Potassium Phosphate, Tribasic → (3S,6R)-1-[6-(4-Cyano-3,5-difluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide

HRID 2367312Notes

Reaction equation

HRID 2367312 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[C:33]([F:34])=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:38])#[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[C:33]([F:34])=[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:38])#[N:27]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 51357955(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamideHCID 55252910(4-Cyano-3,5-difluorophenyl)boronic acid

Product 1

HCID 58504510(3S,6R)-1-[6-(4-Cyano-3,5-difluorophenyl)-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamideYield 63.8%

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 (600 mg, 1.64 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (390 mg, 2.13 mmol, 1.3 equiv), Pd2(dba)3 (113 mg, 0.12 mmol, 0.075 equiv), tricyclohexylphosphine (69 mg, 0.246 mmol, 0.15 equiv), and K3PO4 (592 mg, 2.79 mmol, 1.7 equiv) were charged to a seal tube, followed by addition of 1,4-dioxane (12 mL) and water (4 mL). The mixture was bubbled with argon for 10 minutes, capped and heated at 100° C. for 20 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc afforded the title compound (490 mg). LC-MS (ES) m/z=469 [M+H]+.

Workup

  1. customThe mixture was bubbled with argon for 10 minutes
  2. customcapped
  3. filtrationThe mixture was filtered through celite
  4. concentrationthe filtrate was concentrated in vacuo
  5. customThe resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL)
  6. dry with materialthe organic layer was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification by silica gel column chromatography
  10. washelution of 1% EtOAc in CHCl3 to 100% EtOAc

Sources & evidence

ORD record
ord-1acbfe7f839e451eae95ce1a8278f780
Source dataset
uspto-grants-2014_04
Patent number
US08697685B2

Reaction notes

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