1-Bromo-2,4-difluoro-5-nitrobenzene

To a suspension of [1-] bromo-2, 4-difluorobenzene (53.0 mmol, 6.00 mL) in concentrated [H2SO4] (38.5 mL) at [0 C] was added dropwise concentrated HN03 (34.0 mL) maintaining internal temperature below [20 C.] The resulting mixture was stirred for 10 min at [0 C, ] then poured into ice/water with vigorous stirring. The mixture was extracted with [ET20] (3 x 100 mL). The combined organic extracts were washed with aqueous [NAHC03] solution (3 x 100 mL) and brine, dried over [MGSO4, ] filtered and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc: hexanes 1: 9) to afford 5-bromo-2, 4- difluoronitrobenzene as a yellow oil (12.2 g, [97percent). LH] NMR (400 MHz, [CDC13)] [5] 8.45 (t, 1H, J = 7.5 Hz), 7.16 (dd, 1H, J = 11.0, 8.6 Hz); ESMS [M/E] : 240, 238, 223, 221, 112To a 0 C. mixture of 1-bromo-2, 4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and H2SO4 (76.8 mL) was added HNO3 (68.0 mL) over 45 min at such a rate that the internal temperature was < 7 C. The resulting mixture was stirred for 1 h at 0 C., poured into ice water (400 mL), stirred vigorously for 2-3 min and extracted with CH2Cl2 (400 mL). The CH2Cl2 extract was washed with brine (1'500 mL), dried over Na2SO4, filtered and evaporated to give the product as a yellow oil (23.5 g, 95percent). 1H NMR (300 MHz, CDCl3) ' 7.14 (ddd, J=0.3, 7.8, 9.9 Hz, 1H), 8.39 (t, J=7.2 Hz, 1H).1-BROMO-2, 4-DIFLUORO-5-NITROBENZENE: 1-Bromo-2, 4-difluoro-5-nitrobenzene: To a 0° C. mixture of 1-bromo-2, 4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and HTo a 0° C. mixture of 1-bromo-2, 4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and H1-Bromo-2, 4-difluoro-5-nitrobenzene: To a 0° C. mixture of 1-bromo-2, 4-difluorobenzene (20.0 g, 11.7 mL, 0.100 mol) and HTo a 0° C. mixture of 1-bromo-2, 4-difluorobenzene (20.0 g; 11.7 mL; 0.100 mol) and HStep D: To a suspension of l-bromo-2, 4-difluorobenzene (1 1.7 mL, 104 mmol) in 96 mL concentrated HTo a suspension of l-bromo-2, 4-difluorobenzene (lOg, 52.1mmol, l.Oeq) in cold H2SO4 (37.9mL) was added Conc.HN01-Bromo-2, 4-difluoro-5-nitrobenzene: A solution of 1 -bromo-2, 4-difluoro-5-nitrobenzene (1 .806 g, 7.59 mmol) in N-Methyl-2- pyrrolidone (NMP) (3 mL) was treated with DIEA (3.98 ml_, 22.77 mmol), followed by a solution of N-isobutyltetrahydro-2H-pyran-4-amine (1 .313 g, 8.35 mmol) in N-Methyl-2- pyrrolidone (NMP) (12 mL). The reaction was stirred at 110C under Ar for 23 hours and then cooled to rt. The mixture was diluted with Et20, washed with 1 N HCI, sat. NaHC03, Brine, dried over Na2S04, filtered, and concentrated. Purification with column chromatography (0-40% EtOAc/Hexane) afforded N-(4-bromo-5-fluoro-2-nitrophenyl)-N- isobutyltetrahydro-2H-pyran-4-amine (1 .5138 g, 4.03 mmol, 53.2 % yield) as bright yellow oil that slowly became orange solid. 1H NMR (400MHz, CHLOROFORM-d) delta ppm 8.00 (d, J=7.3 Hz, 1 H), 6.92 (d, J=10.6 Hz, 1 H), 3.99 (dd, J=2.9, 11 .5 Hz, 2H), 3.32 (t, J=11 .7 Hz, 2H), 3.16 - 3.03 (m, 1 H), 2.88 (d, J=7.1 Hz, 2H), 1 .89 - 1 .62 (m, 5H), 0.90 (d, J=6.4 Hz, 6H). LCMS (ESI) m/z calcd for Ci5H2oBrFN203: 374.06. Found: 375.3/377.2 (M+1 )+.Step E: A mixture of Pd2dba3 (1.924 g, 2.101 mmol), and PPh3 (2.204 g, 8.404 mmol) was dissolved in toluene (200 mL), degassed and then stirred 10 minutes at ambient temperature. A solution of 1 -bromo-2, 4-difluoro-5 -nitrobenzene (10 g, 42.02 mmol) in toluene (200 mL) was then added to the above solution, followed by tributyl(vinyl)stannane (18.40 mL, 63.03 mmol). The mixture was refluxed for 2 hours, then poured into a mixture of aqueous NaF and diethyl ether. The residue was purified using silica gel column chromatography with 5-10-20% acetone in hexanes to provide l, 5-difluoro-2-nitro-4- vinylbenzene (6 g, 32.41 mmol, 77.13% yield) as yellow oil.5-Bromo-2, 4-difluoronitrobenzene (2.36 g, 10 mmol) was dissolved in a mixed solvent of ethanol / water (5/1, 24 mL), and iron powder (1.68 g, 30 mmol) and ammonium chloride ( 1.60g, 30mmol), stir evenly, heat up the reaction after dripping, TLC monitor, the raw materials are completely reacted after 6h, suction filtration under mild heat conditions after stopping the reaction, the filtrate is selected (PE / EA = 10/1), the column is shallow Yellow oil 1.73 g, yield: 68.21%.A 250-mL RB-flask, charged with To a solution of (2S, 6S)-4-benzyl-l, 2, 6-trimethylpiperazine (3 g, 13.4 mmol, 1.3 eq) in ethanol (90 mL) was added TEA (2 mL, 15.449 mmol, 1.5 eq) at RT under argon atmosphere, then after 30min, 1 -bromo-2, 4-difluoro-5 -nitrobenzene (4.5 mL, 10.299mmol, leq) was added at RT. Then the reaction mass was heated to 85 C for 16 h. The reaction was monitored by TLC, and TLC analysis indicated formation of polar spot. The reaction mixture was concentrated under reduced pressure to give crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh) using 3% methanol in DCM as an eluent to give (2S, 6S)-4-(4-bromo- 5-fluoro-2-nitrophenyl)-l, 2, 6-trimethylpiperazine (3 g, 46.8% yield) as yellow liquid. LCMS: [M+H]+ 347.96.To a stirred solution of (2R, 6R)-l, 2, 6-trimethylpiperazine (4g, 32.9 mmol, 1.3 eq) in ethanol (20 mL) was added TEA (5.23 mL, 37.5 mmol, 1.5 eq) at RT under argon atmosphere. After 30 min, 1 -bromo-2, 4-difiuoro-5 -nitrobenzene (preparation shown in Example 196 Step 4) was added (6 g, 25.0 mmol, 1 eq) at RT. Then the reaction mixture was heated to 85C for 16h. TLC analysis indicated formation of polar spot. The reaction mixture was concentrated under reduced pressure gave crude product. The crude product was purified by column chromatography (silica gel 230-400 mesh) using 1-1.5% methanol in DCM as an eluent afforded (2R, 6R)-4-(4-bromo-5-fluoro-2-nitrophenyl)-l , 2, 6- trimethylpiperazine (2.8 g, 32.2% yield) as yellow liquid. LCMS: [M+H]+ 345.85.To a solution of tert-butyl trans-3-methoxy-4-((2- methoxyethyl)(methyl)amino)pyrrolidine-l-carboxylate (0.14 g, 0.48 mmol) in DCM (5 mL) was added TFA (0.19 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in toluene (1 mL). The solution of deprotected amine was added dropwise to a rapidly stirring mixture of l -bromo-2, 4-difluoro-5- nitrobenzene (0.120 g, 0.48 mmol), potassium carbonate (0.033 g, 0.24 mmol) and N, N-diisopropylethylamine (0.085 mL, 0.48 mmol) in toluene (2 mL) at room temperature. After stirring for 20 minutes at room temperature the reaction mixture was heated to 45 C for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic extracts were dried over magnesium sulfate. After removal of the inorganics by filtration the filtrate was concentrated to dryness and the residue was purified by flash chromatography [1 -10% MeOH/DCM + 0.5% NH4OH] to afford trans- l-(4-bromo-5-fluoro-2-nitrophenyl)-4- methoxy-N-(2-methoxyethyl)-N-methylpyrrolidin-3-amine (0.034 g, 17%). ln NMR (500MHz, METHANOL-d4) delta = 8.01 (d, J=7.3 Hz, 1H), 6.94 (d, J=11.9 Hz, 1H), 4.05 (q, J=4.8 Hz, 1H), 3.54 (dd, J=5.9, 10.8 Hz, 1H), 3.52 - 3.47 (m, 2H), 3.44 - 3.39 (m, 1H), 3.37 (s, 3H), 3.33 (s, 3H), 3.29 - 3.23 (m, 2H), 3.11 (dd, J=4.5, 10.9 Hz, 1H), 2.82 - 2.74 (m, 1H), 2.73 - 2.65 (m, 1H), 2.35 (s, 3H).A solution of tert-butyl (R)-3-(methyl(2, 2, 2- trifluoroethyl)amino)pyrrolidine-l-carboxylate (0.54 g, 1.93 mmol) in DCM (5 mL) was treated with TFA (3.0 mL) at room temperature. After stirring ovemight at room temperature the volatiles were removed under a stream of air. The TFA salt of the deprotected amine was suspended in toluene (3 mL) and potassium carbonate (0.40 g, 2.9 mmol) was added carefully in portions. A solution of l-bromo-2, 4-difluoro-5- nitrobenzene (0.46 g, 1.93 mmol) in toluene (3 mL) was added dropwise and the reaction was warmed to 50 C. After 3 h the reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The layers were separated and the aqueous layer was extracted with an additional portion of EtOAc. The combined extracts were dried over magnesium sulfate and after removal of the inorganics by filtration the filtrate was concentrated onto celite. Purification by flash chromatography [10-50% EtOAc/hexanes] afforded (R)-l-(4-bromo-5-fluoro-2-nitrophenyl)-N-methyl- N-(2, 2, 2-trifluoroethyl)pyrrolidin-3-amine (0.40 g, 52 %). LCMS [M+H]+: 400.2.A solution of 1 -bromo-2, 4-difluoro-5 -nitrobenzene (0.22 g, 0.95 mmol) in PhMe (1 mL) was slowly added to a rapidly stirring mixture of (R)-N- ethyl-N-methylpyrrolidin-3-amine (0.12 g, 0.95 mmol) and K2C03 (0.065 g, 0.47 mmol) in PhMe (2 mL) at 45 C. After 4 h the heat was turned off and the reaction was allowed to stir at room temperature for 18 h. The reaction mixture was concentrated onto celite and purification by flash chromatography [0.5-10% MeOH/DCM + 0.5% NH4OH] afforded (R)-l-(4-bromo-5-fluoro-2-nitrophenyl)-N- ethyl-N-methylpyrrolidin-3-amine (0.22 g, 66 %). LCMS [M+H]+: 346.3.A solution of l-bromo-2, 4-difluoro-5-nitrobenzene (0.225 g, 0.945 mmol) in PhMe (1 mL) was slowly added to a rapidly stirring mixture of trans - -^chichiomicronchiomicron-^- dimethylpyrrolidin-3-amine (0.13 g, 0.95 mmol) and K2CO3 (0.065 g, 0.47 mmol) in PhMe (2 mL) at room temperature. After stirring for 15 minutes the reaction was warmed to 45 C for 5 h. The reaction was cooled to room temperature and partitioned between H20 (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with an additional portion of EtOAc. The combined organic extracts were concentrated onto celite and purification by flash chromatography [1-10% MeOH/DCM + 0.5% NH4OH] afforded /rara-l-(4-bromo-5-fluoro-2-nitrophenyl)-4- fluoro-N, N-dimethylpyrrolidin-3-amine (0.25 g, 76 %). LCMS [M+H]+: 350.3.A suspension of 3-N-boc-3-(methylamino)pyrrolidine (1.33 g, 6.64 mmol) and K2CO3 (0.459 g, 3.32 mmol) in toluene (10 ml) was stirred for 5 min at room temperature. Then a solution of 1 -bromo-2, 4-difiuoro-5 -nitrobenzene (1.580 g, 6.64 mmol) in toluene (1 ml) was added dropwise from a pipette (2 ml of toluene were used to rinse the vial) and the reaction was stirred at 50 C for 3 h 30 min. Then the reaction mixture was partitionned into water and DCM and the product was extracted by DCM (3x20mL). The organic phase was dried over MgSC>4 and after filtration and solvents removal, the crude material was dry loaded and purified by flash chromatography [0-10% MeOH/DCM] to afford the desired tert-butyl (l-(4- bromo-5-fluoro-2-nitrophenyl)pyrrolidin-3-yl)(methyl)carbamate (2.17 g, 5.19 mmol, 78 % yield) as an orange oil. LCMS [M+H]+ 418.2.

Molecular Weight:237.99
XLogP3:2.6
Hydrogen Bond Acceptor Count:4
Exact Mass:236.92370
Monoisotopic Mass:236.92370
Topological Polar Surface Area:45.8
Heavy Atom Count:12
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes