Hydrochloric Acid → HCID 87379532, compound

HRID 335951Notes

Reaction equation

HRID 335951 reaction equation
[Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C:16](=O)[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12][CH:11]=3.[CH3:25][Mg]Br.Cl>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C:16](=[CH2:25])[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12][CH:11]=3

Participants

5

Reactant 3

HCID 313Hydrochloric AcidHCID 87379552HCID 87379552, compoundHCID 178418573HCID 178418573, compound2×

Product 1

HCID 87379532HCID 87379532, compoundYield 59%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
40 °C

Procedure

3-Bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one (3.75 g, 9.64 mmol) was suspended in dry THF (100 mL) and cooled in an ice bath under nitrogen. Methylmagnesium bromide (3.0 M in diethyl ether, 10 mL, 30.0 mmol) was added dropwise and the mixture stirred for an additional 10 min before removing from the ice bath. Additional THF (300 mL) and methylmagnesium bromide (15 mL, 4.5 eq) was added slowly. Once the solids had completely dissolved the reaction was stirred for 5 min. It was quenched by careful addition of 5 N HCl. Water (600 mL) and EtOAc (500 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude alcohol was dissolved in dry THF (200 mL) and treated with hydrogen chloride (4.0 M solution in 1,4-dioxane, 7 mL, 28.0 mmol). The solution was heated to 40° C. for 1 h. The solution was evaporated to dryness under reduced pressure and further dried under high vacuo. The crude 3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5-methylene-5H-chromeno[2,3-c]pyridine (2.20 g, 5.68 mmol, 59.0% yield) was used without purification. It was dissolved in dry THF (80 mL) and cooled in an ice bath under nitrogen. Silver cyanate (2.5 g, 16.68 mmol) was added and the mixture stirred. A solution of iodine (1.45 g, 5.71 mmol) in dry THF (20 mL) was added dropwise. After 30 min the colour of iodine had been consumed and the supernatant was clear. Diethyl ether (200 mL) was added and the mixture filtered through a pad of celite. The filtrate was treated with ammonia (2.0 M solution in methanol, 80 mL, 160 mmol) and the flask sealed. It was stirred overnight. The solution was evaporated to dryness under reduced pressure. The crude solids were triturated with diethyl ether and filtered through a sintered glass frit. The solids were dried under high vacuo to give the desired 3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (2.25 g, 5.05 mmol, 89% yield). MS m/z=445.0, 446.9 [M+H]+. Calculated for C19H11BrF2N4O2: 444.0. Separation of the stereoisomers using SCF gave optically pure (5R)-3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (MS m/z=445.0, 447.0 [M+H]) and (5S)-3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine

Workup

  1. temperaturecooled in an ice bath under nitrogen
  2. custombefore removing from the ice bath
  3. dissolutionOnce the solids had completely dissolved the reaction
  4. stirringwas stirred for 5 min
  5. customIt was quenched by careful addition of 5 N HCl
  6. additionWater (600 mL) and EtOAc (500 mL) were added
  7. additionthe phases mixed
  8. customseparated
  9. dry with materialThe organic was dried with magnesium sulfate
  10. customevaporated to dryness under reduced pressure
  11. dissolutionThe crude alcohol was dissolved in dry THF (200 mL)
  12. customThe solution was evaporated to dryness under reduced pressure
  13. customfurther dried under high vacuo

Sources & evidence

ORD record
ord-1d72e3edc3744215a97fbee94c1a3158
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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