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

HRID 2209137Notes

Reaction equation

HRID 2209137 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]([OH:40])([CH3:39])[CH3:38])=[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]([OH:40])([CH3:39])[CH3:38])=[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 227143062-(5-Bromo-1,3-thiazol-2-yl)propan-2-olHCID 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 117843094(R)-4-((R)-1-((3-cyclopropyl-6-(2-(2-hydroxypropan-2-yl)thiazol-5-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-oneYield 15.1%

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: (167.0 mg, 0.405 mmol), 2-(5-bromothiazol-2-yl)propan-2-ol (90.0 mg, 0.405 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.55 mL, 0.55 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (10.6 mg, 0.009 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, 26.1 mg (yield 15.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.60-7.53 (broad s, 1H), 5.97 (s, 1H), 5.52-5.36 (m, 1H), 3.73-3.64 (m, 1H), 3.46-3.35 (m, 1H), 3.24-3.15 (m, 1H), 2.94-2.75 (m, 1H), 2.36-2.28 (m, 2H), 1.52 (d, J=1.2 Hz, 6H), 1.41 (d, J=6.2 Hz, 3H), 1.17-1.10 (m, 2H), 1.10-0.99 (m, 2H) ppm; MS (ESI+) m/z 428.06 (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, 26.1 mg (yield 15.1%)

Sources & evidence

ORD record
ord-bbc9bfaa408245e280c06d5cf2103173
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

Loading…