4-Methylmorpholine → HCID 20719109, compound

HRID 1250781Notes

Reaction equation

HRID 1250781 reaction equation
[O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:25]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH2:32])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.C1COCC1>[C:25]([O:29][C:30](=[O:37])[C@H:31]([CH2:33][CH:34]([CH3:35])[CH3:36])[NH:32][C:7]([C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[O:6]1)=[O:9])([CH3:28])([CH3:27])[CH3:26]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 636468(2S)-5-oxooxolane-2-carboxylic acidHCID 7022311tert-butyl (2S)-2-amino-4-methylpentanoate

Product 1

HCID 20719109HCID 20719109, compound

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of (S)-(+)-5-oxo-tetrahydrofuran-2-carboxylic acid (1.0 g, 7.68 mmols) and N-methylmorpholine (0.84 ml, 7.68 mmols) in anhydrous/THF anhydrous dioxan 2/1 (15 ml), cooled at −15° C. was added dropwise, under stirring, the equivalent quantity of isobutylchloroformate (1.04 ml, 7.68 mmols). After 30 minutes a solution of L-leucine tertbutylester (1.44 g, 7.68 mmols) and anhydrous THF (5 ml) was slowly added, maintaining the mixture under stirring at −15° C. for two hours. The reaction mixtures was diluted with CH2Cl2 (70 ml) and washed with NaCl saturated solution (20 ml) KHSO4 1M (20+10 ml), NaHCO3 saturated solution (20+10 ml) and NaCl saturated solution (20 ml). The organic phase was dried on Na2SO4 and concentrated at reduced pressure. The raw product was purified through chromatography on silica gel (CH2Cl2/i-PrOH 98/2). By grinding in n-hexane the solid raw residue, the N-{[(S)-(5-Oxo-tetrahydrofuran-2-yl)carbonyl]}-L-leucine tertbutyl-ester was obtained as white crystals: 920 mg (40%); m.p. 79-81° C.; [a]D22=−25° (1, methanol); IR (CHCl3): 3415, 2934, 1788, 1727, 1677, 1517, 1369, 1149 cm−1; 1H-NMR (CDCl3): d 0.87 and 0.97 [two s, 6, CH2CH(CH3)2], 1.18-1.62 [m, 3, CH2CH(CH3)2 and 1.40 (s, 9, C(CH3)3], 2.15-2.80 (m, 4, ring CH2CH2), 4.25-4.55 (m, 1, ring CH), 4.62-4.88 (m, 1, aCH), 6.56 (d, 1, NH, J=8 Hz). Calculated for C15H25NO5: C, 60.18; H, 8.42; N, 4.68. Found C, 60.12; H, 8.61; N, 4.65%.

Workup

  1. additionwas added dropwise
  2. temperaturemaintaining the mixture
  3. stirringunder stirring at −15° C. for two hours
  4. customThe reaction mixtures
  5. washwashed with NaCl saturated solution (20 ml) KHSO4 1M (20+10 ml), NaHCO3 saturated solution (20+10 ml) and NaCl saturated solution (20 ml)
  6. customThe organic phase was dried on Na2SO4
  7. concentrationconcentrated at reduced pressure
  8. customThe raw product was purified through chromatography on silica gel (CH2Cl2/i-PrOH 98/2)
  9. customBy grinding in n-hexane the solid raw residue

Sources & evidence

ORD record
ord-65a122386b9c43698bb71a713498157b
Source dataset
uspto-grants-2002_01
Patent number
US06339160B1

Reaction notes

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