4-Methylmorpholine → HCID 22825258, compound

HRID 2164488Notes

Reaction equation

HRID 2164488 reaction equation
[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.[CH2:24](OC(Cl)=O)[CH:25]([CH3:27])[CH3:26].[NH2:32][C@H:33]([C:43]([NH:45][C@H:46]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C:48](=[O:50])[NH2:49])=[O:44])[CH2:34][CH2:35][C:36](=[O:42])[O:37]C(C)(C)C>CN(C=O)C.CC(O)=O.CO.C(Cl)(Cl)Cl.C(Cl)Cl>[C:54]([O:53][C:51](=[O:52])[C@H:46]([CH2:47][C:48](=[O:50])[NH2:49])[NH:45][C:43](=[O:44])[C@H:33]([CH2:34][CH:35]([C:25]([CH3:27])([CH3:26])[CH3:24])[C:36](=[O:42])[OH:37])[NH:32][C:4](=[O:6])[C@H:2]([CH3:3])[NH:1][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH3:55])([CH3:56])[CH3:57]

Participants

10

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 736104N-carbobenzyloxyalanineHCID 131714164HCID 131714164, compound

Product 1

HCID 22825258HCID 22825258, compound

Reagents, catalysts & solvents 5

HCID 176Acetic AcidSolventHCID 887MethanolSolvent2×HCID 6212ChloroformSolventHCID 6228DimethylformamideSolvent2×HCID 6344DichloromethaneSolvent

Procedure

A solution of Z-Ala-OH (118.5 g, 0.53 mol, 1.05 eq.) in DMF (400 mL) was placed in a 2-l 3-neck creased round bottom flask fitted with a thermometer, mechanical stirrer, dropping funnel and immersed in a dry ice-acetone bath at -15°. The reaction was carried out under an atmosphere of N2, cooled to -15° and pre-cooled (-20°) N-methylmorpholine (80.9 g, 0.80 mol, 1.58 eq.) added. After stirring for 4 min at -15°, the reaction mixture was cooled to -25° and precooled (-20°) isobutylchloroformate (72.5 g, 0.53 mol, 1.05 eq.) added portionwise over a 2 min period (temperature) must not exceed -15°). The reaction mixture stirred for an additional 4 min at -25° and a precooled (-20°) solution of H-Glu(OtBu)-Asn-OtBu (189 g, 0.506 mol) in DMF (350 mL)-CH2Cl2 (150 mL) added as rapidly as possible while maintaining -15° to -20° (4 minutes). After the addition was complete the reaction mixture was stirred at -15° for 30 min and at 25° for 3 h. The reaction mixture was filtered and the filter cake washed with DMF (2×50 mL). The filtrate was evaporated in vacuo and the resultant syrup immediately poured into H2O (3.5 l). The suspension was stirred for 18 h and the product collected by filtration and washed with H2O (2×500 mL) and dried in vacuo. A total of 575.6 g (93.9%) was prepared in 2 batches. Recrystallization from EtOH (3.5 l):H2O (5 l) gave 533.4 g (91.1%); mp 174°-176°; [α]D25 -35.48° (c 1, MeOH); Rf 0.25 (CHCl3 :MeOH:AcOH; 80 -20-5).

Workup

  1. customfitted with a thermometer, mechanical stirrer
  2. customimmersed in a dry ice-acetone bath at -15°
  3. temperaturecooled to -15°
  4. additionadded
  5. temperaturethe reaction mixture was cooled to -25°
  6. additionadded portionwise over a 2 min period (temperature) must not
  7. customexceed -15°
  8. stirringThe reaction mixture stirred for an additional 4 min at -25°
  9. temperaturewhile maintaining -15° to -20° (4 minutes)
  10. additionAfter the addition
  11. stirringwas stirred at -15° for 30 min and at 25° for 3 h
  12. filtrationThe reaction mixture was filtered
  13. washthe filter cake washed with DMF (2×50 mL)
  14. customThe filtrate was evaporated in vacuo
  15. additionthe resultant syrup immediately poured into H2O (3.5 l)
  16. stirringThe suspension was stirred for 18 h
  17. filtrationthe product collected by filtration
  18. washwashed with H2O (2×500 mL)
  19. customdried in vacuo
  20. customA total of 575.6 g (93.9%) was prepared in 2 batches
  21. customRecrystallization from EtOH (3.5 l)
  22. customH2O (5 l) gave 533.4 g (91.1%)

Sources & evidence

ORD record
ord-b061fb9121d54a8d98a817694bef0188
Source dataset
uspto-grants-1985_03
Patent number
US04504415

Reaction notes

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