Cesium carbonate → HCID 86686828, compound

HRID 402927Notes

Reaction equation

HRID 402927 reaction equation
[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([F:26])[CH:16]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:13]2=[O:27])=[CH:10][CH:9]=[CH:8][C:7]=1[C:28]1[CH:29]=[C:30](Br)[C:31]2[N:32]([N:34]=[CH:35][N:36]=2)[CH:33]=1)(=[O:3])[CH3:2].[NH2:38][C:39]1[N:44]=[CH:43][C:42]([C:45]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:22]([C:17]1[CH:18]=[C:19]2[C:14](=[C:15]([F:26])[CH:16]=1)[C:13](=[O:27])[N:12]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([C:28]3[CH:29]=[C:30]([NH:38][C:39]4[CH:40]=[CH:41][C:42]([C:45]([N:47]5[CH2:52][CH2:51][O:50][CH2:49][CH2:48]5)=[O:46])=[CH:43][N:44]=4)[C:31]4[N:32]([N:34]=[CH:35][N:36]=4)[CH:33]=3)[C:6]=1[CH2:5][O:4][C:1](=[O:3])[CH3:2])[N:21]=[CH:20]2)([CH3:24])([CH3:23])[CH3:25]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59259223(6-Aminopyridin-3-yl)(morpholino)methanoneHCID 866868292-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetate

Product 1

HCID 86686828HCID 86686828, compoundYield 95%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

In a 100 ml flask, 2-(8-bromo-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)benzyl acetate (250 mg, 443 μmol, Eq: 1.00), (6-aminopyridin-3-yl)(morpholino)methanone (110 mg, 532 μmol, Eq: 1.2) and cesium carbonate (722 mg, 2.21 mmol, Eq: 5.0) were combined with dioxane (31.3 ml) to give an orange suspension. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (38.4 mg, 66.4 μmol, Eq: 0.15) and tris(dibenzylideneacetone)dipalladium(0) (20.3 mg, 22.1 μmol, Eq: 0.05) were added. The solution was degassed with Ar for 10 min. The reaction was heated at 100° C. for 18 h. The reaction mixture was diluted with 200 ml DCM. MgSO4 was added and the mixture was stirred. The solid was removed by filtration and washed several times with DCM. The combined filtrate and washes were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM gradient). The resulting residue was triturated with Et2O. The solid was filtered, and then washed with Et2O. The solid was dried overnight at 50° C. to give acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-{8-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-benzyl ester (289 mg, 95%). LC/MS-ESI observed [M+H]+ 691.

Workup

  1. customto give an orange suspension
  2. customThe solution was degassed with Ar for 10 min
  3. additionThe reaction mixture was diluted with 200 ml DCM
  4. additionMgSO4 was added
  5. customThe solid was removed by filtration
  6. washwashed several times with DCM
  7. concentrationThe combined filtrate and washes were concentrated in vacuo
  8. customThe crude material was purified by flash chromatography (silica gel, 40 g, 5% to 10% MeOH in DCM gradient)
  9. customThe resulting residue was triturated with Et2O
  10. filtrationThe solid was filtered
  11. washwashed with Et2O
  12. customThe solid was dried overnight at 50° C.

Sources & evidence

ORD record
ord-79a68c6fdda14f8d821071a0fd6fa702
Source dataset
uspto-grants-2014_06
Patent number
US08742098B2

Reaction notes

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