HCID 117992217, compound → HCID 117992057, compound

HRID 625983Notes

Reaction equation

HRID 625983 reaction equation
[CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@H:11]([C:13]1[C:14]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[N:15][CH:16]=[N:17][C:18]=1Cl)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@H:11]([C:13]1[C:18]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[N:17][CH:16]=[N:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

3

Reactant 1

HCID 117992217HCID 117992217, compound

Product 1

HCID 117992057HCID 117992057, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
37.5 °C

Procedure

(R)-tert-butyl 4-(5-(4-(benzyloxy)-4-oxobutan-2-yl)-6-chloropyrimidin-4-yl)piperazine-1-carboxylate (1710 g) was dissolved in THF (4.0 L) and placed in a nitrogen-purged 5 gallon autoclave. Isopropanol (6.0 L) was added. The reaction mixture was sparged with nitrogen gas 5 times (25 psi), and the autoclave was heated to 35-40° C. A slurry of palladium acetate (81 g) and dppp (163 g) in isopropanol (2.0 L) was added at 40-45° C. and stirred. The reaction mixture was sparged with nitrogen gas 3 times (25 psi) and stirred for 20 minutes at 40-45° C. to dissolve the solids. A slurry of potassium carbonate, 325 mesh (299 g) in isopropanol (2.0 L) was added at 40-45° C. with stirring. The reaction mixture was sparged with nitrogen gas 5 times (25 psi), then sparged with carbon monoxide gas 5 times (40 psi). The autoclave was sparged with carbon monoxide gas to 55 psi. The reaction mixture was stirred at 50° C. and 55 psi (carbon monoxide gas) for a minimum of 50 hours and monitored by TLC and HPLC. The reaction mixture was cooled to room temperature and transferred into a filtration bottle. Silica gel (400 g) and Celite® (400 g) were added, and the reaction mixture was stirred open to air for 2 hours. The reaction mixture was filtered using a silica gel pad (1000 g) in a scintered funnel (D×H, 8×14 inches) and washed with ethyl acetate (4-5 L) and concentrated under vacuum to yield the product as viscous dark brown oil (contains residual dppp[O]2. Yield=1900 g (˜100%, contains residual dppp[O]2), structure confirmed by 1H-NMR (CDCl3).

Workup

  1. custompurged 5 gallon autoclave
  2. additionIsopropanol (6.0 L) was added
  3. customThe reaction mixture was sparged with nitrogen gas 5 times (25 psi)
  4. additionA slurry of palladium acetate (81 g) and dppp (163 g) in isopropanol (2.0 L) was added at 40-45° C.
  5. customThe reaction mixture was sparged with nitrogen gas 3 times (25 psi)
  6. stirringstirred for 20 minutes at 40-45° C.
  7. dissolutionto dissolve the solids
  8. additionA slurry of potassium carbonate, 325 mesh (299 g) in isopropanol (2.0 L) was added at 40-45° C.
  9. stirringwith stirring
  10. customThe reaction mixture was sparged with nitrogen gas 5 times (25 psi)
  11. customsparged with carbon monoxide gas 5 times (40 psi)
  12. customThe autoclave was sparged with carbon monoxide gas to 55 psi
  13. stirringThe reaction mixture was stirred at 50° C.
  14. customfor a minimum of 50 hours
  15. temperatureThe reaction mixture was cooled to room temperature
  16. additionSilica gel (400 g) and Celite® (400 g) were added
  17. stirringthe reaction mixture was stirred open to air for 2 hours
  18. filtrationThe reaction mixture was filtered
  19. washwashed with ethyl acetate (4-5 L)
  20. concentrationconcentrated under vacuum

Sources & evidence

ORD record
ord-1c9abb2e7f9d4628baf216d04c0fbad3
Source dataset
uspto-grants-2016_04
Patent number
US09309204B2

Reaction notes

Loading…