Cesium carbonate → [2-(2,6-Dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amine

HRID 2366250Notes

Reaction equation

HRID 2366250 reaction equation
Cl[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([O:18][CH3:19])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[N:27]=[CH:26][N:25]=[C:24]([NH2:28])[CH: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]([O:18][CH3:19])[CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:28][C:24]3[CH:23]=[C:22]([CH3:21])[N:27]=[CH:26][N:25]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1

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 867233164-Chloro-2-(2,6-dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridine

Product 1

HCID 66801632[2-(2,6-Dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)-amineYield 26.2%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
85 °C

Procedure

A mixture of 4-chloro-2-(2,6-dichloro-4-methoxyphenyl)thiazolo[5,4-c]pyridine (0.113 g, 0.328 mmol), 6-methylpyrimidin-4-ylamine (0.031 g, 0.328 mmol), XantPhos (0.019 g, 0.033 mmol), Pd2(dba)3 (0.015 g, 0.0164 mmol) and Cs2CO3 (0.213 g, 0.655 mmol) in dioxane (3 mL) was degassed with a stream of argon and the reaction mixture was heated at 85° C. for 18 hours. After cooling to room temperature and standing at room temperature for 56 hours, additional XantPhos (0.019 g) and Pd2(dba)3 (0.015 g) were added. The resultant mixture was then degassed with a stream of argon and heated at 110° C. for 1 hour using microwave irradiation. Additional XantPhos (0.010 g), Pd2(dba)3 (0.008 g) and 6-methylpyrimidin-4-ylamine (0.006 g) were added and the resulting suspension was then degassed with a stream of argon and heated at 110° C. for 1 hour using microwave irradiation. The crude reaction mixture was filtered through Celite® and the filtrate was concentrated under reduced pressure. The resultant residue was purified by column chromatography on silica gel eluting with 0-2% MeOH in DCM followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 30 minute gradient 10-80%, 0.1% HCO2H in CH3CN/H2O) to afford the title compound as an off-white solid (36 mg, 26% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.91 (s, 1H), 8.54 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.73 (s, 1H), 7.36 (s, 2H), 3.92 (s, 3H), 2.49 (s, 3H). LCMS (Method D): RT=3.65 min, m/z: 418 [M+H+].

Workup

  1. customwas degassed with a stream of argon
  2. temperatureAfter cooling to room temperature
  3. additionadditional XantPhos (0.019 g) and Pd2(dba)3 (0.015 g) were added
  4. customThe resultant mixture was then degassed with a stream of argon
  5. temperatureheated at 110° C. for 1 hour
  6. custommicrowave irradiation
  7. additionAdditional XantPhos (0.010 g), Pd2(dba)3 (0.008 g) and 6-methylpyrimidin-4-ylamine (0.006 g) were added
  8. customthe resulting suspension was then degassed with a stream of argon
  9. temperatureheated at 110° C. for 1 hour
  10. custommicrowave irradiation
  11. customThe crude reaction mixture
  12. filtrationwas filtered through Celite®
  13. concentrationthe filtrate was concentrated under reduced pressure
  14. customThe resultant residue was purified by column chromatography on silica gel eluting with 0-2% MeOH in DCM
  15. customC18 on a 30 minute gradient 10-80%, 0.1% HCO2H in CH3CN/H2O

Sources & evidence

ORD record
ord-7a99f753d4384ade9e5d990ca3164ca8
Source dataset
uspto-grants-2014_04
Patent number
US08697708B2

Reaction notes

Loading…