1-(2-phenylmethoxyphenyl)ethanone

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: A mixture of the starting compound 1A (3.000 g, 13.258 mmol), N-tert-butoxycarbonyl-phenylalaninal (3.305 g, 13.258 mmol), tert-butyl cyanoacetate (1.872 g, 13.258 mmol), ammonium acetate (3.066 g, 39.774 mmol) and 1,2-dimethoxyethane (5.0 mL) was heated at reflux for 6 hrs. After cooled to room temperature, the mixture was extracted with ethyl acetate and saturated NaHCO3 solution. The separated organic phase was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-{1-[(tert-butoxycarbonyl)amino]-2-phenylethyl}-1,4-dihydro-3-pyridinecarboxylate as a yellow solid (1.281 g, yield; 16%). was heated at reflux for 6 hrs the mixture was extracted with ethyl acetate and saturated NaHCO3 solution The separated organic phase was washed with water and brine successively dried over Na2SO4 filtered concentrated under reduced pressure The residue was triturated with diisopropyl ether

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

Procedure: A mixture of the starting compound 1A (3.500 g, 15.47 mmol), starting compound 2B (3.299 g, 15.47 mmol), tert-butyl cyanoacetate (2.184 g, 15.47 mmol), ammonium acetate (3.577 g, 46.40 mmol) and 1,2-dimethoxyethane (17 mL) was heated at reflux for 3.5 hrs. After cooled to room temperature, the mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane: ethyl acetate, 4:1) to give tert-butyl 2-amino-6-[2-(benzyloxy)phenyl]-4-[1-(tert-butoxycarbonyl)-3-piperidinyl]nicotinate. (1.892 g, yield; 22%). was heated at reflux for 3.5 hrs the mixture was concentrated under reduced pressure the residue was partitioned between ethyl acetate and water The separated organic phase was washed with brine dried over Na2SO4 filtered concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (hexane: ethyl acetate, 4:1)

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2′-benzyloxyacetophenone (starting compound 1A) (10.00 g, 44.19 mmol), tert-butyl 3-formyl-1-piperidine carboxylate (starting compound 2B) (10.37 g, 44.61 mmol), malononitrile (3.21 g, 48.61 mmol), and ammonium acetate (17.03 g, 220.97 mmol) in toluene (50 mL) was stirred at 150° C. for 2 hrs. After cooled to room temperature, the reaction mixture was diluted with ethyl acetate. The organic phase was washed with water and saturated brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1). The purified compound (yellow oil) was recrystallized from ethanol to give tert-butyl 3- {2-amino-6-[2-(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate as a white solid. (5.83 g, yield; 27%). After cooled to room temperature The organic phase was washed with water and saturated brine dried over Na2SO4 filtered concentrated The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) The purified compound (yellow oil) was recrystallized from ethanol

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

Procedure: To a cold (0° C.) solution of 3-benzyloxypicolinonitrile (2.50 g, 11.9 mmmol) in tetrahydrofuran (100 mL) was added dropwise 0.92M methyl magnesium bromide in tetrahydrofuran (150 mL, 138 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for 4 hrs. The reaction mixture was poured into water (2000 mL) and acidified with 10% sulfuric acid (500 mL). After being stirred for 30 min, the reaction mixture was poured into saturate aqueous NaHCO3 solution slowly and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtrated, and evaporated. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/3) to give 1-(2-benzyloxy-phenyl)-ethanone as a colorless oil (2.49 g, yield; 92%). at room temperature for 4 hrs After being stirred for 30 min the reaction mixture was poured into saturate aqueous NaHCO3 solution slowly extracted with ethyl acetate The organic phase was washed with brine dried over Na2SO4 filtrated evaporated The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane=1/3)

