1-methoxy-2-[2-(2-methoxyethoxy)ethoxy]ethane

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:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The following were introduced into 282 ml of triglyme: 112.8 grams of 2-nitro-5-chloro-trifluoromethylbenzene, 64.1 grams of 5,5-dimethyl-hydantoin and 33.5 grams of cuprous oxide. The mixture was heated to about 215° C.±5° C. for 4 hours, then cooled to 20° C. and filtered. The triglyme solution was recovered and a 22 Be ammonia solution (1V), toluene (1V) and demineralized water (4V) were added to the solution of triglyme (1V). The solution was stirred at 20° C. for 15 minutes, then cooled to about -10° C. and stirred again at -10° C. After washing and drying, 47.6 grams of the desired product were obtained. The mixture was heated to about 215° C.±5° C. for 4 hours filtered The triglyme solution was recovered a 22 Be ammonia solution (1V), toluene (1V) and demineralized water (4V) were added to the solution of triglyme (1V) cooled to about -10° C. stirred again at -10° C After washing drying

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-benzyl-4-ethoxy-7-allyloxysaccharin (0.25 g) and triglyme was heated at 200° C. for 20 minutes, examined for extent of reaction by thin layer chromatography, heated at 200° C. for 20 minutes more, stirred overnight and poured into ice-water. The resulting tacky, brown solid was dissolved in dichloromethane. The dichloromethane solution was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and stripped of dichloromethane. Column chromatography of the residue (0.29 g) on silica using dichloromethane and dichloromethane-acetone (up to 99:1) as eluants afforded 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (90 mg, 36% yield) whose mass spectrogram showed a molecular ion at mass 373. examined for extent of reaction by thin layer chromatography heated at 200° C. for 20 minutes more The dichloromethane solution was washed with saturated aqueous sodium chloride solution dried over sodium sulfate

Conditions: temp:200.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-benzyl-4-ethoxy-7-allyloxysaccharin (0.25 g) and triglyme was heated at 200° C. for 20 minutes, examined for extent of reaction by thin layer chromatography, heated at 200° C. for 20 minutes more, stirred overnight and poured into ice-water. The resulting tacky, brown solid was dissolved in dichloromethane. The dichloromethane solution was washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and stripped of dichloromethane. Column chromatography of the residue (0.29 g) on silica using dichloromethane and dichloromethane-acetone (up to 99:1) as eluants afforded 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (90 mg, 36% yield) whose mass spectrogram showed a molecular ion at mass 373. examined for extent of reaction by thin layer chromatography heated at 200° C. for 20 minutes more The dichloromethane solution was washed with saturated aqueous sodium chloride solution dried over sodium sulfate

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

Procedure: A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles) is slowly added to a cooled (−78° C.) solution of 2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles) in THF (180 mL). After stirring for one hour, the reaction is warmed to 0° C. for two hours, then quenched with 2N HCl (16.8 mL) and diluted with ether. The organic layer is isolated and washed with twice with distilled water and brine, then dried over MgSO4. The organic solution is concentrated to give the title compound as a yellow oil. quenched with 2N HCl (16.8 mL) diluted with ether The organic layer is isolated washed with twice with distilled water and brine dried over MgSO4 The organic solution is concentrated

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

Procedure: A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles) is slowly added to a cooled (−78° C.) solution of 2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles) in THF (180 mL). After stirring for one hour, the reaction is warmed to 0° C. for two hours, then quenched with 2N HCl (16.8 mL) and diluted with ether. The organic layer is isolated and washed with twice with distilled water and brine, then dried over MgSO4. The organic solution is concentrated to give the title compound as a yellow oil. quenched with 2N HCl (16.8 mL) diluted with ether The organic layer is isolated washed with twice with distilled water and brine dried over MgSO4 The organic solution is concentrated

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

Procedure: A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles) is slowly added to a cooled (−78° C.) solution of 2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles, example 22) in THF (180 mL). After stirring for one hour, the reaction is warmed to 0° C. for two hours, then quenched with 2N HCl (16.8 mL) and diluted with ether. The organic layer is isolated and washed with twice with distilled water and brine, then dried over MgSO4. The organic solution is concentrated to give the title compound as a yellow oil. quenched with 2N HCl (16.8 mL) diluted with ether The organic layer is isolated washed with twice with distilled water and brine dried over MgSO4 The organic solution is concentrated

