Potassium Carbonate → 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(4'-fluoro-3-methyl-4-biphenylyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 525165Notes

Reaction equation

HRID 525165 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[C:4]([CH3:25])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:30]5[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=5)=[CH:3][C:4]=4[CH3:25])[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 2856454-Fluorophenylboronic acidHCID 710875134-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 682610635-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-(4'-fluoro-3-methyl-4-biphenylyl)-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 58.1%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent

Conditions

Temperature
150 °C

Procedure

A microwave vial was charged with 4-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60.0 mg, 0.148 mmol), (4-fluorophenyl)boronic acid (20.71 mg, 0.148 mmol), PdCl2(dppf) (5.42 mg, 7.40 μmmol), K2CO3 (51.2 mg, 0.370 mmol), 1,4-dioxane (3 mL) and water (1 mL). The reaction was purged with nitrogen, sealed and heated in a microwave reactor at 150° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DMSO, filtered through a syringe filter and purified by reverse phase HPLC (Gilson, YMC-Pack ODS-A C18 5 μm 75×30 mm column, 10-90% MeCN/water+0.1% TFA, 2×1 mL injections). The appropriate fractions were concentrated to remove a majority of the MeCN. The remaining aqueous mixture (product had oiled out) was extracted with two portions of dichloromethane. The combined dichloromethane layers were dried over Na2SO4, filtered, concentrated under reduced pressure and dried to constant weight under vacuum to provide the title product (36 mg, 0.086 mmol, 57.8% yield) as a yellow solid. MS(ES)+ m/e 421.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.75 (d, J=4.04 Hz, 1H), 7.75-7.86 (m, 2H), 7.73 (br. s., 1H), 7.58-7.66 (m, 1H), 7.42 (td, J=8.34, 4.29 Hz, 1H), 7.33 (t, J=8.84 Hz, 2H), 3.59-3.88 (m, 1H), 3.46-3.59 (m, 1H), 2.82-3.38 (m, 2H), 2.28-2.49 (m, 3H), 2.12-2.20 (m, 3H), 1.87-2.07 (m, 1H), 1.39-1.76 (m, 2H), 0.59-0.76 (m, 4H).

Workup

  1. customThe reaction was purged with nitrogen
  2. customsealed
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. dissolutionthe residue was dissolved in DMSO
  5. filtrationfiltered through a syringe
  6. filtrationfilter
  7. custompurified by reverse phase HPLC (Gilson, YMC-Pack ODS-A C18 5 μm 75×30 mm column, 10-90% MeCN/water+0.1% TFA, 2×1 mL injections)
  8. concentrationThe appropriate fractions were concentrated
  9. customto remove a majority of the MeCN
  10. extractionwas extracted with two portions of dichloromethane
  11. dry with materialThe combined dichloromethane layers were dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated under reduced pressure
  14. customdried to constant weight under vacuum

Sources & evidence

ORD record
ord-5e7cbf2a5fbb478f861128e61e9dc353
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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