1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid t-butyl ester

HRID 965134Notes

Reaction equation

HRID 965134 reaction equation
[O:1]=[C:2]1[CH2:20][CH2:19][C:18]2=[CH:21][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:22][CH:23]([CH3:37])[CH2:24][CH:25]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:26](O)=[O:27].O[N:39]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>CN(C=O)C>[C:33]([O:32][C:30](=[O:31])[CH2:29][CH:25]([C:26](=[O:27])[NH:39][C@H:20]1[CH2:19][C:18]2=[CH:21][N:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=32)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:1])[CH2:24][CH:23]([CH3:37])[CH3:22])([CH3:36])([CH3:35])[CH3:34]

Participants

6

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 99427122-Isobutyl-succinic acid-4-t-butyl esterHCID 13172074010-Oxo-1,9-diaza-tricyclo[11.6.1.014,19]eicosa-13(20),14(19),15,17-tetraene

Product 1

HCID 67693565(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid t-butyl ester

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a stirred solution of (11S)-11-amino-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraene (654 mg) and racemic 4-methyl-2-t-butoxycarbonylmethylpentanoic acid (800 mg) in 30 mL of anhydrous DMF under argon was added 1-hydroxybenzotriazole (360 mg), followed by EDCI (940 mg). The mixture was left to stir overnight and then the DMF was removed under reduced pressure. The residue was taken up in a mixture of CH2Cl2 (100 mL) and 1.5% cold HCl (100 mL) and transferred to a separatory funnel. The organic phase was isolated and washed consecutively with 1.5% HCl (100 mL), 5% NaHCO3 (100 mL) and brine (100 mL). The CH2Cl2 phase was dried (MgSO4), filtered and concentrated providing a semicrystalline product, (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid t-butyl ester. The two individual stereoisomers of this compound were separated by chromatography on silica gel with ethyl acetate/hexane as eluant. The less polar stereoisomer had a melting point of 154°-157° C., [α]D24 43.9°, c=23.8 mg/2 mL CHCl3, while the more polar stereoisomer had a melting point of 168°-171° C., [α]D24 =-19.1°, c=11.86 mg/2 mL CHCl3.

Workup

  1. waitThe mixture was left
  2. customthe DMF was removed under reduced pressure
  3. additionThe residue was taken up in a mixture of CH2Cl2 (100 mL) and 1.5% cold HCl (100 mL)
  4. customtransferred to a separatory funnel
  5. customThe organic phase was isolated
  6. washwashed consecutively with 1.5% HCl (100 mL), 5% NaHCO3 (100 mL) and brine (100 mL)
  7. dry with materialThe CH2Cl2 phase was dried (MgSO4)
  8. filtrationfiltered
  9. concentrationconcentrated

Sources & evidence

ORD record
ord-9af374aab8324ab4a32e911869c04614
Source dataset
uspto-grants-1998_06
Patent number
US05773428

Reaction notes

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