Reaktion #1509599
ord-bd1cf98265024579b97c9a6465a97c55
Reaktionsgleichung
Reaktionsbedingungen
Aufarbeitung
- 1SonstigeIn a clean dry
- 2Einengenconcentrated to dryness under reduced pressure
- 3workup.DISSOLUTIONThe substrate was re-dissolved in anhydrous toluene (20 vol)
- 4Einengenconcentrated to dryness
- 5workup.DISSOLUTIONThe substrate was dissolved in DCM (5 vol)
- 6Sonstigethe internal temperature below −16° C. (1.02 eq)
- 7Temperaturthen warmed to 0° C. over 20 minutes
- 8workup.STIRRINGstirred for an additional 20 minutes
- 9SonstigeThe reaction was quenched with water (2 vol)
- 10SonstigeThe bath was removed
- 11Temperaturto warm to room temperature (15-20° C.)
- 12workup.STIRRINGstirred (20 minutes)
- 13WaschenThe reaction was rinsed to a larger vessel
- 14workup.ADDITIONwas added to the reaction
- 15workup.STIRRINGThe reaction was stirred at room temperature for 15-36 hours
- 16Sonstigeformed in situ
- 17EinengenThe reaction was concentrated to dryness or near dryness at reduced pressure
- 18workup.ADDITIONThe resulting material was diluted with DCM (25-40 vol)
- 19Waschenwashed pH 10 buffer (NaHCO3/Na2CO3 (aq), 10 vol)
- 20ExtraktionThe aqueous phase was back extracted with 25 vol of DCM
- 21Einengenthe combined organic layers were concentrated to dryness
- 22SonstigeThe resulting free amine was purified by silica gel chromatography
- 23EinengenThe pooled fractions were concentrated at reduced pressure
- 24Sonstigeto remove ACN
- 25workup.ADDITIONThe resulting aqueous layer was diluted with DCM (40 vol) and with 30 vol of a pH 10
- 26workup.ADDITIONThe layers were mixed well
- 27Sonstigeseparated
- 28ExtraktionThe aqueous phase was back extracted with 25 vol of DCM
- 29Einengenthe combined organic layers were concentrated to dryness
- 30Filtrationfiltered as a solution in 3:1 DCM/pentane
- 31Einengenconcentrated to dryness (0.80 wts)
Vorschrift
In a clean dry reaction vessel (flask C) ER-076349 (1 wt, 1 eq) was dissolved in anhydrous toluene (20 vol) and concentrated to dryness under reduced pressure. The substrate was re-dissolved in anhydrous toluene (20 vol) and concentrated to dryness. The substrate was dissolved in DCM (5 vol), and the solution placed under an argon atmosphere. Collidine (0.66 wts, 4.0 eq) was added as a single portion. Pyridine, as a solution in DCM (Flask B), was added as a single portion (5 mole %). The resulting mixture in flask C was cooled to an internal temperature of −20 to −25° C. A DCM solution of Ts2O was added drop-wise keeping the internal temperature below −16° C. (1.02 eq). The reaction was stirred at −20 to −25° C. for 80 minutes then warmed to 0° C. over 20 minutes and stirred for an additional 20 minutes. The reaction was quenched with water (2 vol). The bath was removed, and the reaction allowed to warm to room temperature (15-20° C.) and stirred (20 minutes). The reaction was rinsed to a larger vessel using the IPA (100 vol) and aqueous ammonium hydroxide (100 vol) was added to the reaction. The reaction was stirred at room temperature for 15-36 hours, monitoring for the disappearance of the tosylate (ER-082892) and epoxide (ER-809681) which formed in situ. The reaction was concentrated to dryness or near dryness at reduced pressure. The resulting material was diluted with DCM (25-40 vol) and washed pH 10 buffer (NaHCO3/Na2CO3 (aq), 10 vol). The aqueous phase was back extracted with 25 vol of DCM and the combined organic layers were concentrated to dryness. The resulting free amine was purified by silica gel chromatography using a buffered ACN/water mobile phase. The pooled fractions were concentrated at reduced pressure to remove ACN. The resulting aqueous layer was diluted with DCM (40 vol) and with 30 vol of a pH 10 buffered stock solution (NaHCO3/Na2CO3). The layers were mixed well and separated. The aqueous phase was back extracted with 25 vol of DCM and the combined organic layers were concentrated to dryness. The resulting free amine was polish filtered as a solution in 3:1 DCM/pentane and concentrated to dryness (0.80 wts) to afford B-1939.