First Enantioselective Synthesis of Aptazepine

Abstract

Aptazepine (2-methyl-1,3,4,14b-tetrahydro-2H,10Hpyrazino[1,2-a]pyrrolo[2,1-c][1,4]benzodiazepine), a potent tetracyclic antidepressant, was synthesized in both its enantiopure forms by using an asymmetric transfer hydrogenation in a key step. Reduction of the prochiral imine 7 gave the products (R)-and (S)-8 in 63% and 61% ee, respectively, but a single crystallization improved the enantiomeric purity to 98% ee. The final (R)-and (S)aptazepines were prepared in four subsequent steps. The absolute configuration of intermediate (S)-8 was determined by X-ray crystallography.

The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine

“…Alternatively the condensation of N -chloroacetyl-2-benzylaniline and subsequent reaction with potassium phthalimide proposed by Moffett [15] may be used for this step with comparable results. The imine 6 was then transformed to the enantiomerically enriched amine 7 with the aid of asymmetric transfer hydrogenation (ATH) process [8,10–11]. …”

“…As in our synthesis of aptazepine [8], we initially used the chiral ruthenium complex 11 which contain (1 R ,2 R )- or (1 S ,2 S )- N -tosyl-1,2-cyclohexanediamine as chiral ligand (Fig. 2).…”

“…Subsequently, the synthetic procedure developed by us for aptazepine was applied [8]. Amide 8 was obtained in 94% yield by reacting amine 7 and ethyl chloro(oxo)acetate in dichloromethane in the presence of triethylamine.…”

“…For the commercial manufacture of mianserin enantiomers both the above mentioned processes are rather unjustified economically and the most advantageous method could be the enantioselective synthesis. Considering our experience in asymmetric synthesis of structurally similar aptazepine [8], we applied this protocol to the preparation of ( S )-mianserin. The key step in the proposed synthetic pathway is the enantioselective reduction of an endocyclic imine that led to the chiral amine.…”