Acetic Acid → Pnu-288034

HRID 2180347

Reaktionsgleichung

Reaktionsgleichung von HRID 2180347
[O:1]=[S:2]1(=[O:24])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([NH:15]C(=O)OCC(C)C)=[CH:10][C:9]=2[F:23])[CH2:4][CH2:3]1.[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[Li+:30].CO.[C:33]([O:36][C@H:37]([CH2:43]Cl)[CH2:38][NH:39][C:40](=[O:42])[CH3:41])(=[O:35])C.C(O)(=O)C>C1COCC1.O>[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[Li+:30].[O:24]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:43][C@H:37]([CH2:38][NH:39][C:40](=[O:42])[CH3:41])[O:36][C:33]3=[O:35])=[CH:10][C:9]=2[F:23])[CH2:4][CH2:3]1

Komponenten

9

Edukt 5

HCID 176Acetic AcidHCID 887MethanolHCID 7357675(2S)-1-Acetamido-3-chloropropan-2-yl acetateHCID 9925157Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamateHCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)

Produkt 2

HCID 9931003Pnu-288034Ausbeute 73 %HCID 236647642-Propanol, 2-methyl-, lithium salt (1:1)

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittel3×

Reaktionsbedingungen

Temperatur
7.5 °C

Versuchsvorschrift

A slurry of lithium t-butoxide (18.0 g, 223.5 mmol, 3.00 eq) in THF (100 ml) is prepared. Isobutyl 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluorophenylcarbamate (27.0 g, 74.5 mmol) is dissolved in THF (180 ml) then added to the lithium t-butoxide slurry while maintaining less than 20° C. The mixture is stirred for 15 min then methanol (6.1 ml, 149 mmol, 2.0 eq) is added. (S)-N-[2-(acetyloxy)-3-chloropropyl]acetamide (28.9 g, 149 mmol, 2.0 eq) is dissolved in THF (1100 mL) and added to the reaction mixture over 1 h while maintaining the reaction temperature between 15 and 17° C. The cloudy light yellow/brown solution is stirred at 15 to 16° C. for 16 h. The reaction is then quenched with concentrated acetic acid (8.6 ml, 149 mmol, 2.0 eq) while maintaining less than 20° C. Water (75 ml) is added via addition funnel over 3 min. The phases are separated and the organic phase washed with water (20 ml). The organic phase is concentrated to approximately 200 ml total volume. Isopropanol (300 ml) is added slowly to the stirred orange solution via syringe pump at a rate of 2 ml/min. The yellow slurry is then cooled to approximately 5 to 10° C. and stirred for 30 min. The product is collected by vacuum filtration, washed with cold isopropanol (2×100 ml) and dried in vacuo at 60° C. overnight to give the title compound (22.0 g, 73%): HPLC retention time=3.0 min (99.8 area %); HPLC detection at 254 nm, isocratic elution solvent: 479.5 g buffer (1 l water, 1.57 g ammonium formate, formic acid to pH=3.2) and 409.1 g acetonitrile.

Aufarbeitung

  1. temperaturewhile maintaining less than 20° C
  2. additionadded to the reaction mixture over 1 h
  3. temperaturewhile maintaining the reaction temperature between 15 and 17° C
  4. stirringThe cloudy light yellow/brown solution is stirred at 15 to 16° C. for 16 h
  5. temperaturewhile maintaining less than 20° C
  6. customThe phases are separated
  7. washthe organic phase washed with water (20 ml)
  8. concentrationThe organic phase is concentrated to approximately 200 ml total volume
  9. additionIsopropanol (300 ml) is added slowly to the stirred orange solution via syringe pump at a rate of 2 ml/min
  10. stirringstirred for 30 min
  11. filtrationThe product is collected by vacuum filtration
  12. washwashed with cold isopropanol (2×100 ml)
  13. customdried in vacuo at 60° C. overnight

Quellen und Nachweise

ORD-Eintrag
ord-dab73cb6cf414171b4fe7e65fe10c439
Quelldatensatz
uspto-grants-2005_05
Patentnummer
US06887995B2

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