4-Methylmorpholine → HCID 86757730, compound

HRID 1250784Notes

Reaction equation

HRID 1250784 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[C:36]([O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH:45]([CH3:47])[CH3:46])[NH2:43])([CH3:39])([CH3:38])[CH3:37]>C1COCC1.CCOC(C)=O>[C:36]([O:40][C:41](=[O:48])[C@H:42]([CH2:44][CH:45]([CH3:46])[CH3:47])[NH:43][C:17](=[O:19])[C@@H:12]1[CH2:13][CH2:14][C:15](=[O:16])[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:39])([CH3:38])[CH3:37]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 6376481-(Phenylmethyl) (2S)-5-oxo-1,2-pyrrolidinedicarboxylateHCID 12451443tert-butyl (2S)-2-amino-4-methylpentanoate hydrochloride

Product 1

HCID 86757730HCID 86757730, compound

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-15 °C

Procedure

To a solution of N-benzyloxycarbonyl-L-pyroglutamic acid (1.6 g, 6.0 mmols) and N-methylmorpholine (0.66 ml, 6.0 mmols) in anhydrous THF (10 ml), cooled at −15° C. was added dropwise under stirring an equivalent quantity of isobutylchloroformate (0.82 ml, 6.0 mmols). After 10 minutes a solution of L-leucine tertbutylester hydrochloride (1.34 g, 6.0 mmols) and N-methylmorpholinee (0.66 ml, 6.0 mmols) in anhydrous THF (9 ml) was slowly added maintaining the temperature at −15° C. for 2 hours. The reaction mixture was diluted with EtOAc (70 ml) and washed with saturated NaCl solution (20 ml), KHSO4 1M (20+10 ml), saturated NaHCO3 solution (20+10 ml) and saturated NaCl solution (20 ml). The organic phase was dried on Na2SO4 and the solvent was removed at reduced pressure. The crystallization of raw material from EtOAc/n-hexane gave N-benzyloxycarbonyl-L-pyroglutamyl-L-leucine tertbutylester as white crystals: 2.0 g (77%); m.p. 130-1° C.; [a]D22=−70° (1, methanol); IR (CHCl3); 3420, 2958, 1794, 1723, 1514, 1303, 1152 cm−1; 1H-NMR (CDCl3): d 0.8-0.91 [m, 6, CH2CH(CH3)2], 1.20-1.67 [m, 3, CH2CH(CH3)2 and 1.43 (s, 9, OC(CH3)3], 2.00-2.93 (m, 4, CH2CH2 of pGlu), 4.27-4.61 (m, 2, 2 aCH), 5.22 (s, 2, CH2 benzylico), 6.24 (d, 1, NH, J=8 Hz), 7.28 (s, 5, benzylic aromatics). Calculated for C23H32N2O6: C, 63.87; H, 7.46; N, 6.48; Found C, 64.20; H, 7.60; N, 6.48%.

Workup

  1. additionwas added dropwise
  2. washwashed with saturated NaCl solution (20 ml), KHSO4 1M (20+10 ml), saturated NaHCO3 solution (20+10 ml) and saturated NaCl solution (20 ml)
  3. customThe organic phase was dried on Na2SO4
  4. customthe solvent was removed at reduced pressure
  5. customThe crystallization of raw material from EtOAc/n-hexane

Sources & evidence

ORD record
ord-eeef8591998447ff8563fbc531d2d2ff
Source dataset
uspto-grants-2002_01
Patent number
US06339160B1

Reaction notes

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