Formic Acid → 5-chloro-1-((3-(2,2-dimethylpropyl)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl)-1H-benzimidazole-6-carbonitrile

HRID 1423848Notes

Reaction equation

HRID 1423848 reaction equation
[Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([NH:13][CH2:14][CH:15]2[CH2:30][CH2:29][CH2:28][C:17]3([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:18]3)[CH2:16]2)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+].[CH:33](O)=O.C(OC)(OC)OC.C(O)(C(F)(F)F)=O>CCO.O.[Fe]>[Cl:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[N:13]([CH2:14][CH:15]3[CH2:30][CH2:29][CH2:28][C:17]4([O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[CH2:18]4)[CH2:16]3)[CH:33]=[N:10][C:8]=2[CH:9]=1

Participants

9

Reactant 5

HCID 284Formic AcidHCID 6422Trifluoroacetic acidHCID 9005Trimethyl orthoformateHCID 25517Ammonium ChlorideHCID 711161382-Chloro-5-(((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile

Product 1

HCID 780802835-chloro-1-((3-(2,2-dimethylpropyl)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl)methyl)-1H-benzimidazole-6-carbonitrileYield 57%

Reagents, catalysts & solvents 3

HCID 23925IronCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Conditions

Temperature
75 °C

Procedure

A suspension of 2-chloro-5-(((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)amino)-4-nitrobenzonitrile (0.236 g, 0.543 mmol), iron (325 mesh) (0.152 g, 2.71 mmol), and ammonium chloride (0.015 g, 0.271 mmol) in EtOH (3 mL) and water (0.5 mL) was stirred at 75° C. for 45 min. The reaction was cooled to rt and filtered through a pad of celite. The celite was washed with EtOAc, and the combined filtrates were partitioned between EtOAc and saturated sodium bicarbonate solution and 1 N NaOH (1:1). The organic layer was dried over Na2SO4, filtered, and concentrated to a purple foam. This residue was dissolved in formic acid (0.060 mL, 1.56 mmol) and trimethyl orthoformate (1.72 mL, 15.6 mmol). The resulting solution was stirred at rt for 18 h. The reaction mixture was concentrated and redissolved in EtOAc. The organic solution was washed with saturated sodium bicarbonate solution and concentrated. The crude product was purified using reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 16 minute run; 50 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 30-70% solvent A) to afford the title compound (0.125 g, 57% yield) as the TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 4.07 (ddd, J=7.53, 14.56, 24.85 Hz, 2H), 3.36 (dd, J=8.53, 24.09 Hz, 2H), 3.00 (dd, J=14.31, 32.37 Hz, 2H), 2.37-2.52 (m, 1H), 2.03 (d, J=16.81 Hz, 1H), 1.94 (dd, J=2.01, 12.80 Hz, 1H), 1.64-1.82 (m, 3H), 1.31-1.44 (m, 1H), 1.22 (t, J=12.80 Hz, 1H), 0.98-1.11 (m, 1H), 0.95 (s, 9H). MS (m/z) 415.2 (M+H+).

Workup

  1. temperatureThe reaction was cooled to rt
  2. filtrationfiltered through a pad of celite
  3. washThe celite was washed with EtOAc
  4. customthe combined filtrates were partitioned between EtOAc and saturated sodium bicarbonate solution and 1 N NaOH (1:1)
  5. dry with materialThe organic layer was dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated to a purple foam
  8. stirringThe resulting solution was stirred at rt for 18 h
  9. concentrationThe reaction mixture was concentrated
  10. dissolutionredissolved in EtOAc
  11. washThe organic solution was washed with saturated sodium bicarbonate solution
  12. concentrationconcentrated
  13. customThe crude product was purified
  14. customreverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 16 minute run; 50 mL/min flow rate with at-column dilution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 30-70% solvent A)

Sources & evidence

ORD record
ord-8eea3a9793634007959b62a325c014aa
Source dataset
uspto-grants-2015_01
Patent number
US08927585B2

Reaction notes

Loading…