4-Bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine

Vinyl magnesium bromide (400 ml, 1.0 M in THF) was added slowly to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (20 g, 84.74 mmol) in dry THF (800 ml) at -78°C. The reaction mixture was slowly warmed to -20°C and stirred at same temperature for a period of 8 h. Reaction mixture was quenched with 20 percent of NHTo a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 0.042 mol) in anhydrous THF (150 mL), a solution of vinylmagnesium bromide (17 g, 0.127 mol) in THF was added dropwise at -30 to -50 °C. The reaction mixture was stilTed at -30 to -40 °C for 2 h. Then the reaction mixture was poured into saturated aqueous NH4C1 solution and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2504, filtered and concentrated under reduced pressure and the residue was purified by column chromatography to provide 4-bromo-7-chloro-]H-pyrrolo[2, 3-c]pyridine ( 3 g, 3 1percent): ‘H NMR: (DMSO-d6) 3 12.45 (s, 1H), 8.04 (s, 1H), 7.79-7.78 (m, 1H), 6.59-6.58 (d, J = 2.0, 1H).To a solution of compound 10 (250 mg; 1.05 mmol) in dry THF (10 ml) under argon at -78 °C was added dropwise a 1.42 M solution of vinylmagnesium bromide in THF (6 ml, 8.4 mmol; prepared by dilution of 1.7 M solution of in THF (50 ml) with THF (12 ml)). The reaction mixture was stirred at the same temperature for another 1.5 h and then it was quenched by addition of NH4Cl sat. (30 ml). The THF-layer was separated and the aqueous layer was extracted with EtOAc (2×10 ml). Combined organic layers (THF with EtOAc extracts) were dried over Na2SO4 and concentrated to afford 270 mg of yellow oily material which was treated with DCM (10 ml). Light-yellow solid was filtered and dried in oven (45 °C) to give compound 11 (70 mg, 29percent).5-Bromo-2-chloro-3-nitro-pyridine (20.2 g, 85.07 mmol, 1 equiv.) was dissolved in dry tetrahydrofuran (100 mL) under nitrogen atmosphere, and the solution was cooled to -78° C. Bromo(vinyl)magnesium (1 M, 340 mL, 4 equiv.) was added to the solution, and the reaction mixture was stirred at -78° C. for 4 h. LCMS analysis showed that the reaction was completed. The solution of compound 1 (30 g, 0.13 mol) in THF (1.5 L) was cooled to -78 °C. Then a solution of vinyl magnesium in THF (508 mL, 1N, 0.51 mol) was added dropwise to the above solution maintained below -40 °C. The mixture was stirred for 3 hrs at -78 °C before being quenched with saturated aqueous NHA solution of compound 1 (30 g, 0.13 mol) in THF (1.5 L) was cooled to 78 °C. Vinylmagnesium in THF (508 mL, 1N, 0.51 mol) was added dropwise to the above solution and the temperature was maintained below 40 °C. The mixture was stirred for 3 h at 78 °C before being quenched with saturated aqueous NH4Cl solution. The layers were separated, the aqueous layer was extracted with EtOAc (3 500 mL), and the combined organic layer was washed with brine and concentrated.The crude product was purified by silica gel column chromatography to obtain compound 2 (5 g, 17percent). Compound 2 (4.0 g, 17.2 mmol) was dissolved in freshly prepared NaOMe (20 mL). CuI(3.2 g, 17.2 mmol) was added and the mixture was microwave-irradiated at 110 °C and stirred for3 h. After reaction completion, EtOAc and H2O were added, then the suspension was filtered andthe filtrate was separated. The organic layer was concentrated to give crude product, which waspurified by column chromatography to give compound 3 (1.8 g, 45percent). A mixture of compound 3(0.7 g, 3.8 mmol), 3-methyl-1, 2, 4-triazole (6.4 g, 76.8 mmol), copper powder (0.49 g, 7.68 mmol), and KOH (0.43 g, 7.68 mmol) was heated to melt at 170–175 °C while being protected by N2 atmosphere. After consumption of the starting material, EtOAc and H2O were added to the mixture, and the suspension was filtered and the filtrate was collected. The organic layer was concentrated to give