Ethyl bromoacetate → tert-Butyl (2S,4S)-2-[(2-ethoxy-2-oxoethoxy)methyl]-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate

HRID 602482Notes

Reaction equation

HRID 602482 reaction equation
[OH:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:22])[CH3:21])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[H-].[Na+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>O1CCCC1>[CH2:55]([O:54][C:52](=[O:53])[CH2:51][O:1][CH2:2][C@@H:3]1[CH2:7][C@H:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH:20]([CH3:21])[CH3:22])[N:12]=2)=[O:10])[CH2:5][N:4]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH3:56]

Participants

6

Reactant 4

HCID 7748Ethyl bromoacetateHCID 24758Sodium hydrideHCID 2855718-Crown-6HCID 67270520tert-Butyl (2S,4S)-2-(hydroxymethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate

Product 1

HCID 67271444tert-Butyl (2S,4S)-2-[(2-ethoxy-2-oxoethoxy)methyl]-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylateYield 71.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a stirred solution of tert-butyl (2S,4S)-2-(hydroxymethyl)-4-{[(1-isopropyl-1H-indazol-3-yl) carbonyl]amino}pyrrolidine-1-carboxylate (358 mg, 0.89 mmol, step 2 of Example 7) in tetrahydrofuran (7 mL) was added sodium hydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) at 0° C. Then to the solution was added 18-crown-6 (164 mg, 0.45 mmol) and a solution of ethyl bromoacetate (446 mg, 2.67 mmol) in tetrahydrofuran (5 mL) at 0° C. It was stirred overnight rising to room temperature. The resulting mixture was quenched by addition of water and it was extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 310 mg (71%) of the title compound as a colorless oil.

Workup

  1. customat 0° C
  2. customrising to room temperature
  3. customThe resulting mixture was quenched by addition of water and it
  4. extractionwas extracted with ethyl acetate (10 mL×3)
  5. washThe organic layer was washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated
  8. customThe resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1)

Sources & evidence

ORD record
ord-2b778158d1a74f7f924bf923c859edb8
Source dataset
uspto-grants-2011_03
Patent number
US07906532B2

Reaction notes

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