(2S,4R)-tert-butyl 2-(azidomethyl)-4-hydroxypyrrolidine-1-carboxylate → (2S,4R)-tert-butyl 2-(azidomethyl)-4-(5-cyclopropylpyrazin-2-yloxy)-pyrrolidine-1-carboxylate

HRID 1184605Notes

Reaction equation

HRID 1184605 reaction equation
[N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3].CC(C)([O-])C.[K+].Br[C:25]1[CH:30]=[N:29][C:28]([CH:31]2[CH2:33][CH2:32]2)=[CH:27][N:26]=1>O1CCCC1.O>[N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([O:10][C:25]2[CH:30]=[N:29][C:28]([CH:31]3[CH2:33][CH2:32]3)=[CH:27][N:26]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N+:2]=[N-:3]

Participants

6

Reactant 3

HCID 14117020(2S,4R)-tert-butyl 2-(azidomethyl)-4-hydroxypyrrolidine-1-carboxylateHCID 23665647Potassium tert-butoxideHCID 457876352-Bromo-5-cyclopropylpyrazine

Product 1

HCID 86680519(2S,4R)-tert-butyl 2-(azidomethyl)-4-(5-cyclopropylpyrazin-2-yloxy)-pyrrolidine-1-carboxylateYield 59.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of the product from Example 174B (98 mg, 0.404 mmol) in tetrahydrofuran (1 mL) was added potassium-t-butoxide (63.5 mg, 0.566 mmol) followed by addition of 2-bromo-5-cyclopropylpyrazine (Combi-Phos Inc; 89 mg, 0.445 mmol). After stirring at room temperature for 24 hours, the mixture was diluted with water and extracted with ethyl acetate (2×20 mL). The combined ethyl acetate extracts were dried over Na2SO4, filtered, and concentrated under a stream of nitrogen. The residue was purified by flash chromatography on a 12 g silica gel column, eluting with 5% ethyl acetate/hexanes for 3 minutes then a gradient to 100% ethyl acetate over 20 minutes to afford the title compound as a colorless oil (87 mg, 59.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.3 Hz, 1H), 5.44-5.39 (m, 1H), 4.12-4.04 (m, 1H), 3.71 (dd, J=12.4, 5.3 Hz, 1H), 3.64 (d, J=12.3 Hz, 1H), 3.57 (dd, J=12.4, 4.6 Hz, 1H), 3.39 (dd, J=12.4, 3.2 Hz, 1H), 2.30-2.06 (m, 3H), 1.41 (s, 9H), 0.97-0.90 (m, 2H), 0.87-0.81 (m, 2H).

Workup

  1. extractionextracted with ethyl acetate (2×20 mL)
  2. dry with materialThe combined ethyl acetate extracts were dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under a stream of nitrogen
  5. customThe residue was purified by flash chromatography on a 12 g silica gel column
  6. washeluting with 5% ethyl acetate/hexanes for 3 minutes

Sources & evidence

ORD record
ord-f862187a85554846841e281e1a7163d7
Source dataset
uspto-grants-2014_03
Patent number
US08669255B2

Reaction notes

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