Nitrogen → (R)-4-((R)-1-((5-(1-(tert-butyl)-1H-pyrazol-3-yl)-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one

HRID 2209143Notes

Reaction equation

HRID 2209143 reaction equation
[CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[CH:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.[C:31]([N:35]1[CH:39]=[CH:38][C:37](I)=[N:36]1)([CH3:34])([CH3:33])[CH3:32].C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[C:31]([N:35]1[CH:39]=[CH:38][C:37]([C:11]2[CH:10]=[C:9]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:30])[CH2:26]3)[CH3:24])[C:8]3[N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=[N:6][C:7]=3[CH:12]=2)=[N:36]1)([CH3:34])([CH3:33])[CH3:32]

Participants

8

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 691921701-(tert-butyl)-3-iodo-1H-pyrazoleHCID 123319683(R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one

Product 1

HCID 117843433(R)-4-((R)-1-((5-(1-(tert-butyl)-1H-pyrazol-3-yl)-1-cyclopropyl-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-oneYield 60.2%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 6344DichloromethaneSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
100 °C

Procedure

To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one: (120 mg, 0.292 mmol), 1-(tert-butyl)-3-iodo-1H-pyrazole (145.9 mg, 0.584 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give yellow solids, 71.6 mg (yield 60.2%). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.59 (broad s, 2H), 7.27 (s, 1H), 6.71 (d, J=2.3 Hz, 1H), 4.78 (p, J=5.9 Hz, 1H), 3.70 (m, 1H), 3.46-3.35 (m, 1H), 3.21 (m, 1H), 2.88-2.72 (m, 1H), 2.41-2.25 (m, 2H), 1.57 (s, 9H), 1.32 (d, J=5.9 Hz, 3H), 1.14-1.06 (m, 2H), 1.06-0.95 (m, 2H) ppm; MS (ESI+) m/z 408 (M+H).

Workup

  1. customTo a microwave tube equipped with a stirring bar
  2. additionwas added
  3. customThe tube was sealed
  4. washthe resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1)
  5. dry with materialdried over anhydrous Na2SO4
  6. filtrationfiltered
  7. customremoved solvents in vacuo
  8. customto give yellow solids, 71.6 mg (yield 60.2%)

Sources & evidence

ORD record
ord-ad09d54b09544e679e52b47048fa4a45
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

Loading…