Chlorosulfonic acid → 4-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonyl chloride

HRID 1920481Notes

Reaction equation

HRID 1920481 reaction equation
FC1C=CC=CC=1S(F)(=O)=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20].C[Si](C(F)(F)F)(C)C.CN([S+](N(C)C)N(C)C)C.C[Si-](F)(F)(C)C.[Cl:50][S:51](O)(=[O:53])=[O:52]>C(COC)OC.C1(C)C=CC=CC=1.ClCCl.O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:51]([Cl:50])(=[O:53])=[O:52])=[CH:15][C:14]=1[S:19]([C:22]([F:23])([F:24])[F:25])(=[O:20])=[O:21]

Participants

10

Reactant 5

HCID 24638Chlorosulfonic acidHCID 552549(Trifluoromethyl)trimethylsilaneHCID 9795567Tris(dimethylamino)sulfonium difluorotrimethylsilicateHCID 141952602-Fluorobenzene-1-sulfonyl fluorideHCID 157316611-Fluoro-2-(trifluoromethylsulfonyl)benzene2×

Product 1

HCID 569728674-Fluoro-3-(trifluoromethylsulfonyl)benzenesulfonyl chloride

Reagents, catalysts & solvents 4

HCID 1140TolueneSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 80711,2-DimethoxyethaneSolvent

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.

Workup

  1. customis typically performed below room temperature in a solvent
  2. customis typically performed at about room temperature in a solvent

Sources & evidence

ORD record
ord-d1f1b296a65d4b2589ca072876c382ee
Source dataset
uspto-grants-2012_05
Patent number
US08168784B2

Reaction notes

Loading…