Cesium carbonate → 3-Chloro-5-fluoro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

HRID 2366230Notes

Reaction equation

HRID 2366230 reaction equation
Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([F:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]>[Cl:20][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:19])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[C:15]#[N:16]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 5728526-Methylpyrimidin-4-amineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 867233154-(4-Bromothiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluorobenzonitrile

Product 1

HCID 569532043-Chloro-5-fluoro-4-[4-(6-methyl-pyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrileYield 37.8%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
70 °C

Procedure

A mixture of 4-(4-bromo-thiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluoro-benzonitrile (0.087 g, 0.24 mmol), 4-amino-6-methylpyrimidine (0.024 g, 0.22 mmol), Pd2(dba)3 (0.011 g, 0.01 mmol), XantPhos (0.014 g, 0.02 mmol) and cesium carbonate (0.192 g, 0.59 mmol) in dioxane (2.4 mL) was degassed with nitrogen and heated to 70° C. for 16 hours. The reaction mixture was diluted with DCM and water, and then filtered through Celite®. The layers of the filtrate were separated and the organic layer dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-5% MeOH in DCM and triturated with acetonitrile to give the desired compound as a yellow solid (0.033 g, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.63 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.27 (t, J=1.3 Hz, 1H), 8.22 (dd, J=9.0, 1.4 Hz, 1H), 7.85 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.39 (s, 3H). LCMS (Method C): RT=3.30 min, m/z: 397 [M+H+].

Workup

  1. customwas degassed with nitrogen
  2. additionThe reaction mixture was diluted with DCM and water
  3. filtrationfiltered through Celite®
  4. customThe layers of the filtrate were separated
  5. dry with materialthe organic layer dried over Na2SO4
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by silica gel flash chromatography
  8. washeluting with 0-5% MeOH in DCM
  9. customtriturated with acetonitrile

Sources & evidence

ORD record
ord-a0b80589bd1f4c16a4b77336b4ce1084
Source dataset
uspto-grants-2014_04
Patent number
US08697708B2

Reaction notes

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