Cyanogen Bromide → 7-Bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazin]-2'-amine

HRID 931580Notes

Reaction equation

HRID 931580 reaction equation
[NH2:1][C:2]1([CH2:19][CH2:20][OH:21])[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.C([O-])(=O)C.[Na+].[N:27]#[C:28]Br>CCO>[Br:18][C:5]1[CH:4]=[C:3]2[C:2]3([CH2:19][CH2:20][O:21][C:28]([NH2:27])=[N:1]3)[C:15]3[CH:14]=[C:13]([Cl:16])[N:12]=[C:11]([F:17])[C:10]=3[O:9][C:8]2=[CH:7][CH:6]=1

Participants

5

Reactant 3

HCID 10476Cyanogen BromideHCID 517045Sodium AcetateHCID 866583632-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol

Product 1

HCID 584659037-Bromo-3-chloro-1-fluoro-5',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazin]-2'-amineYield 44.7%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of 2-(5-amino-7-bromo-3-chloro-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)ethanol (13 g, 34.8 mmol) in EtOH (50 mL) was added sodium acetate (5.71 g, 69.6 mmol) followed by the dropwise addition of cyanogen bromide (3.0M solution in DCM; 13.92 ml, 41.8 mmol). The resulting mixture was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure, washed with water and extracted with DCM. The combined organic layers were dried over Na2SO4, concentrated under reduced pressure and azeotropically dried with toluene. The obtained residue was dissolved in DCM and TFA (40 mL) was added to the solution. The resulting mixture was stirred at RT for 30 min. The mixture was carefully quenched with aqueous, saturated NaHCO3 solution and extracted with DCM. The combined organics were dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by chromatography (0-3% MeOH/DCM) to afford 7-bromo-3-chloro-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-2′-amine (6.2 g, 15.55 mmol, 44.7% yield) as a light yellow solid.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. washwashed with water
  3. extractionextracted with DCM
  4. dry with materialThe combined organic layers were dried over Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. dry with materialazeotropically dried with toluene
  7. dissolutionThe obtained residue was dissolved in DCM
  8. additionTFA (40 mL) was added to the solution
  9. stirringThe resulting mixture was stirred at RT for 30 min
  10. customThe mixture was carefully quenched with aqueous, saturated NaHCO3 solution
  11. extractionextracted with DCM
  12. dry with materialThe combined organics were dried over Na2SO4
  13. concentrationconcentrated under reduced pressure
  14. customThe obtained residue was purified by chromatography (0-3% MeOH/DCM)

Sources & evidence

ORD record
ord-81b7cfaafa2748cb823a655aaa1b290f
Source dataset
uspto-grants-2016_03
Patent number
US09296759B2

Reaction notes

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