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

Procedure: A mixture of 2′-hydroxyacetophenone (68.1 g, 0.500 mol), benzylbromide (94.1 g, 0.550 mol) and K2CO3 (103 g, 0.750 mol) in acetone (1.0 L) was heated at reflux, and the stirring was continued overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure to give 1-[2-(benzyloxy)phenyl]ethanone as a colorless oil. (100 g, yield; 88%) was heated at reflux the mixture was concentrated under reduced pressure The residue was diluted with water extracted with ethyl acetate The separated organic phase was washed with brine dried over MgSO4 filtered concentrated under reduced pressure The crude product was purified by distillation under reduced pressure

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

Procedure: DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid (61 mg, 0.294 mmol)) (prepared by the method used for the synthesis of Intermediate 25, starting from 2′-benzyloxyacetophenone) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (99 mg, 0.294 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with ethylacetate to afford 54 mg (37.7% Yield) of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 490, 94.4%. 1H NMR (300 MHz, DMSO-d6): δ9.9 (s, 1H), 8.65 (t, 1H), 7.5 (t, 1H), 7.3 (m, 7H), 6.95 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (s, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H). prepared by the method was added to the reaction mixture extracted with ethyl acetate dried over sodium sulfate concentrated under reduced pressure The residue was purified by washing with ethylacetate

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

Procedure: DIPEA (133 mg, 1.03 mmol) was added to a stirred solution of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid (61 mg, 0.294 mmol)) (prepared by the method used for the synthesis of Intermediate 25, starting from 2′-benzyloxyacetophenone) in DMF (2 mL) followed by HOBt (41.7 mg, 0.308 mmol) and EDCI.HCl (59 mg, 0.308 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (99 mg, 0.294 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure The residue was purified by washing with ethylacetate to afford 54 mg (37.7% Yield) of 5-(3-hydroxy-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 490, 94.4%. 1H NMR (300 MHz, DMSO-d6): δ9.9 (s, 1H), 8.65 (t, 1H), 7.5 (t, 1H), 7.3 (m, 7H), 6.95 (m, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (s, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H). prepared by the method was added to the reaction mixture extracted with ethyl acetate dried over sodium sulfate concentrated under reduced pressure The residue was purified by washing with ethylacetate

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

Procedure: To a solution of 1-(2-hydroxy-phenyl)-ethanone (5 g, 0.03672 mole) in DMF (75 mL) was added NaH (60% w/w dispersion in oil) (1.66 g, 0.0416 mole) and the resulting mixture was stirred at ambient temperature for 15 minutes. Benzyl bromide (7.23 g, 0.0422 mole) was then added and the mixture as stirred for an additional 4 hours. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 8.4 g (100%) of 1-(2-benzyloxy-phenyl)-ethanone. LCMS: 227.1 (M+1)+, 84.14%. To a mixture of THF (200 mL) and NaH (60% w/w dispersion in oil) (4.4 g, 0.11 mole) cooled to 0° C. was added diethyl oxalate (10.73 g, 0.07345 mole). The resulting mixture was heated to reflux for 15 minutes. After cooing to ambient temperature, 1-(2-benzyloxy-phenyl)-ethanone (8.3 g, 0.0376 mole) was added dropwise over a period of 45 minutes. The resulting mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched with cold aqueous NH4Cl solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (4% ethyl acetate in hexane) to afford 8.7 g (71%) of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester. LCMS: 327.12 (M+1)+, 78.6%. A solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole), acetic acid (20 mL) and hydrazine hydrate (0.632 g, 0.01264 mole) was heated to reflux for 3 hours. The reaction mixture was then poured into iced water basified with saturated aqueous NaHCO3 solution and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.703 g (100%) of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester. LCMS: 323.13 (M+1)+, 97.14%. The resulting mixture was heated to reflux for 15 minutes After cooing to ambient temperature The resulting mixture was heated to 55° C. for 30 minutes The reaction mixture was then quenched with cold aqueous NH4Cl solution the product was extracted with ethyl acetate The ethyl acetate layer was washed with water, brine solution dried over sodium sulfate concentrated under reduced pressure The resulting residue was purified by column chromatography