Trifluoroacetic acid → 2-amino-1-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethanone

HRID 909252

Reaction equation

HRID 909252 reaction equation
C(O)(C(F)(F)F)=O.[O:8]=[C:9]([N:19]1[CH2:24][CH2:23][N:22]2[CH:25]=[CH:26][CH:27]=[C:21]2[CH:20]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][NH:11]C(=O)OC(C)(C)C.C(=O)([O-])[O-].[K+].[K+].ClCCCl.CCO>C(Cl)Cl.O>[NH3:11].[NH2:11][CH2:10][C:9]([N:19]1[CH2:24][CH2:23][N:22]2[CH:25]=[CH:26][CH:27]=[C:21]2[CH:20]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:8]

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 229016121,2-Dichloroethane ethanolHCID 67401960tert-butyl 2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethylcarbamate

Product 2

HCID 222AmmoniaHCID 579740192-amino-1-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethanoneYield 52.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

TFA (20 ml) was added to a solution of (1.6 g, 4.6 mmol) of tert-butyl 2-oxo-2-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethylcarbamate in DCM (20 ml), and stirring was carried out for 1 h at RT. The mixture was then diluted with water, while cooling (ice-bath), and adjusted to pH 10 with 20% aq. potassium carbonate solution. The aqueous phase was saturated with sodium chloride, and extraction with chloroform was then carried out. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. CC (DCE/EtOH/conc. aq. NH3 5:1:0.06) yielded 298 mg (1.2 mmol, 26%) of 2-amino-1-(1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)ethanone (A23). 2. Acylation Reactions 3. Method A The corresponding tetrahydropyrrolopyrazine (1.1 mmol), NEt3 (263 μl, 1.9 mmol) and HATU (380 mg, 1.0 mmol) were added to a solution of the corresponding butanoic acid derivative (S1 or S2). The reaction solution was stirred for 2 d at RT and then concentrated in vacuo. The crude products were purified by CC (EA/DCM 1:9→1:1). 4. Method B CDI (286 mg, 1.76 mmol) was added to a solution of (1.68 mmol) of the corresponding acid in DCM (27 ml), and stirring was carried out for 1 h at RT. The corresponding amine (1.68 mmol) was then added, and stirring was carried out for a further 16 h at RT. A 4N aq. ammonium chloride solution was then added and the phases were separated. The aqueous phase was extracted twice more with DCM. The organic phases were combined and washed with a 1M sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The crude product was purified by CC (ethyl acetate). 5. Method C The corresponding acid (1.05 mmol) and PS diimide (1.18 g, ˜1.4 mmol) were added to a solution of the corresponding amine structural unit (0.7 mmol) in DCM (20 ml). Shaking was then carried out for 2 h at RT. The resin was then filtered off and washed several times with DCM and MeOH. The filtrate was concentrated in vacuo. CC (DCE/ethanol 20:1) with the residue yielded the corresponding product.

Workup

  1. temperaturewhile cooling (ice-bath)
  2. extractionThe aqueous phase was saturated with sodium chloride, and extraction with chloroform
  3. dry with materialThe organic phase was dried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-437a5c239f9a4f2f837b58085a92531b
Source dataset
uspto-grants-2011_09
Patent number
US08017772B2

Linked notes

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