3-BROMO-5-AZAINDOLE

3-bromo-5-azaindole[00145] Referring now to the Scheme 1 as shown in Fig. 1 , a solution of 3.0128g(25.51 mmol) of 5-azaindole (Atlantic SciTech Group) in 50 ml. of acetonitrile was placed in a 250 ml. three-neck round-bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen bleed, and cooling ice bath. A total of 17.1Og (76.53 mmol, 3 eg.) of solid CuBr2 was added portion-wise to the flask at 17°C in 10 min. The resulting green suspension was stirred at room temperature until no starting material was observed by TLC (approximately 1-2 hours, Rf = 0.23 for 5-azaindole and 0.49 for 3- bromo-5-azaindole in EtOAc/MeOH=9:1 ). The reaction mixture was cooled to 10°C and then was slowly quenched by addition of IN ammonia in methanol solution (1 1OmL). The resulting blue solution was concentrated on rotavap at room temperature, and the residue was extracted with ethyl acetate (3 x 80 ml_). The organic extract was dried over Na5-Azaindole (118 mg, 1.00 mmol) and copper(II) bromide (669 mg, 3.00 mmol) were mixed with MeCN (10 mL) and stirred for 1.5 h. To the mixture was added 2 M ammonia in MeOH (12 mL) and the resulting suspension was added to water (40 mL) and extracted with EtOAc (2 x 60 mL). The organic layers were combined and washed with brine and evaporated to yield the title compound (190 mg, 32percent). MS (ESI+) m/z = 197, 199 (M+H)5-Azaindole (118 mg, 1.00 mmol) and copper(II) bromide (669 mg, 3.00 mmol) were mixed with MeCN (10 mL) and stirred for 1.5 h. General procedure: The title compound of Preparation 20 (95 mg, 0.72 mmol) was dissolved in 7 ml acetonitrile. Copper(II) bromide (482 mg, 2.16 mmol) was added and the mixture was stirred at room temperature for 1 h. Ammonium hydroxide solution (7M in methanol , 5 ml) was added and the mixture was stirred at room temperature for 30 min. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 147 mg (0.70 mmol, 97%) of the title compound as an oil. Purity 90%. [0292] 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 8.61 (br. s., 1 H), 7.59 (d, J=8.51 Hz, 1 H), 7.45 (d, J=2.75 Hz, 1 H), 7.06 (d, J=8.51 Hz, 1 H), 2.71 (s, 3H). [0293] UPLC/MS (3 min) retention time 0.55 min. [0294] LRMS: m/z 211, 213 (M+1).General procedure: PREPARATION 21 3-Bromo-5-methyl-1 H-pyrrolo[3, 2-fe]pyridine The title compound of Preparation 20 (95 mg, 0.72 mmol) was dissolved in 7 ml acetonitrile. Copper(ll) bromide (482 mg, 2.16 mmol) was added and the mixture was stirred at room temperature for 1 h. Ammonium hydroxide solution (7M in methanol , 5 ml) was added and the mixture was stirred at room temperature for 30 min. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 147 mg (0.70 mmol, 97%) of the title compound as an oil. Purity 90%. 1 H N MR (300 MHz, CHLOROFORM-d) delta ppm 8.61 (br. s., 1 H), 7.59 (d, J=8.51 Hz, 1 H), 7.45 (d, J=2.75 Hz, 1 H), 7.06 (d, J=8.51 Hz, 1 H), 2.71 (s, 3 H). UPLC/MS (3 min) retention time 0.55 min. LRMS: m/z 21 1 , 213 (M+1 ).N-BOC-To a mixture of Intermediate 1 (1.80 g, 9.14 mmol) in DCM (60 mL) was added di-tert- butyl dicarbonate (2.18 g, 10.0 mmol) followed by 4-dimethylaminopyridine (122 mg, 1.00 mmol). After 80 min the solution was diluted with DCM (20 mL) and washed with 0.1 M HC1 (25, 10 mL) and brine. The organic layer