1,2-Dimethoxyethane → (R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1-methyl-1H-pyrazol-4-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

HRID 73741Notes

Reaction equation

HRID 73741 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].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]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>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=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

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 72545604(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(1-methyl-1H-pyrazol-4-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 2.2, 60 mg, 0.134 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (42 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 15% to 45% in 14 min) to yield the title compound as a white solid. LC-MS (Condition 2) tR=1.61 min, m/z=448.2/449.2 [M+H]+, m/z=446.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.71-1.80 (m, 1H) 1.81-1.91 (m, 1H) 2.98 (d, J=11.25 Hz, 1H) 3.25-3.39 (m, 0.2H) 3.44-3.53 (m, 1H) 3.89 (s, 3H) 4.22 (s, 1H) 4.84 (s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.53 (s, 1H) 7.84 (d, J=5.38 Hz, 2H) 7.86-7.88 (m, 1H) 7.94 (d, J=2.45 Hz, 1H) 8.67 (d, J=2.45 Hz, 1H) 10.14 (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-a5ccc75f8f7f44aba9c02f17315314dd
Source dataset
uspto-grants-2014_09
Patent number
US08829195B2

Reaction notes

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