5-METHOXY-1H-PYRROLO[2,3-B]PYRIDINE

Tan solid

5-Methoxy-1H-pyrrolo[2, 3-b]pyridine (30). 5-Methoxy-1H-pyrrolo[2, 3-b]pyridine (30) 2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2, 3-b]pyridin-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (38); [00424] To a solution of 5-bromo-lH-pyrrolo[2, 3-b]pyridine (2.00 g, 10.2 mmol) inN, N-dimethylformamide (30 mL) was added a 25percent weight solution in methanol of sodium methoxide (46.4 mL, 203 mmol) followed by copper(I) bromide (2.91 g, 20.3 mmol). The reaction mixture was heated at 140 °C for 2.5 hours, after it was cooled to room temperature and concentrated to remove most of the NN-dimethylformamide. Water (100 mL) was added followed by saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with EtOAc (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography (Biotage) using using 0 to 50percent ethyl acetate in hexanes over 60 minutes to afford 5-methoxy-lH-pyrrolo[2, 3-b]pyridine(0.680 g, 4.59 mmol, 45percentyield) as a green solid. NMR (400 MHz, CDC1To 5-bromo-7-azaindole (67, 500.0 mg, 2.53 mmol) in N, N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120 In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (67, 2.3 g, 11.7 mmol) was dissolved in 75 mL N, N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100 °C under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride: ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30percent to 70percent ethyl acetate in hexanes to give a yellow solid (104, 0.27 g, 15.6percent). MS(ESI) [M + HTo a solution of 5-bromo-1H-pyrrolo[2, 3-b]pyridine (prepared as in Example 7, 10 g, 50.8 mmol) in N, N-dimethylformamide (200 mL) and methanol (150 mL) at 25° C. was added sodium (100 g, 185.1 mmol) and copper(I) bromide (14.56 g, 101.5 mmol) under a nitrogen atmosphere. The mixture was then heated at reflux for 5 h. After cooling, the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3.x.300 mL), and washed with a saturated aqueous ammonium chloride solution, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford 5-methoxy-1H-pyrrolo[2, 3-b]pyridine (5.8 g, 77.3percent) as a light yellow solid: LC/MS m/e calcd for CStep 1-Preparation of 5-methoxy-1H-pyrrolo[2, 3-b]pyridine (17)To 5-bromo-7-azaindole (1, 500.0 mg, 2.53 mmol) in N, N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120° C. under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20percent ethyl acetate in hexane to give white solid (17, 140 mg, 28percent). MS (ESI)[M+HSynthesis of 5-Methoxy-lH-pyrrolo[2, 3-b]pyridine 2 and related compounds.[0147] 5-Methoxy-lH-pyrrolo[2, 3-b]pyridine 2 was synthesized in one step from 5-bromo-lH- pyrrolo[2, 3-b]pyridine 1 as described in Scheme 1.Scheme 1Step 1 - Preparation of5-Methoxy-lH-pyrrolo[2, 3-b]pyridine (2):[0148] T 5 b 7 i d l (1 500 0 2 53 l) i N N di th lf mamide (8 mL) were Step 1-Preparation of 5-methoxy-1H-pyrrolo[2, 3-b]pyridine (17)To 5-bromo-7-azaindole (1, 500.0 mg, 2.53 mmol) in N, N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120° C. under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20percent ethyl acetate in hexane to give white solid (17, 140 mg, 28percent). MS (ESI)[M+HIn an alternative method, 2.3 g (1 1.7 mmol) 5-bromo-7-azaindole (1, 2.3 g. 11.7 mmol) was dissolved in 75 mL N, N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0, 6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100 A mixture of 5-bromo-7-azaindole (100 g) and dimethyl formamide (800 mL)were cooled 5-10 Sodium methoxide (275 g), copper (I) iodide (194 g), and methanol (450 mL) were added and the temperature was raised to 95-100 °C and stirred for 2 hours. Aft er cooling to 35°C, ethyl acetate (1 L) and aqueous