4-chloro-2-methylbutanoyl chloride

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

Procedure: A mixture of 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)thiophene and 4.0 g of 2-methyl-4-chlorobutyryl chloride dissolved with 100 ml benzene was refluxed for about 72 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed while eluting with a 90/10 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 3.75 g of 4-chloro-N-[3-cyano-4-(1,1-dimethylethyl)-2-thienyl]-2-methylbutanamide. mp=115°-116° C. Yield 57%. was refluxed for about 72 hours The solvent was evaporated under reduced pressure the residue was chromatographed while eluting with a 90/10 mixture of Skellysolve B/ethyl acetate Fractions containing the major component the solvent was evaporated

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

Procedure: To 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)furan and 4.3 g of 2-methyl-4-chlorobutyryl chloride was added 150 ml of toluene. The reaction mixture was allowed to reflux for about 72 hours. The mixture was washed once with 1N hydrochloric acid, once with 2N sodium hydroxide and finally with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed over silica gel while eluting with an 80/20 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 1.3 g of N-[3-cyano-4-(1,1-dimethylethyl)-2-furyl]-3-methyl-2-pyrrolidinone. mp=88°-90° C. Yield 21%. to reflux for about 72 hours The mixture was washed once with 1N hydrochloric acid, once with 2N sodium hydroxide and finally with water The organic phase was dried over anhydrous magnesium sulfate filtered concentrated under vacuum The residue was chromatographed over silica gel while eluting with an 80/20 mixture of Skellysolve B/ethyl acetate Fractions containing the major component the solvent was evaporated

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

Procedure: To a solution of 2.4 g of 3-(1,1-dimethylethyl)-5-aminoisothiazole dissolved in 150 ml of toluene under nitrogen was added 2.3 g of 2-methyl-4-chlorobutyric acid chloride. The reaction mixture was refluxed for about 24 hours and cooled. The solvent was evaporated under reduced pressure, and the product was isolated from the residue by chromatography over silica gel eluting with an ethyl acetate/Skellysolve B solvent mixture. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford, following crystallization from toluene/Skellysolve B, 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide. Yield 12%. mp 144°-146° C. The reaction mixture was refluxed for about 24 hours cooled The solvent was evaporated under reduced pressure the product was isolated from the residue by chromatography over silica gel eluting with an ethyl acetate/Skellysolve B solvent mixture Fractions containing the major component the solvent was evaporated to afford crystallization from toluene/Skellysolve B, 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide

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

Procedure: To a solution of 2.4 g of 3-(1,1-dimethylethyl)-5-aminoisothiazole dissolved in 150 ml of toluene under nitrogen was added 2.3 g of 2-methyl-4-chlorobutyric acid chloride. The reaction mixture was refluxed for about 24 hours and cooled. The solvent was evaporated under reduced pressure, and the product was isolated from the residue by chromatography over silica gel eluting with an ethyl acetate/Skellysolve B solvent mixture. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford, following crystallization from toluene/Skellysolve B, 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide. Yield 12%. mp 144°-146° C. The reaction mixture was refluxed for about 24 hours cooled The solvent was evaporated under reduced pressure the product was isolated from the residue by chromatography over silica gel eluting with an ethyl acetate/Skellysolve B solvent mixture Fractions containing the major component the solvent was evaporated to afford crystallization from toluene/Skellysolve B, 0.5 g of 4-chloro-N-[3-(1,1-dimethylethyl)-5-isothiazolyl]-2-methylbutanamide

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

Procedure: To a stirred solution of 7 g of 3-(1,1-dimethylethyl)-5-aminoisoxazole dissolved in 50 ml ethyl acetate was added 5.05 g of triethylamine at room temperature. As the solution continued to stir, 8 g of 2-methyl-4-chlorobutyric acid chloride was added to the reaction mixture over a 15 minute period. The reaction was allowed to stir for about 3 days and the precipitated triethylamine hydrochloride salt was collected by filtration and washed with ethyl acetate. The solvent was evaporated from the filtrate under reduced pressure and the residue was recrystallized from diethyl ether to afford 4-chloro-N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2-methylbutanamide as a solid. mp 135°-137° C. to stir for about 3 days the precipitated triethylamine hydrochloride salt was collected by filtration washed with ethyl acetate The solvent was evaporated from the filtrate under reduced pressure the residue was recrystallized from diethyl ether

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

Procedure: To a stirred solution of 7 g of 3-(1,1-dimethylethyl)-5-aminoisoxazole dissolved in 50 ml ethyl acetate was added 5.05 g of triethylamine at room temperature. As the solution continued to stir, 8 g of 2-methyl-4-chlorobutyric acid chloride was added to the reaction mixture over a 15 minute period. The reaction was allowed to stir for about 3 days and the precipitated triethylamine hydrochloride salt was collected by filtration and washed with ethyl acetate. The solvent was evaporated from the filtrate under reduced pressure and the residue was recrystallized from diethyl ether to afford 4-chloro-N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2-methylbutanamide as a solid. mp 135°-137° C. to stir for about 3 days the precipitated triethylamine hydrochloride salt was collected by filtration washed with ethyl acetate The solvent was evaporated from the filtrate under reduced pressure the residue was recrystallized from diethyl ether

