2-Bromo-1-fluoro-4-nitrobenzene

Light yellow solid

To a solution of l-bromo-2-fluorobenzene (35.0 g, 200 mmol) in 200 mL of concentrated sulfuric acid was added 20 mL of 68percent nitric acid. The temperature of the mixture was maintained below 20 Step 31a. Example 31Preparation of 7-(4-(3-ethynyl-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide (Compound 75)Step 31a. 2-Bromo-1-fluoro-4-nitrobenzene (compound 0602); To a solution of 1-bromo-2-fluorobenzene (35.0 g, 200 mmol) in 200 mL of concentrated sulfuric acid was added 20 mL of 68percent nitric acid. The temperature of the mixture was maintained below 20° C. After the addition was completed, the mixture was stirred at 10° C. overnight, then diluted with ice water. The resulting solid was collected by filtration. The solid was recrystallized from petroleum ether to give the title compound 0602 as a yellow solid (38 g, 89percent): m.p. 55.8-56.7° C., 100 g (0.57 mol) of 1-bromo-2-fluorobenzene and 570 mL of concentrated sulfuric acid were placed in a 1 L four-necked round bottom flask equipped with a stirrer, a Liebig condenser, a 50 mL dropping funnel and a thermometer, , Cooled to 0 ° C. and then 47 mL of 68percent nitric acid was added dropwise at a temperature not exceeding 40 ° C. Subsequently, the mixture was cooled to 20 ° C. and postreacted at the same temperature for 3 hours. The obtained reaction solution was poured into 3150 g of crushed ice, the precipitated crystals were recovered by filtration, further washed thoroughly with 1.5 L of water, and dried overnight in a vacuum dryer at 40 ° C. Subsequently, the resulting crude crystals were further recrystallized with petroleum ether to obtain 103.1 g (yield 82.2percent) of the title compound.Step 1a. In a 20 L 4- necked RB flask, fitted with a mechanical stirrer, reflux condenser, add DM water (550 ml), cone. Sulphuric acid (6.2 L, 113 M), 4- EPO Sodium nitrate (20 g, 0.235 mol) was added to 200 mL of concentrated sulfuric acid under stirring and cooling with an ice bath. Fluorobenzene (20 g, 0.21 mol) was added dropwise (at a temperature bellow 10 °C). After 2 h the resulting mixture was poured out into crushed ice and transferred to a separatory funnel using EtOAc (2 100 mL). Organic phase was washed with sat. aq. NaHCO 3 (50 mL) and brine (50 mL) and dried over MgSO 4 . After evaporation of solvent the residue was distilled in vacuo to give 1-fluoro-4-nitrobenzene. Yield 16.7 g (57percent); yellowish oil; bp 94−98 °C (15 mmHg) (lit. [7] bp 90−92 °C (13−14 mmHg)); 1 H NMR (400 MHz, CDCl 3 ): δ 8.25–8.34 (m, 2H), 7.19–7.24 (m, 2H). Bromine (18 mL, 0.19 mol) was added dropwise to the mixture of iron powder (0.20 g, 3.6 mmol) and 1-fluoro-4-nitrobenzene (16.6 g, 0.12 mol) being stirred and heated at 140 °C during 10 h. The second portion of the iron (1 g, 18 mmol) was added and the mixture was heated further at 140 °C for 6 h. After cooling to the ambient temperature the resulting mixture was poured out into water with sodium sulfite and transferred to a separatory funnel using Et 2 O (2 × 100 mL). Organic phase was washed with sat. aq. Na 2 SO 3 (50mL) and brine (50 mL), dried over MgSO 4 and concentrated in vacuo. The residue was treated with hexane (50 mL), the resulting crystals were filtered and air-dried. Yield: 17.7 g (67percent); pale purple solid; mp 58–60 °C (lit. [8] mp 58–59 °C); 1 H NMR (400 MHz, CDCl 3 ): δ 8.53 (dd, J = 5.8, 2.8 Hz, 1), 8.22–8.29 (m, 1), 7.32 (t, J = 7.2 Hz, 1).EXAMPLE 4

Molecular Weight:220.00
XLogP3:2.5
Hydrogen Bond Acceptor Count:3
Exact Mass:218.93312
Monoisotopic Mass:218.93312
Topological Polar Surface Area:45.8
Heavy Atom Count:11
Complexity:161
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes