5-Bromo-2-nitrobenzaldehyde

Preparation of 5-bromo-2-nitro-benzaIdehyde (105):[0192] Compound 104 (11.63 g (42.9 mmol)) was dissolved in 500 mL 1 : 1 mixture of THF and water. To this solution 34.3 g (160 mmol) NaIOCompound 7.4 (11.63 g (42.9 mmol)) was dissolved in 500 mL 1:1 mixture of THF and water. To this solution 34.3 g (160 mmol) NaIO4 was added and the mixture was stirred at room temperature for 1 hr while the dark solution became pale yellow with a heavy precipitate. The solid material was filtered off, washed twice with 100 mL ethyl acetate and the organic phases were pooled and evaporated to dryness. The residue was filtered through a 400 mL silica gel pad using toluene for elution to get 7.08 g (71percent) of the title compound; H1-NMR (DMSO-d6): ?(ppm) 10.10 (s, 1H), 8.09-7.99 (m, 3H).Under ice-water bath conditions, To a 1L round bottom flask 289ml three mass fraction of 98percent sulfuric acid (5.4mol), 64 ml of Compound II (0.54 mol) was added dropwise slowly with stirring, Plus completed, After the temperature of the system dropped to 10 ° C, 27 ml of nitric acid (0.59 mol) in a mass ratio of 65percent was slowly added dropwise to the system, Plus complete TLC monitoring, The reaction was complete for 4 hours, The reaction was slowly poured into 2 L of ice water, Filtration, The filter cake was washed with water, Wash to the filtrate without acid, The solid was recrystallized from n-hexane and ethyl acetate to give 91 g of compound III as a white solid, Yield 73.1percent.To concentrated nitric acid (10 mL) in concentrated sulfuric acid (120 mL) at 5°C was added 3- bromobenzaldehyde (11.7 mL, 100 mmol) dropwise. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto ice and the resulting precipitate removed by filtration, dissolved in dichloromethane, dried over MgSOThe concentrated sulfuric acid (70 mL) and 70percent concentrated nitric acid (5 mL) were mixed under ice-3-Bromobenzaldehyde (10 g, 54 mmol) was added.After 6 h reaction at room temperature, The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried and concentrated. The crude product was beaten (ethyl acetate / petroleum ether = 1/5, v / v) and dried to give 5-brom0-2-nitrobenzaldehyde (8.5 g) in a yield of 68.4percent.31a) 10049] Therefore an alternative approach was adopted in which benzaldehyde 11 was nitrated to the known benzaldehyde 12, which in turn was subjected to reductive amination by condensing it with ammonium hydroxide, using sodium borohydride as reducing agent to produce amine 13 in high yield. Acetylation amine 13 generated acetamide 14, which was reacted with tert-butyl piperazine- 1 -carboxylate under l3uchwald-Hartwig conditions to afford intermediate 15 in good yield. Reduction of nitro group of 15 over Pd——C in a Parr apparatus produced intermediate 16 in 91percent yield high yield. Exposure of intermediate 16 under basic conditions rendered the desired diamine 17 in good yield after colunm purifications. Reaction of 17 with CDI in THF, heating the mixture at 80° C. for 6 hours, gave access to the key intermediate 10 in an overall yield of 33percent from 14. Exposure of intermediate 10 to trifluoroacetic acid in a mixture of methanol and dichloromethane finally thrnished the desired key intermediate 18 (scheme 2).Step A: Potassium nitrate (49.2 g, 0.486 mol) was added to 240 g of cooled sulfuric acid in a three neck round bottom flask, keeping the temperature below 25 °C. This was followed by the slow addition of 3-bromobenzaldehyde (30.0 g, 0.162 mol). Once the addition was complete, the mixture was allowed to gradually warm to room temperature overnight. The mixture was then poured into 500 mLs of ice water, resulting in a light yellow precipitate. The solids were collected by filtration and dried under vacuum for several hours. Purification of the crude product was done in the following way: The collected solids were divided into two lots and each lot purified using two 340 g Biotage Snap Cartridges in series with 3: 1 Hexanes:EtOAc as the eluant. Obtained 20 g of 5-bromo-2-nitrobenzaldehyde (54percent) as a light yellow solid. NMR (400 MHz, CDC1Step a: To an ice cold cone, sulphuric acid (400 mL) was added fuming nitric acid (200 mL) and to this solution was added 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise within 15 min. The reaction mixture was stirred for 10 min at same temperature at which time TLC showed complete reaction. The reaction mixture was quenched in ice water and filtered to afford a mixture of products which was purified by flash column chromatography eluting with EtOAc/hexane (1-5 percent) to give 5-bromo-2-nitrobenzaldehyde (ii) as white solid (60 g, 48 percent).5-Bromo-2-nitrobenzaldehyde (ii) To ice cold conc. sulphuric acid (400 mL) was added fuming nitric acid (200 mL) dropwise followed by 3-bromobenzaldehyde (i) (100 g, 0.540 mol) dropwise over 15 min. Fuming nitric acid (200 mL) was added to sulphuric acid (400 mL) at 0 °C and then 3- bromobenzaldehyde (100 g, 0.54 mol) was added dropwise in 15 minutes. After stirring for 10minutes at the same temperature, the reaction mixture was poured into ice water and filtered to afford the mixture of products which was purified by flash column chromatography eluting with PE / EtOAc (100 / 1 to 20 / 1) to give 5-bromo-2-nitrobenzaldehyde as white solid (60 g, 48 percent). ‘H-NMR (CDC13, 400 MHz) 10.41 (s, 1H), 8.028.06 (m, 2H), 7.88 (s, 1H). MS (M+H): 230 /232.Fuming nitric acid (200 mL) was added to sulphuric acid (400 mL) at 0 °C and then 3-bromobenzaldehyde (100 g, 0.54 mol) was added dropwise in 15 minutes. After stirring for 1010 minutes at the same temperature, the reaction mixture was poured into ice water and filtered toafford the mixture of products which was purified by flash column chromatography eluting withPE I EtOAc (100 I 1 to 20 I 1) to give 5-bromo-2-nitrobenzaldehyde as white solid (60 g, 48 percent).1H-NMR (CDCh, 400 MHz) 8 10.41 (s, 1H), 8.02~8.06 (m, 2H), 7.88 (s, 1H). MS (M+Ht: 230I 232.Treatment of 1 (986 mg, 6.53 mmol) with NBS (878 mg, 4.93 mmol) in H2SO4 (conc. 5.0 mL), as described in the paper gave after chromatography (hexanes/EtOAc, 8:2) the following fractions in order of elution: (I) 4-bromo-2-nitrobenzaldehyde (2)N-Bromosuccinimide (NBS) (1.48 g, 8.32 mmol) was added to a solution of 1 (1.01 g, 6.71 mmol) in H2SO4 (concentrated 5.0 mL). The resulting mixture was stirred at ambient temperature (3 h). The reaction was quenched with ice and extracted with ethyl acetate (320mL). The combined organic phases were washed with saturated NaCl (aqueous, 30 mL), dried (MgSO4), and filtered through a silica gel plug, and the solvents were evaporated under reduced pressure. The resulting brown oil was purified by column chromatography (hexanes=EtOAc, 8:2) to afford the following fractions in order of elution: (I) 7 (28 mg, 0.09 mmol, 1percent) as an off-white solid; (II) 2 (328 mg, 21percent), 4 (140 mg, 9percent), and 3, 4-dibromo-2-nitrobenzaldehyde (6) (94 mg, 5percent); (III) 5 (310 mg, 20percent), 8 (65 mg, 3percent), 1 (168 mg, 17percent); (IV) 3 (54 mg, 0.23 mmol, 4percent).Treatment of 1 (504 mg, 3.33 mmol) and NBS (1.48 g, 8.30 mmol) in H2SO4 (3.0 mL) as described above provided after purification by chromatography (hexanes/EtOAc, 85:15) the following fractions in order of elution: (I) 7 (65 mg, 0.21 mmol, 9percent); (II) 2 (153 mg, 20percent), 4 (58 mg, 8percent), and 6 (128 mg, 12percent); (III) 5 (108 mg, 14percent), 8 (129 mg, 13percent), and 1 (17 mg, 3percent); (IV) 3 (57 mg, 0.25 mmol, 8percent).

Molecular Weight:230.02
XLogP3:2.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:228.93746
Monoisotopic Mass:228.93746
Topological Polar Surface Area:62.9
Heavy Atom Count:12
Complexity:192
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes