1-FLUORO-2-[(TRIFLUOROMETHYL)SULFONYL]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:

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: EXAMPLE 13 (80 g) was charged to a reactor fitted with overhead stirrer, nitrogen inlet, condenser, scrubber, temperature probe and heating bath. Chlorosulfonic acid (307 g) was added slowly through an additional funnel. The mixture was then heated up to 120° C. and held for 22 hours at 120° C. The mixture was cooled down to room temperature. Thionyl chloride (118 g) was added to the reaction mixture in one portion at ambient temperature. The mixture was stirred at 25° C. for 24 hours. A sample was pulled and HPLC showed the reaction was completed with 1.1% of the sulfonic acid left. Isopropyl acetate (775 g) was cooled down to −50° C. Water (600 g) was charged to isopropyl acetate solution. The reaction mixture was transferred slowly to the isopropyl acetate/ice mixture through an additional funnel. The internal temperature increased to 0.8° C. during the addition. The cold reaction mixture was warmed up 15° C. and layers were separated. The organic layer was used in the next step (EXAMPLE 15) without isolation. fitted with overhead stirrer, nitrogen inlet, condenser scrubber, temperature probe and heating bath The mixture was cooled down to room temperature left The internal temperature increased to 0.8° C. during the addition The cold reaction mixture was warmed up 15° C. layers were separated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Mesityl-2-fluorophenyl iodonium triflate (Sanford M et al. JACS, 2005, 127, 7330 and Widdowson, D. et al. Tetrahedron Letters 2000, 41, 5393.) (0.1 g, 0.204 mmol), sodium trifluoromethanesulfinate (0.035 g, 0.224 mmol) and copper(I) oxide (2.92 mg, 0.020 mmol) were weighed into a reactor equipped with a magnetic stir bar. N,N-dimethylformamide (1 mL) was added, the reactor was capped and heated at 25° C. for 24 hours. HPLC analysis of the crude reaction mixture indicated the formation of the title compound. equipped with a magnetic stir bar the reactor was capped HPLC analysis of the crude reaction mixture

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

Procedure: The solution of EXAMPLE 12 (44.3 g) in a solution of 450 ml was added to a round bottomed flask fitted with overhead stirrer, nitrogen inlet, cold-water bath and temperature probe. It was cooled down to 12° C. (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF (6.1 g), was added in one portion. Ruppert's reagent (370 g, CH3SiCF3) was charged slowly to the reaction mixture while maintaining the internal temperature less than 23° C. The reaction was completed after addition. Water (220 g) was added to quench the reaction, the layers were separated, and the organic layer was washed twice with 220 g of water. The organic solution was distilled under vacuum with the bath temperature at 50° C. Heptanes (500 g) were added to the residue, and the mixture was distilled down until the solvent was removed. 1H NMR (400 MHz, CDCl3) δ 8.01-8.05 (m, 1H), 7.84-7.87 (m, 1H), 7.44-7.48 (m, 1H), 7.36-7.39 (m 1H). fitted with overhead stirrer, nitrogen inlet was added in one portion while maintaining the internal temperature less than 23° C after addition to quench the reaction the layers were separated the organic layer was washed twice with 220 g of water The organic solution was distilled under vacuum with the bath temperature at 50° C Heptanes (500 g) were added to the residue the mixture was distilled down until the solvent was removed

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

Procedure: Scheme 2 shows two routes used to make 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). One route involves reacting commercially available 2-fluorobenzenesulfonyl chloride (11) with TBAF (tetra-n-butylammonium fluoride) to provide 2-fluorobenzenesulfonyl fluoride (12). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 2-Fluorobenzenesulfonyl fluoride (12) can be converted to 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) by reaction with Ruppert's reagent (CH3SiCF3) catalyzed by (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF. The reaction is typically performed at about room temperature in a solvent such as but not limited to tetrahydrofuran, dichloromethane, toluene, dimethoxyethane, or mixtures thereof. 1-Fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) can be reacted with chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14). The reaction is typically performed at an elevated temperature before cooling for the addition of SO2Cl2, used to quench the chlorosulfonic acid. 4-Fluoro-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (15) can be prepared from 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14) by reacting the latter with aqueous ammonium hydroxide. The reaction is typically performed in a solvent such as acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl alcohol, isopropyl acetate, dimethoxyethane, dichloromethane, toluene, or mixtures thereof. (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine (16), prepared as described in U.S. Pat. No. 7,390,799 B2, can be reacted with 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (15) in the presence of a base such as but not limited to triethylamine, to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). The reaction is typically performed at elevated temperatures in a solvent such as but not limited to ethyl acetate. is typically performed below room temperature in a solvent is typically performed at about room temperature in a solvent