* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Example 15Synthesis of 3-Methoxy-1-(2-(4-r4-(1-methyl-1 H-π .2.41triazol-3-yl)-phenvπ-3,6- dihvdro-σH-pyridin-i-ylVσ-oxo-ethvO-pyrrolidine^-carboxylic acid T3-(2- isopropoxy-pyridin-4-yl)-1 H-indazol-5-yll-amide Step 1 :Preparation of 4-Bromo-2-lsopropoxy-pyridine To the stirred solution of 4-bromo-2-fluoro-pyridine 17BV (4.12 g, 23.41 mmole) in 50 mL anhydrous IPA in a 150 mL pressure vessel was added 2.627 g(23.41 mmole) of solid potassium tert-butoxide under dry N2 gas. The pressure vessel was tightly sealed and heated at 80 0C for 3 hours. The pressure vessel was cooled to 0 0C in ice-bath before opening. The contents of the pressure vessel were transferred to 250 mL RBF and concentrated to a small volume. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with saturated NaCI solution and dried over MgSO4. The solvent was evaporated and resulting clear oil was purified on RediSep 80 g cartridge eluting with 20:1 Hexanes/EtOAc to give clear oil 18BV (4.2 g, 83percent).
With potassium tert-butylate; at 80℃; for 3h;Inert atmosphere;
Example 15Synthesis of 3-Methoxy-1-(2-(4-r4-(1-methyl-1 H-? .2.41triazol-3-yl)-phenv?-3,6- dihvdro-?H-pyridin-i-ylV?-oxo-ethvO-pyrrolidine^-carboxylic acid T3-(2- isopropoxy-pyridin-4-yl)-1 H-indazol-5-yll-amide Step 1 :Preparation of 4-Bromo-2-lsopropoxy-pyridine To the stirred solution of 4-bromo-2-fluoro-pyridine 17BV (4.12 g, 23.41 mmole) in 50 mL anhydrous IPA in a 150 mL pressure vessel was added 2.627 g(23.41 mmole) of solid potassium tert-butoxide under dry N2 gas. The pressure vessel was tightly sealed and heated at 80 0C for 3 hours. The pressure vessel was cooled to 0 0C in ice-bath before opening. The contents of the pressure vessel were transferred to 250 mL RBF and concentrated to a small volume. The resulting mixture was partitioned between EtOAc and H2O. The organic phase was separated, washed with saturated NaCI solution and dried over MgSO4. The solvent was evaporated and resulting clear oil was purified on RediSep 80 g cartridge eluting with 20:1 Hexanes/EtOAc to give clear oil 18BV (4.2 g, 83%).
[000653] 60% NaH (1.04 g, 26 mmol) was added in two portions to isopropyl alcohol (30 mL) at room temperature (about 30 C) under N2. The mixture was stirred at 60 C for 30 min. Compound 103 A (2 g, 11.36 mmol) was added in two portions and the mixture was stirred at reflux 4 h and at 80 C overnight. The solution was concentrated in vacuo. Water (100 mL) and ethyl acetate (200 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with water (10 mL x 2), brine (10 mL x 2) and dried over anhydrous sodium sulphate. After filtration the solvent was removed in vacuo. The crude product was subjected to flash chromatography (silica, ethyl acetate in petroleum, 0-10% v/v) to offer Compound 103B.
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 20 - 100℃;Inert atmosphere;
Step 2Preparation of 3-(2-lsopropoxy-pyridin-4-yl)-5-nitro-1-trityl-1 H-indazole To the stirred solution of 4.20 g (19.4 mmole) <strong>[1142194-24-8]4-bromo-2-isopropoxy-pyridine</strong> 18BV in 150 ml_ anhydrous DMSO, 7.39 g (29.1 mmole) of bis(pinacolato)diboron, 5.704 g (58.2 mmole) of potassium acetate, and 1.584 g (1.94 mmole) of Pd(dppf)CI2 were added at r.t. under dry N2 gas. The mixture was degassed couple of times with dry N2 gas. The dark orange mixture was heated at 100 0C for 2 hours. The dark colored mixture was allowed to cool to r.t. 75 ml_ of H2O was added followed by 9.396 g (19.4 mmole) of i -Trityl-5-Nitroindazole, 13.401 g (96.96 mmole) of potassium carbonate, and 2.246 g (1.94 mmole) of PdTetrakis(Triphenylphosphine) were added at r.t. under dry N2 gas. The mixture was degassed couple of times with dry N2 gas. The dark colored mixture was heated at 100 0C overnight. The mixture was allowed to cool to r.t. and diluted with 1 :1 mixture of H2O/EtOAc.The diluted mixture was filtered through the pad of Celite and Celite pad was liberally washed with EtOAc. The contents were transferred to a separation funnel and shaken well. The organic phase was separated and washed couple of times with saturated NaCI solution, dried over MgSO4 and evaporated to dryness. The dark colored gum was purified on RediSep 330 g cartridge eluting with Hexanes, 5% EtOAc/Hexane and 10% EtOAc/Hexanes, gave 3.24 g (31 %) pale yellow solid 19BV.
