Azetidine → 3-[1-(4-Azetidin-1-ylbenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylpropanoic acid

HRID 1776781Notes

Reaction equation

HRID 1776781 reaction equation
Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])=[CH:4][CH:3]=1.[NH:39]1[CH2:42][CH2:41][CH2:40]1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:39]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:37][CH:38]=2)[CH2:42][CH2:41][CH2:40]1

Participants

6

Reactant 4

HCID 10422AzetidineHCID 27342152-(Di-tert-butylphosphino)biphenylHCID 23665647Potassium tert-butoxideHCID 90415263ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate

Product 1

HCID 904167113-[1-(4-Azetidin-1-ylbenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzimidazol-2-yl]-2,2-dimethylpropanoic acidYield 48%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
95 °C

Procedure

To a 5 mL microwave vial were added a stirbar, ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (100 mg, 0.2 mmol), azetidine (20 mg, 0.4 mmol), JohnPhos (32 mg, 0.12 mmol), t-BuOK (35 mg, 0.4 mmol), and Pd2(dba)3 (60 mg, 0.07 mmol). The vial was capped and flushed with N2 before adding 3 mL of N2 sparged toluene. The resulting mixture was heated at 95° C. for 18 hours. The vial was cooled to RT and concentrated to dryness. The resulting residue was dissolved in MeOH (9 mL) and THF (9 mL). To the solution was added 5% aqueous NaOH (2 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled to RT and acidified to ˜pH=4-5 with 6 N HCl, then extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and purified by prep-HPLC to give the title compound (50 mg, 30%). MS (ESI): mass calcd. for C32H32N4O3, 520.25; m/z found, 521.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.35 (d, J=8.9, 1H), 8.05 (d, J=8.6, 1H), 7.93 (d, J=7.8, 1H), 7.82-7.69 (m, 2H), 7.60 (t, J=7.6, 1H), 7.33-7.20 (m, 3H), 7.08-6.97 (m, 2H), 6.92 (d, J=8.3, 1H), 6.38 (d, J=8.3, 1H), 5.50-5.36 (m, 4H), 3.79 (t, J=7.2, 2H), 3.35-3.32 (m, 2H), 3.14 (s, 2H), 2.40-2.25 (m, 2H), 1.28 (s, 6H).

Workup

  1. customThe vial was capped
  2. customflushed with N2
  3. additionbefore adding 3 mL of N2
  4. customsparged toluene
  5. temperatureThe vial was cooled to RT
  6. concentrationconcentrated to dryness
  7. dissolutionThe resulting residue was dissolved in MeOH (9 mL)
  8. additionTo the solution was added 5% aqueous NaOH (2 mL)
  9. temperatureThe mixture was cooled to RT
  10. extractionextracted with EtOAc (3×20 mL)
  11. dry with materialThe combined organic layers were dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated to dryness
  14. custompurified by prep-HPLC

Sources & evidence

ORD record
ord-e3e92a90230f4bbf827c56bbe9ed617d
Source dataset
uspto-grants-2016_02
Patent number
US09265770B2

Reaction notes

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