Cyclopropylamine → 1-cyclopropyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea

HRID 1093191Notes

Reaction equation

HRID 1093191 reaction equation
[CH:1]12[N:8]([C:9]3[N:14]=[C:13]([C:15]4[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=4)[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:23]=[CH:24][C:10]=34)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1.[N:46]([C:49]1[CH:54]=[CH:53]C(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCC3COC4)N=2)=CC=1)=[C:47]=[O:48]>ClCCl.C(N(CC)CC)C>[CH:49]1([NH:46][C:47]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:23]=[CH:24][C:10]4=[C:9]([N:8]4[CH:5]5[CH2:6][CH2:7][CH:1]4[CH2:2][O:3][CH2:4]5)[N:14]=3)=[CH:16][CH:17]=2)=[O:48])[CH2:54][CH2:53]1

Participants

7

Reactant 4

HCID 69828CyclopropylamineHCID 94429TriphosgeneHCID 66589057HCID 66589057, compoundHCID 866293728-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane

Product 1

HCID 574245441-cyclopropyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}ureaYield 41%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

A solution of 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (30 mg, 0.074 mmol) in dichloromethane (1 mL) was treated with triethylamine (0.05 mL), followed by a solution of triphosgene (11 mg, 0.037 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, cyclopropylamine (17 mg, 0.30 mmol)—was added to the 8-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After being left 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 Gemini 21 mm×100 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 60% or 75% acetonitrile over 30 minutes to provide 1-cyclopropyl-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea (15 mg, 41%). MS (ES+): 488.2 (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 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 60% or 75% acetonitrile over 30 minutes

Sources & evidence

ORD record
ord-973161265a1342ad9988afe4c1cbacc2
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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