Hydrochloric Acid → HCID 86654068, compound

HRID 1948132Notes

Reaction equation

HRID 1948132 reaction equation
[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:29]4[C:30](=[O:34])[N:31]([CH3:33])[CH2:32][C:28]=4[CH:27]=[CH:26][N+:25]=3[O-])[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[C:12](OC)[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].Cl.O>CCO.[Fe]>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[C:29]4[C:30](=[O:34])[N:31]([CH3:33])[CH2:32][C:28]=4[CH:27]=[CH:26][N:25]=3)[C:20]([C:36]([F:38])([F:39])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]

Participants

6

Reactant 3

HCID 313Hydrochloric Acid2×HCID 962Water2×HCID 178476850HCID 178476850, compound

Product 1

HCID 86654068HCID 86654068, compoundYield 52.6%

Reagents, catalysts & solvents 2

HCID 23925IronCatalystHCID 702EthanolSolvent

Procedure

A solution of diethyl[3-methoxy-4-({4-[(2-methyl-5-oxido-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (Example 310, 35.0 mg, 0.0587 mmol) in EtOH (2.0 mL) was charged with iron (6.9 mg, 0.12 mmol) and heated to reflux. The reaction mixture was charged with 1 M of HCl in H2O (0.07 mL, 0.07 mmol) and stirred at reflux for 10 minutes. Additional 1 M of HCl in H2O (0.03 mL, 0.03 mmol) was added to the reaction mixture and stirred at reflux for 10 minutes. The reaction mixture was filtered through a pad of celite. The filtrate was quenched with NaHCO3 (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to a yellow solid. The crude material was purified by silica gel chromatography on an ISCO Combi-flash Rf system using DCM/MeOH (100:0→95:5) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (17.0 mg, 50%). The material was re-purified by HPLC. The fractions containing product were combined and concentrated to yield a white solid (4.3 mg, 13%). 1H NMR (DMSO-d6, 400 MHz): δ=8.71 (br. s., 1H), 8.60 (d, J=5.05 Hz 1H), 8.54 (s, 1H), 8.47 (br. s., 1H), 8.32 (s, 1H), 7.41 (d, J=5.05 Hz, 1H), 6.95 (s, 1H), 6.85-6.92 (m, 1H), 4.57 (s, 2H), 3.90-4.01 (m, 4H), 3.84 (s, 3H), 3.21 (s, 1H), 3.06 (s, 3H), 1.19 (t, J=6.95 Hz, 6H). MS (ES+): m/z 581.10 [MH+] (TOF, polar).

Workup

  1. temperatureheated to reflux
  2. temperatureat reflux for 10 minutes
  3. stirringstirred
  4. temperatureat reflux for 10 minutes
  5. filtrationThe reaction mixture was filtered through a pad of celite
  6. customThe filtrate was quenched with NaHCO3 (10 mL)
  7. extractionextracted with EtOAc (15 mL)
  8. washThe organic layer was washed with brine
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure to a yellow solid
  12. customThe crude material was purified by silica gel chromatography on an ISCO Combi-flash Rf system
  13. additionThe fractions containing product
  14. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-62505566a20f4c1c95e421bf4755194f
Source dataset
uspto-grants-2013_03
Patent number
US08399433B2

Reaction notes

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