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b 4-Bromo-2,5-difluorobenzonitrile <strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (1.82 g, 8.3 mmol) and hydroxylamin-O-sulphonic acid (1.1 eq., 1.03 g) in water (40 ml) were heated to 100° C. for 6 h, cooled and extracted with ethyl acetate. The organic layer was dried (sodium sulphate) and evaporated to give the title compound as a pale yellow solid (1.2 g). 1H NMR 300 MHz (CDCl3) 7.51 (1H, t), 7.39 (1H, t).
a 4-Bromo-2,5-difluorobenzaldehyde n-Butyllithium (1.95M in hexanes, 10.2 ml)) was added dropwise to a stirred solution of 1,4-dibromo-2,5-difluorobenzene (5 g, 18.4 mmol) in diethyl ether (60 ml) at -70° C. After 1 h, the solution was warmed to 0° C. over 1 h, diluted with water, the layers separated and the ether layer dried over sodium sulphate and evaporated. Purification by column chromatography (Biotage), eluding with 5percent ethyl acetate/hexane, gave a yellow oil (1.82 g). 1H NMR 300 MHz (CDCl3) 10.28 (1H, s), 7.61 (1H, dd), 7.48 (1H, dd).
With ammonium chloride; In tetrahydrofuran; N,N-dimethyl-formamide;
Method 6 4-Bromo-2,5-difluorobenzaldehyde To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at -40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise. After 1 h at -40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at -40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate. The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74percent) as a solid. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 10.28 (d, 1H) 7.61 (dd, 1H) 7.48 (dd, 1 H).
Example 31 Preparation of 4-bromo-2,5-difluorobenzaldehyde [0289] 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at -78 C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at -78 C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20% ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86%): 1H NMR (400 MHz, CDCl3): delta 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H).
66.7%
To a stirred solution of XXXII-1 (12 g, 44.1 mmol) in THF (150 mL) was added dropwise of XXXII-1A (44.1 mmol, 34 mL, 1.3 M) at -40 C. After stirred 1 h at -40 C., DMF (64 g, 882 mmol) was added and the mixture was stirred overnight. NH4Cl (aq., 2M) was added and the mixture was extracted with EtOAc. The organic phase was dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (PE/EA=10/1) to afford XXXII-2 (6.5 g, yield: 66.7%).
55.8%
To a solution of l,4-dibromo-2,5-difluorobenzene (15 g, 55 mmol) in toluene (600 mL) cooled to -78 C was added butyllithium (22 mL, 55 mmol) and the reaction was kept at -78 C for 30 minutes. N,N-dimethylformamide (4.4 g, 61 mmol) was added and the reaction was stirred for 2 hours while warming to ambient temperature. To the reaction was added water (200 mL) and EtOAc (400 mL) and the organic layers were separated. The organic layer was washed with brine (200 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with 5% EtOAc/Hexane to yield 4-bromo-2,5-difluorobenzaldehyde (6.7 g, 55.8%).
37%
n-Butyl lithium (3.6 ml,7.7 mmol) was added drop wise to a solution of 1,4- dibromo-2,5-difluoro-benzene (2g, 7.35mmol) in dry ether at -78C under nitrogen atmosphere and the resulting mixture was stirred at -78C for 30 minutes. This was followed by the addition of DMF (0.85ml, 11.03mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5% ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2% ethyl acetate in hexane) to afford 600mg of the product (37% yield).1H NM (CDC13, 300 MHZ): delta 10.27-10.26 (d, 1H), 7.61-7.57 (t, 1H), 7.49- 7.44 (q, 1H)
To a Et2O solution (200 mL) containing 1,4-dibromo-2,5-difluorobenzene (19.72 g, 72.5 mmol) cooled to -78 degrees C. was added 30.5 mL of a 2.5 M hexanes solution of n-BuLi (76.2 mmol). The resulting green solution was stirred for 20 min at -78 degrees C. when DMF (7.95 g, 10.8 mmol) was added. The reaction was stirred for 30 min and then quenched with H2O. The organics were taken up in EtOAc and washed with sat. NaHSO4 followed by drying over MgSO4. The solvent was removed in vacuo and the residual oil purified on the Biotage (2-5% EtOAc/hexanes) yielding 11.4 g (51.7 mmol) of 4-bromo-2,5-difluorobenzaldehyde. 1H NMR (400 MHz, CDCl3) delta 10.2 (s, 1H), 7.57 (m, 1H), 7.45 (m, 1H) ppm.
