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O N N B O
N N OH
Rx-ID: 29261853 View in Reaxys 1/3 Yield 100 % Conditions & References 4 :Intermediate 4 : 1 -Benzyl- 1 H-pyrazol-4-ol 1-Benzyl-4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (Aldrich, 700 mg, 2.46 mmol) was dissolved in THF (6 ml_) and cooled to 0°C. NaOH 2.5 M (2 ml_, 4.93 mmol) and H202 30percent solution in water (503 μΙ, 4.93 mmol) were added and the reaction mixture was stirred at room temperature for 45 min. Then the pH was adjusted to 2 by the addition of aqueous HCI 2 M and the mixture was extracted with dichloromethane. The organic layer was dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using cyclohexane/EtOAc as eluant. The expected fractions were combined and evaporated under reduced pressure to give the title compound 1 -benzyl- 1 H-pyrazol-4-ol (500 mg, quantitative yield). LCMS: (M+H)+ = 175 ; Rt = 0.61 min. Stage 1: With hydrogen peroxide, sodium hydroxide in tetrahydrofuran, water, Time= 0.75h, T= 0 - 20 °C Stage 2: With hydrochlorid acid in tetrahydrofuran, water, pH= 2 Patent; GLAXOSMITHKLINE LLC; DAUGAN, Alain Claude-Marie; LAMOTTE, Yann; MIRGUET, Olivier; WO2012/119978; (2012); (A1) English View in Reaxys 77 % Compound 244.2. l-Benzyl-lH-pyrazol-4-ol Compound 244.2. l-Benzyl-lH-pyrazol-4-ol. Into a 100-mL three neck round- bottom flask, was placed a solution of l-benzyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (compound 244.1, 3.47 g, 12.2 mmol) in tetrahydrofuran (35 mL). Sodium hydroxide (980 mg, 24.5 mmol) was added and then the mixture was cooled to 0 °C. Hydrogen peroxide (2.51 mL, 24.4 mmol) was carefully added drop-wise and the resulting mixture was stirred for 2 h at room temperature. The reaction was carefully quenched with aqueous a2S203(sat.) (20 mL). The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with brine (2 x 150 mL), dried ( a2S04), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/1) as eluent to furnish the title compound as a white solid (1.64 g, 77percent). With hydrogen peroxide, sodium hydroxide in tetrahydrofuran, Time= 2h, T= 0 - 20 °C Patent; 3-V BIOSCIENCES, INC.; HEUER, Timothy Sean; OSLOB, Johan D.; MCDOWELL, Robert S.; JOHNSON, Russell; YANG, Hanbiao; EVANCHIK, Marc; ZAHARIA, Cristiana A.; CAI, Haiying; HU, Lily W.; WO2015/95767; (2015); (A1) English View in Reaxys 77 % With hydrogen peroxide, sodium hydroxide in tetrahydrofuran, water, Time= 0.666667h, T= 0 - 20 °C Westaway, Susan M.; Preston, Alex G. S.; Barker, Michael D.; Brown, Fiona; Brown, Jack A.; Campbell, Matthew; Chung, Chun-Wa; Drewes, Gerard; Eagle, Robert; Garton, Neil; Gordon, Laurie; Haslam, Carl; Hayhow, Thomas G.; Humphreys, Philip G.; Joberty, Gerard; Katso, Roy; Kruidenier, Laurens; Leveridge, Melanie; Pemberton, Michelle; Rioja, Inma; Seal, Gail A.; Shipley, Tracy; Singh, Onkar; Suckling, Colin J.; Taylor, Joanna; Thomas, Pamela; Wilson, David M.; Lee, Kevin; Prinjha, Rab K.; Journal of Medicinal Chemistry; vol. 59; nb. 4; (2016); p. 1370 - 1387 View in Reaxys 23.A :l-Benzyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lΗ-pyrazole (700 mg,2.46 mmol) was dissolved in THF (6 mL) and cooled to 0 0C. NaOH (2 M in water, 4.93 mmol, 2.5 mL) and H2O2 (30percent in water, 503 μl, 4.93 mmol) were added and the reaction mixture was stirred at RT for 45 min. Then the pH was adjusted to 2 by the addition of aqueous HCl (2 M) and the mixture was extracted with DCM (3x 10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA) to give the title compound. MS (m/z): 175.0 [M+H+] Stage 1: With water, hydrogen peroxide, sodium hydroxide in tetrahydrofuran, T= 0 - 20 °C Stage 2: With hydrochlorid acid in tetrahydrofuran, water, pH= 2
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Patent; JERINI AG; GIBSON, Christoph; SCHNATBAUM, Karsten; TRADLER, Thomas; PFEIFER, Jochen; SCHARN, Dirk; REIMER, Ulf; RICHTER, Uwe; HUMMEL, Gerd; REINEKE, Ulrich; LOCARDI, Elsa; PASCHKE, Matthias; WO2010/31589; (2010); (A1) English View in Reaxys Intermediate (39): 1-benzyl-1H-pyrazol-4-ol 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (18 mL) and cooled to 0° C. 2N NaOH (7.03 mL, 14.06 mmol) and 30percent peroxide (14.07 mL) were added and the reaction was stirred at room temperature for 45 minutes. The reaction was acidified to pH=2 by addition of 2N HCl and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 1-benzyl-1H-pyrazol-4-ol (1.54 g) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 7.25-7.21 (m, 3H), 7.08-7.07 (m, 3H), 6.91 (s, 1H), 5.06 (s, 2H). Stage 1: With hydrogen peroxide, sodium hydroxide in tetrahydrofuran, water, Time= 0.75h, T= 0 - 20 °C Stage 2: With hydrochlorid acid in tetrahydrofuran, water, T= 20 °C , pH= 2 Patent; PFIZER INC.; US2012/202834; (2012); (A1) English View in Reaxys