Sodium Carbonate → 1-(((5S,7S)-7-methyl-3-((4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

HRID 715544Notes

Reaction equation

HRID 715544 reaction equation
Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH2:13][C@@:12]3([CH2:18][CH2:17][CH2:16][C@@:15]([CH2:20][N:21]4[C:25]5[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=5[N:23]=[CH:22]4)([CH3:19])[CH2:14]3)[O:11][C:10]2=[O:32])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:39][N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1>O1CCOCC1.O.C([O-])(O)=O.[Na+]>[CH3:19][C@:15]1([CH2:20][N:21]2[C:25]3[CH:26]=[C:27]([C:30]#[N:31])[CH:28]=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH2:16][CH2:17][CH2:18][C@:12]2([O:11][C:10](=[O:32])[N:9]([CH2:8][C:4]3[CH:3]=[C:2]([C:43]4[CH:42]=[N:41][N:40]([CH3:39])[CH:44]=4)[CH:7]=[CH:6][N:5]=3)[CH2:13]2)[CH2:14]1

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 712276681-(((5S,7S)-3-((4-bromopyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

Product 1

HCID 712269681-(((5S,7S)-7-methyl-3-((4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrileYield 98.9%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 312751,4-DioxaneSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a microwave vial was added 1-(((5S,7S)-3-((4-bromopyridin-2-yl)methyl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (100 mg, 0.202 mmol), sodium carbonate (64.3 mg, 0.607 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (63.1 mg, 0.303 mmol), and PdCl2(dpV) (14.80 mg, 0.020 mmol) in 1,4-Dioxane (3.0 mL) and Water (1.000 mL). The mixture was subjected to the microwave at 120° C. for 20 minutes. The mixture was diluted with saturated NaHCO3 and extracted with DCM (3×). The combined DCM extracts were passed through a phase separator and concentrated. The residue was purified via reverse HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water TFA 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-7-methyl-3-((4-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)methyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (99 mg, 94%). 1H NMR (400 MHz, DMSO-d6) δ 8.50-8.61 (m, 3H), 8.38 (s, 1H), 8.22 (s, 1H), 7.85 (d, J=8.28 Hz, 1H), 7.73-7.82 (m, 2H), 7.61 (dd, J=8.28, 1.25 Hz, 1H), 4.53 (dd, J=21.83, 16.31 Hz, 2H), 4.07-4.20 (m, 2H), 3.93 (s, 3H), 3.28 (dd, J=19.07, 8.78 Hz, 2H), 1.97 (d, J=13.30 Hz, 1H), 1.79 (d, J=14.56 Hz, 1H), 1.52-1.73 (m, 3H), 1.25-1.49 (m, 3H), 1.05 (s, 3H). MS (m/z) 496.3 (M+H+).

Workup

  1. extractionextracted with DCM (3×)
  2. concentrationconcentrated
  3. customThe residue was purified via reverse HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water TFA 20-60%, 50 mL/min, 15 min)

Sources & evidence

ORD record
ord-e54b9793e7eb45a7888485c624da2b27
Source dataset
uspto-grants-2015_11
Patent number
US09187464B2

Reaction notes

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