3-(bromomethyl)benzenesulfonyl chloride

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

Procedure: N-Bromosuccinimide (6.27 g, 0.035 mole), m-toluenesulfonyl chloride (6.72 g, 0.035 mole), and benzoyl peroxide (0.67 g, 0.0019 mole) were combined in CCl4 (40 mL) and heated at reflux 2 h. The reaction mixture was filtered and washed with CCl4. The filtrate was concentrated to give m-bromomethylbenzenesulfonyl chloride, 9.74 g, as a viscous yellow oil. heated at reflux 2 h The reaction mixture was filtered washed with CCl4 The filtrate was concentrated

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

Procedure: To a mixture of (S)-proline methyl ester hydrochloride salt (1.6 g, 9.65 mmol) in THF (20 mL) was added Et3N (1.34 mL, 9.65 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min and cooled back down to 0° C. 3-Bromomethyl-benzenesulfonyl chloride (2.6 g, 9.65 mmol) and Et3N (1.34 mL, 9.65 mmol) were then added to the slurry. The resulting mixture was stirred at room temperature for 3 h and then diluted with EtOAc (100 mL). The organic phase was washed with water (2×50 mL), brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by chromatography via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to give 550 mg of (S)-methyl 1-((3-(bromomethyl)-phenyl)sulfonyl)pyrrolidine-2-carboxylate that was used in the next step without further purification. This residue was taken up in acetone (20 mL) and transferred to a microwave vial. (S)-tert-butyl ((3-hydroxyphenyl)(phenyl)methyl)carbamate (I8, 251 mg, 1.82 mmol) and K2CO3 (546 mg, 1.82 mmol) were added, and the mixture was heated to 130° C. under microwaves irradiation for 1 h. The mixture was stirred at room temperature for 18 h and partitioned between EtOAc (50 mL) and water (20 mL). The layers were separated and the aqueous phase extracted with EtOAc (3×30 mL). The combined organic phases were washed with brine (30 mL) and dried over MgSO4. The mixture was filtered and the solvent was removed in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% EtOAc in isohexane, to give the title compound (636 mg, 60%). cooled back down to 0° C The resulting mixture was stirred at room temperature for 3 h The organic phase was washed with water (2×50 mL), brine (20 mL) dried over MgSO4 The solvent was removed in vacuo the crude product was purified by chromatography via silica gel chromatography eluting with 0-20% EtOAc in isohexane

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

Procedure: Add N-bromosuccinimide (9.34 g, 52.5 mmol) and AIBN (5 mg, 0.32 mmol) to a solution of 3-methyl-benzenesulfonyl chloride (10.0 g, 52.5 mmol) in carbon tetrachloride (52 mL), and heat the solution at reflux for 12 hours. Filter the mixture to remove solids and condense under reduced pressure to afford a thick oil. Purify by flash chromatography to yield the title compound as an off-white crystalline solid (5.24 g, 19.4 mmol): 1H NMR (CDCl3) δ 4.54 (s, 2H), 7.62 (m, 1H), 7.78 (m, 1H), 7.98 (m, 1H), 8.06 (m, 1H). heat the solution at reflux for 12 hours Filter the mixture to remove solids and condense under reduced pressure to afford a thick oil Purify by flash chromatography

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

Procedure: Add N-bromosuccinimide (9.34 g, 52.5 mmol) and AIBN (5 mg, 0.32 mmol) to a solution of 3-methyl-benzenesulfonyl chloride (10.0 g, 52.5 mmol) in carbon tetrachloride (52 mL), and heat the solution at reflux for 12 hours. Filter the mixture to remove solids and condense under reduced pressure to afford a thick oil. Purify by flash chromatography to yield the title compound as an off-white crystalline solid (5.24 g, 19.4 mmol): 1H NMR (CDCl3) δ 4.54 (s, 2H), 7.62 (m, 1H), 7.78 (m, 1H), 7.98 (m, 1H), 8.06 (m, 1H). heat the solution at reflux for 12 hours Filter the mixture to remove solids and condense under reduced pressure to afford a thick oil Purify by flash chromatography

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

Procedure: A solution of 4-[3-(bromomethyl)benzenesulfonyl]-1-(4-cyanobenzyl)-2-piperazinone (1.21 g) obtained from 1-(4-cyanobenzyl)-2-piperazinone hydrochloride and 3-(bromomethyl)benzenesulfonyl chloride according to a method described in Reference Example 6 and imidazole (613 mg) in DMF (20 ml) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol containing 10% ammonia solution=85:15) to give pale yellow amorphous of 1-(4-cyanobenzyl)-4-[3-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-2-piperazinone (734 mg).

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

Procedure: A solution of 4-[3-(bromomethyl)benzenesulfonyl]-1-(4-cyanobenzyl)-2-piperazinone (1.21 g) obtained from 1-(4-cyanobenzyl)-2-piperazinone hydrochloride and 3-(bromomethyl)benzenesulfonyl chloride according to a method described in Reference Example 6 and imidazole (613 mg) in DMF (20 ml) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate: methanol containing 10% ammonia solution=85: 15) to give pale yellow amorphous of 1-(4-cyanobenzyl)-4-[3-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-2-piperazinone (734 mg).

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

Procedure: N-Bromosuccinimide (6.27 g, 0.035 mole), m-toluenesulfonyl chloride (6.72 g, 0.035 mole), and benzoyl peroxide (0.67 g, 0.0019 mole) were combined in CCl4 (40 mL) and heated at reflux 2 h. The reaction mixture was filtered and washed with CCl4. The filtrate was concentrated to give m-bromomethylbenzenesulfonyl chloride, 9.74 g, as a viscous yellow oil. heated at reflux 2 h The reaction mixture was filtered washed with CCl4 The filtrate was concentrated