ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate → 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid

HRID 1056155Notes

Reaction equation

HRID 1056155 reaction equation
[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[NH:11][C:12]([C:20]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:21]=2[N:22]=[C:23]([NH:31][CH2:32][C:33]([F:34])([F:35])[F:36])[C:24]([CH3:30])=[N:25]3)=[CH:13][C:14]=1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 1

HCID 89783480ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate

Product 1

HCID 897846432-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acidYield 85.3%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 3283Diethyl EtherSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

A glass microwave reaction vessel was charged with ethyl 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylate (301b) (380 mg, 0.75 mmol) and LiOH monohydrate (157 mg, 3.74 mmol) in dioxane (5 mL) and water (2.5 mL). The tube was sealed and the reaction mixture was stirred and heated at 110° C. for 3 h. After cooling to RT, the reaction mixture was diluted with Et2O and water and the layers were separated. The Et2O layer was discarded. The aq. layer was acidified with 2 M HCl (aq.) and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 2-(((tert-butoxycarbonyl)amino)methyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid (308 mg, 0.64 mmol) as an orange solid. m/z (ESI, +ve) 480.2 (M+H)+. The orange solid (308 mg) was dissolved in 4 mL of dioxane and treated with a 4 M solution of HCl in 1,4-dioxane (4.68 mL, 18.72 mmol) at RT. The reaction mixture was stirred at RT overnight and was then concentrated. The solid was suspended with 1/1 Et2O/hexanes and collected by filtration to give 2-(aminomethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (301c) (255 mg, 0.61 mmol, 82% yield) as a red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br. s., 1H), 8.37 (t, J=5.77 Hz, 2H), 7.95 (dt, J=7.48, 0.76 Hz, 1H), 7.77 (t, J=6.16 Hz, 1H), 7.71 (dt, J=7.97, 0.81 Hz, 1H), 7.46 (t, J=7.82 Hz, 1H), 7.42 (dd, J=2.35, 0.39 Hz, 1H), 4.38-4.49 (m, 2H), 4.34 (q, J=5.35 Hz, 2H), 2.60 (s, 3H). 19F NMR (377 MHz, DMSO-d6) δ ppm −69.61 (s, 3F). m/z (ESI, +ve) 363.0 (M-NH2)′.

Workup

  1. customA glass microwave reaction vessel
  2. customThe tube was sealed
  3. temperatureAfter cooling to RT
  4. customthe layers were separated
  5. extractionextracted with EtOAc (3×)
  6. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated

Sources & evidence

ORD record
ord-d8c0a60c5e1648d6b9a9e210c582fc89
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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