Reaktion #81339

ord-6ede56528a6441a599f85bdee9c987ba

Reaktionsgleichung

CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
TFA
CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
N-(N-(N-(N-(1,1-Dimethylethoxycarbonyl)-L-alanyl)-L-alanyl)-L -prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien-21-yl] ester
CCCCC(=O)O
valeric acid
On1nnc2ccccc21
N-hydroxy-benzotriazole
CN1CCOCC1
N-methylmorpholine
C(=NC1CCCCC1)=NC1CCCCC1
dicyclohexylcarbodiimide
→
CCCCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)OC(O)C(=O)[C@@]1(OC(=O)CC)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C)C(C)C
N-(N-(N-(N -(valeroyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien -21-yl] ester
Ausbeute 64.0%

Edukte

CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
TFA
CCC(=O)O[C@]1(C(=O)C(O)OC(=O)[C@@H](NC(=O)[C@@H]2CCCN2C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
N-(N-(N-(N-(1,1-Dimethylethoxycarbonyl)-L-alanyl)-L-alanyl)-L -prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien-21-yl] ester
CCCCC(=O)O
valeric acid
On1nnc2ccccc21
N-hydroxy-benzotriazole
CN1CCOCC1
N-methylmorpholine
C(=NC1CCCCC1)=NC1CCCCC1
dicyclohexylcarbodiimide

Reagenzien

Keine

Lösungsmittel

ClCCl
dichloromethane
ClCCl
dichloromethane

Reaktionsbedingungen

Detaillierte Bedingungen
See reaction.notes.procedure_details.

Aufarbeitung

  1. 1
    Filtrationthe precipitated urea is filtered off
  2. 2
    workup.ADDITIONthe filtrate is diluted with 40 ml of dichloromethane
  3. 3
    Waschenwashed with 40 ml each of 0.5N NaOH, 0.5N HCl and saturated sodium chloride solution
  4. 4
    Sonstigedried on sodium sulfate
  5. 5
    Einengenconcentrated by evaporation i.vac
  6. 6
    Sonstigeafter removal of the solvent i.vac
  7. 7
    Sonstigeis chromatographed

Vorschrift

307 mg (0.35 mmol) of H-Ala-Ala-Pro-Val-O-MPP x TFA (Example 3), 36 μl (0.33 mmol) of valeric acid, 52 mg (0.35 mmol) of N-hydroxy-benzotriazole and 74 μl (0.66 mmol) of N-methylmorpholine are dissolved in 40 ml of dichloromethane, mixed with a solution of 84 mg (0.41 mmol) of dicyclohexylcarbodiimide in 10 ml of dichloromethane and stirred for 4 hours at room temperature. For working-up, the precipitated urea is filtered off, the filtrate is diluted with 40 ml of dichloromethane and washed with 40 ml each of 0.5N NaOH, 0.5N HCl and saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation i.vac. The residue that remains after removal of the solvent i.vac. is chromatographed. Gradient chromatography on 200 g of silica gel 60 (dichloromethane→dichloromethane/methanol 95:5) yields 180 mg (64%) of N-(N-(N-(N -(valeroyl)-L-alanyl)-L-alanyl)-L-prolyl)-L-valine [11β,21-dihydroxy-3,20-dioxo-6α-methyl-17-propionyloxy-pregna-1,4-dien -21-yl] ester and, after recrystallization, 157 mg (56%) in crystalline form from dichloromethane/diisopropyl ether/hexane.

Quelle

DOI: 10.6084/m9.figshare.5104873.v1Patent: US05616573uspto-grants-1997_04