Carbon Dioxide → HCID 59490926, compound

HRID 1396684Notes

Reaction equation

HRID 1396684 reaction equation
BrC1[CH:3]=[C:4]2[C:8](=CC=1F)NN=[CH:5]2.[H-].[Na+].[C:14](=[O:16])=[O:15].C([Li])CCC.CCCCCC.CN(C=O)C.Cl.[F:34][C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[N:40][NH:41]2)=[CH:37][C:36]=1[CH:44]=[O:45]>O1CCCC1.CCOC(C)=O.CN(C1C=CN=CC=1)C.CC(C)=O>[F:34][C:35]1[CH:43]=[C:42]2[C:38]([CH:39]=[N:40][N:41]2[C:14]([O:16][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:15])=[CH:37][C:36]=1[CH:44]=[O:45]

Participants

13

Reactant 8

HCID 280Carbon DioxideHCID 313Hydrochloric AcidHCID 6228DimethylformamideHCID 8058HexaneHCID 24758Sodium hydrideHCID 468639235-Bromo-6-fluoro-1H-indazoleHCID 579172916-fluoro-1H-indazole-5-carbaldehydeHCID 178418339Butyllithium

Product 1

HCID 59490926HCID 59490926, compoundYield 81%

Reagents, catalysts & solvents 4

HCID 142844-(Dimethylamino)pyridineCatalystHCID 180AcetoneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A solution of 5-bromo-6-fluoro-1H-indazole (29D, 3.50 g, 16.28 mmol) in tetrahydrofuran (200.00 mL) was treated with sodium hydride (60% in mineral oil, 1.172 g) at 0° C. and stirred at room temperature for 20 minutes. The reaction mixture was cooled to −78° C. (dry ice and acetone) and treated with 2.5 M of n-butyl lithium in hexane (8.2 mL, 20.3 mmol) dropwise. The reaction mixture was stirred at that temperature for 20 minutes and treated with DMF (5.06 mL, 65.11 mmol). The reaction mixture was slowly warmed to room temperature when the viscous solution turn fluidic and stirring was efficient. Analysis of TLC (40% EtOAc/Hexanes) indicated complete conversion of starting material to product. The reaction mixture was acidified with aq. HCl taken up in EtOAc (500 mL) washed with aq. HCl (100 mL), brine (100 mL), dried (MgSO4), filtered, concentrated in vacuo and used as it is in next step. A solution of product 6-fluoro-1H-indazole-5-carbaldehyde (2.3 g) in THF (100 mL) was treated with di-tort-butyldicarbonate (3.56 g, 16.28 mmol) and DMAP (300 mg) and stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residue was purified using chromatography (SiO2, EtOAc/Hexanes gradient 0-40%) to yield [2e] tert-butyl 6-fluoro-5-formyl-1H-indazole-1-carboxylate (29E, 3.5 g; Yield=81%) as a colorless solid.

Workup

  1. stirringThe reaction mixture was stirred at that temperature for 20 minutes
  2. temperatureThe reaction mixture was slowly warmed to room temperature when the viscous solution turn fluidic
  3. stirringstirring
  4. washwashed with aq. HCl (100 mL), brine (100 mL)
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. stirringstirred at room temperature for 3 hours
  9. concentrationThe reaction mixture was concentrated in vacuo
  10. customthe residue was purified

Sources & evidence

ORD record
ord-19274526b4a24c19b373da71f53d4de2
Source dataset
uspto-grants-2014_12
Patent number
US08901139B2

Reaction notes

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