Dimethyl Sulfoxide → (S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

HRID 1472379Notes

Reaction equation

HRID 1472379 reaction equation
[CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CS(C)=O.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C@:27]3([N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]3)[C:26]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][C:21]=3[O:20][C:17]2=[CH:18][CH:19]=1>O.CCOC(C)=O.[Cl-].[Na+].O>[Br:13][C:14]1[CH:15]=[C:16]2[C@:27]3([N:32]=[C:31]([NH2:33])[CH2:30][O:29][CH2:28]3)[C:26]3[CH:25]=[C:24]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])[N:23]=[CH:22][C:21]=3[O:20][C:17]2=[CH:18][CH:19]=1

Participants

8

Reactant 4

HCID 679Dimethyl SulfoxideHCID 6404Neopentyl alcoholHCID 24758Sodium hydrideHCID 58465879(S)-7-bromo-3-chloro-2',6'-dihydrospiro[chromeno [2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

Product 1

HCID 67440039(S)-7-bromo-3-(neopentyloxy)-2',6'-dihydrospiro[chromeno[2,3-c]pyridine-5,3'-[1,4]oxazin]-5'-amine

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

A vial was charged with 2,2-dimethylpropan-1-ol (100 mg, 1.130 mmol) and DMSO (1130 μL). Sodium hydride (60% in mineral oil; 45.2 mg, 1.130 mmol) was added. The vial was placed in a 100° C. oil bath for 5 min. the reaction mixture was cooled to room temperature and (S)-7-bromo-3-chloro-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (86 mg, 0.226 mmol) was added in one portion. The vial was sealed and heated in a 100° C. oil bath for 2 h. The mixture was cooled to room temperature, then diluted with water and EtOAc. Brine was added, and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, and concentrated. The residue was purified by chromatography (0-100% EtOAc/Hexane) to give (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine as a light-yellow solid. Step 2: A vial was charged with (S)-7-bromo-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (51 mg, 0.118 mmol), 2-fluoropyridin-3-ylboronic acid (33.2 mg, 0.236 mmol), potassium phosphate (75 mg, 0.354 mmol), and bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium(II) (4.18 mg, 5.90 μmol). The vial was flushed with Ar (g), then dioxane (442 μL) and water (147 μL) were added in sequence. The vial was sealed and heated in a Biotage Initiator microwave reactor for 20 min at 90° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The residue was purified by chromatography (30% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (S)-7-(2-fluoropyridin-3-yl)-3-(neopentyloxy)-2′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazin]-5′-amine (46.23 mg) as an off-white solid. MS m/z=449.2 [M+H]+.

Workup

  1. customwas placed in a 100° C.
  2. customfor 5 min.
  3. customThe vial was sealed
  4. temperatureheated in a 100° C. oil bath for 2 h
  5. temperatureThe mixture was cooled to room temperature
  6. customthe layers were separated
  7. extractionThe aq. layer was extracted with EtOAc (2×)
  8. dry with materialThe combined organic extracts were dried over sodium sulfate
  9. concentrationconcentrated
  10. customThe residue was purified by chromatography (0-100% EtOAc/Hexane)

Sources & evidence

ORD record
ord-dc3f0e6cd0d7412d9bece092a1a51bb1
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

Loading…