2-propoxyethanol

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (WO00/24745, page 48, preparation 2) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) were dissolved in tetrahydrofuran (150 mL) and the solution cooled to 0° C. The solution was treated with diisopropyl azodicarboxylate (14.2 mL, 70 mmol) and the reaction mixture stirred at 0° C. for 3 hours before being allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 and then again eluting with dichloromethane to yield the title product. 1H NMR (CD3OD, 400 MHz) δ: 0.82 (t, 3H), 1.47 (q, 2H), 3.34 (t, 2H), 3.78 (t, 2H), 3.91 (s, 6H), 4.76 (t, 2H). MS APCI+ m/Z 316 [MH]+ to warm to room temperature The reaction mixture was concentrated in vacuo the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 again eluting with dichloromethane

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

Procedure: To a solution of 2-propoxy-1-ethanol (1.5 g, 14.4 mmol) and triethylamine (2.2 g, 21.6 mmol) in dichloromethane (20 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (3.86 g, 15.1 mmol) in dichloromethane (10 mL) dropwise over 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours. The mixture was then poured into water (50 mL) and acidified with 2N aqueous hydrochloric acid (15 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane:ethyl acetate (9:3), to give the title compound (2.2 g, 48%) as a colourless oil. The aqueous layer was extracted with dichloromethane the combined organic layers were dried over sodium sulfate filtered concentrated in vacuo to give a crude residue This was purified by column chromatography on silica gel (50 g) eluting with hexane:ethyl acetate (9:3)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropyl azodicarboxylate (14.2 mL, 70 mmol) was added to an ice-cooled solution of 4-nitro-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (EP 1241170, prep 10) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) in tetrahydrofuran (150 mL), and the reaction stirred at 0° C. for 2.5 hours, then allowed to stir at room temperature for a further 18 hours. The reaction was concentrated in vacuo and the residue purified by column chromatography on silica gel using ethyl acetate:pentane as eluant, and then re-columned using dichloromethane as eluant to afford the title compound as a solid, 14 g. to stir at room temperature for a further 18 hours The reaction was concentrated in vacuo the residue purified by column chromatography on silica gel

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

Procedure: 2-Propoxyethanol (1.89 g, 18.1 mmol) was dissolved in 50 mL THF, treated with potassium tert-butoxide (3.05 g, 27.2 mmol), stirred to uniform solution, placed in an addition funnel, and added dropwise to a solution of 2,6-difluoropyridine in 50 mL THF. After stirring overnight at room temperature, the solution was diluted with brine and extracted with ether. The ether extracts were combined and dried over Na2SO4, then concentrated in vacuo to yield 2-fluoro-6-(2-propoxyethoxy)-pyridine (3.33 g, 93%) as a yellow oil. placed in an addition funnel After stirring overnight at room temperature extracted with ether dried over Na2SO4 concentrated in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (WO00/24745, page 48, preparation 2) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) were dissolved in tetrahydrofuran (150 mL) and the solution cooled to 0° C. The solution was treated with diisopropyl azodicarboxylate (14.2 mL, 70 mmol) and the reaction mixture stirred at 0° C. for 3 hours before being allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 and then again eluting with dichloromethane to yield the title product. 1H NMR (CD3OD, 400 MHz) δ: 0.82 (t, 3H), 1.47 (q, 2H), 3.34 (t, 2H), 3.78 (t, 2H), 3.91 (s, 6H), 4.76 (t, 2H). MS APCI+ m/Z 316 [MH]+ to warm to room temperature The reaction mixture was concentrated in vacuo the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 again eluting with dichloromethane

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dimethyl 4-nitro-1H-pyrazole-3,5-dicarboxylate (WO00/24745, page 48, preparation 2) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) were dissolved in tetrahydrofuran (150 mL) and the solution cooled to 0° C. The solution was treated with diisopropyl azodicarboxylate (14.2 mL, 70 mmol) and the reaction mixture stirred at 0° C. for 3 hours before being allowed to warm to room temperature. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 and then again eluting with dichloromethane to yield the title product. 1H NMR (CD3OD, 400 MHz) δ: 0.82 (t, 3H), 1.47 (q, 2H), 3.34 (t, 2H), 3.78 (t, 2H), 3.91 (s, 6H), 4.76 (t, 2H). MS APCI+ m/Z 316 [MH]+ to warm to room temperature The reaction mixture was concentrated in vacuo the residue purified by column chromatography on silica gel eluting with ethyl acetate:pentane 15:85 again eluting with dichloromethane

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

Procedure: 26.0 g of sodium 2-chloro-5-nitrobenzenesulfonate and 5.0 g of sodium silicate (Na2O.nSiO2 wherein n is about 3) were suspended in 120 ml of 2-propoxyethanol. To the suspension was added dropwise with stirring a solution containing 5.0 g of sodium hydroxide dissolved in 5 ml of water at 65° C. for 10 minutes. After completion of the addition, the reaction mixture was stirred at 65° C. for 3 hours and the insoluble materials were removed by filtration under suction. The solids which deposited from the filtrate upon standing were removed by filtration. The filtrate was concentrated to a dry solid. 100 ml of ethanol was added to the residue to form crystals. The crystals were recovered by filtration, washed with isopropyl alcohol and dried at 50° C. Yield: 14.1 g. The compound at first melted at 70° to 74° C., then solidified at about 130° C. and again melted at 206° to 209° C. To the suspension was added dropwise After completion of the addition the reaction mixture was stirred at 65° C. for 3 hours the insoluble materials were removed by filtration under suction upon standing were removed by filtration The filtrate was concentrated to a dry solid 100 ml of ethanol was added to the residue to form crystals The crystals were recovered by filtration washed with isopropyl alcohol dried at 50° C solidified at about 130° C.

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

Procedure: 26.0 g of sodium 2-chloro-5-nitrobenzenesulfonate and 5.0 g of sodium silicate (Na2O.nSiO2 wherein n is about 3) were suspended in 120 ml of 2-propoxyethanol. To the suspension was added dropwise with stirring a solution containing 5.0 g of sodium hydroxide dissolved in 5 ml of water at 65° C. for 10 minutes. After completion of the addition, the reaction mixture was stirred at 65° C. for 3 hours and the insoluble materials were removed by filtration under suction. The solids which deposited from the filtrate upon standing were removed by filtration. The filtrate was concentrated to a dry solid. 100 ml of ethanol was added to the residue to form crystals. The crystals were recovered by filtration, washed with isopropyl alcohol and dried at 50° C. Yield: 14.1 g. The compound at first melted at 70° to 74° C., then solidified at about 130° C. and again melted at 206° to 209° C. To the suspension was added dropwise After completion of the addition the reaction mixture was stirred at 65° C. for 3 hours the insoluble materials were removed by filtration under suction upon standing were removed by filtration The filtrate was concentrated to a dry solid 100 ml of ethanol was added to the residue to form crystals The crystals were recovered by filtration washed with isopropyl alcohol dried at 50° C solidified at about 130° C.

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