2,2-Dimethyl-1,3-dioxane-4,6-dione → (3R)-benzyl 3'-methyl-6'-oxo-2',5',6',7'-tetrahydrospiro[cyclopentane-1,4'-pyrazolo[3,4-b]pyridine]-3-carboxylate

HRID 331101Notes

Reaction equation

HRID 331101 reaction equation
O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.C[C:18]1([CH3:26])[O:23]C(=O)CC(=O)O1.[CH3:27][C:28]1[CH:32]=[C:31]([NH2:33])[NH:30][N:29]=1>CN1CCCC1=O>[CH3:27][C:28]1[NH:29][N:30]=[C:31]2[C:32]=1[C:2]1([CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:3]1)[CH2:26][C:18](=[O:23])[NH:33]2

Participants

5

Reactant 3

HCID 162492,2-Dimethyl-1,3-dioxane-4,6-dioneHCID 86668857(R)-benzyl 3-oxocyclopentanecarboxylateHCID 178418690HCID 178418690, compound

Product 1

HCID 136350236(3R)-benzyl 3'-methyl-6'-oxo-2',5',6',7'-tetrahydrospiro[cyclopentane-1,4'-pyrazolo[3,4-b]pyridine]-3-carboxylate

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
80 °C

Procedure

To (R)-benzyl 3-oxocyclopentanecarboxylate (0.4 g, 1.833 mmol) were sequentially added N-methylpyrrolidone (3 mL), 2,2-dimethyl-1,3-dioxane-4,6-dione (0.264 g, 1.833 mmol) and 3-methyl-1H-pyrazol-5-amine (0.178 g, 1.833 mmol) at room temperature. The contents heated to 80° C. (oil bath temp.) for 75 min, and stirred at room temperature for additional 48 hours. The reaction mixture was partitioned between ethyl acetate (40 mL) and 1N hydrogen chloride (15 mL). The ethyl acetate layer was separated and sequentially washed with 1N sodium hydroxide (15 mL), brine (20 mL), dried over sodium sulfate, concentrated and subjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Fractions corresponding to the desired product were isolated and concentrated. The residue that was obtained was partitioned between dichloromethane (20 mL) and saturated aqueous sodium bicarbonate solution. The dichloromethane layer was separated, dried over sodium sulfate and concentrated to yield a solid (33 mg, 0.097 mmol, 5.31%). It was used as such for the subsequent step without further purification. MS (ESI) m/z 340.16 (M+H)+

Workup

  1. customat room temperature
  2. customThe reaction mixture was partitioned between ethyl acetate (40 mL) and 1N hydrogen chloride (15 mL)
  3. customThe ethyl acetate layer was separated
  4. washsequentially washed with 1N sodium hydroxide (15 mL), brine (20 mL)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customsubjected to preparative HPLC (Phenomex Luna AXIA 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA)

Sources & evidence

ORD record
ord-470ed9a5fd3f403d9b3c82ce7b4dacb0
Source dataset
uspto-grants-2014_11
Patent number
US08877749B2

Reaction notes

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