methyl 2-(2-fluoro-4-hydroxyphenyl)acetate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-[(1S,2R)-2-{1-[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]piperidin-4-yl}cyclopropyl]ethanol (0.900 g, 3.20 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (Intermediate 1, 0.707 g, 3.84 mmol) in 10 ml anhydrous dichloromethane, triphenylphosphine, polymer-bound (2.52 g, 12.6 mmol), and di-tert-butyl azodicarboxylate (1.47 g, 6.40 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite and concentrated. The residue was purified on Biotage column (100 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 448.2 (M+H)+. It was filtered by Celite concentrated The residue was purified on Biotage column (100 g silica gel)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-methylcyclopropyl 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate (Intermediate 9, 0.484 g, 1.81 mmol) in 5 ml anhydrous dichloromethane at RT was added a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (0.400 g, 2.17 mmol) in 10 ml anhydrous dichloromethane, triphenylphosphine, polymer-bound (1.42 g, 4.10 mmol), and di-tert-butyl azodicarboxylate (0.834 g, 3.61 mmol). The reaction mixture was stirred at RT for 3 hours. It was filtered by Celite and concentrated. The residue was purified on Biotage column (50 g silica gel) using a gradient eluent of 0-50% ethyl acetate in hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 434.2 (M+H)+. It was filtered by Celite concentrated The residue was purified on Biotage column (50 g silica gel)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: DIAD (0.955 ml, 4.91 mmol) was added to a stirred mixture of 2-[(1S,2R)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethanol (1 g, 3.27 mmol), methyl (2-fluoro-4-hydroxyphenyl)acetate (0.724 g, 3.93 mmol) and triphenylphosphine (1.288 g, 4.91 mmol) in toluene (10 ml). The mixture was stirred at RT for 5 hrs. The mixture was diluted with ethyl acetate (20 mL), washed with brine, dried over MgSO4, filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 472 (M+H)+. washed with brine dried over MgSO4 filtered the solvent evaporated in vacuo The residue was purified by column chromatography on silica gel, Biotage 100M

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (1.3 g, 4.61 mmol) in 15 ml anhydrous dichloromethane at RT was added a solution of 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (1.02 g, 1.70 mmol) in 5 ml of anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 3.63 g, 10.5 mmol) and di-tert-butyl azodicarboxylate (2.13 g, 9.23 mmol). The mixture was stirred at RT for 3 hours, filtered through Celite and concentrated. The residue was purified by column chromatography on silica gel (Biotage 100 g) using a gradient eluent of 0-50% ethyl acetate in hexanes (1500 ml) to afford the title compound. LC/MS (m/z) 448.2 (M+H)+. filtered through Celite concentrated The residue was purified by column chromatography on silica gel (Biotage 100 g)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To an RT solution of methyl (2-fluoro-4-hydroxyphenyl)acetate (1.60 g, 5.49 mmol) in 15 ml of anhydrous dichloromethane was added a solution of 2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethanol (2.10 g, 7.22 mmol) in 20 ml anhydrous dichloromethane, followed by triphenylphosphine (polymer-bound, 4.32 g, 16.5 mmol), and di-tert-butyl azodicarboxylate (2.53 g, 11.0 mmol). The mixture was stirred at RT for 3 hours, filtered through Celite and concentrated. The residue was purified by column chromatography (50 g silica gel) using a gradient eluent of 0-50% ethyl acetate:hexanes (1000 ml) to afford the title compound. LC/MS (m/z) 458.3 (M+H)+. filtered through Celite concentrated The residue was purified by column chromatography (50 g silica gel)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-{(1S,2R)-2-[1-(5-Methoxypyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (1.2 g, 4.33 mmol), methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (0.956 g, 5.19 mmol) and triphenylphosphine (1.702 g, 6.49 mmol) were dissolved in dichloromethane (20 ml). The mixture was stirred at RT under N2 for 5 min and diisopropyl azodicarboxylate (1.274 ml, 6.49 mmol) was added. The mixture was stirred at RT overnight. The mixture was diluted with DCM (50 ml), washed with water, dried and evaporated. The crude material was purified by column chromatography on silica gel (50 g SNAP, 5˜30% EtOAc in hexane) to afford the desired product which contains some impurities. This material was re-purified by column chromatography on silica gel (50 g SNAP, 2˜5% EtOAc in DCM) to afford the title compound. LC/MS (m/z): 444 (M+H)+. Rf was 0.4 @ 30% EtOAc in hexanes (blue spot on CAM stain). The mixture was stirred at RT overnight washed with water dried evaporated The crude material was purified by column chromatography on silica gel (50 g SNAP, 5˜30% EtOAc in hexane)