ethyl 1-(hydroxymethyl)cyclobutane-1-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A solution of lithium aluminum-tri-tert-butoxyhydride 1.0M in THF (100.0 mL, 100.0 mmol) is added at −78° C. to a solution of diethyl 1,1-cyclobutanedicarboxylate (10.0 g, 50.0 mmol) in anhydrous THF (50.0 mL). After stirring the reaction mixture at room temperature for 14 h, 10% aqueous KHSO4 solution is added and the reaction mixture diluted with ethyl acetate. After separating the two phases, the organic phase is washed with water and brine and dried over anhydrous Na2SO4. Filtration and removal of the solvent under reduced pressure affords 5.0 g of 1-hydroxymethyl-cyclobutanecarboxylic acid ethyl ester that is used in the next step without further purification. Yield: 63%; m/z 159 [M+H]. After separating the two phases the organic phase is washed with water and brine dried over anhydrous Na2SO4 Filtration and removal of the solvent under reduced pressure

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

Procedure: Sodium hydroxide pellets (1.48 g, 37 mmol) was added to a stirred mixture of ethyl 1-hydroxymethylcyclobutanecarboxylate (4.14 g, 26.1 mmol), water (4 ml) and 95% ethanol (20 ml). The resulting mixture was stirred at room temperature overnight, then concentrated on a roatry evaporator. The residue was treated with toluene (100 ml). Evaporation of this mixture gave a flaky resiude which was further dried under high vacuum. The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml). The resulting mixture was stirred at room temperature for 18 hour, then heated on a steam bath for 20 minutes. It was cooled to room temperature, added crushed ice, then slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring. It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml). The extract was washed with water (4×100 ml), dried, filtered and evaporated to yield the desired product as a yellow oil: NMR (CDCl3) δ=1.82-2.7 (9H, m containing a singlet at 2.07δ), 4.40 (2H, s), 11.46 (H, bs). concentrated on a roatry evaporator The residue was treated with toluene (100 ml) Evaporation of this mixture gave a flaky resiude which was further dried under high vacuum The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml) The resulting mixture was stirred at room temperature for 18 hour heated on a steam bath for 20 minutes It was cooled to room temperature added crushed ice slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml) The extract was washed with water (4×100 ml) dried filtered evaporated

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

Procedure: A mixture of ethyl 1-benzyloxymethylcyclobutanecarboxylate (6.57 g, 26.5 mmol), 10% palladium on carbon (0.4 g) and ethanol (100 ml) was hydrogenated on a Parr Shaker for 4 hours. The catalyst was removed by filtration. The filtrate was evaporated in vacuo to leave the desired product as a colorless oil: NMR (CDCl3) δ32 1.26 (3H, t, J=7 Hz), 1.8~2.6 (6H, m), 2.61 (H, s), 3.78 (2H, s), 4.15 (2H, q, J=7 Hz). The catalyst was removed by filtration The filtrate was evaporated in vacuo

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (0.2 g, 1.264 mmol) in acetonitrile (2 mL) was added CuI (0.120 g, 0.632 mmol) and the reaction mass was heated to 50° C. 2,2-Difluoro-2-(fluorosulfonyl)acetic acid (0.196 mL, 1.896 mmol) added dropwise to the solution and the reaction mixture was stirred at 50° C. for 4 h. The reaction mixture was cooled to RT and extracted with EtOAc (3×15 mL). The combined organic layer was washed with a 10% aqueous solution of NaHCO3, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 223A as a brown oil (0.2 g, 76%). 1H NMR (300 MHz, DMSO-d6) δ ppm 6.94-6.39 (m, 1H), 4.16-3.99 (m, 4H), 2.41-2.17 (m, 2H), 2.08-1.73 (m, 4H), 1.26-1.09 (m, 3H). The reaction mixture was cooled to RT extracted with EtOAc (3×15 mL) The combined organic layer was washed with a 10% aqueous solution of NaHCO3 dried over Na2SO4 filtered the filtrate concentrated

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

Procedure: To a solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.3 mmol) and N,N-diethylethanamine (1.5 g, 8.2 mmol) in CH2Cl2 (30 ml) was added methanesulfonyl chloride (869 mg, 7.6 mmol). The mixture was stirred for 6 hours at ambient temperature. After dilution with CHCl3 and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to give ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.2 g). After dilution with CHCl3 and H2O, the organic layer was washed with H2O dried over MgSO4 concentrated in vacuo

