4-(4-broMo-3-(hydroxyMethyl)phenoxy)benzonitrile

Class white powder

lOOg of 4-(4-bromo-3-fonnylphenoxy) benzonitrile (VI) was dissolved in 500mL of methanol at 25-30 °C and then cooled to 10-15 °C. 6.2 g of sodium borohydride was added to the reaction mass at 10-15 °C for 60-90 mm. The temperature of the reaction mass was raised to 15-20 °C. After completion of the reaction, 1000 mL of water was added to the reaction mass, stirred forlhr at 25-30 °C. The solid obtained was filtered under vacuum, washed with water and dried under vacuum below 55 °C to obtain 4-(4-bromo-3-(hydroxymethyl) phenoxy) benzonitrile (V).Yield percent: 99.0; Purity percent: 99.02Will be 30.2g (0.1mol) 4-[(4-bromo-3-formyl)phenoxy)]benzonitrile (compound of formula I), 400 ml of methanol was added to the reaction kettle. 1.89 g (0.1 mol) of sodium borohydride was added in portions. After the addition, stirring was continued for 4 h at 25 ° C until the reaction of the starting material was complete. Recovering methanol, Add 1000ml of water to beat, filter, Drying to obtain a solid 27.8, yield 92percent;In a round bottom flask, under nitrogen atmosphere, a mixture of 4-(4-bromo-3- formylphenoxy)benzonitrile (compound A) (28.1 g, 93 mmol) and methanol (1 12 ml) was prepared and cooled to 0 °C. To the resulting suspension, a solution of sodium borohydride (1 .79 g, 46.5 mmol), water (5.9 ml) and 1 M NaOH (0.2 ml) was added dropwise for 15 minutes. The reaction mixture was stirred for 1 hour at 0 °C and 3M HCI was added until pH 4.5. Afterwards, water (1 12 ml) was added and the suspension was stirred for 1 hour at room temperature. The resulting solid was filtered and purified by recrystallization from a mixture of methanol to give 4-(4-bromo-3-(hydroxymethyl)phenoxy)benzonitrile (compound B). Yield: 80percent Purity by HPLC: >99.9percent 225 g (1 mol) of 4- (3- (hydroxymethyl) phenoxy) benzonitrile (compound of formula III), 1000ml of acetonitrile, 17.2g (0.1mol) of p-toluenesulfonic acid were added to the reaction kettle, 196g (1.1mol) of NBS was added to the reactor in batches at 25 C. After the addition was completed, the mixture was refluxed for 6h.Recover acetonitrile, add water, filter, and dry to obtain 290 g of white solid with a yield of 95%;Trityl chloride (68.75 gm) was added to a stirred solution of methylene chloride (100 ml) at 25C - 30C. DIPEA (45.8 ml) was added to the reaction mixture and heated to 40C - 45C. The solution of 27.1 g (197 mmol) of K2CO3, 12.13 g (100.3 mmol) of 4-fluorobenzonitrile of formula (IV), 34.2 g (98.3 mmol) of 1-bromo-4-trimethylsilanoxy-2-trimethylsilanoxymethyl benzene of formula (III), obtained as described in Example 2, and 60 mL of DMSO are placed under nitrogen in a previously anhydrified flask. The reaction mixture is heated to 105 C. and kept at the same temperature for 2 hours. Then, 120 mL of toluene and 240 mL of H2O are added, the phases are separated and the organic phase is washed with a solution of 10% K2CO3. The organic phase is allowed to cool down to room temperature and the product is allowed to crystallize providing 19.7 g 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzonitrile of formula (II) with a yield of 66%. 1H-NMR (DMSO-d6, 300 MHz) delta (ppm): 7.85-7.80 (2H, m) 7.62 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=3.0 Hz), 7.13-7.11 (2H, m) 6.98 (1H, dd, J=3.0, J=8.4 Hz), 4.47 (2H, s)2-bromo-5-hydroxybenzyl alcohol II (20.3 g, 0.1 mol) was sequentially added to a three-necked flask.N, N-dimethylformamide (50 mL), potassium carbonate (27.6 g, 0.2 mol)After the addition of p-fluorobenzonitrile (14.5 g, 0.12 mol), the reaction system was warmed to 80-90 C, and the reaction was completed by TLC. The mixture was slowly added to water (250 mL) and quenched.Filtration, drying to give a white solid, intermediate III, HPLC purity 93.5%, yield 96.2%.27.2 g (197 mmol) of K2CO3, 11.9 g (98.5 mmol) of 4-fluorobenzonitrile of formula (IV), 20.0 g (98.5 mmol) of 2-bromo-5-hydroxy-benzyl alcohol of formula (III), obtained as described in Example 1, and 80 mL of DMSO are placed under nitrogen in a previously anhydrified flask. The mixture is heated to 125 C. and maintained at said temperature for 4 hours. 240 mL of H2O are added and the precipitate is filtered off and washed with H2O until reaching a neutral pH value. The solid is dried and analyzed by HPLC (yield of 70%). The mixture is then dissolved in 70 mL hot toluene and allowed to crystallize while cooling the solution down to room temperature obtaining 16.3 g of 4-(4-bromo-3-hydroxymethyl-phenoxy)-benzonitrile of formula (II) with a yield of 54%. 1H-NMR (DMSO-d6, 300 MHz) delta (ppm): 7.85-7.80 (2H, m) 7.62 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=3.0 Hz), 7.13-7.11 (2H, m) 6.98 (1H, dd, J=3.0, J=8.4 Hz), 4.47 (2H, s).

Molecular Weight:304.14
XLogP3:3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:302.98949
Monoisotopic Mass:302.98949
Topological Polar Surface Area:53.2
Heavy Atom Count:18
Complexity:306
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes