2-Amino-4-methylpyridine → (4-Methyl-pyridin-2-yl)-[6-(2-pyridin-3-yl-thiazol-5-yl)-pyridin-2-yl]-amine

HRID 1854621Notes

Reaction equation

HRID 1854621 reaction equation
Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[N:10][CH:9]=2)[N:3]=1.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[S:12][C:11]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)=[N:10][CH:9]=3)[N:3]=2)[CH:25]=1

Participants

7

Reactant 4

HCID 15332-Amino-4-methylpyridineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 533113132-Bromo-6-(2-pyridin-3-yl-thiazol-5-yl)-pyridine

Product 1

HCID 53262538(4-Methyl-pyridin-2-yl)-[6-(2-pyridin-3-yl-thiazol-5-yl)-pyridin-2-yl]-amine

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolvent

Conditions

Temperature
110 °C

Procedure

A sealed tube was charged with 2-bromo-6-(2-pyridin-3-yl-thiazol-5-yl)-pyridine (125 mg, 0.392 mmol), 2-amino-4-methylpyridine (51 mg, 0.471 mmol), Pd(OAc)2 (1.8 mg, 8.01 μmol), BINAP (7.4 mg, 11.9 μmol), Cs2CO3 (255 mg, 0.782 mmol), and anhydrous and degassed toluene (2 ml) and heated to 110° C. with stirring for 48 h. The cooled reaction mixture was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®, eluting with cyclohexane/ethyl acetate 100/0 to 0/100. The solid obtained was then triturated in methanol, filtered and dried to afford the title compound as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ=9.74 (s, 1H), 9.15 (d, J=2.1 Hz, 1H), 8.68 (m, 1H), 8.59 (s, 1H), 8.31 (m, 1H), 8.10 (d, J=5.1 Hz, 1H), 7.93 (s, 1H), 7.72 (dd, J=8.2-7.6 Hz, 1H), 7.66-4.40 (m, 3H), 6.77 (d, J=4.9 Hz, 1H), 2.37 (s, 3H). (APCI+) m/z 346 (M+H)+.

Workup

  1. customanhydrous and degassed toluene (2 ml)
  2. customThe cooled reaction mixture
  3. extractionextracted with ethyl acetate
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. customevaporated under reduced pressure before purification by column chromatography on SiO2 using combiflash Companion®
  8. washeluting with cyclohexane/ethyl acetate 100/0 to 0/100
  9. customThe solid obtained
  10. customwas then triturated in methanol
  11. filtrationfiltered
  12. customdried

Sources & evidence

ORD record
ord-f7e5e71ae8be495e8338936bba2e004f
Source dataset
uspto-grants-2015_02
Patent number
US08962665B2

Reaction notes

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