Methyl 4-bromo-2,6-difluorobenzoate

Off-white powder

Preparation of Methyl [(25)-l -{(2S)-2-[5-(4-{2-[(2S - l-{(25)-2-[(methoxycarbonyl)amino]-3- methy I butanoyl } pyrrolidin-2-yl]- 1 H-imidazol-5-y 1 } - 1 , 10b-dihydrofuro[2, 3 , 4-W]xanthen-9-y I)- l / -imidazol-2-yl]pyrrolidin-l -yl}-3-methyl- l -oxobutan-2-yl]carbamate (Compound 15); Step A - Synthesis of Compound Int-23a; To a stirred solution of 4-bromo-2, 6-dibromobenzoic acid (47 g, 0.2 mol) in methanol (500 mL) was added SOClTo a solution of 4-bromo-2, 6-difluorobenzoic acid (1.00 g, 4.22 mmol) in 30 mL methanol was added TMS-Cl (1.1 ml, 8.61 mmol), and the mixture was heated at 60 °C under N4-bromo-2, 6-difluoro-benzoic acid (5.15 g, 21.7 mmol) obtained in Step A was dissolve in 54 mL of MeOH.SOCl2 (2.4 mL, 32.6 mmol) was added thereto, and the mixture was stirred for 3 hours under reflux. The reaction solutionwas concentrated under reduced pressure, diluted with sodium bicarbonate aqueous solution, and extracted with EtOAc.The organic layer was collected and dried with MgSO4 to obtain the title compound (2.9 g, 53percent).1H-NMR (CDCl3) δ 7.16 (2H, m), 3.95 (3H, s)Thionylchloride (6.12 mL, 84.4 mmol) was added dropwise to dry methanol (100 mL) at-20 00 4-Bromo-2, 6-difluorobenzoic acid (10 g, 42.2 mmol)) was added and the reaction mixturewas heated under reflux 0/n. The mixture was concentrated in vacuo and traces of hydrochloricacid were co-evaporated with methanol (3 times). The residue crystallized upon standing giving11 .8 g of the title compound.Step A - Synthesis of Compound Int-23aTo a stirred solution of 4-bromo-2, 6-dibromobenzoic acid (47 g, 0.2 mol) in methanol (500 mL) was added SOClTo a 100-mL round-bottom flask was added 4-bromo-2, 6-difluorobenzoic acid l04a(3.5 g, 14.77 mmol, 1.0 equiv.) and methanol (10 mL) Thionyl chloride (3.3 g, 2.0 equiv.)was added dropwise at 0°C Vith stirring. The resulting mixture was stirred at room15 temperature overnight. 100 mL of water/ice was added to quench the reaction. The aqueousmixture vvas extracted with ethyl acetate (200 rnL x 2), :md the combined organic layers werewa5hed with brine (200 mL x 2), dried over anhydrous sodium sulfate, and concentratedunder vacuum to a residue which '.vas purified by silica gel column chromatography eluting, .vith ethy 1 acetate/petroleum ether (O~o-4percent). Removal of sol vents afforded methy 1 4-bromo-20 2, 6-difluorobenzoate l 04b (1.2 g, 32percent) as a colorless oil.41(a) Step 1. Intermediate 36; Preparation of 4-(3, 3-dimethylbut-1-ynyl)-2, 6-difluorobenzoic acid; Methyl 4-bromo-2, 6-difluorobenzoate 4-bromo-2, 6-difluorobenzoic acid (7 g, 0.03 mol), methyl iodide (2.8 mL, 0.045 mol) and potassium carbonate (12.22 g, 0.08842 mol) were placed in 100 mL acetone in a sealed tube and heated at 50° C. overnight. The reaction was cooled, partitioned between EtOAc and water. The organic layer was dried (Na

Molecular Weight:251.02
XLogP3:2.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:249.94410
Monoisotopic Mass:249.94410
Topological Polar Surface Area:26.3
Heavy Atom Count:13
Complexity:189
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes