2-benzoylcyclohexan-1-one

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The title compound was prepared in 65.5% yield after chromatography (silica gel, hexane/ethyl acetate 4:1) from 2-benzoylcyclohexanone and p-methoxybenzyl acrylate using a similar method to that used in Preparation 2. (M+ 394.13, 53%). Rf. 0.39 (silica, hexane/ethyl acetate (2:1). 1H-NMR (300 MHz, CDCl3): =1.38-1.49 (m, 1 H) , 1.68-1.82 (m, 3H), 1.98-2.57 (m, 7H), 2.82-2.91 (m, 1H), 3.82 (s, 3H), 5.03 (s, 2H), 6.87 (d, 2H), 7.26 (d, 2H) , 7.42 (t, 2H), 7.56 (t, 1H), 7.88 (d, 2H) ppm. Analysis %: Found: C, 73.05; H, 6.74; C24H26O5 requires C, 73.08; H, 6.64. that used in Preparation 2

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: 5.7 g (22.1 mmol) of ethyl (S)-2-amino-3-(3′-methylaminobiphenyl-4-yl)propionate and 5.8 g (28.7 mmol) of 2-benzoylcyclohexanone are dissolved in 10 ml of anisole. 0.6 g of 10% palladium-on-charcoal are added and the reaction medium is then refluxed using a Dean-Stark apparatus for 16 h. The cooled reaction medium is filtered through celite, rinsed with ethyl acetate and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 5.9 g of desired product are isolated with a 49% yield. the reaction medium is then refluxed for 16 h The cooled reaction medium is filtered through celite rinsed with ethyl acetate concentrated The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture

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

Procedure: 5.7 g (22.1 mmol) of ethyl (S)-2-amino-3-(3′-methylaminobiphenyl-4-yl)propionate and 5.8 g (28.7 mmol) of 2-benzoylcyclohexanone are dissolved in 10 ml of anisole. 0.6 g of 10% palladium-on-charcoal are added and the reaction medium is then refluxed using a Dean-Stark apparatus for 16 h. The cooled reaction medium is filtered through celite, rinsed with ethyl acetate and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with a 7/3 heptane/ethyl acetate mixture. 5.9 g of desired product are isolated with a 49% yield. the reaction medium is then refluxed for 16 h The cooled reaction medium is filtered through celite rinsed with ethyl acetate concentrated The residue obtained is purified by chromatography on a column of silica eluted with a 7/3 heptane/ethyl acetate mixture

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

Procedure: Compound IVc is obtained in 50% yield as a yellow powder, according to Example 4, from 4-cyclohex-1-enyl-morpholine (40.96 g, 0.25 mol, obtained in Example 1), triethylamine (35.35 g, 0.35 mol), benzoyl chloride (49.19 g, 0.35 mol), toluene (380 mL) and 20% aqueous HCl (125 mL). Compound IVc is obtained in 50% yield as a yellow powder

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

Procedure: Compound IVc is obtained in 50% yield as a yellow powder, according to Example 4, from 4-cyclohex-1-enyl-morpholine (40.96 g, 0.25 mol, obtained in Example 1), triethylamine (35.35 g, 0.35 mol), benzoyl chloride (49.19 g, 0.35 mol), toluene (380 mL) and 20% aqueous HCl (125 mL). Compound IVc is obtained in 50% yield as a yellow powder

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 2-benzoylcyclohexanone (90.9 g, 0.45 mol), L-tyrosine methyl ester (78.0 g, 0.40 mol) in anisole (1000 ml) is added 5% palladium on carbon (20 g), then the mixture is heated to reflux for 2 h while the resulting water is removed by a Dean-Stark apparatus. The mixture is cooled to 80° C., and the Pd/C is filtered and washed with anisole (3×60 ml). The mixture is cooled to 40° C., hexane (1000 ml) is added and the mixture kept at −20° C. for 48 h. The solid is filtered and washed with hexane (5×200 ml) to yield the crude 2-((2-benzoylphenyl)-amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester. The crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2×50 ml), and dried under a vacuum to give the title compound (60.2 g, 40.1%). the mixture is heated is removed by a Dean-Stark apparatus the Pd/C is filtered washed with anisole (3×60 ml) The mixture is cooled to 40° C. hexane (1000 ml) is added The solid is filtered washed with hexane (5×200 ml) to yield the crude 2-((2-benzoylphenyl)-amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester is refluxed for 30 min After cooled to 0° C. the product is filtered washed with methanol (2×50 ml) dried under a vacuum

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

Procedure: The title compound was prepared in 65.5% yield after chromatography (silica gel, hexane/ethyl acetate 4:1) from 2-benzoylcyclohexanone and p-methoxybenzyl acrylate using a similar method to that used in Preparation 2. (M+ 394.13, 53%). Rf. 0.39 (silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.38-1.49 (m, 1H), 1.68-1.82 (m, 3H), 1.98-2.57 (m, 7H), 2.82-2.91 (m, 1H), 3.82 (s, 3H), 5.03 (s, 2H), 6.87 (d, 2H), 7.26 (d, 2H), 7.42 (t, 2H), 7.56 (t, 1H), 7.88 (d, 2H) ppm. Analysis %: Found: C, 73.05; H, 6.74; C24H26 O5 requires: C, 73.08; H, 6.64. that used in Preparation 2

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

Procedure: A mixture of 2-benzoylcyclohexanone (1.00 g), sodium ethoxide (404 mg) in ethanol (5 mL) was stirred for 3.5 hours at room temperature. The reaction was quenched by adding 1N hydrochloric acid (1 mL). The solvent was evaporated off, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give ethyl 7-oxo-7-phenylheptanoate as a brown oil (1.33 g). The reaction was quenched by adding 1N hydrochloric acid (1 mL) The solvent was evaporated off the residue was partitioned between ethyl acetate and water The organic layer was washed with brine dried over magnesium sulfate evaporated

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

Procedure: A mixture of 20 g of 2-benzoyl-cyclohexanone, 21.6 g of ethyl pyruvate and 0.2 g of p-toluenesulfonic acid is heated at 150° for 15 hours. There is removed that fraction which distills at 1 mm (Hg up to 150°) and the residue is heated for 10 hours at 230° with 5 parts by weight of pyridine hydrochloride. After cooling the raw reaction products are poured in water and extracted with ether. The residue which is obtained after evaporation of the solvent is steam distilled. The part which does not distil is extracted with ether, the ether solution is dried well over sodium sulfate and to the dried solution there is added diethylamine until a clearly alkaline pH is reached. There thus precipitates a mixture of diethylamine salts from which, through fractional crystallization with hexane-ethyl acetate there is obtained the diathylamine salt of m-benzoyl-hydratropic acid m.p. 102°-104°. The free acid is obtained therefrom with the usual techniques. is heated at 150° for 15 hours There is removed that fraction which distills at 1 mm (Hg up to 150°) and the residue is heated for 10 hours at 230° with 5 parts by weight of pyridine hydrochloride After cooling the raw reaction products extracted with ether The residue which is obtained after evaporation of the solvent distilled The part which does not distil is extracted with ether the ether solution is dried well over sodium sulfate and to the dried solution there is added diethylamine until a clearly alkaline pH There thus precipitates a mixture of diethylamine salts from which through fractional crystallization with hexane-ethyl acetate there