1,2-Dibromoethane → Methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-5-oxopentanoate

HRID 1690110Notes

Reaction equation

HRID 1690110 reaction equation
BrCCBr.[Mg].Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:9]([O:22][CH3:23])[CH:8]=1.FC1C=CC=CC=1COC1C=CC=CC=1OC.[O:41]=[C:42]1[N:46]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:45]([C:54]([O:56][CH3:57])=[O:55])[CH2:44][CH2:43]1>C1COCC1.C(OCC)C.C(O)(C)C>[CH3:53][C:50]([O:49][C:47]([NH:46][C@@H:45]([CH2:44][CH2:43][C:42]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:9]([O:22][CH3:23])[CH:8]=1)=[O:41])[C:54]([O:56][CH3:57])=[O:55])=[O:48])([CH3:51])[CH3:52]

Participants

9

Reactant 5

HCID 78391,2-Dibromoethane2×HCID 5462224MagnesiumHCID 108684851-O-tert-butyl 2-O-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylateHCID 594689134-Bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzeneHCID 667002841-Fluoro-2-({[2-(methyloxy)phenyl]oxy}methyl)benzene

Product 1

HCID 59468971Methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-[4-{[(2-fluorophenyl)methyl]oxy}-3-(methyloxy)phenyl]-5-oxopentanoateYield 46.1%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 3776IsopropanolSolventHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-65 °C

Procedure

1,2-Dibromoethane (1064, 232 mg, 1.233 mmol) was added to a suspension of magnesium (300 mg, 12.33 mmol) in dry THF (3 mL). Then a solution of 4-bromo-1-{[(2-fluorophenyl)methyl]oxy}-2-(methyloxy)benzene (D54, 2.40 g, 8.22 mmol) in dry THF (17 ml) was added dropwise. The mixture was heated under reflux for 1.5 h. The Grignard formation was followed via HPLC (Rt(HPLC, 1-fluoro-2-({[2-(methyloxy)phenyl]oxy}methyl)benzene): 5.59 min, Rt (HPLC, D54): 6.24 min). When the reaction stopped, additional 1,2-dibromoethane (0.1 eq) was added. After Grignard formation was complete, the mixture was added dropwise to a solution of 1-(1,1-dimethylethyl) 2-methyl (2S)-5-oxo-1,2-pyrrolidinedicarboxylate (D1, 1 g, 4.11 mmol) in dry THF (20 ml) at −65° C. Stirring at −65° C. was continued for 3.5 h. Then isopropanol and diethylether were added, the organic layer was washed with aqueous ammonium chloride solution, dried (Na2SO4) and evaporated. The residue was purified with flash chromatography using a cyclohexanes/ethyl acetate (40% to 100%) gradient to afford the title compound (900 mg, 46%). MS: (ES/+) m/z: 376 [M-BOC+], C25H30FNO7 requires 475; HPLC: 0.84 min, m/z: 476 [MH+], 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.6 (m, 2H), 7.4 (m, 2H), 7.3-7.2 (m, 4H), 5.2 (s, 2H), 4.1 (m, 1H), 3.8 (s, 3H), 3.6 (s, 3H), 3.2-3.0 (m, 2H), 2.1-2.0 (m, 1H), 1.9 (m, 1H), 1.4 (s, 9H).

Workup

  1. temperatureThe mixture was heated
  2. temperatureunder reflux for 1.5 h
  3. custom5.59 min, Rt (HPLC, D54)
  4. custom6.24 min
  5. washthe organic layer was washed with aqueous ammonium chloride solution
  6. dry with materialdried (Na2SO4)
  7. customevaporated
  8. customThe residue was purified with flash chromatography

Sources & evidence

ORD record
ord-2a0f54ca134041c48e2de28c7abeef46
Source dataset
uspto-grants-2012_04
Patent number
US08153623B2

Reaction notes

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