ethyl 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-flu

To a three-necked flask was added 100 g of 5-hydroxy-7-azaindole (746 mmol), 141 g of methyl 2, 4-difluorobenzoate(821 mmol), 237 g of potassium phosphate (1.12 mol) and 500 mL of diethylene glycol dimethyl Ether, 110 ° C for 24 h (HPLC to monitor 5-hydroxy-7-azaindole).The reaction solution was concentrated to dryness, and 2L of ethyl acetate and 2 L of water were added. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated to dry crude.The crude product was heated to reflux with 1260 mL of ethyl acetate. The mixture was slowly added dropwise to a solution of 1260 mL ofpetroleum ether. After 1 h of dropping, the mixture was stirred for 1 h, slowly cooled to 25 ° C, filtered and dried to give163g of pale white solidRate of 76.5percent.HPLC purity 98percent.Under a nitrogen atmosphere, 1H-pyrrolo[2, 3-b]pyridin-5-ol (1.0 g, 7.45 mmol), Methyl 2, 4-difluorobenzoate (1.6 g, 9.31 mmol), Potassium phosphate (2.05g, 9.69mmol)Add to 20mL diglyme solution, The reaction solution was stirred at 115 ° C for about 10 h.Plate analysis until the starting material is completely reacted.The reaction solution was cooled to room temperature, then quenched with water and ethyl acetate.Collect organic phase, Purification by column chromatography gave a white solid product (1.3 g).The yield was 62percent.1H-pyrrolo [2, 3-b] pyridin-5-ol(1.20 g, 8.95 mmol, 1.03 eq) and methyl 2, 4-difluorobenzoate (1.5 g, 8.71 mmol, 1.0 eq) were added to 20 mL of diethylene glycol dimethyl ether, followed by addition of potassium phosphate heptahydrate (3.5 G, 14.0 mmol, 1.6 eq) under nitrogen atmosphere at 115 ° C overnight. TLC point plate analysis, as well as raw materials, most of which produce ortho products. TLC point plate analysis, as well as raw materials, add 0.3g 2, 4-difluorobenzoic acid methyl ester and 0.5g potassium phosphate heptahydrate, continue to react overnight. And then TLC point board analysis, the effect is not very good, as well as raw materials. (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, spin-dried column, PE / EA (v / v) = 3/1 column, white Solid 525mg. Yield 22.2percent.To a mixture of methyl 2, 4-difluoro benzoate (1.0 g) in 1, 4-dioxane (20 mL), 5-hydroxypyrrolo[2, 3-b]pyridine (779 mg) and K3P04 (1.47 g) were added at 34°C and heated to90°C. The reaction mixture is stirred at the same temperature for 23 hours. K3P04 (396mg) was added at 90°C to the reaction mixture and stirred for another 24 hours at thesame temperature. Cooled the reaction mixture to 32°C and filtered on a celite bed.Washed the celite bed with ethyl acetate (20 mL) and evaporated the solvent in the filtrateto obtain crude product. The crude product was purified by column chromatography using60-120 silica gel mesh and 10-50percent ethyl acetate- hexane as eluent to obtain the titlecompound as white solid. Yield: 588 mg; Purity by HPLC: 98.73percentA mixture of formula 8 (R=methyl and X=F, 100 g), formula 7 (152 g), potassium phosphate (190 g), and diglyme were stirred at 1 1 Ο°C for 20-22 hours. Afte r cooling, the reaction mixture was filtered through a Celite bed and the filtrate was washed with diglyme (150 mL). Activated carbon (10 g) was charged and the mixture was stirred for 1 hour. The reaction mass was filtered through a Celite bed and the filtrate was washed with diglyme. Water (3000 mL)was added to the mother liquor and the mixture was stirred at 0- 5°C for 2 hours. The mixture was then filtered and the obtained solid was washed with water (450 mL) then dried at 60°C under vacuum. Toluene was added and the mixture was stirred at 80°C. After cooling to 0-5°C, the reaction mixture stirred for 2 hours, filtered, and the obtained solid was washed with chilled toluene. The solid was suck dried then dried under vacuum (50mm Hg) at 50 (80g, Yield: 0.8 w/w).To a solution of the compound of formula X (20 g, 72 mmol), methanol (800 ml)A solution of concentrated sulfuric