Potassium Phosphate, Tribasic → (S)-7-(3,4-difluorophenyl)-3-methoxy-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 1472416Notes

Reaction equation

HRID 1472416 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C@:15]3([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]3)[C:14]3[CH:13]=[C:12]([O:22][CH3:23])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[F:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]3[C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]4[CH:13]=[C:12]([O:22][CH3:23])[N:11]=[CH:10][C:9]=4[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:29][C:30]=1[F:31]

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27343373,4-Difluorobenzeneboronic acidHCID 58465867(S)-7-bromo-3-methoxy-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465984(S)-7-(3,4-difluorophenyl)-3-methoxy-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 89.4%

Reagents, catalysts & solvents 1

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)Catalyst

Conditions

Temperature
100 °C

Procedure

A microwave vial was charged with (S)-7-bromo-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.075 g, 0.199 mmol). 3,4-difluorophenylboronic acid (0.063 g, 0.399 mmol), potassium phosphate (0.127 g, 0.598 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7.06 mg, 9.97 μmol) were added. The vial was flushed with Ar (g), then dioxane (0.748 mL) and water (0.249 mL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 30 min at 100° C. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-100% EtOAc/Hexanes) to afford (S)-7-(3,4-difluorophenyl)-3-methoxy-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.073 g, 0.178 mmol, 89% yield) as an off-white solid. [M+H]+=410.4

Workup

  1. customThe vial was flushed with Ar (g)
  2. additiondioxane (0.748 mL) and water (0.249 mL) were added in sequence
  3. customThe vial was sealed
  4. additionThe reaction was diluted with ethyl acetate
  5. washwashed with water
  6. extractionThe aqueous layer was extracted with ethyl acetate
  7. washthe combined organic layers were washed with brine
  8. dry with materialdried with sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated
  11. customThe material was purified via column chromatography (0-100% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-d6bf8de29c084e019b22fea9f50dc27b
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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