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

HRID 1045925Notes

Reaction equation

HRID 1045925 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]([Cl: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]>[Cl: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 866551378-[(2,5-Dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one

Product 1

HCID 670759622-[4-[[5-Chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acidYield 63%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

Sodium tert-butoxide (805 mg, 8.38 mmol) was added to a suspension of 2-(4-aminopyrazol-1-yl)acetic acid dihydrochloride (498 mg, 2.33 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-[(2,5-dichloropyridin-4-yl)amino]-2-methyl-3,4-dihydroisoquinolin-1-one (300 mg, 0.93 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (86 mg, 0.15 mmol) were added and the resulting suspension was purged with nitrogen. tris(dibenzylideneacetone)dipalladium(0) (68.2 mg, 0.075 mmol) was added and the mixture 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 mixture was evaporated and the residue 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 solution was washed with CH2Cl2 (100 mL), filtered and then evaporated. The residue was triturated with a 1:1 mixture of CH2Cl2/MeOH (150 mL) and the resulting solid filtered and then washed with a 1:1 mixture of CH2Cl2/MeOH. The combined filtrates were evaporated to leave 2-[4-[[5-chloro-4-[(2-methyl-1-oxo-3,4-dihydroisoquinolin-8-yl)amino]pyridin-2-yl]amino]pyrazol-1-yl]acetic acid (250 mg, 63% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.96 (2H, t), 3.06 (3H, s), 3.57 (2H, t), 4.71 (2H, s), 6.81 (1H, s), 6.89 (1H, d), 7.40 (1H, s), 7.43-7.50 (2H, m), 7.90 (1H, d), 8.01 (1H, s), 8.86 (1H, s), 11.23 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=427.33 and 429.29.

Workup

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

Sources & evidence

ORD record
ord-a80638bddc974900850b3e080239fbc6
Source dataset
uspto-grants-2013_10
Patent number
US08569298B2

Reaction notes

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