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methyl 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tert-butyl methyl ether; at 120℃; for 1h;
General procedure: A solution of [Ir(COD)OMe]2 (5mol%), dtbpy (5 mol%) and B2pin2 (1.2mol %) in MTBE (0.4M) wasprepared in a sealed vial and an aliquot then added to a thick-walled microwave synthesis vial containing the starting pyridine . The vessel was sealed with a crimp top septum cap and shaken until allof the substrate was dissolved. The reaction mixture was stirred on a magnetic stirring block or irradiated in a microwave reactor for the stated time and temperature. Upon completion, the volatiles were removed in vacuo to afford the crude borylated product. To the crude mixture under N2, was added palladium catalyst (5 mol%), base (2 eq.), aryl halide (1.1 - 2eq.) and the stated solvent. The reaction was heated at the stated temperature for the stated time. The reaction mixture was diluted with water and extracted into EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the crude product. This was dry-loaded onto silica geland purified by silica gel flash column chromatography using the stated solvent system.
General procedure: Method (ii): Under anhydrous condition, to a solution of acetonitrile (2.5 equiv.) in DME (c0.8mol.L1) cooled at -78C, BuLi (1 .6N in hexane - 2.5 equiv.) was added dropwise. The mixturewas stirred for 1 hour at -78C, then a solution of the acid derivative A (acid chloride or ester -1.0 equiv.) in DME (cf=0.15 mol.L1)was added dropwise. The reaction mixture was stirred at -78C for 1 hour and then was allowed to warm to room temperature and the next step wasperformed.Acetic acid (10.0 equiv.) was added and hydrazine D, HCI salt (1.0 equiv.) was introduced. The reaction mixture was warmed for 18 hours at 100C. After cooling, the reaction mixture was concentrated and the residue was coevaporated twice with toluene before hydrolysis with saturated aqueous NaHCO3 solution. The precipitate was collected, washed with water and dried under reduced pressure at 60C with P205 for 18 hours.:_Compound 2: 2-(2-Fluoro-pyridin-4-yI)-4H-pyrazolo[1, 5-a]quinazolin-5 -one.Compound 2 was obtained according to general procedure 1(u), starting from 2-fluoro- isonicotinic acid methyl ester in presence of 2-hydrazino-benzoic acid as a brown solid in 83%yield.1H-NMR (400 MHz, DMSO): 6.64 (s, 1H, Ar); 7.53-7.57 (m, 1H, Ar); 7.71 (bs 1H, Ar); 7.91-7.96(m, 2H, Ar); 8.16-8.21 (m, 2H, Ar); 8.33 (d, J5.2 Hz, 1H, Ar); 12.42 (bs, 1H, NH).MZ (M+H) = 281.3.
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 18h;
To a stirred suspension of H-1 b (100 mg, 0.83 mmol) and Cs2C03 (405 mg, 1.24 mmol, 1 .5 eq.) in NMP (1 .0 ml.) is added K-1 b (263 mg, 1.66 mmol, 2.0 eq.). The reaction mixture is stirred at 100 C for 18 h. After full conversion the reaction mixture is taken up in water. The mixture is extracted with DCM, the combined organic phases are dried over MgS04, filtrated and the solvent is evaporated under reduced pressure. The crude product is purified using reverse phase chromatography to afford pure product L-1 an (yield: 25 % - 52 mg, 0.21 mmol; HPLC-MS: (M+H)+ = 254, tRet. = 1.00 min, method VAS).
To a mixture of sodium hydride (60% dispersion in mineral oil, 64.5 mg, 1.61 mmol) in tetrahydrofuran (8 mL) at ambient temperature was added cyclopropanol (94.0 mg, 1.61 mmol) dropwise and the reaction mixture was allowed to stir for 15 min after cessation of gas evolution. Methyl 2-fluoroisonicotinate (250 mg, 1.61 mmol) was added dropwise and the reaction mixture was allowed to stir for 16 h at ambient temperature. The reaction mixture was diluted with ethyl acetate and water and the layers separated and the aqueous layer adjusted to pH = 1 with an aqueous solution of hydrochloric acid (1 M). The layers were separated and the organic layer concentrated under reduced pressure. The residue was purified by preparative HPLC, eluting with acetonitrile:water - 0:100 to 95:5 to afford the title compound. MS: m/z = 180.0 [M+H]