5-BroMo-1-Methyl-7-azaind...

To a solution of 5-bromo-1H-pyrrolo[2, 3-bjpyndine (1.5 g, 7.6 mmol) in DMF (10 mL) was addedNaH (365 mg, 9.1 mmol) at 0 °C. The mixture was stirred at rt for 1.5 hrs. Mel (1.4 g, 9.8 mmol) was added and stirred at rt overnight. The reaction was quenched with sat. NH4C1 solution (10 mL) and separated between water (20 mL) and EA (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4. The solvent was removed to give 5-bromo-1-methyl-1H-pyrrolo[2, 3- bjpyndine (1.7 g, yield: quantitative) as pale yellow crystal. ‘HNMR (300 MHz, CDC13): = 8.34 (d, J= 2.1 Hz, 1H), 8.01 (d, J 2.4 Hz, 1H), 7.18 (d, J= 3.6 Hz, 1H), 6.39 (d, J= 3.3 Hz, 1H), 3.86 (s, 3H).Step 1 5-bromo-1-methyl-1H-pyrrolo[2, 3-b]pyridine (Compound 1-2) (0150) At 0° C., a solution of compound 5-bromo-1H-pyrrolo[2, 3-b]pyridine (5 g, 25.4 mmol, commercially available) in DMF was added to a solution of sodium hydride (4.32 g, 30.5 mmol) in 40 ml of DMF, and vigorously stirred at 0° C. for 0.5 h, and then methyl iodide (1.22 g, 30.5 mmol) was added, and stirred vigorously at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was poured into ice water. After the solids were completely precipitated, the solids were filtered and dissolved in dichloromethane and methanol (10:1), washed with water three times, and dried. The organic layer was separated, and concentrated under reduced pressure to give compound 1-2 (5.4 g, 99percent). The product was used directly in the next step. MS m/z (ESI): 211.0 [M+H]+.To a solution of 5-bromo-1H-pyrrolo[2, 3-b]pyridine (96percent pure, 3.88 g, 14.6 mmol) in dimethylacetamide (70 mL) was carefully added sodium hydride (60percent suspension in oil, 0.76 g, 19.0 mmol). The mixture was stirred at rt for 30 min and methyl iodide (3.14 g, 22.1 mmol) was slowly added as a solution in dimethylacetamide (10 mL). After additional 4 h water (150 mL) was added and the resulting mixture was extracted with DCM (3 × 100 mL). The combined organic phases were washed with water, dried over MgSO4, and evaporated. Column chromatographic purification (SiO2, CH/EtOAc, 1:1) yielded a colorless solid [3.88 g, 97percent yield].Mp: 59 – 60 °C (CH/EtOAc).1H-NMR (300 MHz, CDCl3): δ = 3.86 (s, 3H, 11-CH3), 6.39 (d, 3JH, H = 3.5 Hz, 1H, 3-CH), 7.18 (d, 3JH, H = 3.5 Hz, 1H, 2-CH), 8.01 (d, 4JH, H = 2.1 Hz, 1H, 4-CH), 8.34 (d, 4JH, H = 2.1 Hz, 1H, 6-CH) ppm.13C-NMR (75 MHz, CDCl3): δ = 31.6 (q, C-11), 99.1 (d, C-3), 111.7 (s, C-5), 122.2 (s, C-9), 130.7 (d, C-2), 130.9 (d, C-4), 143.5 (d, C-6), 146.4 (s, C-8) ppm.ESI(+)-MS: calcd. for C8H7BrN2 + H+, 210.9865/212.9845; found 210.9866/212.9906.General procedure: To a cold solution of appropriate pyrrolo-pyridines 8a, c, e (2.5 mmol) in anhydrous toluene (25 mL), t-BuOK (0.38 g, 3.4 mmol) and TDA-1 (1 or 2 drops) were added at 0 °C. The reaction mixture was stirred at room temperature for 3 h and then MeI (2.5 mmol, 0.2 mL) was added at 0 °C. TLC analysis (ethyl acetate) revealed that methylation was complete after 1 h. The solvent was evaporated under reduced pressure. The residue was treated with water, extracted with DCM (3 × 20 mL), dried (Na[00357] Intermediate 23a: 5-bromo-1 -methyl-pyrrolo[2, 3-b]pyridine[00358] 5-Bromo-1H-pyrrolo[2, 3-b]pyridin (2.OOg, 10.l5mmol) and NaH (609mg, 15.23mmol) werestirred under N2 in DMF (4OmL) for 1 hour at room temperature. lodomethane (0.95mL, 15.23mmol)was added and left