1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine) → 2-[4-[[5-Fluoro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid

HRID 1045938Notes

Reaction equation

HRID 1045938 reaction equation
CC(C)([O-])C.[Na+].Cl.Cl.[NH2:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.Cl[C:20]1[CH:25]=[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[CH2:33][CH2:32]3)[C:23]([F:39])=[CH:22][N:21]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.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]>[F:39][C:23]1[C:24]([NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[C:31]3[C:36]=2[C:35](=[O:37])[N:34]([CH3:38])[CH2:33][CH2:32]3)=[CH:25][C:20]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[N:21][CH:22]=1

Participants

7

Reactant 4

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 23676156Sodium t-butoxideHCID 67075935(4-Amino-1H-pyrazol-1-yl)acetic acid dihydrochlorideHCID 866551428-[(2-Chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one

Product 1

HCID 670754132-[4-[[5-Fluoro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acidYield 108.3%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

Reaction performed in 2 batches: sodium tert-butoxide (778 mg, 8.09 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (481 mg, 2.25 mmol) in 1,4-dioxane (15 mL) at 22° C. under an atmosphere of nitrogen. The mixture was stirred and sonicated for 5 minutes and then 8-[(2-chloro-5-fluoropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (275 mg, 0.90 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (84 mg, 0.15 mmol) were added and the resulting suspension purged with nitrogen. Tris(dibenzylideneacetone)dipalladium (66 mg, 0.072 mmol) was added and the mixture was purged with nitrogen. The mixture was heated at 150° C. for 60 minutes in a microwave reactor and then allowed to cool to room temperature. The two batches were combined and the mixture was evaporated. The residue was partitioned between CH2Cl2 (150 mL) and a 0.1N solution of NaOH (150 mL). The aqueous layer was separated, washed with CH2Cl2 (100 mL) and then adjusted to pH4 with 2N HCl solution. The aqueous mixture was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL). The mixture was filtered and the residue washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to give 2-[4-[[5-fluoro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (400 mg, 54% yield); Mass spectrum: m/z (ESI+) (M+H)+ =411.37.

Workup

  1. customReaction
  2. customsonicated for 5 minutes
  3. customthe resulting suspension purged with nitrogen
  4. customthe mixture was purged with nitrogen
  5. temperatureto cool to room temperature
  6. customthe mixture was evaporated
  7. customThe residue was partitioned between CH2Cl2 (150 mL)
  8. customThe aqueous layer was separated
  9. washwashed with CH2Cl2 (100 mL)
  10. washThe aqueous mixture was washed with CH2Cl2 (100 mL)
  11. filtrationfiltered
  12. customevaporated
  13. customThe residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL)
  14. filtrationThe mixture was filtered
  15. washthe residue washed with a 1:1 mixture of CH2Cl2/MeOH
  16. customThe combined filtrates were evaporated

Sources & evidence

ORD record
ord-ebc7f244acc0459aa465374c305eabe6
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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