3-oxo-2-phenylpropanenitrile

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

Procedure: 4-Aryl-3-aminopyrazoles such as 4-phenyl-2H-pyrazol-3-ylamine may be prepared according to the procedures described in patent EP269,859 and illustrated in scheme 8, by reacting benzeneacetonitrile with orthoformic acid triethyl ester to give 3-oxo-2-phenyl-propionitrile which is reacted with hydrazine.

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

Procedure: To a suspension of sodium methoxide (10.8 g) in benzene (300 ml) is added dropwise with stirring a mixture of ethyl formate (16.28 g) and phenylacetonitrile (23.4 g) under ice cooling. After 30 minutes, the ice bath is taken off. After reacting for 3 hours, ice water is added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed with 0.5 N sodium hydroxide solution (100 ml×3), and the aqueous layer and the washings are combined and adjusted to pH 3-4 with conc. hydrochloric acid. The mixture is stirred under ice cooling for 20 minutes, and the resulting precipitate is separated by filtration and washed with water to give α-formylphenylacetonitrile (21.13 g). The product is used in the subsequent procedure without further purification. is added dropwise After reacting for 3 hours the aqueous layer is separated The organic layer is washed with 0.5 N sodium hydroxide solution (100 ml×3) The mixture is stirred under ice cooling for 20 minutes the resulting precipitate is separated by filtration washed with water

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

Procedure: To a suspension of sodium methoxide (10.8 g) in benzene (300 ml) is added dropwise with stirring a mixture of ethyl formate (16.28 g) and phenylacetonitrile (23.4 g) under ice cooling. After 30 minutes, the ice bath is taken off. After reacting for 3 hours, ice water is added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed with 0.5 N sodium hydroxide solution (100 ml×3), and the aqueous layer and the washings are combined and adjusted to pH 3-4 with conc. hydrochloric acid. The mixture is stirred under ice cooling for 20 minutes, and the resulting precipitate is separated by filtration and washed with water to give α-formylphenylacetonitrile (21.13 g). The product is used in the subsequent procedure without further purification. is added dropwise After reacting for 3 hours the aqueous layer is separated The organic layer is washed with 0.5 N sodium hydroxide solution (100 ml×3) The mixture is stirred under ice cooling for 20 minutes the resulting precipitate is separated by filtration washed with water

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

Procedure: The α-formylphenylacetonitrile obtained above is dissolved in methanol-water (1:1-10:1, 200 ml), and to the solution is added with stirring semicarbazide hydrochloride (9.95 g) under ice cooling. After taking off the ice bath, the mixture is reacted for 12 hours. The reaction mixture is neturalized with 5N sodium hydroxide solution. The mixture is stirred for 20 minutes, and the resulting precipitate is separated by filtration, washed with water and dried to give 3-amino-2-carbamoyl-4-phenylpyrazole (16.82 g). This product is used in the subsequent procedure without further purification. the mixture is reacted for 12 hours the resulting precipitate is separated by filtration washed with water dried

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

Procedure: To a suspension of sodium methoxide (5.56 g) in benzene (200 ml) is added dropwise with stirring a mixture of ethyl formate (8.14 g) and phenylacetonitrile (11.7 g) under ice cooling. After 30 minutes, the ice bath is taken off. After reacting for 3 hours, ice water is added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed with 0.5 N sodium hydroxide solution (50 ml×3), and the aqueous layer and the washings are combined and adjusted to pH 3-4 with conc. hydrochloric acid. The mixture is stirred under ice cooling for 20 minutes, and the resulting precipitate is separated by filtration and washed with water to give α-formylphenylacetonitrile. The product is used in the subsequent procedure without further purification. is added dropwise After reacting for 3 hours the aqueous layer is separated The organic layer is washed with 0.5 N sodium hydroxide solution (50 ml×3) The mixture is stirred under ice cooling for 20 minutes the resulting precipitate is separated by filtration washed with water

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-hydrazinobenzoic acid (0.15 g, 0.8 mmol) and 3-oxo-2-phenyl-propionitrile (0.116 g, 0.8 mmol) in acetic acid (0.2 mL) was heated in a microwave (Personal Chemistry SmithSynthesizer) at 150° C. for 10 minutes. The precipitated product was filtered, washed with methanol and diethyl ether and dried. 1H NMR (DMSO-d6) δ 12.10 (s, 1H), 8.10-8.19 (m, 3H) 7.88-7.96 (m, 1H), 7.59 (d, J=7.3 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.42 (t, J=7.6 Hz, 2 Hz), 7.28 (t, J=7.3 Hz, 1H). The precipitated product was filtered washed with methanol and diethyl ether dried

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

Procedure: A 20.0 g. amount of sodium hydride (50% in oil) is added portionwise with stirring to a solution of 20.0 g. of phenylacetonitrile and 40.0 ml. of ethyl formate in 200 ml. of sodium dried benzene. The mixture is heated on a steam bath to start the reaction and after the vigorous reaction has subsided, the mixture is heated on the steam bath for 2 hours with stirring. Ethanol is then added dropwise to decompose the excess sodium hydride. The mixture is then swamped with n-hexane and the precipitate is collected and washed with n-hexane. The precipitate is suspended in water then an excess of dilute hydrochloric acid is added and the product is extracted with ether. The ether extracts are dried and evaporated. The residue is crystallized from acetone-n-hexane to give 12.0 g. of the product of the Example m.p. 161°-163° C. Reference: D. J. Brown and T. C. Lee, J. Chem. Soc. (C), 214 (1970). The mixture is heated on a steam bath the reaction after the vigorous reaction the mixture is heated on the steam bath for 2 hours with stirring the precipitate is collected washed with n-hexane an excess of dilute hydrochloric acid is added the product is extracted with ether The ether extracts are dried evaporated The residue is crystallized from acetone-n-hexane to give 12.0 g

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Oxo-2-phenylpropanenitrile was prepared by addition of a mixture of phenylacetonitrile (0.90 g, 7.68 mmol) and ethyl formate (0.85 g, 11.5 mmol) dropwise to a stirred suspension of sodium hydride (0.41 g of 60%, 10 mmol) in tetrahydrofuran (4.5 mL). Reaction was rapid and exothermic. After heating in an oil bath at 50° C. for 20 min., the mixture was carefully acidified with dilute HCl and extracted with ethyl acetate. Extracts were washed with water, saturated NaCl solution, dried (MgSO4) and stripped to give 0.96 g (86%) of off-white solid, m. p. 148-153° C., Rf 0.5 (silica gel, ethanol:ethyl acetate:hexane=1:4:4). Reaction extracted with ethyl acetate Extracts were washed with water, saturated NaCl solution dried (MgSO4)

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

Procedure: 4-Aryl-3-aminopyrazoles such as 4-phenyl-2H-pyrazol-3-ylamine may be prepared according to the procedures described in patent EP269,859 and illustrated in scheme 8, by reacting benzeneacetonitrile with orthoformic acid triethyl ester to give 3-oxo-2-phenyl-propionitrile which is reacted with hydrazine.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Oxo-2-phenylpropanenitrile was prepared by addition of a mixture of phenylacetonitrile (0.90 g, 7.68 mmol) and ethyl formate (0.85 g, 11.5 mmol) dropwise to a stirred suspension of sodium hydride (0.41 g of 60%, 10 mmol) in tetrahydrofuran (4.5 mL). Reaction was rapid and exothermic. After heating in an oil bath at 50° C. for 20 min., the mixture was carefully acidified with dilute HCl and extracted with ethyl acetate. Extracts were washed with water, saturated NaCl solution, dried (MgSO4) and stripped to give 0.96 g (86%) of off-white solid, m.p. 148-153° C., Rf 0.5 (silica gel, ethanol:ethyl acetate:hexane=1:4:4). Reaction extracted with ethyl acetate Extracts were washed with water, saturated NaCl solution dried (MgSO4)

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

Procedure: 4-Aryl-3-aminopyrazoles such as 4-phenyl-2H-pyrazol-3-ylamine may be prepared according to the procedures described in patent EP269,859 and illustrated in the following scheme, by reacting benzeneacetonitrile with orthoformic acid triethyl ester to give 3-oxo-2-phenyl-propionitrile which is reacted with hydrazine.

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

Procedure: 4-Aryl-3-aminopyrazoles such as 4-phenyl-2H-pyrazol-3-ylamine may be prepared according to the procedures described in patent EP269,859 and illustrated in scheme 8, by reacting benzeneacetonitrile with orthoformic acid triethyl ester to give 3-oxo-2-phenyl-propionitrile which is reacted with hydrazine.