ethyl 3-cyclopentyl-3-oxopropanoate

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium pellets (3.1 g, 135 mmol) were dissolved in ethanol (100 ml) under nitrogen at room temperature and a solution of diethyloxalate (18.4 ml, 135 mmol) and 1-cyclopentylethanone (16.7 g, 149 mmol) was added dropwise at room temperature over 30 minutes. The reaction was diluted with ethanol (100 ml), heated to 60° C. and stirred at this temperature for 2 hours. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) and extracted with diethylether (300 ml) and ethyl acetate (300 ml). The combined organic extracts were dried over MgSO4, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (6:1, by volume) to give 3-cyclopentyl-3-oxo-propionc acid ethyl ester (23.8 g) as an orange oil. 1H NMR (400 MHz, CDCl3): δ=14.38-14.65 (1H, brs), 6.83 (1H, s), 4.30-4.39 (2H, quart), 2.82-2.92 (1H, quin), 1.83-1.96 (2H, m), 1.57-1.83 (6H, 2×m), 1.33-1.40 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 211. After cooling to room temperature the reaction was poured onto ice-cold 2N HCl (200 ml) extracted with diethylether (300 ml) and ethyl acetate (300 ml) The combined organic extracts were dried over MgSO4 concentrated under reduced pressure the residue was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (6:1, by volume) to give 3-cyclopentyl-3-oxo-propionc acid ethyl ester (23.8 g) as an orange oil

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

Procedure: The title compound was prepared using a method analogous to that described in Tetrahedron 1998, 44, 1603-1607: To a suspension of iodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was added BF3.OEt2 (2.1 mL, 16.3 mmol). The resulting mixture was added to 3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) and stirred at rt overnight. The mixture was concentrated to half the total volume, quenched with satd. aq. NaHCO3, and extracted with CHCl3 (2×). The combined organic layers were dried and concentrated and the crude residue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%). 1H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H), 1.9-1.5 (m, 8H). The mixture was concentrated to half the total volume quenched with satd aq. NaHCO3, and extracted with CHCl3 (2×) The combined organic layers were dried concentrated the crude residue purified (EtOAc/hexanes)

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

Procedure: The title compound was prepared using a method analogous to that described in Tetrahedron 1998, 44, 1603-1607: To a suspension of iodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was added BF3.OEt2 (2.1 mL, 16.3 mmol). The resulting mixture was added to 3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) and stirred at rt overnight. The mixture was concentrated to half the total volume, quenched with satd. aq. NaHCO3, and extracted with CHCl3 (2×). The combined organic layers were dried and concentrated and the crude residue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%). 1H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H), 1.9-1.5 (m, 8H). The mixture was concentrated to half the total volume quenched with satd aq. NaHCO3, and extracted with CHCl3 (2×) The combined organic layers were dried concentrated the crude residue purified (EtOAc/hexanes)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-cyclopentyl-3-oxo-propionic acid ethyl ester (5.0 g, 27.4 mmol) and guanidine hydrochloride (3.1 g, 33.0 mmol) in MeOH (50 mL) at 23° C. was added potassium tert-butoxide, portionwise (16.7 g. 149 mmol) over 15 min with vigorous stirring and the reaction warmed to 60° C. The reaction was cooled to room temperature (rt) and stirred overnight and the precipitated salt was removed by filtration. The solution was concentrated to approximately 10 mL then diluted with 10 mL of water and adjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL). The resulting precipitate was filtered and dried via suction then vacuum to yield a white solid (4.3 g, 87%) that was used without further purification. 1H NMR (MeOD): 10.71-10.54 (m, 1H), 6.58-6.32 (m, 2H), 5.44-5.37 (m, 1H), 2.66 (p, J=8.1, 1H), 1.91-1.73 (m, 2H), 1.72-1.48 (m, 6H). The reaction was cooled to room temperature (rt) stirred overnight the precipitated salt was removed by filtration The solution was concentrated to approximately 10 mL then diluted with 10 mL of water adjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL) The resulting precipitate was filtered dried via suction

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3-cyclopentyl-3-oxo-propionic acid ethyl ester (5.0 g, 27.4 mmol) and guanidine hydrochloride (3.1 g, 33.0 mmol) in MeOH (50 mL) at 23° C. was added potassium tert-butoxide, portionwise (16.7 g. 149 mmol) over 15 min with vigorous stirring and the reaction warmed to 60° C. The reaction was cooled to room temperature (rt) and stirred overnight and the precipitated salt was removed by filtration. The solution was concentrated to approximately 10 mL then diluted with 10 mL of water and adjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL). The resulting precipitate was filtered and dried via suction then vacuum to yield a white solid (4.3 g, 87%) that was used without further purification. 1H NMR (MeOD): 10.71-10.54 (m, 1H), 6.58-6.32 (m, 2H), 5.44-5.37 (m, 1H), 2.66 (p, J=8.1, 1H), 1.91-1.73 (m, 2H), 1.72-1.48 (m, 6H). The reaction was cooled to room temperature (rt) stirred overnight the precipitated salt was removed by filtration The solution was concentrated to approximately 10 mL then diluted with 10 mL of water adjusted to pH=5 by the addition of 6.0 N HCl (6.1 mL) The resulting precipitate was filtered dried via suction

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

Procedure: The title compound was prepared in 72% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-cyclopentyl-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.

