Synthesis of new phthalazinedione derivatives

“Abstract.” Heterocycles containing phthalazine moiety have been a subject of great interest. They have been reported by their anticonvulsant, cardiotonic and vasorelaxant activities. Despite the number of available methods for their synthesis, the development of new synthetic methods for the efficient preparation of heterocycles containing phthalazine fragment is an interesting challenge. Therefore, we have synthesized new phthalazine-1,4-dione derivatives by introduction of halogenoalkyl substituents on the NH-nucleophilic groups. The described synthetic route will allow us to condense a nitrogen heterocyclic ring on the phthalazinone moiety and obtain a new tricyclic scaffold with promising pharmacological properties.


Introduction
The discovery of the first naturally occurring pyridazine derivative (pyridazomycin) meant a milestone in the recognition of the potential of the 1,2-diazine core as a valuable unit in medicinal chemistry. 1In particular, 3 oxo derivatives [pyridazin-3(2H)one scaffold] have shown a wide range of biological actions, specially on targets that play a key role in cardiovascular diseases. 2Hydralazine is also a hydrazine derivative used clinically as a vasodilator and antihypertensive agent. 3More recently, several 4substituted phthalazin-1-one have been reported because they afforded total relaxation on isolated rat aorta rings pre-contracted with phenylephrine at micromolar concentration. 4Azelastine is a relevant member of this family of compounds which has also demonstrated to induce vasorelaxation in vitro assays, more over of other interesting pharmacological activities. 5th these precedents and with the aim of preparing new derivatives with potential pharmacological activity, we have synthesized new phthalazinone derivatives in which, 4-substituent of azelastine is replaced by a carbonyl group. 6Additionally halogenoalkyl substituents with different chain length have been introduced on the NH-nucleophilic groups. 7Finally, using a nucleophilic reaction the halogen group was substituted by an azide group. 8e described derivatives bearing N-alkylazide groups will allow us to condense a nitrogen heterocyclic ring on the phthalazinone moiety obtaining a new tricyclic scaffold with promising pharmacological properties. 9, 10unstable derivative and it was not isolated following the described procedure.
Finally, by nucleophilic substitution of the halogen groups, were obtained the azide derivatives 3a, 3b and 3c.
All the new derivatives were obtained in good yields.

Chemistry
The phthalazine-1,4-dione derivatives were efficiently synthesized according to the synthetic protocol outlined in Scheme 1.

Conclusions
Series of new N, N-dialkylphthalazine-1,4-dione derivatives were synthesized in two or three steps starting from 4-chlorophthalic anhydride.This versatile and efficient route, let to afford huge family of compounds that can be considered a useful intermediates for the preparation of new tricyclic compounds.
The 4-chlorophtalic anhydride (5.48 mmol), methyl-hidrazine 98% (6.025mmol) and montmorillonite KSF clay (5 g) were mixed and grinded properly in a mortar, and placed in a clean and dry beaker.The reaction mixture was first preheated in a microwave oven for 15 minutes in periods of 1 minute each one (power 350 W) and the heating continued for 1 minute (power 450 W) and other minute (600 W) for completion of the reaction.The reaction mixture was cooled to the room temperature and the resulting product extracted with CH 2 Cl 2 /MeOH (9/1) (4 X 25 mL).The montmorillonite KSF clay was filtered off and the solvent removed by rotary.