Lithium Hexamethyldisilazide → 1-(1,1-Dimethylethyl) 2-methyl (2R,5R)-2-[(2Z)-4-bromo-2-buten-1-yl]-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate

HRID 1690105Notes

Reaction equation

HRID 1690105 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:19]([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46]Br>C1COCC1>[Br:42][CH2:43]/[CH:44]=[CH:45]\[CH2:46][C@@:19]1([C:28]([O:30][CH3:31])=[O:29])[CH2:18][CH2:17][C@H:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[CH:15][CH:14]=2)[N:20]1[C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 5354994(Z)-1,4-dibromobut-2-eneHCID 594689471-(1,1-Dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate

Product 1

HCID 594689311-(1,1-Dimethylethyl) 2-methyl (2R,5R)-2-[(2Z)-4-bromo-2-buten-1-yl]-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylateYield 38.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-30 °C

Procedure

To a solution of 1-(1,1-dimethylethyl) 2-methyl (2S,5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-1,2-pyrrolidinedicarboxylate (D34, 0.2 g, 0.47 mmol) in dry THF (2 mL) at −78° C. was added LiHMDS (0.51 mL of a 1M solution in THF, 0.51 mmol). The mixture was allowed to warm to −30° C. and stirred for 30 min at this temperature. The yellow slurry was cooled to −78° C. and (2Z)-1,4-dibromo-2-butene (0.30 mL, 2.81 mmol) was added. The reaction mixture was left under stirring for 40 min and then quenched with a saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (9:1) affording the title compound (101 mg, 38%); Rt (HPLC) 7.42 min. MS: (ES/+) m/z: 462 and 464 [MH+-Boc]; C28H33BrFNO5 requires 562.

Workup

  1. temperatureThe yellow slurry was cooled to −78° C.
  2. waitThe reaction mixture was left
  3. stirringunder stirring for 40 min
  4. customquenched with a saturated ammonium chloride solution
  5. extractionThe aqueous layer was extracted with ethyl acetate
  6. dry with materialdried (Na2SO4)
  7. customevaporated
  8. customThe crude material was purified by chromatography on silica gel

Sources & evidence

ORD record
ord-30310bf6881549deaac7d84b4e09ec2c
Source dataset
uspto-grants-2012_04
Patent number
US08153623B2

Reaction notes

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