Trifluoroacetic acid → 5-(2-Ethylsulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine

HRID 1959413Notes

Reaction equation

HRID 1959413 reaction equation
[CH2:1]([S:3]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][NH:10][CH2:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].CCN(CC)CC.C(OC([N:28]([C:36]1[C:41]([C:42]2[O:43][C:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[N:45][N:46]=2)=[N:40][C:39](Br)=[CH:38][N:37]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH2:1]([S:3]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][N:10]([C:39]3[N:40]=[C:41]([C:42]4[O:43][C:44]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)=[N:45][N:46]=4)[C:36]([NH2:28])=[N:37][CH:38]=3)[CH2:11]2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2]

Participants

8

Reactant 4

HCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 59471994Tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamateHCID 662133722-ethylsulfonyl-3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole

Product 1

HCID 667452965-(2-Ethylsulfonyl-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl)-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amineYield 43.8%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

2-ethylsulfonyl-3,3a,4,5,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole (36.34 mg, 0.1779 mmol) and Et3N (54.01 mg, 74.39 μL, 0.5337 mmol) were added to a solution of tert-butyl N-tert butoxycarbonyl-5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-ylcarbamate (100 mg, 0.1779 mmol) in DMF (2 mL) and the resulting solution heated at 100° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (5 mL) and washed successively with water (2×5 mL) followed by brine (1×5 mL). The organic layer was concentrated in vacuo to leave a solid. The solid was dissolved in CH2Cl2 (10 mL) and trifluoroacetic acid (405.7 mg, 274.1 μL, 3.558 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and the reaction mixture then concentrated in vacuo to an oil. The oil was redissolved in CH2Cl2 (20 ml) and concentrated in vacuo to leave a solid. The solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the product (34.4 mg, 40% yield); 1H NMR (400 MHz, DMSO) d 1.25 (t, 3H), 3.1-3.2 (m, 4H), 3.25-3.3 (m, 2H), 3.4-3.45 (m, 2H), 3.5-3.7 (m, 4H), 6.75 (s, 2H), 7.6-7.65 (m, 3H) and 8.05-8.1 (m, 2H) ppm; MS (ES+) 442.1

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washwashed successively with water (2×5 mL)
  3. concentrationThe organic layer was concentrated in vacuo
  4. customto leave a solid
  5. concentrationthe reaction mixture then concentrated in vacuo to an oil
  6. dissolutionThe oil was redissolved in CH2Cl2 (20 ml)
  7. concentrationconcentrated in vacuo
  8. customto leave a solid
  9. customThe solid was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]
  10. customThe fractions were collected
  11. customfreeze-dried

Sources & evidence

ORD record
ord-6850a7fb394d47d4ab0dc19976be9391
Source dataset
uspto-grants-2013_04
Patent number
US08410112B2

Reaction notes

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