to stir for 4 hours. The reaction was quenched with 1 M NaOH (2OmL), then extracted with EtOAc (4 x 25mL), washed with brine (4 x 25mL) and dried over Na2SO4. The compound was purified via column chromatography using an eluent of 0-75percent EtOAc in petroleum etherto yield 5-bromo-1-methyl-pyrrolo[2, 3-b]pyridine (1 .00mg, 4.76mmol, 47percent yield) as a yellowsolid.1H NMR (CDCI3, 400MHz) O/ppm: 8.36 (1H, d, J= 2.0Hz), 8.03 (1H, d, J= 2.0Hz), 7.21 (1H, d, J=3.6Hz), 6.41 (1H, d, J= 3.6Hz), 3.89 (3H, 5).MS Method 2: RT: 1.65 mi m/z210.9 [M+H], 212.9 [M+H]To a solution of 5-bromo-1H-pyrrolo[2, 3-bjpyndine (1.5 g, 7.6 mmol) in DMF (10 mL) was addedNaH (365 mg, 9.1 mmol) at 0 C. The mixture was stirred at rt for 1.5 hrs. Mel (1.4 g, 9.8 mmol) was added and stirred at rt overnight. The reaction was quenched with sat. NH4C1 solution (10 mL) and separated between water (20 mL) and EA (20 mL). The organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4. The solvent was removed to give 5-bromo-1-methyl-1H-pyrrolo[2, 3- bjpyndine (1.7 g, yield: quantitative) as pale yellow crystal. 'HNMR (300 MHz, CDC13): = 8.34 (d, J= 2.1 Hz, 1H), 8.01 (d, J 2.4 Hz, 1H), 7.18 (d, J= 3.6 Hz, 1H), 6.39 (d, J= 3.3 Hz, 1H), 3.86 (s, 3H).Step 1 5-bromo-1-methyl-1H-pyrrolo[2, 3-b]pyridine (Compound 1-2) (0150) At 0 C., a solution of compound 5-bromo-1H-pyrrolo[2, 3-b]pyridine (5 g, 25.4 mmol, commercially available) in DMF was added to a solution of sodium hydride (4.32 g, 30.5 mmol) in 40 ml of DMF, and vigorously stirred at 0 C. for 0.5 h, and then methyl iodide (1.22 g, 30.5 mmol) was added, and stirred vigorously at room temperature for 3 h. The reaction progress was monitored by TLC. After completion of the reaction, the reaction solution was poured into ice water. After the solids were completely precipitated, the solids were filtered and dissolved in dichloromethane and methanol (10:1), washed with water three times, and dried. The organic layer was separated, and concentrated under reduced pressure to give compound 1-2 (5.4 g, 99%). The product was used directly in the next step. MS m/z (ESI): 211.0 [M+H]+.To a solution of 5-bromo-1H-pyrrolo[2, 3-b]pyridine (96% pure, 3.88 g, 14.6 mmol) in dimethylacetamide (70 mL) was carefully added sodium hydride (60% suspension in oil, 0.76 g, 19.0 mmol). The mixture was stirred at rt for 30 min and methyl iodide (3.14 g, 22.1 mmol) was slowly added as a solution in dimethylacetamide (10 mL). After additional 4 h water (150 mL) was added and the resulting mixture was extracted with DCM (3 × 100 mL). The combined organic phases were washed with water, dried over MgSO4, and evaporated. Column chromatographic purification (SiO2, CH/EtOAc, 1:1) yielded a colorless solid [3.88 g, 97% yield].Mp: 59 - 60 C (CH/EtOAc).1H-NMR (300 MHz, CDCl3): delta = 3.86 (s, 3H, 11-CH3), 6.39 (d, 3JH, H = 3.5 Hz, 1H, 3-CH), 7.18 (d, 3JH, H = 3.5 Hz, 1H, 2-CH), 8.01 (d, 4JH, H = 2.1 Hz, 1H, 4-CH), 8.34 (d, 4JH, H = 2.1 Hz, 1H, 6-CH) ppm.13C-NMR (75 MHz, CDCl3): delta = 31.6 (q, C-11), 99.1 (d, C-3), 111.7 (s, C-5), 122.2 (s, C-9), 130.7 (d, C-2), 130.9 (d, C-4), 143.5 (d, C-6), 146.4 (s, C-8) ppm.ESI(+)-MS: calcd. for C8H7BrN2 + H+, 210.9865/212.9845; found 210.9866/212.9906.General procedure: To a cold solution of appropriate pyrrolo-pyridines 8a, c, e (2.5 mmol) in anhydrous toluene (25 mL), t-BuOK (0.38 g, 3.4 mmol) and TDA-1 (1 or 2 drops) were added at 0 C. The reaction mixture was stirred at room temperature for 3 h and then MeI (2.5 mmol, 0.2 mL) was added at 0 C. TLC analysis (ethyl acetate) revealed that methylation was complete after 1 h. The solvent was evaporated under reduced pressure. The residue was treated with water, extracted with DCM (3 × 20 mL), dried (Na2SO4), evaporated and purified by column chromatography using DCM/ethyl acetate (9/1) as eluent to give derivatives 8b, d, f [42].