Bromoacetonitrile → 2-((5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)acetonitrile

HRID 455594Notes

Reaction equation

HRID 455594 reaction equation
[NH2:1][C:2]1([CH2:19][OH:20])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[CH:6][CH:7]=2.CC(C)([O-])C.[Li+].Br[CH2:28][C:29]#[N:30]>C1COCC1>[NH2:1][C:2]1([CH2:19][O:20][CH2:28][C:29]#[N:30])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:18])=[CH:6][CH:7]=2

Participants

5

Reactant 3

HCID 11534Bromoacetonitrile2×HCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)2×HCID 86658370(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol

Product 1

HCID 866583712-((5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)acetonitrileYield 78%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent4×

Procedure

A 3-neck RBF was charged with (5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methanol (20.7 g, 57.6 mmol) and THF (10 mL). The flask was equipped with two addition funnels which were charged with lithium tert-butoxide solution (1.0M in THF; 98 mL, 98 mmol) and a solution of bromoacetonitrile (6.82 mL, 98 mmol) in THF (10 mL), respectively. The two solutions were added simultaneously to the stirring solution at ambient temperature over a time period of 3 hours. Upon complete addition, the addition funnels were recharged with lithium tert-butoxide solution, 1.0 M in THF (98 mL, 98 mmol) and a solution of bromoacetonitrile (6.82 mL, 98 mmol) in THF (10 mL), respectively. The two solutions were added simultaneously to the stirring solution at ambient temperature over a time period of 3 hours. The reaction was quenched with saturated aqueous ammonium chloride solution and stirred for 16 hours. The reaction was diluted with water and EtOAc. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure, and the resulting black solid was triturated with ether and filtered to afford a brown precipitate. The filtrate was further concentrated and purified by chromatography (50-100% EtOAc/hexanes). The solids obtained through trituration and purification by chromatography were combined to afford 2-((5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)methoxy)acetonitrile (17.9 g, 44.9 mmol).

Workup

  1. customThe flask was equipped with two addition funnels which
  2. additionThe two solutions were added simultaneously to the stirring solution at ambient temperature over a time period of 3 hours
  3. additionUpon complete addition
  4. additionThe two solutions were added simultaneously to the stirring solution at ambient temperature over a time period of 3 hours
  5. customThe reaction was quenched with saturated aqueous ammonium chloride solution
  6. additionThe reaction was diluted with water and EtOAc
  7. customThe organic layer was separated
  8. extractionthe aqueous layer was extracted twice with EtOAc
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over sodium sulfate
  11. concentrationThe solution was concentrated under reduced pressure
  12. customthe resulting black solid was triturated with ether
  13. filtrationfiltered
  14. customto afford a brown precipitate
  15. concentrationThe filtrate was further concentrated
  16. custompurified by chromatography (50-100% EtOAc/hexanes)
  17. customThe solids obtained through trituration and purification by chromatography

Sources & evidence

ORD record
ord-c6edc7a081da40b9a9c4b8bee8378c61
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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