Hydrochloric Acid → Di-tert-butyl (4R)-4-{[5-(benzyloxy)pyridin-2-yl]methyl}-N-(tert-butoxycarbonyl)-L-glutamate

HRID 591282Notes

Reaction equation

HRID 591282 reaction equation
[C:1]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50]Br)=[N:48][CH:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>O1CCCC1>[CH2:36]([O:43][C:44]1[CH:45]=[CH:46][C:47]([CH2:50][C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[N:48][CH:49]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 2733832Lithium HexamethyldisilazideHCID 797999495-(Benzyloxy)-2-(bromomethyl)pyridineHCID 86647571Di-tert-butyl Boc-L-glutamate

Product 1

HCID 70957109Di-tert-butyl (4R)-4-{[5-(benzyloxy)pyridin-2-yl]methyl}-N-(tert-butoxycarbonyl)-L-glutamateYield 73.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-75 °C

Procedure

540 mg (1.50 mmol) of di-tert-butyl Boc-glutamate (prepared according to J. Peptide Res. 2001, 58, 338) were dissolved in 6 mL of tetrahydrofuran and cooled to −75° C. 3.45 mL (3.45 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran were added dropwise and the mixture was stirred at −75° C. for another 60 minutes. 460 mg (1.65 mmol) of 5-(benzyloxy)-2-(bromomethyl)pyridine in 5 mL of tetrahydrofuran were then added dropwise, and after stirring 2 hours at −75° C., 3.45 mL of 2N aqueous hydrochloric acid were added, and after stirring another 30 minutes at −75° C., the cooling bath was removed and the mixture was allowed to warm up to room temperature. The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic layer was dried over magnesium sulfate and evaporated. The crude residue was purified by column chromatography on silica gel (ethyl acetate in hexane 0%→100%) to give 610 mg of the desired compound as yellowish oil (66% yield).

Workup

  1. stirringafter stirring 2 hours at −75° C.
  2. stirringafter stirring another 30 minutes at −75° C.
  3. customthe cooling bath was removed
  4. temperatureto warm up to room temperature
  5. customThe mixture was partitioned between dichloromethane and aqueous sodium bicarbonate
  6. dry with materialthe organic layer was dried over magnesium sulfate
  7. customevaporated
  8. customThe crude residue was purified by column chromatography on silica gel (ethyl acetate in hexane 0%→100%)

Sources & evidence

ORD record
ord-b1699b109f90479ab077bf600c5e98db
Source dataset
uspto-grants-2016_01
Patent number
US09238631B2

Reaction notes

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