Water → 2-tert-Butyl-5-(2-methyl-3-(5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one

HRID 872178Notes

Reaction equation

HRID 872178 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)[C:5](=[O:8])[NH:6][N:7]=1.[C:16]([C:20]1[S:21][C:22]2[C:27](=[O:28])[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31](B4OC(C)(C)C(C)(C)O4)[C:30]=3[CH3:44])[CH2:25][C:23]=2[N:24]=1)([CH3:19])([CH3:18])[CH3:17].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>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:20]1[S:21][C:22]2[C:27](=[O:28])[N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:2]4[CH:3]=[C:4]([NH:9][C:10]5[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=5)[C:5](=[O:8])[NH:6][N:7]=4)[C:30]=3[CH3:44])[CH2:25][C:23]=2[N:24]=1)([CH3:19])([CH3:18])[CH3:17]

Participants

8

Reactant 5

HCID 962WaterHCID 62657Potassium Phosphate, TribasicHCID 112698722-Dicyclohexylphosphino-2',6'-dimethoxybiphenylHCID 666132646-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)pyridazin-3(2H)-oneHCID 666348992-tert-Butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one

Product 1

HCID 569292312-tert-Butyl-5-(2-methyl-3-(5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-oneYield 31%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
110 °C

Procedure

A 5 mL pressure tube was charged with 6-chloro-4-(1-methyl-1H-pyrazol-3-ylamino)pyridazin-3(2H)-one 109g (20.0 mg, 0.089 mmol), 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f (43.9 mg mg, 0.11 mmol), 1.27 M of potassium phosphate in water (0.15 mL, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.1 mg, 0.0044 mmol), S-Phos (4.4 mg, 0.011 mmol), and 1,4-dioxane (1.4 mL). The mixture was purged with nitrogen, sealed, and heated at 110° C. overnight. The reaction mixture was cooled to room temperature, and filtered through Celite®. The filter cake was washed with methylene chloride/methanol (˜9:1). The filtrate was concentrated. The residue was purified on silica eluted with a gradient of 0 to 3.5% methanol in methylene chloride. The material obtained was further purified by reverse phase HPLC: C-18 column, eluted with a gradient of 0 to 80% acetonitrile in water over 20 min with 0.05% trifluoroacetic acid to afford 2-tert-butyl-5-(2-methyl-3-(5-(1-methyl-1H-pyrazol-3-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one (109) (13 mg, 31%). M+1476.2. 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 9.17 (s, 1H), 7.72 (s, 1H), 7.48 (d, J=2.2, 1H), 7.44 (dd, J=5.3, 3.9, 1H), 7.32 (dd, J=6.5, 2.7, 2H), 6.08 (d, J=2.3, 1H), 4.91 (s, 2H), 3.67 (s, 3H), 2.07 (s, 3H).

Workup

  1. customThe mixture was purged with nitrogen
  2. customsealed
  3. temperatureThe reaction mixture was cooled to room temperature
  4. filtrationfiltered through Celite®
  5. washThe filter cake was washed with methylene chloride/methanol (˜9:1)
  6. concentrationThe filtrate was concentrated
  7. customThe residue was purified on silica
  8. washeluted with a gradient of 0 to 3.5% methanol in methylene chloride
  9. customThe material obtained
  10. customwas further purified by reverse phase HPLC
  11. washC-18 column, eluted with a gradient of 0 to 80% acetonitrile in water over 20 min with 0.05% trifluoroacetic acid

Sources & evidence

ORD record
ord-9709656a637e474ab530d1ac27a13105
Source dataset
uspto-grants-2015_03
Patent number
US08975260B2

Reaction notes

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