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

HRID 2405345Notes

Reaction equation

HRID 2405345 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.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]3[C:40](=[CH:41][CH:42]=2)[NH:39][CH:38]=[CH:37]3)O1.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:34]5[CH:35]=[C:36]6[C:40](=[CH:41][CH:42]=5)[NH:39][CH:38]=[CH:37]6)=[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 27347725-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indoleHCID 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 682611345-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(1H-indol-5-yl)-2-methylphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneYield 53.2%

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 microwaveable 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 (100 mg, 0.247 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (60.0 mg, 0.247 mmol), PdCl2(dppf) (9.03 mg, 0.012 mmol), K2CO3 (85 mg, 0.617 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 (58 mg, 0.131 mmol, 53.2% yield) as a white solid. MS(ES)+ m/e 442.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (d, J=4.04 Hz, 1H), 11.21 (br. s., 1H), 7.90 (s, 1H), 7.74 (br. s., 1H), 7.57-7.67 (m, 1H), 7.43-7.54 (m, 2H), 7.32-7.43 (m, 2H), 6.51 (d, J=2.27 Hz, 1H), 3.60-3.89 (m, 1H), 3.47-3.59 (m, 1H), 3.39-2.86 (m, 2H), 2.28-2.49 (m, 3H), 2.13-2.21 (m, 3H), 1.96 (d, J=9.35 Hz, 1H), 1.41-1.75 (m, 2H), 0.60-0.76 (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, 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-0fedee7ab8c4486880c0223d969b11c5
Source dataset
uspto-grants-2014_08
Patent number
US08802864B2

Reaction notes

Loading…