ammonium chloride solution (200 g of ammonium chloride was dissolved in 600 mL water) were added, the reaction mixture was stirred for 4hours and the reaction mass was filtered through a Celite bed. The filtrate was washed thrice with ethyl acetate (400 mL x 3). Ethyl acetate (800 mL) and 30 percent aqueous ammonium chloride solution (1600 mL) were added, the reaction mixture was stirred, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (400 mL) and the combined ethyl acetate layers were washed with 30percent aqueous ammonium chloride solution (200 mL)until the blue colour disappeared. The ethyl acetate layer was concentrated under vacuum at 50 Toluene (200 mL)was charged to the residue at 50°C and the reaction mass was stirred for 15 minutes. After cooling to 5-1 Ο°C, the reaction mixture was stirred for 2 hours then filtered. The obtained solid was washed with chilled toluene (50 mL) then dried under vacuum oven at 50°C for 4 hours (58 g, Yield: 0.29w/w).A solution of (30). To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL) was added 25% (w/w) MeONa (48 mL, 210 mmol) followed by copper (I) bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at 140 C for 2.5. It was then cooled and concentrated to remove DMF. Water (100 mL) was added followed by saturated aqueous NaHCO3 (20 mL). The mixture was extracted with AcOEt (3x), the combined organic extracts dried (MgSO4) and concentrated. The solid residue was purified by SGC using AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green solid (0.58 g, 78%); 1H NMR (400 MHz, CDCl3) delta 3.90 (s, 3H), 6.45 (d, J = 2.3 Hz, 1H), 7.33 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH). (30) To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL) was added 25% (w/w) MeONa (48 mL, 210 mmol) followed by copper (1) bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at 140 C. for 2.5. It was then cooled and concentrated to remove DMF. Water (100 mL) was added followed by saturated aqueous NaHCO3 (20 mL). The mixture was extracted with AcOEt (3*), the combined organic extracts dried (MgSO4) and concentrated. The solid residue was purified by SGC using AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green solid (0.58 g, 78%); 1H NMR (400 MHz, CDCl3) delta 3.90 (s, 3H), 6.45 (d, J=2.3 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH).2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2, 3-b]pyridin-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (38); [00424] To a solution of 5-bromo-lH-pyrrolo[2, 3-b]pyridine (2.00 g, 10.2 mmol) inN, N-dimethylformamide (30 mL) was added a 25% weight solution in methanol of sodium methoxide (46.4 mL, 203 mmol) followed by copper(I) bromide (2.91 g, 20.3 mmol). The reaction mixture was heated at 140 C for 2.5 hours, after it was cooled to room temperature and concentrated to remove most of the NN-dimethylformamide. Water (100 mL) was added followed by saturated aqueous sodium bicarbonate solution (20 mL). The mixture was extracted with EtOAc (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated to a residue. Purification was achieved by silica gel chromatography (Biotage) using using 0 to 50% ethyl acetate in hexanes over 60 minutes to afford 5-methoxy-lH-pyrrolo[2, 3-b]pyridine(0.680 g, 4.59 mmol, 45%yield) as a green solid. NMR (400 MHz, CDC13) delta (ppm): 9.90 (br. s, 1H), 8.10 (m, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 6.44 (m, 1H), 3.89 (s, 3H).