Methylamine → tert-butyl 4-[6-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

HRID 1093181Notes

Reaction equation

HRID 1093181 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)[N:15]=[CH:16][C:11]3=[C:10]([N:30]3[CH2:36][CH:35]4[O:37][CH:32]([CH2:33][CH2:34]4)[CH2:31]3)[N:9]=2)=[CH:4][CH:3]=1.ClC(Cl)(O[C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.CN.[N-:52]=[C:53]=O>ClCCl.O1CCCC1>[CH3:53][NH:52][C:42]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]3[N:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:21][CH2:22]4)[N:15]=[CH:16][C:11]3=[C:10]([N:30]3[CH2:31][CH:32]4[O:37][CH:35]([CH2:34][CH2:33]4)[CH2:36]3)[N:9]=2)=[CH:6][CH:7]=1)=[O:48]

Participants

7

Reactant 4

HCID 6329MethylamineHCID 94429TriphosgeneHCID 105034IsocyanateHCID 66588990tert-butyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate

Product 1

HCID 25261390tert-butyl 4-[6-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

A solution of tert-butyl 4-(6-(4-aminophenyl)-4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (130 mg, 0.26 mmol) in dichloromethane (5 mL) was treated with triphosgene (37 mg, 0.12 mmol) as a solution in dichloromethane (2 mL). After the passage of five minutes, the appropriate nucleophile—in this case, 2.0 M methylamine solution in tetrahydrofuran (2 mL)—was added to the resulting isocyanate mixture. After 30 minutes of stirring at room temperature, the mixture was concentrated to dryness under reduced pressure. The residue was purified via 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. After the concentration of fractions under reduced pressure, tert-butyl 4-[6-{4-[(methylcarbamoyl)amino]phenyl}-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate was obtained. MS (ES+): 563.4 (M+H)+

Workup

  1. concentrationthe mixture was concentrated to dryness under reduced pressure
  2. customThe residue was purified via reverse-phase high performance liquid chromatography
  3. washa gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile

Sources & evidence

ORD record
ord-e83754a6ac95437f9853ab0bb7e0e086
Source dataset
uspto-grants-2012_03
Patent number
US08129371B2

Reaction notes

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