6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide → 6-Chloro-2-hydroxy-N-methoxy-N-methyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzene sulfonamide

HRID 1024555Notes

Reaction equation

HRID 1024555 reaction equation
[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:10])=[O:9])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2OCC)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:37][C@H:38]1[O:42][C@@H:41]([C@H:43]([NH2:46])[CH2:44][CH3:45])[CH2:40][CH2:39]1>CC#N.CCO>[Cl:1][C:2]1[C:7]([S:8]([N:11]([O:13][CH3:14])[CH3:12])(=[O:9])=[O:10])=[C:6]([OH:15])[C:5]([NH:16][C:17]2[C:20](=[O:21])[C:19](=[O:22])[C:18]=2[NH:46][C@@H:43]([C@H:41]2[CH2:40][CH2:39][C@@H:38]([CH3:37])[O:42]2)[CH2:44][CH3:45])=[CH:4][CH:3]=1

Participants

5

Reactant 2

HCID 568442936-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide2×HCID 86638630(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamine para-toluenesulfonate salt3×

Product 1

HCID 446290606-Chloro-2-hydroxy-N-methoxy-N-methyl-3-{2-[(R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamino]-3,4-dioxo-cyclobut-1-enylamino}-benzene sulfonamide

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

To a stirred suspension of 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N-methoxy-N-methyl-benzenesulfonamide (Intermediate A) (7 g, 17.91 mmol) in MeCN (2 ml) and EtOH (1 ml) under N2 at RT was added ((R)-1-((2R,5R)-5-methyl-tetrahydro-furan-2-yl)-propylamine para-toluenesulfonate salt (Intermediate E) (5.67 g, 17.91 mmol) and TEA (0.999 ml, 7.16 mmol) and the reaction mixture was heated at 50° C. for 16 hours. Further TEA was added (2.48 ml, 17.91 mmol) and the reaction was heated at 50° C. for 1 hour then 60° C. for 20 hours. Further TEA (2.48 ml, 17.91 mmol) and Intermediate E (1.13 g, 3.58 mmol) was added and the reaction was heated at 60° C. for 17.5 hours. The reaction mixture was concentrated in vacuo and partitioned between EtOAc and 1M HCl (aq). The aqueous layer was adjusted to pH 5 using 2M NaOH (aq) and extracted using EtOAc. The EtOAc layers were combined and washed with saturated sodium bicarbonate (aq), water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The resulting residue was recrystallised from toluene to give a light brown solid; [M+H]+ 488.2. 1H NMR (DMSO) 0.9 (3H, t, CH3), 1.2 (3H, d, CH3), 1.3 (1H, m) 1.6 (3H, m) 1.9 (2H, m) 3.6 (3H, s, CH3), 3.6 (3H, s, CH3), 3.9 (2H, m) 4.0 (1H, m), 7.2 (1H, d), 8.1 (1H, d), 8.2 (1H, d), 9.5 (1H, s), 10.1 (1H, s).

Workup

  1. additionFurther TEA was added (2.48 ml, 17.91 mmol)
  2. temperaturethe reaction was heated at 50° C. for 1 hour
  3. temperaturethe reaction was heated at 60° C. for 17.5 hours
  4. concentrationThe reaction mixture was concentrated in vacuo
  5. custompartitioned between EtOAc and 1M HCl (aq)
  6. extractionextracted
  7. washwashed with saturated sodium bicarbonate (aq), water and brine
  8. dry with materialThe organic layer was dried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customThe resulting residue was recrystallised from toluene
  11. customto give a light brown solid

Sources & evidence

ORD record
ord-aef6fee178574f3c94ab4f1c74bb37dc
Source dataset
uspto-grants-2014_05
Patent number
US08722925B2

Reaction notes

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