N'-hydroxy-2-phenylethanimidamide

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

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

Procedure: A solution of 40 g. (0.27 mole) of crude phenylacetamide oxime in 200 ml. of dry toluene is treated with 45.9 g. (0.27 mole) of chloroacetic anhydride in 100 ml. of toluene. The resultant mixture is then refluxed and the water formed is removed by means of a Dean Stark trap. The mixture is refluxed for 3-4 hours after which it is cooled and extracted once with 150 ml. of water and four times with 100 ml. of a saturated sodium bicarbonate solution. The toluene solution is then dried over magnesium sulfate and the solvent is removed in vacuo. Upon distillation of the residue, 3-benzyl-5-chloromethyl-1,2,4-oxadiazole, 19.8 g. having a b.p. of 100-108 (0.04 mm) is obtained. is removed by means of a Dean Stark trap The mixture is refluxed for 3-4 hours after which it is cooled extracted once with 150 ml The toluene solution is then dried over magnesium sulfate the solvent is removed in vacuo Upon distillation of the residue, 3-benzyl-5-chloromethyl-1,2,4-oxadiazole, 19.8 g of 100-108 (0.04 mm) is obtained

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

Procedure: To a solution of 2-benzamidoisonicotinic acid (0.35 g, 1.44 mmol) and N,N-dimethylformamide (0.1 mL) in dichloromethane (5 mL) was added oxalyl chloride (0.15 mL, 1.73 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 hour and concentrated in vacuo to dryness. The residue was dissolved in N,N-dimethylformamide (2 mL) and added to a solution of N′-hydroxy-2-phenylacetimidamide (0.24 g, 1.59 mmol) and pyridine (0.3 mL, 3.70 mmol) in N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate (40 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was dissolved in toluene (10 mL), followed by the addition of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (0.53 g, 2.16 mmol). The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was purified by column chromatography to give N-[4-(3-benzyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-benzamide as a colorless solid (0.06 g 12%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.69 (s, 1H), 8.46 (d, J=4.9 Hz, 1H), 7.94-7.91 (m, 2H), 7.72-7.69 (m, 1H), 7.62-7.48 (m, 3H), 7.39-7.24 (m, 5H), 4.16 (s, 2H); MS (ES+) m/z 357.5 (M+1). concentrated in vacuo to dryness The residue was dissolved in N,N-dimethylformamide (2 mL) The reaction mixture was stirred at ambient temperature for 3 hours washed with water (20 mL) and brine (20 mL) The organic solution was dried over anhydrous sodium sulphate filtered concentrated in vacuo The residue was dissolved in toluene (10 mL) The mixture was refluxed for 1 hour concentrated in vacuo The residue was purified by column chromatography

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

Procedure: To a solution of 2-benzamidoisonicotinic acid (0.35 g, 1.44 mmol) and N,N-dimethylformamide (0.1 mL) in dichloromethane (5 mL) was added oxalyl chloride (0.15 mL, 1.73 mmol) at ambient temperature. The resulting mixture was stirred at ambient temperature for 1 hour and concentrated in vacuo to dryness. The residue was dissolved in N,N-dimethylformamide (2 mL) and added to a solution of N′-hydroxy-2-phenylacetimidamide (0.24 g, 1.59 mmol) and pyridine (0.3 mL, 3.70 mmol) in N,N-dimethylformamide (1 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 3 hours, diluted with ethyl acetate (40 mL), washed with water (20 mL) and brine (20 mL). The organic solution was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was dissolved in toluene (10 mL), followed by the addition of (methoxycarbonylsulfamoyl)triethylammonium hydroxide (0.53 g, 2.16 mmol). The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was purified by column chromatography to give N-[4-(3-benzyl-[1,2,4]oxadiazol-5-yl)-pyridin-2-yl]-benzamide as a colorless solid (0.06 g 12%): mp 150-151° C.; 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 8.69 (s, 1H), 8.46 (d, J=4.9 Hz, 1H), 7.94-7.91 (m, 2H), 7.72-7.69 (m, 1H), 7.62-7.48 (m, 3H), 7.39-7.24 (m, 5H), 4.16 (s, 2H); MS (ES+) m/z 357.5 (M+1). concentrated in vacuo to dryness The residue was dissolved in N,N-dimethylformamide (2 mL) The reaction mixture was stirred at ambient temperature for 3 hours washed with water (20 mL) and brine (20 mL) The organic solution was dried over anhydrous sodium sulphate filtered concentrated in vacuo The residue was dissolved in toluene (10 mL) The mixture was refluxed for 1 hour concentrated in vacuo The residue was purified by column chromatography

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

Procedure: Benzyl cyanide (1 g, 8.5 mmol) and hydroxylamine (50% in water, 1.04 cm3, 17 mmol, 2 eq) in EtOH (8.5 cm3) were reacted in the same manner as in the preparation of N′-hydroxybenzimidamide (EtOAc used in extraction) to give the product N′-hydroxy-2-phenylacetimidamide (1.04 g, 81.9%) as a pale yellow solid, mp 63.5-64.5° C. (lit 57-59° C.).

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

Procedure: Benzyl cyanide (1 g, 8.5 mmol) and hydroxylamine (50% in water, 1.04 cm3, 17 mmol, 2 eq) in EtOH (8.5 cm3) were reacted in the same manner as in the preparation of N′-hydroxybenzimidamide (EtOAc used in extraction) to give the product N′-hydroxy-2-phenylacetimidamide (1.04 g, 81.9%) as a pale yellow solid, mp 63.5-64.5° C. (lit 57-59° C.).

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

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

Procedure: The title compouhd was obtained according to the same procedure as described in Example 32 except that phenylacetoamide oxime (1.50 g, 0.0100 mole) and t-butyl pentafluoropropionate (6.66 g, 0.0300 mole) were used. The title compouhd was obtained

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

Procedure: The title compouhd was obtained according to the same procedure as described in Example 32 except that phenylacetoamide oxime (1.50 g, 0.0100 mole) and t-butyl pentafluoropropionate (6.66 g, 0.0300 mole) were used. The title compouhd was obtained

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

Procedure: The title compouhd was obtained according to the same procedure as described in Example 32 except that phenylacetoamide oxime (1.50 g, 0.0100 mole) and t-butyl pentafluoropropionate (6.66 g, 0.0300 mole) were used. The title compouhd was obtained

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

Procedure: Under a nitrogen atmosphere, dry tetrahydrofuran (90 ml) was added to diisopropylamine (14.5 ml, 0.105 mole, 5.23 mole) and then to the solution was added a 15% solution of butyllithium in n-hexane (64 ml, 0.100 mole, 5.0 eq.) with cooling below 0° C. After keeping the mixture at 0° C. for 30 minutes, it was cooled at -75° C. The mixture of t-butyl trifluoroacetate (10.21 g, 0.0600 mole, 3 eq.), phenylacetamide oxime (3.00 g, 0.0200 mole) and dry tetrahydrofuran (45 ml) was added dropwise, keeping the mixture below -72° C. After the mixture was stirred at -75° C. for 1 hour, it was allowed to warm to room temperature over 1 hour. To the mixture was added 10% hydrochloric acid (90 ml, 0.246 mole) and refluxed for 2.5 hours. The reaction mixure was distilled under reduced pressure to remove tetrahydrofuran and n-hexane. The resulting residue was adjusted above pH 13 with a 48% solution of sodium hydroxide and extracted with methylene chloride. After the extract was dried with anhydrous sodium sulfate, the solvent was distilled off. The resulting residue was purified by column chromatography on alumina and silica gel to give the title compound (0.60 g, 13.1%). This product was recrystallized from cyclohexane to give colorless needles, m.p. 92.0°-93.0° C. The structure of this compound was confirmed by IR, NMR and UV. with cooling below 0° C at 0° C. for 30 minutes was added dropwise the mixture below -72° C to warm to room temperature over 1 hour refluxed for 2.5 hours The reaction mixure was distilled under reduced pressure to remove tetrahydrofuran and n-hexane extracted with methylene chloride After the extract was dried with anhydrous sodium sulfate the solvent was distilled off The resulting residue was purified by column chromatography on alumina and silica gel

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

Procedure: First, 15.0 grams (0.1 mole) of phenyl acetamide oxime was combined with 100 milliliters of dry acetone in a 250 milliliter flask fitted with a thermometer and dropping funnel. The solution was stirred and cooled to 0° C. Next, 12.7 grams (0.1 mole) of 2-chloro propionyl chloride and 10.1 grams (0.1 mole) of triethyl amine was added. During the additions, the temperature was maintained at 0 to 5° C. After the additions were complete, the reaction mass was stirred at room temperature for 30 minutes and then was filtered free of salt. The filtrate was evaporated in vacuo at 50° and the residue was taken up in 300 milliliters of toluene. The toluene solution was charged to a 500 milliliter flask fitted with a Dean Stark water trap, 0.1 gram of toluene sulfonic acid was added, and the solution was heated under reflux until water ceased to be evolved. The toluene solution was then treated with activated carbon, filtered and evaporated in vacuo at 50° C. to yield 21.2 grams (95% of theory) of 3-benzyl-5-(1-chloroethyl)1,2,4-oxadiazole. nD30 1.5040. fitted with a thermometer During the additions, the temperature was maintained at 0 to 5° C the reaction mass was stirred at room temperature for 30 minutes was filtered free of salt The filtrate was evaporated in vacuo at 50° The toluene solution was charged to a 500 milliliter flask fitted with a Dean Stark water trap, 0.1 gram of toluene sulfonic acid was added the solution was heated under reflux until water The toluene solution was then treated with activated carbon filtered evaporated in vacuo at 50° C.