2-cyclopropylethanol

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:

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: The title compound was prepared according to the method of Example 335, substituting 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 2-cyclopropane ethanol in place of isobutanol (yield: 0.1472 g, 100%). mp 111-117° C. 1H NMR (300 MHz, DMSO d6) δ −0.01 (m, 2H), 0.31 (m, 2H), 0.60 (m, 1H), 1.49 (q, J=6 Hz, 2H), 3.29 (s, 3H), 4.48 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.65 (m, 2H), 7.91 (m, 2H), 8.06 (m, 2H), 8.17 (s, 1H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21FN2O4S: C, 61.67; H, 4.94; N, 6.54. Found: C, 61.59; H, 5.02; N, 6.45.

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

Procedure: To a solution of 2-cyclopropylethanol (2.1 g, 24.4 mmol) in dichloromethane (50 ml) at 0° C. under nitrogen was added triethylamine (4.1 ml, 1.3 mol equiv). Methanesulphonyl chloride (2.5 ml, 1.3 mol equiv) was added dropwise and the reaction stirred for 16 hours at room temperature. Water (30 ml) and dichloromethane (30 ml) were added. The organic phase was washed with water (2×50 ml) and then dried over anhydrous MgSO4. The solution was then filtered and the solvent removed in vacuo to give the title compound as an oil (4.0 g). The organic phase was washed with water (2×50 ml) dried over anhydrous MgSO4 The solution was then filtered the solvent removed in vacuo

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

Procedure: Methyl 4-hydroxybenzoate (8.83 g, 58.0 mmol), 2-cyclopropylethanol (5.13 g, 59.6 mmol), and triphenylphosphine (15.7 g, 59.9 mmol) were dissolved in THF (250 mL). Then, diethyl azodicarboxylate (29.8 mL, 40% toluene solution, 59.6 mmol) was added thereto under ice-cooling while stirring. The mixture was stirred at room temperature for 2 days, and then water (200 mL) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting residue was dissolved in diethyl ether. The produced precipitate was removed by filtration, and diethyl ether was evaporated. This filtration procedure was repeated twice, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 20:1, v/v) to give an oily substance (13.2 g). All this oily substance was dissolved in ethanol (200 mL), and a 2 M lithium hydroxide aqueous solution (60 mL, 120 mmol) was added thereto. The mixture was stirred at 60° C. for 50 minutes, and then 10% hydrochloric acid (40 mL) was added thereto under ice-cooling. The resulting mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was suspended in diisopropyl ether, and the precipitate was collected by filtration and dried under reduced pressure to give 9.28 g of the title compound (powder, yield: 78%). under ice-cooling The mixture was stirred at room temperature for 2 days The resulting mixture was extracted with ethyl acetate twice washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated The resulting residue was dissolved in diethyl ether The produced precipitate was removed by filtration, and diethyl ether was evaporated This filtration procedure the residue was purified by silica gel column chromatography (hexane ethyl acetate, 20:1, v/v) to give an oily substance (13.2 g) The mixture was stirred at 60° C. for 50 minutes under ice-cooling The resulting mixture was extracted with ethyl acetate twice washed with saturated brine dried over anhydrous magnesium sulfate Then, the solvent was evaporated the precipitate was collected by filtration dried under reduced pressure

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

Procedure: Methyl 4-hydroxybenzoate (8.83 g, 58.0 mmol), 2-cyclopropylethanol (5.13 g, 59.6 mmol), and triphenylphosphine (15.7 g, 59.9 mmol) were dissolved in THF (250 mL). Then, diethyl azodicarboxylate (29.8 mL, 40% toluene solution, 59.6 mmol) was added thereto under ice-cooling while stirring. The mixture was stirred at room temperature for 2 days, and then water (200 mL) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting residue was dissolved in diethyl ether. The produced precipitate was removed by filtration, and diethyl ether was evaporated. This filtration procedure was repeated twice, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 20:1, v/v) to give an oily substance (13.2 g). All this oily substance was dissolved in ethanol (200 mL), and a 2 M lithium hydroxide aqueous solution (60 mL, 120 mmol) was added thereto. The mixture was stirred at 60° C. for 50 minutes, and then 10% hydrochloric acid (40 mL) was added thereto under ice-cooling. The resulting mixture was extracted with ethyl acetate twice. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated. The resulting residue was suspended in diisopropyl ether, and the precipitate was collected by filtration and dried under reduced pressure to give 9.28 g of the title compound (powder, yield: 78%). under ice-cooling The mixture was stirred at room temperature for 2 days The resulting mixture was extracted with ethyl acetate twice washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated The resulting residue was dissolved in diethyl ether The produced precipitate was removed by filtration, and diethyl ether was evaporated This filtration procedure the residue was purified by silica gel column chromatography (hexane ethyl acetate, 20:1, v/v) to give an oily substance (13.2 g) The mixture was stirred at 60° C. for 50 minutes under ice-cooling The resulting mixture was extracted with ethyl acetate twice washed with saturated brine dried over anhydrous magnesium sulfate Then, the solvent was evaporated the precipitate was collected by filtration dried under reduced pressure

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

Procedure: To a stirring solution of sodium tert.-butoxide (13.45 g) in DME (80 ml) was added dropwise under nitrogen a solution of 2-cyclopropylethanol (12.1 g) in DME (40 ml) over 5 min. After 30 min 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (11.84 g) was added and the stirring mixture refluxed for 20 h. After cooling the mixture was treated with water and extracted twice with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a hydrophobic frit and evaporated to a brown oil. This was re-evaporated twice from toluene then purified on a silica column using an ISCO Companion, eluting with methanol:ethyl acetate (0-12%) to give the title compound. Yield 6.53 gm. the stirring mixture refluxed for 20 h After cooling the mixture extracted twice with ethyl acetate The combined extracts were washed with water brine, dried evaporated to a brown oil This was re-evaporated twice from toluene then purified on a silica column eluting with methanol

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-cyclopropylethanol (3.45 g) in DME (20 mL) was added sodium tert-butoxide (3.86 g) gradually. The reaction was stirred under nitrogen for 30 mins, then 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (2.54 g) and DME (20 mL) were added. The reaction was heated to reflux (110° C.) overnight, then for another 8 h. The reaction was quenched into water (100 mL) and extracted with EtOAc (2×100 mL). The organics were combined and washed with brine (100 mL) and dried using a hydrophobic frit. The resultant oil was azeotroped with toluene (×2) to give a gum. This was triturated with Et2O (cooled CO2/acetone bath) until the title compound was obtained as a yellow powder (1.579 g) which was placed under high vacuum for 24 h. The reaction was heated for another 8 h The reaction was quenched into water (100 mL) extracted with EtOAc (2×100 mL) washed with brine (100 mL) dried The resultant oil was azeotroped with toluene (×2) to give a gum This was triturated with Et2O (cooled CO2/acetone bath) until the title compound