Nitrogen → HCID 59536649, compound

HRID 1922182Notes

Reaction equation

HRID 1922182 reaction equation
N#N.[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([OH:20])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+].[Cl:23][C:24]1[N:29]=[C:28]([CH3:30])[C:27](F)=[CH:26][CH:25]=1>CC(N(C)C)=O>[CH2:3]([N:10]1[CH2:14][CH2:13][C@H:12]([C@@H:15]([O:20][C:27]2[C:28]([CH3:30])=[N:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

6

Reactant 4

HCID 947NitrogenHCID 24758Sodium hydrideHCID 198673766-Chloro-3-fluoro-2-methylpyridineHCID 59536627HCID 59536627, compound

Product 1

HCID 59536649HCID 59536649, compoundYield 67%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Procedure

Charge a 200 mL round bottom flask equipped with a Claisen adaptor, thermal couple and N2 inlet with (S)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)-pyrrolidine (5.69 g, 23 mmoles) and DMA (58 mL). Add NaH (1.29 g, 32.2 mmoles) in one portion with stirring and stir at room temperature for 1 hour. Add 6-chloro-3-fluoro-2-methylpyridine (3.52 g, 24.15 mmoles) in one portion with stirring and then stir at room temperature for 24 hours. Quench the reaction mixture with H2O (120 mL) and extract with MTBE (120 mL). Wash the organic layer with H2O (2×60 mL), followed by brine (60 mL), and then dry over Na2SO4. Filter, concentrate, and then purify the crude material (in toluene) by loading onto silica (225 g, wet with toluene) and eluting with the following: hexanes (2×500 mL), 15% MTBE/hexanes (16×500 mL), 50% MTBE/hexanes (8×500 mL). Concentrate the appropriate fractions to give (S)-1-benzyl-3-((S)-1-(6-chloro-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine as a light yellow oil (5.77 g, 15.47 mmoles, 67% yield, purity >98%). 1H NMR (300 MHz, CDCl3) δ 7.38-7.20 (m, 5H), 7.06 (s, 2H), 4.32-4.20 (m, 1H), 3.68-3.48 (m, 2H) 2.78-2.64 (m, 2H), 2.64-2.30 (m, 2H), 2.42 (s, 3H), 2.28-2.20 (m, 1H), 2.05-1.85 (m, 1H), 1.82-1.52 (m, 4H), 1.48-1.34 (m, 1H), 0.92 (d, 3H, J=6.45 Hz), 0.88 (d, 3H, J=6.45 Hz). LC/MS=373.2 (M), 375.3 (M+2).

Workup

  1. additionCharge a 200 mL round bottom flask
  2. customequipped with a Claisen adaptor
  3. stirringstir at room temperature for 24 hours
  4. customQuench the reaction mixture with H2O (120 mL)
  5. extractionextract with MTBE (120 mL)
  6. washWash the organic layer with H2O (2×60 mL)
  7. dry with materialdry over Na2SO4
  8. filtrationFilter
  9. concentrationconcentrate
  10. custompurify the crude material (in toluene)
  11. washeluting with the following: hexanes (2×500 mL), 15% MTBE/hexanes (16×500 mL), 50% MTBE/hexanes (8×500 mL)
  12. concentrationConcentrate the appropriate fractions

Sources & evidence

ORD record
ord-b8724809dea944018e0a799512095945
Source dataset
uspto-grants-2012_05
Patent number
US08173821B2

Reaction notes

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