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

HRID 2209126Notes

Reaction equation

HRID 2209126 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.Br[C:32]1[S:33][CH:34]=[C:35](Cl)[N:36]=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])=[CH:10][C:11]([C:32]4[S:33][CH:34]=[CH:35][N:36]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 947NitrogenHCID 10340Sodium CarbonateHCID 151419642-Bromo-4-chloro-1,3-thiazoleHCID 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 117843126(R)-4-((R)-1-((1-cyclopropyl-5-(thiazol-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-oneYield 6.1%

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-((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: (300 mg, 0.729 mmol), 2-bromo-4-chlorothiazole (144.8 mg, 0.729 mmol), 1,2-dimethoxyethane (3 mL), 1 N Na2CO3 aqueous solution (2.41 mL, 2.41 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (84.3 mg, 0.073 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2.5 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, 16.4 mg (yield 6.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.73 (d, J=3.3 Hz, 1H), 7.62-7.57 (m, 2H), 7.45-7.42 (m, 1H), 4.82 (p, J=5.9 Hz, 1H), 3.72 (m, 1H), 3.45-3.36 (m, 1H), 3.27-3.15 (m, 1H), 2.90-2.74 (m, 1H), 2.37-2.20 (m, 2H), 1.34 (d, J=6.0 Hz, 3H), 1.16-1.09 (m, 2H), 1.09-0.98 (m, 2H) ppm; MS (ESI+) m/z 369 (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 yellow solids, 16.4 mg (yield 6.1%)

Sources & evidence

ORD record
ord-88da36c1453e4666b212bd28f7a7f3e6
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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