Potassium Carbonate → HCID 178456328, Verbindung

To a flame-dried flask was added 2-(4-isopropyl-piperazin-1-yl)-isonicotinonitrile (1.09 g, 4.75 mmol) and anhydrous THF (5 ml). To this stirred solution under nitrogen atmosphere was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (4.75 ml, 1.0 equiv) via syringe. The reaction mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate solution (7.78 ml) was added, followed by water (7.8 ml), K2CO3 (0.59 g, 4.27 mmol, 0.9 equiv), and a solution of 2-bromo-3′-chloro-4′-fluoroacetophenone (1.19 g, 4.75 mmol, 1.0 equiv) in chloroform (20 ml). After stirring overnight, the aqueous phase was separated and extracted with chloroform. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in glacial acetic acid (10 ml) and heated to 50° C. for 1 hour. The mixture was cooled to room temperature and partitioned between aqueous 1N NaOH solution and ethyl acetate. The organic phase was removed, and the aqueous phase was saturated with NaCl and extracted again with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Purification of the residue by flash column chromatography (CH2Cl2 grading to 10% methanol/0.5% ammonium hydroxide/CH2Cl2) provided the desired product, which was converted to its hydrochloride salt (MeOH/ethereal HCl; 0.92 g). MS m/z 400 (M++1).

1. stirringAfter stirring overnight
2. customthe aqueous phase was separated
3. extractionextracted with chloroform
4. dry with materialdried over anhydrous magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. dissolutionThe residue was dissolved in glacial acetic acid (10 ml)
8. temperatureheated to 50° C. for 1 hour
9. temperatureThe mixture was cooled to room temperature
10. custompartitioned between aqueous 1N NaOH solution and ethyl acetate
11. customThe organic phase was removed
12. extractionextracted again with ethyl acetate
13. dry with materialdried over anhydrous magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customPurification of the residue by flash column chromatography (CH2Cl2 grading to 10% methanol/0.5% ammonium hydroxide/CH2Cl2)

ORD-Eintrag

ord-c9a37085e78e48368e76c676d9ebc41f

Quelldatensatz

uspto-grants-2003_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US06514966B2