Sodium hydride → HCID 66742800, compound

HRID 1259354Notes

Reaction equation

HRID 1259354 reaction equation
[C:1]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:2][C:3]([O:5]C(C)(C)C)=O.[H-].[Na+].[C:18]([C:20]1([N:25]([C:31]2[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH:35]=2)[C:26](=[O:30])[CH:27]=[C:28]=[CH2:29])[CH2:24][CH2:23][O:22][CH2:21]1)#[N:19]>C1COCC1>[CH3:29][C:28]1[C:27]2[C:26](=[O:30])[N:25]([C:31]3[CH:32]=[N:33][N:34]([CH2:36][C:37]([F:40])([F:38])[F:39])[CH:35]=3)[C:20]3([CH2:24][CH2:23][O:22][CH2:21]3)[C:18]=2[NH:19][C:3](=[O:5])[C:2]=1[C:1]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 68324Di-tert-butyl malonateHCID 86661972HCID 86661972, compound

Product 1

HCID 66742800HCID 66742800, compoundYield 52.4%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

As shown in step 24-iii of Scheme 24, to a solution of ditert-butyl propanedioate (3.579 g, 3.705 mL, 16.55 mmol) in THF (50 mL) at 23° C. was added NaH (496.4 mg, 12.41 mmol). After stirring for 20 minutes, a solution of Compound 2076 (2.70 g, 8.275 mmol) in THF (50 mL) was added. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (100 mL) and partitioned between water and EtOAc (150 mL each). The organics were separated, washed with brine (200 mL) containing 1 N HCl (10 mL aq), washed with brine (150 mL), dried (magnesium sulfate), filtered and concentrated under reduced pressure. The residue was purified by medium pressure silica gel chromatography (0-100% EtOAc in hexanes) to provide intermediate tert-butyl 4′-methyl-2′,5′-dioxo-6′-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-1′,2′,4,5,5′,6′-hexahydro-2H-spiro[furan-3,7′-pyrrolo[3,4-b]pyridine]-3′-carboxylate (2.03 g, 4.334 mmol) as a pale yellow solid: ESMS (M+H) 469.31; 1H NMR (DMSO-d6, 300 MHz) δ 12.80 (br s, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 5.17 (q, J=9, 2 H), 4.18 (d, J=12, 1 H), 3.90 (m, 2H), 3.75 (m, 1H), 2.45 (m, 1H), 2.44 (s, 3H), 2.33 (m, 1H), 1.52 (s, 9H).

Workup

  1. waitAfter 1 hour
  2. customthe reaction was quenched with saturated aqueous ammonium chloride (100 mL)
  3. custompartitioned between water and EtOAc (150 mL each)
  4. customThe organics were separated
  5. washwashed with brine (200 mL)
  6. additioncontaining 1 N HCl (10 mL aq)
  7. washwashed with brine (150 mL)
  8. dry with materialdried (magnesium sulfate)
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was purified by medium pressure silica gel chromatography (0-100% EtOAc in hexanes)

Sources & evidence

ORD record
ord-2dc0a045c0f843778d548c0d6ee05e1f
Source dataset
uspto-grants-2013_06
Patent number
US08466288B2

Reaction notes

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