96.7% |
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Example 27: Synthesis of 5-Bromo-l-(2,6-difluorobenzyl)-lH-pyrazoIeStep 1: 2-(2,6-Difluorobenzyl)-l-hydroxy-lH-pyrazole<strong>[81945-73-5]1-Hydroxypyrazole</strong> (49.3 mg, 0.59 mmol, 1.0 eq) was mixed with 165.8 mg (0.80 mmol, 1.36 eq) of 2,6-difluorobenzyl bromide in -1-2 mL of anhydrous CHCl3 under argon. The mixture was heated at 80 0C for 18 h under inert atmosphere in a sealed flask without condenser. The residue was partitioned between 37 weight percent aqueous HCl and toluene. The aqueous layer was collected and the toluene fraction extracted again with 37 weight percent aqueous HCl. The combined aqueous HCL fractions were neutralized with 5N aqueous NaOH to pH~l 1-12 and then back-extracted with 3 x 30 mL of CHCl3. The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to yield 86.3 mg (70.1% yield) of 2-(2,6- difluorobenzyl)-l -hydroxy- lH-pyrazole as a tan brown solid. 1H NMR (CDCl3 300 MHz) delta 7.37 (m, IH), 7.18 (d, IH), 6.95 (t, 2H), 6.85 (d, IH), 6.11 (t, IH), 5.43 (s, 2.00 H). LC/MS (ES) M+l=211.2Step 2: 5-Bromo-l-(2,6-difluorobenzyl)-lH-pyrazole2-(2,6-Difluorobenzyl)-l -hydroxy- lH-pyrazole (81.2 mg, 0.386 mmol, l.Oeq) and 5ml of anhydrous CHCl3 were combined in a flame-dried 25 mL round-bottom flask under argon and cooled in an ice/water bath. A solution Of POBr3 (398.1 mg, 1.39 mmol, 3.60 eq) in 3 mL of CHCl3 was added using a syringe in aliquots over an hour period with stirring. The reaction solution was warmed to room temperature and stirred for 16 hours. The CHCl3 was removed in vacuo and the resulting orange mixture was neutralized with saturated aqueous NaHCO3 and extracted with 3 x 30 mL of diethyl ether. The combined ether fractions were washed with brine, dried over Na2SO4 and concentrated in vacuo to yield 101.5 mg (96.7% yield) of 5 -bromo-1 -(2,6- difluorobenzyl)- lH-pyrazole as a hygroscopic orange-tan colored solid. 1H NMR (CDCl3 300 MHz) delta 7.51 (d, IH), 7.34 (m, IH), 6.94 (t, 2H), 6.29 (d, IH), 5.50 (s, 2H). LC/MS (ES) M+l= 273.1, 275.1 |