Reaktion #5650

Reaktionsgleichung

1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethanol

sodium hydride

THF

THF

THF

(R)-2-bromohexanoic acid

THF

→

desired compound

Ausbeute 60.0%

2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-phenylethoxy)hexanoic acid

Ausbeute 60.0%

Lösungsmittel

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONThe addition
2. 2
   workup.WAITafter stiring for an hour
3. 3
   workup.STIRRINGto facilitate stirring
4. 4
   workup.ADDITIONThe addition
5. 5
   workup.WAITtook approximately 1.75 h
6. 6
   SonstigeThe suspension was removed from the oil bath 45 min
7. 7
   workup.ADDITIONafter addition
8. 8
   Sonstigequenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M)
9. 9
   EinengenThe solution was then concentrated under reduced pressure at 35° C.
10. 10
    Extraktionthe resulting liquid extracted with 3×100 mL of diethyl ether
11. 11
    Sonstigeto remove the unreacted alcohol
12. 12
    workup.ADDITIONThe aqueous phase was mixed with 300 mL of CH2Cl2
13. 13
    workup.STIRRINGThe layers were shaken
14. 14
    Sonstigeseparated
15. 15
    Extraktionthe aqueous phase was extracted with 2×300 mL of CH2Cl2
16. 16
    TrocknenThe combined organic phase was dried (MgSO4)
17. 17
    Filtrationfiltered
18. 18
    Einengenconcentrated under reduced pressure
19. 19
    SonstigeThe crude product was purified by column chromatography (silica gel, 1.5% HOAc-5% iPrOH-35% THF-hexane)

Vorschrift

1(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethanol (European Patent Application No. EP364804, published Apr. 25, 1991) (43.13 g, 147.2 mmol) in 200 mL dry THF was added dropwise to the suspension of sodium hydride (60% dispersion in oil, 12.36 g, 309.1 mmol) in 136 mL dry THF and 22.7 mL DMF at 45° C. oil bath temperature under N2 atmosphere. The addition took approximately 1 h. The mixture was allowed to stir at 45° C. for additional 3 h. The gray suspension turned white after stiring for an hour and became very viscous. An additional 36 mL of dry THF was added to facilitate stirring. A solution of (R)-2-bromohexanoic acid (31.57 g, 161.9 mmol) in 180 mL THF was added dropwise to the thick, white suspension at 45° C. The addition took approximately 1.75 h. The suspension was removed from the oil bath 45 min after addition was completed and quenched immediately with careful addition of 120 mL of pH 7 phosphate buffer (0.3 M). The solution was then concentrated under reduced pressure at 35° C. and the resulting liquid extracted with 3×100 mL of diethyl ether to remove the unreacted alcohol. The aqueous phase was mixed with 300 mL of CH2Cl2 and acidified to pH 2 with 200 mL of 1 M sodium hydrogen sulfate. The layers were shaken and separated, then the aqueous phase was extracted with 2×300 mL of CH2Cl2. The combined organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1.5% HOAc-5% iPrOH-35% THF-hexane) to obtain 36.35 g (88.32 mmol, 60%) of the desired compound as a low-melting solid: Rf 0.30 (EtOAc-hexane 5:2); 1H NMR (CDCl3) δ 0.8 (d, 3 H), 0.95 (m, 5 H), 1.2-1.9 (m, 22 H), 3.0 (q, 2 H), 3.2 (m, 4 H), 3.55 (m, 2 H), 3.65 (m, 2 H), 3.8 (t, 1 H),4.4 (q, 1 H), 7.3 (m, 5 H).

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