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

HRID 924116Notes

Reaction equation

HRID 924116 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]([Cl: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>[Cl:18][C:15]([F:17])([F:16])[O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)[CH:3]=2)=[CH:9][CH:10]=1

Participants

8

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 86702621(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide

Product 1

HCID 89908235(R)-N-(4-(Chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)-3-(pyrimidin-5-yl)benzamide

Reagents, catalysts & solvents 3

HCID 178418476HCID 178418476, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolvent

Procedure

(R)-3-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide (Stage 243.1, 80 mg, 0.173 mmol), pyrimidin-5-ylboronic acid (42.9 mg, 0.347 mmol), Pd(PPh3)2Cl2 (12.16 mg, 0.017 mmol) and Na2CO3 (73.5 mg, 0.693 mmol) were added to a MW vial and treated with a mixture of DME (735 μL), water (210 μL) and EtOH (105 μL). The vial was sealed, evacuated/purged with argon and subjected to MW irradiation at 125° C. for 15 min, diluted with DCM (2 mL), treated with Si-Thiol (Silicycle, 1.43 mmol/g, 72.2 mg, 0.104 mmol). The RM was centrifuged, the supernatant was filtered and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH+1% NH4OH from 1% to 10% MeOH+1% NH4OH). Product was further purified by preparative SFC (Column DEAP, isocratic 6% in 6 min) to yield the title product as a white solid. UPLC-MS (Condition 3) tR=1.01 min, m/z=461.1 [M+H]+, m/z=459.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.81 (m, 1H) 1.82-1.94 (m, 1H) 2.68 (d, J=9.66 Hz, 1H) 2.98-3.10 (m, 2H) 3.18-3.27 (m, 1H) 4.17-4.26 (m, 1H) 4.89 (d, J=3.55 Hz, 1H) 6.99 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.90 (m, 3H) 7.95 (dd, J=8.80, 2.20 Hz, 1H) 8.87 (s, 2H) 9.17 (s, 1H) 10.12 (s, 1H).

Workup

  1. customThe vial was sealed
  2. customevacuated/purged with argon
  3. customsubjected to MW irradiation at 125° C. for 15 min
  4. additiondiluted with DCM (2 mL)
  5. filtrationthe supernatant was filtered
  6. customthe solvent was evaporated off under reduced pressure
  7. customto give a residue which
  8. customwas purified by flash chromatography (RediSep® Silica gel column, 12 g, DCM/MeOH+1% NH4OH from 1% to 10% MeOH+1% NH4OH)
  9. customProduct was further purified by preparative SFC (Column DEAP, isocratic 6% in 6 min)

Sources & evidence

ORD record
ord-b998bf85c28a43769e371d7ad5ef39cc
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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