Cesium carbonate → HCID 118556245, compound

HRID 2199777Notes

Reaction equation

HRID 2199777 reaction equation
[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C(OC)=CC=C(OC)C=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:60]1[S:61][CH:62]=[C:63]([C:65]#[N:66])[N:64]=1>C(O)(C)(C)C>[C:1]([O:5][C:6](=[O:14])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:60]2[S:61][CH:62]=[C:63]([C:65]#[N:66])[N:64]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 1514172(3R)-3-Aminopiperidine, 3-BOC protectedHCID 25112535BrettphosHCID 454804392-Bromo-1,3-thiazole-4-carbonitrile

Product 1

HCID 118556245HCID 118556245, compound

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Procedure

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%).

Workup

  1. customThe mixture was degassed under vacuum (˜50 mmHg)
  2. customwhile sonicating
  3. additionthe flask then charged with argon
  4. customDegassing
  5. customthe flask evacuated
  6. temperatureheating mantle
  7. temperatureheated
  8. temperatureto reflux under argon for 5 hours
  9. additionpoured into water (1 L)
  10. extractionextracted with ethyl acetate (3×200 mL)
  11. washthe combined organic extracts washed with brine (2×200 mL)
  12. dry with materialdried over sodium sulfate
  13. filtrationfiltered
  14. concentrationconcentrated in vacuo
  15. customThe residue was purified by chromatography
  16. washeluted from 10% up to 40% ethyl acetate in hexanes at a flow rate of 100 mL/min Product
  17. additioncontaining fractions
  18. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-173683d25f194e809d762b1d0147d9b0
Source dataset
uspto-grants-2016_06
Patent number
US09359345B2

Reaction notes

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