4-Methylmorpholine → HCID 13685963, compound

HRID 1980760Notes

Reaction equation

HRID 1980760 reaction equation
C(N1CCC[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O.ClC(OCC(C)C)=O.CN1CCOCC1.NC(CO)C(C)C.[C:41]([N:51]1[CH2:64][CH2:63][CH2:62][C@H:52]1[C:53]([NH:55][C@H:56]([CH2:60][OH:61])[CH:57]([CH3:59])[CH3:58])=[O:54])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>C(OCC)(=O)C.CCCCCC>[C:41]([N:51]1[CH2:64][CH2:63][CH2:62][C@H:52]1[C:53]([NH:55][CH:56]([CH2:60][OH:61])[CH:57]([CH3:59])[CH3:58])=[O:54])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42].[C:41]([N:51]1[CH2:64][CH2:63][CH2:62][C@H:52]1[C:53]([NH:55][C@@H:56]([CH2:60][OH:61])[CH:57]([CH3:59])[CH3:58])=[O:54])([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42]

Participants

9

Reactant 5

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 79019ValinolHCID 101987Benzyloxycarbonyl-L-prolineHCID 13685962HCID 13685962, compound

Product 2

HCID 13685963HCID 13685963, compoundHCID 54157566HCID 54157566, compound

Reagents, catalysts & solvents 2

HCID 8058HexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

N-Carbobenzoxy-L-prolyl-DL-valinol was prepared by reacting 9.97 g (40 mmol) N-carbobenzoxy-L-proline, 5.46 g (40 mmol) isobutyl chloroformate, 4.05 g (40 mmol) N-methylmorpholine, and 4.13 g (40 mmol) DL-valinol substantially according to the mixed anhydride procedure described in Example 1. A portion, 1.00 g, of crude product was dissolved in 120 mL ethyl acetate, and 80 mL n-hexane were added. This solution was stirred vigorously and seeded with a crystal of N-carbobenzoxy-L-prolyl-L-valinol. After 5 minutes, crystalline product (100 mg) was separated by filtration. High performance liquid chromatography (HPLC) indicated that the product contained 76% N-carbobenzoxy-L-prolyl-D-valinol (L-D isomer) and 24% N-carbobenzoxy-L-prolyl-L-valinol (L-L isomer). HPLC analysis was conducted using a 4.6 mm ID×25 cm column packed with 5-6 μm diameter particles of porous silica, and a linear gradient (3→100% B in 30 minutes), using 1-chlorobutane as solvent A and 1:1 methanol/acetonitrile as solvent B. A first peak (11.2 minutes) was the desired L-D isomer, and a second peak (11.6 minutes) was the L-L isomer, characterized in Example 2 above. HPLC separation was repeated with a series of 5 mg injections to give a total of 64 mg (0.19 mmol) pure N-carbobenzoxy-L-prolyl-D-valinol. This product could also be isolated directly from the crude reaction product by a series of fractional crystallizations from ethyl acetate/n-hexane, then ethanol/n-hexane. Pure N-carbobenzoxy-L-prolyl-D-valinol melted at 118.0°-118.2°, α25D-27.6°, (C=1.01 g/100 mL in acetone).

Workup

  1. customcrystalline product (100 mg) was separated by filtration
  2. customa linear gradient (3→100% B in 30 minutes)
  3. customA first peak (11.2 minutes)
  4. customa second peak (11.6 minutes)
  5. customHPLC separation

Sources & evidence

ORD record
ord-abfeaed8325d43f29fe44d7639290c3e
Source dataset
uspto-grants-1985_04
Patent number
US04511390

Reaction notes

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