Methane → (R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

HRID 2088901Notes

Reaction equation

HRID 2088901 reaction equation
Cl.Cl.Cl.[N:4]1([CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:13]=[C:12]2[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:29]1[C:30]2[C@H:38]([CH3:39])[CH2:37][C:36](=[O:40])[NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.N12CCCN=C1CCCCC2.C>C(O)CC.C(OCCCC)(=O)C>[CH3:39][C@H:38]1[C:30]2[C:29]([N:25]3[CH2:24][CH2:23][CH:22]([C:12]4[N:11]([CH2:10][CH2:9][N:4]5[CH2:5][CH2:6][CH2:7][CH2:8]5)[CH:15]=[C:14]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[N:13]=4)[CH2:27][CH2:26]3)=[N:34][CH:33]=[N:32][C:31]=2[NH:35][C:36](=[O:40])[CH2:37]1

Participants

7

Reactant 4

HCID 297MethaneHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 671120104-(1-(2-(Pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochlorideHCID 86666575(R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

Product 1

HCID 67112053(R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-oneYield 109%

Reagents, catalysts & solvents 2

HCID 10311-PropanolSolvent3×HCID 31272Butyl AcetateSolvent

Procedure

Charge 4-(1-(2-(Pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride (300 g, 1.0 equiv), (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (146.2 g, 1.0 equiv) and n-propanol (3.0 L) to a 12-L reaction flask. Stir the reaction mixture and add 1,8-diazabicyclo[5.4.0]undec-7-ene (394.3 g, 3.5 equiv) over ten minutes. Heat the reaction to 90° C. for 8 hours, and allow to cool to room temperature over 12 hours. Displace the n-propanol with n-butyl acetate to a total volume of 3-L and a residual n-propanol content of 11% (w/w). Heat the organic solution to 50-60° C. and wash with brine (2.25 L). Back-extract the aqueous phase with nButyl acetate (1.5 L) and combine the organic layers. Wash the combined organic layers with water (2×450 mL) at 50-60° C. Separate the organic layer and add activated charcoal (75 g, 0.25 equiv) and stir at 50-60° C. for 30 min. Filter the slurry and rinse the solids with n butyl acetate (1.5 L). Wash with water (1 L), separate the organic phase and azeotropically dry the organic phase to remove water. At 50-60° C., add heptanes (3.0 L) cool to 40° C. and add seed crystals. Allow the slurry to cool to room temperature over ˜12 h. Cool to 0-5° C., filter the slurry and wash with heptanes (2×900 mL). Dry in vacuo and isolate (R)-5-Methyl-4-(4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a white solid (365.3 g, 64%). MS (ES) m/z=494 [M]+.

Workup

  1. temperatureHeat
  2. customthe reaction to 90° C. for 8 hours
  3. temperatureHeat the organic solution to 50-60° C.
  4. washwash with brine (2.25 L)
  5. extractionBack-extract the aqueous phase with nButyl acetate (1.5 L)
  6. washWash the combined organic layers with water (2×450 mL) at 50-60° C
  7. customSeparate the organic layer
  8. stirringstir at 50-60° C. for 30 min
  9. filtrationFilter the slurry
  10. washrinse the solids with n butyl acetate (1.5 L)
  11. washWash with water (1 L)
  12. customseparate the organic phase
  13. customazeotropically dry the organic phase
  14. customto remove water
  15. additionAt 50-60° C., add heptanes (3.0 L)
  16. temperaturecool to 40° C.
  17. additionadd seed crystals
  18. temperatureAllow the slurry to cool to room temperature over ˜12 h
  19. temperatureCool to 0-5° C.
  20. filtrationfilter the slurry
  21. washwash with heptanes (2×900 mL)
  22. customDry in vacuo

Sources & evidence

ORD record
ord-25adf51283f0425da7fb097a174d8bfb
Source dataset
uspto-grants-2013_05
Patent number
US08436002B2

Reaction notes

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