Nitrogen → HCID 67520656, compound

HRID 1926407Notes

Reaction equation

HRID 1926407 reaction equation
C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:36]1[S:37][C:38]2[C:44]([F:45])=[CH:43][CH:42]=[C:41]([C:46]([F:49])([F:48])[F:47])[C:39]=2[N:40]=1.C(=O)([O-])[O-].[K+].[K+].N#N>O1CCOCC1.O>[F:45][C:44]1[C:38]2[S:37][C:36]([C:23]3[C:22]([NH2:34])=[N:21][CH:20]=[C:19]([C:17]4[CH:16]=[N:15][N:14]([CH:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)[CH:18]=4)[CH:24]=3)=[N:40][C:39]=2[C:41]([C:46]([F:49])([F:47])[F:48])=[CH:42][CH:43]=1

Participants

7

Reactant 4

HCID 947NitrogenHCID 11430Potassium CarbonateHCID 534879604-[4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-3-yl]pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl esterHCID 675207732-Chloro-7-fluoro-4-trifluoromethyl-1,3-benzothiazole

Product 1

HCID 67520656HCID 67520656, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of 4-{4-[6-amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB8) (60 mg, 0.127 mmol, 1 eq), 2-chloro-7-fluoro-4-trifluoromethyl-1,3-benzothiazole (42 mg, 0.153 mmol, 1.2 eq), and potassium carbonate (43 mg, 0.317 mmol, 2.5 eq) in 20% aq. dioxane (15 mL) was bubbledN2 gas for 15 min. Catalyst PdCl2dppf (5 mol %) was added to the stirred solution and N2 gas bubbling continued for another 10 min. The reaction mixture was then heated at 80° C. for 2 h. Cooling of the reaction mixture and evaporation of dioxane under reduced pressure yielded a brown residue. It was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield a yellowish-green solid. It was purified by column chromatography (50% ethyl acetate in hexane) to afford the BOC-protected title compound as yellowish-green solid; MS(ES+): m/z=563 [MH+]. To a solution of this Boc derivative (40 mg, 0.07 mmol) at 0-5° C. in dry DCM (10 ml) was added 4M HCl in dioxane (0.2 ml) dropwise and stirred the reaction mixture overnight at rt. Removed solvent under reduced pressure to afford the title compound as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=9.06-8.96 (brm, 1H), 8.85-8.73 (brm, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.42 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.17 (very brs, 1H), 8.09 (s, 1H), 8.03 (dd, J=5.2, 8.4 Hz, 1H), 7.59 (t, J=8.4 Hz, 1H), 4.56-4.46 (mc, 1H), 3.41 (brd, J=12.4 Hz, 2H), 3.12 (brq, J=11.4 Hz, 2H), 2.31-2.11 (m, 4H). MS(ES+): m/z=463.05 (100) [MH+], 380.02 (80) [MH+-piperidine]. HPLC: tR=2.29 min (polar—5 min, ZQ2).

Workup

  1. customfor 15 min
  2. custombubbling
  3. temperatureCooling of the reaction mixture and evaporation of dioxane under reduced pressure
  4. customyielded a brown residue
  5. extractionextracted with ethyl acetate (3×20 mL)
  6. washThe combined organic layers were washed with water (20 mL) and brine (20 mL)
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customto yield a yellowish-green solid
  11. customIt was purified by column chromatography (50% ethyl acetate in hexane)

Sources & evidence

ORD record
ord-19dd0f064b1f4ffa8a54a956b2dfefdb
Source dataset
uspto-grants-2012_05
Patent number
US08178668B2

Reaction notes

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