ethyl 2-(4-oxocyclohexyl)acetate

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 three liter round bottom flask was charged with ethyl (4-oxocyclohexyl)acetate (100 g, 0.588 mol) and ethanol (400 mL). Sodium hydroxide (25.8 g, 0.645 mol) was added, and the reaction was stirred at room temperature for 1 hour. Next, triethyl phosphonoacetate (128 mL, 0.645 mol) was added, and the reaction was then cooled to 0° C. A solution of NaOEt in EtOH (21% solution, 242 mL) was added dropwise to the reaction over 1 hour. The reaction was warmed to room temperature and stirred for 1 hour. HOAc (84 mL) was added, followed by ammonium formate (74 g) and 5% Pd/C (10 g). The reaction was heated to 60° C. for 6 hours and then cooled to room temperature. The solids were filtered off and the filtrate was concentrated. The residue was taken up in EtOAc (2 L) and washed with 1N HCl (2×500 mL), H2O (500 mL), and brine (500 mL). The organic layer was concentrated to an oil and azeotroped with toluene (2 L). The residue was purified by flash chromatography on silica gel (0 to 50% EtOAc/Hexanes containing 1% HOAc). This afforded 4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid as a mixture of cis and trans isomers. the reaction was then cooled to 0° C The reaction was warmed to room temperature stirred for 1 hour The reaction was heated to 60° C. for 6 hours cooled to room temperature The solids were filtered off the filtrate was concentrated washed with 1N HCl (2×500 mL), H2O (500 mL), and brine (500 mL) The organic layer was concentrated to an oil azeotroped with toluene (2 L) The residue was purified by flash chromatography on silica gel (0 to 50% EtOAc/Hexanes containing 1% HOAc) This afforded 4-(2-ethoxy-2-oxoethyl)cyclohexanecarboxylic acid as a mixture of cis and trans isomers

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

Procedure: Reaction of ethyl 2-(4-oxocyclohexyl)acetate with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. afforded the product

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

Procedure: 74.0 G. of 4-oxocyclohexaneacetic acid ethyl ester and 1200 ml. of anhydrous ether were placed in a 3 l. three-necked flask, provided with a thermometer, nitrogen inlet, dropping funnel, condenser and stirrer. The solution was cooled to -10° by means of a dry ice-acetone bath, and 64.0 g. of bromine was added dropwise over a period of 30-40 minutes. The resulting colorless solution was washed three times with 100 ml. of water, then two times with 125 ml. of cold saturated sodium bicarbonate solution followed by 100 ml. of water. The combined aqueous solutions were extracted twice with 150 ml. of ether. The combined ether extracts were dried over anhydrous magnesium sulfate, and the ether was removed by distillation from a steam bath at atmospheric pressure to give a residue of crude 3-bromo-4-oxocyclohexaneacetic acid ethyl ester, weighing 105 g. three-necked flask, provided with a thermometer, nitrogen inlet The solution was cooled to -10° by means of a dry ice-acetone bath The resulting colorless solution was washed three times with 100 ml The combined aqueous solutions were extracted twice with 150 ml The combined ether extracts were dried over anhydrous magnesium sulfate the ether was removed by distillation from a steam bath at atmospheric pressure

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

Procedure: Trifluoromethanesulfonic anhydride (11.9 mL, 70.86 mmol) was added portionwise to a solution of 2,6-di-tert-butyl-4-methylpyridine (18.19 g, 88.58 mmol) in DCM (250 mL). A solution of ethyl 2-(4-oxocyclohexyl)acetate (10.88 g, 59.05 mmol, CAS 58012-34-3) in DCM (100 mL) was then added dropwise and the reaction mixture was allowed to stir open to air and at room temperature overnight. The reaction mixture was washed with water, saturated Na2CO3, saturated brine, dried over MgSO4 and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (16.05 g, 86%) as a yellow oil. The reaction mixture was washed with water, saturated Na2CO3, saturated brine dried over MgSO4 evaporated to afford crude product The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in isohexane Pure fractions were evaporated to dryness

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

Procedure: To a cooled (0° C.) suspension of methyl triphenylphosphonium bromide (8.58 g, 23.5 mmol) in THF (60 mL) was added KOtBu (3.17 g, 28.3 mmol) in portions under N2. The reaction was slowly warmed to rt and stirred for 1 h. The resulting mixture was cooled to 0° C. and added a solution of ethyl 2-(4-oxocyclohexyl)acetate (2.9 g, 15.7 mmol) in THF (15 mL). The resulting mixture was stirred at RT for 2 h and at 50° C. overnight. After cooling to RT, the reaction was quenched by addition of saturated NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes) gave the product as colorless oil (2.11 g, 73.7%). To a cooled The resulting mixture was cooled to 0° C. The resulting mixture was stirred at RT for 2 h and at 50° C. overnight After cooling to RT the reaction was quenched by addition of saturated NH4Cl extracted with EtOAc washed with brine dried over Na2SO4 Purification by flash column chromatography (eluent: 20% EtOAc in hexanes)

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

Procedure: To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetate (from Step 1, Example 77, 4.71 g, 19.44 mmol) in acetonitrile (45 mL) was added 6N HCl aqueous solution (45 mL). The resulting mixtures was stirred at rt for 2 h and neutralized with solid NaHCO3 to pH 8, extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4. Filtration and evaporation to dryness gave the ketone product as colorless oil (2.97 g, 78.1%). extracted with EtOAc The organic phase was washed with brine dried over Na2SO4 Filtration and evaporation to dryness

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of ethyl 2-(4-oxocyclohexyl)acetate (736 mg, 4 mmol) and N-(2-aminoethyl)methanesulfonamide; 2,2,2-trifluoroacetic acid salt (1.26 g, 5 mmol) in dichloromethane (6 mL) was added triethylamine (690 μL, 5 mmol) followed by Titanium (IV) ethoxide (420 μL, 2 mmol, technical grade). The resulting cloudy mixture was stirred for 4 hours then concentrated under reduced pressure. The residue was taken up in methanol (6 mL). This mixture was cooled to −78° C. To the resulting mixture was added sodium borohydride (187 mg, 4.8 mmol). On complete addition, the cold bath was allowed to expire and stirring continued for 15.5 hours. The resulting mixture was concentrated under reduced pressure to give a thick paste. This residue was taken up in dichloromethane (40 mL). To this mixture was added Na2CO3 (5.5 mL, saturated aqueous solution). The resulting mixture was stirred for 5 minutes. To this mixture was added celite (1.8 g). This mixture was stirred for 5 minutes then filtered through a pad of celite. The filtrate is washed with saturated aqueous Na2CO3, dried over magnesium sulfate and concentrated to give the title compound as a 6:1 mixture of trans: cis isomers. This material was used without further purification. then concentrated under reduced pressure On complete addition stirring continued for 15.5 hours The resulting mixture was concentrated under reduced pressure to give a thick paste The resulting mixture was stirred for 5 minutes To this mixture was added celite (1.8 g) This mixture was stirred for 5 minutes then filtered through a pad of celite The filtrate is washed with saturated aqueous Na2CO3 dried over magnesium sulfate concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-(N-[2-(amino)-ethyl]-amino)-pyridine (685 mg, 5 mmol) and ethyl 2-(4-oxocyclohexyl)acetate (786 mg, 4 mmol) was added dichloromethane (4 mL) followed by titanium ethoxide (420 μL, 2 mmol, technical grade). The resulting mixture was stirred for 4 hr then concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and cooled to −78° C. To this solution was added sodium borohydride (228 mg, 6 mmol). On complete addition, the cold bath was removed and stirring continued for 1.25 hr. The mixture was diluted with dichloromethane and poured into saturated sodium carbonate solution (15 mL). The organic phase was separated, dried over magnesium sulfate and concentrated to give the crude title compound as a 6:1 mixture trans:cis isomers. This mixture was used without further purification. then concentrated under reduced pressure On complete addition the cold bath was removed stirring continued for 1.25 hr The mixture was diluted with dichloromethane poured into saturated sodium carbonate solution (15 mL) The organic phase was separated dried over magnesium sulfate concentrated

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

Procedure: 50 ml of a 1N aqueous solution of hydrochloric acid was added to a solution of 5.0 g of ethyl 4-oxocyclohexylacetate ethylene acetal, as obtained in Example 58, in 50 ml of acetone. The reaction mixture was stirred for 10 minutes at room temperature, neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate, and then concentrated by evaporation under reduced pressure. The resulting residue was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 100 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 3.9 g of the title compound as an oil. concentrated by evaporation under reduced pressure The resulting residue was extracted with ethyl acetate The organic extract was washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate concentrated by evaporation under reduced pressure with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent

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

Procedure: To a cooled (0° C.) suspension of methyl triphenylphosphonium bromide (8.58 g, 23.5 mmol) in THF (60 mL) was added KOtBu (3.17 g, 28.3 mmol) in portions under N2. The reaction was slowly warmed to rt and stirred for 1 h. The resulting mixture was cooled to 0° C. and added a solution of ethyl 2-(4-oxocyclohexyl)acetate (2.9 g, 15.7 mmol) in THF (15 mL). The resulting mixture was stirred at RT for 2 h and at 50° C. overnight. After cooling to RT, the reaction was quenched by addition of saturated NH4Cl, extracted with EtOAc, washed with brine, dried over Na2SO4. Purification by flash column chromatography (eluent: 20% EtOAc in hexanes) gave the product as colorless oil (2.11 g, 73.7%). To a cooled The resulting mixture was cooled to 0° C. The resulting mixture was stirred at RT for 2 h and at 50° C. overnight After cooling to RT the reaction was quenched by addition of saturated NH4Cl extracted with EtOAc washed with brine dried over Na2SO4 Purification by flash column chromatography (eluent: 20% EtOAc in hexanes)