ethyl methanimidate;hydrochloride

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

Procedure: To a solution of 20 mg (45 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of toluene was added ethyl formimidate hydrochloride (6.4 mg, 58 μmol). The reaction mixture was heated to reflux for 14 h and then the reaction was concentrated under reduced pressure. Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 40 min) provided the title compound as a colorless film. The reaction mixture was heated to reflux for 14 h the reaction was concentrated under reduced pressure Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 40 min)

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

Procedure: To a solution of 20 mg (45 μmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide (Example 51) in 0.2 mL of toluene was added ethyl formimidate hydrochloride (6.4 mg, 58 μmol). The reaction mixture was heated to reflux for 14 h and then the reaction was concentrated under reduced pressure. Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 40 min) provided the title compound as a colorless film. The reaction mixture was heated to reflux for 14 h the reaction was concentrated under reduced pressure Separation by reversed phase HPLC (10 to 90% AcCN/H2O in 40 min)

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

Procedure: To a solution of 13 mg of piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate in 1 ml of anhydrous ethanol, 4 mg of ethyl formimidate hydrochloride was added, followed by 13 hours' stirring at room temperature. The reaction liquid was condensed to dry solid. Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1), 9 mg of the title compound was obtained as a colorless solid. The reaction liquid condensed to dry solid Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1)

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

Procedure: Ethyl formimidate hydrochloride (0.555 g, 5 mmole), 2,2,2-trifluoroethylamine hydrochloride (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2Cl2 and treated with 1 ml H2O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2Cl2. The combined organic phase is dried and the CH2Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. δ1.333 t (CH3CH2); 3.8 q (j=10 c.p.s., CF3CH2) 4.23 q (j=7.5, CH3CH2O); 7.6 S (H--C=N). The organic phase is separated the aqueous extracted twice with 10 ml portions of CH2Cl2 The combined organic phase is dried the CH2Cl2 distilled through a Vigreauxe column

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

Procedure: Ethyl formimidate hydrochloride (0.555 g, 5 mmole), 2,2,2-trifluoroethylamine hydrochloride (0.677 g, 5 mmole) and potassium carbonate (0.345 g, 2.5 mmole) are suspended in 20 ml CH2Cl2 and treated with 1 ml H2O. The mixture is shaken vigorously for 3 minutes. The organic phase is separated and the aqueous extracted twice with 10 ml portions of CH2Cl2. The combined organic phase is dried and the CH2Cl2 distilled through a Vigreauxe column to give the Ethyl N-(2,2,2-trifluoroethyl)formimidate. n.m.r. δ1.333 t (CH3CH2); 3.8 q (j=10 c.p.s., CF3CH2) 4.23 q (j=7.5, CH3CH2O); 7.6 S (H--C=N). The organic phase is separated the aqueous extracted twice with 10 ml portions of CH2Cl2 The combined organic phase is dried the CH2Cl2 distilled through a Vigreauxe column

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

Procedure: N-{4-[2-(4-Aminophenyl)ethyl]-1,3-thiazol-2-yl}acetamide (150 mg) was dissolved in THF (2 ml) and pH=7 buffer (2 ml). Then, ethyl imidoformate hydrochloride (1.26 g) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with CH3CN/water (7:3) as an eluent. The oil was purified again by preparative silica gel chromatography with CHCl3/MeOH (5:1) as an eluent to give N-[4-(2-{4-[(iminomethyl)amino]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide (110 mg) as pale brown oil. concentrated in vacuo The residue was purified by flash column chromatography over silica gel with CH3CN/water (7:3) as an eluent The oil was purified again by preparative silica gel chromatography with CHCl3/MeOH (5:1) as an eluent

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

Procedure: 3-tert-Butyl-3H-imidazole-4-carbaldehyde was prepared from ethyl formimidate hydrochloride (Aldrich) and tert-butylamine in the same manner as 3-cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).

