Ethyl 2-hydroxyisobutyrate → Bindarit

HRID 1805899Notes

Reaction equation

HRID 1805899 reaction equation
C([O:3][C:4](=[O:9])[C:5]([OH:8])([CH3:7])[CH3:6])C.[H-].[Na+].[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28]Cl)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[CH2:12]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:3])=[O:9])=[N:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1

Participants

7

Reactant 4

HCID 6653Ethyl 2-hydroxyisobutyrateHCID 14798Sodium HydroxideHCID 24758Sodium hydrideHCID 532606481-Benzyl-3-(chloromethyl)-1H-indazole

Product 1

HCID 71354Bindarit

Reagents, catalysts & solvents 2

HCID 1140TolueneSolvent2×HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
90 °C

Procedure

Ethyl-2-hydroxyisobutyrate (18.5 g, 140 mmol, 1.2 eq.), toluene (100 mL) and DMF (20 mL) were placed in a three-necked flask fitted with a mechanical stirrer and a reflux condenser under an inert atmosphere. A dispersion of 60% NaH (5.6 g, 140 mmol, 1.2 eq.) was added to the mixture in portions over a period of approximately 1.5 hours. A solution of 1-benzyl-3-chloromethyl-1H-indazole (30 g, 117 mmol, 1 eq.) in toluene (90 mL) and DMF (60 mL) was then added dropwise. The reaction mixture was heated to approximately 90° C. and kept at that temperature until the reaction was complete (checked by TLC, approximately 10 hours). After cooling to room temperature the mixture was washed with acidified water and water. The organic phase was concentrated under reduced pressure and the oily residue obtained was treated with 10 M NaOH (36 mL) at reflux temperature for at least 3 hours. The product, which was precipitated out by the addition of concentrated HCl, was filtered and dried. Yield: 32.3 g of white solid (85%).

Workup

  1. customfitted with a mechanical stirrer and a reflux condenser under an inert atmosphere
  2. custom(checked by TLC, approximately 10 hours)
  3. temperatureAfter cooling to room temperature the mixture
  4. washwas washed with acidified water and water
  5. concentrationThe organic phase was concentrated under reduced pressure
  6. customthe oily residue obtained
  7. temperatureat reflux temperature for at least 3 hours
  8. customThe product, which was precipitated out by the addition of concentrated HCl
  9. filtrationwas filtered
  10. customdried

Sources & evidence

ORD record
ord-2c18832d61fa488fbdcc6bd55ad55ec3
Source dataset
uspto-grants-2013_01
Patent number
US08354544B2

Reaction notes

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