To isopropanol (12 ml) under Ar was added 55% sodium hydride in oil (343 mg, 7 86 mmol) in two portions After 30 mm stir?ng at rt was added 4-bromo-2-chloropyridine (Aldrich, Buchs Switzerland, 1.01 g, 5.24 mmol) and the reaction mixture was heated with microwave irradiation to 15O C for 30 mm The reaction mixture was concentrated, quenched with saturated aqueous NaHCO3 and extracted with EtOAc The organic layer was washed with brine, dried over Na2SO4. filtered and evaporated The crude product was purified by MPLC (heptane/EtOAc 0% to 20%) to give the title compound as an oil (HPLC tR 3 58 min (Method A), M+H - 216, 218 MS-ES).
With tris-(dibenzylideneacetone)dipalladium(0); johnphos; sodium t-butanolate; In 1,4-dioxane; at 80 - 100℃;Inert atmosphere;
General procedure: To 1.76 mmol of the appropriate amine in 10 mL dioxane are added 1.76 mmol pyridyl halide, 7.02 mmol NaOtBu, 0.70 mmol 2-(di-tert-butylphosphino)biphenyl and 0.18 mmol Pd2(dba)3. The mixture is degassed thoroughly and stirred at 45 C over night. The reaction mixture is filtered, the solvent removed in vacuo and the residue is purified by HPLC.
INTERMEDIATE 21 4-(3 -Iodo- 1 H-pyrazol- 1 -ylV2-isopropoxypyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.30 g, 1.547 mmol) in DMSO (7.73 mL) was added sodium hydride (60% in oil, 0.068 g, 1.701 mmol). The resulting mixture was stirred for 0.5 h before 4-bromo-2-isopropoxypyridine (0.334 g, 1.547 mmol) was added. The reaction mixture was stirred at 80 C overnight. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 24 g, 0-10 % EtOAc in hexanes) to give 4-(3 -iodo- 1 H-pyrazol- l-yl)-2-isopropoxypyridine, as a white solid. LCMS calc. = 330.00; found = 329.91. (Mu+Eta)+. NMR (500 MHz, CDC13): 5 8.17 (d, J= 5.7 Hz? 1 H); 7.78 (d, J= 2.6 Hz, 1 H); 7.20 (dd, J= 5.7, 1.9 Hz, 1 H); 6.93 (d, J= 1.9 Hz, 1 H); 6.64 (d, J= 2.5 Hz, 1 H); 5.34 (m, 1 H); 1.36 (d, J = 6.2 Hz, 6 H).
[000654] To a solution of Compound 103B (13 g, 60 mmol) in THF (300 mL) was added n-BuLi (2.4 M, 25 mL) at -60 C under N2 and the resultant mixture was stirred for 0.5 h, then a solution of Compound A4 (8 g, 20 mmol) in THF (50 mL) was added, then the mixture was stirred at -60 C for 1 h. After reaction monitored by LC-MS and TLC, added saturated NH4C1 solution (50 mL), extracted with ethyl acetate (100 mL x 3), washed with brine (100 mL x 2), and dried over anhydrous sodium sulphate. The crude product was purified with column chromatography (ethyl acetate in petroleum, 0-20% v/v) to offer Compound 103C.
With bis-triphenylphosphine-palladium(II) chloride; In toluene; at 100℃; for 1.5h;Inert atmosphere;
Step 1 : 2-isopropoxy-4-vinylpyridine To a stirred solution of <strong>[1142194-24-8]4-bromo-2-isopropoxypyridine</strong> (3.0 g, 13.9 mmol) in 90 mL toluene was added vinyl tri-n-butylstannane (4.7 mL, 16 mmol) and the solution was sparged with nitrogen gas. Bis(triphenylphosphine)palladium(II) chloride (975 mg, 1.4 mmol) was added and the mixture was heated to 100 C for 1.5 h. The mixture was cooled to RT and the solvent was removed in vacuo. The crude product was chromatographed on a 80 g S1O2 column using 0-30% EtOAc:hexane over 30 min at 60 mL/min. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound.