Sodium hydride → (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methyl-oxetan-3-ylmethyl ester

HRID 409433Notes

Reaction equation

HRID 409433 reaction equation
[CH3:1][C:2]1([CH2:6][OH:7])[CH2:5][O:4][CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:19][C:20]([N:22]2[CH2:26][C@@H:25]([N:27]([CH2:40][C:41]3[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=3)[C:28]3[N:33]=[CH:32][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:30][N:29]=3)[CH2:24][C@H:23]2[CH2:55][CH3:56])=O)=CC=1)([O-])=O>C1COCC1>[CH3:1][C:2]1([CH2:6][O:7][C:20]([N:22]2[CH2:26][C@@H:25]([N:27]([CH2:40][C:41]3[CH:42]=[C:43]([C:51]([F:52])([F:53])[F:54])[CH:44]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:46]=3)[C:28]3[N:29]=[CH:30][C:31]([C:34]4[CH:35]=[N:36][N:37]([CH3:39])[CH:38]=4)=[CH:32][N:33]=3)[CH2:24][C@H:23]2[CH2:55][CH3:56])=[O:19])[CH2:5][O:4][CH2:3]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1378373-Methyl-3-oxetanemethanolHCID 59614333(2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester

Product 1

HCID 42634951(2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methyl-oxetan-3-ylmethyl esterYield 64.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a mixture of 3-methyl-3-oxetanemethanol (0.202 mmol; 20.6 mg) and sodium hydride (60% oil dispersion in mineral oil, 0.202 mmol; 8.1 mg) in THF (0.5 mL) is added a solution of (2R,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 4-nitro-phenyl ester (0.101 mmol; 67 mg) in THF (0.5 mL). The reaction mixture is stirred for 1 hour at room temperature, then quenched with saturated aqueous ammonium chloride. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc), followed by another silica gel column chromatography (eluent: dichloromethane/methanol) to give (2R,4S)-4-{(3,5-Bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-ethyl-pyrrolidine-1-carboxylic acid 3-methyl-oxetan-3-ylmethyl ester (40.7 mg, 64%); ESI-MS m/z: 626 [M+1]+, Retention time 2.19 min (condition A).

Workup

  1. customquenched with saturated aqueous ammonium chloride
  2. extractionThe product is extracted three times with EtOAc
  3. washThe combined organic layer is washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe obtained residue is purified by silica gel column chromatography (eluent: n-hexane/EtOAc)

Sources & evidence

ORD record
ord-9a4def734007493aa900a0fbea9663b4
Source dataset
uspto-grants-2014_06
Patent number
US08759365B2

Reaction notes

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