2-phenethylcyclohexan-1-one synthesis

622-24-2 Synthesis

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Yield:1138-44-9 58%

Reaction Conditions:

Stage #1: cyclohexanone N-cyclohexyliminewith sec.-butyllithium in tetrahydrofuran at -78; for 1 h;
Stage #2: 2-phenylethyl chloride in tetrahydrofuran at 20; for 24 h;
Stage #3: with hydrogenchloride in tetrahydrofuran;water;

Steps:

20

Cyclohexylamine Compound 20a (4.64 g, 46.50 mmol) was added to a solution of cyclohexanone Compound 2a (4.0 g, 46.50 mmol) in benzene (100 mL) at ambient temperature under a N₂atmosphere. The mixture was refluxed at 80° C. for 5 hours, using a Dean Stark apparatus for the removal of water, and concentrated to dryness. The crude product was purified by distillation at aspirator pressure to afford cyclohexyl-cyclohexylidene-amine Compound 20b (7.33 g, 88%) as a clear oil. s-BuLi (28.0 mL, 1.3 M) was added slowly to a solution of Compound 20b (7.0 g) in THF (50 mL) at -78° C. The mixture stirred for 1 hr at -78° C. and then (2-chloro-ethyl)-benzene Compound 20c (5.11 g, 36.4 mmol) in THF (10 mL) was added dropwise. The reaction mixture was stirred for 24 hrs while warming to r.t. The reaction was quenched with 1N HCl (5 mL), then diluted with water (100 mL) and EtOAc (500 mL). The organic layer was washed with brine, separated and dried with anhydrous sodium sulfate, then filtered and concentrated in vacuo to yield a crude product. Purification by flash chromatography (eluted with 10% EtOAc in Hexane) afforded 2-phenethyl-cyclohexanone Compound 20d (4.05 g, 20.0 mMol, 58%) as a yellow oil. Compound 20d was carried forward in place of Compound 2a using the procedure of Example 11 to provide 2-(2,2-dimethoxy-acetyl)-6-phenethyl-cyclohexanone Compound 20e. Using the procedure of Example 10, Compound 20e was used in place of [3-(4-fluoro-benzylidene)-2-oxo-cyclohexyl]-oxo-acetic acid ethyl ester Compound 10c and (4-fluoro-phenyl)-hydrazine Compound 20f was used in place of (2,4-dichloro-phenyl)-hydrazine Compound 10d to provide 1-[1-(4-fluoro-phenyl)-7-phenethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl]-2,2-dimethoxy-ethanone Compound 20g. Using the procedure of Example 11, Compound 20g was used in place of [3-(4-fluoro-benzylidene)-2-oxo-cyclohexyl]-oxo-acetic acid ethyl ester Compound 11d to provide 1-(4-fluoro-phenyl)-7-phenethyl-4,5,6,7-tetrahydro-1H-indazole-3-carbaldehyde Compound 20h. Using the procedure of Example 11, Compound 20h was used in place of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carbaldehyde Compound 11e and (methylsulfonyl)(1-phenyl-ethyl)-carbamic acid tert-butyl ester Compound 20i was used in place of (methylsulfonyl)[(1R)-1-phenyl-ethyl]-carbamic acid tert-butyl ester Compound 11f to provide Compound 258. Using the procedure of Example 11, Compound 20h was used in place of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carbaldehyde Compound 11e and (methylsulfonyl)(1-cyclohexyl-ethyl)-carbamic acid tert-butyl ester Compound 20j was used in place of (methylsulfonyl)[(1R)-1-phenyl-ethyl]-carbamic acid tert-butyl ester Compound 11f to provide Compound 259.

References:

US2005/228034,2005,A1 Location in patent:Page/Page column 120-122

5414-21-1 Synthesis