Potassium Phosphate, Tribasic → (3S,6R)-1-[6-(4-Cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide

HRID 2367298Notes

Reaction equation

HRID 2367298 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])[CH2:11]2)[CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:37])#[N:27].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:30][C:29]=1[F:37])#[N:27]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 2783130(4-Cyano-3-fluorophenyl)boronic acidHCID 51357955(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide

Product 1

HCID 58504379(3S,6R)-1-[6-(4-Cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamideYield 69.8%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (300 mg, 0.82 mmol), (4-cyano-3-fluorophenyl)boronic acid (176 mg, 1.07 mmol, 1.3 equiv), Pd2(dba)3 (56 mg, 0.061 mmol, 0.075 equiv), tricyclohexylphosphine (34.5 mg, 0.123 mmol, 0.15 equiv) and K3PO4 (296 mg, 1.39 mmol, 1.7 equiv) were charged to a 30 mL microwave vial, followed by addition of 1,4-dioxane (6 mL) and water (2 mL). The mixture was bubbled with argon for 10 minutes, and heated at 100° C. for 20 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and brine (20 mL). The organic was dried (Na2SO4), filtered and concentrated in vacuo to give a residue. This crude material was purified by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc to afford the title compound (258 mg). LC-MS (ES) m/z=451 [M+H]+.

Workup

  1. customThe mixture was bubbled with argon for 10 minutes
  2. filtrationThe mixture was filtered through celite
  3. concentrationthe filtrate was concentrated in vacuo
  4. customThe residue was partitioned between EtOAc (75 mL) and brine (20 mL)
  5. dry with materialThe organic was dried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customto give a residue
  9. customThis crude material was purified by silica gel column chromatography
  10. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

Sources & evidence

ORD record
ord-146ea991379a42c5a964911bc1f6f502
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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