4-Aminopyridine → Tert-butyl 7-(6-(4-(3-pyridin-4-ylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.hydrochloride

HRID 1093200Notes

Reaction equation

HRID 1093200 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:15]=[CH:16][C:11]3=[C:10]([N:22]3[CH2:29][CH:28]4[O:30][CH:24]([CH2:25][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)[CH2:23]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl:38]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.NC1C=CN=CC=1.N(C1C=CC(C2N=C3N(CC(F)(F)F)N=CC3=C([N:80]3[CH2:87][CH:86]4O[CH:82](C[N:84]([C:89]([O:91]C(C)(C)C)=O)[CH2:85]4)[CH2:81]3)N=2)=CC=1)=C=O>ClCCl.O1CCCC1.C(N(CC)CC)C>[ClH:38].[N:80]1[CH:81]=[CH:82][C:85]([NH:84][C:89](=[O:91])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:13]=[C:12]4[N:14]([CH2:17][C:18]([F:20])([F:21])[F:19])[N:15]=[CH:16][C:11]4=[C:10]([N:22]4[CH2:29][CH:28]5[O:30][CH:24]([CH2:25][N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]5)[CH2:23]4)[N:9]=3)=[CH:6][CH:7]=2)=[CH:86][CH:87]=1

Participants

8

Reactant 4

HCID 17274-AminopyridineHCID 94429TriphosgeneHCID 66589151tert-butyl 7-(6-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylateHCID 86629374tert-butyl 7-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate

Product 1

HCID 66588973Tert-butyl 7-(6-(4-(3-pyridin-4-ylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1h-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.hydrochloride

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8471TriethylamineSolvent

Procedure

A solution of tert-butyl 7-(6-(4-aminophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.48 g, 0.92 mmol) in dichloromethane (15 mL) was treated with triethylamine (1.2 mL), followed by a solution of triphosgene (0.14 g, 0.46 mmol). After the passage of 5 minutes, a solution of 4-aminopyridine (0.26 g, 2.8 mmol) in warm tetrahydrofuran was added to the tert-butyl 7-(6-(4-isocyanatophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (“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 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 65% acetonitrile to provide tert-butyl 7-(6-(4-(3-pyridin-4-ylureido)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate.hydrochloride as pale golden flakes. (282 mg, 45%). MS (ES+): 640.3 (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 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 65% acetonitrile

Sources & evidence

ORD record
ord-34d213040e7e438c9223cee0612195f2
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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