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Potassium Carbonate → tert-butyl 4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]piperidine-1-carboxylate

HRID 1520080
ノート
印刷プレビュー

反応式

HRID 1520080 の反応式
[C:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH:15]1C2CCCC1CCC2.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][N:29]=[C:28]2[C:34]1[N:35]=[N:36][N:37]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)=[O:46])=[CH:41][CH:40]=2)[CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CN(C=O)C.O>[BH3:15].[N:47]1([C:45]([C:42]2[CH:41]=[CH:40][C:39]([N:37]3[CH:38]=[C:34]([C:28]4[C:27]5[C:31](=[CH:32][CH:33]=[C:25]([CH2:14][CH:11]6[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]6)[CH:26]=5)[NH:30][N:29]=4)[N:35]=[N:36]3)=[CH:44][CH:43]=2)=[O:46])[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1
参加物実験手順後処理出典と根拠反応ノート

参加物

9

反応物 4

HCID 11430Potassium CarbonateHCID 789669-Borabicyclo(3.3.1)nonaneHCID 27568081-Boc-4-Methylenepiperidine2 回HCID 574046585-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole

生成物 2

HCID 6331Borane
HCID 67981478
tert-butyl 4-[(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)methyl]piperidine-1-carboxylate
収率 87%

試薬・触媒・溶媒 3

HCID 962Water溶媒2 回HCID 6228Dimethylformamide溶媒HCID 8028Tetrahydrofuran溶媒2 回

実験手順

A degassed solution of 1-N-Boc-4-methylene-piperidine (48 mg; 0.24 mmol; 1.1 eq.) and 9-BBN (0.5 M 0.44 mL of a 0.5 M solution in THF; 0.22 mmol; 1.0 eq.) in THF (0.5 mL) was heated at 800 for 1 h in a sealed tube. This solution was allowed to cool to RT and cannulated to a degassed mixture of 5-bromo-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole (100 mg; 0.22 mmol; 1.0 eq.), PdCl2dppf (1 mg; 0.001 mmol; 0.01 eq.) and potassium carbonate (76 mg; 0.55 mmol; 2.5 eq.) in DMF (1 mL) and water (0.1 mL). The resulting mixture was heated at 65° C. O/N. As the reaction was not complete, a second solution of borane was prepared (from 0.24 mmol of 1-N-Boc-4-methylene-piperidine) and added to the reaction mixture which was heated at 65° C. for one more night. The reaction mixture was poured into water and extracted twice with EtOAc. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10) gave the title compound as a yellow powder (110 mg, 87%). 1H NMR (300 MHz, DMSO-d6) δ 13.29 (brs, 1H), 9.36 (s, 1H), 8.21-8.08 (m, 3H), 7.74-7.65 (m, 2H), 7.56-7.48 (m, 1H), 7.32-7.23 (m, 1H), 4.04-3.81 (m, 2H), 3.79-3.36 (m, 8H), 2.83-2.56 (m, 3H), 1.84-1.50 (m, 3H), 1.49-1.39 (m, 1H), 1.37 (s, 9H), 1.21-0.91 (m, 2H). HPLC (max plot) 86.0%; Rt 4.36 min. UPLC/MS: (MS−) 470.2 (M-tBuOCO).

後処理

  1. temperatureThe resulting mixture was heated at 65° C
  2. additionadded to the reaction mixture which
  3. temperaturewas heated at 65° C. for one more night
  4. extractionextracted twice with EtOAc
  5. washCombined organic phases were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 90:10)

出典と根拠

ORDレコード
ord-257db6f62f984566b028b2833f1ca78b
出典データセット
uspto-grants-2015_07
DOI
10.6084/m9.figshare.5104873.v1
特許番号
US09073892B2

反応ノート

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