Acetic Acid → Way-196025

HRID 1180795Notes

Reaction equation

HRID 1180795 reaction equation
[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[CH:16]=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:29])=[O:28])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:41][C:42](=[O:53])[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH:51]=O)=[CH:45][CH:44]=1)C.C([SiH](CC)CC)C.B(F)(F)F.CCOCC.FC(F)(F)C(O)=O.[OH-].[Na+].C(O)(=O)C>ClCCl.O.C1(C)C=CC=CC=1.C1COCC1>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:51][CH2:50][CH2:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([OH:53])=[O:41])=[CH:44][CH:45]=2)=[C:15]1[CH2:24][CH2:25][NH:26][S:27]([CH2:30][C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:29])=[O:28])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1

Participants

12

Reactant 7

HCID 176Acetic AcidHCID 6422Trifluoroacetic acidHCID 8000Boron trifluoride etherateHCID 12052TriethylsilaneHCID 14798Sodium HydroxideHCID 2757377Ethyl 4-(3-oxopropyl)benzoateHCID 11455537N-[2-(1-benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethylphenyl)-methanesulfonamide

Product 1

HCID 10290302Way-196025Yield 81.4%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-20 °C

Procedure

N-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-C-(2,6-dimethyl-phenyl)-methanesulfonamide (300 g, 552 mmol), 4-(3-Oxo-propyl)-benzoic acid ethyl ester (250 g, 1.21 mol), triethylsilane (192 g, 1.66 mol), and dichloromethane (2.9 L) were combined, stirred, and cooled to −20° C. A solution of boron trifluoride etherate (55.0 g, 322 mmol) in dichloromethane (10 mL) was added to the reaction mixture over 9 min. After 35 min, trifluoroacetic acid (63 g, 553 mmol) was added to the reaction mixture. After 40 min, the reaction mixture was filtered cold through a celite pad into aqueous sodium bicarbonate (138 g/1.5 L). The organic layer was concentrated to 1.2 L g, then ethanol (1.5 L) was added. The solution was concentrated to 1.2 L. THF (450 mL) and a solution of aqueous sodium hydroxide (221 g, 2.76 mol) were added. The reaction mixture was then warmed to reflux for 30 min. The mixture was cooled to 50° C. Toluene (1.5 L), water (300 mL) and acetic acid (166 g, 2.76 mol) were added. The organic and aqueous phases were separated and the organic phase was concentrated to 1.2 L. Toluene (600 mL) was added and the mixture was concentrated to 1.2 L. The mixture was cooled to room temperature and stirred for 16 h. The solid was collected by filtration, washed with cold toluene (3×300 mL), and dried to give 317 g (81%) of the title compound.

Workup

  1. waitAfter 40 min
  2. filtrationthe reaction mixture was filtered cold through a celite pad into aqueous sodium bicarbonate (138 g/1.5 L)
  3. concentrationThe organic layer was concentrated to 1.2 L g
  4. additionethanol (1.5 L) was added
  5. concentrationThe solution was concentrated to 1.2 L
  6. temperatureThe reaction mixture was then warmed
  7. temperatureto reflux for 30 min
  8. temperatureThe mixture was cooled to 50° C
  9. customThe organic and aqueous phases were separated
  10. concentrationthe organic phase was concentrated to 1.2 L
  11. additionToluene (600 mL) was added
  12. concentrationthe mixture was concentrated to 1.2 L
  13. temperatureThe mixture was cooled to room temperature
  14. stirringstirred for 16 h
  15. filtrationThe solid was collected by filtration
  16. washwashed with cold toluene (3×300 mL)
  17. customdried

Sources & evidence

ORD record
ord-51521ba1ae764485850764bcdae1e4e6
Source dataset
uspto-grants-2007_10
Patent number
US07282594B2

Reaction notes

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