Triethylamine → (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 2088915Notes

Reaction equation

HRID 2088915 reaction equation
Cl[C:2]1[C:3]2[C@H:11]([CH3:12])[CH2:10][C:9](=[O:13])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(N(CC)CC)C.[N:21]1([CH2:26][CH2:27][N:28]2[CH:32]=[C:31]([CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:30]=[C:29]2[CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(OCC)(=O)C.O.CN1CCCC1=O>[CH3:12][C@H:11]1[C:3]2[C:2]([N:42]3[CH2:41][CH2:40][CH:39]([C:29]4[N:28]([CH2:27][CH2:26][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25]5)[CH:32]=[C:31]([CH:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[N:30]=4)[CH2:44][CH2:43]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][C:9](=[O:13])[CH2:10]1

Participants

8

Reactant 4

HCID 8471TriethylamineHCID 14798Sodium HydroxideHCID 671119654-(1-(2-pyrrolidin-1-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-1H-imidazol-2-yl)-piperidineHCID 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 42%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
110 °C

Procedure

Combine (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (53.55 g, 270.96 mmol), triethylamine (37.77 mL, 1.1 eq), 4-(1-(2-pyrrolidin-1-yl-ethyl)-4-(tetrahydro-pyran-4-yl)-1H-imidazol-2-yl)-piperidine (81.9 g, 1.0 eq) and N-methylpyrrolidinone (246 mL). Stir at 110° C. overnight. Cool the reaction mixture to room temperature and dilute with ethyl acetate (400 mL) and water (1200 mL). Adjust the pH to 10 with 2 M aqueous sodium hydroxide and separate layers. Wash the aqueous phase with ethyl acetate (2×200 mL). Wash the organics with aqueous saturated sodium chloride. Add water (1 L) to the organics and adjust the pH to 3 with aqueous 85% phosphoric acid. Separate the layers and wash the resulting acidic aqueous phase with ethyl acetate (2×200 mL). Adjust the pH of the aqueous phase to 10 with 2 M aqueous sodium hydroxide. Extract with ethyl acetate (3×200 mL). Wash the organics with saturated aqueous sodium chloride (250 mL), dry over anhydrous magnesium sulfate, and concentrate in vacuo. Purify the residue by HPLC (Chiralpak AD, 70/30 hexanes/isopropyl alcohol w/0.2% dimethylethylamine) to give the final compound (51.0 g, 42%). MS (ES) m/z=494 [M]+.

Workup

  1. temperatureCool the reaction mixture to room temperature
  2. customseparate layers
  3. washWash the aqueous phase with ethyl acetate (2×200 mL)
  4. washWash the organics with aqueous saturated sodium chloride
  5. customSeparate the layers
  6. washwash the resulting acidic aqueous phase with ethyl acetate (2×200 mL)
  7. extractionExtract with ethyl acetate (3×200 mL)
  8. washWash the organics with saturated aqueous sodium chloride (250 mL)
  9. dry with materialdry over anhydrous magnesium sulfate
  10. concentrationconcentrate in vacuo
  11. customPurify the residue by HPLC (Chiralpak AD, 70/30 hexanes/isopropyl alcohol w/0.2% dimethylethylamine)

Sources & evidence

ORD record
ord-8e7a322b6a274dd891665ba47396e052
Source dataset
uspto-grants-2013_05
Patent number
US08436002B2

Reaction notes

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