Hydrochloric Acid → Methyl 2-(4-tert-butylphenyl)isonicotinate hydrochloride

HRID 1963153Notes

Reaction equation

HRID 1963153 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>CO.[Cl-].[Na+].O.Cl[Pd]Cl.C(Cl)Cl>[ClH:1].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 27343204-tert-Butylphenylboronic acidHCID 2736842Methyl 2-chloropyridine-4-carboxylate

Product 1

HCID 66731754Methyl 2-(4-tert-butylphenyl)isonicotinate hydrochlorideYield 77%

Reagents, catalysts & solvents 4

HCID 24290Palladium ChlorideCatalystHCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

Methyl 2-chloroisonicotinate (7 g, 40.80 mmol), 4-tert-butylphenylboronic acid (10 g, 56.17 mmol), potassium carbonate (3.5 g, 25.32 mmol) and PdCl2 (dppf) (0.9 g, 1.24 mmol) were mixed in methanol (30 mL) in two equal portions in 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. The solids were removed by filtration and the filtrate evaporated to yield a dark red slurry. DCM and brine were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phases dried over MgSO4 and evaporated. The crude was dissolved in MTBE (180 mL) and the solids filtered off. Hydrogen chloride (4 M in dioxane, 10.20 mL, 40.80 mmol) was added dropwise during stirring and a suspension was formed. The suspension was stirred at room temperature for 1 h. The solid was collected by filtration and washed with MTBE. Methyl 2-(4-tert-butylphenyl)isonicotinate hydrochloride (9.6 g, 77%) was isolated as a dark brown solid. 1H NMR (400 MHz, dmso) δ 1.30 (s, 9H), 3.92 (s, 3H), 7.53 (d, 2H), 7.80 (dd, 1H), 8.04 (d, 2H), 8.29 (s, 1H), 8.85 (d, 1H), 9.86 (br, 1H). MS m/z 270 (M+H)+

Workup

  1. customThe vials were capped
  2. customThe solids were removed by filtration
  3. customthe filtrate evaporated
  4. customto yield a dark red slurry
  5. customthe phases separated
  6. extractionThe water phase (pH 9) was extracted with DCM
  7. dry with materialthe combined organic phases dried over MgSO4
  8. customevaporated
  9. dissolutionThe crude was dissolved in MTBE (180 mL)
  10. filtrationthe solids filtered off
  11. customa suspension was formed
  12. stirringThe suspension was stirred at room temperature for 1 h
  13. filtrationThe solid was collected by filtration
  14. washwashed with MTBE

Sources & evidence

ORD record
ord-e8c51903a52c43cb8ed653bd689927af
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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