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

HRID 2209129Notes

Reaction equation

HRID 2209129 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:40][C:35]2=[CH:36][N:37]=[CH:38][CH:39]=[C:34]2[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]([CH:32]4[S:40][C:35]5=[CH:36][N:37]=[CH:38][CH:39]=[C:34]5[CH2:33]4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:2][CH2:3]1

Participants

8

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 121308452-Bromothieno[2,3-c]pyridineHCID 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 117843006(4R)-4-((1R)-1-((3-cyclopropyl-6-(2,3-dihydrothieno[2,3-c]pyridin-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneYield 22.2%

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-((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: (165.5 mg, 0.401 mmol), 2-bromothieno[2,3-c]pyridine (128.9 mg, 0.602 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (1.20 mL, 1.20 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (23.2 mg, 0.02 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 brown solids, 37.4 mg (yield 22.2%). 1H NMR (300 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.77 (dd, J=5.5, 1.1 Hz, 1H), 7.59 (s, 1H), 5.52 (p, J=6.0 Hz, 1H), 3.72 (m, 1H), 3.50-3.36 (m, 1H), 3.24 (m, 1H), 2.99-2.80 (m, 1H), 2.36 (dd, J=8.6, 1.3 Hz, 2H), 1.48 (d, J=6.1 Hz, 3H), 1.15 (m, 2H), 1.12-1.00 (m, 2H) ppm; MS (ESI+) m/z 420.14 (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 brown solids, 37.4 mg (yield 22.2%)

Sources & evidence

ORD record
ord-07936d2972374222ba0992049bbcffbd
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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