Hydrochloric Acid → 7-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

HRID 240457Notes

Reaction equation

HRID 240457 reaction equation
[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[F:29][C:30]([F:42])([F:41])[C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][CH:11]3[C:26](=[O:27])[N:14]4[CH2:15][CH2:16][N:17]([S:37]([C:33]5[CH:34]=[CH:35][CH:36]=[C:31]([C:30]([F:42])([F:41])[F:29])[CH:32]=5)(=[O:39])=[O:38])[CH2:18][CH:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 27332503-(Trifluoromethyl)benzenesulfonyl chlorideHCID 86680465tert-butyl 7-[(5-cyclopropylpyrazin-2-yl)oxy]-6-oxohexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

Product 1

HCID 866804667-[(5-cyclopropylpyrazin-2-yl)oxy]-2-{[3-(trifluoromethyl)phenyl]-sulfonyl}hexahydropyrrolo[1,2-a]pyrazin-6(2H)-oneYield 91%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent2×

Procedure

To a solution of the product from Example 207C (40 mg, 0.107 mmol) in 1,4-dioxane (0.5 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 90 minutes and then concentrated in vacuo. To the residue was added CH2Cl2 (1 mL), 3-(trifluoromethyl)-benzene-1-sulfonyl chloride (0.021 mL, 0.130 mmol) and triethylamine (0.045 mL, 0.324 mmol), and the resulting mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between water and CH2Cl2, and the organic layer was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2 to give the title compound (47 mg, 90%). 1H NMR (300 MHz, CDCl3) δ ppm 0.84-1.04 (m, 4H) 1.55-1.65 (m, 0.6H) 1.89-2.50 (m, 4H) 2.85-2.98 (m, 0.4H) 3.00-3.20 (m, 1H) 3.69-3.84 (m, 0.4H) 3.83-3.96 (m, 1.6H) 3.95-4.07 (m, 1H) 4.20 (dd, J=13.22, 2.37 Hz, 1H) 5.43 (dd, J=8.14, 5.09 Hz, 0.6H) 5.57 (t, J=7.63 Hz, 0.4H) 7.74 (t, J=7.80 Hz, 1H) 7.86-7.99 (m, 3H) 8.00-8.04 (m, 1H) 8.07-8.13 (m, 1H); MS (ESI) m/z 483 (M+H)+.

Workup

  1. concentrationconcentrated in vacuo
  2. stirringthe resulting mixture was stirred at room temperature for 90 minutes
  3. customThe mixture was partitioned between water and CH2Cl2
  4. dry with materialthe organic layer was dried over Na2SO4
  5. customThe drying agent was removed by filtration
  6. concentrationthe filtrate was concentrated in vacuo
  7. customThe crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% CH3OH in CH2Cl2

Sources & evidence

ORD record
ord-b8c82276ca7142cea175e36aa26bdb47
Source dataset
uspto-grants-2014_02
Patent number
US08648074B2

Reaction notes

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