[00425] To a mixture of 5-methoxy-lH-pyrrolo[2, 3-b]pyridine (670 mg, 4.52 mmol), and benzyltributylammonium bromide (70.5 mg, 0.226 mmol) in dichloromethane (20 mL) was added powdered sodium hydroxide (561 mg, 14.0 mmol). The reaction mixture was cooled to 0 C, after which 4-methylbenzene-l-sulfonyl chloride (991 mg, 5.20 mmol) was added portionwise. The mixture was stirred at 0 C for 15 min then warmed to room temperature where it was stirred for two hours, extracted with toluene (2 x 50 mL), dried (sodium sulfate), filtered and concentrated. The crude product was triturated in ether and filtrated to afford the compound 5-methoxy-l-tosyl-lH-pyrrolo[2, 3-b]pyridine (1.21 g, 4.01 mmol, 89% yield) as a solid. 1H NMR (400 MHz, CDC13) delta (ppm): 8.15 (s, 1H), 8.05 (m, 2H), 7.66 (m, 1H), 7.25 - 7.30 (m, 3H), 6.51 (m, 1H), 3.83 (s, 3H), 2.35 (s, 3H).[00426] To a -60 C solution of 5-methoxy-l-tosyl-lH-pyrrolo[2, 3-b]pyridine (1.20 g, 3.97 mmol) in tetrahydrofuran (25 mL) was added 2M intetrahydrofuran/ethylbenzene/toluene solution of lithium diisopropyl amide (3.97 mL, 7.94 mmol). The reaction mixture was stirred at -60 C for 30 minutes, after which iodomethane (0.298 mL, 4.76 mmol) was added, after which the reaction mixture was room temperature. Upon warming, the reaction was poured into ice water, extracted with ethyl acetate (3 x 50 mL), washed with water (3 x 50 mL), saturated sodium chloride solution (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated. Purification was achieved by silica gel chromatography (Biotage) using 0 to 50% ethyl acetate in hexanes to afford 5-methoxy-2- methyl-l-tosyl-lH-pyrrolo[2, 3-b]pyridine (0.550 g, 1.74 mmol, 44 % yield). NMR (400 MHz, CDC13) delta (ppm): 8.08 (s, 1H), 7.96 (d, 2H), 7.26 (m, 2H), 7.16 (m, 1H), 6.20 (s, 1H), 3.83 (s, 3H), 2.69 (s, 3H), 2.35 (s, 3H).[00427] A solution of 5-methoxy-2-methyl-l-tosyl-lH-pyrrolo[2, 3-b]pyridine (1.14 g, 3.60 mmol) and sodium hydroxide (14.4 g, 360 mmol) in methanol (70 mL) and water (70 mL) was heated at 80 C for 30 minutes, after which it was cooled to room temperature, poured into to ice water, extracted with ethyl acetate (3 x 50 mL), washed with saturated sodium chloride solution (3 x 50 mL), dried (magnesium sulfate), filtered and concentrated to afford 5-methoxy-2-methyl-lH-pyrrolo[2, 3-b]pyridine (0.550 g, 3.39 mmol, 94 % yield) as a solid. NMR (400 MHz, CDC13) delta (ppm): 9.48 (b, 1H), 7.97 (m, lH), 7.33 (m, 1H), 6.10 (m' 1H), 3.89 (s, 3H) 2.49 (s, 3H). This material was used in the subsequent step without any purification.[00428] 2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2, 3-b]pyridin-3-yl)-N- (2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a yellow solid in 55% yield starting from l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[2, 3-b]pyridin using general procedure D. NMR (400 MHz, CDC13) delta (ppm): 9.13 (br. s, 1H), 8.10 - 8.17 (m, 3H), 7.25 - 7.27 (m, 3H), 7.14 (d, 1H), 7.06 (m, 2H), 5.55 (s, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.70 (s, 3H).[00429] 2-(l-(4-chlorobenzyl)-5-methoxy-2-methyl-lH-pyrrolo[3, 2-b]pyridin-3-yl)-N- (2-methoxypyridin-4-yl)-2-oxoacetamide was synthesized as a solid starting from methoxy-2- methyl-lH-pyrrolo[3, 2-b]pyridine using general route 2. NMR (400 MHz, CD3OD) delta (ppm): 8.02 (d, 1H), 7.69 (d, 1H), 7.33 (m, 3H), 7.21 - 7.23 (m, 1H), 7.06 (d, 2H), 6.56 (d, 1H), 5.51 (s, 2H), 3.90 (s, 3H), 3.52 (s, 3H), 2.81 (s, 3H).To 5-bromo-7-azaindole (67, 500.0 mg, 2.53 mmol) in N, N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120 0C under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20% ethyl acetate in hexane to give white solid (104, 140 mg, 28%). MS(ESI)[M+H+]+ = 149.1.In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (67, 2.3 g, 11.7 mmol) was dissolved in 75 mL N, N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100 C under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride: ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30% to 70% ethyl acetate in hexanes to give a yellow solid (104, 0.27 g, 15.6%). MS(ESI) [M + H+J+= 149.2.