Sodium hydride → HCID 91826336, compound

HRID 873996Notes

Reaction equation

HRID 873996 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][NH:12][C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:30]1[CH2:33][O:32][CH2:31]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:30]4[CH2:33][O:32][CH2:31]4)[C:11]=3[C:10](=[O:17])[N:9]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 133566863-IodooxetaneHCID 178434165HCID 178434165, compound

Product 1

HCID 91826336HCID 91826336, compoundYield 23.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 27) (100 mg, 0.271 mmol) in DMF (3 mL) was added under Ar NaH (13.01 mg, 0.325 mmol) at 0° C. The reaction mixture was stirred for 30 min at rt. 3-Iodooxetane (0.030 mL, 0.352 mmol) was added. The reaction mixture was stirred for 30 min at rt, quenched with a saturated aqueous solution of sodium bicarbonate (75 mL), and extracted with EtOAc (2×75 mL). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (75 mL), dried on Na2SO4 and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%), followed by preparative achiral SFC (column: PPU, 250×30 mm, 5 μm, 100 A, Princeton; eluent: MeOH/scCO2; gradient: 1 min 20% MeOH, 20-25% MeOH in 6 min, 25-50% MeOH in 1 min, 1.5 min 50% MeOH; flow: 100 mL/min) to afford 27 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-1-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 135) and ten fractions containing the impure title compound. These fractions were collected and evaporated to afford after a second SFC purification 16 mg of 4-(4-chlorophenyl)-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methyl-2-(oxetan-3-yl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(2H)-one (title compound). tR: 0.81 min (LC-MS 2); ESI-MS: 425.1 [M+H]+ (LC-MS 2); Rf=0.25 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.92 (s, 3H) 2.02 (s, 3H) 3.36 (s, 3H) 4.84-5.03 (m, 4H) 5.56-5.69 (m, 1H) 6.12 (s, 1H) 7.14-7.29 (m, 2H) 7.31-7.38 (m, 2H) 7.39-7.42 (m, 1H) 7.73 (d, J=2.74 Hz, 1H).

Workup

  1. stirringThe reaction mixture was stirred for 30 min at rt
  2. customquenched with a saturated aqueous solution of sodium bicarbonate (75 mL)
  3. extractionextracted with EtOAc (2×75 mL)
  4. washThe combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate (75 mL)
  5. customdried on Na2SO4
  6. customevaporated
  7. customThe residue was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%)
  8. customfollowed by preparative achiral SFC (column: PPU, 250×30 mm, 5 μm, 100 A, Princeton; eluent: MeOH/scCO2; gradient: 1 min 20% MeOH, 20-25% MeOH in 6 min, 25-50% MeOH in 1 min, 1.5 min 50% MeOH; flow: 100 mL/min)

Sources & evidence

ORD record
ord-250e2c6a95b14d0fa1d4ed1ffd7319ea
Source dataset
uspto-grants-2015_03
Patent number
US08975417B2

Reaction notes

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