Sodium Carbonate → 1-Benzyl-5-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester

HRID 2191098Notes

Reaction equation

HRID 2191098 reaction equation
[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[Cl:59][C:60]1[CH:65]=[CH:64][C:63](B(O)O)=[CH:62][CH:61]=1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:17]([O:16][C:14]([C:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]=1[C:63]1[CH:64]=[CH:65][C:60]([Cl:59])=[CH:61][CH:62]=1)=[O:15])[CH3:18]

Participants

10

Reactant 6

HCID 10340Sodium Carbonate2×HCID 67749Trifluoromethanesulfonic anhydrideHCID 742994-Chlorophenylboronic acidHCID 81531DiisopropylethylamineHCID 419705Ethyl 3-oxo-1-(phenylmethyl)-4-piperidinecarboxylateHCID 86644017Na2CO3 CH2Cl2

Product 1

HCID 594381281-Benzyl-5-(4-chloro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl esterYield 48.7%

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-30 °C

Procedure

In a 1500 mL four necked flask (with mechanical stirrer) 22 g (84.2 mmol) ethyl N-benzyl-3-oxo-4-piperidine-carboxylate (from the HCl-salt by aq.Na2CO3/CH2Cl2-extraction) and 43.5 mL (252 mmol) DIPEA were dissolved in 300 mL DCM. The amber solution was cooled to −20° C. to −30° C. 28.5 g (101 mmol) trifluoromethanesulfonic anhydride were added drop wise over a period of 45 min. The dark brown solution was stirred for 2 h at −20° C./−30° C. 300 mL water and 300 mL 10% Na2CO3 aq. was added and the mixture was stirred for 15 min at 5-10° C. The organic layer was separated and the aqueous layer was extracted twice with 150 mL DCM. The combined organic layers were dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and dissolved in 500 mL dioxane. 15.8 g (101 mmol) 4-chlorophenylboronic acid, 93 mL Na2CO3 aq. (2M) and 3.8 g (3.36 mmol) tetrakis(triphenylphosphine)palladium(0) was added and the mixture was heated to reflux over night. After cooling to room temperature, the mixture was diluted with 400 g ice-water and extracted twice with 400 mL ethyl acetate. The organic layers were extracted once with 500 mL brine. After drying over Na2SO4 the filtrate was evaporated to dryness. The black oil was absorbed on 60 g isolute HM-N and purified by column chromatography to yield 14.6 g (48%) of the title compound as viscous yellow oil. MS (m/e): 356.3 [(M+H)+].

Workup

  1. temperatureThe amber solution was cooled to −20° C. to −30° C
  2. stirringthe mixture was stirred for 15 min at 5-10° C
  3. customThe organic layer was separated
  4. extractionthe aqueous layer was extracted twice with 150 mL DCM
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. customThe filtrate was evaporated to dryness
  8. dissolutiondissolved in 500 mL dioxane
  9. temperaturethe mixture was heated
  10. temperatureto reflux over night
  11. temperatureAfter cooling to room temperature
  12. extractionextracted twice with 400 mL ethyl acetate
  13. extractionThe organic layers were extracted once with 500 mL brine
  14. dry with materialAfter drying over Na2SO4 the filtrate
  15. customwas evaporated to dryness
  16. customThe black oil was absorbed on 60 g
  17. custompurified by column chromatography

Sources & evidence

ORD record
ord-9e7e9c6970c34d2ca816aa02f3ed4677
Source dataset
uspto-grants-2012_12
Patent number
US08324248B2

Reaction notes

Loading…