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

HRID 455673Notes

Reaction equation

HRID 455673 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][CH:23]([F:25])[F:24])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.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][CH:23]([F:25])[O:22][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C@:15]4([N:20]=[C:19]([NH2:21])[CH2:18][O:17][CH2:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:32]1[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=1)=[CH:7][CH:6]=3

Participants

5

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27832702-Fluoropyridine-3-boronic acidHCID 67438254(S)-7-bromo-3-(difluoromethoxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 58465990(S)-3-(difluoromethoxy)-7-(2-fluoropyridin-3-yl)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amineYield 72.1%

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-(difluoromethoxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.056 g, 0.136 mmol). 2-fluoropyridin-3-ylboronic acid (0.038 g, 0.272 mmol), potassium phosphate (0.087 g, 0.408 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (4.81 mg, 6.79 μmol) were added. The vial was flushed with Ar (g), then dioxane (0.509 mL) and water (0.170 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 EtOAc and washed with water. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (0-10% MeOH/DCM) to afford (S)-3-(difluoromethoxy)-7-(2-fluoropyridin-3-yl)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (0.042 g, 0.098 mmol) as a light yellow solid. [M+H]+=429.0

Workup

  1. customThe vial was flushed with Ar (g)
  2. additiondioxane (0.509 mL) and water (0.170 mL) were added in sequence
  3. customThe vial was sealed
  4. additionThe reaction was diluted with EtOAc
  5. washwashed with water
  6. extractionThe aqueous layer was extracted with EtOAc
  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 (0-10% MeOH/DCM)

Sources & evidence

ORD record
ord-e9d69913c7c546d8a21faf058519005e
Source dataset
uspto-grants-2013_07
Patent number
US08497264B2

Reaction notes

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