ethyl 2-(1-hydroxycyclobutyl)acetate

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

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

Procedure: H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl (1-hydroxycyclobutyl)acetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the solution reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m). for an additional hour at 80° C The mixture was cooled in an ice-water bath The mixture was extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

Procedure: H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl (1-hydroxycyclobutyl)acetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the solution reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m). for an additional hour at 80° C The mixture was cooled in an ice-water bath The mixture was extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

Procedure: Trimethylchlorosilane (1.14 mL, 8.92 mmol) was added by syringe to a suspension of zinc powder (7.97 g, 0.122 mol) in absolute Et2O (200 mL). The mixture was stirred for 15 minutes at room temperature, heated to reflux, the heat source was removed, and ethyl bromoacetate (10.3 mL, 92.9 mmol) was added at such a rate that the ether solution gently boiled. After being heating for one hour at reflux, the mixture was stirred for one additional hour at room temperature. A solution of cyclopentanone (6.00 g, 75.9 mmol) in ether (30 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. The mixture was stirred for 1 hour at room temperature and poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether, the combined organic phases were dried over K2CO3 and the solvent was evaporated to yield the title compound as a colorless oil (6.50 g, 54%). 1H-NMR (400 MHz, CDCl3) δ 1.29 (3H, t, J=7.3 Hz), 1.47-1.64 (1H, m), 1.76-1.87 (1H, m), 1.93-2.06 (2H, m), 2.12-2.22 (2H, m), 2.67 (2H, s), 3.70 (1H, s), 4.19 (2H, q, J=7.3 Hz). heated to reflux the heat source was removed After being heating for one hour at reflux the mixture was stirred for one additional hour at room temperature was maintained at 19-20° C. by intermittent cooling The mixture was stirred for 1 hour at room temperature The aqueous phase was extracted with ether the combined organic phases were dried over K2CO3 the solvent was evaporated

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

Procedure: H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl 1-hydroxycyclobutylacetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the mixture reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m). for an additional hour at 80° C The mixture was cooled in an ice-water bath The mixture was extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

Procedure: H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl 1-hydroxycyclobutylacetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the mixture reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m). for an additional hour at 80° C The mixture was cooled in an ice-water bath The mixture was extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

Procedure: Trimethylchlorosilane (1.14 mL, 8.92 mmol) was added by syringe to a suspension of zinc powder (7.97 g, 0.122 mol) in absolute Et2O (200 mL). The mixture was stirred for 15 minutes at room temperature. The mixture was then heated to reflux, the heat source was removed, and ethyl bromoacetate (10.3 mL, 92.9 mmol) was added at such a rate that the ether solution gently boiled. The mixture was refluxed one hour then stirred for an additional hour at room temperature. A solution of cyclopentanone (6.00 g, 75.9 mmol) in ether (30 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. After being one hour of stirring at room temperature, the mixture was poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether and the combined phases were dried over K2CO3. Filtration and evaporation of the solvent yielded the title compound as a colorless oil (6.50 g, 54%). 1H-NMR (400 MHz, CDCl3) δ 1.29 (3H, t, J=7.3 Hz), 1.47-1.64 (1H, m), 1.76-1.87 (1H, m), 1.93-2.06 (2H, m), 2.12-2.22 (2H, m), 2.67 (2H, s), 3.70 (1H, s), 4.19 (2H, q, J=7.3 Hz). The mixture was then heated to reflux the heat source was removed The mixture was refluxed one hour then stirred for an additional hour at room temperature was maintained at 19-20° C. by intermittent cooling After being one hour of stirring at room temperature The aqueous phase was extracted with ether the combined phases were dried over K2CO3 Filtration and evaporation of the solvent

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

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

Procedure: The title compound, white solid (58 mg, 52%), MS (ISP) m/z=443.5 [(M+H)+], mp 155° C., was prepared in accordance with the general method of example 2 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and ethyl 2-(1-hydroxy-cyclobutyl)-acetate.

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

Procedure: H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl (1-hydroxycyclobutyl)acetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the solution reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m). for an additional hour at 80° C The mixture was cooled in an ice-water bath The mixture was extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo

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

Procedure: Trimethylchlorosilane (1.14 mL, 8.92 mmol) was added by syringe to a suspension of zinc powder (7.97 g, 0.122 mol) in absolute Et2O (200 mL). The mixture was stirred for 15 minutes at room temperature, heated to reflux, the heat source was removed, and ethyl bromoacetate (10.3 mL, 92.9 mmol) was added at such a rate that the ether solution gently boiled. After being heating for one hour at reflux, the mixture was stirred for one additional hour at room temperature. A solution of cyclopentanone (6.00 g, 75.9 mmol) in ether (30 mL) was added while the temperature of the mixture was maintained at 19-20° C. by intermittent cooling. The mixture was stirred for 1 hour at room temperature and poured into iced 25% ammonia (400 mL). The aqueous phase was extracted with ether, the combined organic phases were dried over K2CO3 and the solvent was evaporated to yield the title compound as a colorless oil (6.50 g, 54%). 1H-NMR (400 MHz, CDCl3) δ 1.29 (3H, t, J=7.3 Hz), 1.47-1.64 (1H, m), 1.76-1.87 (1H, m), 1.93-2.06 (2H, m), 2.12-2.22 (2H, m), 2.67 (2H, s), 3.70 (1H, s), 4.19 (2H, q, J=7.3 Hz). heated to reflux the heat source was removed After being heating for one hour at reflux the mixture was stirred for one additional hour at room temperature was maintained at 19-20° C. by intermittent cooling The mixture was stirred for 1 hour at room temperature The aqueous phase was extracted with ether the combined organic phases were dried over K2CO3 the solvent was evaporated

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

Procedure: H2SO4 (2.20 mL, 41.3 mmol) was slowly added to a mixture of ethyl 1-hydroxycyclobutylacetate (6.45 g, 40.8 mmol) and benzonitrile (40 mL, 0.392 mol) at room temperature. The mixture was stirred for 1 hour at room temperature, then for an additional hour at 80° C. The mixture was cooled in an ice-water bath, and 2N NaOH solution was added until the mixture reached pH=7. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Flash chromatography (AcOEt:Hexane=5:1) of the residue gave the title compound as a colorless solid (5.40 g, 51%). 1H-NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J=7.3 Hz), 1.84-2.07 (2H, m), 2.22-2.32 (2H, m), 2.44-2.55 (2H, m), 3.05 (2H, s), 4.11 (2H, q, J=7.3 Hz), 6.73 (1H, s), 7.39-7.52 (3H, m), 7.72-7.79 (2H, m). for an additional hour at 80° C The mixture was cooled in an ice-water bath The mixture was extracted with ethyl acetate the combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated in vacuo