Sodium Bicarbonate → 6-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923939ノート

反応式

HRID 923939 の反応式
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][CH:24]([C:27]([OH:30])([CH3:29])[CH3:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])(O)=O.[Na+]>COCCOC.CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:30][C:27]([CH:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:35]3[CH:36]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1)([CH3:29])[CH3:28]

参加物

8

反応物 3

HCID 516892Sodium BicarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 899078115-Bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

生成物 1

HCID 1181952506-(3-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

試薬・触媒・溶媒 4

HCID 178418476HCID 178418476、化合物触媒HCID 702Ethanol溶媒HCID 80711,2-Dimethoxyethane溶媒HCID 8857Ethyl Acetate溶媒

反応条件

温度
95 °C

実験手順

5-Bromo-6-(3-(2-hydroxypropan-2-yl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 113.1, 98 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (49.6 mg, 0.4 mmol) were dissolved in DME (0.8 mL) and EtOH (0.12 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, then Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling at RT, the RM was dissolved in EtOAc, washed with brine, dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white solid. HPLC (Condition 4) tR=4.94 min, UPLC-MS (Condition 3) tR=1.01 min, m/z=532.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.08 (m, 6H) 1.58-1.83 (m, 2H) 1.99-2.15 (m, 1H) 3.05-3.23 (m, 3H) 3.25-3.35 (m, 1H) 4.29 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.75-7.87 (m, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.14 (s, 1H).

後処理

  1. customthe RM was flushed with argon
  2. temperatureAfter cooling at RT
  3. washwashed with brine
  4. dry with materialdried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH)
  7. additiontreated with Si-Thiol (80 mg) in MeOH

出典と根拠

ORDレコード
ord-a252b90c489d461fbb690113f7204062
出典データセット
uspto-grants-2016_03
特許番号
US09278981B2

反応ノート

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