Water → 7-[(r)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-thiazol-4-ylfuro[3,2-c]pyridin-6-ylamine

HRID 911963Notes

Reaction equation

HRID 911963 reaction equation
Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[N:33]=[CH:34][S:35][CH:36]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:32]3[N:33]=[CH:34][S:35][CH:36]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]

Participants

7

Reactant 5

HCID 962WaterHCID 10796Cesium carbonateHCID 312751,4-Dioxane2×HCID 454803194-(Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole3×HCID 578127253-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]furo[3,2-c]pyridin-6-ylamine

Product 1

HCID 578125407-[(r)-1-(2,6-Dichloro-3-fluorophenyl)-ethoxy]-3-thiazol-4-ylfuro[3,2-c]pyridin-6-ylamine

Reagents, catalysts & solvents 1

HCID 15220664Palladium--triphenylphosphane (1/1)Catalyst

Conditions

Temperature
105 °C

Procedure

To a solution of 3-bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine (32.6 mg, 0.0776 mmol) and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (18.0 mg, 0.0854 mmol) in 1,4-dioxane (1.1 mL, 14 mmol) in a microwave reactor tube were added PS-PPh3-Pd (0.10 mmol/g loading; 45 mg, 0.0045 mmol; Argonaut) and a solution of Cs2CO3 (52.1 mg, 0.160 mmol) in H2O (0.33 mL, 18 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 min. Further 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (21 mg, 0.099 mmol) was added, and the reaction mixture was heated in the microwave reactor to 105° C. for 30 min. A solution of the remaining 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole (61 mg, 0.29 mmol) in 1,4-dioxane (0.30 mL, 3.8 mmol) was added to the reaction mixture, which was then heated to 105° C. for 45 min. The resin was filtered off and washed with DCM. The combined filtrate and washings were diluted with DCM to 50 mL, washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was submitted to MDP for purification. The product fractions were combined and dried in vacuo overnight. The product was chromatographed on an SCX column (500 mg/3 mL), and the fraction eluting with NH3/MeOH was concentrated and dried in vacuo to give the title compound as an off-white film. 1H NMR (CDCl3, 400 MHz): δ=8.91 (d, J=2.4 Hz, 1H), 8.43 (s, 1H), 7.98 (s, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.29 (dd, J=4.8, 8.0 Hz, 1H), 7.06 (dd, J=8.0, 8.8 Hz, 1H), 6.62 (q, J=6.8 Hz, 1H), 5.29 (brs, 2H), 1.91 (d, J=6.8 Hz, 3H). MS (ES+): m/z=423.90/425.88/427.86 (98/100/28) [MH+], 234.00 (25) [MH+−3-F-2,6-di-Cl-Ph-CH═CH2]. HPLC: tR=3.33 min (polar—5 min, ZQ3).

Workup

  1. customThe tube was sealed
  2. customevacuated
  3. additionrefilled with nitrogen (3×)
  4. temperaturethe reaction mixture was heated in the microwave reactor to 105° C. for 30 min
  5. temperaturewas then heated to 105° C. for 45 min
  6. filtrationThe resin was filtered off
  7. washwashed with DCM
  8. additionThe combined filtrate and washings were diluted with DCM to 50 mL
  9. washwashed with water and brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe residue was submitted to MDP for purification
  14. customdried in vacuo overnight
  15. customThe product was chromatographed on an SCX column (500 mg/3 mL)
  16. washthe fraction eluting with NH3/MeOH
  17. concentrationwas concentrated
  18. customdried in vacuo

Sources & evidence

ORD record
ord-b0d87423925e4c8abb04d922af0a7502
Source dataset
uspto-grants-2011_09
Patent number
US08022206B2

Reaction notes

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