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

Procedure: A 2M triglyme solution of sodium borohydride (16.0 mL, 32.1 mmoles) is slowly added to a cooled (−78° C.) solution of 2-cyanomethoxy-3-methylbenzaldehyde (11.25 g, 64.2 mmoles, example 22) in THF (180 mL). After stirring for one hour, the reaction is warmed to 0° C. for two hours, then quenched with 2N HCl (16.8 mL) and diluted with ether. The organic layer is isolated and washed with twice with distilled water and brine, then dried over MgSO4. The organic solution is concentrated to give the title compound as a yellow oil. quenched with 2N HCl (16.8 mL) diluted with ether The organic layer is isolated washed with twice with distilled water and brine dried over MgSO4 The organic solution is concentrated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of zinc powder (2.29 g, 0.035 mol) and triglyme (17.5 mL) was added TMSBr (0.45 mL, 0.004 mol) under nitrogen, and the mixture was stirred at 70° C. for 1.5 h. After the reaction mixture was cooled to room temperature, ethyl bromodifluoroacetate (5.41 mL, 0.042 mol) was added while maintaining the internal temperature at 22 to 27° C., and the mixture was stirred at 20° C. for 30 min and then cooled to 0° C. After addition of a solution of isopropyl 5-bromopyrazine-2-carboxylate (II, 4.48 g, 0.017 mol) in DMA (51 mL) to the reaction mixture, the resulting mixture was warmed to 20° C. Copper bromide (CuBr, 5.02 g, 0.035 mol) was added in fifth portions over 1 h followed by stirring the mixture for 30 min. The resulting mixture was transferred into a pre-cooled (ice bath) mixture of an aqueous sodium chloride solution (6.3%, 55.5 g), concentrated hydrochloric acid (14.7 mL) and toluene (70 mL), and the resulting mixture was vigorously stirred. After phase separation, the organic layer was washed twice with an aqueous sodium chloride solution (5.7%, 35 g and 2.9%, 35 g) to afford 74.2 g of a toluene solution of isopropyl 5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrazine-2-carboxylate (III). After the reaction mixture was cooled to room temperature while maintaining the internal temperature at 22 to 27° C. the mixture was stirred at 20° C. for 30 min cooled to 0° C the resulting mixture was warmed to 20° C by stirring the mixture for 30 min a pre-cooled the resulting mixture was vigorously stirred After phase separation the organic layer was washed twice with an aqueous sodium chloride solution (5.7%, 35 g and 2.9%, 35 g)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of zinc powder (2.29 g, 0.035 mol) and triglyme (17.5 mL) was added TMSBr (0.45 mL, 0.004 mol) under nitrogen, and the mixture was stirred at 70° C. for 1.5 h. After the reaction mixture was cooled to room temperature, ethyl bromodifluoroacetate (5.41 mL, 0.042 mol) was added while maintaining the internal temperature at 22 to 27° C., and the mixture was stirred at 20° C. for 30 min and then cooled to 0° C. After addition of a solution of isopropyl 5-bromopyrazine-2-carboxylate (II, 4.48 g, 0.017 mol) in DMA (51 mL) to the reaction mixture, the resulting mixture was warmed to 20° C. Copper bromide (CuBr, 5.02 g, 0.035 mol) was added in fifth portions over 1 h followed by stirring the mixture for 30 min. The resulting mixture was transferred into a pre-cooled (ice bath) mixture of an aqueous sodium chloride solution (6.3%, 55.5 g), concentrated hydrochloric acid (14.7 mL) and toluene (70 mL), and the resulting mixture was vigorously stirred. After phase separation, the organic layer was washed twice with an aqueous sodium chloride solution (5.7%, 35 g and 2.9%, 35 g) to afford 74.2 g of a toluene solution of isopropyl 5-(2-ethoxy-1,1-difluoro-2-oxoethyl)pyrazine-2-carboxylate (III). After the reaction mixture was cooled to room temperature while maintaining the internal temperature at 22 to 27° C. the mixture was stirred at 20° C. for 30 min cooled to 0° C the resulting mixture was warmed to 20° C by stirring the mixture for 30 min a pre-cooled the resulting mixture was vigorously stirred After phase separation the organic layer was washed twice with an aqueous sodium chloride solution (5.7%, 35 g and 2.9%, 35 g)