Reaktion #2009364

Reaktionsgleichung

6-chloro-3-fluoro-2-methylpyridine

N2

(S)-1-benzyl-3-((S)-1-hydroxy-3-methylbutyl)-pyrrolidine

NaH

→

(S)-1-benzyl-3-((S)-1-(6-chloro-2-methyl-3-pyridyloxy)-3-methylbutyl)-pyrrolidine

Ausbeute 67.0%

Lösungsmittel

DMA

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONCharge a 200 mL round bottom flask
2. 2
   Sonstigeequipped with a Claisen adaptor
3. 3
   workup.STIRRINGstir at room temperature for 24 hours
4. 4
   SonstigeQuench the reaction mixture with H2O (120 mL)
5. 5
   Extraktionextract with MTBE (120 mL)
6. 6
   WaschenWash the organic layer with H2O (2×60 mL)
7. 7
   Trocknendry over Na2SO4
8. 8
   FiltrationFilter
9. 9
   Einengenconcentrate
10. 10
    Sonstigepurify the crude material (in toluene)
11. 11
    Wascheneluting with the following: hexanes (2×500 mL), 15% MTBE/hexanes (16×500 mL), 50% MTBE/hexanes (8×500 mL)
12. 12
    EinengenConcentrate the appropriate fractions

Vorschrift

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).

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