Cesium carbonate → (S)-6-tert-Butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl) phthalazin-1(2H)-one

HRID 1185158Notes

Reaction equation

HRID 1185158 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:5](=[O:8])[NH:6][CH:7]=1.C([O:30][CH2:31][C:32]1[C:33]([N:47]2[N:56]=[CH:55][C:54]3[C:49](=[C:50]([F:61])[CH:51]=[C:52]([C:57]([CH3:60])([CH3:59])[CH3:58])[CH:53]=3)[C:48]2=[O:62])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C([O-])([O-])=O.[Cs+].[Cs+]>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].O.O1CCOCC1>[C:57]([C:52]1[CH:53]=[C:54]2[C:49](=[C:50]([F:61])[CH:51]=1)[C:48](=[O:62])[N:47]([C:33]1[C:32]([CH2:31][OH:30])=[C:37]([C:2]3[CH:3]=[C:4]([NH:9][C:10]4[CH:15]=[CH:14][C:13]([N:16]5[CH2:21][CH2:20][N:19]([CH:22]6[CH2:25][O:24][CH2:23]6)[CH2:18][C@@H:17]5[CH3:26])=[CH:12][N:11]=4)[C:5](=[O:8])[NH:6][CH:7]=3)[CH:36]=[CH:35][N:34]=1)[N:56]=[CH:55]2)([CH3:60])([CH3:58])[CH3:59]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 75806TricyclohexylphosphineHCID 86683972(2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetateHCID 86684015(S)-5-Chloro-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)pyridin-2(1H)-one

Product 1

HCID 86684016(S)-6-tert-Butyl-8-fluoro-2-(3-(hydroxymethyl)-4-(5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)pyridin-2-yl) phthalazin-1(2H)-oneYield 18%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A sealed tube equipped with a magnetic stirrer was charged with 138c (150 mg, 0.40 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (495.6 mg, 1.2 mmol), Pd2(dba)3 (36.6 mg, 0.040 mmol), P(cy)3(44.6 mg, 0.16 mmol), Cs2CO3 (391.2 mg, 1.2 mmol), dioxane (8 mL), and water (0.2 mL). After three cycles of vacuum/argon flush, the mixture was heated at 120° C. for 4 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 40:1 ethyl acetate/methanol and further purified by reverse-phase prep-HPLC to afford 138 (48 mg, 18%) as a yellow solid. MS-ESI: [M+H]+ 667.3. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.55 (d, J=3.0 Hz, 1H), 8.44 (s, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.79 (dd, J=1.0 Hz, 13.0 Hz, 1H), 7.54 (d, J=5.0 Hz, 1H), 7.39 (dd, J=2.5 Hz, 9.0 Hz, 1H), 7.26-7.23 (m, 2H), 4.97-4.95 (m, 1H), 4.58-4.54 (m, 2H), 4.48-4.46 (m, 1H), 4.43-4.41 (m, 1H), 4.38-4.37 (m, 2H), 3.69-3.68 (m, 1H), 3.41-3.39 (m, 1H), 3.11-3.09 (m, 1H), 2.97-2.93 (m, 1H), 2.56-2.54 (m, 1H), 2.35-2.32 (m, 2H), 2.21-2.17 (m, 1H), 1.40 (s, 9H), 0.94 (d, J=6.5 Hz, 3H),

Workup

  1. customA sealed tube equipped with a magnetic stirrer
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureAfter this time the reaction was cooled to room temperature
  4. filtrationIt was then filtered
  5. customthe filtrate was evaporated under reduced pressure
  6. customThe residue was purified by silica-gel column chromatography
  7. washeluting with 40:1 ethyl acetate/methanol
  8. customfurther purified by reverse-phase prep-HPLC

Sources & evidence

ORD record
ord-f7d0fbcbf8dd4fe8ae2aedbc2dab32fe
Source dataset
uspto-grants-2014_03
Patent number
US08669251B2

Reaction notes

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