1-Hydroxybenzotriazole → HCID 71493953, compound

HRID 1486987Notes

Reaction equation

HRID 1486987 reaction equation
[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:48][C:49]1([F:54])[CH2:53][CH2:52][NH:51][CH2:50]1.CCN(C(C)C)C(C)C>ClCCl.CO>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:51]3[CH2:52][CH2:53][C:49]([F:54])([F:48])[CH2:50]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:23])[CH:8]=1

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid

Product 1

HCID 71493953HCID 71493953, compoundYield 9.2%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

In a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (4) (1 g, 1.0 eq.) was charged in dichloromethane (20 mL, 20 V). The reaction mixture was cooled to 0° C. HOBT (0.461 g, 1.2 eq.), EDC.HCl (0.819 g, 1.5 eq.), 3,3-Difluoropyrrolidine hydrochloride (0.490 g, 1.2) and DIPEA (0.731 mL, 1.5 eq.) was added to the reaction mixture. The clear reaction mixture was stirred at 0° C. for 1.5 h. The progress of the reaction was followed by TLC using 5% methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was quenched in water (50 mL). Organic layer was separated and aqueous layer was extracted with dichloromethane (20×2). The combined organic layer was washed with brine solution, dried over Na2SO4 and concentrated by rotary evaporation (25° C., 20 mm Hg) to afford 0.67 g of crude compound. The crude compound was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collection (25 mL fractions). The compound started eluting from 0.9% to 1.0% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.115 g Yield (9.2%).

Workup

  1. customIn a 100 mL, 3N round-bottomed flask equipped with nitrogen inlet
  2. customReaction mixture
  3. customwas quenched in water (50 mL)
  4. customOrganic layer was separated
  5. extractionaqueous layer was extracted with dichloromethane (20×2)
  6. washThe combined organic layer was washed with brine solution
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated by rotary evaporation (25° C., 20 mm Hg)
  9. customto afford 0.67 g of crude compound
  10. customThe crude compound was purified by column chromatography
  11. washstarted eluting in MeOH in gradient manner
  12. customstarting with fraction collection (25 mL fractions)
  13. washThe compound started eluting from 0.9% to 1.0% methanol in dichloromethane
  14. additionFractions containing such TLC profile
  15. customwere collected together

Sources & evidence

ORD record
ord-edddab07d6d946a3af27967227ec2518
Source dataset
uspto-grants-2016_08
Patent number
US09428490B2

Reaction notes

Loading…