Hydrochloric Acid → 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine

HRID 1529337Notes

Reaction equation

HRID 1529337 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([N:24]4[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1.Cl.CC(O)C>CO.CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]2[C:15]([C:18]3[CH:19]=[C:20]([N:24]4[CH2:25][CH2:26][CH:27]([NH2:30])[CH2:28][CH2:29]4)[CH:21]=[N:22][CH:23]=3)=[CH:16][NH:17][C:12]2=[CH:11][CH:10]=1

Participants

6

Reactant 3

HCID 313Hydrochloric Acid2×HCID 3776IsopropanolHCID 67960079tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate

Product 1

HCID 679598531-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 21226129Dichloromethane methanolSolvent

Conditions

Temperature
50 °C

Procedure

A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (79 mg, 0.120 mmol, 88% pure) in THF (2 mL) was treated with NaOH 5M (0.048 mL, 0.239 mmol). The reaction mixture was heated to reflux (bath temperature 80° C.). After 1 h, NaOH 5M (0.45 mL, 0.96 mmol, 8.0 equiv) was further added. After 23 h, the solution was cooled to 23° C., concentrated in vacuo and purified by silica gel chromatography (eluent: 1-7% MeOH/DCM), affording tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (31 mg, 51%). MS (ESI, pos. ion) m/z: 506.2 (M+1). A solution of tert-butyl 1-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (31 mg, 0.061 mmol) in MeOH (0.5 mL) was treated with HCl, 5-6n in IPA (0.123 mL, 0.613 mmol). The reaction was heated to 50° C. under N2. After 2 h, the reaction was cooled to 23° C. and the product (as HCl salt) was free-based using a Silicycle Si-propylsulfonic acid ion exchange column (catalog # R51230B). The compound was slurried in MeOH/DCM 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-(5-(5-(2,6-difluorophenyl)-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-amine MS (ESI, pos. ion) m/z: 406.3 (M+1).

Workup

  1. temperaturethe reaction was cooled to 23° C.
  2. customIt was flushed with MeOH (50 mL)
  3. concentrationThe final filtrate was concentrated

Sources & evidence

ORD record
ord-e91b04f78bac4949b5773b78bfd2adb9
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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