ethyl 2-methyl-4-oxocyclohex-2-ene-1-carboxylate

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

Procedure: To the solution of KOtBu (1.0 M in tBuOH, 10.7 mL) at 25 cC was added Hagemann's ester (1.0 mL, 5.324 mmol). The mixture was stirred for 10 min at 25° C. and then to the mixture was added 1-[2-(4-chloromethyl-phenoxy)ethyl]piperidine hydrochloride (1.54 g, 5.324 mmol). The mixture was refluxed for 3 h. The tBuOH was distilled off, then the reaction mixture was diluted with water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The organic extracts were acidified with 1N HCl (100 mL). The layers were separated and the diethyl ether layer was discarded. The aqueous layer was then basicified to pH 11 with 10% NaOH (aq) and extracted with diethyl ether to yield 2-methyl-4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-2-enecarboxylic acid ethyl ester as dark amber oil. The mixture was refluxed for 3 h The tBuOH was distilled off the reaction mixture was diluted with water and diethyl ether The layers were separated the aqueous layer was extracted with diethyl ether The layers were separated extracted with diethyl ether

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

Procedure: A mixture of ethyl 2-methyl-4-oxo-2-cyclohexenecarboxylate (2.0 kg, 91.2%, 10.98 moles), β-mercaptopropionic acid (1.165 kg, 10.98 moles), p-toluenesulfonic acid (ptsa) monohydrate (0.710 kg, 3.73 moles) and pyridine (0.304 kg, 3.84 moles) in toluene is heated to reflux temperature, heated at reflux temperatures for 7 hours using a Dean Stark trap for removal of water, allowed to cool to room temperature over a 17 hour period, cooled to 5° C., treated with trifluoroacetic anhydride (TFAA) (2.306 kg, 10.98 moles) at 50°-12° C., treated with methanesulfonic acid (0.053 kg, 0.55 moles), allowed to warm to room temperature, held at room temperature until reaction is complete by HPLC analysis and quenched with water. The phases are separated. The organic phase is washed with water and distilled to remove the toluene. The remaining pot residue is treated with isopropyl alcohol (1.89 kg), cooled to 45° C., treated with heptane (1.65 kg), and cooled to room temperature. The resultant mixture is filtered and the filtercake is washed sequentially with a 1:1 isopropanol:heptane mixture (0.735 kg) and heptane (1.37 kg). The washed filtercake is dried in vacuo to give the title product as a white crystalline solid, 0.931 kg (36% yield) 98.4% purity, identified by HPLC analysis. is heated to reflux temperature heated at reflux temperatures for 7 hours for removal of water cooled to 5° C. to warm to room temperature held at room temperature until reaction quenched with water The phases are separated The organic phase is washed with water distilled to remove the toluene The remaining pot residue is treated with isopropyl alcohol (1.89 kg) cooled to 45° C. treated with heptane (1.65 kg) cooled to room temperature The resultant mixture is filtered the filtercake is washed sequentially with a 1:1 isopropanol The washed filtercake is dried in vacuo

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

Procedure: This material is prepared according to the procedure for Preparation 6 wherein Hagemann's ester (ethyl 2-methyl-4-oxocyclohex-2-enyl-1-carboxylate) is substituted for carvone and ethyl 3-chloropropionate is substituted for ethyl vinyl ketone. This material is prepared

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

Procedure: This material is prepared according to the procedure for Preparation 6 wherein Hagemann's ester (ethyl 2-methyl-4-oxocyclohex-2-enyl-1-carboxylate) is substituted for carvone and ethyl 3-chloropropionate is substituted for ethyl vinyl ketone. This material is prepared

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

Procedure: To the solution of KOtBu (1.0 M in tBuOH, 10.7 mL) at 25 cC was added Hagemann's ester (1.0 mL, 5.324 mmol). The mixture was stirred for 10 min at 25° C. and then to the mixture was added 1-[2-(4-chloromethyl-phenoxy)ethyl]piperidine hydrochloride (1.54 g, 5.324 mmol). The mixture was refluxed for 3 h. The tBuOH was distilled off, then the reaction mixture was diluted with water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The organic extracts were acidified with 1N HCl (100 mL). The layers were separated and the diethyl ether layer was discarded. The aqueous layer was then basicified to pH 11 with 10% NaOH (aq) and extracted with diethyl ether to yield 2-methyl-4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-2-enecarboxylic acid ethyl ester as dark amber oil. The mixture was refluxed for 3 h The tBuOH was distilled off the reaction mixture was diluted with water and diethyl ether The layers were separated the aqueous layer was extracted with diethyl ether The layers were separated extracted with diethyl ether

