4-Methylmorpholine → N-Benzyloxycarbonyl-gamma-t-butyl-L-glutamyl-L-asparagine t-butyl ester

HRID 2295933Notes

Reaction equation

HRID 2295933 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:22]([O-])=[O:23])[CH2:13][CH:14]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:15]([O-:17])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[C:40]([O:44][C:45](=[O:52])[C@H:46]([CH2:48][C:49](=[O:51])[NH2:50])[NH2:47])([CH3:43])([CH3:42])[CH3:41]>C1COCC1.CO.CC(O)=O.C(Cl)(Cl)Cl.CCOCC.CN(C=O)C>[C:40]([O:44][C:45](=[O:52])[C@H:46]([CH2:48][C:49](=[O:51])[NH2:50])[NH:47][C:22](=[O:23])[C@H:12]([CH2:13][CH:14]([C:18]([CH3:20])([CH3:19])[CH3:21])[C:15](=[O:16])[OH:17])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:43])([CH3:41])[CH3:42]

Participants

11

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 6995006L-Asparagine tert-butyl esterHCID 131713361N-Benzyloxycarbonyl-gamma-t-butyl-L-glutamate

Product 1

HCID 22825257N-Benzyloxycarbonyl-gamma-t-butyl-L-glutamyl-L-asparagine t-butyl ester

Reagents, catalysts & solvents 6

HCID 176Acetic AcidSolventHCID 887MethanolSolvent2×HCID 3283Diethyl EtherSolventHCID 6212ChloroformSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

N-Benzyloxycarbonyl-γ-t-butyl-L-glutamate (50.7 g, 0.15 mol) in 300 ml freshly distilled THF was placed in a 2-liter 3-neck round bottom flask fitted with a thermometer, mechanical stirrer and dropping funnel and immersed in a dry ice-alcohol bath at -15°. N-Methylmorpholine (16.8 ml, 0.15 mol) was added dropwise. The temperature was maintained at -15° and isobutyl chloroformate (19.7 ml, 0.15 mol) was added dropwise over a 2-minute period. The reaction mixture was stirred an additional 2 minutes at -15° and a precooled solution of L-asparagine t-butyl ester (25.6 g, 0.136 mol) dissolved in 270 ml THF and 30 ml DMF was added dropwise over a 4-minute period while the temperature was maintained at -15°. The reaction mixture was stirred at -15° for 30 minutes and at 25° for 2.5 hours, evaporated in vacuo and the residue dissolved in EtOAc and washed with 10% NaHCO3 (2×300 ml), saturated NaCl solution (30 ml), 1 M citric acid (2×300 ml) and saturated NaCl solution (300 ml). The organic layer was dried over MgSO4, filtered and evaporated in vacuo to yield a thick oil. The oil was crystallized from EtOAc-ether to yield 34.5 g. Trituration of the mother liquid with ether gave an additional 31.1 g. Total yield 65.6 g (95%); mp 139° dec; Rf 0.22 (CHCl3 :CH3OH:AcOH:80-2-0.4). The analytical sample was prepared by recrystallization from methanol-ether; mp 142°-144.5°; [α]D25 -19.14° (c 1, CH3OH). Anal. calcd. for C25H37N3O8 (507.6): C, 59.16; H, 7.35; N, 8.28. Found: C, 59.24; H, 7.34; N, 8.40.

Workup

  1. customfitted with a thermometer, mechanical stirrer
  2. customimmersed in a dry ice-alcohol bath at -15°
  3. temperatureThe temperature was maintained at -15°
  4. temperaturewas maintained at -15°
  5. stirringThe reaction mixture was stirred at -15° for 30 minutes and at 25° for 2.5 hours
  6. customevaporated in vacuo
  7. dissolutionthe residue dissolved in EtOAc
  8. washwashed with 10% NaHCO3 (2×300 ml), saturated NaCl solution (30 ml), 1 M citric acid (2×300 ml) and saturated NaCl solution (300 ml)
  9. dry with materialThe organic layer was dried over MgSO4
  10. filtrationfiltered
  11. customevaporated in vacuo
  12. customto yield a thick oil
  13. customThe oil was crystallized from EtOAc-ether
  14. customto yield 34.5 g

Sources & evidence

ORD record
ord-920651cc6ef744cd9c3e62aebe449b28
Source dataset
uspto-grants-1984_01
Patent number
US04426324

Reaction notes

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