Triethylamine → 2-Hydroxyethyl(4-{4-[(1s,4s)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate

HRID 1093204Notes

Reaction equation

HRID 1093204 reaction equation
[C@H:1]12[CH2:28][C@H:4]([N:5]([C:7]3[N:12]=[C:11]([C:13]4[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=4)[N:10]=[C:9]4[N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[N:21]=[CH:22][C:8]=34)[CH2:6]1)[CH2:3][O:2]2.C(N(CC)CC)C.ClC(Cl)(O[C:40](=[O:46])[O:41][C:42](Cl)(Cl)Cl)Cl.N(C1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C[C@@H]4C[C@H]3CO4)N=2)=CC=1)=[C:49]=[O:50]>ClCCl.C(O)CO>[OH:50][CH2:49][CH2:42][O:41][C:40](=[O:46])[NH:17][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:10]=[C:9]3[N:20]([CH2:23][C:24]([F:26])([F:27])[F:25])[N:21]=[CH:22][C:8]3=[C:7]([N:5]3[CH2:6][C@@H:1]4[CH2:28][C@H:4]3[CH2:3][O:2]4)[N:12]=2)=[CH:19][CH:18]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 665890974-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)anilineHCID 87063250(1s,4s)-5-(6-(4-Isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

Product 1

HCID 1317294912-Hydroxyethyl(4-{4-[(1s,4s)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate

Reagents, catalysts & solvents 2

HCID 174Ethylene GlycolSolventHCID 6344DichloromethaneSolvent2×

Procedure

A solution of 4-(4-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (26 mg, 0.07 mmol) in dichloromethane (2 mL) was treated with triethylamine (86 μL), followed by a solution of triphosgene (10 mg, 0.03 mmol) in dichloromethane (1 mL). After the passage of 20 minutes, the appropriate nucleophile—in the case, ethylene glycol (excess)—was added to the (1S,4S)-5-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (“isocyanate”) mixture. After standing overnight at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 15% acetonitrile/85% of 0.1% aqueous trifluoroacetic acid to 88% acetonitrile to provide 2-hydroxyethyl(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate. MS (ES+): 479.2 (M+H)+

Workup

  1. concentrationthe reaction mixture was concentrated to dryness under reduced pressure
  2. customThe residue was purified by reverse-phase high performance liquid chromatography
  3. washa gradient elution of 15% acetonitrile/85% of 0.1% aqueous trifluoroacetic acid to 88% acetonitrile

Sources & evidence

ORD record
ord-47402a8007ba4d849335a7c10fd97253
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

Loading…