| 93% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 72h; |
12
Preparation of l-(benzyloxy)-4-bromo-2-fluorobenzeneBenzyl bromide (17.12 mL, 143.98 mmol) was added dropwise to 4-bromo-2-fluorophenol (25 g, 130.89 mmol) and potassium carbonate (36.2 g, 261.78 mmol) in DMF (250 mL). The resulting mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ether (300 mL), and the solution was washed sequentially with water (2 x 500 mL) and saturated brine (250 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford an oil which was scratched to give a solid. The solid was triturated with isohexane, filtered and dried to give l-(benzyloxy)-4-bromo-2- fluorobenzene (34 g, 93%) as a solid.IH NMR (399.9 MHz, DMSO-d6) δ 5.19 (2H, s), 7.24 (IH, m), 7.32 - 7.47 (6H, m), 7.54 (IH, m). |
| 86% |
With potassium carbonate In butanone for 20h; Heating; |
|
| 86.6% |
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; |
24.1 Step-1: Synthesis of l-(benzyloxy)-4-bromo-2-fluorobenzene
Step-1: Synthesis of l-(benzyloxy)-4-bromo-2-fluorobenzene To a solution of 4-bromo-2-fluorophenol (10 g, 52.3 mmol) in DMF (70 mL), were added potassium carbonate (8.7 g, 62.8 mmol) and benzyl bromide (9.85 g, 57.5 mmol) sequentially at room temperature. The resulting mixture was stirred at room temperature for 12 h, completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate. The organic layer was dried over anhydrous Na2S04i concentrated under reduced pressure. The crude compound was purified over 230-400 mesh silica gel column chromatography using 8% EtOAc in n-hexane to afford l-(benzyloxy)-4-bromo-2-fluorobenzene (12.7 g, 86.6%). |
| 83% |
With potassium carbonate In acetone for 5h; Heating / reflux; |
72.1
EXAMPLE 72; Preparation of tert-butyl (lS)-2- [4- (benzyloxy)-3 fluorophenyl]-l-[(2S)-oxiran-2-yl] ethylcarbamate; 17 Scheme 4 BnBr 1) Mn THF rflux e iJ-O H O- o HO F reflux 5 h BnO F 2) CuBr. SMe2 0 reflux 5 h ref) ux5h'" J THF,-25 °C i o BnOC 13 / Bn0 O 0 15 14 14 14 1) Dowex 50WX2-400 2) (Boc) 20 THF In 0 H.,,'0 1)'*"/, OMe PPTS 0 H OH oye 0 i BnO 2) AcBr Et3N BnO BnO N f) T F 3) KOH F 17 16 Step 1; Preparation of l-Benzyloxy-2-fluoro-4-bromobenzene 13; To a stirred suspension of pulverized K2CO3 (49 g, 350 mmol) in 250 mL of acetone is added 6.5 mL (11.3 g, 59 mmol) of 2-fluoro-4- bromophenol and 7 mL (10 g, 59 mmol) of benzyl bromide. The mixture is refluxed under nitrogen 5 h. It is cooled and filtered, washing the residual K2CO3 with acetone. Removal of the solvent leaves 17 g of an off-white solid. This is triturated twice with hexanes, redissolved in 250 mL of CH2Cl2, and washed successively with 10% Na2CO3, water, and brine. The organic phase is dried over Na2SO4 and treated with decolorizing charcoal. Filtration and evaporation affords 1-benzyloxy-2-fluoro-4-bromobenzene 13 (13.7g, 49 mmol, 83%) as a colorless oil which crystallizes to a white solid |
|
With potassium carbonate In butanone |
|
|
With potassium carbonate In acetone at 20℃; for 18h; |
4.1
Step 1. 1-(Bromomethyl)benzene (4.92 g, 28.8 mmol) and K2CO3 (3.98 g, 28.8 mmol) were added to a solution of 4-bromo-2-fluorophenol (5.0 g, 26 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 hours. Water (100 mL) and EtOAc (100 mL) were added, the organic layer was separated and dried over MgSO4 and concentrated to give 1-(benzyloxy)-4-bromo-2-fluorobenzene as a yellow solid 7.06 g. 1H NMR (400 MHz, CDCl3): δ 7.24-7.41 (m, 5H), 7.20 (m, 1H), 7.16 (m, 1H), 6.82 (m, 1H), 5.10 (m, 2H). |
|
With potassium carbonate In acetone at 20℃; for 18h; |
Compound 1a (26 g), benzyl bromide (23 g), potassium carbonate (56.4 g) and acetone (150 mL) were placed in a flask and stirred for 18 h at room temperature, followed by filtration and washing of the filtrate with acetone. Concentration of the liquid gave an oil which was next dissolved in EtOH (150 mL) and washed with 50 ml water and 50 mL brine. After drying with magnesium sulfate, and filtratration, the liquid was concentrated to give an oil, which solidified on standing (37.8 g compound 2a collected). |
|
With potassium carbonate In N,N-dimethyl-formamide |
93.1
4-bromo-2-fluorophenol (2.557 g, 13.39 mmol) and (bromomethyl)benzene (1.590 ml, 13.39 mmol) in DMF (20ml) were treated with K2CO3 (3.70 g, 26.8 mmol) overnight. The reaction was then diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide the title compound. LCMS (APCI) m/e 282 (M+H). |
|
With potassium carbonate In butanone |
1.1 1.1
1.1 Synthesis of 1-benzyloxy-4-bromo-2-fluorobenzene 210.0 g (1.10 mol) of 4-bromo-2-fluorophenol are dissolved in 1.1 l of ethyl methyl ketone, and 175.0 g (1.27 mol) of potassium carbonate and 150.0 ml (1.26 mol) of benzyl bromide are added. The mixture is refluxed for 5 h and stirred at room temperature for 16 h. The batch is filtered, and the filtrate is concentrated to dryness. The crude product is crystallised from heptane at reduced temperature. |
| 3.89 g |
With potassium carbonate In acetonitrile at 100℃; |
53.1 Step 1: Preparation of 1-benzyloxy-4-bromo-2-fluoro-benzene
A mixture of 4-bromo-2-fluoro-phenol (3.0 g, 15.7 mmol), bromomethylbenzene (4.0 g,23.6 mmol) and potassium carbonate (4.3 g, 31,4 mmoi) in acetonitrile (30 mL) was heated withstirring at 100 °C overnight. The resulting reaction mixture was cooled to rt, diluted with water (50 mL) and extracted with EA (30 mL) for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (eluting with 2% EA in PE) to give 1 -benzyloxy-4-bromo-2-fluoro-benzene (3.89 g). |
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