Potassium Phosphate, Tribasic → Tert-butyl 3-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate

HRID 517981Notes

Reaction equation

HRID 517981 reaction equation
CC1(C)C(C)(C)OB([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)=[C:11]([C:29]([F:32])([F:31])[F:30])[CH:10]=2)O1.[NH2:34][C:35]1[C:36]([C:44]#[N:45])=[N:37][C:38](Cl)=[CH:39][C:40]=1[NH:41][CH3:42].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CCOC(C)=O.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].C(Cl)Cl.O>[NH2:34][C:35]1[C:40]([NH:41][CH3:42])=[CH:39][C:38]([C:9]2[CH:28]=[CH:27][C:12]([O:13][CH2:14][CH2:15][CH:16]3[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:19]3)=[C:11]([C:29]([F:31])([F:32])[F:30])[CH:10]=2)=[N:37][C:36]=1[C:44]#[N:45]

Participants

10

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 576575713-Amino-6-chloro-4-methylamino-pyridine-2-carbonitrileHCID 67294290Tert-butyl 3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate

Product 1

HCID 67294695Tert-butyl 3-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of tert-butyl 3-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate (413 mg) in dioxane (3 ml) was added to a flask charged with 3-amino-6-chloro-4-(methylamino)picolinonitrile (160 mg), tris(dibenzylideneacetone)dipalladium (0) (40.1 mg), tricyclohexylphosphine (29.5 mg) and potassium phosphate (372 mg). Water (1.2 ml) was added and the reaction was placed under a nitrogen atmosphere and heated to 100° C. for 2 hours. The mixture was allowed to cool to room temperature then diluted with EtOAc (150 ml) filtered through celite and washed with water (2×100 ml) and brine (50 ml). Organics were dried over sodium sulphate and solvent evaporated under reduced pressure to afford crude product as a brown oil. Purification by flash chromatography (50 g silica column, DCM to 5% MeOH in DCM mobile phase) afforded product still containing minor impurities. DCM was added to the residue causing solid to crash out of solution. The solid was collected by filtration and washed with ether to yield desired product tert-butyl 3-(2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethyl)azetidine-1-carboxylate.

Workup

  1. temperatureto cool to room temperature
  2. filtrationfiltered through celite
  3. washwashed with water (2×100 ml) and brine (50 ml)
  4. dry with materialOrganics were dried over sodium sulphate and solvent
  5. customevaporated under reduced pressure
  6. customto afford crude product as a brown oil
  7. customPurification by flash chromatography (50 g silica column, DCM to 5% MeOH in DCM mobile phase)
  8. customafforded product
  9. additionstill containing minor impurities
  10. filtrationThe solid was collected by filtration
  11. washwashed with ether

Sources & evidence

ORD record
ord-5452c535990c4e6f885b5556cd67f6fd
Source dataset
uspto-grants-2015_08
Patent number
US09115126B2

Reaction notes

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