the crude product, which was purified by column chromatography to give compound 4 (0.23 g, 26percent).A solution of compound 4 (0.23 g, 1 mmol) in THF (12 mL) was cooled to 10 °C, and EtMgBr (0.47 g, 3.5 mmol) was added dropwise at 10 °C, followed by the addition of pyridine (0.3 mL). The slurrywas cooled to 45 °C, and the ethyl 2-chloro-2-oxoacetate (0.55 g, 4 mmol) was added dropwise at 45 °C. The temperature was allowed to rise to 10 °C and the mixture was stirred for 1h. Afterreaction completion, the mixture was quenched with IPA (2 mL) and H2O (20 mL). The mixture wasextracted with EtOAc, and the organic layer was washed with brine and concentrated to the givecrude product which was purified by column chromatography to give compound 5 (0.17 g, 52percent).Compound 5 (0.17 g, 0.52 mmol) was dissolved in MeOH (5 mL). NaOH (0.041 g, 1.03 mmol) and H2O(2 mL) were added and the mixture was stirred at 25 C for 6 h. HCl (1N) was added to adjust the pH to 6, and the mixture was concentrated to give compound 6 (0.29 g) as crude product.Vinyl magnesium bromide (400 ml, 1.0 M in THF) was added slowly to a stirred solution of 5-bromo-2-chloro-3-nitropyridine (20 g, 84.74 mmol) in dry THF (800 ml) at -78C. The reaction mixture was slowly warmed to -20C and stirred at same temperature for a period of 8 h. Reaction mixture was quenched with 20 % of NH4CI (600 ml) and the product was extracted with ethyl acetate (2 x 500 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried and concentrated. The obtained crude was triturated with diethyl ether (2 x 100 ml) to afford the title compound as a brown solid (8 g, 40 %). 1H NMR (400 MHz, DMSO-dg) delta 12.48 (bs, 1H), 8.07 (s, 1H), 7.82 (t, J=3.2 Hz, 1H), 6.61 (s, 1H); LC/MS: 232 (M+l)+.To a solution of 5-bromo-2-chloro-3-nitropyridine (10 g, 0.042 mol) in anhydrous THF (150 mL), a solution of vinylmagnesium bromide (17 g, 0.127 mol) in THF was added dropwise at -30 to -50 C. The reaction mixture was stilTed at -30 to -40 C for 2 h. Then the reaction mixture was poured into saturated aqueous NH4C1 solution and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2504, filtered and concentrated under reduced pressure and the residue was purified by column chromatography to provide 4-bromo-7-chloro-]H-pyrrolo[2, 3-c]pyridine ( 3 g, 3 1%): 'H NMR: (DMSO-d6) 3 12.45 (s, 1H), 8.04 (s, 1H), 7.79-7.78 (m, 1H), 6.59-6.58 (d, J = 2.0, 1H).To a solution of compound 10 (250 mg; 1.05 mmol) in dry THF (10 ml) under argon at -78 C was added dropwise a 1.42 M solution of vinylmagnesium bromide in THF (6 ml, 8.4 mmol; prepared by dilution of 1.7 M solution of in THF (50 ml) with THF (12 ml)). The reaction mixture was stirred at the same temperature for another 1.5 h and then it was quenched by addition of NH4Cl sat. (30 ml). The THF-layer was separated and the aqueous layer was extracted with EtOAc (2×10 ml). Combined organic layers (THF with EtOAc extracts) were dried over Na2SO4 and concentrated to afford 270 mg of yellow oily material which was treated with DCM (10 ml). Light-yellow solid was filtered and dried in oven (45 C) to give compound 11 (70 mg, 29%).5-Bromo-2-chloro-3-nitro-pyridine (20.2 g, 85.07 mmol, 1 equiv.) was dissolved in dry tetrahydrofuran (100 mL) under nitrogen atmosphere, and the solution was cooled to -78 C. Bromo(vinyl)magnesium (1 M, 340 mL, 4 equiv.) was added to the solution, and the reaction mixture was stirred at -78 C. for 4 h. LCMS analysis showed that the reaction was completed. The reaction was quenched with saturated ammonium chloride (150 mL). The aqueous phase was extracted with ethyl acetate (3*150 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography (silica gel, eluting with a 1/1 mixture of ethyl acetate and petroleum ether) to afford 4-bromo-7-chloro-1H-pyrrolo[2, 3-c]pyridine as a yellow solid (4.12 g, 21% yield).The solution of