acid (7.6 g, 72 mmol)The temperature was raised to reflux, keeping the reflux reaction 24-36 hours.In the control of raw materials to end, stop heating. Concentrated solvent, The residue was neutralized with 2N aqueous sodium hydroxide solution and the aqueous phase was usedEA was extracted three times, the organic phases were combined, washed once with saturated aqueous sodium chloride solution, Dried over anhydrous sodium sulfate and the solvent was concentrated to give 20.3 g of the compound of formula XI.Yield: 20.3 g, yield: 96.5percent.The mixture of (S)-6-(2- (2-cyclopropylphenyl) pyrrolidin-1-yl) -2-azaspiro [3.3] heptane (28.3 g, 0.1 mmol), methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-fluorobenzoate (31.57 g, 0.11 mmol), Na 2CO 3 (106 g, 1 mol) in DMF (500 mL) was heated to 105 C and stirred for overnight. After cooled to room temperature, the reaction mixture was diluted with EA (1000 mL), washed with brine (1000 mL 2), dried over Na 2SO 4 and concentrated in vacuum to afford a residue, which was purified by chromatography column on silica gel (eluent: EA/PE = 1/5 to 1/1) to give the product (11.2 g) as an off-white solid. MS (ESI, m/e) [M+1] + 548.9.The mixture of methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-fluorobenzoate (100 g), 2, 2-dimethoxy-7-azaspiro [3.5] nonane hydrochloride (116 g, 1.5 eq.) and DBU (160 g, 3.0 eq.) in NMP (500 mL) was stirred for 16 hours at 85 C. After the reaction was completed, the mixture was cooled to 50 ± 5C and citric acid in water (2%, 5 L) was added drop-wise into the system under stirring. After filtered, the cake was collected and dissolved with DCM (1.5 L). The solution of crude product was washed with citric acid in water (2%, 1.5 L), saturated aq. NaHCO 3 (1.5 L) and 15%aq. NaCl (1.5 L), and then dried over anhydrous Na 2SO 4. Silica gel (100 g) was added into the solution of crude product under stirring and then filtered. The filtrate was concentrated to 300 mL. MTBE (500mL) was poured into the system. After stirred for 2 hours, the cake was collected after filtration and was dried in vacuum to give an off-white solid (192 g, yield: 72.1%). 1H NMR (400 MHz, DMSO-d 6) delta ppm: 11.63 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 3.2 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 2.4 Hz, J = 9.2 Hz, 1H), 6.39-6.36 (m, 2H), 3.64 (s, 3H), 3.17-3.12 (m, 4H), 3.01 (s, 6H), 1.86 (s, 4H), 1.54-1.50 (m, 4H). MS (ESI, m/e) [M+1] + 451.9.2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-fluorobenzoate (2.08g, 7.3 mmol) and 7-azaspiro [3.5] nonan-2-one hydrochloride (3.83g, 21.9 mmol) in DMSO (40 mL) was stirred at 110 C for 2 days. After cooled to room temperature, the reaction mixture was poured into water (200 mL) under stirring. Then the precipitated solid was filtered and the filtered cake was further purified by column chromatography on silica gel (eluent: MeOH/DCM = 1/50 to 1/30) to obtain methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy)-4-(2-oxo-7-azaspiro [3.5] nonan-7-yl) benzoate as a yellow oil (470 mg). MS (ESI, m/e) [M+1] + 405.9.The mixture of (S)-2-(2- (2-cyclopropylphenyl) pyrrolidin-1-yl) -7-azaspiro [3.5] nonane (6.2 g, 20 mmol), methyl 2- ((1H-pyrrolo [2, 3-b] pyridin-5-yl) oxy) -4-fluorobenzoate (6.89 g, 24 mmol), Na 2CO 3 (21.2 g, 200 mmol) in DMF (100 mL) was heated to 105 C and stirred overnight. After cooling down to room temperature, the reaction mixture was diluted with EA (300 mL), washed with brine (300mL 2), dried over Na 2SO 4 and concentrated in vacuum. The resulted residue was purified by chromatography column on silica (eluent: EA/PE, 1/5 to 1/1) to give the product (6.3 g) as an off-white solid. MS (ESI, m/e) [M+1] + 576.9.

Molecular Weight:286.26
XLogP3:2.8
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:286.07537038
Monoisotopic Mass:286.07537038
Topological Polar Surface Area:64.2
Heavy Atom Count:21
Complexity:382
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes