Acetic Acid → 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-1-(2-hydroxyethyl)-4,5-dihydropyrrolo-[3,4-c]pyrazol-6(1H)-one

HRID 873934Notes

Reaction equation

HRID 873934 reaction equation
[NH:1]([CH2:3][CH2:4][OH:5])[NH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=3)[C:16](=[O:27])[C:15](=O)[CH:14]2[C:29](=O)[CH2:30][CH3:31])=[CH:9][CH:8]=1.CC(O)=O.S(=O)(=O)(O)N>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][CH3:31])=[N:2][N:1]([CH2:3][CH2:4][OH:5])[C:15]=3[C:16](=[O:27])[N:17]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:9][CH:8]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5987Sulfamic AcidHCID 80172-HydrazinoethanolHCID 1177027665-(4-Chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-propionylpyrrolidine-2,3-dione

Product 1

HCID 918263174-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-ethyl-1-(2-hydroxyethyl)-4,5-dihydropyrrolo-[3,4-c]pyrazol-6(1H)-oneYield 45%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent2×

Conditions

Temperature
90 °C

Procedure

To a solution of 2-hydrazinylethanol (76 mg, 1.0 mmol) in MeOH (2 mL) was added 5-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-propionylpyrrolidine-2,3-dione (Step 60.1) (204 mg, 0.5 mmol) and the reaction mixture was heated for 1 hr at 70° C. and for 0.5 hr at 90° C. in the MW. The volume of MeOH was reduced to 1 mL and AcOH (2 mL) and sulfamic acid (97 mg, 1.0 mmol) were added. The reaction mixture was heated for 1 h at 110° C. in the MW. The reaction mixture was concentrated under reduced pressure. The residue was basified with 20% K2CO3 solution and extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was first purified by silica gel column chromatography (hexane/EtOAc/MeOH 80:20:2 to 0:10:1) then further purified by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 15-20% in 6 min_total 11 min) to afford the title product (97 mg, 0.225 mmol, 45% yield) as colorless foam. tR: 0.84 min (LC-MS 2); ESI-MS: 427 [M+H]+ (LC-MS 2); Rf=0.21 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (t, J=7.6 Hz, 3H) 2.01 (s, 3H) 2.25-2.48 (m, 2H) 3.37 (s, 3H) 3.44 (t, J=6.3 Hz, 1H) 3.95-4.05 (m, 2H) 4.43 (dd, J=5.6, 3.7 Hz, 2H) 5.50 (s, 1H) 6.91-7.03 (m, 4H) 7.25 (d, J=8.3 Hz, 2H).

Workup

  1. additionwere added
  2. temperatureThe reaction mixture was heated for 1 h at 110° C. in the MW
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. extractionextracted with EtOAc
  5. washCombined organic layers were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe crude material was first purified by silica gel column chromatography (hexane/EtOAc/MeOH 80:20:2 to 0:10:1)
  10. customthen further purified by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 15-20% in 6 min_total 11 min)

Sources & evidence

ORD record
ord-1a545f7d288842278c1765c251286647
Source dataset
uspto-grants-2015_03
Patent number
US08975417B2

Reaction notes

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