ethyl 2-cyano-2-cyclopropylacetate

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

Procedure: To a solution of ethyl cyano(cyclopropyl)acetate (27 g) obtained in Step A of Example 103 in toluene (400 mL) were added cesium carbonate (88 g), tetrabutylammonium bromide (5.8 g) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (40 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 0.5 M hydrochloric acid (400 mL), and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45 g). extracted with ethyl acetate The obtained organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

Procedure: To a solution of sodium hydride (60% in mineral oil, 38 g) and diethyl carbonate (97 mL) in toluene (240 mL) was added dropwise a solution of cyclopropylacetonitrile (32 g) in toluene (120 mL) over 40 min with heating under reflux, and the mixture was heated under reflux for additional 2 hr. The mixture was neutralized with acetic acid (120 mL) in an ice bath, water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was distilled (boiling point 69-72° C., 4.0 mmHg) to give the title compound (50 g). with heating under reflux the mixture was heated under reflux for additional 2 hr the mixture was extracted with ethyl acetate The obtained organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was distilled (boiling point 69-72° C., 4.0 mmHg)

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

Procedure: To a solution of sodium hydride (60% in mineral oil, 38 g) and diethyl carbonate (97 mL) in toluene (240 mL) was added dropwise a solution of cyclopropylacetonitrile (32 g) in toluene (120 mL) over 40 min with heating under reflux, and the mixture was heated under reflux for additional 2 hr. The mixture was neutralized with acetic acid (120 mL) in an ice bath, water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was distilled (boiling point 69-72° C., 4.0 mmHg) to give the title compound (50 g). with heating under reflux the mixture was heated under reflux for additional 2 hr the mixture was extracted with ethyl acetate The obtained organic layer was washed with saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was distilled (boiling point 69-72° C., 4.0 mmHg)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: IN NaOH (3.26 ml, 3.26 mmol) was added to a solution of cyano-cyclopropyl-acetic acid ethyl ester (0.5 g, 3.26 mmol) in THF (15 ml). After 4 hours stirring at 25° C., the reaction mixture was evaporated in vacuo, re-dissolved in water (20 ml) and neutralized by the addition of 1N HCl solution (3.26 ml). This mixture was then extracted with EtOAc (3×20 ml) and the combined, dried (Na2SO4) organics evaporated in vacuo to give impure cyano-cyclopropyl-acetic acid as a clear oil. This material was used without any further purification in the preparation of Example 4B. the reaction mixture was evaporated in vacuo re-dissolved in water (20 ml) neutralized by the addition of 1N HCl solution (3.26 ml) This mixture was then extracted with EtOAc (3×20 ml) dried (Na2SO4) organics evaporated in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: IN NaOH (3.26 ml, 3.26 mmol) was added to a solution of cyano-cyclopropyl-acetic acid ethyl ester (0.5 g, 3.26 mmol) in THF (15 ml). After 4 hours stirring at 25° C., the reaction mixture was evaporated in vacuo, re-dissolved in water (20 ml) and neutralized by the addition of 1N HCl solution (3.26 ml). This mixture was then extracted with EtOAc (3×20 ml) and the combined, dried (Na2SO4) organics evaporated ill vacuo to give impure cyano-cyclopropyl-acetic acid as a clear oil. This material was used without any further purification in the preparation of Example 4B. the reaction mixture was evaporated in vacuo re-dissolved in water (20 ml) neutralized by the addition of 1N HCl solution (3.26 ml) This mixture was then extracted with EtOAc (3×20 ml) dried (Na2SO4) organics evaporated ill vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: IN NaOH (3.26 ml, 3.26 mmol) was added to a solution of cyano-cyclopropyl-acetic acid ethyl ester (0.5 g, 3.26 mmol) in THF (15 ml). After 4 hours stirring at 25° C., the reaction mixture was evaporated in vacuo, re-dissolved in water (20 ml) and neutralized by the addition of IN IICl solution (3.26 ml). This mixture was then extracted with EtOAc (3×20 ml) and the combined, dried (Na2SO4) organics evaporated in vacuo to give impure cyano-cyclopropyl-acetic acid as a clear oil. This material was used without any further purification in the preparation of Example 4B. the reaction mixture was evaporated in vacuo re-dissolved in water (20 ml) neutralized by the addition of IN IICl solution (3.26 ml) This mixture was then extracted with EtOAc (3×20 ml) dried (Na2SO4) organics evaporated in vacuo

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

Procedure: Into a stirred solution of 38.72 g (0.253 mol) of ethyl 2-cyano-2-cyclopropylacetate (preparation described by R. W. J. Carney and J. Wojtkunski, Org. Prep. Proced. Int., 5, 25 (1973)) in 17.7 mL (0.303 mol) of anhydrous ethanol under a dry N2 atmosphere was introduced 10.0 g (0.274 mol) of gaseous hydrogen chloride with ice cooling. The mixture was allowed to warm to room temperature and stand for 72 hours. The reaction was diluted with 100 mL of anhydrous ethanol, 70 mL of ammonia in ethanol (4.17M) was added slowly at room temperature and the reaction was stirred for 3 hours. The reaction mixture was filtered to remove the ammonium chloride, and the solvent was removed to afford the title compound as a viscous off-white oil, which was taken directly to the next step. was added slowly at room temperature The reaction mixture was filtered to remove the ammonium chloride the solvent was removed

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

Procedure: To a solution of ethyl cyano(cyclopropyl)acetate (27 g) obtained in Step A of Example 103 in toluene (400 mL) were added cesium carbonate (88 g), tetrabutylammonium bromide (5.8 g) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (40 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 0.5 M hydrochloric acid (400 mL), and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45 g). extracted with ethyl acetate The obtained organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)