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

HRID 923854Notes

Reaction equation

HRID 923854 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][C:29]1[N:34]=[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.O.CCO>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:32]3[CH:31]=[N:30][C:29]([CH3:28])=[N:34][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 457872822-Methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineHCID 86702593(R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

Product 1

HCID 89908448(R)-6-(3-Hydroxypyrrolidin-1-yl)-5-(2-methylpyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

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, 60 mg, 0.134 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (44.4 mg, 0.202 mmol), Pd(PPh3)2Cl2 (9.44 mg, 0.013 mmol) and Na2CO3 (42.8 mg, 0.403 mmol) were added to a MW vial and treated with DME (570 μL), EtOH (81 μL) and water (163 μL). The vial was sealed, evacuated/purged with argon, and subjected to MW irradiation at 80° C. with stirring for 2 h, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 52.9 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 12, 20% for 0.2 min then 20% to 50% in 12 min) to yield the title compound as a white solid. UPLC-MS (condition 1) tR=1.82 min, m/z=458.2 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.80 (m, 1H) 1.79-1.92 (m, 1H) 2.69 (s, 3H) 2.91 (d, J=11.00 Hz, 1H) 3.14-3.49 (m, 3H) 4.13-4.28 (m, 1H) 4.83 (br. s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.80-7.91 (m, 2H) 8.05 (d, J=2.45 Hz, 1H) 8.75 (s, 2H) 8.78 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).

Workup

  1. customThe vial was sealed
  2. customevacuated/purged with argon
  3. customsubjected to MW irradiation at 80° C.
  4. additiondiluted 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 12, 20% for 0.2 min

Sources & evidence

ORD record
ord-85a390e97e19417089044b2d6c99e236
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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