3,4-dihydro-2H-pyran → 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

HRID 1093163Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1093163
[Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:31]1[CH:36]=[CH:35][CH2:34][CH2:33][CH2:32]1>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][O:31]3)[N:9]=[CH:10][C:5]2=[C:4]([N:11]2[CH2:17][CH:16]3[O:18][CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[N:3]=1

Komponenten

5

Edukt 3

HCID 80803,4-dihydro-2H-pyranHCID 521998p-Toluenesulfonic acid monohydrateHCID 201118843-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane

Produkt 1

HCID 576542796-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (21 mmol) is taken up as a suspension in dry ethyl acetate (50 mL). Following the addition of 4-toluenesulfonic acid monohydrate (25 mg), the mixture is heated to 60° C. and 3,4-dihydro-2H-pyran (2.5 mL) is added in drops. The reaction mixture is maintained at 60° C. for 18 hours and is then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography. Following concentration of fractions, 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine is obtained. 6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.1 mmol) is coupled to 4-acetamidophenylboronic acid (0.83 g, 4.6 mmol) with tetrakis(triphenylphosphine) palladium (0) (2.5 mol %), 2 M aqueous sodium carbonate solution, and ethylene glycol dimethyl ether (DME) and under microwave irradiation (175 C, 10 min). Following an aqueous workup and flash chromatography, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is obtained. N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide (1.2 mmol) is taken up in dioxane (5 mL), treated with 4 M hydrogen chloride in dioxane (5 mL), and allowed to stir at room temperature for 3 days. The slurry is concentrated and purified by reverse phase preparative high performance liquid chromatography, employing a Phenomenex Prodigy 250 mm×21.2 mm 5 μm column and a 5% acetonitrile/95% water/0.1% trifluoroacetic acid to 100% acetonitrile gradient over 40 minutes. After concentration, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is provided.

Aufarbeitung

  1. temperatureThe reaction mixture is maintained at 60° C. for 18 hours
  2. concentrationis then concentrated under reduced pressure
  3. customThe residue is purified by flash silica gel chromatography

Quellen und Nachweise

ORD-Eintrag
ord-d1d2e8dccd33492bb449e91cfcfc201c
Quelldatensatz
uspto-grants-2012_03
Patentnummer
US08129371B2

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