Phenylacetic Acid → Phenylacetylglutamine t-butyl ester

HRID 2372702Notes

Reaction equation

HRID 2372702 reaction equation
[C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C@H](C(O)=O)CCC(=O)N.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:45]([O:49][C:50](=[O:58])[C@H:51]([CH2:53][CH2:54][C:55](=[O:57])[NH2:56])[NH2:52])([CH3:48])([CH3:47])[CH3:46]>CN(C)C=O.C(N(CC)CC)C>[C:45]([O:49][C:50](=[O:58])[C@H:51]([CH2:53][CH2:54][C:55](=[O:57])[NH2:56])[NH:52][C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:48])([CH3:46])[CH3:47]

Participants

8

Reactant 5

HCID 999Phenylacetic Acid2×HCID 5961L-GlutamineHCID 10868DicyclohexylcarbodiimideHCID 80170N-HydroxysuccinimideHCID 15602445H-Gln-OtBu hydrochloride

Product 1

HCID 53814505Phenylacetylglutamine t-butyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Procedure

As shown in reaction scheme I (FIG. 1), phenylacetic acid 1 (1250 mg; 1.84 mmol) was coupled to a protected glutamine 4 (protected in this case by a lower alkyl such as t-butyl group) by first dissolving the phenyl acetic acid in anhydrous dimethylformamide (8 ml). N-hydroxysuccinimide 2 (254 mg; 2.2 mmol) was added followed by addition of dicyclohexylcarbodiimide (456 mg; 2.2 mmol) to produce N-succinimidphenylacetate 3. The reaction mixture was stirred for ten hours and precipitated dicyclohexyl urea was filtered off. The filtrate containing 3 was returned to a reaction flask to which a carboxy-protected glutamine such as L-glutamine t-butyl-ester hydrochloride 4 (439 mg; 1.84 mmol) was added. pH was adjusted to 9 with triethylamine, and the reaction mixture was stirred for 24 hours to produce phenylacetylglutamine t-butyl ester 5. Precipitated crystals were filtered off, and the filtrate containing 5 after concentration in vacuum was purified by column chromatography on silica gel using ethyl acetate-methanol (95:5) as an eluent. Yield 299 mg of desired material, mp. 132°-133° C. 1H-NMR (60 MHz) (CDCl3) δ ppm: 1.4 (s,9H); 1.8-2.4 (mult,4H); 3.6 (s,2H); 4.5 (mult,1H); 5.5 (broad,1H); 6.3 (mult,2H); 7.3 (s,5H). Mass Spectrum (DEI/DIP): 321 (M+H)+, 320 M+, 264 (M-C4H8)+, 247 (M-OC4H9)+. The t-butyl ester 5 (295 mg; 0.924 mmole) of phenylacetylglutamine was deprotected (i.e., the t-butyl carboxy protecting group was removed) by dissolving 5 in methylene chloride (4 ml) and adding trifluoroacetic acid (4 ml). After 45 minutes, the reaction mixture was evaporated in vacuum and the oily residue crystallized from tetrahydrofurane (THF), to give colorless crystals of phenylacetyl glutamine 6. 1H-NMR(300 MHz)(CDCl3 /CD3OD) δ ppm 1.9-2.05 (mult,1H); 2.13-2.36 (mult,3H); 3.58 (s,2H); 4.5 (mult,1H); 7.23-7.38 (mult,5H); Mass Spectrum (pos.FAB, MeOH):265 (M+H)+ (100%).

Workup

  1. customto produce N-succinimidphenylacetate 3
  2. customprecipitated dicyclohexyl urea
  3. filtrationwas filtered off
  4. additionThe filtrate containing 3
  5. customwas returned to a reaction flask to which
  6. stirringthe reaction mixture was stirred for 24 hours

Sources & evidence

ORD record
ord-b8fccd9b39a54eb69ab2a523d74f6539
Source dataset
uspto-grants-1992_03
Patent number
US05100807

Reaction notes

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