Isopropyl Acetate → 4-[[(1R)-3-(4-Morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide

HRID 1920482Notes

Reaction equation

HRID 1920482 reaction equation
[OH-].[NH4+].C(OC(C)C)(=O)C.[N:10]1([CH2:16][CH2:17][C@@H:18]([NH2:27])[CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.F[C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=1[S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40]>C(N(CC)CC)C.C1(C)C=CC=CC=1.ClCCl.C(COC)OC.C(O)(C)C.C(OCC)(=O)C.O1CCCC1.C(#N)C>[N:10]1([CH2:16][CH2:17][C@@H:18]([NH:27][C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][C:30]=2[S:39]([C:42]([F:43])([F:45])[F:44])(=[O:41])=[O:40])[CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1

Participants

13

Reactant 4

HCID 7915Isopropyl AcetateHCID 14923Ammonium HydroxideHCID 250584524-Fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamideHCID 25058453(R)-4-Morpholino-1-(phenylthio)-2-butylamine

Product 1

HCID 250584544-[[(1R)-3-(4-Morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]benzenesulfonamide

Reagents, catalysts & solvents 8

HCID 1140TolueneSolventHCID 3776IsopropanolSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 80711,2-DimethoxyethaneSolventHCID 8471TriethylamineSolventHCID 8857Ethyl AcetateSolvent

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. customto quench the chlorosulfonic acid
  2. custom4-Fluoro-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (15) can be prepared from 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14)

Sources & evidence

ORD record
ord-cfb01356518c4b4690192ba7f749caaf
Source dataset
uspto-grants-2012_05
Patent number
US08168784B2

Reaction notes

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