Potassium Phosphate, Tribasic → (E)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9'-xanthen]-5-amine

HRID 529402Notes

Reaction equation

HRID 529402 reaction equation
Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:29])=[CH:9][C:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:11][C:12]=3[C:13]32[CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)=[CH:4][CH:3]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(N)CC1C=CC=CC=1.OP(O)(O)=O>>[F:29][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:36]4[C:31]([F:30])=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:3][CH:4]=3)[C:13]3([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]3)[C:12]=2[CH:11]=[C:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:9]=1

Participants

5

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 62885Benzeneethanamine, alpha-methyl-, phosphate (1:1)HCID 27832702-Fluoropyridine-3-boronic acidHCID 68279423(E)-7'-bromo-4'-fluoro-2'-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9'-xanthen]-5-amine

Product 1

HCID 60164518(E)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-2'-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9'-xanthen]-5-amine

Procedure

A vial was charged with (E)-7′-bromo-4′-fluoro-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine (158 mg, 0.341 mmol), 2-fluoropyridin-3-ylboronic acid (96 mg, 0.682 mmol), potassium phosphate (217 mg, 1.023 mmol), and AmPhos (12.07 mg, 0.017 mmol) were added. The vial was flushed with Ar (g), then 1,4-dioxane (1279 μL) and water (426 μL) were added in sequence. The vial was heated to 90° for 45 min. The mixture was cooled to RT and extracted with EtOAc (3×). The combined organic extracts were concentrated, and the crude product was purified by chromatography on silica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (E)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(neopentyloxy)-6,7-dihydro-2H-spiro[[1,4]oxazepine-3,9′-xanthen]-5-amine as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.24 (td, J=1.5, 4.8 Hz, 1 H), 8.10 (ddd, J=1.9, 7.5, 10.4 Hz, 1 H), 7.64-7.53 (m, 2 H), 7.49 (ddd, J=1.9, 5.0, 7.3 Hz, 1 H), 7.34 (d, J=8.3 Hz, 1 H), 6.95 (dd, J=2.7, 12.4 Hz, 1 H), 6.81 (dd, J=1.4, 2.7 Hz, 1 H), 6.11 (br. s., 2 H), 3.84-3.69 (m, J=4.2 Hz, 2 H), 3.67-3.54 (m, 4 H), 2.98-2.75 (m, 2 H), 1.06-0.95 (m, 9 H). MS m/z=480.2. Calc'd for C27H28F2N3O3: 480.2. The purified racemates (58 mg) were separated using a chiral SFC column, eluting with 55% MeOH with diethylamine, to afford (S)-enantiomer (peak 1) and (R)-enantiomer (peak 2) as white solids.

Workup

  1. additionwere added
  2. customThe vial was flushed with Ar (g)
  3. addition1,4-dioxane (1279 μL) and water (426 μL) were added in sequence
  4. temperatureThe vial was heated to 90° for 45 min
  5. extractionextracted with EtOAc (3×)
  6. concentrationThe combined organic extracts were concentrated
  7. customthe crude product was purified by chromatography on silica gel (
  8. addition10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM)

Sources & evidence

ORD record
ord-2e1c995566b7428d94069bf227307ffd
Source dataset
uspto-grants-2016_05
Patent number
US09346827B2

Reaction notes

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