2-Methoxyethanol → N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamide

HRID 930953Notes

Reaction equation

HRID 930953 reaction equation
C(P(CCCC)CCCC)CCC.[CH3:14][O:15][CH2:16][CH2:17]O.O1CCCC1.[F:24][C:25]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:30][C:29]=1[C:40]1[C:41]2[CH:50]=[CH:49][NH:48][C:42]=2[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:17][CH2:16][O:15][CH3:14])[S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:30][C:29]=1[C:40]1[C:41]2[CH:50]=[CH:49][NH:48][C:42]=2[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1

Participants

6

Reactant 4

HCID 80192-MethoxyethanolHCID 8028TetrahydrofuranHCID 13831TributylphosphineHCID 71600087Mivebresib

Product 1

HCID 71616058N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]-N-(2-methoxyethyl)ethanesulfonamideYield 4.24%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Procedure

To a 4 mL vial was added (azidocarbonyl) dipiperidine (ADDP) (25.9 mg, 0.102 mmol) in anhydrous toluene. The vial was introduced into a dry box and tributylphosphine (41.5 mg, 3 eq, 0.205 mmol) was added to the vial. This mixture was shaken until the solution turned clear. To this solution was added a solution of 2-methoxyethanol in anhydrous tetrahydrofuran (1.2 equivalents, 0.082 mmol, 6.24 mg). This mixture was stirred for 10 minutes at ambient temperature. To this mixture was added a solution of Example 36e (0.068 mmol, 31.4 mg) in anhydrous toluene/anhydrous tetrahydrofuran (1:1 v/v) (1 mL). The reaction mixture was stirred at room temperature overnight in the dry box. The reaction mixture was concentrated to dryness and the residue purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to provide the title compound (4.24%, 1.5 mg). 1H NMR (400 MHz, DMSO d6/D2O) δ ppm 7.49 (d, J=2.75 Hz, 1H), 7.38-7.43 (m, 1H), 7.37 (d, J=2.75 Hz, 1H), 7.35-7.36 (m, 1H), 7.34 (d, J=2.75 Hz, 1H), 7.22-7.27 (m, 1H), 7.05-7.11 (m, 1H), 6.87 (d, J=8.54 Hz, 1H), 6.30 (d, J=2.75 Hz, 1H), 3.78-3.81 (m, 2H), 3.57 (s, 3H), 3.37 (t, J=5.65 Hz, 2H), 3.20 (s, 3H), 3.16 (t, J=7.32 Hz, 2H), 1.26 (t, J=7.48 Hz, 3H). ESI+ m/z=518.0 (M+H)+.

Workup

  1. additionThe vial was introduced into a dry box
  2. stirringThis mixture was stirred for 10 minutes at ambient temperature
  3. stirringThe reaction mixture was stirred at room temperature overnight in the dry box
  4. concentrationThe reaction mixture was concentrated to dryness
  5. customthe residue purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water)

Sources & evidence

ORD record
ord-ed6bbfdc51244f648aba175e8c01327f
Source dataset
uspto-grants-2016_03
Patent number
US09296741B2

Reaction notes

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