Hydrochloric Acid → 3-((2-((5-Fluoro-4-methylpyridin-2-yl)amino)-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid

HRID 629190Notes

Reaction equation

HRID 629190 reaction equation
Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:10]([O:18][CH3:19])=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=[O:13])[C:5]([C:20](=[O:23])[NH:21][CH3:22])=[CH:4][N:3]=1.[F:24][C:25]1[C:26]([CH3:32])=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>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].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.O>[F:24][C:25]1[C:26]([CH3:32])=[CH:27][C:28]([NH:31][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[C:10]([O:18][CH3:19])=[C:11]([CH:15]=[CH:16][CH:17]=3)[C:12]([OH:14])=[O:13])[C:5]([C:20](=[O:23])[NH:21][CH3:22])=[CH:4][N:3]=2)=[N:29][CH:30]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 2733832Lithium HexamethyldisilazideHCID 220636705-Fluoro-4-methylpyridin-2-amineHCID 901347923-((2-Chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid

Product 1

HCID 901350173-((2-((5-Fluoro-4-methylpyridin-2-yl)amino)-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acidYield 97%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 25112535BrettphosCatalystHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A reaction vial was charged with 3-((2-chloro-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid (600 mg, 1.787 mmol), 5-fluoro-4-methylpyridin-2-amine (316 mg, 2.502 mmol), BrettPhos (38.4 mg, 0.071 mmol) and Pd2(dba)3 (32.7 mg, 0.036 mmol) and the contents were flushed with nitrogen before adding dioxane (2 mL) and DMA (1 mL). The resulting slurry was sparged with additional nitrogen for ˜1 minutes, then LiHMDS (1 M in THF) (3.93 mL, 3.93 mmol) was added and the resulting dark amber colored solution was heated in a preheated heating block at 110° C. for 2 h, then cooled to room temperature. The reaction mixture was added to water (80 mL) and the pH was adjusted with aq. 1N HCl to ˜3 causing a solid to precipitate from solution. After stirring the slurry at room temperature for ˜4 h, the solid was collected by vacuum filtration, rinsed with water, and dried on the filter to afford 3-((2-((5-fluoro-4-methylpyridin-2-yl)amino)-5-(methylcarbamoyl)pyridin-4-yl)amino)-2-methoxybenzoic acid (736 mg, 1.730 mmol, 97% yield) as a beige solid. HPLC (Method N) RT=2.45 minutes. LCMS (m+1)=426.

Workup

  1. customA reaction
  2. customthe contents were flushed with nitrogen
  3. additionbefore adding dioxane (2 mL) and DMA (1 mL)
  4. customThe resulting slurry was sparged with additional nitrogen for ˜1 minutes
  5. temperaturecooled to room temperature
  6. customto precipitate from solution
  7. filtrationthe solid was collected by vacuum filtration
  8. washrinsed with water
  9. customdried on the
  10. filtrationfilter

Sources & evidence

ORD record
ord-da48b8c1e3f34e4ba4edf1fb986e135d
Source dataset
uspto-grants-2016_04
Patent number
US09315494B2

Reaction notes

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