Potassium Hydroxide → Mivebresib

HRID 632744Notes

Reaction equation

HRID 632744 reaction equation
[F:1][C:2]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11](S(CC)(=O)=O)[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:22]1[C:23]2[CH:32]=[CH:31][N:30](S(C3C=CC(C)=CC=3)(=O)=O)[C:24]=2[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1.[OH-].[K+]>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.O1CCCC1.O>[F:1][C:2]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:22]1[C:23]2[CH:32]=[CH:31][NH:30][C:24]=2[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1

Participants

6

Reactant 2

HCID 14797Potassium HydroxideHCID 89657386N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide

Product 1

HCID 71600087MivebresibYield 82%

Reagents, catalysts & solvents 3

HCID 5974Hexadecyltrimethylammonium BromideCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide (5.3 g, 7.5 mmol), potassium hydroxide (8.43 g, 150 mmol), and N,N,N-trimethylhexadecan-1-aminium bromide (0.137 g, 0.375 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was heated at 90° C. for 16 hours. Tetrahydrofuran was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized to pH=7 using 10% HCl. The aqueous layer was then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate). The desired fractions were combined and concentrated. The residue was triturated with 20 mL of acetonitrile to provide N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide Form I (2.82 g, 82% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.23 (t, J=7.3 Hz, 3H), 3.11 (q, J=7.3 Hz, 2H), 3.53 (s, 3H), 6.27-6.22 (m, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.13-6.93 (m, 2H), 7.19 (dd, J=8.8, 2.7 Hz, 1H), 7.32-7.25 (m, 2H), 7.42-7.31 (m, 2H), 9.77 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 460.1 (M+H)+.

Workup

  1. customTetrahydrofuran was removed under reduced pressure
  2. customthe residue was partitioned between water and ethyl acetate
  3. extractionThe aqueous layer was then extracted with ethyl acetate
  4. washThe combined organic layers were washed with saturated aqueous sodium chloride
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by flash chromatography (silica gel, ethyl acetate)
  9. concentrationconcentrated
  10. customThe residue was triturated with 20 mL of acetonitrile

Sources & evidence

ORD record
ord-84de987904554c3a8b70d60c6823ea29
Source dataset
uspto-grants-2016_04
Patent number
US09321765B2

Reaction notes

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