Sodium Carbonate → (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

HRID 1529369Notes

Reaction equation

HRID 1529369 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.[Cl:45][C:46]1[N:51]=[C:50](Cl)[CH:49]=[CH:48][N:47]=1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Cl:45][C:46]1[N:51]=[C:50]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[N:8]=[C:9]3[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]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH2:33]3)[CH:28]=[N:27][CH:26]=2)[CH:49]=[CH:48][N:47]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 775312,4-DichloropyrimidineHCID 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 86709777(3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylateYield 86%

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 (600 mg, 0.99 mmol), 2,4-dichloropyrimidine (192 mg, 1.29 mmol, Fluka) and Pd(PPh3)4 (57 mg, 0.050 mmol). The tube was sealed and evacuated under vacuum and back-filled with N2 three times. 2 M Na2CO3 (2.48 mL, 4.95 mmol) and dioxane (5 mL) were added. The reaction was stirred and heated in at 100° C. for 3 h. After cooling to RT, the organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by silica gel chromatography, eluting with a gradient of 0-60% EtOAc in hexanes, to provide (3R)-tert-butyl 3-(6-(5-(2-chloropyrimidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (505 mg, 0.85 mmol, 86% yield) as a pale yellow solid. MS (ESI, pos. ion) m/z: 592.1 (M+1).

Workup

  1. customA glass microwave reaction vessel
  2. customThe tube was sealed
  3. customevacuated under vacuum
  4. additionback-filled with N2 three times
  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 was purified by silica gel chromatography
  11. washeluting with a gradient of 0-60% EtOAc in hexanes

Sources & evidence

ORD record
ord-27dc4ab8bfb244ffb93a6352a8307db4
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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