of (2-amino-5-bromophenyl)methanol (10 g, 49.5 mmol) and MnO2 (25.8 g, 296.6 mmol) in CH2Cl2 (400 mL) was stirred at RT overnight. LCMS showed the reaction was completed. The solid was filtered off, and the filtrate was concentrated to give the title compound as a light yellow solid (8 g, 81%), which was directly used in next step without further purification. MS (ES+) C7H6BrNO requires: 199. found: 200, 202 [M+H]+. The solid was filtered off the filtrate was concentrated

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-amino-5-bromobenzaldehyde (29) (6 g, 30.0 mmol) and urea (30) (27 g, 450.0 mmol) was heated to 180° C. and stirred for 5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, and the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. 6-bromoquinazolin-2-ol (31)(6 g, 89%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 224. found: 225, 227 [M+H]+. The reaction mixture was cooled to room temperature the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture