1,2-Dimethoxyethane → (R)-5'-Cyano-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

HRID 923872Notes

Reaction equation

HRID 923872 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].CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][CH:39]=[C:40]([CH:43]=2)[C:41]#[N:42])O1.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>[C:41]([C:40]1[CH:43]=[C:36]([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:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)[CH:37]=[N:38][CH:39]=1)#[N:42]

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 164142165-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 118195202(R)-5'-Cyano-2-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-[3,3'-bipyridine]-5-carboxamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 200 mg, 0.448 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (206 mg, 0.896 mmol), Pd(PPh3)2Cl2 (31.5 mg, 0.045 mmol) and Na2CO3 (143 mg, 1.345 mmol) were added to a MW vial and treated with a mixture of DME (1.902 mL), water (543 μL) and EtOH (272 μL). The vial was sealed, evacuated/purged with argon and then the RM was subjected to MW irradiation at 120° C. for 10 min, then cooled to RT and finally treated with Si-Thiol (1.27 mmol/g, 176 mg, 0.224 mmol) overnight. The RM was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative HPLC (Condition 12, 25% for 0.2 min then 25% to 55% in 14 min.) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=2.30 min, m/z=470.0-471.0 [M+H]+, m/z=468.0-469.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.79 (m, 1H) 1.80-1.92 (m, 1H) 2.86 (d, J=11.25 Hz, 1H) 3.16-3.27 (m, 2H) 3.34-3.44 (m, 1H) 4.17-4.24 (m, 1H) 4.70-5.04 (m, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.82-7.88 (m, 2H) 8.09 (d, J=2.45 Hz, 1H) 8.40 (t, J=2.08 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.90 (d, J=1.96 Hz, 1H) 9.02 (d, J=1.96 Hz, 1H) 10.17 (s, 1H).

Workup

  1. customThe vial was sealed
  2. customevacuated/purged with argon
  3. customthe RM was subjected to MW irradiation at 120° C. for 10 min
  4. filtrationThe RM was filtered
  5. customthe solvent was evaporated off under reduced pressure
  6. customto give a residue which
  7. customwas purified by preparative HPLC (Condition 12, 25% for 0.2 min

Sources & evidence

ORD record
ord-8bd8217915c1413e8a65d99fc2ef78e6
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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