Hydrochloric Acid → HCID 178507875, compound

HRID 1529264Notes

Reaction equation

HRID 1529264 reaction equation
O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:17]=[C:18]4[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][NH:22][C:19]4=[N:20][CH:21]=3)=[CH:13][CH:14]=2)[C:9]([C:29]2[N:34]=[C:33]([N:35]3[CH2:40][CH2:39][CH:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37][CH2:36]3)[CH:32]=[N:31][CH:30]=2)=[N:8]1.Cl>O1CCOCC1>[F:28][C:25]([F:26])([F:27])[C:24]1[C:18]2[C:19](=[N:20][CH:21]=[C:16]([C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[NH:7][N:8]=[C:9]4[C:29]3[N:34]=[C:33]([N:35]4[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]4)[CH:32]=[N:31][CH:30]=3)[CH:17]=2)[NH:22][N:23]=1

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 178452838HCID 178452838, compound

Product 1

HCID 178507875HCID 178507875, compound

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

A suspension of tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (compound 1e) (150 mg, 0.269 mmol), crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 6a (177 mg, 0.57 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol, Strem) and aqueous Na2CO3, 2.0 M (0.27 mL, 0.54 mmol) in dioxane (3 mL) was capped, degassed and backfilled with argon. The reaction was heated at 120° C. in a microwave for 45 min. The reaction mixture was diluted with EtOAc (75 mL) and washed with saturated NaHCO3 solution (50 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0.5-3.5% MeOH/DCM), affording tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (94 mg, 52% yield). MS (ESI, pos. ion) m/z: 664.3 (M+1). A solution of tert-butyl 1-(6-(1-(tetrahydro-2H-pyran-2-yl)-5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (87 mg, 0.13 mmol) in dioxane (3 mL) was treated with HCl, 36.5-38.0% (0.11 mL, 1.31 mmol). The reaction mixture was heated at 90° C. After 3 h, the reaction mixture was cooled to 23° C. and concentrated. The residue (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was diluted in MeOH and added to a pad of the resin (wetted and flushed with 10 mL MeOH). It was flushed with MeOH (50 mL), and then the product was “released” using 2.0 M NH3 in MeOH solution (50 ml). The final filtrate was concentrated, affording 1-(6-(5-(3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine. MS (ESI, pos. ion) m/z: 480.2 (M+1).

Workup

  1. temperaturethe reaction mixture was cooled to 23° C.
  2. concentrationconcentrated
  3. additionThe compound was diluted in MeOH
  4. additionadded to a pad of the resin (wetted and flushed with 10 mL MeOH)
  5. customIt was flushed with MeOH (50 mL)
  6. concentrationThe final filtrate was concentrated

Sources & evidence

ORD record
ord-8abf5e78d2d6493ab58367ed0bcc9d8c
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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