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

Procedure: To the solution of KOtBu (1.0 M in tBuOH, 10.7 mL) at 25 cC was added Hagemann's ester (1.0 mL, 5.324 mmol). The mixture was stirred for 10 min at 25° C. and then to the mixture was added 1-[2-(4-chloromethyl-phenoxy)ethyl]piperidine hydrochloride (1.54 g, 5.324 mmol). The mixture was refluxed for 3 h. The tBuOH was distilled off, then the reaction mixture was diluted with water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The organic extracts were acidified with 1N HCl (100 mL). The layers were separated and the diethyl ether layer was discarded. The aqueous layer was then basicified to pH 11 with 10% NaOH (aq) and extracted with diethyl ether to yield 2-methyl-4-oxo-3-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-cyclohex-2-enecarboxylic acid ethyl ester as dark amber oil. The mixture was refluxed for 3 h The tBuOH was distilled off the reaction mixture was diluted with water and diethyl ether The layers were separated the aqueous layer was extracted with diethyl ether The layers were separated extracted with diethyl ether

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

Procedure: Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (2.0 g, 10.98 mmol) is dissolved in MeOH (40 ml) and water (4.0 ml) to give a yellow solution. Ammonium formate (8.31 g, 132 mmol) is added and stirred at RT until the suspension dissolves to form a solution. Palladium on carbon (0.117 g, 1.098 mmol) is added and the reaction mixture is stirred at 70° C. for 1 hour. The mixture is filtered through Celite® (filter material) and washed with MeOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous portion is diluted with sat. sodium bicarbonate and washed with EtOAc. The pH is adjusted to pH 14 using 1M NaOH and the aqueous is extracted with EtOAc. The combined organic extracts are dried MgSO4, filtered and concentrated in vacuo to afford the title compound; [MH]+ 186.24. dissolves to form a solution the reaction mixture is stirred at 70° C. for 1 hour The mixture is filtered through Celite® (filter material) washed with MeOH The filtrate is concentrated in vacuo the residue is partitioned between EtOAc and water The aqueous portion is diluted with sat. sodium bicarbonate washed with EtOAc the aqueous is extracted with EtOAc filtered concentrated in vacuo

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

Procedure: Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (2.0 g, 10.98 mmol) is dissolved in MeOH (40 ml) and water (4.0 ml) to give a yellow solution. Ammonium formate (8.31 g, 132 mmol) is added and stirred at RT until the suspension dissolves to form a solution. Palladium on carbon (0.117 g, 1.098 mmol) is added and the reaction mixture is stirred at 70° C. for 1 hour. The mixture is filtered through Celite® (filter material) and washed with MeOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous portion is diluted with sat. sodium bicarbonate and washed with EtOAc. The pH is adjusted to pH 14 using 1M NaOH and the aqueous is extracted with EtOAc. The combined organic extracts are dried MgSO4, filtered and concentrated in vacuo to afford the title compound; [MH]+ 186.24. dissolves to form a solution the reaction mixture is stirred at 70° C. for 1 hour The mixture is filtered through Celite® (filter material) washed with MeOH The filtrate is concentrated in vacuo the residue is partitioned between EtOAc and water The aqueous portion is diluted with sat. sodium bicarbonate washed with EtOAc the aqueous is extracted with EtOAc filtered concentrated in vacuo

Conditions: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyllithium (170 mL of a 1.6 M solution with Et2O, 260 mmol) was added to a stirring mixture of copper (I) iodide (25 g, 130 mmol) and Et2O (130 mL), at −40° C. under a nitrogen atmosphere. After stirring for 10 min at −40° C., ethyl 2-methyl-4-oxo-2-cyclohexene-1-carboxylate (12 g, 66 mmol) was added. After stirring for 30 min at −40° C., the reaction mixture was allowed to warm to −20° C. After stirring for 90 min at −20° C., saturated aqueous ammonium chloride and EtOAc were added sequentially, the mixture was partitioned between more saturated aqueous ammonium chloride and EtOAc, the layers were separated, the organic material washed sequentially with saturated aqueous ammonium chloride (2×) and brine, dried (Na2SO4), filtered, and the filtrate was concentrated. The residue was dissolved with DCM, silica gel (39 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (gradient elution; 19:1 to 9:1 hexane-EtOAc) to give ethyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (8.9 g, 68% yield; racemic mixture) as a clear yellow oil. After stirring for 30 min at −40° C. to warm to −20° C After stirring for 90 min at −20° C. the mixture was partitioned between more saturated aqueous ammonium chloride and EtOAc the layers were separated the organic material washed sequentially with saturated aqueous ammonium chloride (2×) and brine dried (Na2SO4) filtered the filtrate was concentrated The residue was dissolved with DCM, silica gel (39 g) was added to the solution the volatiles were removed under reduced pressure

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

Procedure: To a Parr flask was added 10% palladium on carbon (wet degussa type) (4.47 g, 4.20 mmol) in EtOH (378 ml). Then ethyl 2-methyl-4-oxo-2-cyclohexene-1-carboxylate (23.65 ml, 140 mmol) and 5 N hydrochloric acid (1.679 ml, 8.40 mmol) were added into the reaction mixture. The atmosphere of the flask was degassed, and then filled with hydrogen (50 psi). The mixture was allowed to stir under hydrogenation conditions 30 min. The progress of the reaction was monitored by LC/MS and TLC (50% EtOAc/hexane; potassium permanganate stain), which suggested reaction completion. The mixture was filtered through a pad of celite and the filter cake was rinsed with EtOH. The mixture was concentrated in-vacuo. The crude material was purified by chromatography through an Interchim (15 micron) silica-gel column (220 g), eluting with a gradient of 0-50% EtOAc in hexane, to provide (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (18.277 g, 99 mmol, 70.9% yield) (Racemic) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.19 (dtt, 2H), 2.85 (td, J=4.25, 8.31 Hz, 1H), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.06, 8.75, 14.72 Hz, 1H), 2.01-2.21 (m, 2H), 1.29 (t, J=7.14 Hz, 3H), 0.98 (d, J=6.85 Hz, 3H); LCMS (ESI) m/z 185.0 (M+H)+. The atmosphere of the flask was degassed filled with hydrogen (50 psi) reaction completion The mixture was filtered through a pad of celite the filter cake was rinsed with EtOH The mixture was concentrated in-vacuo The crude material was purified by chromatography through an Interchim (15 micron) silica-gel column (220 g) eluting with a gradient of 0-50% EtOAc in hexane

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

Procedure: To a Parr flask was added 10% palladium on carbon (wet degussa type) (4.47 g, 4.20 mmol) in EtOH (378 ml). Then ethyl 2-methyl-4-oxo-2-cyclohexene-1-carboxylate (23.65 ml, 140 mmol) and 5 N hydrochloric acid (1.679 ml, 8.40 mmol) were added into the reaction mixture. The atmosphere of the flask was degassed, and then filled with hydrogen (50 psi). The mixture was allowed to stir under hydrogenation conditions 30 min. The progress of the reaction was monitored by LC/MS and TLC (50% EtOAc/hexane; potassium permanganate stain), which suggested reaction completion. The mixture was filtered through a pad of celite and the filter cake was rinsed with EtOH. The mixture was concentrated in-vacuo. The crude material was purified by chromatography through an Interchim (15 micron) silica-gel column (220 g), eluting with a gradient of 0-50% EtOAc in hexane, to provide (1S,2R)-ethyl 2-methyl-4-oxocyclohexanecarboxylate (18.277 g, 99 mmol, 70.9% yield) (Racemic) as light-yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.19 (dtt, 2H), 2.85 (td, J=4.25, 8.31 Hz, 1H), 2.43-2.58 (m, 4H), 2.31 (ddd, J=6.06, 8.75, 14.72 Hz, 1H), 2.01-2.21 (m, 2H), 1.29 (t, J=7.14 Hz, 3H), 0.98 (d, J=6.85 Hz, 3H); LCMS (ESI) m/z 185.0 (M+H)+. The atmosphere of the flask was degassed filled with hydrogen (50 psi) reaction completion The mixture was filtered through a pad of celite the filter cake was rinsed with EtOH The mixture was concentrated in-vacuo The crude material was purified by chromatography through an Interchim (15 micron) silica-gel column (220 g) eluting with a gradient of 0-50% EtOAc in hexane

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

Procedure: Ethyl 2-methyl-4-oxocyclohex-2-enecarboxylate (2.0 g, 10.98 mmol) is dissolved in MeOH (40 ml) and water (4.0 ml) to give a yellow solution. Ammonium formate (8.31 g, 132 mmol) is added and stirred at RT until the suspension dissolves to form a solution. Palladium on carbon (0.117 g, 1.098 mmol) is added and the reaction mixture is stirred at 70° C. for 1 hour. The mixture is filtered through Celite® (filter material) and washed with MeOH. The filtrate is concentrated in vacuo and the residue is partitioned between EtOAc and water. The aqueous portion is diluted with sat. sodium bicarbonate and washed with EtOAc. The pH is adjusted to pH14 using 1M NaOH and the aqueous is extracted with EtOAc. The combined organic extracts are dried MgSO4, filtered and concentrated in vacuo to afford the title compound; [MH]+186.24. dissolves to form a solution the reaction mixture is stirred at 70° C. for 1 hour The mixture is filtered through Celite® (filter material) washed with MeOH The filtrate is concentrated in vacuo the residue is partitioned between EtOAc and water The aqueous portion is diluted with sat. sodium bicarbonate washed with EtOAc the aqueous is extracted with EtOAc filtered concentrated in vacuo