Reaktion #563486

Reaktionsgleichung

(3S,4S)-3-hexyl-4-((R)-2-hydroxy tridecyl)-2-oxetanone

triphenylphosphine

N-formyl-L-leucine

diisopropylazodicarboxylate

→

title compound

Ausbeute 83.0%

Orlistat

Ausbeute 83.0%

Lösungsmittel

tetrahydrofuran

tetrahydrofuran

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONwas continuously added
2. 2
   workup.STIRRINGthe reaction mixture was stirred for 4 hours
3. 3
   Temperaturwhile slowly raising its temperature
4. 4
   SonstigeAfter removing the solvent, 832 mL of hexane
5. 5
   workup.ADDITIONwas added
6. 6
   workup.STIRRINGthe reaction mixture was stirred for 5 hours
7. 7
   SonstigeThe formed solid was removed
8. 8
   Filtrationby filtration
9. 9
   Waschenthe hexane layer thereof was washed with 499 mL of 55% methanol/
10. 10
    workup.DISTILLATIONdistilled water three times
11. 11
    TrocknenThe remaining organic layer was dried over anhydrous magnesium sulfate
12. 12
    Filtrationfiltered
13. 13
    Sonstigethe solvent was removed under a reduced pressure
14. 14
    workup.ADDITIONThen, 2.5 L of hexane was added
15. 15
    Temperaturthe reaction mixture was cooled to 10° C.
16. 16
    workup.STIRRINGstirred for 1 hour
17. 17
    workup.ADDITIONfollowed by addition of a seed of orlistat solid
18. 18
    TemperaturThe reaction mixture was slowly cooled to 0° C. again
19. 19
    workup.STIRRINGstirred overnight
20. 20
    FiltrationThe obtained solid was filtered
21. 21
    Waschenwashed with 500 mL of cold hexane
22. 22
    Sonstigedried

Vorschrift

166 g of (3S,4S)-3-hexyl-4-((R)-2-hydroxy tridecyl)-2-oxetanone obtained from Reference Example 1 was dissolved in 830 mL of tetrahydrofuran. After the addition of 160 g of triphenylphosphine (PPh3) and 86 g of N-formyl-L-leucine, the reaction mixture was cooled to 0° C. A mixed solution where 120 mL of diisopropylazodicarboxylate (DIAD) was diluted in 332 mL of tetrahydrofuran, was continuously added thereto over 1.5 hours. After stirring for further 30 minutes, the reaction mixture was stirred for 4 hours while slowly raising its temperature. After removing the solvent, 832 mL of hexane was added thereto, and the reaction mixture was stirred for 5 hours. The formed solid was removed therefrom by filtration, and the hexane layer thereof was washed with 499 mL of 55% methanol/distilled water three times. The remaining organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under a reduced pressure. Then, 2.5 L of hexane was added thereto, and the reaction mixture was cooled to 10° C. and stirred for 1 hour, followed by addition of a seed of orlistat solid. The reaction mixture was slowly cooled to 0° C. again, and stirred overnight. The obtained solid was filtered, washed with 500 mL of cold hexane, and dried, to obtain 192.5 g of the title compound (yield: 83%) as a white solid.

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