With hydrogenchloride; sodium hydroxide; sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; In dichloromethane; water; ethyl acetate;
Method 10 4-(4-bromo-2,5-difluorobenzyl)morpholine <strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (15.8 g, 60.8 mmol) was dissolved in dichloromethane (150 mL) and stirred under nitrogen. Morpholine (5.83 mL, 66.9 mmol) was added followed by sodium triacetoxyborohydride (16.74 g, 79.0 mmol) portionwise (4*). The mixture was stirred at ambient temperature over night. The reaction was quenched with saturated NaHCO3 (aq, 80 mL). The phases were separated. To the organic phase was added hydrochloric acid (aq, 2M, 80 mL). The mixture was stirred for 20 min. A solid was isolated by filtration. To the solid was 2M NaOH (60 mL), H2O (60 mL) and EtOAc (100 mL) added. The mixture was stirred for 15 min. The phases were separated and the organic phase was concentrated to give the title compound as a solid (17.8 g, 60.9 mmol, 100percent. 1H NMR (500 MHz, DMSO-d6) delta ppm 7.69 (dd, 5.83 Hz, 1H) 7.42 (dd, 1H) 3.53-3.60 (m, 4H) 3.48 (d, 2H) 2.30-2.47 (m, 4H). MS (ES+) m/z 292 (M+H)+.
With sodium tris(acetoxy)borohydride; sodium hydrogencarbonate; triethylamine; In 1,1-dichloroethane;
Method 5 (S)-4-(4-Bromo-2,5-difluorobenzyl)-3-methylmorpholine <strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (331 mg, 1.5 mmol), (S)-3-methylmorpholine hydrochloride (206 mg, 1.50 mmol) and sodium triacetoxyborohydride (461 mg, 2.18 mmol) were mixed in dichloroethane (5 mL). Triethylamine (0.230 mL, 1.65 mmol) was added and the resulting mixture was stirred at RT under argon atmosphere for 24 h. NaHCO3 (25 mL) was added and the mixture was extracted with dichloromethane (3*25 mL).
difluorobenzylamino)ethanol was prepared as described below:<strong>[357405-75-5]4-Bromo-2,5-difluorobenzaldehyde</strong> (1.0 g, 4.52 mmol) was dissolved in degassed DCE (25 mL) and stirred under nitrogen. 2-Aminoethanol (0.238 mL, 4.52 mmol) was added followed by sodium triacetoxyborohydride (2.398 g, 11.31 mmol) portionwise. The mixture was stirred at room temperature for 3 hours. Sodium carbonate (aq) was added. The phases were separated and the organic phase was extracted with HC1 (2M, aq). The aquous phase was neutralized with KOH (s) and was extracted with dichloromethane (x3). The combined organic phases were dried and evaporated to give the title compound (1.2 g, 90percent) that was used without further purification.MS (APCI+) m/z 266 [M+H]+.
[00351] Step 2: To a solution of tert-butyl 2-aminoethylcarbamate (4.86 g, 30.3 mmol) in THF (500 mL) was added <strong>[357405-75-5]4-bromo-2,5-difluorobenzaldehyde</strong> (6.7 g, 30.3 mmol) followed by acetic acid (1.93 mL, 33.3 mmol) and the reaction was stirred for 30 minutes. Sodium triacetoxyhydroborate (9.64 g, 45.5 mmol) was added and the reaction was stirred overnight at ambient temperature. To the reaction was added sodium hydrogen carbonate (121 mL, 121 mmol, a saturated aqueous solution) and the reaction was stirred for 30 minutes followed by addition of benzyl carbonochloridate (4.31 mL, 30.3 mmol). The reaction was stirred at ambient temperature for 4 hours. The reaction was partitioned between EtOAc (500 mL) and water (500 mL) and the organic layer was separated. The organic layer was washed with brine (100 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with DCM to give benzyl 4-bromo-2,5-difluorobenzyl(2-((tert- butoxycarbonyl)amino)ethyl)carbamate (13 g, 26.0 mmol, 85.9percent yield).
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