2-cyclopropylacetonitrile

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

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

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

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

Procedure: A mixture of cyclopropyl acetonitrile (28 mmol) and was treated with n-BuLi (28 mmol) at −78° C. in tetrahydrofuran and was stirred for 1 hour. Addition of (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (14.32 mmol) was done to the reaction mixture and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and was extracted with ethyl acetate. The organic layer was concentrated, dried and evaporated to afford a residue which was purified on silica gel column chromatography to provide title compound in 64% yield. M.P. 170-72° C. and MS (M+1)=431 (H+, 100%) for M.F.=C22H27FN4O4. stirred overnight The reaction mixture was quenched with saturated ammonium chloride solution was extracted with ethyl acetate The organic layer was concentrated dried evaporated to afford a residue which was purified on silica gel column chromatography

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

Procedure: A −78° C. solution of diisopropylamine (1.3 mL, 9.0 mmol), under a nitrogen atmosphere in dry tetrahydrofuran (20 mL), was treated dropwise with 2.5 N n-butyllithium (3.6 mL, 9.0 mmol) and stirred for 10 minutes. The solution was treated dropwise with cyclopropylacetonitrile (0.8 g, 3.5 mmol) and stirred at −78° C. for 15 minutes. A solution of 4-tert-butoxy-2,5-difluoro-3-methoxypyridine (0.8 g, 3.5 mmol)[Example 7] in dry tetrahydrofuran (5 mL) was added and stirred for 1 hour at −78° C. followed by 1 hour at 0° C. The mixture was quenched with saturated ammonium chloride and extracted with diethylether. The combined extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.98 (s, 3H), 3.77 (d, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.62-0.54 (m, 2H), 0.50-0.42 (m, 1H), 0.35-0.30 (m, 1H). MSCI: m/z=279 (MH+). stirred at −78° C. for 15 minutes stirred for 1 hour at −78° C. followed by 1 hour at 0° C The mixture was quenched with saturated ammonium chloride extracted with diethylether The combined extracts were washed with brine dried over sodium sulfate the solvent removed in vacuo The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1:4)

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

Procedure: A −78° C. solution of diisopropylamine (1.3 mL, 9.0 mmol), under a nitrogen atmosphere in dry tetrahydrofuran (20 mL), was treated dropwise with 2.5 N n-butyllithium (3.6 mL, 9.0 mmol) and stirred for 10 minutes. The solution was treated dropwise with cyclopropylacetonitrile (0.8 g, 3.5 mmol) and stirred at −78° C. for 15 minutes. A solution of 4-tert-butoxy-2,5-difluoro-3-methoxypyridine (0.8 g, 3.5 mmol)[Example 7] in dry tetrahydrofuran (5 mL) was added and stirred for 1 hour at −78° C. followed by 1 hour at 0° C. The mixture was quenched with saturated ammonium chloride and extracted with diethylether. The combined extracts were washed with brine, dried over sodium sulfate, and the solvent removed in vacuo. The residue was purified by column chromatography, eluting with ethyl acetate/hexanes (1:4) to afford the title compound (0.9 g). 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 3.98 (s, 3H), 3.77 (d, 1H), 1.55-1.48 (m, 1H), 1.42 (s, 9H), 0.62-0.54 (m, 2H), 0.50-0.42 (m, 1H), 0.35-0.30 (m, 1H). MSCI: m/z=279 (MH+). stirred at −78° C. for 15 minutes stirred for 1 hour at −78° C. followed by 1 hour at 0° C The mixture was quenched with saturated ammonium chloride extracted with diethylether The combined extracts were washed with brine dried over sodium sulfate the solvent removed in vacuo The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1:4)

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

Procedure: The mixture of (S)-N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.86 mmol), cyclopropylacetonitrile (5.73 mmol), ammonium acetate (catalytic) in 100 ml of toluene was heated at reflux temperature for 5 to 6 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate water mixture, dried and evaporated to give crude product. The crude product was recrystallized from ethyl acetate to furnish title compound in 69% yield. was heated at reflux temperature for 5 to 6 hours extracted with ethyl acetate water mixture dried evaporated to give crude product The crude product was recrystallized from 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:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was equipped with stirrer, reflux condenser, thermometer, and charged with 75 ml of water and 36.8 grams (0.75 mole) sodium cyanide. Stirring was commenced and there was added 8.5 grams of tricapryl(methyl)ammonium chloride (ALIQUAT 336 phase-transfer catalyst) followed by 67.5 grams (0.50 mole) of the bromide product mixture comprising 55.7% cyclopropylmethyl bromide, 37.2% bromocyclobutane, and 7.1% bromobutene. The mixture slowly exothermed to about 50° C. After about 1 hour, heating was commenced so as to maintain the temperature of the mixture at 45° C. After 7 hours, gas chromatographic analysis of the organic phase indicated that cyclopropylmethyl bromide and 4-bromo-1-butene (i.e., bromobutene) were consumed, that cyclobutyl bromide was unchanged, and that cyclopropylacetonitrile and 1-cyano-3-butene were formed. The ratio (area %) of cyclopropylacetonitrile to 1-cyano-3-butene was 88:12. A minute trace (less than 1 area %) of cyanocyclobutane was detected. A flask was equipped with stirrer reflux condenser slowly exothermed to about 50° C heating After 7 hours were consumed

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A flask was equipped with stirrer, reflux condenser, thermometer, and charged with 75 ml of water and 36.8 grams (0.75 mole) sodium cyanide. Stirring was commenced and there was added 8.5 grams of tricapryl(methyl)ammonium chloride (ALIQUAT 336 phase-transfer catalyst) followed by 67.5 grams (0.50 mole) of the bromide product mixture comprising 55.7% cyclopropylmethyl bromide, 37.2% bromocyclobutane, and 7.1% bromobutene. The mixture slowly exothermed to about 50° C. After about 1 hour, heating was commenced so as to maintain the temperature of the mixture at 45° C. After 7 hours, gas chromatographic analysis of the organic phase indicated that cyclopropylmethyl bromide and 4-bromo-1-butene (i.e., bromobutene) were consumed, that cyclobutyl bromide was unchanged, and that cyclopropylacetonitrile and 1-cyano-3-butene were formed. The ratio (area %) of cyclopropylacetonitrile to 1-cyano-3-butene was 88:12. A minute trace (less than 1 area %) of cyanocyclobutane was detected. A flask was equipped with stirrer reflux condenser slowly exothermed to about 50° C heating After 7 hours were consumed

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

Procedure: To 7 g (0.3 mol) of freshly cut sodium chunks in 220 mL dry ether under nitrogen and external ice cooling was added a solution of 25 mL (0.3 mol) ethyl formate followed by a solution of 25 g (0.3 mol) cyclopropylacetonitrile in 50 mL dry ether, and the mixture was stirred at room temperature for 2 days. 19 mL (0.3 mol) glacial acetic acid was added whilst maintaining the internal temperature at 10-12° C., the solids were filtered off and the filtrate was concentrated at below 20° C. The residue was treated with 300 mL (0.6 mol) 2 M hydrazine in THF, 5 mL glacial acetic acid and heated at reflux for 2 hours. After cooling, the mixture was concentrated and the desired product was obtained by kugelrohr distillation. The product was used in the next step without further purification. whilst maintaining the internal temperature at 10-12° C. the solids were filtered off the filtrate was concentrated at below 20° C heated at reflux for 2 hours After cooling the mixture was concentrated

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

Procedure: To 7 g (0.3 mol) of freshly cut sodium chunks in 220 mL dry ether under nitrogen and external ice cooling was added a solution of 25 mL (0.3 mol) ethyl formate followed by a solution of 25 g (0.3 mol) cyclopropylacetonitrile in 50 mL dry ether, and the mixture was stirred at room temperature for 2 days. 19 mL (0.3 mol) glacial acetic acid was added whilst maintaining the internal temperature at 10-12° C., the solids were filtered off and the filtrate was concentrated at below 20° C. The residue was treated with 300 mL (0.6 mol) 2 M hydrazine in THF, 5 mL glacial acetic acid and heated at reflux for 2 hours. After cooling, the mixture was concentrated and the desired product was obtained by kugelrohr distillation. The product was used in the next step without further purification. whilst maintaining the internal temperature at 10-12° C. the solids were filtered off the filtrate was concentrated at below 20° C heated at reflux for 2 hours After cooling the mixture was concentrated