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

HRID 1093217Notes

Reaction equation

HRID 1093217 reaction equation
[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH3:25])[N:23]=[CH:24][C:10]=13)[CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1.[N:42]([C:45]1[CH:50]=[CH:49]C(C2N=C3N(C)N=CC3=C(N3CC4OC(CC4)C3)N=2)=CC=1)=[C:43]=[O:44]>ClCCl>[CH:45]1([NH:42][C:43]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH3:25])[N:23]=[CH:24][C:10]4=[C:9]([N:3]4[CH2:2][CH:1]5[O:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:14]=3)=[CH:16][CH:17]=2)=[O:44])[CH2:50][CH2:49]1

Participants

6

Reactant 4

HCID 69828CyclopropylamineHCID 94429TriphosgeneHCID 665889994-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)anilineHCID 866293783-(6-(4-isocyanatophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Product 1

HCID 252629491-cyclopropyl-3-{4-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (51 mg, 0.15 mmol) in dichloromethane (4 mL) was treated with triphosgene (23 mg, 0.08 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, cyclopropylamine (104 μL, 10 equivalents, 1.5 mmol)—was added to the 3-(6-(4-isocyanatophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. 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 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 90% acetonitrile to provide 1-cyclopropyl-3-{4-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea. MS (ES+): 420.2 (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 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 90% acetonitrile

Sources & evidence

ORD record
ord-8c453ae97030409faf40978182054d30
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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