1,2-Dimethoxyethane → (R)-5-(Furan-3-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 525648Notes

Reaction equation

HRID 525648 reaction equation
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].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1.C([O-])([O-])=O.[Na+].[Na+].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.CCO.O>[O:28]1[CH:32]=[CH:31][C:30]([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]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:29]1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2734358Furan-3-boronic acidHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118045033(R)-5-(Furan-3-yl)-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

A mixture of (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.1, 60 mg, 0.134 mmol), furan-3-ylboronic acid (22.6 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol), Na2CO3 (42.8 mg, 0.403 mmol), DME (570 μL), water (163 μL) and EtOH (81 μL) in a MW vial was sealed, evacuated/purge with argon and subjected to MW irradiation at 120° C. for 10 min. The RM was diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 46.7 mg, 0.067 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 9, 25% for 0.2 min then 25% to 55% in 14 min) to yield the title compound as a white solid. LC-MS (Condition 2) tR=1.92 min, m/z=434.1-435.2 [M+H]+, m/z=432 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.81 (m, 1H) 1.82-1.92 (m, 1H) 3.07 (d, J=11.49 Hz, 1H) 3.30-3.45 (m, 1H) 3.48-3.57 (m, 2H) 4.21-4.27 (m, 1H) 6.68 (s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.76 (t, J=1.59 Hz, 1H) 7.83 (s, 1H) 7.84-7.88 (m, 2H) 7.98 (d, J=2.45 Hz, 1H) 8.70 (d, J=2.45 Hz, 1H) 10.16 (s, 1H).

Workup

  1. customwas sealed
  2. customevacuated/purge with argon
  3. customsubjected to MW irradiation at 120° C. for 10 min
  4. additionThe RM was diluted with THF (1 mL)
  5. filtrationfiltered
  6. customthe filtrate was evaporated off under reduced pressure
  7. customto give a residue which
  8. customwas purified by preparative HPLC (Condition 9, 25% for 0.2 min

Sources & evidence

ORD record
ord-9f0a6e2546b84c829e04f26631332ab1
Source dataset
uspto-grants-2016_05
Patent number
US09340537B2

Reaction notes

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