[00357] Intermediate 23a: 5-bromo-1 -methyl-pyrrolo[2, 3-b]pyridine[00358] 5-Bromo-1H-pyrrolo[2, 3-b]pyridin (2.OOg, 10.l5mmol) and NaH (609mg, 15.23mmol) werestirred under N2 in DMF (4OmL) for 1 hour at room temperature. lodomethane (0.95mL, 15.23mmol)was added and left to stir for 4 hours. The reaction was quenched with 1 M NaOH (2OmL), then extracted with EtOAc (4 x 25mL), washed with brine (4 x 25mL) and dried over Na2SO4. The compound was purified via column chromatography using an eluent of 0-75% EtOAc in petroleum etherto yield 5-bromo-1-methyl-pyrrolo[2, 3-b]pyridine (1 .00mg, 4.76mmol, 47% yield) as a yellowsolid.1H NMR (CDCI3, 400MHz) O/ppm: 8.36 (1H, d, J= 2.0Hz), 8.03 (1H, d, J= 2.0Hz), 7.21 (1H, d, J=3.6Hz), 6.41 (1H, d, J= 3.6Hz), 3.89 (3H, 5).MS Method 2: RT: 1.65 mi m/z210.9 [M+H], 212.9 [M+H]To a mixture of 5-bromo- l/f-pyrrolo[2, 3-b]pyridine (207 mg, 1.05 mmol), sodium hydride (29 mg, 1.21 mmol) in tetrahydrofuran (5 mL) was added iodomethane (164 mg, 1.15 mol) then stirred for 2h at room temperature. The reaction mixture was carefully quenched with water then extracted with ethyl acetate (3x). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give 5- bromo-1 -methyl- l/f-pyrrolo[2, 3-b]pyridine. MS (EI) for C8H7BrN2: 209, 211 (MH+, Br pattern).NaH (55% suspension in oil, 95 mg, about 213 mmol) is added to a sol. of 5-bromo-1 H-pyrrolo[2, 3-b]pyridine (350 mg, 1.78 mmol) in THF (2 mL) at 0 C. The mixture is stirred for 15 min, and Mel (0.17 mL, 2.7 mmol) is added. The mixture is stirred for 30 min at 0 C, and little water was added. The solvents were removed under reduced pressure. Purification of the residue by automated FC (Buchi, EtOAc / heptane 1 :99' 3:97' 5:95' 8:92, 20 g silicagel, flow 18 mL/min) yields the title product. LC-MS: tR = 0.81 min, MH+ = 211.02 (conditions 3).[0653] To a stirred solution of 5-bromo-1H-pyrrolo [2, 3-bj pyridine (2 g, 10 mmol) in DMSO (20 mL) at room temperature under an argon atmosphere were added potassium hydroxide (852 mg, 15 mmol) and methyl iodide (1.95 mL, 30 mmol). The reaction mixture was warmed to room temperature and stirred for 4 h. After consumption of starting material (by TLC), the reaction mixture was diluted with ice cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, filteredand concentrated in vacuo to obtain 5-bromo-1-methyl-1H-pyrrolo [2, 3-bj pyridine (2.1 g, crude) as colorless syrup used in the next step without further purification.LCMS: 98.9%; 212.7 (M+3); (column; Ascentis Express C-18 (50 x 3.0 mm, 2.7 jtm); RT 2.49 mm; mobile phase: 0.025% Aq TFA+5% ACN: ACN+5% 0.025% Aq TFA; T/B%:0.01/5, 0.5/5, 3/100, 5/100; flow rate: 1.2 mL/min) (Gradient); TLC: 30% EtOAc/ Hexane (R1: 0.6).

Molecular Weight:211.06
XLogP3:2
Hydrogen Bond Acceptor Count:1
Exact Mass:209.97926
Monoisotopic Mass:209.97926
Topological Polar Surface Area:17.8
Heavy Atom Count:11
Complexity:151
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes