ethyl cyclohexanecarboxylate

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:

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

Procedure: In a 4 mL vial charged with a stir bar, (3R)-3-fluoro-N-[5-(hydroxymethyl)-1,3-thiazol-2-yl]pyrrolidine-1-carboxamide (43 mg, 0.18 mmol, Example 36B) was added followed by copper iodide (8 mg, 0.04 mmol) and cesium carbonate (88 mg, 0.27 mmol). A loose cap with septum was placed on the vial and then the vial was placed under vacuum for 30 minutes. The solid mixture was purged with nitrogen gas a couple of times. Then ethyl 2-cyclohexanecarboxylate (12 mg, 0.07 mmol) dissolved in dry dimethyl sulfoxide (0.4 mL) was added to the mixture followed by 1,3-dichloro-5-iodobenzene (60 mg, 0.22 mmol) dissolved in dry dimethyl sulfoxide (0.7 mL). The vial was capped and the resulting mixture was shaken at room temperature for 1 hour followed by shaking at 95° C. overnight. Then 1 mL of concentrated ammonium hydroxide solution was added. The reaction was filtered and concentrated to dryness. The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound. In a 4 mL vial charged with a stir bar A loose cap with septum The solid mixture was purged with nitrogen gas a couple of times was added to the mixture The vial was capped by shaking at 95° C. overnight The reaction was filtered concentrated to dryness The residue was purified by reverse phase HPLC (C18, gradient 10-95% acetonitrile/water/0.1% trifluoroacetic acid)

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

Procedure: 4-Dodecylaniline (15.7 g) was dissolved in 100 mL of benzene and then 2-ethoxycarbonylcyclohexane (10.2 g) was added, followed by 0.20 g of p-toluenesulfonic acid. The reaction mixture was stirred for three days and then refluxed for 2 hours with the separation of H2O. The benzene was evaporated from this mixture, which was then dissolved in 100 mL of phenyl ether and refluxed for 45 minutes. At the end of this time the reaction mixture was allowed to cool and the precipitated product was filtered off. This crude product was purified by flash chromatography (20% ethyl acetate/CH2Cl2) and then recrystallized from 1,2-dichloroethane/methanol to give 1.31 g, mp 225°-226°. The benzene was evaporated from this mixture, which was then dissolved in 100 mL of phenyl ether refluxed for 45 minutes to cool the precipitated product was filtered off This crude product was purified by flash chromatography (20% ethyl acetate/CH2Cl2) recrystallized from 1,2-dichloroethane/methanol to give 1.31 g, mp 225°-226°

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

Procedure: 4-Dodecylaniline (15.7 g) was dissolved in 100 mL of benzene and then 2-ethoxycarbonylcyclohexane (10.2 g) was added, followed by 0.20 g of p-toluenesulfonic acid. The reaction mixture was stirred for three days and then refluxed for 2 hours with the separation of H2O. The benzene was evaporated from this mixture, which was then dissolved in 100 mL of phenyl ether and refluxed for 45 minutes. At the end of this time the reaction mixture was allowed to cool and the precipitated product was filtered off. This crude product was purified by flash chromatography (20% ethyl acetate/CH2Cl2) and then recrystallized from 1,2-dichloroethane/methanol to give 1.31 g, mp 225°-226°. The benzene was evaporated from this mixture, which was then dissolved in 100 mL of phenyl ether refluxed for 45 minutes to cool the precipitated product was filtered off This crude product was purified by flash chromatography (20% ethyl acetate/CH2Cl2) recrystallized from 1,2-dichloroethane/methanol to give 1.31 g, mp 225°-226°

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

Procedure: A solution of lithium isopropylamidide was prepared from 300 cm3 butyl lithium 1.5 M in hexane and 52 g of diisopropylamine. At -40° C. 62.4 g (0.4 mole) of ethyl cyclohexyl-carboxylate were added, then at -80° C. 17.6 g of acetaldehyde were also added. The solvent was evaporated off and the mixture was poured into acid ice water. After extraction with benzene the ether was distilled off and a colourless liquid was obtained. At -40° C at -80° C The solvent was evaporated off the mixture was poured into acid ice water After extraction with benzene the ether was distilled off a colourless liquid was obtained

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

Procedure: To a solution of cis-(2-(3-methylbutylamino)-cyclohexanecarboxylic acid ethyl ester (58.7 mg, 0.243 mmol) in N,N-dimethylformamide (5.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 162.0 mg, 0.486 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.49 mL, 0.49 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methylbutyl)amino]-cyclohexanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C24H36N4O7S2 556.20, found 557.3 [M+H+]. the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration The filtrate was concentrated dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of dicyclohexylamine (15.55 g, 85.77 mmol) in THF (90 mL) 1.6 M n-BuLi in hexane (48.0 mL, 76.8 mmol) was added with stirring over 50 min at temperature between −20° C. and −15° C. The orange suspension was stirred 10 min at −20° C. and then warmed up to 0° C. To this suspension a solution of cyclohexanecarboxylic acid ethyl ester (10.0 g, 64.0 mmol) in THF (30 mL) was added over 15 min at 0° C. The resulting solution was stirred 30 min at 0° C. then 1-bromo-2-ethylbutane (14.79 g, 89.6 mmol) in THF (37.5 mL) was added at the same temperature over 15 min. Stirring was continued 5 h at 0° C. and overnight at room temperature. At 5° C. cold water (25 mL) was added, followed by 2N HCl (60 mL). The white suspension was filtered and the filter cake was washed with water and ethyl acetate. The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (16.0 g) was distilled at 60° C. (0.05 mbar) to give 12.1 g (79%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester as colorless oil, purity 97% (GC area) (cyclohexanecarboxylic acid dicyclohexylamide as impurity: not detectable in distilled product and 0.7% in crude product). The orange suspension was stirred 10 min at −20° C. The resulting solution was stirred 30 min at 0° C. Stirring was continued 5 h at 0° C. and overnight at room temperature The white suspension was filtered the filter cake was washed with water and ethyl acetate The organic phase of the filtrate was washed with sat. aq. NaHCO3 and with aq. NaCl The aqueous phases were extracted with ethyl acetate dried over sodium sulfate concentrated The crude product (16.0 g) was distilled at 60° C. (0.05 mbar)

Conditions: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (2.37 g, 23.4 mmol) in THF (12 mL) 1.6 M n-BuLi in hexane (13.2 mL, 21.09 mmol) was added with stirring over 20 min at −65° C. The suspension was warmed up to −40° C. and then added via a teflon tube over 20 min to a stirred solution of cyclohexanecarboxylic acid ethyl ester (2.196 g, 14.1 mmol) in THF (20 mL) at −65° C. The resulting solution was stirred 1 h at −65° C., then 1-bromo-2-ethylbutane (3.714 g, 22.5 mmol) in THF (10 mL) was added at −65° C. over 20 min. The solution was stirred 1.5 h at −65° C. and then overnight without a cooling bath while slowly warming up to room temperature. At 5° C. ice-water (15 mL) was added, followed by 2N HCl (30 mL). The organic phase was diluted with ethyl acetate and washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (3.4 g) was distilled at 50° C. (0.01 mbar) to give 2.6 g (77%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester as a colorless oil, purity 92.6% (GC area) (cyclohexanecarboxylic acid diisopropylamide as impurity: 3.8% in dist. product and 3.1% in crude product) The suspension was warmed up to −40° C. The resulting solution was stirred 1 h at −65° C. The solution was stirred 1.5 h at −65° C. overnight without a cooling bath while slowly warming up to room temperature washed with sat. aq. NaHCO3 and with aq. NaCl The aqueous phases were extracted with ethyl acetate dried over sodium sulfate concentrated The crude product (3.4 g) was distilled at 50° C. (0.01 mbar)

Conditions: temp:-65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diisopropylamine (2.37 g, 23.4 mmol) in THF (12 mL) 1.6 M n-BuLi in hexane (13.2 mL, 21.09 mmol) was added with stirring over 20 min at −65° C. The suspension was warmed up to −40° C. and then added via a teflon tube over 20 min to a stirred solution of cyclohexanecarboxylic acid ethyl ester (2.196 g, 14.1 mmol) in THF (20 mL) at −65° C. The resulting solution was stirred 1 h at −65° C., then 1-bromo-2-ethylbutane (3.714 g, 22.5 mmol) in THF (10 mL) was added at −65° C. over 20 min. The solution was stirred 1.5 h at −65° C. and then overnight without a cooling bath while slowly warming up to room temperature. At 5° C. ice-water (15 mL) was added, followed by 2N HCl (30 mL). The organic phase was diluted with ethyl acetate and washed with sat. aq. NaHCO3 and with aq. NaCl. The aqueous phases were extracted with ethyl acetate. The organic phases were combined, dried over sodium sulfate and concentrated. The crude product (3.4 g) was distilled at 50° C. (0.01 mbar) to give 2.6 g (77%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester as a colorless oil, purity 92.6% (GC area) (cyclohexanecarboxylic acid diisopropylamide as impurity: 3.8% in dist. product and 3.1% in crude product) The suspension was warmed up to −40° C. The resulting solution was stirred 1 h at −65° C. The solution was stirred 1.5 h at −65° C. overnight without a cooling bath while slowly warming up to room temperature washed with sat. aq. NaHCO3 and with aq. NaCl The aqueous phases were extracted with ethyl acetate dried over sodium sulfate concentrated The crude product (3.4 g) was distilled at 50° C. (0.01 mbar)