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

Procedure: Sodium hydroxide pellets (1.48 g, 37 mmol) was added to a stirred mixture of ethyl 1-hydroxymethylcyclobutanecarboxylate (4.14 g, 26.1 mmol), water (4 ml) and 95% ethanol (20 ml). The resulting mixture was stirred at room temperature overnight, then concentrated on a rotary evaporator. The residue was treated with toluene (100 ml). Evaporation of this mixture gave a flaky residue which was further dried under high vacuum. The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml). The resulting mixture was stirred at room temperature for 18 hours, then heated on a steam bath for 20 minutes. It was cooled to room temperature, added crushed ice, then slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring. It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml). The extract was washed with water (4×100 ml), dried, filtered and evaporated to yield the desired product as a yellow oil: NMR (CDCl3) δ=1.82-2.7 (9H, m containing a singlet at 2.076δ), 4.40 (2H, s), 11.46 (H, bs). concentrated on a rotary evaporator The residue was treated with toluene (100 ml) Evaporation of this mixture gave a flaky residue which was further dried under high vacuum The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml) The resulting mixture was stirred at room temperature for 18 hours heated on a steam bath for 20 minutes It was cooled to room temperature added crushed ice slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml) The extract was washed with water (4×100 ml) dried filtered evaporated

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

Procedure: Sodium hydroxide pellets (1.48 g, 37 mmol) was added to a stirred mixture of ethyl 1-hydroxymethylcyclobutanecarboxylate (4.14 g, 26.1 mmol), water (4 ml) and 95% ethanol (20 ml). The resulting mixture was stirred at room temperature overnight, then concentrated on a rotary evaporator. The residue was treated with toluene (100 ml). Evaporation of this mixture gave a flaky residue which was further dried under high vacuum. The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml). The resulting mixture was stirred at room temperature for 18 hours, then heated on a steam bath for 20 minutes. It was cooled to room temperature, added crushed ice, then slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring. It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml). The extract was washed with water (4×100 ml), dried, filtered and evaporated to yield the desired product as a yellow oil: NMR (CDCl3) δ=1.82-2.7 (9H, m containing a singlet at 2.076δ), 4.40 (2H, s), 11.46 (H, bs). concentrated on a rotary evaporator The residue was treated with toluene (100 ml) Evaporation of this mixture gave a flaky residue which was further dried under high vacuum The final residue was treated with pyridine (25 ml) and acetic anhydride (15 ml) The resulting mixture was stirred at room temperature for 18 hours heated on a steam bath for 20 minutes It was cooled to room temperature added crushed ice slowly treated with concentrated HCl (12N, 30 ml) with vigorous stirring It was extracted with a mixture of diethyl ether (120 ml) and methylene chloride (40 ml) The extract was washed with water (4×100 ml) dried filtered evaporated

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

Procedure: A mixture of ethyl 1-benzyloxymethylcyclobutanecarboxylate (6.57 g, 26.5 mmol), 10% palladium on carbon (0.4 g) and ethanol (100 ml) was hydrogenated on a Parr Shaker for 4 hours. The catalyst was removed by filtration. The filtrate was evaporated in vacuo to leave the desired product as a colorless oil: NMR (CDCl3) δ=1.26 (3H, t, J=7 Hz), 1.8~2.6 (6H, m), 2.61 (H, s), 3.78 (2H, s), 4.15 (2H, q, J=7 Hz). The catalyst was removed by filtration The filtrate was evaporated in vacuo

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In tetrahydrofuran (11 mL) were dissolved 5-bromo-4-methylpyridin-2-ol (639 mg), ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (538 mg) and triphenylphosphine (1.07 g), 40% diethyl azodicarboxylate-toluene solution (1.86 mL) was added dropwise to the solution at room temperature, and then, the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (638 mg). was added dropwise to the solution at room temperature The reaction mixture was cooled to room temperature concentrated under reduced pressure the precipitated solid was removed by filtration The filtrate was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In tetrahydrofuran (11 mL) were dissolved 5-bromo-4-methylpyridin-2-ol (639 mg), ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (538 mg) and triphenylphosphine (1.07 g), 40% diethyl azodicarboxylate-toluene solution (1.86 mL) was added dropwise to the solution at room temperature, and then, the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (638 mg). was added dropwise to the solution at room temperature The reaction mixture was cooled to room temperature concentrated under reduced pressure the precipitated solid was removed by filtration The filtrate was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10)

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

Procedure: To a solution of ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (1.0 g, 6.3 mmol) and N,N-diethylethanamine (1.5 g, 8.2 mmol) in CH2Cl2 (30 ml) was added methanesulfonyl chloride (869 mg, 7.6 mmol). The mixture was stirred for 6 hours at ambient temperature. After dilution with CHCl3 and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to give ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.2 g). After dilution with CHCl3 and H2O, the organic layer was washed with H2O dried over MgSO4 concentrated in vacuo