Phosphoric Acid → 3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-one

HRID 1472302Notes

Reaction equation

HRID 1472302 reaction equation
OP(O)(O)=O.[Br:6][C:7]1[CH:8]=[N:9][C:10]([O:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O>O>[Br:6][C:7]1[CH:15]=[C:11]2[C:12](=[O:14])[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([I:23])[CH:21]=3)[O:16][C:10]2=[N:9][CH:8]=1

Participants

4

Reactant 2

HCID 1004Phosphoric AcidHCID 574756375-Bromo-2-(4-iodophenoxy)nicotinic acid

Product 1

HCID 574756483-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-oneYield 85.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
117.5 °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. Step 2: A 5 L 3-neck flask equipped with an overhead stirrer, a thermometer and nitrogen inlet was charged with PPA (4 Kg, 1942 mL) (115% H3PO4) and heated to 115-120° C. 5-Bromo-2-(4-iodophenoxy)nicotinic acid (400 g, 952 mmol) was charged portion wise to the hot PPA. The viscous mixture was then allowed to stir overnight (16-18 h) at 115-120° C. The dark viscous mixture was cooled to 60-65° C. and poured slowly onto a mixture of ice (3000 g) and water (2000 mL) under mechanical stirring. The light brown slurry was allowed to stir overnight and filtered at RT. The wet cake was washed with water (2×1000 mL) followed by IPA (1500 mL) and hexane (2×1000 mL). The solid was dried to obtain 326.4 g of 3-Bromo-7-iodo-5H-chromeno[2,3-b]pyridine-5-one as a grey solid.

Workup

  1. customStep 2: A 5 L 3-neck flask equipped with an overhead stirrer
  2. temperatureThe dark viscous mixture was cooled to 60-65° C.
  3. stirringto stir overnight
  4. filtrationfiltered at RT
  5. washThe wet cake was washed with water (2×1000 mL)
  6. customThe solid was dried

Sources & evidence

ORD record
ord-80d2cd0059a7472a8afa773610393afb
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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