[0495] Compound 139, 5-bromo-7-azaindole, was prepared from commercially available 7-azaindole by following the procedure published by Mazeas, Daniel; Guillaumet, Gerald; Marie-Claude Viaud, Heterocycles, 1999, V50 (2), 1065-1080. Compound 140 is prepared by heating the bromide 139 with sodium methoxide in dimethyl formamide in presence of cuprous bromide as described by Mazeas, Daniel; Guillaumet, Gerald; Marie- Claude Viaud, HETEROCYCLES, 1999, v50 (2), 1065-1080, from which the aldehyde 138 is prepared by Vilsmeier-Haack reaction.Nitrogen protection was applied to the 2L four-necked bottle, and 72.0g was added.(0.3mol, 1.0eq)Compound 2 obtained in the step (2) and 720 ml of tetrahydrofuran, Cool down to -10 ± 5 C, And controlled to add 204.0g (0.75mol, 2.5eq) at this temperature2.5 M n-butyllithium in hexane solution, and the reaction was continued at this temperature for 2.5 hours after the dropwise addition.Then 26.3 g (0.36 mol, 1.2 eq) was added dropwise at this temperature.N, N-dimethylformamide, After the addition was completed, stir at -10 ± 5 C for 6 hours until the reaction was complete.The mixture in the bottle was kept at 0 ± 5 C and slowly poured into 216 g of 35% concentrated hydrochloric acid.And the reaction was quenched at 0±5 C, and the reaction solution was heated to 40-45 C for 2 hours.After the reaction is completed, the organic layer is layered and removed.The aqueous phase is neutralized with sodium hydroxide to pH = 11 to 12, Then, it was extracted twice with tetrahydrofuran, and the combined organic phases were washed once with saturated brine.Combine the organic phase to recover the solvent and then crystallize35.3g product, yield 79%;48.0 g (0.35 mol, 1.0 eq) of the compound 2-amino-3-methyl-5-methoxypyridine obtained in the step (1) and 240 g of tetrahydrofuran were added to a 2 L four-necked flask.After all the materials were dissolved, 207.9 g (0.76 mol, 2.2 eq) of a 2.5 M solution of n-butyllithium in hexane was added dropwise at -5 C, and reacted at -5 C for 1-2 hours.Then 83.4g (0.38mol, 1.1eq)Di-tert-butyl dicarbonate was added to the reaction solution at -5 C, and maintained at -5 C for 3 hours.Then, 207.9 g (0.76 mol, 2.2 eq) was added dropwise to the reaction solution at -5 C.2.5M n-butyllithium in hexane and keep at -5 C for 1-2 hours.Maintain -5 C will be 30.5g (0.42mol, 1.2eq)N, N-dimethylformamide is added dropwise to the above reaction solution, And continue to react at this temperature for 6-8 hours, and the reaction mixture is quenched with hydrochloric acid.Layered, The aqueous layer is neutralized with a base to pH = 11-12, and the aqueous layer is extracted with an organic solvent.The organic layer is washed with water, and the organic layer is crystallized to obtain 7.0 g of a product, and the purity is 96.6%.Yield 14%;To a solution of 5-bromo-1H-pyrrolo[2, 3-b]pyridine (prepared as in Example 7, 10 g, 50.8 mmol) in N, N-dimethylformamide (200 mL) and methanol (150 mL) at 25 C. was added sodium (100 g, 185.1 mmol) and copper(I) bromide (14.56 g, 101.5 mmol) under a nitrogen atmosphere. The mixture was then heated at reflux for 5 h. After cooling, the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate (3×300 mL), and washed with a saturated aqueous ammonium chloride solution, brine, and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford

Molecular Weight:148.16
XLogP3:1.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:148.063662883
Monoisotopic Mass:148.063662883
Topological Polar Surface Area:37.9
Heavy Atom Count:11
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes