Triphosgene → HCID 57424525, compound

HRID 1093188Notes

Reaction equation

HRID 1093188 reaction equation
C12OC(CC1)CN(C1N=C(C3C=CC(N)=CC=3)N=C3N(CC(F)(F)F)N=CC=13)C2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[O:42]1[CH2:47][CH2:46][N:45]([C:48]2[N:53]=[CH:52][C:51]([NH2:54])=[CH:50][CH:49]=2)[CH2:44][CH2:43]1.[N:55]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2[N:69]=[C:68]3[N:70]([CH2:73][C:74]([F:77])([F:76])[F:75])[N:71]=[CH:72][C:67]3=[C:66]([N:78]3[CH2:84][CH:83]4[O:85][CH:80]([CH2:81][CH2:82]4)[CH2:79]3)[N:65]=2)=[CH:60][CH:59]=1)=[C:56]=[O:57]>ClCCl.C(N(CC)CC)C>[N:45]1([C:48]2[N:53]=[CH:52][C:51]([NH:54][C:56]([NH:55][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[N:69]=[C:68]5[N:70]([CH2:73][C:74]([F:76])([F:77])[F:75])[N:71]=[CH:72][C:67]5=[C:66]([N:78]5[CH2:84][CH:83]6[O:85][CH:80]([CH2:81][CH2:82]6)[CH2:79]5)[N:65]=4)=[CH:60][CH:59]=3)=[O:57])=[CH:50][CH:49]=2)[CH2:46][CH2:47][O:42][CH2:43][CH2:44]1

Participants

7

Reactant 4

HCID 94429TriphosgeneHCID 1040596-(Morpholino)pyridin-3-amineHCID 574246364-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamineHCID 86629371HCID 86629371, compound

Product 1

HCID 57424525HCID 57424525, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8471TriethylamineSolvent

Procedure

A solution of 4-[4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenylamine (50 mg, 0.12 mmol) in dichloromethane (4 mL) was treated with triethylamine (0.16 mL), followed by a solution of triphosgene (19 mg, 0.064 mmol) in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, 6-morpholinopyridin-3-amine (86 mg, 0.48 mmol)—was added to the 3-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-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 Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile over 30 minutes to provide 1-(6-morpholin-4-ylpyridin-3-yl)-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea.TFA (18 mg, 21%). MS (ES+): 610.2 (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 100% acetonitrile over 30 minutes

Sources & evidence

ORD record
ord-758a2f757ee247bfa8e0548543c38b52
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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