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Step 1: Methyl 2-amino-4-fluoro-3-methylbenzoateA solution (1.0 M) of <strong>[129833-28-9]2-amino-4-fluoro-3-methylbenzoic acid</strong> in dry MeOH was treated with SOCl2 (1.5 eq.). The reaction mixture was stirred overnight at RT. After evaporation of the solvent the residue was treated with aqueous NaHC?3 (saturated solution) and extracted with EtOAc. The combined organic layers were dried. Evaporation of the solvent afforded (77%) the title compound as a solid. 1H NMR(400 MHz, DMSO-dg, 300 K) ? 2.01 (s, 3H), 3.82 (s, 3H), 5.96 (bs, 2H), 6.34 (t, IH, J 8.3), 7.72 (t, IH, J 8.8). MS (ES+) m/z 184 (M+H)+.
First Step <strong>[129833-28-9]2-amino-4-fluoro-3-methylbenzoic acid</strong> [which can be synthesized, for example, by the method described in J. Med. Chem. 1991, 34, 217] (11.4 g, 67.45 mmol) and an NMP solution (24 mL) of urea (12.14 g, 20.23 mmol) were stirred at 180C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water (60 mL) and the precipitated solid was collected by filtration. The solid was washed in turn with water and ethyl acetate and then dried to obtain 10.0 g of 7-fluoro-8-methyl-2,4-quinazolinedione. [Show Image] 1H-NMR (400 MHz, DMSO-d6) d (ppm): 2.22 (s, 3H), 7.01 (t, 1H, J = 9.0 Hz), 7.81 (dd, 1H, J = 8.4, 6.8 Hz), 10.61 (br, 1H), 11.38 (br, 1H); ESI-MS (m/z): 195 [M+H]+.
N-(7-amino-4-chloro-1-methyl-1H-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide[ No CAS ]
[ 129833-28-9 ]
[ 205445-52-9 ]
tert-butyl (S)-(1-(3-(4-chloro-3-(N-(4-methoxybenzyl)methylsulfonamido)-1-methyl-1H-indazol-7-yl)-7-fluoro-8-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
120 mg
To a dry reaction vial under nitrogen was added (S)-2-((fer?- butoxycarbonyl)amino)-3-(3,5-difluorophenyl)propanoic acid (45 mg, 0.149 mmol), 2- amino-4-fluoro-3-methylbenzoic acid (25.2 mg, 0.149 mmol) and anhydrous Pyridine (0.9 mL). The reaction was flushed with argon, treated with diphenyl phosphite (125 , (1645) 0.646 mmol) and heated at 75 C for 80 min. The reaction was treated with N-(7-amino-4- chloro-1 -methyl- lH-indazol-3-yl)-N-(4-methoxybenzyl)methanesulfonamide (Int 17d, 59 mg, 0.149 mmol) and heated at 75 C for 18 h. The solvent was removed under a gentle stream of nitrogen and the crude matenal was purified via silica gel chromatography (80 g SiC column, 0-100% ethyl acetate :hexanes) to afford the title compound, 120 mg. (1646) LC/MS m/z = 755.3 (M-55); 833.3 (M+Na). Column: Waters Aquity UPLC BEH CI 8, 2.1 mm x 50 mm, 1.7 mupiiota particles; Mobile Phase A: 100% water with 0.05% TFA; (1647) Mobile Phase B: 100% acetonitnle with 0.05% TFA; Temperature: 40 C; Gradient: 2 %B to 98 %B over 1.5 min, then a 1.5 min hold at 100 %B; Flow: 0.8 mL/min; Detection: UV (220 nm); Retention Time: 1.94 min.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 22 - 70℃; for 16h;
To a solution of <strong>[129833-28-9]2-amino-4-fluoro-3-methylbenzoic acid</strong> (1 equiv, Enamine, CAS 129833-28-9) in DMF (0.12 M) was added N-chlorosuccinimide (1 equiv, Sigma-Aldrich, CAS 128-09-6) at 22 C. The resulting solution was stirred and heated to 70 C. for 16 hours. LCMS analysis revealed product formation. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography using a Teledyne ISCO silica cartridge, eluting with 0 to 100% EtOAc in hexanes gradient. The desired fractions were combined and concentrated to afford the title compound (58% yield).
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