cyclopentylmethyl methanesulfonate

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

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

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

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

Procedure: 1,2,4-Triazole-3-thiol (49.0 g; 0.484 mol) and 86% potassium hydroxide (32.0 g; 0.484 mol) were dissolved in methanol (500 ml) and refluxed for 1 h. The solution was then evaporated to dryness, and the residue redissolved in methanol (500 ml). Cyclopentylmethyl methanesulfonate (86.0 g; 0.484 mol) was added, the solution stirred under reflux for 8 h, and at room temperature overnight. The solution was evaporated and the residue dissolved in ether (500 ml) and water (1 1). The aqueous layer was separated and extracted with another portion of ether (500 ml). The ether solutions were combined, washed with saturated brine (500 ml), dried (MgSO4), filtered and evaporated, to afford cyclopentylmethyl 1,2,4-triazol-3-yl sulfide (85.0 g; 96%) as a waxy, white solid. NMR - d(CDCl3 ; 60 MHz) 1.0-2.4 (10H, m), 3.2 (2H, d, J=7 Hz), 8.1 (1H, s) and 13.4 (1H, br s). refluxed for 1 h The solution was then evaporated to dryness the residue redissolved in methanol (500 ml) under reflux for 8 h at room temperature overnight The solution was evaporated the residue dissolved in ether (500 ml) The aqueous layer was separated extracted with another portion of ether (500 ml) washed with saturated brine (500 ml) dried (MgSO4) filtered evaporated

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclopentanemethanol (50.0 g; 0.484 mol) and methane-sulfonyl chloride (67.0 g; 0.581 mol) in toluene (500 ml) were stirred and cooled to 4° C. Triethylamine (68.0 g; 0.678 mol) was added dropwise with external cooling so that the reaction temperature remained below 20° C. The reaction mixture is stirred under dry nitrogen at room temperature overnight. The reaction mixture was quenched with water (500 ml) and ether (500 ml), the organic phase separated, washed with water (500 ml) and saturated brine (500 ml) and dried (MgSO4). The solution is filtered and the solvent evaporated, to afford cyclopentylmethyl methanesulfonate (86.0 g; 100% yield) as a colorless liquid. NMR - d(CDCl3 ; 60 MHz) 0.8-2.6 (9H, m), 3.1 (3H, s) and 4.15 (2H, d, J=8 Hz). with external cooling so that the reaction temperature remained below 20° C The reaction mixture was quenched with water (500 ml) and ether (500 ml) the organic phase separated washed with water (500 ml) and saturated brine (500 ml) dried (MgSO4) The solution is filtered the solvent evaporated

Conditions: temp:4.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Cyclopentanemethanol (50.0 g; 0.484 mol) and methane-sulfonyl chloride (67.0 g; 0.581 mol) in toluene (500 ml) were stirred and cooled to 4° C. Triethylamine (68.0 g; 0.678 mol) was added dropwise with external cooling so that the reaction temperature remained below 20° C. The reaction mixture is stirred under dry nitrogen at room temperature overnight. The reaction mixture was quenched with water (500 ml) and ether (500 ml), the organic phase separated, washed with water (500 ml) and saturated brine (500 ml) and dried (MgSO4). The solution is filtered and the solvent evaporated, to afford cyclopentylmethyl methanesulfonate (86.0 g; 100% yield) as a colorless liquid. NMR - d(CDCl3 ; 60 MHz) 0.8-2.6 (9H, m), 3.1 (3H, s) and 4.15 (2H, d, J=8 Hz). with external cooling so that the reaction temperature remained below 20° C The reaction mixture was quenched with water (500 ml) and ether (500 ml) the organic phase separated washed with water (500 ml) and saturated brine (500 ml) dried (MgSO4) The solution is filtered the solvent evaporated

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

Procedure: Methanesulfonyl chloride (25.5 mL) was added dropwise to a solution of cyclopentanemethanol (32.4 mL) and triethylamine (46 mL) in dichloromethane (500 ml) at 0° C. After stirring overnight at room temperature, the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again. Following drying over sodium sulfate, the solvent was removed under vacuum, affording crude cyclopentylmethyl methanesulfonate (ca. 50 g) as a colourless oil. A mixture of this product and sodium iodide in acetone (600 ml) was heated at reflux in the dark for 16 hours. After cooling to room temperature, the reaction mixture was poured into petrol ether/water 2:1 (1.5 L) under stirring. The organic layer was washed twice with water, dried (Na2SO4) and carefully concentrated under reduced pressure (50 mm; temperature of the bath <30° C.). The residue was distilled in vacuo. The title product was obtained as a light yellow oil (39 g), by collecting the fraction boiling at 101-102°/70 mm. the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again Following drying over sodium sulfate the solvent was removed under vacuum

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

Procedure: Methanesulfonyl chloride (25.5 mL) was added dropwise to a solution of cyclopentanemethanol (32.4 mL) and triethylamine (46 mL) in dichloromethane (500 ml) at 0° C. After stirring overnight at room temperature, the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again. Following drying over sodium sulfate, the solvent was removed under vacuum, affording crude cyclopentylmethyl methanesulfonate (ca. 50 g) as a colourless oil. A mixture of this product and sodium iodide in acetone (600 ml) was heated at reflux in the dark for 16 hours. After cooling to room temperature, the reaction mixture was poured into petrol ether/water 2:1 (1.5 L) under stirring. The organic layer was washed twice with water, dried (Na2SO4) and carefully concentrated under reduced pressure (50 mm; temperature of the bath <30° C.). The residue was distilled in vacuo. The title product was obtained as a light yellow oil (39 g), by collecting the fraction boiling at 101-102°/70 mm. the mixture was sequentially washed with water, 2% hydrochloric acid, 4% aqueous sodium bicarbonate and water again Following drying over sodium sulfate the solvent was removed under vacuum

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

Procedure: 2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with cyclopentylmethyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione as a colorless oil. Yield (0.295 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz, 2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H), 2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m, 2H), 0.65 (d, J=6.85 Hz, 3H).

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

Procedure: 2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with cyclopentylmethyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione as a colorless oil. Yield (0.295 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz, 2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H), 2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m, 2H), 0.65 (d, J=6.85 Hz, 3H).

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

Procedure: 2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with cyclopentylmethyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione as a colorless oil. Yield (0.295 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz, 2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H), 2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m, 2H), 0.65 (d, J=6.85 Hz, 3H).

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

Procedure: 2-((2R,3R)-3-Hydroxy-3-(3-hydroxyphenyl)-2-methylpropyl)isoindoline-1,3-dione (82) was reacted with cyclopentylmethyl methanesulfonate following the method described for Example 72 to give 2-((2R,3R)-3-(3-(cyclopentylmethoxy)phenyl)-3-hydroxy-2-methylpropyl)isoindoline-1,3-dione as a colorless oil. Yield (0.295 g, 61%). 1H NMR (400 MHz, DMSO-d6) δ 7.75-7.80 (m, 4H), 7.13 (t, J=7.8 Hz, 1H), 6.83-6.88 (m, 2H), 6.66-6.69 (m, 1H), 5.30 (d, J=4.5 Hz, 1H), 4.38-4.41 (m, 1H), 3.77 (d, J=7.0 Hz, 2H), 3.70 (dd, J=5.5, 13.7 Hz, 1H), 3.40 (dd, J=9.4, 13.7 Hz, 1H), 2.20-2.30 (m, 2H), 1.70-1.78 (m, 2H), 1.46-1.62 (m, 4H), 1.26-1.34 (m, 2H), 0.65 (d, J=6.85 Hz, 3H).