Hydrochloric Acid → (+/-)-tert-butyl 4-(3-amino-6-((1R,3R)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate

HRID 596020Notes

Reaction equation

HRID 596020 reaction equation
[C:1](N[C:5]([OH:7])=[O:6])(O)=O.C(OC([NH:15][C:16]1[C:17]([C:30]2[CH:38]=[CH:37][C:33](C([O-])=O)=[C:32]([F:39])[CH:31]=2)=[N:18][C:19]([CH:22]2[CH2:27][CH2:26][C:25](=[O:28])[CH:24]([F:29])[CH2:23]2)=[CH:20][N:21]=1)=O)(C)(C)C.Cl.O1CCOC[CH2:42]1.[C:47](=[O:50])([O-])[O-:48].[Na+].[Na+].[CH2:53]1[CH2:57]OC[CH2:54]1>O>[NH2:15][C:16]1[C:17]([C:30]2[CH:38]=[CH:37][C:33]([C:5]([O:7][C:53]([CH3:54])([CH3:57])[CH3:42])=[O:6])=[C:32]([F:39])[CH:31]=2)=[N:18][C:19]([C@@H:22]2[CH2:27][CH2:26][C:25](=[O:28])[C@H:24]([F:29])[CH2:23]2)=[CH:20][N:21]=1.[NH2:15][C:16]1[C:17]([C:30]2[CH:38]=[CH:37][C:33]([C:47]([O:48][C:53]([CH3:54])([CH3:57])[CH3:1])=[O:50])=[C:32]([F:39])[CH:31]=2)=[N:18][C:19]([C@H:22]2[CH2:27][CH2:26][C:25](=[O:28])[C@@H:24]([F:29])[CH2:23]2)=[CH:20][N:21]=1

Participants

9

Reactant 6

HCID 313Hydrochloric AcidHCID 8028TetrahydrofuranHCID 10340Sodium CarbonateHCID 312751,4-DioxaneHCID 13267551IminodicarbonsaureHCID 1317346174-(3-((Tert-butoxycarbonyl)amino)-6-(3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate

Product 2

HCID 118049846(+/-)-tert-butyl 4-(3-amino-6-((1R,3R)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoateYield 27.2%HCID 118054653(+/-)-tert-butyl 4-(3-amino-6-((1S,3S)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoateYield 13.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

To a solution of Imidodicarbonic acid, 4-(3-((tert-butoxycarbonyl)amino)-6-(3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate, 1,3-bis(1,1-dimethylethyl) ester (10.44 g, 17.29 mmol) in THF (57.6 mL) was added 4 M HCl in dioxane (130 mL, 519 mmol) at room temperature. The reaction mixture was stirred for 3-4 h, which was monitored by LCMS to prevent more of the t-butyl ester from hydrolyzing to carboxylic acid. The reaction was cooled in water bath, and neutralized with saturated sodium carbonate. The resulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography eluting with 0-100% of EtOAc/heptane to provide (+/−)-tert-butyl 4-(3-amino-6-((1R,3R)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (1.9 g, 4.71 mmol, 27.2%) and (+/−)-tert-butyl 4-(3-amino-6-((1S,3S)-3-fluoro-4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (926 mg, 2.295 mmol, 13.3%). LCMS (m/z): 404.3 (MH+), 0.84 min and 404.3 (MH+), 0.84 min respectively.

Workup

  1. extractionThe resulting mixture was extracted with EtOAc three times
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography
  7. washeluting with 0-100% of EtOAc/heptane

Sources & evidence

ORD record
ord-0384c5bf5dd9484f8c3206a694e8cca5
Source dataset
uspto-grants-2016_01
Patent number
US09242996B2

Reaction notes

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