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

Procedure: To a vigorously stirred solution of saturated aqueous Na2CO3 (50 mL) and methylene chloride (50 ml) was added solid ethylformimidate hydrochloride salt (8.98 g, 82 mol). After stirring for several minutes the aqueous layer was separated and extracted with additional methylene chloride (3×50 ml). The combined organic layers were dried (MgSO4) and filtered. To the stirred solution was added 5-(2-chlorophenyl)-2H-pyrazol-3-ylamine (I-3A-9a; 5.27 g, 27 mmol) in methylene chloride (50 mL) and then glacial acetic acid (2.67 ml, 46.6 mmol), dropwise. A cloudy precipitate began to form as the acetic acid was added. After stirring overnight, the solids were collected by vacuum filtration, washed with methylene chloride, and then dried, in vacuo, to give intermediate I-3A-9b, contaminated with ˜25% of the corresponding dimer (MW=396; 2 pyrazoles+1 formamidine), as a solid (5.7 g, 75%): +APcI MS (M+1) 221.1; 1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.62-7.30 (m, 4H), 6.48 (s, 1H), 1.92 (s, 3H). was separated extracted with additional methylene chloride (3×50 ml) The combined organic layers were dried (MgSO4) filtered was added After stirring overnight the solids were collected by vacuum filtration washed with methylene chloride dried, in vacuo to give intermediate I-3A-9b

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl imidoformate hydrochloride (608 mg, 5.55 mmol) was added to a solution of 2-methyl-4-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-1H-imidazol-1-amine (148 mg, 0.554 mmol) in ethanol (5 mL), and the reaction mixture was heated at 75° C. for 66 hours. Additional ethyl imidoformate hydrochloride (300 mg, 2.74 mmol) was added, and heating was continued for 8 hours. A final charge of ethyl imidoformate hydrochloride (300 mg, 2.74 mmol) was followed by maintaining the reaction at 75° C. for an additional 18 hours. The reaction mixture was cooled, concentrated in vacuo and diluted with ethyl acetate. This organic layer was washed with saturated aqueous sodium bicarbonate solution, washed with saturated aqueous sodium chloride solution and dried over sodium sulfate. Filtration and removal of solvent under reduced pressure, followed by purification using silica gel chromatography (Eluant: 10% methanol in dichloromethane) provided the product as a yellow solid. Yield: 70 mg, 0.24 mmol, 43%. LCMS m/z 295.5 (M+1). 1H NMR (400 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.20 and 2.25 (2 s, 3H), 2.43 (br s, 3H), 3.68 (s, 3H), 6.14 and 6.30 (2 s, 1H), 7.26-7.30 (m, 3H), 7.35 (br d, J=8 Hz, 2H), 7.84 and 7.81 (2 s, 1H). heating by maintaining the reaction at 75° C. for an additional 18 hours The reaction mixture was cooled concentrated in vacuo diluted with ethyl acetate This organic layer was washed with saturated aqueous sodium bicarbonate solution washed with saturated aqueous sodium chloride solution dried over sodium sulfate Filtration and removal of solvent under reduced pressure followed by purification

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

Procedure: Sodium (1S,5R,6S)-2-[7-(2-aminoethyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (45.7 mg) was suspended in 3 ml of water under ice cooling. Ethylformimidate hydrochloride (46 mg) was added to the suspension. While adjusting the mixture to pH 8 to 9 by the addition of an aqueous sodium carbonate solution, the mixture was stirred at that temperature for one hr, and then at room temperature for 1.5 hr. The reaction product was then purified by column chromatography on Cosmosil 40C18-PREP (a 20% aqueous methanol solution) to prepare 5.4 mg of the title compound. at room temperature for 1.5 hr The reaction product was then purified by column chromatography on Cosmosil 40C18-PREP (a 20% aqueous methanol solution) to prepare 5.4 mg of the title compound

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

Procedure: To a solution of 13 mg of piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate in 1 ml of anhydrous ethanol, 4 mg of ethyl formimidate hydrochloride was added, followed by 13 hours' stirring at room temperature. The reaction liquid was condensed to dry solid. Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1), 9 mg of the title compound was obtained as a colorless solid. The reaction liquid condensed to dry solid Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1)

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

Procedure: To a solution of 13 mg of piperidin-4-yl(2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate in 1 ml of anhydrous ethanol, 4 mg of ethyl formimidate hydrochloride was added, followed by 13 hours' stirring at room temperature. The reaction liquid was condensed to dry solid. Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1), 9 mg of the title compound was obtained as a colorless solid. The reaction liquid condensed to dry solid Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1)