Sodium Hydroxide → Asenapine

Participants

Reaction Conditions

Reaction Steps

Aluminium trichloride (4.1 g, 30.8 mmol, 2 eq.) was added to THF (20 ml) at 0° C. while stirring under inert nitrogen atmosphere and cooling with an ice bath. LiAlH4 (3.6 g, 94.7 mmol, 6 eq.) was then added portionwise while stirring over 15 minutes. After the addition was complete the resulting grey mixture was stirred for 15 minutes at −10° C., while cooling with an ice-acetone bath. Additional THF (10 ml) was added. Then a solution of trans-5-chloro-2,3,3a,12b-tetrahydro-2-ethoxycarbonyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (Example 18; 5.4 g, 15.7 mmol) in THF (20 ml) was added dropwise over 15 minutes to the in situ prepared alane reagent while stirring and cooling at −10° C. After the addition was complete the reaction mixture was stirred for an additional hour at −10° C. and then for 30 minutes while warming to room temperature. The resulting reaction mixture was carefully poured out in portions to dilute aqueous NaOH (75 ml 30% NaOH and 175 ml water) in a 1000 ml Erlenmeyer flask. After 15 minutes stirring the mixture was extracted with toluene (3×150 ml). The combined organic layers were dried with Na2SO4. Evaporation under vacuum gave crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (asenapine) (3.26 g, 11.44 mmol) in 73% c.y. as a brown oil. According to LC-MS ca. 60% pure. MS: M+1=286, 288 found. 1H-NMR (CDCl3) δ (ppm) identical data as above.

Provenance & Evidence