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With n-Butyl nitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 3.5h;
Step G (2): 3-bromo-5-(methoxycarbonyl)benzoic acid.; To a mixture of copper (II) bromide (5.5 g, 24.6 mmol), 7-butyl nitrite (3.17g, 30.75 mmol) and acetonitrile (300 mL) was added <strong>[28179-47-7]3-amino-5-(methoxycarbonyl)benzoic acid</strong> (Step G (1), 4.0 g, 20.5 mmol) in aceonitrile (300 mL) over 30 min at 0 0C and the mixture was warmed up and stirred at rt for 3 h. H2O was added and acetonitrile was removed. Ethyl acetate (600 mL) was added and the mixture was washed with 3N HCl, H2O, dried over Na2SO4, and concentrated in vacuo to give the title compound (97% yield): 1H NMR (CDCl3, 500 MHz) delta ppm 3.96 (3H, s), 8.41 (IH, s), 8.41 (IH, s), 8.67 (IH, m). MS (ESI) (M-HX 259.02.
68%
Step 2: Preparation of 3-bromo-5-(methoxycarbonyl)benzoic acid[00143] 3-Amino-5-(methoxycarbonyl)benzoic acid (1.0 g, 5.12 mmol, 1 eq.) was dissolved in 15% HBr (22.5 mL) at RT, then cooled to 0 0C with stirring. A 2.5 M aqueous solution OfNaNO2 (2.3 mL, 5.64 mmol, 1.1 eq.) was added slowly via an addition funnel to generate the diazonium salt. In a separate flask, CuBr was partially dissolved in 15% HBr (9 mL) and cooled to 0 0C with stirring, to which the <n="89"/>diazonium salt solution was subsequently added. A slight exotherm was observed. The reaction was stirred at RT for 30 minutes then carefully heated at 70 0C for 1 hour. The reaction was worked up by filtering off insoluble material as crude product. The solids were dissolved in water/EtOAc and the layers separated. The aqueous layer was extracted again with EtOAc. The organic layers were combined, dried over sodium sulfate and concentrated to give an off-white solid. The product was purified over silica gel in 1 : 1 hexanes/EtOAc to 100% EtOAc to 4: 1 methylene chloride/MeOH to yield 3-bromo-5-(methoxycarbonyl)benzoic acid (0.90 g, 3.47 mmol, 68% yield) as a white solid. MS found: (M - H)+ = 257/259.
34%
With n-Butyl nitrite; copper(ll) bromide; In acetonitrile; at 0 - 30℃; for 1.5h;
14.0 g (62.7 mmol) copper-(II)-bromide and 12.0 ml (102.6 mmol) n-butylnitrite in 300 ml acetonitrile were combined with 10.0 g (51.2 mmol) 6.3-a, suspended in 300 ml acetonitrile, while cooling with an ice bath. The reaction solution was stirred for 1.5 hours at 30 C., then evaporated to dryness i. vac. Then the residue was combined with dichloromethane and washed with 3N HCl and water. The organic phase was dried and evaporated to dryness using the rotary evaporator. The residue was combined with diethyl ether and the precipitate was filtered off. Yield 4.5 g (34%) 6.3-b. ES-MS (M+H)+=257/259 (bromine isotopes) RT(HPLC-MS)=2.87 min
With n-Butyl nitrite; copper(ll) bromide; In acetonitrile; at 0 - 20℃; for 1.41667h;
A mixture of copper (II) bromide (5.55 g, 24.9 mmol), n-butyl nitrite (3.21 g, 31.2 mmol) and acetonitrile (90 mL) was stirred in a round bottom flask at 0 C. 3-Amino-5-(methoxycarbonyl)benzoic acid (4.05 g, 20.77 mmol) was added as a slurry in warm aceonitrile (210 mL) over 25 min. and the mixture was stirred at room temeprature for 1 h. The mixture was concentrated and partitioned between dichloromethane and 3N hydrochloric acid. The organic layer was separated, dried over MgSO4, and concentrated in vacuo to give the title compound (5.3 g): 1H NMR (CD3OD, 500 MHz) delta ppm 3.97 (3H, s), 8.34-8.36 (2H, m), 8.58 (1H, m).
With dimethylsulfide borane complex; In tetrahydrofuran; at 0 - 60℃; for 12.5h;
Method 125; Methyl 3-bromo-5-(hydroxymethyl)benzoate; A solution of 3-bromo-5-(methoxycarbonyl)benzoic acid (Method 97; 1.2 g, 4.6 5 mmol) in anhydrous THF (20 ml) was treated with BH3-dimethyl sulfide (2.0 M in THF, 3.5 ml, 6.9 mmol) dropwise under nitrogen at 0 C. The mixture was stirred at 0 C for 30 min then heated up to 60 C for 12 hours. The reaction mixture was quenched with H2O-acetic acid (1 :2) (3 ml) and then diluted with EtOAc. The organics were washed with NaHCO3 (sat) and then dried with NaCl (sat) followed by Na2SO4 (s). The solvents were removed under 10 reduced pressure to give the desired product.
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