(2R)-3-chloropropane-1,2-diol

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

Procedure: A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (250 mg, 659 μmol), (R)-3-chloro-1,2-propanediol (609 mg, 6.59 mmol) in isopropanol (8 mL) and 3 M aq. NaOH (2 mL) is stirred at 60° C. for 15 h. The mixture is diluted with EA and washed with brine, 1 M aq. NaOH and again with brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (297 mg) as a pale yellow oil; LC-MS**: tR=0.87 min, [M+H]+=454.26. washed with brine, 1 M aq. NaOH and again with brine extract is dried over Na2SO4 filtered concentrated The crude product is purified on prep

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

Procedure: A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (250 mg, 659 μmol), (R)-3-chloro-1,2-propanediol (609 mg, 6.59 mmol) in isopropanol (8 mL) and 3 M aq. NaOH (2 mL) is stirred at 60° C. for 15 h. The mixture is diluted with EA and washed with brine, 1 M aq. NaOH and again with brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (297 mg) as a pale yellow oil; LC-MS**: tR=0.87 min, [M+H]+=454.26. washed with brine, 1 M aq. NaOH and again with brine extract is dried over Na2SO4 filtered concentrated The crude product is purified on prep

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

Procedure: To a solution of 4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (79 mg, 0.263 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.6 mL), (R)-3-chloro-propane-1,2-diol (148 mg, 1.31 mmol) is added. The mixture is stirred at rt for 2 h, then at 65° C. for 16 h before another portion of (R)-3-chloro-propane-1,2-diol (119 mg, 1.05 mmol) is added. Stirring is continued at 65° C. for 24 h. The reaction mixture is diluted with water and extracted with diethyl ether. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM containing 4% of 7 N NH3 in methanol to give (2R)-3-{4-[5-(5-ethyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol as an off-white solid; LC-MS: tR=0.99 min; [M+1]+=375.13; 1H NMR (CDCl3): δ 7.83 (s, 2H), 7.80 (d, J=3.8 Hz, 1H), 6.93 (d, J=3.8 Hz, 1H), 4.20-4.11 (m, 1H), 3.97-3.93 (m, 1H), 3.91 (dd, J=11.5, 4.3 Hz, 1H), 3.85 (dd, J=11.5, 5.5 Hz, 1H), 2.97 (q, J=7.5 Hz, 2H), 2.39 (s, 6H), 1.41 (t, J=7.5 Hz, 3H). Stirring is continued at 65° C. for 24 h extracted with diethyl ether extract is dried over MgSO4 filtered evaporated The crude product is purified by chromatography on prep

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

Procedure: To N,N-dimethylformamide (40 ml) solution of (R)-(−)-3-chloro-1,2-propanediol (7 g), under ice-cooling and stirring condition, were added tert-butyldimethylchlorosilane (10.6 g) and imidazole (5.2 g), then stirred at a room temperature overnight. Ice-water (120 ml) was added to the reaction mixture, and extracted with ethyl acetate (50 ml) 3 times, the extracts were combined together and washed with an aqueous solution being saturated with sodium chloride, then dried over anhydrous magnesium sulfate. After being filtrated under a reduced pressure, the filtrate was concentrated, there was obtained (R)-(−)-1-(tert-butyldimethylsilanyloxy)-3-chloropropan-2-ol (13.24 g, yield: 92.4%) as colorless liquid product. stirred at a room temperature overnight extracted with ethyl acetate (50 ml) 3 times washed with an aqueous solution dried over anhydrous magnesium sulfate After being filtrated under a reduced pressure the filtrate was concentrated

