Reaktion #10717

Reaktionsgleichung

LiOMe

5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde

4-acetylbenzoic acid

MeOH

→

4-[3-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-E-acryloyl]-benzoic acid

Ausbeute 87.0%

Lösungsmittel

H2O

H2O

heptane

DMF

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigefitted with a mechanical stirrer and nitrogen inlet adapter
2. 2
   workup.ADDITIONwas added in one portion
3. 3
   Sonstigethe reaction mixture was transferred to a separatory funnel
4. 4
   Waschento rinse the reaction vessel
5. 5
   workup.ADDITIONthis rinse was also added to the seperatory funnel
6. 6
   WaschenThe combined aqueous was washed with iPrOAc (500 mL)
7. 7
   workup.WAITThe resulting heterogeneous solution was aged for 30 min
8. 8
   Filtrationthe precipitate was filtered
9. 9
   Waschenwashed with 70% EtOH (100 mL)
10. 10
    Trocknendried on the filter funnel under a stream of N2 affording desired acid 5 as a crude yellow solid
11. 11
    workup.ADDITIONThe crude dry product and THF (260 mL) were charged into a clean reaction vessel
12. 12
    Sonstigefitted with a mechanical stirrer and nitrogen inlet adapter
13. 13
    workup.ADDITIONHeptane (30 mL) was slowly added to the resulting solution over 30 min
14. 14
    Sonstigeaged resulting in crystallization
15. 15
    workup.WAITaged for an additional 1 h
16. 16
    Filtrationfiltered
17. 17
    WaschenThe reaction vessel was then rinsed with 70% EtOH (100 mL)
18. 18
    workup.ADDITIONthis rinse was added to the filter cake
19. 19
    SonstigeThe wet cake was then transferred to a clean reaction vessel
20. 20
    workup.ADDITIONcontaining 70% EtOH (750 mL)
21. 21
    FiltrationThe product was then filtered
22. 22
    Waschenrinsed with fresh 70% EtOH (100 mL)
23. 23
    Trocknendried on the filter funnel under a stream of N2
24. 24
    Sonstigedried to a constant weight in the vacuum oven (40° C., 20 inHg)

Vorschrift

An alternative procedure: 5-(Benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (42.3 g), 4-acetylbenzoic acid (22.1 g), MeOH (250 mL) and DMF (600 mL) were sequentially charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter. After complete dissolution, LiOMe (10.5 g) was added in one portion and the resulting solution was aged at 40° C. for 2 h. Upon completion, as determined by HPLC, the reaction mixture was transferred to a separatory funnel containing cold H2O (800 mL, precooled to 10 deg C.). An additional 400 mL cold H2O was used to rinse the reaction vessel and this rinse was also added to the seperatory funnel. The combined aqueous was washed with iPrOAc (500 mL) and then acidified to a pH of 3 with 6 N HCl (ca. 60 mL). The resulting heterogeneous solution was aged for 30 min and then the precipitate was filtered, washed with 70% EtOH (100 mL) and dried on the filter funnel under a stream of N2 affording desired acid 5 as a crude yellow solid. The crude dry product and THF (260 mL) were charged into a clean reaction vessel fitted with a mechanical stirrer and nitrogen inlet adapter. Heptane (30 mL) was slowly added to the resulting solution over 30 min and then aged resulting in crystallization. Additional heptane (270 mL) was added over 1 h, aged for an additional 1 h and then filtered. The reaction vessel was then rinsed with 70% EtOH (100 mL) and this rinse was added to the filter cake. The wet cake was then transferred to a clean reaction vessel containing 70% EtOH (750 mL) and the resulting heterogeneous mixture was stirred overnight. The product was then filtered, rinsed with fresh 70% EtOH (100 mL) and then dried on the filter funnel under a stream of N2. The semi-wet cake was then transferred to clean trays and dried to a constant weight in the vacuum oven (40° C., 20 inHg) affording 52.05 g (87% yield) of desired 4-[3-(5-benzo[b]thiophen-2-yl-2,4-dimethoxy-phenyl)-E-acryloyl]-benzoic acid 5 as a yellow crystalline solid, m.p. 231–232° C. (dec.). HPLC assay of this solid indicated >99.9 LCAP. 1H-NMR identical as above.

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