Bromide ion → [5-(5-Chloro-2-methoxypyridin-3-yl)-2-(methylthio)pyrimidin-4-yl]methanol

HRID 531227Notes

Reaction equation

HRID 531227 reaction equation
Br[C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].[Br-]>C(#N)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:12][C:13]1[CH:14]=[C:15]([C:2]2[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1

Participants

7

Reactant 4

HCID 259Bromide ionHCID 11430Potassium CarbonateHCID 44754881(5-Chloro-2-methoxypyridin-3-yl)boronic acidHCID 66524860(5-Bromo-2-(methylthio)pyrimidin-4-yl)methanol2×

Product 1

HCID 118022065[5-(5-Chloro-2-methoxypyridin-3-yl)-2-(methylthio)pyrimidin-4-yl]methanol

Reagents, catalysts & solvents 2

HCID 178454861HCID 178454861, compoundCatalystHCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

[5-Bromo-2-(methylthio)pyrimidin-4-yl]methanol (INTERMEDIATE 1, 1.9 g, 8.08 mmol), 5-chloro-2-methoxypyridin-3-ylboronic acid (1.51 g, 8.08 mmol) and K2CO3 (3.35 g, 24.24 mmol) were added to a round bottom flask, which was then evacuated and charged with nitrogen 3 times. THF (30 mL) and water (6 mL) were then added. After evacuating and charging again with nitrogen, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.527 g, 0.808 mmol) was added and the reaction heated for 30 minutes at 50° C. LCMS showed 80% conversion to product plus 20% unreacted bromide. The reaction was diluted with 15 mL acetonitrile and filtered through a 4 g C18 cartridge, eluting with 50 mL acetonitrile until the filtrate was colorless. The filtrate was then concentrated. Silica gel chromatography using a 0-50% isopropyl acetate/hexanes linear gradient followed by an isocratic hold of 50% isopropyl acetate/hexanes gave an 80/20 inseparable mixture of title compound and recovered starting material, which was more thoroughly purified later in the synthetic route. LCMS (M+H)+: 298.3 Title compound. LCMS (M+H)+: 237.1 Starting material (INTERMEDIATE 1).

Workup

  1. customwhich was then evacuated
  2. additioncharged with nitrogen 3 times
  3. additionTHF (30 mL) and water (6 mL) were then added
  4. customAfter evacuating
  5. additionwas added
  6. filtrationfiltered through a 4 g C18 cartridge
  7. washeluting with 50 mL acetonitrile until the filtrate
  8. concentrationThe filtrate was then concentrated
  9. customgave

Sources & evidence

ORD record
ord-54f1e3c931fd4c45b57e18717d99751a
Source dataset
uspto-grants-2016_05
Patent number
US09353101B2

Reaction notes

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