Acetic Acid → 5-Bromo-2-(4-iodophenoxy)nicotinic acid

HRID 931540Notes

Reaction equation

HRID 931540 reaction equation
[H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18].CC(O)=O>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([I:3])=[CH:5][CH:6]=2)=[C:16]([CH:20]=1)[C:17]([OH:19])=[O:18]

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 108944-IodophenolHCID 24758Sodium hydrideHCID 27633425-Bromo-2-chloronicotinic acid

Product 1

HCID 574756375-Bromo-2-(4-iodophenoxy)nicotinic acidYield 86.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
0 °C

Procedure

A 3-neck 12 L flask equipped with an overhead stirrer, thermometer, condenser and nitrogen inlet was charged with NaH (186.1 g, 4.653 mol) and DMF (1500 mL). The slurry was cooled to 0° C. and a solution of 4-iodophenol (488.6 g, 2.221 mol) in DMF (1500 mL) and added. The temperature of the reaction mixture was maintained below 25-30° C. during this addition. After complete addition, the cooling bath was promptly removed and the mixture continued to stir at RT for 1 h. 5-Bromo-2-chloronicotinic acid (500 g, 2.115 mol) was then added to the slurry portion wise. The reaction mixture was heated to 115° C. overnight. The dark brown reaction mixture was cooled to 20° C. and diluted with water (2 L). The reaction mixture was acidified using HOAc (845 ml). The black homogenous solution (pH=5) was allowed to stir for 1 h at RT and poured slowly onto ice-water (20 L). The slurry was filtered at RT, washed with water (2×2 L) and dried in air to give 765 g of 5-Bromo-2-(4-iodophenoxy)-nicotinic acid as light orange solid.

Workup

  1. customA 3-neck 12 L flask equipped with an overhead stirrer
  2. temperatureThe temperature of the reaction mixture was maintained below 25-30° C. during this addition
  3. additionAfter complete addition
  4. customthe cooling bath was promptly removed
  5. temperatureThe reaction mixture was heated to 115° C. overnight
  6. temperatureThe dark brown reaction mixture was cooled to 20° C.
  7. stirringto stir for 1 h at RT
  8. additionpoured slowly onto ice-water (20 L)
  9. filtrationThe slurry was filtered at RT
  10. washwashed with water (2×2 L)
  11. customdried in air

Sources & evidence

ORD record
ord-585a525263434c2ba6e5dbd8d3c28ac5
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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