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

Procedure: To a stirred solution of 7 g of 3-amino-5-(1,1-dimethylethyl)isoxazole and 5.05 g triethylamine dissolved in 100 ml ethyl acetate was added 7.75 g of 2-methyl-4-chlorobutyric acid chloride dropwise. The mixture was stirred for about 16 hours at room temperature and the precipitated salt was collected by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene:diethyl ether. Fractions containing the major component as indicated by thin layer chromatography were combined and concentrated under vacuum to provide 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide. Yield 54%. This material was used in the following reaction without additional purification. the precipitated salt was collected by filtration washed with ethyl acetate The filtrate was concentrated under reduced pressure the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene Fractions containing the major component concentrated under vacuum

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

Procedure: To a stirred solution of 7 g of 3-amino-5-(1,1-dimethylethyl)isoxazole and 5.05 g triethylamine dissolved in 100 ml ethyl acetate was added 7.75 g of 2-methyl-4-chlorobutyric acid chloride dropwise. The mixture was stirred for about 16 hours at room temperature and the precipitated salt was collected by filtration and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene:diethyl ether. Fractions containing the major component as indicated by thin layer chromatography were combined and concentrated under vacuum to provide 7 g of 4-chloro-N-[5-(1,1-dimethylethyl)-3-isoxazolyl]-2-methylbutanamide. Yield 54%. This material was used in the following reaction without additional purification. the precipitated salt was collected by filtration washed with ethyl acetate The filtrate was concentrated under reduced pressure the residue was chromatographed over silica gel while eluting with a 1:1 (v/v) mixture of toluene Fractions containing the major component concentrated under vacuum

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

Procedure: A mixture of 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)thiophene and 4.0 g of 2-methyl-4-chlorobutyryl chloride dissolved with 100 ml benzene was refluxed for about 72 hours. The solvent was evaporated under reduced pressure and the residue was chromatographed while eluting with a 90/10 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 3.75 g of 4-chloro-N-[3-cyano-4-(1,1-dimethylethyl)-2-thienyl]-2-methylbutanamide. mp=115°-116° C. Yield 57%. was refluxed for about 72 hours The solvent was evaporated under reduced pressure the residue was chromatographed while eluting with a 90/10 mixture of Skellysolve B/ethyl acetate Fractions containing the major component the solvent was evaporated

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

Procedure: To 4.0 g of 2-amino-3-cyano-4-(1,1-dimethylethyl)furan and 4.3 g of 2-methyl-4-chlorobutyryl chloride was added 150 ml of toluene. The reaction mixture was allowed to reflux for about 72 hours. The mixture was washed once with 1N hydrochloric acid, once with 2N sodium hydroxide and finally with water. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed over silica gel while eluting with an 80/20 mixture of Skellysolve B/ethyl acetate. Fractions containing the major component were combined and the solvent was evaporated therefrom to afford 1.3 g of N-[3-cyano-4-(1,1-dimethylethyl)-2-furyl]-3-methyl-2-pyrrolidinone. mp=88°-90° C. Yield 21%. to reflux for about 72 hours The mixture was washed once with 1N hydrochloric acid, once with 2N sodium hydroxide and finally with water The organic phase was dried over anhydrous magnesium sulfate filtered concentrated under vacuum The residue was chromatographed over silica gel while eluting with an 80/20 mixture of Skellysolve B/ethyl acetate Fractions containing the major component the solvent was evaporated

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

Procedure: 40 g. of 2-methylbutyrolactone was converted to 45 g. of 4-chloro-2-methylbutryl chloride (b.p. 70°-72° C at 15 mm.) by the method detailed in Example 4. The acid chloride (15.5 g.) was reduced to the corresponding aldehyde, condensed with 5-chlorosalicylhydroxamic acid and the resulting intermediate was ring-closed according to the method described in Example 3. The product melted at 144°-146° C. after recrystallization from a mixture of trichloroethylene and hexane. the resulting intermediate was ring-closed The product melted at 144°-146° C. after recrystallization from a mixture of trichloroethylene and hexane

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

Procedure: 40 g. of 2-methylbutyrolactone was converted to 45 g. of 4-chloro-2-methylbutryl chloride (b.p. 70°-72° C at 15 mm.) by the method detailed in Example 4. The acid chloride (15.5 g.) was reduced to the corresponding aldehyde, condensed with 5-chlorosalicylhydroxamic acid and the resulting intermediate was ring-closed according to the method described in Example 3. The product melted at 144°-146° C. after recrystallization from a mixture of trichloroethylene and hexane. the resulting intermediate was ring-closed The product melted at 144°-146° C. after recrystallization from a mixture of trichloroethylene and hexane