1,2-Dimethoxyethane → (R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

HRID 923830Notes

Reaction equation

HRID 923830 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][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>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:21]2[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)=[O:6])=[CH:3][C:2]=2[C:32]2[CH:33]=[N:28][CH:29]=[N:30][CH:31]=2)[CH2:23]1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 86702591(R)-3-bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Product 1

HCID 118195099(R)-4-(3-Hydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

(R)-3-Bromo-4-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 2.1, 80 mg, 0.180 mmol), pyrimidin-5-ylboronic acid (66.8 mg, 0.539 mmol), Pd(PPh3)2Cl2 (7.57 mg, 10.78 μmol) and Na2CO3 (57.1 mg, 0.539 mmol) were added to a MW vial and treated with a mixture of DME (762 μL), water (218 μL) and EtOH (109 μL). The vial sealed, evacuated/purged with argon and then the RM was subjected to MW irradiation at 80° C. for 2 h. The RM was cooled to RT, diluted with THF (1 mL), treated with Si-Thiol (Silicycle, 1.27 mmol/g, 70.7 mg, 0.090 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2)) to yield the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.37 min, m/z=445.0 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.70-1.81 (m, 1H) 1.82-1.93 (m, 1H) 2.68 (dd, J=10.15, 1.10 Hz, 1H) 2.97-3.11 (m, 2H) 3.17-3.27 (m, 1H) 4.17-4.25 (m, 1H) 4.87 (d, J=3.67 Hz, 1H) 6.98 (d, J=9.05 Hz, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.79-7.90 (m, 3H) 7.94 (dd, J=8.80, 2.20 Hz, 1H) 8.86 (s, 2H) 9.16 (s, 1H) 10.09 (s, 1H).

Workup

  1. customThe vial sealed, evacuated/purged with argon
  2. customthe RM was subjected to MW irradiation at 80° C. for 2 h
  3. additiondiluted with THF (1 mL)
  4. filtrationfiltered
  5. customthe filtrate was evaporated off under reduced pressure
  6. customto give a residue which
  7. customwas purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc-EtOH+0.1% NH4OH (8:2), from 30% to 80% EtOAc-EtOH+0.1% NH4OH (8:2))

Sources & evidence

ORD record
ord-55912f3c3611407ebb81280e590621e4
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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