Sodium Bicarbonate → (R)-6'-(Hydroxymethyl)-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

HRID 923860

反応式

HRID 923860 の反応式
Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[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].[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.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:28][CH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1

参加物

7

反応物 3

HCID 516892Sodium BicarbonateHCID 441182556-(Hydroxymethyl)pyridine-3-boronic acidHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

生成物 1

HCID 118195311(R)-6'-(Hydroxymethyl)-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

試薬・触媒・溶媒 3

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

反応条件

温度
90 °C

実験手順

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89 mg, 0.2 mmol) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid (61.2 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was diluted in MeOH, treated with Si-Thiol (100 mg), the resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH) afforded the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=475.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.77-1.86 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.11-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.12-4.22 (m, 1H) 4.61 (d, J=5.87 Hz, 2H) 4.84 (d, J=3.13 Hz, 1H) 5.47 (t, J=5.87 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.53 (d, J=8.21 Hz, 1H) 7.74-7.88 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).

後処理

  1. customthe RM was flushed with argon
  2. temperatureAfter cooling to RT
  3. washwashed with brine
  4. dry with materialThe organic phase was dried over Na2SO4
  5. customevaporated to dryness under reduced pressure
  6. additionThe residue was diluted in MeOH
  7. additiontreated with Si-Thiol (100 mg)
  8. filtrationthe resin was filtered off
  9. customthe solvent was evaporated off under reduced pressure
  10. customto give a residue which
  11. customwas purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH)

出典と根拠

ORDレコード
ord-804f311df1e34ffd9a16a706415409f2
出典データセット
uspto-grants-2016_03
特許番号
US09278981B2

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