3-(bromomethyl)benzoyl chloride

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 vessel containing 20 g (about 0.093 mol) of crude α-bromo-m-toluoyl chloride and 6 g (0.10 mol) of isopropyl alcohol in 50 ml of ether is added, with cooling, about 10 g (0.093 mol) of 2,6-lutidine. After about 3 hours, 4.3 g of solid 2,6-lutidine hydrochloride is filtered off. After an additional 21 hours, 100 ml of ether is added and the mixture is filtered to give an additional 5.4 g of 2,6 -lutidine hydrochloride. The filtrate is washed with 2 × 100 ml of ice water, two 100 ml portions of cold dilute hydrogen bromide, 100 ml of ice water and two 100 ml portions of ice cold sodium bicarbonate solution and the ether layer is dried over calcium sulfate and concentrated under vacuum to yield 17.6 g oil. To this oil is added 16.0 g (0.079 mol) of tributylphosphine in 100 ml of acetonitrile and is heated at reflux under N2 for about 70 minutes then concentrated under vacuum to a black oil. The oil is triturated twice with 200 ml of ether and chromatographed on 150 g acid Woelm Act. I alumina with benzene. The first liter of eluate provides 15.3 g of solid which is crystallized twice from ethylacetate containing a small portion of acetonitrile to yield 6.4 g of m-isopropoxycarbonylbenzyltributylphosphonium bromide, a white solid having a melting point of 151°-153°. is added with cooling 4.3 g of solid 2,6-lutidine hydrochloride is filtered off After an additional 21 hours 100 ml of ether is added the mixture is filtered

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

Procedure: To a vessel containing 20 g (about 0.093 mol) of crude α-bromo-m-toluoyl chloride and 6 g (0.10 mol) of isopropyl alcohol in 50 ml of ether is added, with cooling, about 10 g (0.093 mol) of 2,6-lutidine. After about 3 hours, 4.3 g of solid 2,6-lutidine hydrochloride is filtered off. After an additional 21 hours, 100 ml of ether is added and the mixture is filtered to give an additional 5.4 g of 2,6 -lutidine hydrochloride. The filtrate is washed with 2 × 100 ml of ice water, two 100 ml portions of cold dilute hydrogen bromide, 100 ml of ice water and two 100 ml portions of ice cold sodium bicarbonate solution and the ether layer is dried over calcium sulfate and concentrated under vacuum to yield 17.6 g oil. To this oil is added 16.0 g (0.079 mol) of tributylphosphine in 100 ml of acetonitrile and is heated at reflux under N2 for about 70 minutes then concentrated under vacuum to a black oil. The oil is triturated twice with 200 ml of ether and chromatographed on 150 g acid Woelm Act. I alumina with benzene. The first liter of eluate provides 15.3 g of solid which is crystallized twice from ethylacetate containing a small portion of acetonitrile to yield 6.4 g of m-isopropoxycarbonylbenzyltributylphosphonium bromide, a white solid having a melting point of 151°-153°. is added with cooling 4.3 g of solid 2,6-lutidine hydrochloride is filtered off After an additional 21 hours 100 ml of ether is added the mixture is filtered

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

Procedure: Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (60 mg, 0.47 mmol, 2.00 equiv). To this was added 3-(bromomethyl)benzoyl chloride (75 mg, 0.32 mmol, 1.39 equiv), in portions at 0° C. The resulting solution was stirred for 2.5 h at room temperature. The reaction progress was monitored by LCMS/TLC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water, extracted with 3×10 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 160 mg (88%) of product as a brown solid. Into a 50-mL round bottom flask, was placed at 0° C The resulting mixture was concentrated under vacuum The resulting solution was diluted with 10 mL of water extracted with 3×10 mL of ethyl acetate The resulting mixture was washed with 3×10 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: Into a 50-mL round bottom flask, was placed 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide 8d (100 mg, 0.23 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and N,N-diisopropylethylamine (60 mg, 0.47 mmol, 2.00 equiv). To this was added 3-(bromomethyl)benzoyl chloride (75 mg, 0.32 mmol, 1.39 equiv), in portions at 0° C. The resulting solution was stirred for 2.5 h at room temperature. The reaction progress was monitored by LCMS/TLC. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 10 mL of water, extracted with 3×10 mL of ethyl acetate, and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 160 mg (88%) of product as a brown solid. Into a 50-mL round bottom flask, was placed at 0° C The resulting mixture was concentrated under vacuum The resulting solution was diluted with 10 mL of water extracted with 3×10 mL of ethyl acetate The resulting mixture was washed with 3×10 mL of brine dried over anhydrous sodium sulfate concentrated under vacuum

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

Procedure: This compound was prepared from 3-(bromomethyl)benzoyl chloride and Intermediate 4.1c using the procedure described for the synthesis of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a.

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

Procedure: a mixture of 8 g of 3-(hexadecyloxy)-2-methoxypropanol, 6.22 g of m-bromomethylbenzoyl chloride, 2.11 g of pyridine and 80 ml of tetrahydrofuran was stirred for 48 hours, then filtered and evaporated. The residue was purified by chromatography and crystallized giving 10 g of 3-(bromomethyl)benzoic acid, 3-(hexadecyloxy)-2-methoxypropyl ester as white solid. filtered evaporated The residue was purified by chromatography crystallized

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

Procedure: a solution of 12 g of m-bromomethylbenzoic acid 10.62 g of oxalyl chloride, 100 ml of dichloromethane and 5 drops of dimethylformamide was allowed to stand 48 hours and then evaporated. Hexane and ether were added, the mixture evaporated and the residue distilled on a Kugelroher, giving 12.5 g of m-bromomethylbenzoyl chloride as a yellow liquid. evaporated Hexane and ether were added the mixture evaporated the residue distilled on a Kugelroher

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

Procedure: a mixture of 8 g of 3-(hexadecyloxy)-2-methoxypropanol, 6.22 g of m-bromomethylbenzoyl chloride, 2.11 g of pyridine and 80 ml of tetrahydrofuran was stirred for 48 hours, then filtered and evaporated. The residue was purified by chromatography and crystallized giving 10 g of 3-(bromomethyl)benzoic acid, 3-(hexadecyloxy)-2-methoxypropyl ester as white solid. filtered evaporated The residue was purified by chromatography crystallized

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

Procedure: a solution of 12 g of m-bromomethylbenzoic acid 10.62 g of oxalyl chloride, 100 ml of dichloromethane and 5 drops of dimethylformamide was allowed to stand 48 hours and then evaporated. Hexane and ether were added, the mixture evaporated and the residue distilled on a Kugelroher, giving 12.5 g of m-bromomethylbenzoyl chloride as a yellow liquid. evaporated Hexane and ether were added the mixture evaporated the residue distilled on a Kugelroher

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

Procedure: This compound was prepared from 3-(bromomethyl)benzoyl chloride and Intermediate 4.1c using the procedure described for the synthesis of 2-(2-(3-(chloromethyl)benzamido)-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide 8.1a.