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

Procedure: A mixture of 4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (250 mg, 659 μmol), (R)-3-chloro-1,2-propanediol (609 mg, 6.59 mmol) in isopropanol (8 mL) and 3 M aq. NaOH (2 mL) is stirred at 60° C. for 15 h. The mixture is diluted with EA and washed with brine, 1 M aq. NaOH and again with brine. The org. extract is dried over Na2SO4, filtered and concentrated. The crude product is purified on prep. TLC plates using DCM containing 10% of methanol to give the title compound (297 mg) as a pale yellow oil; LC-MS**: tR=0.87 min, [M+H]+=454.26. washed with brine, 1 M aq. NaOH and again with brine extract is dried over Na2SO4 filtered concentrated The crude product is purified on prep

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

Procedure: To N,N-dimethylformamide (40 ml) solution of (R)-(−)-3-chloro-1,2-propanediol (7 g), under ice-cooling and stirring condition, were added tert-butyldimethylchlorosilane (10.6 g) and imidazole (5.2 g), then stirred at a room temperature overnight. Ice-water (120 ml) was added to the reaction mixture, and extracted with ethyl acetate (50 ml) 3 times, the extracts were combined together and washed with an aqueous solution being saturated with sodium chloride, then dried over anhydrous magnesium sulfate. After being filtrated under a reduced pressure, the filtrate was concentrated, there was obtained (R)-(−)-1-(tert-butyldimethylsilanyloxy)-3-chloropropan-2-ol (13.24 g, yield: 92.4%) as colorless liquid product. stirred at a room temperature overnight extracted with ethyl acetate (50 ml) 3 times washed with an aqueous solution dried over anhydrous magnesium sulfate After being filtrated under a reduced pressure the filtrate was concentrated

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

Procedure: To N,N-dimethylformamide (40 ml) solution of (R)-(−)-3-chloro-1,2-propanediol (7 g), under ice-cooling and stirring condition, were added tert-butyldimethylchlorosilane (10.6 g) and imidazole (5.2 g), then stirred at a room temperature overnight. Ice-water (120 ml) was added to the reaction mixture, and extracted with ethyl acetate (50 ml) 3 times, the extracts were combined together and washed with an aqueous solution being saturated with sodium chloride, then dried over anhydrous magnesium sulfate. After being filtrated under a reduced pressure, the filtrate was concentrated, there was obtained (R)-(−)-1-(tert-butyldimethylsilanyloxy)-3-chloropropan-2-ol (13.24 g, yield: 92.4%) as colorless liquid product. stirred at a room temperature overnight extracted with ethyl acetate (50 ml) 3 times washed with an aqueous solution dried over anhydrous magnesium sulfate After being filtrated under a reduced pressure the filtrate was concentrated

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

Procedure: To a solution of 4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenol (55 mg, 0.163 mmol) in isopropanol (3 mL) and 3 N aq. NaOH (0.5 mL), (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. The mixture is stirred at 65° C. for 72 h before another portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. Stirring is continued at 65° C. for 4 days before a third portion of (R)-3-chloro-1,2-propanediol (98 mg, 0.894 mmol) is added. After stirring for another 48 h, the mixture is diluted with EA (50 mL) and washed with 1 N aq. NaOH (10 mL) followed by brine (10 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. TLC plates with DCM containing 10% of 7 N NH3 in methanol and 5% of methanol to give (R)-3-(4-{5-[2-(ethyl-methyl-amino)-6-methyl-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethyl-phenoxy)-propane-1,2-diol (25 mg) as a yellow solid; LC-MS: tR=0.73 min; [M+1]+=413.14. is added is added After stirring for another 48 h washed with 1 N aq. NaOH (10 mL) dried over MgSO4 filtered concentrated The crude product is purified on prep

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

Procedure: To a solution of 2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (200 mg, 0.569 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), (R)-3-chloro-1,2-propanediol (252 mg, 2.28 mmol) is added. The mixture is stirred at 60° C. for 24 h before another portion of (R)-3-chloro-1,2-propanediol (252 mg, 2.28 mmol) is added. Stirring is continued at 60° C. for 6 days. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA to give 3-{2-ethyl-4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-(R)-propane-1,2-diol (40 mg) as a pale yellow oil; LC-MS: tR=0.84 min; [M+1]+=426.16; 1H NMR (CDCl3): δ 7.90 (s, 1H), 7.88 (s, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 4.20-4.14 (m, 1H), 3.95-3.85 (m, 4H), 2.80-2.74 (m, 4H), 2.70 (s, 3H), 2.42 (s, 3H), 2.24-2.16 (m, 1H), 1.34 (t, J=7.5 Hz, 3H), 1.00 (d, J=6.5 Hz, 6 H). is added washed with sat. aq. NaHCO3 solution extract is dried over MgSO4 filtered evaporated The crude product is purified by chromatography on prep

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

Procedure: Benzyl alcohol (60.54 g, 0.56 mol) was dropped under ice cooling in a suspension of 60% sodium hydride (11.2 g, 0.28 mol) and DMF (300 ml). After emission of hydrogen gas, therein a DMF solution (25 ml) of (R)-3-chloro-1,2-propanediol (15.47 g, 0.14 mol, optical purity 98.7% e.e.) was dropped. The reaction temperature was raised to 60° C. and the mixture was stirred under heating for 2 hours. After completion of the reaction the mixture was cooled on ice bath and neutralized with 6% hydrochloric acid. After removal of water and DMF in vacuo, ethyl acetate was added to the residue, the insoluble materials were filtered off and the filtrate was condensed in vacuo. Thereto acetone (1500 ml) and p-toluenesulfonic acid (1.13 g) were added and the solution was stirred for 5 hours at 25° C. After the reaction was over, the reaction mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 16.228 g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 52%, b.p. 110° C. at 0.3 mmHg). under heating for 2 hours After completion of the reaction the mixture was cooled on ice bath After removal of water and DMF in vacuo, ethyl acetate was added to the residue the insoluble materials were filtered off condensed in vacuo the solution was stirred for 5 hours at 25° C After stirring for 5 minutes acetone was removed in vacuo The crude product was distilled

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

Procedure: Benzyl alcohol (32.90 g, 0.35 mol) was dropped under ice cooling in a suspension of 60% sodium hydride (5.88 g, 0.155 mol) and DMF (150 ml) After emission of hydrogen gas, therein a DMF solution (15 ml) of (R)-3-chloro-1,2-propanediol (8.535 g, 0.078 mol, optical purity 98.7% e.e.) was dropped. The reaction temperature was raised to 60° C. and the mixture was stirred under heating for 2 hours. After completion of the reaction the mixture was cooled on ice bath and neutralized with 6% hydrochloric acid. After removal of water and DMF in vacuo, ethyl acetate was added to the residue, the insoluble materials were filtered off and the filtrate was condensed in vacuo. Thereto acetone (750 ml) and p-toluenesulfonic acid (0.579 g), were added and the solution was stirred for 5 hours at 25° C. After the reaction was over, the mixture was neutralized with triethylamine. After stirring for 5 minutes, acetone was removed in vacuo. The crude product was distilled to give 9.267 g of (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 54%, b.p. 110° C. at 0.3 mmHg). under heating for 2 hours After completion of the reaction the mixture was cooled on ice bath After removal of water and DMF in vacuo, ethyl acetate was added to the residue the insoluble materials were filtered off condensed in vacuo the solution was stirred for 5 hours at 25° C After stirring for 5 minutes acetone was removed in vacuo The crude product was distilled

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

Procedure: p-Toluenesulfonic acid (0.86 g) was added to a mixture of (R)-3-chloro-1,2-propanediol (50.13 g, 0.454 mol, optical purity 98.7% e.e.) and acetone (660 ml) and the resulting mixture was stirred for 12 hours at 25C. After completion of the reaction, acetone was removed in vacuo and the crude product was distilled to give 58.11 g of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (yield 85%, b.p. 63° C. at 25 mmHg). was removed in vacuo the crude product was distilled