Potassium Phosphate, Tribasic → tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate

HRID 1504875Notes

Reaction equation

HRID 1504875 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:11]=[C:12]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]3[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:13]=[N:14][C:15]=2[C:16]#[N:17])[CH:3]=1.[CH3:33][C:34]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][O:36][N:35]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.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].O1CCOCC1>[C:16]([C:15]1[N:14]=[CH:13][C:12]([NH:18][C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]2[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:11][C:10]=1[NH:9][C:4]1[CH:3]=[C:2]([C:38]2[C:34]([CH3:33])=[N:35][O:36][CH:37]=2)[CH:7]=[C:6]([CH3:8])[N:5]=1)#[N:17]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 75806TricyclohexylphosphineHCID 772303803-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazoleHCID 86731656tert-butyl (1S,2R)-2-(5-(4-chloro-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

Product 1

HCID 86731745tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To tert-butyl (1S,2R)-2-(5-(4-chloro-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate (PrepEx 1.7) (50 mg, 0.11 mmol), 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (27 mg, 0.13 mmol), and tricyclohexylphosphine (4 mg, 0.01 mmol) in a nitrogen purged vial was added dioxane (0.6 ml) and potassium phosphate tribasic (1.25 M in water, 0.26 ml, 0.33 mmol). The reaction mixture was purged with nitrogen, and then Pd2 dba3 (5 mg, 0.005 mmol) was added. The reaction vessel was sealed and heated at 100° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes, linear gradient) to give tert-butyl (1S,2R)-2-(6-cyano-5-(6-methyl-4-(3-methylisoxazol-4-yl)pyridin-2-ylamino)pyridin-3-ylamino)cyclohexylcarbamate. MS ESI calc'd. for C27H34N7O3 [M+H]+ 504. found 504.

Workup

  1. customThe reaction mixture was purged with nitrogen
  2. customThe reaction vessel was sealed
  3. washwashed with aqueous saturated sodium bicarbonate solution (10 mL)
  4. customThe organics were separated
  5. dry with materialdried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes, linear gradient)

Sources & evidence

ORD record
ord-8505986d6e2540ad83afe5fe9c53072a
Source dataset
uspto-grants-2015_12
Patent number
US09216173B2

Reaction notes

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