Hydrochloric Acid → (3S)-3-cyclopropyl-1-(2-((1-(1-(methoxyacetyl) azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile

HRID 714848Notes

Reaction equation

HRID 714848 reaction equation
[C:1]([C@@:3]1([CH:32]2[CH2:34][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:23][N:22]([C:24](OC(C)(C)C)=[O:25])[CH2:21]4)[CH:19]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].Cl.O.C(#N)C.[C:40]([O:43][CH2:44]C)(=O)C>>[CH:32]1([C@:3]2([C:1]#[N:2])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:23][N:22]([C:24](=[O:25])[CH2:40][O:43][CH3:44])[CH2:21]5)[CH:19]=4)[N:9]=3)[C:4]2=[O:31])[CH2:34][CH2:33]1

Participants

5

Reactant 4

HCID 313Hydrochloric AcidHCID 8857Ethyl Acetate2×HCID 18373917Acetonitrile--water (1/1)HCID 117840549tert-butyl 3-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate

Product 1

HCID 117840196(3S)-3-cyclopropyl-1-(2-((1-(1-(methoxyacetyl) azetidin-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-oxopyrrolidine-3-carbonitrile

Procedure

To a solution of tert-butyl 3-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (300 mg) obtained in Step C of Example 131 in ethyl acetate (5 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, to a suspension of the reaction mixture in tetrahydrofuran (10 mL) were added triethylamine (1.3 g) and methoxyacetyl chloride (77 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol). The obtained crude product was subjected to HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH4HCO3)), and the obtained fraction was concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (60 mg).

Workup

  1. customThe solvent was evaporated under reduced pressure, to a suspension of the reaction mixture in tetrahydrofuran (10 mL)
  2. additionwere added triethylamine (1.3 g) and methoxyacetyl chloride (77 mg) at room temperature
  3. stirringthe mixture was stirred at room temperature for 3 hr
  4. customThe solvent was evaporated under reduced pressure
  5. additionthe reaction mixture was poured into water
  6. extractionextracted with ethyl acetate
  7. washThe obtained organic layer was washed with saturated brine
  8. dry with materialdried over anhydrous magnesium sulfate
  9. customthe solvent was evaporated under reduced pressure
  10. customThe residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol)
  11. customThe obtained crude product
  12. concentrationthe obtained fraction was concentrated under reduced pressure
  13. customThe residue was recrystallized (ethyl acetate/diisopropyl ether)

Sources & evidence

ORD record
ord-5830fb40fb56414ba4ffde391faa7eec
Source dataset
uspto-grants-2015_11
Patent number
US09187453B2

Reaction notes

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