1-(3-(Benzyloxy)-2-fluoro-6-nitrophenyl)propan-2-one

To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60percent sodium hydride (82 mg, 2.05 mmol). To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60percent sodium hydride (82 mg, 2.05 mmol). To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60percent sodium hydride (82 mg, 2.05 mmol). To a solution of [1- (2, ] 3-difluoro-6-nitrophenyl) -propan-2-one (2.5 g, 82 percent purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 ml) and LiOH*H2O (1.07 g, 25. 58 mmol). The reaction mixture was then heated to 100-110 C and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to Rt, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCI. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5 C and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50 C for 12-15 h to afford of the desired compound (1.6 g) which was 95 percent pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano [3FM, ] 4. [6x50 mm Solvent A: 0.05 percent TFA in MeOH:water (20:80), Solvent B:0.05 percent TFA in [MeOH]: water (20:80), Wavelength: 254 nm Flow Rate: 3 ml/min. Gradient Time: 3 minTo a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60percent sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for 1 hour at ambient temperature. A solution of 1, 2-difluoro-3-(2, 2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was evaporated and the residue was dissolved in THF (2 ml) and 6N hydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hour at ambient temperature and the solvents were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56percent). 1H NMR Spectrum: (CDCl3) 2.35 (s, 3H); 4.25 (s, 2H); 5.25 (s, 2H); 7.0 (dd, 1H); 7.32-7.5 (m, 5H); 8.0 (dd, 1H)To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60percent sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for 1 hour at ambient temperature. A solution of 1, 2-difluoro-3-(2, 2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was evaporated and the residue was dissolved in TBF (2 ml) and 6N hydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hour at ambient temperature and the solvents were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56percent). 1H NMR Spectrum: (CDCl3) 2.35 (s, 3H); 4.25 (s, 2H); 5.25 (s, 2H); 7.0 (dd, 1H); 7.32-7.5 (m, 5H); 8.0 (dd, 1H)To a solution of benzyl alcohol (221 mg, 2.05 mmol) in DMA (1.5 ml) was added 60percent sodium hydride (82 mg, 2.05 mmol). The mixture was stirred for 1 hour at ambient temperature. A solution of 1, 2-difluoro-3-(2, 2-dimethoxypropyl)-4-nitrobenzene (534 mg, 2.05 mmol) in DMA (1.5 ml) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with 1N hydrochloric acid (10 ml) and extracted with ethyl acetate. The organic layer was evaporated and the residue was dissolved in THF (2 ml) and 6N hydrochloric acid (0.3 ml) was added. The mixture was stirred for 1 hour at ambient temperature and the solvents were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene (350 mg, 56percent). 1H NMR Spectrum: (CDCl3) 2.35 (s, 3H); 4.25 (s, 2); 5.25 (s, 2H); 7.0 (dd, 1H); 7.32-7.5 (m, 5H); 8.0 (dd, 1H)A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (9.09 g, 30 mmol) and Raney nickel (5 g) in methanol (100 ml) was heated to 40 C and then a solution of hydrazine in methanol (15 mL) was added dropwise with vigorous stirring over a period of 30 min. After refluxing for 1 h, the reaction mixture was cooled to room temperature, filtered through Celite and concentrated. The crude material was passed through a pad of silica gel eluting with dichloromethane and concentrated in vacuo to provide 5-benzyloxy-4-fluoro-2-methyl-1H-indole (6.1 g, 80 percent) as a yellowish oil. LC/MS; (M+H) + = 256. 3+A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180 C for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2x) and the combined organic layers were washed with brine, dried MgSO4, s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81 percent) as a brown solid. LC/MS; (M+H)+ = 213.2To a solution of compound E from previous step (20.00 g, 66.03. 30 mmol) in methanol under a nitrogen atmosphere (300 ml) at room temperature in the absence of light were added 10 percent Pd/C (2.0 g) and ammonium formate (60.0 g, 0.95 mol). The reaction mixture was stirred for 3.5 h and then diluted with ethyl acetate (200 ml) and filtered through a Celite/silica gel pad. The residue can then be purified by either of the following methods: After concentration in vacuo, the resulting residue was purified by chromatography eluting with 30 percent ethyl acetate/hexanes to afford (7.32 g, 67 percent) of the desired compound as a white solid after trituration with dichloromethane/hexanes. After concentration in vacuo, the residue was dissolved in dichloromethane and passed through a silica gel pad washing with dichloromethane. The filtrate was concentrated in vacuo to afford (6.66 g, 61 percent) of the title compound as a white solidA solution of A solution of To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3. 03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48 percent aqueous solution, 3 mL). After addition, the reaction was heated at 100 C for 30 min and then cooled to room temperature. To this mixture was added 10 [ml] of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3 x 20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.7 g, 80 percent) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+ = 213.2To a solution of [1- (2, ] 3-difluoro-6-nitrophenyl) -propan-2-one (2.5 g, 82 percent purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 ml) and LiOH*H2O (1.07 g, 25. 58 mmol). The reaction mixture was then heated to 100-110 C and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to Rt, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCI. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5 C and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50 C for 12-15 h to afford of the desired compound (1.6 g) which was 95 percent pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano [3FM, ] 4. [6x50 mm Solvent A: 0.05 percent TFA in MeOH:water (20:80), Solvent B:0.05 percent TFA in [MeOH]: water (20:80), Wavelength: 254 nm Flow Rate: 3 ml/min. Gradient Time: 3 min

Molecular Weight:303.28
XLogP3:2.9
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:5
Exact Mass:303.09068609
Monoisotopic Mass:303.09068609
Topological Polar Surface Area:72.1
Heavy Atom Count:22
Complexity:392
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes