2,2-diethoxyacetonitrile

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: In a 2 L three-neck flask, a solution of diethoxyacetonitrile (125 g, 968 mmol) in methanol (300 mL, anhydrous) was treated with a 25 wt % solution of sodium methoxide (21.0 g, 389 mmol) in methanol, producing a slightly exothermic reaction. After cooling, the mixture was stirred at room temperature for 15 h. Upon completion of the reaction, the solvent was slowly evaporated under vacuum. The remaining brown-colored residue was solvated with diethyl ether (1 L), then washed with water (3×500 mL), followed by brine (1×200 mL). The organic layer was dried using magnesium sulfate, the salts filtered, and the solvent evaporated carefully under vacuum to afford 132 g (85% yield) of methyl 2,2-diethoxyethanimidoate as a colorless liquid. producing a slightly exothermic reaction After cooling Upon completion of the reaction the solvent was slowly evaporated under vacuum washed with water (3×500 mL) The organic layer was dried the salts filtered the solvent evaporated carefully under vacuum

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

Procedure: To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70–75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77–78° C. at 20–22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0–5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product. (70–75 h) The reaction mixture was treated to form The latter was filtered off washed with methanol (50 mL) The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C The resulting liquid was dissolved in ether (250 mL) filtered to remove the remaining inorganic salts evaporated again

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

Procedure: To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70–75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77–78° C. at 20–22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0–5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product. (70–75 h) The reaction mixture was treated to form The latter was filtered off washed with methanol (50 mL) The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C The resulting liquid was dissolved in ether (250 mL) filtered to remove the remaining inorganic salts evaporated again

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

Procedure: A solution of diethoxyacetonitrile (75 g, 0.579 mol) in methanol (210 mL) was added at room temperature to a solution of sodium methoxide (28.3 g, 0.522 mol) in methanol (450 mL). The mixture was stirred overnight, and then methanol was evaporated. The residue was diluted with dichloromethane (200 mL) and water (300 mL). The organic layer was separated, and the aqueous one was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over Na2SO4 and evaporated to give 83 g of crude methyl 2,2-diethoxyacetimidate (˜90% yield). A solution of methyl 2,2-diethoxyacetimidate prepared above (0.6208 mol, 125.1 g of 80% purity) in methanol (300 mL) was added to a solution of 2,2-difluoro-N′-methylethanehydrazonamide hydrochloride (0.6208 mol, obtained in Step 1) in methanol (700 mL). Anhydrous sodium acetate (61.1 g, 0.745 mol) was added, and the mixture was stirred at 30° C. for 3 days. The reaction mixture was then evaporated, and the residue subjected to chromatography (ethyl acetate/hexane 1:4→1:1) on a silica gel column, followed by vacuum distillation to give 47.6 g (32.6%) of 5-(diethoxymethyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole. methanol was evaporated The residue was diluted with dichloromethane (200 mL) and water (300 mL) The organic layer was separated the aqueous one was extracted with dichloromethane (2×150 mL) The combined organic layer was dried over Na2SO4 evaporated

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

Procedure: A solution of diethoxyacetonitrile (75 g, 0.579 mol) in methanol (210 mL) was added at room temperature to a solution of sodium methoxide (28.3 g, 0.522 mol) in methanol (450 mL). The mixture was stirred overnight, and then methanol was evaporated. The residue was diluted with dichloromethane (200 mL) and water (300 mL). The organic layer was separated, and the aqueous one was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over Na2SO4 and evaporated to give 83 g of crude methyl 2,2-diethoxyacetimidate (˜90% yield). A solution of methyl 2,2-diethoxyacetimidate prepared above (0.6208 mol, 125.1 g of 80% purity) in methanol (300 mL) was added to a solution of 2,2-difluoro-N′-methylethanehydrazonamide hydrochloride (0.6208 mol, obtained in Step 1) in methanol (700 mL). Anhydrous sodium acetate (61.1 g, 0.745 mol) was added, and the mixture was stirred at 30° C. for 3 days. The reaction mixture was then evaporated, and the residue subjected to chromatography (ethyl acetate/hexane 1:4→1:1) on a silica gel column, followed by vacuum distillation to give 47.6 g (32.6%) of 5-(diethoxymethyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole. methanol was evaporated The residue was diluted with dichloromethane (200 mL) and water (300 mL) The organic layer was separated the aqueous one was extracted with dichloromethane (2×150 mL) The combined organic layer was dried over Na2SO4 evaporated

