Maleic Acid → HCID 178502635、化合物

HRID 432173ノート

反応式

HRID 432173 の反応式
[CH3:1][O:2][N:3]=[C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44]>C(O)C>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]\[C:43]([OH:45])=[O:44].[CH3:1][O:2][N:3]=[C:4]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([C@H:27]3[CH2:32][CH2:31][C@@H:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)[N:18]=2)=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1

参加物

4

反応物 2

HCID 444266Maleic AcidHCID 178502634HCID 178502634、化合物

生成物 1

HCID 178502635HCID 178502635、化合物収率 71.8%

試薬・触媒・溶媒 1

HCID 702Ethanol溶媒2 回

実験手順

A mixture of phenyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-methanone O-methyloxime (intermediate AQ) (0.701 g, 0.0021 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AC) (0.80 g, 0.0018 mol), tetrakis-(triphenylphosphine)palladium (0.125 g, 0.00011 mol) and sodium carbonate (0.48 g, 0.0045 mol) was heated in a mixture of ethylene glycol dimethyl ether (40 mL) and water (20 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (100 mL), the organic layer separated and the aqueous layer further extracted with ethyl acetate twice (70 mL each). The combined organic extracts were dried over magnesium sulfate. The solvents were evaporated under reduced pressure to leave a tan solid which was purified by flash column chromatography on silica using dichloromethane/triethylamine/methanol (96:3:1) as a mobile phase to give cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime as a white solid (0.700 g, 0.00133 mol). Cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime (0.201 g, 0.00039 mol) was dissolved in refluxing ethanol (17 mL) and a preheated solution of maleic acid (0.178 g, 0.0015 mol) in ethanol (8 mL) was added. The mixture was refluxed for 10 min, cooled to ambient temperature and the precipitate collected by filtration, washed with ethyl acetate and dried to give cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate as a white solid (0.212 g, 0.00028 mol): 1H NMR (DMSO-d6, 400 MHz) 8.26 (s, 1H), 7.74 (d, 1H), 7.66 (d, 1H), 7.51 (m, 6H), 7.33 (d, 1H), 6.14 (s, 4H), 4.85 (m, 1H), 3.91 (s, 3H) 3.1 (br, 9H), 2.71 (s, 3H), 2.33 (m, 2H), 2.07 (m, 2H), 1.74 (m, 4H); RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile—0.1M ammonium acetate over 20 min, 1 mL/min) Rt 14.25 min. MS: MH+525.

後処理

  1. temperatureThe mixture was refluxed for 10 min
  2. filtrationthe precipitate collected by filtration
  3. washwashed with ethyl acetate
  4. customdried

出典と根拠

ORDレコード
ord-2ac31cc925b34d5a92346aaa58132836
出典データセット
uspto-grants-2003_12
特許番号
US06660744B1

反応ノート

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