Lithium Hexamethyldisilazide → 5-(Tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione

HRID 1436879Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1436879
C(O[C:4](=[O:17])[C:5]([N:7]([CH3:16])[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:6])C.[F:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[CH2:29][CH2:28][CH:27]=[CH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:12]([O:11][C:9]([CH:8]1[N:7]([CH3:16])[C:5](=[O:6])[C:4]([OH:17])=[C:26]2[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:32][CH:31]=1)[C:25]2=[O:30])=[O:10])([CH3:13])([CH3:14])[CH3:15]

Komponenten

5

Edukt 3

HCID 2733832Lithium HexamethyldisilazideHCID 690647451-(4-Fluorobenzyl)-5,6-dihydropyridin-2-(1H)-oneHCID 86071508Tert-butyl n-[ethoxy(oxo)acetyl]-n-methylglycinate

Produkt 1

HCID 547137575-(Tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel

Reaktionsbedingungen

Temperatur
-78 °C

Versuchsvorschrift

To a cooled (−78° C.) solution of tert-butyl N-[ethoxy(oxo)acetyl]-N-methylglycinate (1.43 g, 5.85 mmol) and 1-(4-fluorobenzyl)-5,6-dihydropyridin-2(1H)-one from Step 3 of Example 1 (1 g, 5 mmol) in anhydrous THF (10 mL) was added LiHMDS (1 M in THF) (1.02 g, 6.09 mmol) dropwise. The reaction mixture was stirred for 10 min. at −78° C., warmed to room temperature for 2.5 hours, then heated to 40° C. After heating for 24 hours, the reaction mixture was quenched with cold diluted HCl, then diluted with methanol, and concentrated under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to give the title compound as a mixture of diastereomers. The appropriate fractions were collected for the first-eluting diastereomer, diastereomer 1, and this material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 15%-85% acetonitrile (0.1% TFA) in H2O (0.1% TFA). For the second eluting diastereomer, diastereomer 2, the appropriate fractions were collected and the material was purified further using reverse phase HPLC on a C18 stationary phase eluting with 10%-60% methanol (0.1% TFA) in H2O (0.1% TFA). Diastercomer 1, the hydrogens at positions 4a and 5 have a trans relationship to one another: 1H NMR (400 MHz, CDCl3) δ 6.84 (m, 2H), 6.62 (t, J=8.7 Hz, 2H), 4.31 (d, J=14.7 Hz, 1H), 4.05 (d, J=14.7 Hz, 1H), 3.43 (d, J=6.5 Hz, 1H), 2.91 (m, 2H), 2.69 (m, 1H), 2.57 (s, 3H), 1.42 (m, 1H), 1.21 (m, 1H), 1.15 (s, 9H) ppm. ES MS M+1=405. Diastereomer 2, the hydrogens at positions 4a and 5 have a cis relationship to one another: 1H NMR (400 MHz, CDCl3) δ 13.07 (s, 1H), 7.22 (m, 2H), 7.02 (t, J=8.7 Hz, 2H), 4.67 (d, J=14.7 Hz, 1H), 4.51 (d, J=14.7 Hz, 1H), 3.82 (d, J=6.5 Hz, 1H), 3.33 (m, 1H), 2.99 (s, 3H), 2.02 (m, 3H), 1.68 (m, 1H), 1.44 (s, 9H) ppm. ES MS M+1=405.

Aufarbeitung

  1. temperaturewarmed to room temperature for 2.5 hours
  2. temperatureheated to 40° C
  3. temperatureAfter heating for 24 hours
  4. customthe reaction mixture was quenched with cold diluted HCl
  5. additiondiluted with methanol
  6. concentrationconcentrated under vacuum
  7. customThe residual material was purified
  8. washeluting with 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA)

Quellen und Nachweise

ORD-Eintrag
ord-16057958e5e2439d8138424d8cab8f12
Quelldatensatz
uspto-grants-2009_11
Patentnummer
US07619086B2

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