1-(4-chlorophenyl)-N-methylmethanamine

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: 0.16 g (1.0 mmol) of (4-chlorobenzyl)-methylamine was dissolved in 30 ml of pyridine, and 0.3 g (1.0 mmol) of N-methyl-N-(2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-carbamoyl chloride was dropwise added, followed by stirring at room temperature for 10 hours. To the reaction solution, 50 ml of water was added, followed by extraction with diethyl ether. The obtained organic phase was washed twice with 30 ml of a dilute citric acid aqueous solution, followed by drying over anhydrous magnesium sulfate. Diethyl ether was distilled off under reduced pressure, and the obtained crude product was purified by silica gel chromatography (developing solvent/n-hexane:ethyl acetate=8:1 to 3:1) to obtain 0.22 g (yield: 52%) of 1-(4-chlorobenzyl)-1,3-dimethyl-3-[2-methyl-1-(4-trifluoromethyl-pyrimidin-5-yl)-propyl]-urea as colorless crystals (melting point: 95-98° C.). followed by extraction with diethyl ether The obtained organic phase was washed twice with 30 ml of a dilute citric acid aqueous solution by drying over anhydrous magnesium sulfate Diethyl ether was distilled off under reduced pressure the obtained crude product was purified by silica gel chromatography (developing solvent/n-hexane:ethyl acetate=8:1 to 3:1)

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: To a solution of 31.1 g (0.2 mole) N-(4-chlorobenzyl)-methylamine and 30.3 g (0.3 mole) triethylamine in 150 ml dry benzene are added in portions at room temperature while stirring 23.8 g (0.2 mole) propargyl bromide. The solution is heated for 17 hours with reflux. After filtering off the solid phase, the the solvent is distilled under vacuum and the remaining residue fractionally distilled under reduced pressure. One thus obtains 30.9 g N-(4-chlorobenzyl)-N-methyl-2-propinylamine (79% of the theory as colorless liquid of the boiling point 86°-106° C./2 Torr. The solution is heated for 17 hours with reflux After filtering off the solid phase the the solvent is distilled under vacuum the remaining residue fractionally distilled under reduced pressure

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

Procedure: To a solution of 31.1 g (0.2 mole) N-(4-chlorobenzyl)-methylamine and 30.3 g (0.3 mole) triethylamine in 150 ml dry benzene are added in portions at room temperature while stirring 23.8 g (0.2 mole) propargyl bromide. The solution is heated for 17 hours with reflux. After filtering off the solid phase, the the solvent is distilled under vacuum and the remaining residue fractionally distilled under reduced pressure. One thus obtains 30.9 g N-(4-chlorobenzyl)-N-methyl-2-propinylamine (79% of the theory as colorless liquid of the boiling point 86°-106° C./2 Torr. The solution is heated for 17 hours with reflux After filtering off the solid phase the the solvent is distilled under vacuum the remaining residue fractionally distilled under reduced pressure

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

Procedure: The compound (300 mg) obtained in Example 208 (2) and triethylamine (101 mg) were dissolved in tetrahydrofuran (30 ml), and thereto was added dropwise methanesulfonyl chloride (115 mg) under ice-cooling. The mixture was stirred at the same temperature for 1.5 hour, and thereto was further added N-methyl-4-chlorobenzylamine (1.04 g), and the mixture was further stirred for one hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (2:1)] to give the title compound (83 mg) as oil. (2)N-[3-(3-Aminopropyl)-4-{[(4-chlorobenzyl)(methyl)amino]methyl}thiazol-2(3H)-ylidene]-4-(trifluoromethoxy)aniline cooling the mixture was further stirred for one hour the mixture was extracted with ethyl acetate The organic layer was washed with a saturated brine dried over sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography [n-hexane:ethyl acetate (2:1)]

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

Procedure: N-Methyl-4-chlorobenzylamine (1.40 g., 9.0 mmol) and 1-chloro-3-methyl-4-isoquinoline acetic acid (770 mg., 3.0 mmol), prepared as in Example 8, were refluxed in 20 ml. p-dioxane for 16 hr. The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide. The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide. The combined basic phases were acidified to pH 6.5 with 6 N hydrochloric acid and extracted with 3×75 ml ethyl acetate. This organic phase was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily residue. Chromatography of this on silica gel eluted with ethyl acetate gave an oil. The title compound was prepared from this oil by treatment with hydrochloric acid gas in ether, filtrate, and drying in vacuo; 52 mg. (4%), m/e 354. were refluxed in 20 ml The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide extracted with 3×75 ml ethyl acetate This organic phase was dried over magnesium sulfate filtered vacuum evaporated to an oily residue Chromatography of this on silica gel eluted with ethyl acetate gave an oil drying in vacuo

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

Procedure: N-Methyl-4-chlorobenzylamine (1.40 g., 9.0 mmol) and 1-chloro-3-methyl-4-isoquinoline acetic acid (770 mg., 3.0 mmol), prepared as in Example 8, were refluxed in 20 ml. p-dioxane for 16 hr. The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide. The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide. The combined basic phases were acidified to pH 6.5 with 6 N hydrochloric acid and extracted with 3×75 ml ethyl acetate. This organic phase was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily residue. Chromatography of this on silica gel eluted with ethyl acetate gave an oil. The title compound was prepared from this oil by treatment with hydrochloric acid gas in ether, filtrate, and drying in vacuo; 52 mg. (4%), m/e 354. were refluxed in 20 ml The cooled reaction mixture was partitioned between 200 ml ether and 50 ml 1 N sodium hydroxide The ether rafinate was extracted with 2×30 ml 1 N sodium hydroxide extracted with 3×75 ml ethyl acetate This organic phase was dried over magnesium sulfate filtered vacuum evaporated to an oily residue Chromatography of this on silica gel eluted with ethyl acetate gave an oil drying in vacuo

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

Procedure: A mixture of 25 mg 2-(3,4-dichloro-phenyl)-4-(4-methanesulfonyl-piperazin-1-yl)-butyric acid (intermediate 1), 24.1 mg (0.075 mmol) TBTU, 11.67 mg (0.075 mmol) (4-chloro-benzyl)-methyl-amine (commercially available) and 0.06 mL N,N-diisopropyl ethylamine in 0.75 mL DMF was shaken at room temperature and subsequently subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 20.7 mg (67%) of the title compound as yellow viscous oil. MS(m/e): 534.2 (MH+). subsequently subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 The product containing fractions were evaporated