1-Bromo-3-chloropropane → HCID 118021543, compound

HRID 2284532Notes

Reaction equation

HRID 2284532 reaction equation
[Li]CCCC.[C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)#[N:7].Br[CH2:22][CH2:23][CH2:24][Cl:25].[NH4+].[Cl-]>O.C1COCC1>[Cl:25][CH2:24][CH2:23][CH2:22][C:8]1([C:6]#[N:7])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1

Participants

7

Reactant 4

HCID 80061-Bromo-3-chloropropane2×HCID 25517Ammonium ChlorideHCID 1514443Tert-butyl 4-cyanopiperidine-1-carboxylate2×HCID 178418339Butyllithium

Product 1

HCID 118021543HCID 118021543, compoundYield 86.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
2.5 °C

Procedure

Charge 1780 g of THF and 86.6 g of diisopropylanmine to R1. Cool the mixture in R1 to −40° C.˜−60° C. Add drop-wise 210.5 g of n-BuLi (1.6 eq) into R1 and stir the mixture for 0.5-1 hour. Charge 890 g of THF then 100.0 g of tert-butyl 4-cyanopiperidine-1-carboxylate into R2. Add the solution of tert-butyl 4-cyanopiperidine-1-carboxylate in R2 drop-wise to R1, controling the temperature at −40° C.˜−60° C. Stir the mixture in R1 for 1˜2 hour. Charge 890 g of THF and 130.5 g of 1-bromo-3-chloro-propane into R2. Add the solution of 1-bromo-3-chloro-propane in R2 drop-wise to R1, control the temperature at −40˜−60° C. Stir the mixture in R1 for 3 hours at −40˜−60° C. then slowly warm the mixture to 20˜25° C. and stir for 13˜16 hours. Cool the mixture to 0˜5° C. Add drop-wise 525 g of NH4Cl (saturated aqueous solution) then 500 g of water into R1. Concentrate the mixture to total weight 1000˜1100 g below 40° C. then add 380 g of MTBE. Stir the mixture at 10˜20° C. for 20-40 minutes then allow to stand for 30˜60 mins Separate the aqueous layer and wash the organic layer with 2×500 g of H2O. Concentrate the mixture to 300 g total weight below 50° C. Add 136 g of n-heptane then concentrate the mixture to 300 g total weight below 50° C. Cool the mixture 0-5° C., then add drop-wise 340 g of n-heptane. Stir the mixture in for 5˜10 hours, then filter the suspension. Rinse the flask with 68.0 g of n-heptane, then wash the cake to provide of tert-butyl 4-(3-chloropropyl)-4-cyano-piperidine-1-carboxylate (118 g, 87.2% Assay, 75.4% yield): mass spectrum (m/z): 231 (M+H-tBu). Transfer the cake to a flask and add 610.0 g of Toluene. Concentrate mixture to 500 g total weight below 50° C. The product is stored as a toluene solution until required.

Workup

  1. temperatureCool the mixture in R1 to −40° C.˜−60° C
  2. customat −40° C.˜−60° C
  3. stirringStir the mixture in R1 for 1˜2 hour
  4. customat −40˜−60° C
  5. stirringStir the mixture in R1 for 3 hours at −40˜−60° C.
  6. temperaturethen slowly warm the mixture to 20˜25° C.
  7. stirringstir for 13˜16 hours
  8. temperatureCool the mixture to 0˜5° C
  9. concentrationConcentrate the mixture to total weight 1000˜1100 g below 40° C.
  10. additionthen add 380 g of MTBE
  11. stirringStir the mixture at 10˜20° C. for 20-40 minutes
  12. waitto stand for 30˜60 mins
  13. customSeparate the aqueous layer
  14. washwash the organic layer with 2×500 g of H2O
  15. concentrationConcentrate the mixture to 300 g total weight below 50° C
  16. additionAdd 136 g of n-heptane
  17. concentrationthen concentrate the mixture to 300 g total weight below 50° C
  18. additionadd drop-wise 340 g of n-heptane
  19. stirringStir the mixture in for 5˜10 hours
  20. filtrationfilter the suspension
  21. washRinse the flask with 68.0 g of n-heptane
  22. washwash the cake

Sources & evidence

ORD record
ord-06499a53bd54498c8573519c056046c2
Source dataset
uspto-grants-2015_09
Patent number
US09145435B2

Reaction notes

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