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NMR Spectrum (DMSOd6): 4.34 (d, 2H), 4.74 (bs, 2H), 5.12 (t, IH), 6.59 (dd, IH), 6.77 (ddd, IH), 6.91 (dd, IH)(3-nitro-2-fluorophenyl)methanol (2.1 g, 12.28 mmol) in solution in AcOEt was reduced with hydrogen (30 Psi) in presence of Pt/C over Ih. The catalyst was removed by filtration and the solvent evaporated to give (3-amino-2-fluorophenyl)methanol as a yellow solid. (1.64 g, 95percent)
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; Inert atmosphere Stage #2: With methanol In tetrahydrofuranInert atmosphere
Intermediate 101: (3-amino-2-fluorophenyl)methanol 3-amino-2-fluorobenzoic acid (APIN, 250 mg, 1.612 mmol) was dissolved in 10 mL of anhydrous THF under N2 atmosphere. Solution was cooled at 0° C. in an ice-water bath. LiAlH4 (FLUKA, 183 mg, 4.83 mmol) was added. Reaction was stirred under nitrogen at room temperature. After 2 h one equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added to the mixture and reaction was stirred at room temperature overnight. Another equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added. After 5 h The reaction mixture was quenched by adding MeOH. Solvent was evaporated to obtain an orange syrup that was dissolved in EtOAc and partitioned with saturated NaHCO3 (aqueous) (10 mL of saturated solution+15 mL of distilled water). Aqueous phase was extracted with EtOAc, organic layers were combined and dried with MgSO4 (anh), filtered off and concentrated. Crude was purified using silica gel cartridge with linear gradient 0-85percent DCM/MeOH to yield the title compound (114 mg, 0.808 mmol, 50.1percent yield) as yellow syrup. 1H NMR (300 MHz, DMSO-d6) δ ppm: 6.50-6.85 (m, 3H), 4.95-5.08 (m, 3H), 4.44 (d, 2H).
With triethylamine; In isopropyl alcohol; at 90℃; for 15.0h;
A solution of 2,4-dichloropyrimidine (300 mg, 2.01 mmol), (3-amino-2- fluorophenyl)methanol (256 mg, 1.81 mmol) and triethylamine (309 mul, 2.22 mmol) in 2- propanol (5 ml) was stirred over a period of 15 hrs at 90C as described in Method 1. Work-up and purification gave (3-(2-chloropyrimidin-4-ylamino)-2 -fluorophenyl) methanol (206 mg, 40.3 %) as a white solid. Mass Spectrum: M+H+ 254. NMR Spectrum (DMSOdbeta): 4.44 (s, 2H), 5.39 (bs, IH), 6.51 (bs, IH), 7.13 (ddd, IH), 7.30 (dd, IH), 7.36 (dd, IH), 8.09 (d, IH), 9.41 (bs, IH)
With hydrogen; In ethyl acetate; under 1551.49 Torr; for 1.0h;
NMR Spectrum (DMSOd6): 4.34 (d, 2H), 4.74 (bs, 2H), 5.12 (t, IH), 6.59 (dd, IH), 6.77 (ddd, IH), 6.91 (dd, IH)(3-nitro-2-fluorophenyl)methanol (2.1 g, 12.28 mmol) in solution in AcOEt was reduced with hydrogen (30 Psi) in presence of Pt/C over Ih. The catalyst was removed by filtration and the solvent evaporated to give (3-amino-2-fluorophenyl)methanol as a yellow solid. (1.64 g, 95%)
With sodium carbonate; In water; at 0℃; for 1.5h;Inert atmosphere;
Intermediate 102: ethyl [2-fluoro-3-(hydroxymethyl)phenyl]carbamate A stirred suspension of sodium carbonate (78 mg, 1.573 mmol) and Intermediate 101 (222 mg, 1.573 mmol) in 10 mL of water was cooled at 0 C. under nitrogen atmosphere. Ethyl chlorocarbonate (ALDRICH, 171 mg, 1.573 mmol) was added dropwise. Reaction was stirred for 1 h 30 min at 0 C. and then allowed to reach room temperature. Crude of reaction was partitioned with Et2O. Organic layers were dried with MgSO4 (anh), filtered and concentrated to obtain the title compound (359 mg, 1.600 mmol, quantitative yield). 1H NMR (300 MHz, DMSO-d6) 8 ppm: 9.21 (br s, 1H), 7.45-7.55 (m, 1H), 7.05-7.22 (m, 2H), 5.24 (br s, 1H), 4.51 (s, 2H), 4.10 (q, 2H), 1.22 (t, 3H). [ES+MS] m/z 214 (MH+).
Intermediate 101: (3-amino-2-fluorophenyl)methanol 3-amino-2-fluorobenzoic acid (APIN, 250 mg, 1.612 mmol) was dissolved in 10 mL of anhydrous THF under N2 atmosphere. Solution was cooled at 0 C. in an ice-water bath. LiAlH4 (FLUKA, 183 mg, 4.83 mmol) was added. Reaction was stirred under nitrogen at room temperature. After 2 h one equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added to the mixture and reaction was stirred at room temperature overnight. Another equivalent of LiAlH4 (FLUKA, 61 mg, 1.62 mmol) was added. After 5 h The reaction mixture was quenched by adding MeOH. Solvent was evaporated to obtain an orange syrup that was dissolved in EtOAc and partitioned with saturated NaHCO3 (aqueous) (10 mL of saturated solution+15 mL of distilled water). Aqueous phase was extracted with EtOAc, organic layers were combined and dried with MgSO4 (anh), filtered off and concentrated. Crude was purified using silica gel cartridge with linear gradient 0-85% DCM/MeOH to yield the title compound (114 mg, 0.808 mmol, 50.1% yield) as yellow syrup. 1H NMR (300 MHz, DMSO-d6) delta ppm: 6.50-6.85 (m, 3H), 4.95-5.08 (m, 3H), 4.44 (d, 2H).
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