Sodium Carbonate → (3R)-tert-butyl 3-(6-(5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

HRID 1529275Notes

Reaction equation

HRID 1529275 reaction equation
[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:14]=2)[C:9]([C:25]2[N:30]=[C:29]([O:31][C@@H:32]3[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)=[N:8]1.Br[C:46]1[CH:51]=[N:50][CH:49]=[C:48]([CH:52]2[CH2:54][CH2:53]2)[N:47]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:52]1([C:48]2[N:47]=[C:46]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[C:9]4[C:25]3[N:30]=[C:29]([O:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][N:34]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33]4)[CH:28]=[N:27][CH:26]=3)[CH:51]=[N:50][CH:49]=2)[CH2:54][CH2:53]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 457883052-Bromo-6-cyclopropylpyrazineHCID 86709761(3R)-tert-butyl 3-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

Product 1

HCID 67959666(3R)-tert-butyl 3-(6-(5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylateYield 70%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A glass microwave reaction vessel was charged with (3R)-tert-butyl 3-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (1.315 g, 2.17 mmol) and Pd(PPh3)4 (0.125 g, 0.11 mmol). The tube was sealed and evacuated under vacuum and back-filled with N2 (g). A solution of 2-bromo-6-cyclopropylpyrazine (0.562 g, 2.82 mmol) in dioxane (1.8 mL) and 2 M Na2CO3 (5.43 mL, 10.86 mmol) were added. The reaction mixture was stirred and heated at 100° C. for 2 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 0% to 40% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(6-cyclopropylpyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (0.910 g, 1.52 mmol, 70% yield) as a yellow foam. MS (ESI, pos. ion) m/z: 598.2 (M+1).

Workup

  1. customA glass microwave reaction vessel
  2. customThe tube was sealed
  3. customevacuated under vacuum
  4. additionback-filled with N2 (g)
  5. temperatureAfter cooling to RT
  6. customthe organic layer was separated
  7. dry with materialdried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customThe crude material was absorbed onto a plug of silica gel
  11. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (80 g)
  12. washeluting with a gradient of 0% to 40% EtOAc in hexanes

Sources & evidence

ORD record
ord-21bf32ab9a914098b7e6c9d454a92910
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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