Ammonium Chloride → acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzyl ester

HRID 1431184Notes

Reaction equation

[C:1]([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:3])[CH3:2].Cl[C:38]1[CH:39]=[C:40]([NH:46][C:47]2[CH:59]=[C:50]3[CH2:51][N:52]([CH:55]4[CH2:58][O:57][CH2:56]4)[CH2:53][CH2:54][N:49]3[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:59]=[C:50]5[CH2:51][N:52]([CH:55]6[CH2:58][O:57][CH2:56]6)[CH2:53][CH2:54][N:49]5[N:48]=4)[C:41](=[O:45])[N:42]([CH3:44])[N:43]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:30]=[CH:29]2)([CH3:33])([CH3:32])[CH3:34]

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 (249 mg, 0.50 mmol), 6-chloro-2-methyl-4-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-2H-pyridazin-3-one (113 mg, 0.34 mmol), potassium phosphate (178 mg, 0.84 mmol) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (16.0 mg, 0.03 mmol) in butanol (8 ml) and water (2 mL) was flushed with argon before (bis[dibenzylideneacetone]dipalladium) (9.65 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 (2×100 mL). The layers were separated and the organic phase dried over magnesium sulfate. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 24 g, 1% to 10% methanol in dichloromethane) to give acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-[1-methyl-5-(5-oxetan-3-yl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzyl ester (113 mg, 54%) as a light yellow solid: mp. 180-185° C.; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.37 (s, 9H) 2.66-2.92 (m, 2H) 3.40-3.83 (m, 6H) 3.98 (t, J=5.48 Hz, 2H) 4.26-4.82 (m, 7H) 6.01 (s, 1H) 7.36-8.00 (m, 6H) 8.50 (d, J=2.64 Hz, 1H) 9.25 (s, 1H).

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 (2×100 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 10% methanol in dichloromethane)

Sources & evidence

ORD record: ord-4eb3740cbe4e4d1580306aef81eb92fd
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08940741B2

Reaction notes

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