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Ethanol → 6-(3-Hydroxy-3-methylazetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 923960
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HRID 923960 반응식
Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[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:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.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.CCOC(C)=O>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=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
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참가 물질

8

반응물 4

HCID 702EthanolHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 899064985-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

생성물 1

HCID 899081486-(3-Hydroxy-3-methylazetidin-1-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

시약·촉매·용매 3

HCID 178418476
HCID 178418476, 화합물
촉매
HCID 80711,2-Dimethoxyethane용매
HCID 8857Ethyl Acetate용매

반응 조건

온도
95 °C

실험 절차

5-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1, 89 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (50 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) and EtOH (120 μL) were added, the mixture was flushed with argon, Pd(PPh3)2Cl2 (17 mg, 0.02 mmol) was added and the RM was heated at 95° C. for 3 h in a pressure safe vial. After cooling at RT, the RM was treated with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH; then second flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=4.74 min, UPLC-MS (Condition 7) m/z=446.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 4H) 3.50-3.64 (m, 3H) 5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.09 (d, J=1.56 Hz, 1H) 8.78 (d, J=1.95 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.20 (s, 1H).

후처리

  1. additionwas added
  2. temperatureAfter cooling at RT
  3. washwashed with brine
  4. dry with materialThe organic phase was dried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. customThe crude product was purified by flash chromatography (RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH
  7. additionthen second flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH

출처 및 근거

ORD 기록
ord-4989b817ea984483b6fade8877d3240a
출처 데이터셋
uspto-grants-2016_03
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09278981B2

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