compound 1 (30 g, 0.13 mol) in THF (1.5 L) was cooled to -78 C. Then a solution of vinyl magnesium in THF (508 mL, 1N, 0.51 mol) was added dropwise to the above solution maintained below -40 C. The mixture was stirred for 3 hrs at -78 C before being quenched with saturated aqueous NH4Cl solution. The layers were separated, the aqueous layer was extracted with EtOAc (3×500 mL) and the combined organic layer was washed with brine and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 2 (5 g, 17%). Compound 2 (4.0 g, 17.2 mmol) was dissolved in freshly prepared NaOMe (20 mL). CuI (3.2 g, 17.2 mmol) was added to the above solution. The mixture was stirred at 110 C under microwave for 3 hrs. After the mixture was completed, the mixture was added EtOAc and H2O, then the suspension was filtered, the filtrate was separated. The organic layer was concentrated to give crude product which was purified by column chromatography to give compound 3 (1.8 g, 45%). A mixture of compound 3 (0.7 g, 3.8 mmol) and 3-methyl-1, 2, 4-triazole (6.4 g, 76.8 mmol) was added copper powder (0.49 g, 7.68 mmol) and KOH (0.43 g, 7.68 mmol). The mixture was heated tomelt at 170-175 C under N2. After the starting material was consumed completely, the mixture was added EtOAc and H2O, then the suspension was filtered, the filtrate was separated. The organic layer was concentrated to give crude product which was purified by column chromatography to give compound 4 (0.23 g, 26%). A solution of compound 4 (0.23 g, 1 mmol) in THF (12 mL) was cooled to -10 C, EtMgBr (0.47 g, 3.5 mmol)was added dropwise at -10 C followed by the addition of pyridine(0.3 mL). The slurry was cooled to -45 C, and the ethyl 2-chloro-2-oxoacetate (0.55 g, 4 mmol) was added dropwise at -45 C. The slurry was allowed to -10 C and stirred at this temperature for 1h. After the reaction was completed, the mixture was quenched with IPA (2mL) and H2O (20 mL). The mixture was extracted with EtOAc, the organic layer was washed with brine and concentrated to give crude product which was purified by column chromatographyto give compound 5 (0.17 g, 52%). A solution of compound 5 (0.17 g, 0.52mmol) in MeOH (5 mL) was added NaOH (0.041 g, 1.03 mmol) and H2O (2mL). The mixture was stirred at 25 C for 6 hrs and then added 1N HCl to adjusted pH 6, the mixture was concentratedto give compound 6 (0.29 g) as crude product.A solution of compound 1 (30 g, 0.13 mol) in THF (1.5 L) was cooled to 78 C. Vinylmagnesium in THF (508 mL, 1N, 0.51 mol) was added dropwise to the above solution and the temperature was maintained below 40 C. The mixture was stirred for 3 h at 78 C before being quenched with saturated aqueous NH4Cl solution. The layers were separated, the aqueous layer was extracted with EtOAc (3 500 mL), and the combined organic layer was washed with brine and concentrated.The crude product was purified by silica gel column chromatography to obtain compound 2 (5 g, 17%). Compound 2 (4.0 g, 17.2 mmol) was dissolved in freshly prepared NaOMe (20 mL). CuI(3.2 g, 17.2 mmol) was added and the mixture was microwave-irradiated at 110 C and stirred for3 h. After reaction completion, EtOAc and H2O were added, then the suspension was filtered andthe filtrate was separated. The organic layer was concentrated to give crude product, which waspurified by column chromatography to give compound 3 (1.8 g, 45%). A mixture of compound 3(0.7 g, 3.8 mmol), 3-methyl-1, 2, 4-triazole (6.4 g, 76.8 mmol), copper powder (0.49 g, 7.68 mmol), and KOH (0.43 g, 7.68 mmol) was heated to melt at 170-175 C while being protected by N2 atmosphere. After consumption of the starting material, EtOAc and H2O were added to the mixture, and the suspension was filtered and the filtrate was collected. The organic layer was concentrated to give the crude product, which was purified by column chromatography to give compound 4 (0.23 g, 26%).A solution of compound 4 (0.23 g, 1 mmol) in THF (12 mL) was cooled to 10 C, and EtMgBr (0.47 g, 3.5 mmol) was added dropwise at 10 C, followed by the addition of pyridine (0.3 mL). The slurrywas cooled to 45 C, and the ethyl 2-chloro-2-oxoacetate (0.55 g, 4 mmol) was added dropwise at 45 C. The temperature was allowed to rise to 10 C and the mixture was stirred for 1h. Afterreaction completion, the mixture was quenched with IPA (2 mL) and H2O (20 mL). The mixture wasextracted with EtOAc, and the organic layer was washed with brine and concentrated to the givecrude product which was purified by column chromatography to give compound 5 (0.17 g, 52%).Compound 5 (0.17 g, 0.52 mmol) was dissolved in MeOH (5 mL). NaOH (0.041 g, 1.03 mmol) and H2O(2 mL) were added and the mixture was stirred at 25 C for 6 h. HCl (1N) was added to adjust the pH to 6, and the mixture was concentrated to give compound 6 (0.29 g) as crude product.To a mixture of 5-bromo-2-chloro-3-nitropyridine (50 g, 210 mmol) in THF (1.40 L) at -78 C was added bromo(vinyl)magnesium (1 M, 842 mL) under N2. The mixture was stirred at -78 C for 4 h then at -20 C for 2 h. LCMS showed that the starting material was consumed completely. The mixture was poured into aqueous NH4Cl (500 mL) and extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with brine (500 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, from 50/ 1 to 1/ 1) to give 4-bromo-7-chloro[pyrrolo[2, 3-c]pyridine as a yellow solid. ESI-MS (m/z):233 (M+H)+.To a solution of 5-bromo-2-chloro-3-nitro-pyridine (7g) in dry tetrahydrofuran (150ml) at -70 C under an atmosphere of nitrogen was added dropwise a solution of vinylmagnesium bromide (1.OM in tetrahydrofuran;94.5ml) over lh. The solution was stirred at -70 C for lh and then quenched with saturated ammonium chloride (150ml) and the aqueous was extracted twice with ethyl acetate. The combined organics were dried (MgS04) and evaporated to give a deep red oil. The residue was triturated with diethyl ether (100ml) and the solid was then filtered off, sucked dry then dried at 40 C under vacuum to afford the title compound (1.75g). NMR (d6-DMSO) 8 6.61 (1H, d), 7.82 (lH, d), 8.07 (IH, s), 12.50 (IH, s). LC/MS t = 2.9min, [MH+] 233 consistent with molecular formula C7(at)81Br3sClN2At room temperature, 4-bromo-7-chloro-lH-pyrrolo[2, 3-c]pyridine (3.00 g, 13.0 mmol) was treated with NaH (778 mg, 19.5 mmol, 60 % in mineral oil) in DMF (30 mL) and stirred for 10 min., followed by the addition of 2-(chloromethoxy)ethyl-trimethyl-silane (2.98 mL, 16.8 mmol). The mixture was stirred at room temperature overnight and diluted with water, extracted with EtOAc, washed with water and brine, dried, and then concentrated. The residue was chromatographed (EtOAc in hexanes, 0-20%) to provide 2-[(4-bromo-7-chloro-pyrrolo[2, 3- c]pyridin-l-yl)methoxy]ethyl-trimethyl-silane (4.02 g, 86%) as a colorless oil, which solidified on standing as white solid. LC-MS 361.3, 363.3, 365.3 [M+H]+, RT 1.76 min.A mixture of 4-bromo-7-chloro-3a, 7a-dihydro-lH-pyrrolo[2, 3-c]pyridine (5.00 g, 21.4 mmol), l-tetrahydropyran-2-yl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)pyrazole (7.15 g, 25.7 mmol), PdCl2(dppf) (1.78 g, 2.14 mmol), and K2CO3 (21 mL, 42 mmol, 2.0 M) in DMF (100 mL) was stirred at 80 C under an argon atmosphere for 4 h. The solvent was removed under vacumn on a rotovap and the residue was suspended in dichloromethane and filtered. The filtrate was washed with water and brine, dried and concentrated to dryness and used directly in Step 2, below. LC-MS 303.3, 305.3 [M+H]+, RT 1.15 min.

Molecular Weight:231.48
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Exact Mass:229.92464
Monoisotopic Mass:229.92464
Topological Polar Surface Area:28.7
Heavy Atom Count:11
Complexity:155
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes