2,2,3,3-Tetramethylcyclopropanemethanol → 5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamide

HRID 1427910Notes

Reaction equation

HRID 1427910 reaction equation
[CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].CC(C)([O-])C.[K+].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23]>CS(C)=O>[Cl:16][C:17]1[C:18]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([CH3:9])[CH3:1])=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[O:23]

Participants

5

Reactant 3

HCID 5441792,2,3,3-TetramethylcyclopropanemethanolHCID 23665647Potassium tert-butoxideHCID 580424175-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide

Product 1

HCID 867028415-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamideYield 10%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (48 mg, 0.37 mmol) in dry DMSO (5 mL) was added potassium t-butoxide (124 mg, 1.11 mmol) at room temperature. After stirring for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (50 mg, 0.20 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs. The mixture was cooled to 0° C., quenched by hydrochloride acid (1N, 30 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (40 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid) to afford the title compound as a white solid (7 mg, 10%). LCMS (ESI) Method A: RT=5.28 min, m/z: 268.1 [M−109]+; 1H-NMR (500 MHz, DMSO-d6): δ 8.13 (br s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.21-7.10 (m, 1H), 4.18 (d, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.10 (s, 6H), 1.03 (s, 6H), 0.74 (t, J=7.5 Hz, 1H).

Workup

  1. stirringthe reaction mixture was stirred at room temperature for 16 hrs
  2. customquenched by hydrochloride acid (1N, 30 mL)
  3. extractionextracted with ethyl acetate (50 mL)
  4. washThe organic layer was washed with water (40 mL×2)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by prep HPLC (20%-50% MeCN in 0.1% formic acid)

Sources & evidence

ORD record
ord-725014a0d3f449ff8da9b17f6954e305
Source dataset
uspto-grants-2015_01
Patent number
US08933236B2

Reaction notes

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