Sodium Carbonate → HCID 178488222, Verbindung

HRID 432312Notizen

Reaktionsgleichung

I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[NH:33][C:34](=[O:43])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([NH:33][C:34](=[O:43])[CH2:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:27]([O:26][CH3:25])[CH:28]=3)[C:10]=12

Komponenten

Reaktionsbedingungen

Temperatur: 85 °C

Versuchsvorschrift

A solution of trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.268 g, 0.607 mmol) in ethylene glycol dimethyl ether (20 mL) was treated with 3-methoxy-4-[(3-phenylpropanoyl)amino]phenylboronic acid (0.200 g, 0.669 mmol), tetrakis(triphenylphosphine)palladium (0.042 g, 0.036 mmol), and a solution of sodium carbonate (0.154, 1.46 mmol) in water (10 mL). The reaction mixture was stirred for 9 h at 85° C. under a nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (0.035 g, 0.03 mmol) was added and the mixture stirred over night (15 h). The organic layer was removed under reduced pressure, and ethyl acetate was added. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel, using 10% methanol in dichloromethane (6 L) as eluent. A second purification on a Supelco flash chromatography column was required, using 20% methanol in dichloromethane as eluent. The second column afforded 0.132 g (38%) of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. The product was sent for preparative HPLC purification (Hypersil C18, 100×21 mm column, 5 μm, 15-100% Acetonitrile gradient over 8min, total run time—10 min, buffer—50 mM Ammonium Acetate, 25 m/min), and afforded 0.026 g of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide. A warm solution of trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (0.026 g, 0.046 mmol) in ethyl acetate was treated with a warm solution of maleic acid (0.016 g, 0.137 mmol) in ethyl acetate. The precipitate was filtered under nitrogen atmosphere and dried under high vacuum to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide tris-maleate.

Aufarbeitung

stirringthe mixture stirred over night (15 h)
customThe organic layer was removed under reduced pressure, and ethyl acetate
additionwas added
customThe layers were partitioned
extractionthe aqueous layer was extracted with ethyl acetate (300 mL)
washThe combined organic layers were washed with water and brine
dry with materialdried over magnesium sulfate
filtrationfiltered
customevaporated under reduced pressure
customThe crude material was purified by flash chromatography on silica gel
customA second purification on a Supelco flash chromatography column

Quellen und Nachweise

ORD-Eintrag: ord-75e32dc38c674526b0412ab6b4e6388e
Quelldatensatz: uspto-grants-2003_12
DOI: 10.6084/m9.figshare.5104873.v1
Patentnummer: US06660744B1

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