Cesium carbonate → 4-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one

HRID 930941Notes

Reaction equation

HRID 930941 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([O:29][CH2:30][CH:31]2[CH2:33][CH2:32]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][N:16](S(C4C=CC(C)=CC=4)(=O)=O)[C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[B-](F)(F)(F)[CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Na+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:31]1([CH2:30][O:29][C:5]2[CH:4]=[CH:3][C:2]([CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:7][C:6]=2[C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH2:33][CH2:32]1

Participants

9

Reactant 5

HCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 45588176Potassium trifluoro[(pyrrolidin-1-yl)methyl]borateHCID 89657532HCID 89657532, compound

Product 1

HCID 896562164-[2-(cyclopropylmethoxy)-5-(pyrrolidin-1-ylmethyl)phenyl]-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-oneYield 11.2%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 218864351,4-Dioxane--water (1/1)Solvent

Conditions

Temperature
140 °C

Procedure

A mixture of Example 314b (100 mg, 0.190 mmol), potassium trifluoro(pyrrolidin-1-ylmethyl)borate (36.2 mg, 0.190 mmol), palladium(II) acetate (2.55 mg, 0.011 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (10.85 mg, 0.023 mmol), and cesium carbonate (185 mg, 0.569 mmol) in 4 mL dioxane/water (9:1) was purged with nitrogen gas and then heated under microwave conditions (Biotage Initiator) at 140° C. for 40 minutes. The reaction mixture was then treated with 2 mL of 4 N NaOH and heated in a microwave oven (Biotage Initiator) at 100° C. for 30 minutes. Water was added. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (silica gel, 2-14% methanol/dichloromethane gradient) to give the title compound (8.0 mg, 11% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.93 (s, 1H), 7.29-7.17 (m, 4H), 7.00 (d, J=8.4 Hz, 1H), 6.11 (dd, J=2.6, 2.2 Hz, 1H), 3.81 (d, J=6.7 Hz, 2H), 3.56 (s, 3H), 3.53 (s, 2H), 2.43 (s, 4H), 1.68 (s, 4H), 1.13-0.98 (m, 1H), 0.48-0.36 (m, 2H), 0.26-0.16 (m, 2H). MS (ESI+) m/z 378.0 (M+H)+.

Workup

  1. temperatureheated in a microwave oven (Biotage Initiator) at 100° C. for 30 minutes
  2. extractionThe mixture was extracted with ethyl acetate
  3. washwashed with saturated aqueous sodium chloride
  4. dry with materialdried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated
  7. customthe residue was purified by flash chromatography (silica gel, 2-14% methanol/dichloromethane gradient)

Sources & evidence

ORD record
ord-f3eeb37fc9cf4a139923754e9c451f17
Source dataset
uspto-grants-2016_03
Patent number
US09296741B2

Reaction notes

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