Triethylamine → 4-chloro-N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide

HRID 1011529Notes

Reaction equation

HRID 1011529 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([C:28]#[N:29])=[CH:23][C:22]=2[F:30])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.N[OH:33].C([N:36]([CH2:39]C)CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([C:28]3[N:36]=[CH:39][O:33][N:29]=3)=[CH:23][C:22]=2[F:30])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 443297Hydroxyamine hydrochlorideHCID 594977814-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide

Product 1

HCID 468980974-chloro-N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamideYield 71.7%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

A mixture of 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (320 mg, 0.70 mmol) (Example 25), hydroxylamine hydrochloride (247 mg, 3.5 mmol), and triethylamine (488 uL, 3.5 mmol) was refluxed in 8 mL ethanol for 3 h. The reaction was concentrated and the residue was partitioned between ethyl acetate and sat. sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and concentrated. The crude intermediate was stirred in 5 mL triethylorthoformate with three drops of boron trifluoride etherate at room temperature overnight. The reaction was purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane to yield 4-chloro-N-(2,5-difluoro-4-(1,2,4-oxadiazol-3-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (250 mg, 71%). 1H NMR (400 MHz, CDCl3) δ ppm 8.81 (s, 1H), 7.70-7.79 (m, 3H), 7.58 (dd, J=10.20, 5.92 Hz, 1H), 7.50 (d, J=8.56 Hz, 2H), 4.54 (d, J=15.60 Hz, 1H), 4.41 (d, J=15.60 Hz, 1H), 3.64 (td, J=7.93, 3.78 Hz, 2H), 3.14 (t, J=10.58 Hz, 1H), 2.52 (br. s., 1H), 1.58-1.74 (m, 3H), 1.45-1.53 (m, 2H), 1.02-1.26 (m, 4H). Analytical HPLC R.T.=22.92 min. MS [M+H]+=498. HRMS [M+H] calc'd 498.1066, found 498.1087. Chiral LC: R.T.=9.84 min., 99% ee. Optical rotation: [α]=−36.66°, CHCl3 (c=4.29 mg/mL).

Workup

  1. concentrationThe reaction was concentrated
  2. customthe residue was partitioned between ethyl acetate and sat. sodium bicarbonate solution
  3. dry with materialThe organic layer was dried over magnesium sulfate
  4. concentrationconcentrated
  5. customThe reaction was purified by flash chromatography on silica gel with 0 to 60% ethyl acetate in hexane

Sources & evidence

ORD record
ord-7d15dfc2fcc742aa9a8a92158109d188
Source dataset
uspto-grants-2011_07
Patent number
US07977362B2

Reaction notes

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