2-(3-BROMOPHENYL)PROPAN-2-OL

Preparation of N- [ (lS, 2R)-3- { [l- (3-bromophenyl)-l- methylethyl] amino}-1- (3, 5-difluorobenzyl)-2-hydroxypropyl] acetamide; 32 Scheme 8 O Br MeMgBr g NaN3 Br '°H Bu OMe OH Nh THF TFA THF 4 | kOH SOH 4 reflux H 19 H HOH H N, 1) TFA-0 zon F F 0 HCI 2) Ac-Im F 31 3) HCI 30 30 F 31 F NaOH HOH H Bu F 32 Step 1; Preparation of 2- (3-bromophenyl)-2-propanol 27; To 75 mmol of methylmagnesium bromide in 25 mL of ether stirring at 6 °C is added, dropwise over 10 min, a solution of methyl-3-bromobenzoate (4.3 g, 20 mmol) in 25 mL of dry THF. The mixture is then allowed to warm to ambient temperature and stirred for 3.5 h, then cooled to 0°C and quenched by dropwise addition of aqueous 10percent HC1. The acidified mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with 1 N NaHC03 and with brine. The solution is dried over Na2SO4, concentrated, and chromatographed over silica gel, eluting with 15percent ethyl acetate in heptane, to afford 4.00 g (18.6 mmol, 93percent) of 2- (3-bromophenyl)-2- propanol 27 as a pale yellow oilTo a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol) in THF (140 mL) at -78 °C was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over NaTo a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol) in THF (140 mL) at −78° C. was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over NaA solution of 3N METHYLMAGNESIUM bromide (6.53 mL, 19.59 mmol, 3 eq) in diethyl ether was cooled to 0 °C and treated with 3-bromoacetophenone (1.3 g, 6.53 MMOL). The reaction was stirred at room temperature for 4 h. The reaction was diluted with ethyl acetate and water. The layers were separated and the organic was washed with saturated sodium bicarbonate, 2N HCI, brine and dried over magnesium sulfate. The solvent was removed at reduced pressure and purified on the MPLC (Biotage) eluted with 5-10percent ethyl acetate-hexane to afford 1.2 g (90 percent) of the product. Rf = 0.22 (silica, ethyl acetate: hexanes, 1: 9) ; H-NMR (DMSO-D6) 8 7.63 (t, J = 1.8 Hz, 1H), 7.45 to 7.35 (m, 2H), 7.25 (t, J = 7.7, 1H), 5.15 (s, 1H), 1.39 (s, 6H).Example 22; Method H-15; Preparation of 2-(3-Bromo-phenyl)-propan-2-ol; A solution of 3N methylmagnesium bromide (6.53 mL, 19.59 mmol, 3 eq) in diethyl ether was cooled to 0 °C and treated with3-bromoacetophenone (1.3 g, 6.53 mmol). The reaction was stirred at room temperature for 4 h. The reaction was diluted with ethyl acetate and water. The layers were separated and the organic was washed with saturated sodium bicarbonate, 2N HCI, brine and dried over magnesium sulfate. The solvent was removed at reduced pressure and purified on the MPLC (Biotage) eluted with 5-10percent ethyl acetate-hexane to afford 1.2 g (90 percent) of the product. Rf = 0.22 (silica, ethyl acetate: hexanes, 1: 9) ; 1H-NMR (DMSO-d6) 6 7.63 (t, J = 1.8 Hz, 1H), 7.45 to 7.35 (m, 2H), 7.25 (t, J = 7. 7, 1H), 5.15 (s, 1H), 1.39 (s, 6H).Preparation of 2-(3-Bromo-phenvl)-propan-2-ol. A solution of 3N methylmagnesium bromide (6.53 mL, 19.59 mmol, 3 eq) in diethyl ether was cooled to 0 A solution of methylmagnesium iodide is prepared from 5.79 ml of methyl iodide and 2.2 g of magnesium turnings in refluxing ether. A solution of 5 g of methyl 3- bromobenzoate in 110 ml of ether is then added dropwise and the mixture is refluxed for 3 hours. The reaction mixture is poured onto ice/saturated NHA solution of methylmagnesium iodide is prepared from 5.79 ml of methyl iodide and 2.2 g of magnesium turnings in refluxing ether. A solution of 5 g of methyl 3- bromobenzoate in 110 ml of ether is then added dropwise and the mixture is refluxed for 3 hours. The reaction mixture is poured onto ice/saturated NH4C1, the phases are separated by settling, the organic phase is washed with 10% aHC03 solution and with saturated NaCl solution, and dried over MgS04, and the solvent is evaporated off under vacuum. 4.98 g of the expected compound are obtained.

Molecular Weight:215.09
XLogP3:2.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:213.99933
Monoisotopic Mass:213.99933
Topological Polar Surface Area:20.2
Heavy Atom Count:11
Complexity:134
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes