1,3-dimethoxypropan-2-ol

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: To a solution of 2-methylquinolin-8-ol (4.10 g, 25.76 mmol), PPh3 (16.89 g, 64.39 mmol) and 1,3-dimethoxypropan-2-ol (4.02 g, 33.48 mmol) in THF (20 mL) was added DIAD (8.40 mL, 41.21 mmol) dropwise at ambient temperature. The reaction mixture was stirred at room temperature for two days. 4 N HCl (7.73 mL, 30.91 mmol in water), water (20 mL), and ethyl acetate (50 mL) were added. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was neutralized with ammonium hydroxide to about pH 9 and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate) to give 8-(1,3-dimethoxypropan-2-yloxy)-2-methylquinoline (6.00 g, 89.15%) as an oil. The aqueous layer was separated washed with ethyl acetate extracted with ethyl acetate (50 mL) The organic layer was separated washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate)

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

Procedure: Diisopropyl azodicarboxylate (1.1 mL, 5.4 mmol) was added in drops to a suspension of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.1 g, 4.1 mmol), 1,3-dimethoxypropan-2-ol (0.65 g, 5.4 mmol), and triphenylphosphine (1.4 g, 5.4 mmol) in tetrahydrofuran (33 mL). When this Mitsunobu reaction was deemed to be complete by LC/MS analysis, the mixture was adsorbed onto flash silica gel and purified by automated flash chromatography (methanol/chloroform) to provide 3-(6-chloro-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane as an amber glass (1.9 g, >100%) contaminated with triphenylphosphine oxide. MS (ES+): 368.2, 370.2 (M+H)+ When this Mitsunobu reaction purified by automated flash chromatography (methanol/chloroform)

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

Procedure: Diisopropyl azodicarboxylate (1.1 mL, 5.4 mmol) was added in drops to a suspension of 3-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (1.1 g, 4.1 mmol), 1,3-dimethoxypropan-2-ol (0.65 g, 5.4 mmol), and triphenylphosphine (1.4 g, 5.4 mmol) in tetrahydrofuran (33 mL). When this Mitsunobu reaction was deemed to be complete by LC/MS analysis, the mixture was adsorbed onto flash silica gel and purified by automated flash chromatography (methanol/chloroform) to provide 3-(6-chloro-1-(1,3-dimethoxypropan-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane as an amber glass (1.9 g, >100%) contaminated with triphenylphosphine oxide. MS (ES+): 368.2, 370.2 (M+H)+ When this Mitsunobu reaction purified by automated flash chromatography (methanol/chloroform)

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

Procedure: 4.3 mL of methanesulfonyl chloride was added dropwise at 5° C. to a stirred solution of 6.0 g of 1,3-dimethoxy-propan-2-ol and 9.0 mL of triethylamine in 60 mL of dichloromethane. Stirring was continued for 72 hours at room temperature, followed by extraction with water. The combined organic extracts were dried (sodium sulfate) and concentrated and the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 2.5 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester as an oil. EI-MS: 198 (M+). followed by extraction with water The combined organic extracts were dried (sodium sulfate) concentrated the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dimethoxypropan-2-ol (12.96 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 1 h. Subsequently, 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise within 20 min. After 1 h, the mixture was admixed with water and extracted by shaking four times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation. The residue was triturated with MtB ether, filtered off with suction and dried. 764 mg of the title compound were isolated. LC-MS rt: 0.74 min [M+H]+: 268.1 (met. a) was added dropwise within 20 min After 1 h extracted by shaking four times with dichloromethane The combined organic phases were dried over magnesium sulfate concentrated by rotary evaporation The residue was triturated with MtB ether filtered off with suction dried

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

Procedure: 4.3 mL of methanesulfonyl chloride was added dropwise at 5° C. to a stirred solution of 6.0 g of 1,3-dimethoxy-propan-2-ol and 9.0 mL of triethylamine in 60 mL of dichloromethane. Stirring was continued for 72 hours at room temperature, followed by extraction with water. The combined organic extracts were dried (sodium sulfate) and concentrated and the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 2.5 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester as an oil. EI-MS: 198 (M+). followed by extraction with water The combined organic extracts were dried (sodium sulfate) concentrated the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v)

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

Procedure: To a solution of 2-methylquinolin-8-ol (4.10 g, 25.76 mmol), PPh3 (16.89 g, 64.39 mmol) and 1,3-dimethoxypropan-2-ol (4.02 g, 33.48 mmol) in THF (20 mL) was added DIAD (8.40 mL, 41.21 mmol) dropwise at ambient temperature. The reaction mixture was stirred at room temperature for two days. 4 N HCl (7.73 mL, 30.91 mmol in water), water (20 mL), and ethyl acetate (50 mL) were added. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was neutralized with ammonium hydroxide to about pH 9 and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate) to give 8-(1,3-dimethoxypropan-2-yloxy)-2-methylquinoline (6.00 g, 89.15%) as an oil. The aqueous layer was separated washed with ethyl acetate extracted with ethyl acetate (50 mL) The organic layer was separated washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate)

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

Procedure: To a solution of 2-methylquinolin-8-ol (4.10 g, 25.76 mmol), PPh3 (16.89 g, 64.39 mmol) and 1,3-dimethoxypropan-2-ol (4.02 g, 33.48 mmol) in THF (20 mL) was added DIAD (8.40 mL, 41.21 mmol) dropwise at ambient temperature. The reaction mixture was stirred at room temperature for two days. 4 N HCl (7.73 mL, 30.91 mmol in water), water (20 mL), and ethyl acetate (50 mL) were added. The aqueous layer was separated and washed with ethyl acetate. The aqueous layer was neutralized with ammonium hydroxide to about pH 9 and extracted with ethyl acetate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate) to give 8-(1,3-dimethoxypropan-2-yloxy)-2-methylquinoline (6.00 g, 89.15%) as an oil. The aqueous layer was separated washed with ethyl acetate extracted with ethyl acetate (50 mL) The organic layer was separated washed with brine dried (sodium sulfate) filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (1:2 hexane/ethyl acetate)

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

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