Hydrogen Peroxide → 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoic acid

HRID 540471Notes

Reaction equation

HRID 540471 reaction equation
[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([O:44]C)=[O:43])[CH:33]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].OO>C1COCC1.O.[O-]S([O-])=O.[Na+].[Na+]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]3[C@H:19]([C:22]4[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH:33]=4)[CH2:20][CH2:21][C@@H:14]23)[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:8]=1

Participants

7

Reactant 3

HCID 784Hydrogen PeroxideHCID 168937Lithium hydroxide, monohydrateHCID 71526552methyl 3-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoate

Product 1

HCID 715265543-[2'-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4'-(trifluoromethyl)biphenyl-3-yl]propanoic acidYield 46.7%

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolventHCID 24437Sodium SulfiteSolvent

Procedure

To methyl 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoate (20 mg, 0.03 mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxide-monohydrate (6.21 mg, 0.148 mmol) and hydrogen peroxide (30%, 33.6 mg, 0.296 mmol). The reaction mixture was stirred at room temperature. Upon completion the reaction was diluted with water (10 mL), and solid Na2SO3 was added to quench hydrogen peroxide. The solution was acidified with aqueous HCl (1 M) and was partitioned with ethyl acetate (20 mL). The organic was dried over sodium sulfate, filtered and concentrated before purification by reverse phase HPLC to yield 3-[2′-{(1R,5S,7aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxotetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanoic acid (9 mg, 0.014 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at a 3:1 ratio. 1H NMR (500 MHz, CDCl3) δ7.87 (s, 1H), 7.82 (s, 2H), 7.75 (s, 1H, minor rotamer), 7.73 (s, 1H, major rotamer) 7.6 (m, 1H) 6.9-7.4 (m, 4H), 6.08 (d, J=8.1 Hz, 1H, major rotamer), 5.15 (t, 1H, minor rotamer) 5.06 (t, J=8.2 Hz, 1H, major rotamer), 4.6 (m, 1H, major rotamer) 4.45 (m, 1H, minor rotamer), 4.98 (m, 1H, minor rotamer), 4.1 (m, 1H), 3.85 (s, 3H, minor rotamer), 3.69 (s, 3H, major rotamer), 2.4-3.1 (m, 4H), 0.9-1.9 (m, 4H). MS ESI calc'd. for C31H25F9NO5 [M+H]+ 662.2. found 662.3. RTA (95% HS): 128 nM

Workup

  1. additionwas added
  2. customto quench hydrogen peroxide
  3. customwas partitioned with ethyl acetate (20 mL)
  4. dry with materialThe organic was dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated before purification by reverse phase HPLC

Sources & evidence

ORD record
ord-7dcc729e09364ae18bd04e7ffbb48edb
Source dataset
uspto-grants-2014_10
Patent number
US08871738B2

Reaction notes

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