was dried (Na2S04), filtered and evaporated to yield the title compound as a light yellow solid (2.47 g, 90%). MS (ESI+) m/z = 299 (M+H)+.To a mixture of Intermediate 1 (1.80 g, 9.14 mmol) in DCM (60 mL) was added di-tert-butyl dicarbonate (2.18 g, 10.0 mmol) followed by 4-dimethylaminopyridine (122 mg, 1.00 mmol). After 80 min the solution was diluted with DCM (20 mL) and washed with 0.1 M HCl (25, 10 mL) and brine. The organic layer was dried (Na2SO4), filtered and evaporated to yield the title compound as a light yellow solid (2.47 g, 90%). MS (ESI+) m/z=299 (M+H)+.5-Azaindole (118 mg, 1.00 mmol) and copper(II) bromide (669 mg, 3.00 mmol) were mixed with MeCN (10 mL) and stirred for 1.5 h. To the mixture was added 2 M ammonia in MeOH (12 mL) and the resulting suspension was added to water (40 mL) and extracted with EtOAc (2 x 60 mL). The organic layers were combined and washed with brine and evaporated to yield the title compound (190 mg, 32%). MS (ESI+) m/z = 197, 199 (M+H)+.5-Azaindole (118 mg, 1.00 mmol) and copper(II) bromide (669 mg, 3.00 mmol) were mixed with MeCN (10 mL) and stirred for 1.5 h. To the mixture was added 2 M ammonia in MeOH (12 mL) and the resulting suspension was added to water (40 mL) and extracted with EtOAc (2*60 mL). The organic layers were combined and washed with brine and evaporated to yield the title compound (190 mg, 32%). MS (ESI+) m/z=197, 199 (M+H)+.Example 164l-{[(3S)-l-(Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2-[4-(lH-pyrrolo[3, 2- c] pyridin-3-yl)phenyl] -5-(trifluor omethyl)- lH-benzimidazole1 - { [(3 S)- 1 -(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl} -2-[4-(4, 4, 5 , 5-tetramethyl- 1 , 3 , 2- dioxaborolan-2-yl)phenyl]-5-(trifluoromethyl)-lH-benzimidazole (120 mg, 0.167 mmol) was dissolved in 1, 4-dioxane (1.5 mL) in a 5 mL microwave vial. To this was added 3- bromo-lH-pyrrolo[3, 2-c]pyridine (32.9 mg, 0.167 mmol), PdCl2(dppf)-CH2Cl2 adduct (6.81 mg, 8.34 muiotaetaomicron), and 2.0 M aqueous potassium carbonate (0.250 mL, 0.501 mmol) with stirring. The vial was purged with nitrogen, sealed and heated at 100 C for six hours. An additional aliquot of PdCl2(dppf)-CH2Cl2 adduct (6.81 mg, 8.34 muetaiotaomicron) was added and the reaction was allowed to stir at 100 C for two days. Additional aliquots of 3-bromo-lH- pyrrolo[3, 2-c]pyridine (11 mg) and PdCl2(dppf)-CH2Cl2 adduct (6.81 mg, 8.34 muiotaetaomicron) were added and the reaction was allowed to stir overnight at 100 C. The reaction mixture was allowed to cool and the pH was adjusted to 7 with 1 N HCl. The reaction mixture was extracted with DCM (3 x 50 mL) and the combined extracts were dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by silica gel column chromatography using a gradient of 1-10% MeOH/DCM, followed by preparative reverse phase HPLC using a gradient of 1% NH4OH(aq)/acetonitrile. The appropriate fractions were combined and evaporated to dryness to afford 9 mg of the titled compound as an off- white solid. (LCMS m/z 529.9, M+H).

Molecular Weight:197.03
XLogP3:1.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:195.96361
Monoisotopic Mass:195.96361
Topological Polar Surface Area:28.7
Heavy Atom Count:10
Complexity:129
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes