Cesium carbonate → 2-(6-(4-(3-Cyano-4-

HRID 1500203노트

반응식

HRID 1500203 반응식
Br[C:2]1[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[C:31]([F:34])([F:33])[F:32])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CCO.COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]([C:15]1[CH:16]=[C:17]([CH:28]=[CH:29][C:30]=1[C:31]([F:32])([F:33])[F:34])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([CH:8]([OH:12])[C:9]([NH2:11])=[O:10])[CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:14]

참가 물질

6

반응물 3

HCID 10796Cesium carbonateHCID 898154332-(6-Bromopyridin-2-yl)-2-hydroxyacetamideHCID 89815591(4-(3-Cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid

생성물 1

HCID 717351082-(6-(4-(3-Cyano-4-

시약·촉매·용매 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 86587095Dimethoxyethane ethanol water용매

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온도
90 °C

실험 절차

A mixture of 3-cyano-4-trifluoromethyl-1-fluorobenzene (70, g, 0.37, mol, Oakwood), 4-hydroxyphenylboronic acid (50, g, 0.36, mol, Boron Molecular), K2CO3, (70, g) and DMF/water (400, mL/40, mL) was heated to 100° C. for 3, h. After cooling to RT, the mixture was diluted with water (1, L) and extracted with EtOAc (1.5, L). The organic layer was washed with water (0.5, L) and brine, concentrated and purified by chromatographed over silica gel with 4% MeOH in chloroform to give (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid as pink solid (50, g, 45%). 1H NMR (400, MHz, CD3OD) 7.70-7.70, (3H, m), 7.35, (1H, d, J=2.4, Hz), 7.24, (1H, dd, J=2.2, & 8.8, Hz), 7.00, (2H, d, J=7.7, Hz). [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17, mg, 0.022 mmol, Aldrich) was added to a mixture of 2-(6-bromopyridin-2-yl)-2-hydroxyacetamide (50, mg, 0.22, mmol), (4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)boronic acid (100, mg, 0.32, mmol) and cesium carbonate (140, mg, 0.43 mmol) in EtOH/DME/water (2, mL/2, mL/1, mL) at room temperature. The reaction mixture was flushed with argon, then, shaken at 90° C. for 3, h. After cooling to RT, the reaction was quenched with water (2, mL), and extracted with EtOAc (10 mL). The organic layer was separated, concentrated and purified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN) to give 2-(6-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-yl)-2-hydroxyacetamide (Cpd. No. 6) as off-white solid (45, mg, 50%). LC/MS: m/z=414.1, [M+H]+, ; 1H NMR (400, MHz, DMSO-d6) 8.15, (2H, d, J=8.4, Hz), 7.93 (1H, d, J=9.2, Hz), 7.82-7.86, (3H, m), 7.37-7.45, (3H, m), 7.26, (2H, d, J=9.2, Hz), 4.95, (1H, s).

후처리

  1. customat room temperature
  2. customThe reaction mixture was flushed with argon
  3. temperatureAfter cooling to RT
  4. customthe reaction was quenched with water (2, mL)
  5. extractionextracted with EtOAc (10 mL)
  6. customThe organic layer was separated
  7. concentrationconcentrated
  8. custompurified by reverse-phase prep HPLC (C18, 0-100% 0.1% TFA in water/0.1% TFA in ACN)

출처 및 근거

ORD 기록
ord-f1cb58d34c27481882818a0755f5e617
출처 데이터셋
uspto-grants-2015_12
특허 번호
US09206127B2

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