Reaktion #2286959

Reaktionsgleichung

(R)-piperidin-3-yl-carbamic acid tert-butyl ester

cesium carbonate

2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-isopropyl-1,1′-biphenyl

2-bromothiazole-4-carbonitrile

→

[(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester

Lösungsmittel

tert-butanol

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe mixture was degassed under vacuum (˜50 mmHg)
2. 2
   Sonstigewhile sonicating
3. 3
   workup.ADDITIONthe flask then charged with argon
4. 4
   SonstigeDegassing
5. 5
   Sonstigethe flask evacuated
6. 6
   Temperaturheating mantle
7. 7
   Temperaturheated
8. 8
   Temperaturto reflux under argon for 5 hours
9. 9
   workup.ADDITIONpoured into water (1 L)
10. 10
    Extraktionextracted with ethyl acetate (3×200 mL)
11. 11
    Waschenthe combined organic extracts washed with brine (2×200 mL)
12. 12
    Trocknendried over sodium sulfate
13. 13
    Filtrationfiltered
14. 14
    Einengenconcentrated in vacuo
15. 15
    SonstigeThe residue was purified by chromatography
16. 16
    Wascheneluted from 10% up to 40% ethyl acetate in hexanes at a flow rate of 100 mL/min Product
17. 17
    workup.ADDITIONcontaining fractions
18. 18
    Einengenconcentrated in vacuo

Vorschrift

To a 500 mL round bottom flask were added (R)-piperidin-3-yl-carbamic acid tert-butyl ester (10.3 g, 51.6 mmol), cesium carbonate (33.6 g, 103 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (BrettPhos, CAS number 1070663-78-3) (369 mg, 688 μmol) and 2-bromothiazole-4-carbonitrile (6.5 g, 34.4 mmol) followed by tert-butanol (225 mL). The mixture was degassed under vacuum (˜50 mmHg) while sonicating and the flask then charged with argon. Degassing repeated twice. Tris-(dibenzylideneacetone)dipalladium(0) (CAS number 51364-51-3) (315 mg, 344 μmol) was added and the flask evacuated and recharged with argon. Repeated twice. The reaction flask was transferred to an aluminum block heating mantle and heated to reflux under argon for 5 hours. The reaction mixture was cooled to ambient temperature and poured into water (1 L), extracted with ethyl acetate (3×200 mL), the combined organic extracts washed with brine (2×200 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography using a 330 g silica column gradient eluted from 10% up to 40% ethyl acetate in hexanes at a flow rate of 100 mL/min Product containing fractions were combined and concentrated in vacuo to give of [(R)-1-(4-cyano-thiazol-2-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester as an off white solid (8.75 g, 78%).

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