Cesium carbonate → 5-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinic acid

HRID 2065576Notes

Reaction equation

HRID 2065576 reaction equation
C[C:2]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:13]1[N:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)=[CH:15][N:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O1CCOCC1>[F:28][CH:26]([F:27])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[N:18][C:13]([NH:11][C:8]3[CH:9]=[N:10][CH:2]=[C:3]([CH:7]=3)[C:4]([OH:6])=[O:5])=[N:14][CH:15]=2)=[CH:24][CH:23]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 337783965-Amino-2-methylnicotinic acidHCID 581719302-Chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine

Product 1

HCID 581719845-(5-(4-(Difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinic acid

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A vial is charged with methyl 5-aminonicotinic acid 18 (1.45 mmol), 2-chloro-5-(4-(difluoromethoxy)phenyl)pyrimidine 17 (1.45 mmol), Pd(OAc)2 (0.22 mmol), xanthphos (0.22 mmol), Cs2CO3 (1.45 mmol) and anhydrous 1,4-dioxane (5 mL). The vial is evacuated and refilled with N2 twice and the mixture is heated in an oil bath at 100° C. for 3 h. The vial is cooled down to it and the reaction mixture is diluted with water (20 mL) and pH neutralized with 10% Na2CO3. The resulting suspension is extracted with DCM:IPA=3:1 (3×50 mL). The organic layer is washed once with brine and dried over Na2SO4. The solvent is removed in vacuum and the orange crude is purified by preparative HPLC (MeCN gradient 20-70%) to afford 5 5-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)nicotinic acid 19. MS (m/z) (M+1)+: 359.1.

Workup

  1. customThe vial is evacuated
  2. additionrefilled with N2 twice
  3. temperatureThe vial is cooled down to it
  4. additionthe reaction mixture is diluted with water (20 mL)
  5. extractionThe resulting suspension is extracted with DCM
  6. washThe organic layer is washed once with brine
  7. dry with materialdried over Na2SO4
  8. customThe solvent is removed in vacuum
  9. customthe orange crude is purified by preparative HPLC (MeCN gradient 20-70%)

Sources & evidence

ORD record
ord-7b3eab83a7824b50bf421e95746dff48
Source dataset
uspto-grants-2012_10
Patent number
US08288540B2

Reaction notes

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