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

Procedure: To a solution of NaOMe (24 mL, 25% wt in MeOH, 0.105 mol, 4.3 mol %) in MeOH (2.4 L) was added diethoxyacetonitrile (310 g, 2.40 mol), and the reaction mixture was stirred at room temperature for 24 h. The solvent was removed in vacuo (300 mbar, 44° C.) and the brown oily residue was dissolved into Et2O (2.4 L). The organic solution was washed with water (3×500 mL) and brine (1×400 mL), and dried over Na2SO4. The solvent was removed in vacuo at 0° C. to yield methyl 2,2-diethoxyethanimidoate (333.32 g, 86%) as a clear liquid. To a solution of NaOMe (25% wt in MeOH, 424 g, 2 mol) and MeOH (2 L), was added ethylhydrazine oxalate (150.14 g, 1 mol), and the mixture was stirred for 10 min. Methyl 2,2-diethoxyethanimidoate (161.2 g, 1 mol) was added, and the mixture was stirred at room temperature for 3 h under a blanket of Nitrogen. The product, (1Z)-2,2-diethoxy-N-ethylethanehydrazonamide was used in situ. The crude (1Z)-2,2-diethoxy-N-ethylethanehydrazonamide was treated with acetimidate hydrochloride (109.6 g, 1 mol) and glacial acetic acid (90 g, 1.5 mol), and the mixture was stirred at room temperature for 24 h under nitrogen. LCMS indicated that no reaction had occurred after 24 h. The solvent was removed under vacuum from the reaction mixture and the residue was stored in the freezer. After 8 days the residue was removed from the freezer, warmed to room temperature, and treated with MeOH (1.5 L), acetic Acid (85.7 mL), and acetimidate HCl (98 g, 0.89 mol) from a new bottle, and this mixture was stirred at room temperature for 24 h. LCMS indicated that the starting materials had been consumed and that some of the desired product was present. The solvent was removed in vacuo and H2O (1.5 L) was added to the residue. The mixture was extracted with DCM (5×1 L), and the combined organic layers were dried over Na2SO4. The solvent was removed under vacuum to afford 163 g of a crude red oil. The product was purified by flash chromatography using 2% MeOH/DMC as eluent (RF=0.3) affording 56.86 g (23%) of 3-(diethoxymethyl)-1-ethyl-5-methyl-1H-1,2,4-triazole as a red oil, which was 96% pure by 1H NMR. The solvent was removed in vacuo (300 mbar, 44° C.) the brown oily residue was dissolved into Et2O (2.4 L) The organic solution was washed with water (3×500 mL) and brine (1×400 mL) dried over Na2SO4 The solvent was removed in vacuo at 0° C.

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

Procedure: A solution of sodium methoxide (3.30 g, 0.0611 mol) in methanol (100 mL) was added at room temperature to a solution of diethoxyacetonitrile (78.9 g, 0.611 mol) in methanol (600 mL). The resulting mixture was stirred at room temperature overnight, and a solution of crude N′-methylpropanehydrazonamide hydrochloride from Step 2 (84.1 g, ˜0.60 mol) in methanol (200 mL) was added. Anhydrous sodium acetate (50.0 g, 0.61 mol) was added, and the resulting mixture was refluxed under an atmosphere of Ar for 20 h. Then methanol was evaporated, and the dark oily residue was extracted with ether (3×250 mL). The ether solution was passed through a layer of silica gel, and the filtrate was evaporated. The residue was distilled in vacuo to give 35.0 g (27%) of the title product (bp 68° C. at 0.1 mm Hg). Note: There is a higher-boiling second fraction (15 g; bp 120° C. at 0.1 mm Hg) that is a triazole impurity containing two acetal groups. the resulting mixture was refluxed under an atmosphere of Ar for 20 h Then methanol was evaporated the dark oily residue was extracted with ether (3×250 mL) the filtrate was evaporated The residue was distilled in vacuo

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

Procedure: A solution of diethoxyacetonitrile (75 g, 0.579 mol) in methanol (210 mL) was added at room temperature to a solution of sodium methoxide (28.3 g, 0.522 mol) in methanol (450 mL). The mixture was stirred overnight, and then the methanol was carefully evaporated (volatile product). The residue was diluted with dichloromethane (200 mL) and water (300 mL). The organic layer was separated, and the aqueous one was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over Na2SO4 and evaporated to give 83 g of crude methyl 2,2-diethoxyethanimidoate (˜90% yield). the methanol was carefully evaporated (volatile product) The residue was diluted with dichloromethane (200 mL) and water (300 mL) The organic layer was separated the aqueous one was extracted with dichloromethane (2×150 mL) The combined organic layer was dried over Na2SO4 evaporated

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

Procedure: A solution of diethoxyacetonitrile (75 g, 0.579 mol) in methanol (210 mL) was added at room temperature to a solution of sodium methoxide (28.3 g, 0.522 mol) in methanol (450 mL). The mixture was stirred overnight, and then the methanol was carefully evaporated (volatile product). The residue was diluted with dichloromethane (200 mL) and water (300 mL). The organic layer was separated, and the aqueous one was extracted with dichloromethane (2×150 mL). The combined organic layer was dried over Na2SO4 and evaporated to give 83 g of crude methyl 2,2-diethoxyethanimidoate (˜90% yield). the methanol was carefully evaporated (volatile product) The residue was diluted with dichloromethane (200 mL) and water (300 mL) The organic layer was separated the aqueous one was extracted with dichloromethane (2×150 mL) The combined organic layer was dried over Na2SO4 evaporated