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-methylpropanoate

HRID 1920793Notes

Reaction equation

HRID 1920793 reaction equation
[CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Si:19]([O:26][C@H:27]([CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([F:58])[CH:52]=1)[CH2:28][O:29][C@@H:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][CH2:39][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]([CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH3:57])=[C:53]([F:58])[CH:52]=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]([CH3:1])[C:40]([O:42][CH3:43])=[O:41])[CH3:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]

Participants

8

Reactant 5

HCID 6328Methyl iodideHCID 7912DiisopropylamineHCID 8058HexaneHCID 58581161Methyl 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}propanoateHCID 178418339Butyllithium

Product 1

HCID 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-methylpropanoateYield 70%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To diisopropylamine (0.45 mL, 3.23 mmol), a 2.69 M solution of n-butyl lithium in hexane (1.20 mL, 3.23 mmol) was added at −78° C. followed by stirring for 15 minutes. After adding anhydrous tetrahydrofuran (2 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}propanoate (615 mg, 1.08 mmol), which had been obtained in Example 179 (179a), in tetrahydrofuran (1 mL) was added thereto and stirred at −78° C. for 0.5 hours. After adding methyl iodide (0.6 mL, 6.46 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 colorless oily substance (446 mg, yield 70%).

Workup

  1. stirringthe mixture was further stirred for 15 minutes at −78° C
  2. additionwas added
  3. stirringstirred at −78° C. for 0.5 hours
  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-57b6afb13fd44d52bd49583d0edaddc8
Source dataset
uspto-grants-2012_05
Patent number
US08173631B2

Reaction notes

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