Potassium Phosphate, Tribasic → HCID 66742797, compound

HRID 449702Notes

Reaction equation

Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][C:20]([OH:24])([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[N:54]=[CH:53][C:52]2[C:47](=[C:48]([F:59])[CH:49]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:51]=2)[C:46]1=[O:60])(=[O:27])[CH3:26].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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]>[C:25]([O:28][CH2:29][C:30]1[C:35]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][C:20]([OH:24])([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[N:54]=[CH:53][C:52]2[C:47](=[C:48]([F:59])[CH:49]=[C:50]([C:55]([CH3:57])([CH3:56])[CH3:58])[CH:51]=2)[C:46]1=[O:60])(=[O:27])[CH3:26]

Participants

Conditions

Temperature: 100 °C

Procedure

This reaction was carried out under similar conditions to those described above instep 7 of preparation of Example 6. A solution of 6-chloro-4-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (150 mg, 429 μmol), 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 (212 mg, 429 μmol), xPhos (20.4 mg, 42.9 μmol) and potassium phosphate (228 mg, 1.07 mmol) in 10 ml of dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (12.3 mg, 21.4 μmol) was added. The reaction mixture was heated to 100° C. for 2 hr. After work up, the product was purified by preparative HPLC on silica gel, using a gradient of 0% to 5% methanol/ethyl acetate. This provided 1:1 ratio of desire compound and 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(4-hydroxy-4-methylpiperidin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate. The reaction mixture was dissolved in methanol (4 ml) and to this was added 2 N NaOH (600 μA). The reaction was stirred at room temperature for 2 h. The methanol was removed by evaporation and the resultant solution was acidified with 1N HCl and extracted with DCM. The resultant organic extract was dried over NaSO4, filtered and concentrated in vacuo. The resultant yellow solid was triturated with ether to afford the desired product as an yellow solid (40 mg, 45.8%). (M+H)+=640.4 m/e. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.24 (m, 3H) 1.31-1.48 (m, 12H) 1.64 (br. s., 2H) 2.35-2.68 (m, 2H) 3.31 (br. s., 2H) 3.52-3.62 (m, 1H) 4.41 (d, J=11.29 Hz, 2H) 7.33-7.60 (m, 7H) 7.75 (d, J=13.30 Hz, 1H) 7.87 (s, 1H) 8.44 (br. s., 1H) 8.52 (br. s., 1H).

Workup

customthose described above instep 7 of preparation of Example 6
customAfter work up, the product was purified by preparative HPLC on silica gel

Sources & evidence

ORD record: ord-3766e45fb6714a9aa2c0e12254d401fe
Source dataset: uspto-grants-2013_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08481540B2

Reaction notes

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