Reaktion #662648

Reaktionsgleichung

(3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one

ethyl 9-iodo-5H-spiro[benzo[b]pyrazolo[1,5-d][1,4]oxazepine-4,1′-cyclopropane]-2-carboxylate

formamidine

sodium methoxide

→

titled compound

Ausbeute 27.0%

(R)-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-5H-spiro[benzo[b]pyrazolo[1,5-d][1,4]oxazepine-4,1′-cyclopropane]-2-carboxamide

Ausbeute 27.0%

Lösungsmittel

ammonium chloride

DMF

methanol

Reaktionsbedingungen

Aufarbeitung

1. 1
   Extraktionextracted with ethyl acetate
2. 2
   TrocknenThe combined organics were dried over sodium sulfate
3. 3
   Einengenconcentrated by rotoevaporation
4. 4
   workup.DISSOLUTIONwas dissolved
5. 5
   workup.DISSOLUTIONin dissolved in DMF/TEA (0.75 mL/0.25 mL)
6. 6
   Sonstigethe mixture sparged with nitrogen
7. 7
   Sonstigethe MW vial was sealed
8. 8
   TemperaturThe mixture was heated at 80° C. (sand bath)
9. 9
   workup.WAITComplete conversion at 30 min
10. 10
    SonstigePurification by reverse phase HPLC

Vorschrift

A solution of ethyl 9-iodo-5H-spiro[benzo[b]pyrazolo[1,5-d][1,4]oxazepine-4,1′-cyclopropane]-2-carboxylate (28 mg, 0.068 mmol) in 2 mL of DMF was treated sequentially with formamidine (0.2 mL) and 25 wt % sodium methoxide in methanol (0.1 mL). The mixture was stirred at room temperature overnight (complete conversion of starting material by LCMS). The mixture was diluted with ammonium chloride solution and extracted with ethyl acetate. The combined organics were dried over sodium sulfate and concentrated by rotoevaporation. Similar to as described elsewhere in the application the crude amide was dissolved in dissolved in DMF/TEA (0.75 mL/0.25 mL) and the mixture sparged with nitrogen. Solid bis(triphenylphosphine)palladium(II)dichloride (4.8 mg, 0.00068 mmol), cuprous iodide (1.3 mg, 0.0068 mmol) and (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one (24 mg. 0.17 mmol) was added and the MW vial was sealed. The mixture was heated at 80° C. (sand bath). Complete conversion at 30 min. Purification by reverse phase HPLC gave 7.2 mg of the titled compound as a colorless solid (27% yield).

Quelle