Nitrogen → (S)-2'-(2,2-difluoropropoxy)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9'-xanthen]-2-amine

HRID 335985Notes

Reaction equation

HRID 335985 reaction equation
[NH2:1][C:2]1[S:3][CH2:4][C@@:5]2([N:28]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:46][C:47]([F:50])([F:49])[CH3:48])(=O)=O)=CC=1.N#N.[I-].[K+]>CN(C=O)C.O.CCOC(C)=O>[F:49][C:47]([F:50])([CH3:48])[CH2:46][O:19][C:16]1[CH:15]=[C:14]([F:20])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:4][S:3][C:2]([NH2:1])=[N:28]3)[C:18]=2[CH:17]=1

Participants

9

Reactant 5

HCID 947NitrogenHCID 4875Potassium IodideHCID 10796Cesium carbonateHCID 567765062,2-Difluoroprop-1-yl toluene-4-sulphonateHCID 67383198(S)-2-amino-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9'-xanthen]-2'-ol

Product 1

HCID 58466319(S)-2'-(2,2-difluoropropoxy)-4'-fluoro-7'-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9'-xanthen]-2-amineYield 4.78%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
160 °C

Procedure

A glass microwave reaction vessel was charged with (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9′-xanthen]-2′-ol (230 mg, 0.58 mmol, prepared as described in Method BB26 and Example 2 but using 7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one), cesium carbonate (302 mg, 0.93 mmol) and 2,2-difluoropropyl 4-methylbenzenesulfonate (159 mg, 0.64 mmol) in DMF (2.5 mL). The reaction mixture was purged with N2 and finally potassium iodide (192 mg, 1.16 mmol) was added. The reaction mixture was stirred and heated in a Initiator microwave reactor at 160° C. for 1.5 h. Then it was diluted with water and extractd by EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc again. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide crude product that was purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g), eluting with a gradient of 15% to 30% to 60% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane to provide (S)-2′-(2,2-difluoropropoxy)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[thiazole-4,9′-xanthen]-2-amine (18 mg, 0.017 mmol, 4.78% yield) as off-white solid. MS m/z=486.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) ppm 1.75 (t, J=19.32 Hz, 3 H) 3.34-3.49 (m, 2 H) 4.19-4.43 (m, 2 H) 6.81 (dd, J=2.89, 1.61 Hz, 1 H) 7.05 (s, 2 H) 7.16 (dd, J=12.28, 2.98 Hz, 1 H) 7.36-7.44 (m, 1 H) 7.50 (ddd, J=7.26, 5.01, 1.91 Hz, 1 H) 7.58-7.66 (m, 2 H) 8.09 (ddd, J=10.34, 7.51, 1.91 Hz, 1 H) 8.25 (dt, J=4.82, 1.55 Hz, 1 H)

Workup

  1. customA glass microwave reaction vessel
  2. additionwas added
  3. customThe layers were separated
  4. extractionthe aqueous layer was extracted with EtOAc again
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto provide crude product that
  10. customwas purified by chromatography through a Redi-Sep pre-packed silica gel column (24 g)
  11. washeluting with a gradient of 15% to 30% to 60% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane

Sources & evidence

ORD record
ord-85737fc5f7c14cfc8bc6dc48bd4d7ad4
Source dataset
uspto-grants-2014_11
Patent number
US08883782B2

Reaction notes

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