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

HRID 2209145Notes

Reaction equation

HRID 2209145 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]([CH:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[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]([CH:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[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 457888105-Bromo-2-(tetrahydropyran-4-yl)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 117844182(R)-4-((R)-1-((3-cyclopropyl-6-(2-(tetrahydro-2H-pyran-4-yl)thiazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneYield 10.1%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

To a microwave tube equipped with a stirring 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: (182.8 mg, 0.443 mmol), 5-bromo-2-(tetrahydro-2H-pyran-4-yl)thiazole (50 mg, 0.201 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.60 mL, 0.60 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (11.6 mg, 0.01 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 light yellow solids, 9.2 mg (yield 10.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.28 (s, 1H), 7.79 (s, 1H), 7.57 (broad s, 1H), 5.49-5.35 (m, 1H), 3.94 (dm, J=11.5 Hz, 2H), 3.73-3.63 (m, 1H), 3.52-3.43 (m, 2H), 3.43-3.36 (m, 1H), 3.27-3.15 (m, 2H), 2.92-2.76 (m, 1H), 2.37-2.28 (m, 2H), 2.05-1.92 (m, 2H), 1.85-1.65 (m, 2H), 1.40 (d, J=6.2 Hz, 3H), 1.17-1.09 (m, 2H), 1.10-0.98 (m, 2H) ppm; MS (ESI+) m/z 454.65 (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 light yellow solids, 9.2 mg (yield 10.1%)

Sources & evidence

ORD record
ord-21f57eb1b77941e1915017b010e5fa12
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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