4-Methoxybenzenesulfonyl chloride → N-[(1S)-1-(2',4-difluoro-1,1'-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide

HRID 2181818Notes

Reaction equation

HRID 2181818 reaction equation
COC1C=CC=CC=1[C@H]1C(C)(C)COP(=O)([O-])O1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@H:33]([NH3+:35])[CH3:34].C(N(CC)CC)C.[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>C(#N)C.COC1C=CC(S(Cl)(=O)=O)=CC=1>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[C@@H:33]([NH:35][S:51]([C:48]1[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:50][CH:49]=1)(=[O:53])=[O:52])[CH3:34]

Participants

6

Reactant 3

HCID 74014-Methoxybenzenesulfonyl chlorideHCID 8471TriethylamineHCID 86594105(1S)-1-(2',4-difluoro-1,1'-biphenyl-2-yl)ethanaminium (4R)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-olate 2-oxide

Product 1

HCID 69354769N-[(1S)-1-(2',4-difluoro-1,1'-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamideYield 89.2%

Reagents, catalysts & solvents 2

HCID 74014-Methoxybenzenesulfonyl chlorideCatalystHCID 6342AcetonitrileSolvent

Procedure

A stirred suspension of (1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethanaminium (4R)-4-(2-methoxyphenyl)-5,5-dimethyl-1,3,2-dioxaphosphinan-2-olate 2-oxide (2.53 g, 5.0 mmol) in acetonitrile (50 mL) was treated sequentially with triethylamine (1.39 mL, 10 mmol) and 4-methoxybenzenesulfonyl chloride (1.04 g, 5.05 mmol). The progress of the reaction was monitored by LCMS. After eight hours, approximately 5% of the starting amine was still present. An additional aliquot of 4-methoxybenzenesulfonyl chloride (52 mg, 0.25 mmol, 5 mole %) was added, and the reaction was stirred at ambient temperature for an additional 16 hours. Monitoring by LCMS indicated complete formation of a single product. The solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with a 5% aqueous sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with a 2 N hydrochloric acid solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a residue. The residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butylether in hexane, to afford N-[(1S)-1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethyl]-4-methoxybenzenesulfonamide (1.8 g, 89%, 99.2% ee), m.p. 133-135° C.;

Workup

  1. customThe solvent was removed in vacuo
  2. dissolutionThe residue was dissolved in dichloromethane
  3. washwashed with a 5% aqueous sodium bicarbonate solution
  4. extractionThe aqueous phase was extracted with dichloromethane
  5. washThe combined organic phase was washed with a 2 N hydrochloric acid solution
  6. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo to a residue
  9. customThe residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g)
  10. washeluting with a gradient of 30%-50% methyl tert-butylether in hexane

Sources & evidence

ORD record
ord-ffd3393458e447a6bf4bb06d24583558
Source dataset
uspto-grants-2005_05
Patent number
US06894061B2

Reaction notes

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