Potassium Phosphate, Tribasic → HCID 56656392, compound

HRID 1431190Notes

Reaction equation

[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21](Cl)[CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:26]([O:29][CH2:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=[CH:33][C:32]=1[N:46]1[N:55]=[CH:54][C:53]2[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:52]=2)[C:47]1=[O:61])(=[O:28])[CH3:27].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:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([C:36]4[C:31]([CH2:30][OH:29])=[C:32]([N:46]5[N:55]=[CH:54][C:53]6[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:57])([CH3:58])[CH3:59])[CH:52]=6)[C:47]5=[O:61])[CH:33]=[CH:34][CH:35]=4)[CH:22]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:26]([O:29][CH2:30][C:31]1[C:32]([N:46]2[N:55]=[CH:54][C:53]3[C:48](=[C:49]([F:60])[CH:50]=[C:51]([C:56]([CH3:58])([CH3:57])[CH3:59])[CH:52]=3)[C:47]2=[O:61])=[CH:33][CH:34]=[CH:35][C:36]=1[C:21]1[CH:22]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:15][N:14]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1)(=[O:28])[CH3:27]

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 4-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-6-chloro-2-methylpyridazin-3(2H)-one (66 mg, 182 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 (90.2 mg, 182 μmol), xPhos (8.7 mg, 18.2 μmol) and potassium phosphate (96.8 mg, 456 μmol) in 10 ml of dioxane/water (9:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (5.24 mg, 9.12 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 desired compound and 2-(5-(5-(1-acetylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetate. The resultant mixture was dissolved in methanol (4 ml) and to this was added 2 N NaOH (468 μl). The reaction was stirred at room temperature for 56 h. The methanol was removed by evaporation and the resultant solution was acidified with 1N HCl and extracted with EtOAc. The organic extract was washed with water, dried over NaSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 4 g, 0% to 50% of MeOH in 50% EtOAc/Hexane) to afford the desired product as a white solid (61 mg, 26.2%). (M+H)+=652.5, 653.7 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.57 (s, 1H), 8.41 (br. s., 1H), 8.28 (br. s., 1H), 8.19 (br. s., 1H), 7.40-7.71 (m, 6H), 6.99 (d, J=8.2 Hz, 1H), 4.80 (d, J=12.9 Hz, 1H), 4.41 (br. s., 2H), 4.11 (q, J=7.0 Hz, 2H), 3.85-3.99 (m, 3H), 3.18 (t, J=12.7 Hz, 1H), 2.52-2.83 (m, 2H), 2.13 (s, 3H), 1.89 (t, J=12.7 Hz, 2H), 1.60 (br. s., 2H), 1.38-1.46 (m, 9H).

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-dd762b94bac049e5921351bf1afd22bd
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08940741B2

Reaction notes

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