2-amino-1-(4-chlorophenyl)ethanone;hydrochloride

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

Procedure: A solution of 4.54 g of 5-chloroisatin in water was reacted with 6.8 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride by the procedure described in example 33, giving 6.27 g of the desired compound as a yellow solid,mp 240°-241° C.

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

Procedure: A solution of 5.4 g of 5,7-dichloroisatin in water was reacted with 7.21 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride by the procedure described in example 33, giving 5.2 g of the desired compound as a yellow solid, mp 260°-261° C.

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

Procedure: A solution of 5.8 g of isatin in water was reacted with 12.0 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride by the procedure described in example 33, giving 8.1 g of the desired compound as a yellow solid, mp 243°-244° C.

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred suspension of 7 g of 5-fluoroisatin in 58 ml of water was added a solution of 9.36 g of sodium hydroxide in 33 ml of water. The solution was heated to 85° C. and a solution of 12 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride in a mixture of 92 ml of ethanol and 40 ml of tetrahydrofuran and 92 ml of water was added drop-wise over 2 hours. After the addition was complete, the solution was refluxed for an additional 30 minutes and then the ethanol and tetrahydrofuran were removed by distillation. The mixture was cooled to 20° C. and filtered through celite. The filtrate was acidified to pH 4 with acetic acid. The solid was filtered off, washed with water and dried, giving 12.8 g of the desired compound as a yellow solid, mp 241°-243° C. was added drop-wise over 2 hours After the addition the solution was refluxed for an additional 30 minutes the ethanol and tetrahydrofuran were removed by distillation The mixture was cooled to 20° C. filtered through celite The solid was filtered off washed with water dried

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

Procedure: In a 10 mL pear-shaped flask, 4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanoic acid (40 mg, 104 μmol) and HATU (39.7 mg, 104 μmol) were combined with DMF (1 ml) to give a colorless solution. After 5 min of stirring, 2-amino-1-(4-chlorophenyl)ethanone HCl (21.5 mg, 104 μmol) was added followed by drop-wise addition of DIEA (47.2 mg, 63.8 μl, 365 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml), washed with brine and H2O, dried over MgSO4, filtered and concentrated in vacuo to give an oil. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate in CH2Cl2) to afford 36 mg (65%) of N-(2-(4-chlorophenyl)-2-oxoethyl)-4,4,4-trifluoro-3-((3-(3-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)butanamide as an oil. MH+=535. to give a colorless solution The reaction mixture was stirred at room temperature overnight washed with brine and H2O dried over MgSO4 filtered concentrated in vacuo to give an oil The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 50% ethyl acetate in CH2Cl2)

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

Procedure: 2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS). for 18 h the cold mixture was filtered The filtrate was diluted with acetic acid (40 mL) Evaporation of the solvents in vacuo

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromo-1-(4-chlorophenyl)ethanone (1.0 eq.) and NaN(CHO)2 (1.1 eq.) in acetonitrile (1.5 mL per mmol) was heated to reflux for 4 h at 105° C. ext. temperature. The formed sodium bromide was removed by filtration and the filtrate concentrated in vacuo. The residue was dissolved in ethanol (2.5 mL per mmol) and conc. aq. hydrochloric acid (0.9 mL per mmol) added at ambient temperature. After stirring for 72 h at room temperature the solids were filtered off and washed with ethanol (1×0.5 mL per mmol). Drying of the solids afforded 2-amino-1-(4-chlorophenyl)ethanone hydrochloride in ca. 50% yield that was used in the next step without purification. was heated The formed sodium bromide was removed by filtration the filtrate concentrated in vacuo The residue was dissolved in ethanol (2.5 mL per mmol) conc. aq. hydrochloric acid (0.9 mL per mmol) added at ambient temperature were filtered off washed with ethanol (1×0.5 mL per mmol) Drying of the solids

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

Procedure: The starting 2-amino-1-(4-chlorophenyl)ethanone hydrochloride was prepared according to the following procedure. The 1-(4-chlorophenyl)ethanone (1.0 eq.) was dissolved in glacial acetic acid (1 ml, per mmol). To this was added a slurry of pyridinium bromide perbromide (1.03 eq.) in acetic acid (1 mL per mmol). The heterogeneous mixture was stirred for 4 h at ambient temperature. After about 30 min. the mixture turned homogeneous. After pouring into ice-water a yellow precipitate was filtered off and washed with water (2×1 mL per mmol of starting ketone). Drying of the precipitate afforded 2-bromo-1-(4-chlorophenyl)ethanone in ca. 90% yield. After about 30 min. the mixture turned homogeneous was filtered off washed with water (2×1 mL per mmol of starting ketone) Drying of the precipitate

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

Procedure: To a well stirred suspension of 20.6 g of 4-chlorophenacylamine hydrochloride in 70 ml of benzene and 70 ml of water which was cooled to below 7° C were added simultaneously 110 ml of 2N NaOH solution and 12.4 g of chloroacetyl chloride dissolved in 30 ml of benzene. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. At the end of this period, the formed precipitate was filtered, and the benzene layer was separated. The aqueous layer was extracted twice with 50 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The residue together with the precipitate obtained above was combined and recrystallized from ethanol to give 14.1 g (57 percent) of N-(4-chlorophenacyl) chloroacetamide. was cooled to below 7° C After the addition stirred at room temperature for 3 hours At the end of this period, the formed precipitate was filtered the benzene layer was separated The aqueous layer was extracted twice with 50 ml of benzene The combined benzene layer was dried over anhydrous sodium sulfate evaporated to dryness The residue together with the precipitate obtained recrystallized from ethanol

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

Procedure: To a well stirred suspension of 20.6 g of 4-chlorophenacylamine hydrochloride in 70 ml of benzene and 70 ml of water which was cooled to below 7° C were added simultaneously 110 ml of 2N NaOH solution and 12.4 g of chloroacetyl chloride dissolved in 30 ml of benzene. After the addition was complete, the reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. At the end of this period, the formed precipitate was filtered, and the benzene layer was separated. The aqueous layer was extracted twice with 50 ml of benzene. The combined benzene layer was dried over anhydrous sodium sulfate, and evaporated to dryness. The residue together with the precipitate obtained above was combined and recrystallized from ethanol to give 14.1 g (57 percent) of N-(4-chlorophenacyl) chloroacetamide. was cooled to below 7° C After the addition stirred at room temperature for 3 hours At the end of this period, the formed precipitate was filtered the benzene layer was separated The aqueous layer was extracted twice with 50 ml of benzene The combined benzene layer was dried over anhydrous sodium sulfate evaporated to dryness The residue together with the precipitate obtained recrystallized from ethanol

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

Procedure: 1000 mg (4.853 mmol) of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride are placed in 20 ml dichloromethane, cooled to 0° C. and treated dropwise with a solution of 363 mg (4.367 mmol) of cyclopropyl isocyanate in 2 ml dichloromethane. It is stirred a further 10 mins at 0° C. and then a solution of 627 mg (4.853 mmol) of N,N-diisopropylethylamine in 4 ml dichloromethane is added dropwise. After two hours' stirring at room temperature the reaction mixture is evaporated and the crude product purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100:1). 1000 mg (73% of theory) of the target compound are obtained. After two hours' stirring at room temperature the reaction mixture is evaporated the crude product purified by flash chromatography on silica gel (eluent: dichloromethane/methanol 100:1) 1000 mg (73% of theory) of the target compound are obtained

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

Procedure: To a stirred solution of N-carbobenzoxy-isonipecotic acid (10.49 g, 39.84 mmol) and 4-methylmorpholine (NMM) (500 mL, 45.0 mmol) in anhydrous dichloromethane (200 mL) under N2 and cooled in an -25° C. bath is added isobutyl chloroformate (5.30 mL, 40.0 mmol) dropwise. Following complete addition, the suspension is stirred for 5 min, then 2-amino-4'-chloroacetophenone hydrochloride (7.4632 g, 36.217 mmol), prepared as in Part A, is added, followed by NMM (10.10 mL, 90.94 mmol). After stirring in the -25° C. bath for 30 min, the suspension is allowed to warm to RT over 1.5 h. To the solid reaction mixture is added half-saturated aqueous sodium bisulfate, dichloromethane, and ethyl acetate. The solids are collected, washed with dichloromethane, and heated to reflux in THF (300 mL) for 30 min. The mixture is filtered and the filtrate concentrated to about 1/20th volume. Diethyl ether is added, the precipitated solids are collected, and dried in vacuo at RT to afford the product as fluffy, white solids. addition is added After stirring in the -25° C. bath for 30 min To the solid reaction mixture The solids are collected washed with dichloromethane heated to reflux in THF (300 mL) for 30 min The mixture is filtered the filtrate concentrated to about 1/20th volume Diethyl ether is added the precipitated solids are collected dried in vacuo at RT to afford the product as fluffy, white solids