Propylphosphonic anhydride → 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbonitrile

HRID 1056172Notes

Reaction equation

HRID 1056172 reaction equation
[C:1]([NH:5][C:6]1[C:7](/[CH:26]=[N:27]/O)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]1[C:7]([C:26]#[N:27])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 2

HCID 111923Propylphosphonic anhydrideHCID 1362179662-[3-(tert-butylamino)-2-[(E)-hydroxyiminomethyl]quinoxalin-5-yl]-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one

Product 1

HCID 717319233-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbonitrileYield 36.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 516892Sodium BicarbonateSolvent

Procedure

A solution of (E)-3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde oxime (308) (26.3 mg, 0.069 mmol) and 1-propanephosphonic acid cyclic anhydride (Alfa Aesar, Ward Hill, Mass.; 50 wt % solution in EtOAc; 0.16 mL, 0.28 mmol) in DMF (2.0 mL) was stirred at 100° C. for 3.5 h. The reaction mixture was then cooled to RT, diluted with saturated aq. NaHCO3 (30 mL), and extracted with 5% MeOH/DCM (2×30 mL). The combined extracts were sequentially washed with water (2×20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was taken up in DMSO (2.0 mL) and purified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 mm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA). Product-containing fractions were combined and neutralized with saturated aq. NaHCO3 (30 mL). The resulting mixture was extracted with 5% MeOH/DCM (2×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbonitrile (8.9 mg, 0.025 mmol, 36% yield) as a red-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.61 (1H, br. s.), 7.98 (1H, dd, J=7.4, 1.2 Hz), 7.73 (1H, dd, J=8.2, 1.2 Hz), 7.52 (1H, t, J=7.8 Hz), 7.12 (1H, d, J=2.3 Hz), 6.95 (1H, br. s.), 6.60 (1H, s), 3.42 (2H, td, J=6.8, 2.2 Hz), 2.84 (2H, t, J=6.8 Hz), 1.53 (9H, s). m/z (ESI, +ve) 361.1 (M+H)+.

Workup

  1. extractionextracted with 5% MeOH/DCM (2×30 mL)
  2. washThe combined extracts were sequentially washed with water (2×20 mL) and brine (20 mL)
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. custompurified by rpHPLC (Phenomenex Gemini C18 column (150×30 mm, 10 mm), 35 mL/min, 5-100% CH3CN/H2O+0.1% TFA)
  7. extractionThe resulting mixture was extracted with 5% MeOH/DCM (2×30 mL)
  8. dry with materialthe combined extracts were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-aeece6441bfd433c9de0410b1523bfbf
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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