Ammonium Chloride → HCID 66742621, compound

HRID 449670Notes

Reaction equation

C([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[N:30]=[CH:29][C:28]2[C:23](=[C:24]([F:35])[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=2)[C:22]1=[O:36])(=O)C.Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:52]=[N:51][C:50]([C@H:53]3[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]3)=[CH:49][N:48]=2)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[Cl-].[NH4+]>C(O)CCC.O>[C:31]([C:26]1[CH:27]=[C:28]2[C:23](=[C:24]([F:35])[CH:25]=1)[C:22](=[O:36])[N:21]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:38]3[CH:39]=[C:40]([NH:46][C:47]4[CH:52]=[N:51][C:50]([C@H:53]5[CH2:57][O:56][C:55]([CH3:58])([CH3:59])[O:54]5)=[CH:49][N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][OH:4])[N:30]=[CH:29]2)([CH3:34])([CH3:32])[CH3:33]

Participants

Conditions

Temperature: 100 °C

Procedure

A solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (307 mg, 0.62 mmol), (S)-6-chloro-4-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-2-methylpyridazin-3(2H)-one (150 mg, 0.44 mmol), potassium phosphate (236 mg, 0.01 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (21.2 mg, 0.04 mmol) in butanol (4 ml) and water (1 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (12.8 mg, 0.02 mmol) was added and the resulting solution heated at 100° C. in for 2 h. The resulting mixture was cooled, poured into a saturated solution of ammonium chloride and extracted with methylene chloride (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was dissolved in dioxane (10 mL) and treated with a lithium hydroxide solution (0.5 mL, 2.0 M), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was poured into a saturated ammonium chloride solution and extracted with methylene chloride (2×150 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 7% methanol in dichloromethane) to give (S)-6-tert-butyl-2-(3-(5-(5-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrazin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-2-(hydroxymethyl)phenyl)-8-fluorophthalazin-1(2H)-one (99 mg, 36%) as a light yellow solid.

Workup

additionwas added
temperatureThe resulting mixture was cooled
extractionextracted with methylene chloride (2×100 mL)
customThe layers were separated
dry with materialthe organic phase dried over magnesium sulfate
filtrationThe mixture was filtered
concentrationconcentrated in vacuo
dissolutionThe residue was dissolved in dioxane (10 mL)
additiontreated with a lithium hydroxide solution (0.5 mL, 2.0 M)
additionThe resulting mixture was poured into a saturated ammonium chloride solution
extractionextracted with methylene chloride (2×150 mL)
customThe layers were separated
dry with materialthe organic phase dried over magnesium sulfate
filtrationThe mixture was filtered
concentrationconcentrated in vacuo
customThe residue was purified by flash chromatography (silica gel, 24 g, 1% to 7% methanol in dichloromethane)

Sources & evidence

ORD record: ord-72bb2f02d1d54f1a8f176641dcc31484
Source dataset: uspto-grants-2013_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08481540B2

Reaction notes

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