Hydrochloric Acid → 1-(2-(2-(5-Chloro-2-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-ylamino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

HRID 592396Notes

Reaction equation

HRID 592396 reaction equation
[C:1]([C:4]1([C:7]2[CH:39]=[CH:38][CH:37]=[CH:36][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]4)[CH:23]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].Cl>C(Cl)Cl.O1CCOCC1>[Cl:17][C:16]1[C:11]([CH2:10][CH2:9][C:8]2[CH:36]=[CH:37][CH:38]=[CH:39][C:7]=2[C:4]2([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]2)=[N:12][C:13]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[CH:23]=2)=[N:14][CH:15]=1

Participants

5

Reactant 2

HCID 313Hydrochloric Acid3×HCID 86712302tert-Butyl 3-(4-(4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate

Product 1

HCID 732967151-(2-(2-(5-Chloro-2-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-ylamino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent3×

Procedure

To a stirred solution of tert-butyl 3-(4-(4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate A21 (0.164 g, 0.297 mmol) in DCM (5 mL) was added 4 M HCl solution in 1,4-dioxane (0.223 mL). The mixture was stirred for 5 hours before additional 4 M HCl in dioxane (3 eq.) was added and the mixture stirred for another 16 hours. Another portion of 4 M HCl in 1,4-dioxane (2 mL) was added and the mixture was stirred for 16 hours. The solvent was removed and the residue was diluted with 1 M HCl aq. (˜5 mL) and washed with EtOAc (2×10 mL). The aqueous layer was basified with 1 M NaOH and extracted with EtOAc (3×10 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give a crude white paste that was purified by flash chromatography (0-100% EtOAc in cyclohexane) to give the title compound as a red oil. Further purification by HPLC (Gradient: 20-100%, Acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) gave the title compound 20 as a clear gum (0.012 g, 9% yield). 1H NMR (300 MHz, MeOD) δ 1.14 (d, J=3.30 Hz, 2H), 1.64 (d, J=3.30 Hz, 2H), 2.32-2.44 (m, 1H), 2.46-2.65 (m, 1H), 3.12-3.26 (m, 4H), 3.43-3.54 (m, 1H), 3.60-3.80 (m, 3H), 5.21-5.32 (m, 1H), 7.23-7.45 (m, 4H), 7.64 (s, 1H), 8.08 (m, 1H), 8.29 (m, 1H). LCMS-C: rt 4.29 min; m/z 452 [M+H]+.

Workup

  1. additionwas added
  2. stirringthe mixture was stirred for 16 hours
  3. customThe solvent was removed
  4. additionthe residue was diluted with 1 M HCl aq. (˜5 mL)
  5. washwashed with EtOAc (2×10 mL)
  6. extractionextracted with EtOAc (3×10 mL)
  7. dry with materialThe combined organics were dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customto give a crude white paste that
  11. customwas purified by flash chromatography (0-100% EtOAc in cyclohexane)

Sources & evidence

ORD record
ord-26fa097cd89b4c65840341d6e43ff621
Source dataset
uspto-grants-2016_01
Patent number
US09238644B2

Reaction notes

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