Hydrochloric Acid → HCID 86698805, compound

HRID 1054813Notes

Reaction equation

HRID 1054813 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][N:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)C(C)(C)OB([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]3)=[CH:25][CH:24]=2)O1.C(=O)([O-])[O-].[K+].[K+].Cl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:35]([N:32]1[CH2:33][CH2:34][N:29]([C:26]2[CH:27]=[CH:28][C:23]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][C:10]=3[Cl:11])[NH:7][N:6]=[C:5]4[C:12]([OH:14])=[O:13])=[CH:24][CH:25]=2)[CH2:30][CH2:31]1)(=[O:37])[CH3:36]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 532171411-(4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethan-1-oneHCID 866987915-bromo-6-chloro-1H-indazole-3-carboxylic acid

Product 1

HCID 86698805HCID 86698805, compoundYield 7.1%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Procedure

To 5-bromo-6-chloro-1H-indazole-3-carboxylic acid (75.0 mg, 0.27 mmol) in a 5 mL microwave vial was sequentially added 1-{4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]piperazin-1-yl}ethanone (89.8 mg, 0.27 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.0 mg, 0.027 mmol), 1,4-dioxane (2 mL) and 2 N aqueous potassium carbonate solution (0.4 mL, 0.81 mmol). The reaction mixture was degassed with argon and subjected to microwave irradiation at 110° C. for 50 minutes. The cooled reaction mixture was acidified to pH 5 with 1 N HCl and diluted with EtOAc (10 mL). The organic layer was washed with brine (6 mL), dried over MgSO4 and concentrated in vacuo. The resulting solid was purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: HOLD at 80.0% H2O/20.0% MeCN for 1.0 min. 80.0% H2O/20.0% MeCN linear to 60.0% H2O/40.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.) to afford the title compound (7.6 mg, 7% yield). MS (ES+) 399.1 (M+H)+. Retention time=2.25 minutes (Column: Waters Atlantis dC18 4.6×50 mm, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: 95:5 A:B linear to 5:95 A:B in 4.0 min, hold at 5:95 A:B to 5.0 min. Flow: 2 ml/min).

Workup

  1. customThe reaction mixture was degassed with argon
  2. customirradiation at 110° C. for 50 minutes
  3. customThe cooled reaction mixture
  4. washThe organic layer was washed with brine (6 mL)
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated in vacuo
  7. customThe resulting solid was purified by reversed phase HPLC (Column: Waters Sunfire C18 19×100, 5 μm; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in MeCN (v/v); Gradient: HOLD at 80.0% H2O/20.0% MeCN for 1.0 min. 80.0% H2O/20.0% MeCN linear to 60.0% H2O/40.0% MeCN in 6.75 min, linear to 0% H2O/100% MeCN to 7.0 min. HOLD at 0% H2O/100% MeCN from 7.0 to 8.0 min. Flow: 30 mL/min.)

Sources & evidence

ORD record
ord-313cda44e5384a47bd565fcc4c06d2c9
Source dataset
uspto-grants-2016_07
Patent number
US09394285B2

Reaction notes

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