1-(chloromethyl)-2-(trifluoromethyl)benzene

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:

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

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

Procedure: A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-2-(trifluoromethyl)benzene (61 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified on a silica SPE column using DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh3)4 (35 mg, 0.030 mmol) and morpholine (174 μl, 2.0 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (50 mg, 26%). The mixture was left The mixture was partitioned between EtOAc and 2M HCl (aq) The organic layer was separated washed with brine dried (MgSO4) concentrated The crude product was purified on a silica SPE column wash through the impurities a 0-5% MeOH/DCM gradient to elute the compound concentrated the residues dissolved in anhydrous DMF (3 ml) The solution was degassed the mixture left to stir at rt under nitrogen for 3 h The crude product was purified by an aminopropyl SPE wash through the impurities a 0-5% AcOH/MeOH gradient to elute the product concentrated by high vacuum

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

Procedure: A solution of 3-butyl-8-chloro-1-[4-(1H-imidazol-4-yl)butyl]-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (150 mg, 0.38 mmol) in anhydrous DMF (3 ml) was treated with 1-(chloromethyl)-2-(trifluoromethyl)benzene (61 μl, 0.42 mmol) and DIPEA (73 μl, 0.42 mmol). The mixture was left to stir at rt under nitrogen for 3 days. The mixture was partitioned between EtOAc and 2M HCl (aq). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The crude product was purified on a silica SPE column using DCM to load the material onto the column and wash through the impurities then a 0-5% MeOH/DCM gradient to elute the compound. The product fractions were combined and concentrated and the residues dissolved in anhydrous DMF (3 ml). The solution was degassed then Pd(PPh3)4 (35 mg, 0.030 mmol) and morpholine (174 μl, 2.0 mmol) were added and the mixture left to stir at rt under nitrogen for 3 h. The crude product was purified by an aminopropyl SPE using MeOH to load the compound onto the column and wash through the impurities then a 0-5% AcOH/MeOH gradient to elute the product. The product fractions were combined and concentrated by high vacuum to leave the title compound as a white solid (50 mg, 26%). The mixture was left The mixture was partitioned between EtOAc and 2M HCl (aq) The organic layer was separated washed with brine dried (MgSO4) concentrated The crude product was purified on a silica SPE column wash through the impurities a 0-5% MeOH/DCM gradient to elute the compound concentrated the residues dissolved in anhydrous DMF (3 ml) The solution was degassed the mixture left to stir at rt under nitrogen for 3 h The crude product was purified by an aminopropyl SPE wash through the impurities a 0-5% AcOH/MeOH gradient to elute the product concentrated by high vacuum

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(4-Hydroxy-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 2; 40 mg, 0.196 mmol) was dissolved in DMF (1 mL). K2CO3 (19 mg, 0.14 mmol), tetrabutylammonium iodide (7 mg, 0.02 mmol), and 1-chloromethyl-2-trifluoromethyl-benzene (36 μL, 0.25 mmol) were added. The reaction mixture was heated at 40° C. for 14 h. The reaction mixture was partitioned between H2O (5 mL) and EtOAc (5 mL). The organic layer was dried (Na2SO4), filtered, evaporated, and purified by chromatography (30% EtOAc/hexanes) to give 3-[4-(2-trifluoromethyl-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (1.3 mg, 2%) as a white solid. HRMS Calcd. for C18H14F3N2O3 (M+H)+, 363.0951. Found: 363.0950. The reaction mixture was partitioned between H2O (5 mL) and EtOAc (5 mL) The organic layer was dried (Na2SO4) filtered evaporated purified by chromatography (30% EtOAc/hexanes)

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

Procedure: 214 g (1.1 mols) of o-trifluoromethylbenzyl chloride are initially introduced into the reaction vessel and are heated to about 150° C. A hot solution, at about 100° C., of 262 g (1 mol) of triphenylphosphine in 115 ml of xylene is added thereto, whilst stirring. Stirring is continued at 150° C. for a short time, the mixture is cooled to 20° C. and the crystal sludge is filtered off and washed with cyclohexane/methylene chloride (7:3). After drying at 170° C. and under 0.1 mm Hg, 412 g (90.2% of the theoretical yield) of o-trifluoromethylbenzyltriphenyl-phosphonium chloride are obtained. Stirring is continued at 150° C. for a short time the mixture is cooled to 20° C. the crystal sludge is filtered off washed with cyclohexane/methylene chloride (7:3) After drying at 170° C. and under 0.1 mm Hg, 412 g (90.2% of the

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

Procedure: To a suspension of sodium iodide (3.85 g, 25.6 mmol, 1 equiv.) in acetonitrile at room temperature under argon is added neat 1-chloromethyl-2-trifluoromethyl-benzene (commercially available from Acros Organics USA). To the resulting milky suspension is added freshly distilled triethyl phosphite (4.26 g, 25.6 mmol, 1 equiv.) and the resulting solution is stirred overnight at room temperature. After that time further triethyl phosphite (2.13 g, 12.9 mmol, 0.5 equiv.) is added and the reaction mixture heated at reflux for 1 hour. After cooling down to room temperature all volatiles were evaporated under reduced pressure. The residue is taken-up in dichloromethane and filtered through paper and the filtrate is concentrated under reduced pressure to yield the desired material as a clear oil pure enough to be used in the following step without further purification (7.46 g, 98%). the reaction mixture heated at reflux for 1 hour After cooling down to room temperature all volatiles were evaporated under reduced pressure filtered through paper the filtrate is concentrated under reduced pressure

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

Procedure: To a suspension of sodium iodide (3.85 g, 25.6 mmol, 1 equiv.) in acetonitrile at room temperature under argon is added neat 1-chloromethyl-2-trifluoromethyl-benzene (commercially available from Acros Organics USA). To the resulting milky suspension is added freshly distilled triethyl phosphite (4.26 g, 25.6 mmol, 1 equiv.) and the resulting solution is stirred overnight at room temperature. After that time further triethyl phosphite (2.13 g, 12.9 mmol, 0.5 equiv.) is added and the reaction mixture heated at reflux for 1 hour. After cooling down to room temperature all volatiles were evaporated under reduced pressure. The residue is taken-up in dichloromethane and filtered through paper and the filtrate is concentrated under reduced pressure to yield the desired material as a clear oil pure enough to be used in the following step without further purification (7.46 g, 98%). the reaction mixture heated at reflux for 1 hour After cooling down to room temperature all volatiles were evaporated under reduced pressure filtered through paper the filtrate is concentrated under reduced pressure