2-Amino-5-cyanopyridine → (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide

HRID 1098166ノート

反応式

HRID 1098166 の反応式
C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1

参加物

5

反応物 3

HCID 8182602-Amino-5-cyanopyridineHCID 16682925TrimethylaluminumHCID 59279503(2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate

生成物 1

HCID 57504516(2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-cyanopyridin-2-yl)propanamide収率 17.6%

試薬・触媒・溶媒 1

HCID 1140Toluene溶媒2 回

反応条件

温度
0 °C

実験手順

Trimethylaluminium (2M in hexane) (0.455 mL, 0.91 mmol) was added to 6-aminonicotinonitrile (104 mg, 0.87 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AB2) (500 mg, 0.79 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature. The temperature was increased to 60° C. and stirred for 4 hours, then heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo and neutralised with citric acid (1M, aq) and then diluted with water (10 ml) and DCM (10 mL). The mixture was poured onto a phase separator and the organic layer was evaporated in vacuo. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were neutralised with MP-carbonate and evaporated to dryness to afford the product (100 mg, 17.6%). m/z (ES+) (M+H)+=719.51; HPLC tR=3.58 min.

後処理

  1. temperatureto warm to room temperature
  2. temperatureThe temperature was increased to 60° C.
  3. stirringstirred for 4 hours
  4. temperatureheated
  5. temperatureat reflux for 24 hours
  6. concentrationThe reaction mixture was concentrated in vacuo
  7. additiondiluted with water (10 ml) and DCM (10 mL)
  8. additionThe mixture was poured onto a phase separator
  9. customthe organic layer was evaporated in vacuo
  10. customThe crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length)
  11. additionFractions containing the desired compound
  12. customevaporated to dryness

出典と根拠

ORDレコード
ord-a3ed486ccbad40879d93ef0e83521b30
出典データセット
uspto-grants-2012_03
特許番号
US08143263B2

反応ノート

読み込み中…