Potassium Carbonate → 3-Bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

HRID 1472367Notes

Reaction equation

HRID 1472367 reaction equation
C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]2[C:21]3([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18](I)[CH:19]=3)[O:14][C:11]2=[N:12][CH:13]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.O>[Br:7][C:8]1[CH:9]=[C:10]2[C:21]3([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:35]4[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=4)[CH:19]=3)[O:14][C:11]2=[N:12][CH:13]=1

Participants

6

Reactant 3

HCID 11430Potassium CarbonateHCID 27832702-Fluoropyridine-3-boronic acidHCID 584658733-Bromo-7-iodo-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine2×

Product 1

HCID 584658843-Bromo-7-(2-fluoropyridin-3-yl)-5',6'-dihydrospiro[chromeno[2,3-b]pyridine-5,4'-[1,3]oxazin]-2'-amine

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
85 °C

Procedure

In a 150-mL resealable flask, potassium carbonate (1.557 g, 11.27 mmol 3-bromo-7-iodo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 25 1.97 g, 4.17 mmol), 2-fluoropyridin-3-ylboronic acid (0.441 g, 3.13 mmol), and PdCl2-dppf-dcm (0.225 g, 0.275 mmol) were suspended in dioxane (18 mL) and water (6 mL). Argon was blown through the vessel, which was sealed and heated in an 85° C. oil bath for 2 h. The reaction was concentrated to remove most of the dioxane. The aqueous residue was diluted further with dilute brine (50 mL), and the aqueous phase was extracted with 10% MeOH-DCM (3×100 mL). The organics were combined, washed with dilute brine (30 mL), dried over sodium sulfate and concentrated. The residue was purified by chromatography (4% MeOH/DCM), to afford (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (1.03 g). MS (m/z) 441/443 (M+H)+. Step 2: Intermediates ((S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (intermediate 26A, 350 mg), and its enantiomer ((R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 26 B, 500 mg) were obtained from racemic (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) using similar chiral separation conditions as described herein for intermediate 10. MS (m/z) 441/443 (M+H)+.

Workup

  1. customwas sealed
  2. concentrationThe reaction was concentrated
  3. customto remove most of the dioxane
  4. additionThe aqueous residue was diluted further with dilute brine (50 mL)
  5. extractionthe aqueous phase was extracted with 10% MeOH-DCM (3×100 mL)
  6. washwashed with dilute brine (30 mL)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated
  9. customThe residue was purified by chromatography (4% MeOH/DCM)

Sources & evidence

ORD record
ord-d6df5fdeea7f47c2b19491c16d10ee70
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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