Acryloyl chloride → N-((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

HRID 928161Notes

Reaction equation

HRID 928161 reaction equation
[NH2:1][C@H:2]1[C@H:6]([F:7])[CH2:5][N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]([CH3:19])[CH3:18])=[C:10]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:9]=2)[CH2:3]1.C([O-])(O)=O.[Na+].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[F:7][C@@H:6]1[CH2:5][N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]([CH3:19])[CH3:18])=[C:10]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:9]=2)[CH2:3][C@H:2]1[NH:1][C:32](=[O:35])[CH:33]=[CH2:34]

Participants

5

Reactant 3

HCID 13140Acryloyl chlorideHCID 516892Sodium BicarbonateHCID 1180736782-((trans)-3-amino-4-fluoropyrrolidin-1-yl)-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine

Product 1

HCID 118073677N-((3R,4R)-4-fluoro-1-(9-isopropyl-6-((1-methyl-1H-pyrazol-4-yl)amino)-9H-purin-2-yl)pyrrolidin-3-yl)acrylamide

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

Crude 2-((trans)-3-amino-4-fluoropyrrolidin-1-yl)-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (assumed 1 mmol ca.) was partitioned between DCM (30 mL) and sat. aq. NaHCO3 (10 mL) and stirred vigorously. Acryloyl chloride (121 μL, 1.5 mmol) was added in one portion and the mixture stirred for 30 min. The mixture was then diluted with DCM (50 mL) and the organic layer was separated, dried over Na2SO4 and evaporated to give a dark residue that was subjected to chiral SFC purification to separate the two trans enantiomers (Chiralpak AD-H 21.2×250 mm 5μ column. Eluted with 30% EtOH (200 proof) in CO2 held 38° C. at 100 bar, ˜60.0 mL/min, UV detection at λ=260 nm. Peak 1(−) elutes 3.99-4.68 min. Peak 2(+) elutes 5.80-6.38 min). Yielded:

Workup

  1. stirringthe mixture stirred for 30 min
  2. customthe organic layer was separated
  3. dry with materialdried over Na2SO4
  4. customevaporated
  5. customto give a dark residue that
  6. customwas subjected to chiral SFC purification
  7. customto separate
  8. washthe two trans enantiomers (Chiralpak AD-H 21.2×250 mm 5μ column. Eluted with 30% EtOH (200 proof) in CO2 held 38° C. at 100 bar, ˜60.0 mL/min, UV detection at λ=260 nm. Peak 1(−) elutes 3.99-4.68 min. Peak 2(+) elutes 5.80-6.38 min)
  9. customYielded

Sources & evidence

ORD record
ord-1956081e56ae432cadaf1828dd9081d1
Source dataset
uspto-grants-2016_03
Patent number
US09290496B2

Reaction notes

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