Nitrogen → (R)-4-((R)-1-((3-cyclopropyl-6-(2-(trifluoromethyl)thiazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one

HRID 2209132Notes

Reaction equation

HRID 2209132 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])=[N: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.Br[C:32]1[S:36][C:35]([C:37]([F:40])([F:39])[F:38])=[N:34][CH:33]=1.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>[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])=[N:10][C:11]([C:32]4[S:36][C:35]([C:37]([F:40])([F:39])[F:38])=[N:34][CH:33]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1

Participants

8

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 665211905-broMo-2-(trifluoroMethyl)thiazoleHCID 131735978(R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one

Product 1

HCID 117843724(R)-4-((R)-1-((3-cyclopropyl-6-(2-(trifluoromethyl)thiazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneYield 16.1%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To a microwave tube equipped with a stifling bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (133.6 mg, 0.324 mmol), 5-bromo-2-(trifluoromethyl)thiazole (90.2 mg, 0.389 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.97 mL, 0.97 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (18.7 mg, 0.016 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 off-white solids, 22.8 mg (yield 16.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.74 (m, 1H), 8.38 (d, J=0.5 Hz, 1H), 8.09 (s, 1H), 7.57 (broad s, 1H), 5.43 (p, J=6.0 Hz, 1H), 3.71 (m, 1H), 3.41 (m, 1H), 3.26-3.18 (m, 1H), 2.82-2.87 (m, 1H), 2.35-2.31 (m, 2H), 1.42 (d, J=6.2 Hz, 3H), 1.14 (m, 2H), 1.11-0.98 (m, 2H) ppm; MS (ESI+) m/z 438 (M+H).

Workup

  1. customTo a microwave tube equipped with a stifling 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 off-white solids, 22.8 mg (yield 16.1%)

Sources & evidence

ORD record
ord-3a0b4105499f4ba686233aa859fc9114
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

Loading…