Water → Ammonia

HRID 1529266Notes

Reaction equation

HRID 1529266 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13](C2CCCCO2)[N:12]=[C:11]3[C:23]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][CH:32]([NH:35]C(=O)OC(C)(C)C)[CH2:31][CH2:30]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1.CC(O)C.O>Cl>[NH3:12].[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[C:23]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]3)[CH:26]=[N:25][CH:24]=2)[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 3

HCID 962WaterHCID 3776IsopropanolHCID 67960074tert-Butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate

Product 2

HCID 222AmmoniaHCID 679596691-(6-(5-(3-Fluorophenyl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-amine

Reagents, catalysts & solvents 1

HCID 313Hydrochloric AcidSolvent

Procedure

A glass microwave reaction vessel was charged with tert-butyl 1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.200 g, 0.359 mmol), 3-fluorophenylboronic acid (0.072 g, 0.515 mmol, Aldrich), Na2CO3 (0.210 g, 1.981 mmol, J. T. Baker) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.022 g, 0.031 mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 140° C. for 15 min. The mixture was partitioned between EtOAc/water. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco, (40 gram)) eluting with 2M NH3 in MeOH:DCM (0:1→1:49) to give 119 mg of tert-Butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 573.2 (M+1). A solution of tert-butyl 1-(6-(5-(3-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.119 g, 0.208 mmol) in HCl, 5-6 N in IPA (5.00 mL, 25.00 mmol) and water (0.5 mL) was heated at 80° C. for 2.5 h. The reaction mixture was cooled to RT and the solid was filtered and washed with IPA. The material was dissolved in DMSO and purified by reverse-phase HPLC (Gilson; Gemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O:0.1% TFA ACN (9:1→1:9). The fractions containing the desired product were combined and concentrated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOH then 2M NH3 in MeOH to give the title compound as a yellow crystalline solid. MS (ESI, pos. ion) m/z: 389.1 (M+1).

Workup

  1. filtrationthe solid was filtered
  2. washwashed with IPA
  3. dissolutionThe material was dissolved in DMSO
  4. custompurified by reverse-phase HPLC (Gilson
  5. washGemini-NX 10μ C18 110 A AXIA, 100×50 mm column) eluting with 0.1% TFA-H2O
  6. additionThe fractions containing the desired product
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue was dissolved in MeOH
  9. washeluting with MeOH

Sources & evidence

ORD record
ord-069fdab10cda4ee287db65a9dada00e0
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

Loading…