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

Procedure: The title compound was prepared in 72% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-cyclopentyl-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.

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

Procedure: DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (25 ml) and put under nitrogen atmosphere. 3-Cyclopentyl-3-oxo-propionic acid ethyl ester (Pharmacore, 3.695 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 304.2 (M+H)+. The mixture was stirred at 90° C. for 2 hours the aqueous layer was extracted with EtOAc (3×50 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

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

Procedure: DBU (2.99 ml; 20.06 mmol; 1.10 eq.) was dissolved in DMF (25 ml) and put under nitrogen atmosphere. 3-Cyclopentyl-3-oxo-propionic acid ethyl ester (Pharmacore, 3.695 g; 20.06 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (2.5 g; 18.23 mmol; 1 eq.) in DMF (5 mL) was added dropwise to the solution at room temperature. The mixture was stirred at 90° C. for 2 hours. Water (50 mL) was added to the cooled reaction mixture and the aqueous layer was extracted with EtOAc (3×50 mL). Combined organics were washed with water and brine, dried over MgSO4 and concentrated under vacuum affording the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 304.2 (M+H)+. The mixture was stirred at 90° C. for 2 hours the aqueous layer was extracted with EtOAc (3×50 mL) Combined organics were washed with water and brine dried over MgSO4 concentrated under vacuum

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

Procedure: To a solution of 2,6-dichlorobenzaldehyde oxime (3.73 g, 19.6 mmol) in N,N-dimethylformamide (12 mL) was added solid N-chlorosuccinimide (2.62 g, 19.6 mmol). The solution was stirred for approximately 1 hour and the poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and concentrated. To a solution of ethyl 3-cyclopentyl-3-oxopropanoate (4.34 g, 23.6 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 25 wt % solution of sodium ethoxide in ethanol (7.4 mL, 24 mmol) quickly. The above imidoyl chloride was added. A solid was seen to precipitate. The mixture was allowed to warm to ambient temperature and stir overnight. The mixture was then poured into water and extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes) to afford ethyl 5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (3.04 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.02 (q, J=7 Hz, 2H), 3.92-3.84 (m, 1H), 2.14-2.06 (m, 2H), 1.84-1.64 (m, 6H), 0.91 (t, J=5 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated to precipitate stir overnight The mixture was then poured into water extracted three times with ethyl acetate the combined organic layers were dried over magnesium sulfate concentrated the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes)

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

Procedure: To a solution of 2,6-dichlorobenzaldehyde oxime (3.73 g, 19.6 mmol) in N,N-dimethylformamide (12 mL) was added solid N-chlorosuccinimide (2.62 g, 19.6 mmol). The solution was stirred for approximately 1 hour and the poured into water and extracted twice with ether. The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate and concentrated. To a solution of ethyl 3-cyclopentyl-3-oxopropanoate (4.34 g, 23.6 mmol) in tetrahydrofuran (5 mL) at 0° C. was added a 25 wt % solution of sodium ethoxide in ethanol (7.4 mL, 24 mmol) quickly. The above imidoyl chloride was added. A solid was seen to precipitate. The mixture was allowed to warm to ambient temperature and stir overnight. The mixture was then poured into water and extracted three times with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes) to afford ethyl 5-cyclopentyl-3-(2,6-dichlorophenyl)-4-isoxazolecarboxylate (3.04 g, 43%). 1H-NMR (400 MHz, DMSO-d6) δ 7.63-7.53 (m, 3H), 4.02 (q, J=7 Hz, 2H), 3.92-3.84 (m, 1H), 2.14-2.06 (m, 2H), 1.84-1.64 (m, 6H), 0.91 (t, J=5 Hz, 3H). extracted twice with ether The combined organic layers containing the crude imidoyl chloride were dried over magnesium sulfate concentrated to precipitate stir overnight The mixture was then poured into water extracted three times with ethyl acetate the combined organic layers were dried over magnesium sulfate concentrated the residue purified by chromatography (silica gel 5% ethyl acetate in hexanes)

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

Procedure: The title compound was prepared using a method analogous to that described in Tetrahedron 1998, 44, 1603-1607: To a suspension of iodosobenzene diacetate (5.2 g, 16.3 mmol) in MeOH (40 mL) was added BF3.0Et2 (2.1 mL, 16.3 mmol). The resulting mixture was added to 3-cyclopentyl-3-oxo-propionic acid ethyl ester (3.0 g, 16.3 mmol) and stirred at rt overnight. The mixture was concentrated to half the total volume, quenched with satd. aq. NaHCO3, and extracted with CHCl3 (2×). The combined organic layers were dried and concentrated and the crude residue purified (EtOAc/hexanes) to yield a colorless oil (1.5 g, 43%). 1H NMR (MeOD): 4.4 (s, 1H), 3.8 (s, 3H), 3.5 (s, 3H), 3.3-3.2 (m, 1H), 1.9-1.5 (m, 8H). The mixture was concentrated to half the total volume quenched with satd aq. NaHCO3, and extracted with CHCl3 (2×) The combined organic layers were dried concentrated the crude residue purified (EtOAc/hexanes)