Methyl iodide → methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2,2-dimethylpropanoate

HRID 1920794Notes

Reaction equation

HRID 1920794 reaction equation
[CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Si:19]([O:26][C@H:27]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([F:59])[CH:53]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CI>O1CCCC1.O>[Si:19]([O:26][C@H:27]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][C@H:47]1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([F:59])[CH:53]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][C:39]([CH3:1])([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:21])[CH3:20]

Participants

8

Reactant 5

HCID 6328Methyl iodideHCID 7912DiisopropylamineHCID 8058HexaneHCID 58580868methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2-methylpropanoateHCID 178418339Butyllithium

Product 1

HCID 58581066methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2,2-dimethylpropanoateYield 68%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To diisopropylamine (0.21 mL, 1.52 mmol), a 2.69 M solution of n-butyl lithium in hexane (0.57 mL, 1.52 mmol) was added at −78° C. followed by stirring for 15 minutes. After adding anhydrous tetrahydrofuran (1.5 mL), the mixture was further stirred for 15 minutes at −78° C. Subsequently, a solution of methyl 3-{2-[(1R)-1-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]propyl}oxy)ethyl]phenyl}-2-methylpropanoate (445 mg, 0.76 mmol), which had been obtained in Example 179 (179b), in tetrahydrofuran (1 mL) was added thereto and stirred at −78° C. for 1 hour. After adding methyl iodide (0.14 mL, 2.28 mmol), the mixture was stirred at room temperature for 17 hours. Upon the completion of the reaction, water was added. After extracting the mixture with ethyl acetate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15) to give the title compound as a pale yellow oily substance (309 mg, yield 68%).

Workup

  1. stirringthe mixture was further stirred for 15 minutes at −78° C
  2. additionwas added
  3. stirringstirred at −78° C. for 1 hour
  4. stirringthe mixture was stirred at room temperature for 17 hours
  5. additionwas added
  6. extractionAfter extracting the mixture with ethyl acetate
  7. distillationthe solvent was distilled off under reduced pressure
  8. customThe residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15)

Sources & evidence

ORD record
ord-cc9abf3f08dd493a88bc3e2a03bfd413
Source dataset
uspto-grants-2012_05
Patent number
US08173631B2

Reaction notes

Loading…