Cesium fluoride → 4-[5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-benzotriazol-6-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

HRID 629302Notes

Reaction equation

HRID 629302 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[C:5]2[CH:17]=[CH:18][N:19]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:4]=2[C:3]1=[O:30].Br[C:32]1[C:33]([O:47][C:48]2[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:49]=2[F:55])=[CH:34][C:35]2[N:39]=[N:38][N:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[C:36]=2[CH:46]=1.[F-].[Cs+]>C(O)CCC.O.C(OCC)(=O)C.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.Cl[Pd]Cl>[F:55][C:49]1[CH:50]=[C:51]([F:54])[CH:52]=[CH:53][C:48]=1[O:47][C:33]1[C:32]([C:6]2[C:5]3[CH:17]=[CH:18][N:19]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)(=[O:21])=[O:22])[C:4]=3[C:3](=[O:30])[N:2]([CH3:1])[CH:7]=2)=[CH:46][C:36]2[N:37]([CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][O:41]3)[N:38]=[N:39][C:35]=2[CH:34]=1

Participants

8

Reactant 3

HCID 25953Cesium fluorideHCID 867210626-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-oneHCID 1180936576-Bromo-5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-benzotriazole

Product 1

HCID 1180936584-[5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-benzotriazol-6-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneYield 72.6%

Reagents, catalysts & solvents 4

HCID 86647055di-tert-butyl(4-dimethylaminophenylphosphine) dichloropalladium(II)CatalystHCID 2631-ButanolSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

A solution of 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.0720 g, 0.168 mmol), 6-bromo-5-(2,4-difluorophenoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-benzotriazole (0.069 g, 0.17 mmol), 4-(di-tert-butylphosphino)-N,N-dimethylaniline-dichloropalladium (2:1) (1.8 mg, 0.00252 mmol), and cesium fluoride (0.0894 g, 0.589 mmol) in 1-butanol (0.765 mL) and water (0.18 mL) was degassed with nitrogen for 5 min and stirred at 110° C. for 1 h. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and washed with brine, dried with magnesium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography (100% hexanes to 80% EtOAc/hexanes) gave the desired product (77 mg, 72%) as a yellow solid that was not entirely pure. This material was used without further purification. LCMS calculated for C32H28F2N5O5S (M+H)+: m/z=632.2. found: 632.1.

Workup

  1. customThe organic layer was separated
  2. washwashed with brine
  3. dry with materialdried with magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customto give a crude residue
  7. customPurification by flash column chromatography (100% hexanes to 80% EtOAc/hexanes)

Sources & evidence

ORD record
ord-7b10ba80e0854b2cb442d2c3767089c2
Source dataset
uspto-grants-2016_04
Patent number
US09315501B2

Reaction notes

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