Cesium carbonate → 3,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrile

HRID 2366244Notes

Reaction equation

HRID 2366244 reaction equation
Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([Cl: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.[CH2:21]([C:23]1[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:22].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]([Cl:19])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:29][C:25]3[CH:24]=[C:23]([CH2:21][CH3:22])[N:28]=[CH:27][N:26]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[C:15]#[N:16]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 219116256-Ethylpyrimidin-4-amineHCID 866689964-(4-Bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile

Product 1

HCID 569525123,5-Dichloro-4-[4-(6-ethylpyrimidin-4-ylamino)thiazolo[5,4-c]pyridin-2-yl]-benzonitrileYield 30.5%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
70 °C

Procedure

A mixture of 4-(4-bromothiazolo[5,4-c]pyridin-2-yl)-3,5-dichlorobenzonitrile (0.095 g, 0.25 mmol), 6-ethylpyrimidin-4-ylamine (29 mg, 0.23 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), XantPhos (14 mg, 0.025 mmol) and cesium carbonate (0.201 g, 0.62 mmol) in dioxane (2.5 mL) was degassed with a stream of nitrogen. The reaction mixture was heated at 70° C. for 16 hours. After cooling to room temperature, the resultant mixture was diluted with water and filtered through Celite® washing with DCM. The aqueous phase was further extracted with DCM and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resultant residue was purified by silica gel flash C18 column chromatography eluting with 0-100% EtOAc in pentane followed by a 20-60% gradient MeOH in H2O+1M HCl (1.25 mL in each 25 mL of eluent). The product containing fractions were combined and concentrated under reduced pressure. The resultant solid was suspended in a mixture DCM/EtOAc/MeOH and washed with a saturated solution of NaHCO3, then dried and concentrated under reduced pressure. Further column chromatography purification on silica gel, eluting with 0-50% EtOAc in DCM, afforded the title compound as a pale yellow solid (30 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.70 (br s, 1H), 8.66 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.39 (s, 2H); 7.84 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.67 (q, J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H). LCMS (Method C): RT=3.81 min, m/z: 427 [M+H+].

Workup

  1. customwas degassed with a stream of nitrogen
  2. temperatureAfter cooling to room temperature
  3. additionthe resultant mixture was diluted with water
  4. filtrationfiltered through Celite®
  5. washwashing with DCM
  6. extractionThe aqueous phase was further extracted with DCM
  7. dry with materialthe combined organic layers were dried (MgSO4)
  8. concentrationconcentrated under reduced pressure
  9. customThe resultant residue was purified by silica gel flash C18 column chromatography
  10. washeluting with 0-100% EtOAc in pentane
  11. additionThe product containing fractions
  12. concentrationconcentrated under reduced pressure
  13. washwashed with a saturated solution of NaHCO3
  14. customdried
  15. concentrationconcentrated under reduced pressure
  16. customFurther column chromatography purification on silica gel
  17. washeluting with 0-50% EtOAc in DCM

Sources & evidence

ORD record
ord-b9347fbc2d1f439fb0b87974dc39c21e
Source dataset
uspto-grants-2014_04
Patent number
US08697708B2

Reaction notes

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