N-[4-(chloromethyl)phenyl]acetamide

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

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

Procedure: To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure. Upon completion of addition After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate The organic layer was separated washed with an aqueous solution saturated with sodium chloride The organic layer was then concentrated under reduced pressure to a residue, which concentrated under reduced pressure

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

Procedure: To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure. Upon completion of addition After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate The organic layer was separated washed with an aqueous solution saturated with sodium chloride The organic layer was then concentrated under reduced pressure to a residue, which concentrated under reduced pressure

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of borane-THF complex (188 mL, 1M solution in tetrahydrofuran), diluted with 200 mL tetrahydrofuran, was cooled to -30° C. under N2 atmosphere. A solution of 4-[(4-acetamidophenyl)methyl]-5-(trifluoromethyl)-3H-pyrazol-3-one (6 g, prepared as in Example 1 (except that 4-acetamidobenzylchloride was reacted with the β-keto ester anion in refluxing xylene) in tetrahydrofuran (300 mL) was added over 0.75 hours and the mixture allowed to warm gradually to ambient temperature with stirring for 15 hours. The reaction mixture was refluxed for 3 hours, then cooled in ice and quenched with aqueous sodium hydroxide solution (24 mL, 2.5N). The mixture was stirred for 2 hours at ice temperature and 15 hours at room temperature. Volatile materials were removed in vacuo on the rotary evaporator. The residue was solubilized in distilled water, brought to pH 7 with dilute, aqueous HCl solution and extracted with ethyl acetate. The extracts were washed with saturated brine solution, dried over MgSO4, filtered and concentrated. The residue was dissolved in isopropyl alcohol saturated with anhydrous HCl and cooled in ice. The precipitate was collected on a suction funnel and dried under vacuum (abderhalden apparatus) to afford the title compound as a pale yellow glass; sinters at 104° C., liquefies 169°-171° C. was added over 0.75 hours to warm gradually to ambient temperature The reaction mixture was refluxed for 3 hours cooled in ice quenched with aqueous sodium hydroxide solution (24 mL, 2.5N) The mixture was stirred for 2 hours at ice temperature and 15 hours at room temperature Volatile materials were removed in vacuo on the rotary evaporator with dilute aqueous HCl solution and extracted with ethyl acetate The extracts were washed with saturated brine solution dried over MgSO4 filtered concentrated The residue was dissolved in isopropyl alcohol saturated with anhydrous HCl cooled in ice The precipitate was collected on a suction funnel dried under vacuum (abderhalden apparatus)

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of borane-THF complex (188 mL, 1M solution in tetrahydrofuran), diluted with 200 mL tetrahydrofuran, was cooled to -30° C. under N2 atmosphere. A solution of 4-[(4-acetamidophenyl)methyl]-5-(trifluoromethyl)-3H-pyrazol-3-one (6 g, prepared as in Example 1 (except that 4-acetamidobenzylchloride was reacted with the β-keto ester anion in refluxing xylene) in tetrahydrofuran (300 mL) was added over 0.75 hours and the mixture allowed to warm gradually to ambient temperature with stirring for 15 hours. The reaction mixture was refluxed for 3 hours, then cooled in ice and quenched with aqueous sodium hydroxide solution (24 mL, 2.5N). The mixture was stirred for 2 hours at ice temperature and 15 hours at room temperature. Volatile materials were removed in vacuo on the rotary evaporator. The residue was solubilized in distilled water, brought to pH 7 with dilute, aqueous HCl solution and extracted with ethyl acetate. The extracts were washed with saturated brine solution, dried over MgSO4, filtered and concentrated. The residue was dissolved in isopropyl alcohol saturated with anhydrous HCl and cooled in ice. The precipitate was collected on a suction funnel and dried under vacuum (abderhalden apparatus) to afford the title compound as a pale yellow glass; sinters at 104° C., liquefies 169°-171° C. was added over 0.75 hours to warm gradually to ambient temperature The reaction mixture was refluxed for 3 hours cooled in ice quenched with aqueous sodium hydroxide solution (24 mL, 2.5N) The mixture was stirred for 2 hours at ice temperature and 15 hours at room temperature Volatile materials were removed in vacuo on the rotary evaporator with dilute aqueous HCl solution and extracted with ethyl acetate The extracts were washed with saturated brine solution dried over MgSO4 filtered concentrated The residue was dissolved in isopropyl alcohol saturated with anhydrous HCl cooled in ice The precipitate was collected on a suction funnel dried under vacuum (abderhalden apparatus)

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

Procedure: Suspend sodium hydride (10.1 g, 0.21 mol) in tetrahydrofuran (300 mL), place under a nitrogen atmosphere and cool to 0° C. Add, by dropwise addition, diethyl methylmalonate (34.8 g, 0.2 mol). Stir for 30 minutes at 0° C. and add 4-acetamidobenzyl chloride (38.6 g, 0.21 mol). Heat at reflux for 5 hours, cool and pour into water (400 mL). Extract with ethyl acetate (3×600 mL), dry (MgSO4) and evaporate the solvent in vacuo to give diethyl methyl-(4-acetamido)benzylmalonate. Heat at reflux for 5 hours cool Extract with ethyl acetate (3×600 mL) dry (MgSO4) evaporate the solvent in vacuo

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

Procedure: Suspend sodium hydride (10.1 g, 0.21 mol) in tetrahydrofuran (300 mL), place under a nitrogen atmosphere and cool to 0° C. Add, by dropwise addition, diethyl methylmalonate (34.8 g, 0.2 mol). Stir for 30 minutes at 0° C. and add 4-acetamidobenzyl chloride (38.6 g, 0.21 mol). Heat at reflux for 5 hours, cool and pour into water (400 mL). Extract with ethyl acetate (3×600 mL), dry (MgSO4) and evaporate the solvent in vacuo to give diethyl methyl-(4-acetamido)benzylmalonate. Heat at reflux for 5 hours cool Extract with ethyl acetate (3×600 mL) dry (MgSO4) evaporate the solvent in vacuo

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

Procedure: To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure. Upon completion of addition After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate The organic layer was separated washed with an aqueous solution saturated with sodium chloride The organic layer was then concentrated under reduced pressure to a residue, which concentrated under reduced pressure

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

Procedure: To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure. Upon completion of addition After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate The organic layer was separated washed with an aqueous solution saturated with sodium chloride The organic layer was then concentrated under reduced pressure to a residue, which concentrated under reduced pressure

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

Procedure: To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure. Upon completion of addition After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate The organic layer was separated washed with an aqueous solution saturated with sodium chloride The organic layer was then concentrated under reduced pressure to a residue, which concentrated under reduced pressure

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

Procedure: Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and N-(4-(chloromethyl)phenyl)acetamide. MS (M−H, 467.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.0 (s, 3H), 3.69s, 3H), 4.23 (s, 4H), 6.78 (d, 2H, J=7.6 Hz), 6.98 (m, 4H), 7.41 (d, 2H, J=8 Hz), 7.94 (d, 2H, J=8 Hz), 8.09 (d, 2H, J=8 Hz), 9.90 (s, 1H).

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

Procedure: To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure. Upon completion of addition After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate The organic layer was separated washed with an aqueous solution saturated with sodium chloride The organic layer was then concentrated under reduced pressure to a residue, which concentrated under reduced pressure