Methylamine → 1-(4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea

HRID 1093224Notes

Reaction equation

HRID 1093224 reaction equation
[CH:1]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:30])([F:29])[F:28])[N:24]=[CH:25][C:11]=34)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.CN.[N:45]([C:48]1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C(N3C4CCCC3COC4)N=2)=CC=1)=[C:46]=[O:47]>ClCCl.O1CCCC1.C(N(CC)CC)C>[CH:5]12[N:9]([C:10]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([NH:20][C:46]([NH:45][CH3:48])=[O:47])=[CH:21][CH:22]=4)[N:13]=[C:12]4[N:23]([CH2:26][C:27]([F:29])([F:28])[F:30])[N:24]=[CH:25][C:11]=34)[CH:1]([CH2:8][CH2:7][CH2:6]1)[CH2:2][O:3][CH2:4]2

Participants

8

Reactant 4

HCID 6329MethylamineHCID 94429TriphosgeneHCID 66589187HCID 66589187, compoundHCID 866293819-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane

Product 1

HCID 574246841-(4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

A solution of 4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (50 mg, 0.12 mmol) in dichloromethane (3 mL) was treated triethylamine (160 μL), followed by triphosgene (27 mg, 0.09 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 2.0 M methylamine solution in tetrahydrofuran (1.2 mL)—was added to the 9-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-3-oxa-9-azabicyclo[3.3.1]nonane (“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 100% acetonitrile to provide 1-(4-(4-(3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)-3-methylurea. MS (ES+): 476.3 (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 100% acetonitrile

Sources & evidence

ORD record
ord-41360635d45b46398c0a5bca6fb9ba62
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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