4-hydroxymorpholine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride) may be synthesized by the following process. To 3′-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2 h at ambient temperature and poured into a mixture of ice and water (500 mL). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3′-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300 Mhz, CDCl3); δ 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, 3H). The mixture was extracted several times with methylene chloride The combined extracts were dried (Na2SO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride) may be synthesized by the following process. To 3′-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2 h at ambient temperature and poured into a mixture of ice and water (500 mL). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3′-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300 Mhz, CDCl3); δ 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, 3H). The mixture was extracted several times with methylene chloride The combined extracts were dried (Na2SO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride) may be synthesized by the following process. To 3′-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2h at ambient temperature and poured into a mixture of ice and water (500 mL). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3′-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300 Mhz, CDCl3); δ 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, 3H). The mixture was extracted several times with methylene chloride The combined extracts were dried (Na2SO4) concentrated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclopentylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 70% diethyl ether in hexanes to give the title compound (0.246 g, 29%) as a white crystalline solid. The reaction mixture was filtered through a pad of Celite™ and Na2SO4 The reaction mixture was stirred at 0° C. for 0.5 h The aqueous phase was separated extracted with dichloromethane (2×30 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclopentylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 70% diethyl ether in hexanes to give the title compound (0.246 g, 29%) as a white crystalline solid. The reaction mixture was filtered through a pad of Celite™ and Na2SO4 The reaction mixture was stirred at 0° C. for 0.5 h The aqueous phase was separated extracted with dichloromethane (2×30 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of cyclohexylmagnesium chloride (2.0 M in diethyl ether, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 50% diethyl ether in hexanes to give the title compound (0.220 g, 24%) as a white crystalline solid. The reaction mixture was filtered through a pad of Celite™ and Na2SO4 The reaction mixture was stirred at 0° C. for 0.5 h The aqueous phase was separated extracted with dichloromethane (2×30 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Activated MnO2 (1.29 g, 14.8 mmol) was added to a solution of N-hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of benzylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×30 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.326 g, 34%) as a white crystalline solid. The reaction mixture was filtered through a pad of Celite™ and Na2SO4 The reaction mixture was stirred at 0° C. for 0.5 h The aqueous phase was separated extracted with dichloromethane (2×30 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Activated MnO2 (0.65 g, 7.41 mmol) was added to a solution of N-hydroxymorpholine (0.25 g, 2.47 mmol) in dichloromethane (15 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 2.47 mL, 4.94 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (15 mL) and dichloromethane (15 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.045 g, 11%) as a white crystalline solid. The reaction mixture was filtered through a pad of Celite™ and Na2SO4 The reaction mixture was stirred at 0° C. for 0.5 h The aqueous phase was separated extracted with dichloromethane (2×20 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Activated MnO2 (0.65 g, 7.41 mmol) was added to a solution of N-hydroxymorpholine (0.25 g, 2.47 mmol) in dichloromethane (15 mL) at 0° C. and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of Celite™ and Na2SO4. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 2.47 mL, 4.94 mmol) at −10° C. The reaction mixture was stirred at 0° C. for 0.5 h and then saturated aqueous ammonium chloride solution (15 mL) and dichloromethane (15 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2×20 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO2 eluting with 25% diethyl ether in hexanes to give the title compound (0.045 g, 11%) as a white crystalline solid. The reaction mixture was filtered through a pad of Celite™ and Na2SO4 The reaction mixture was stirred at 0° C. for 0.5 h The aqueous phase was separated extracted with dichloromethane (2×20 mL) The combined organic layers were dried (Na2SO4) concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The racemate of the morpholinol metabolite of bupropion hydrochloride ((+/−)-(2R*,3R*)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol hydrochloride) may be synthesized by the following process. To 3′-chloropropiophenone (10.0 g, 0.06 mol) in dioxane (50 mL) was added a solution of dioxane dibromide (14.9 g, 0.06 mol) in dioxane (50 mL). The reaction mixture was stirred for 2 h at ambient temperature and poured into a mixture of ice and water (500 mL). The mixture was extracted several times with methylene chloride. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give 14.8 g (85%) of 2-bromo-3′-chloropropiophenone as a pale yellow oil. This was used without further purification. NMR (300 Mhz, CDCl3); δ 7.99 (m, 1H), 7.90 (d, 1H), 7.57 (d, 1H), 7.44 (t, 1H), 5.22 (q, 1H), 1.91 (t, 3H). The mixture was extracted several times with methylene chloride The combined extracts were dried (Na2SO4) concentrated in vacuo