Potassium Phosphate, Tribasic → (R)-2'-(2-fluoropyridin-3-yl)-7'-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine

HRID 1472452Notes

Reaction equation

HRID 1472452 reaction equation
P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1.Br[C:20]1[CH:33]=[CH:32][C:31]2[O:30][C:29]3[C:24](=[CH:25][C:26]([C:34]4[CH:39]=[CH:38][N:37]=[C:36]([F:40])[CH:35]=4)=[CH:27][CH:28]=3)[C@@:23]3([N:45]=[C:44]([NH2:46])[CH2:43][O:42][CH2:41]3)[C:22]=2[CH:21]=1>O1CCOCC1.O.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:9][C:10]1[C:15]([C:20]2[CH:33]=[CH:32][C:31]3[O:30][C:29]4[C:24](=[CH:25][C:26]([C:34]5[CH:39]=[CH:38][N:37]=[C:36]([F:40])[CH:35]=5)=[CH:27][CH:28]=4)[C@@:23]4([N:45]=[C:44]([NH2:46])[CH2:43][O:42][CH2:41]4)[C:22]=3[CH:21]=2)=[CH:14][CH:13]=[CH:12][N:11]=1

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 27832702-Fluoropyridine-3-boronic acidHCID 67438537(R)-2'-bromo-7'-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amine

Product 1

HCID 58465971(R)-2'-(2-fluoropyridin-3-yl)-7'-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9'-xanthen]-5-amineYield 68.5%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

In a microwave vial, sodium carbonate (0.094 g, 0.885 mmol), 2-fluoropyridin-4-ylboronic acid (0.048 g, 0.339 mmol), Pd(PPh3)4 (0.034 g, 0.030 mmol), and (S)-2′-bromo-7′-iodo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.139 g, 0.295 mmol) were suspended in DME (2.5 mL) and water (0.5 mL). Argon gas was blown through the vessel which was sealed and heated in an 80° C. oil bath. After 6 h, the reaction mixture was diluted with brine (10 mL) and the aqueous phase was extracted with 7.5% MeOH-dcm (3×25 mL). The organics were combined, washed with dilute brine (5 mL), dried over sodium sulfate and concentrated. The material was purified through silica gel (33 mL) using 3.5 to 4.5 to 7% MeOH-DCM to afford (R)-2′-bromo-7′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine Step 2: In a microwave vial, the potassium phosphate (0.071 g, 0.334 mmol), PdCl2(AmPhos)2 (7.88 mg, 0.011 mmol), 2-fluoropyridin-3-ylboronic acid (0.020 g, 0.139 mmol), and (R)-2′-bromo-7′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.049 g, 0.111 mmol) were suspended in dioxane (2 mL) and water (0.5 mL). Argon gas was blown through the vessel, which was sealed and heated by microwave at 120° C. for 30 min. The mixture was concentrated, and the residue was diluted with brine (15 mL), and the aqueous phase was extracted with 5% MeOH-dcm (3×25 mL). The organics were combined, dried over sodium sulfate and concentrated. The residue was purified by chromatography (3.5%-4.5% MeOH/DCM) to afford (R)-2′-(2-fluoropyridin-3-yl)-7′-(2-fluoropyridin-4-yl)-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (35 mg, 0.076 mmol). MS (m/z) 457 (M+H)+.

Workup

  1. customwas sealed
  2. concentrationThe mixture was concentrated
  3. additionthe residue was diluted with brine (15 mL)
  4. extractionthe aqueous phase was extracted with 5% MeOH-dcm (3×25 mL)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated
  7. customThe residue was purified by chromatography (3.5%-4.5% MeOH/DCM)

Sources & evidence

ORD record
ord-319fb09b5ebb4f0eb5d5fb4722fb01c1
Source dataset
uspto-grants-2015_04
Patent number
US09012446B2

Reaction notes

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