Potassium Carbonate → 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(1H-indol-6-yl)-2-methylphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

HRID 525164Notes

Reaction equation

HRID 525164 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.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32](B(O)O)[CH:33]=2)[CH:28]=[CH:27]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:32]5[CH:33]=[C:34]6[C:29]([CH:28]=[CH:27][NH:26]6)=[CH:30][CH:31]=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 27632051H-Indol-6-ylboronic 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 710875555-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(1H-indol-6-yl)-2-methylphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 49%

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 (105 mg, 0.259 mmol), 1H-indol-6-ylboronic acid (41.7 mg, 0.259 mmol), PdCl2(dppf) (9.48 mg, 0.013 mmol), K2CO3 (90 mg, 0.648 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 (LCMS indicated complete conversion of starting material to desired product). 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, 3×1 mL injections). The appropriate fractions were concentrated to remove a majority of the MeCN, leaving an aqueous suspension of product. The precipitate was collected by filtration, rinsed with minimal water and dried to constant weight under vacuum to provide the title product (56 mg, 0.127 mmol, 49.0% yield) as a white solid. MS(ES)+ m/e 442.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.74 (d, J=3.79 Hz, 1H), 11.24 (s, 1H), 7.74 (br. s., 1H), 7.70 (s, 1H), 7.64 (d, J=8.34 Hz, 2H), 7.31-7.44 (m, 3H), 6.47 (d, J=2.27 Hz, 1H), 3.63-3.85 (m, 1H), 2.87-3.57 (m, 3H), 2.30-2.47 (m, 3H), 2.13-2.21 (m, 3H), 2.08 (s, 1H), 1.44-1.76 (m, 2H), 0.61-0.78 (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, 3×1 mL injections)
  8. concentrationThe appropriate fractions were concentrated
  9. customto remove a majority of the MeCN
  10. customleaving
  11. additionan aqueous suspension of product
  12. filtrationThe precipitate was collected by filtration
  13. washrinsed with minimal water
  14. customdried to constant weight under vacuum

Sources & evidence

ORD record
ord-b5c4e4190a084b6fb31f648a5bfcc98a
Source dataset
uspto-grants-2016_05
Patent number
US09340529B2

Reaction notes

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