Synthesis of novel [1,2,4]triazolo[4,3-b ]pyridazines

The preparation of some derivatives of the [1,2,4]triazolo[4,3-b ]pyridazine system from ethyl N - benzoyl-(6-chloro[1,2,4]triazolo[4,3-b ]pyridazin-3-yl)glycinate is reported.


Introduction
Recently, we have elaborated a general approach to ethyl N-benzoyl-α-hetero-aryl-glycinates based on the annulation of the 1,2,4-triazole ring on the suitably substituted azine or fused azine derivative (Scheme 1).Since the [1,2,4]triazolo [4,3-b]pyridazine system 2 has attracted great attention in the literature, it seemed worthwhile to explore synthetic utility of compound 1 in the preparation of some other derivatives of this system.In particular, we were interested in the preparation of the amino acid 2. Herein we report on the results of these investigations.

Results and Discussion
Reaction of 1 with hot 1 M sodium hydroxide solution took place on the ethoxycarbonyl group and at the position 6 of the triazolopyridazine system to give 3, which underwent decarboxylation in hot ethanol affording benzamide 4 (Scheme 2).

Scheme 2
Refluxing of 1 in diluted hydrochloric acid (1:1) for 4 h gave hydrochloride 5.This compound was also prepared via a longer reaction sequence starting from hydrazide 6, 3 which was firstly transformed by heating in acetic acid into the chloromethyl substituted triazolopyridazine 7. Substitution of the chloro group with potassium phthalimide in hot N,Ndimethylformamide produced 8, which hydrolyzed in hot hydrochloric acid to give 5 (Scheme 3).

Scheme 3
On the other hand, treatment of 1 with concentrated hydrochloric acid at room temperature for 15 days yielded acid 9, which similarly as 3 underwent decarboxylation by heating in ethanol giving benzamide 10.The latter was also prepared by oxidative cyclization of hydrazone 11. 4 Evidently, strong reaction conditions required for the elimination of the protective groups caused the decarboxylation of 9 making impossible the preparation of the acid 2 (Scheme 4).

Experimental Section
General Procedures.Melting points were determined on a Kofler micro hot stage and are uncorrected. 1H NMR spectra were recorded on Varian EM 360L (60 Hz) in DMSO-d 6 using TMS as internal standard.Elemental analyses for C, H, N were obtained on a Perkin-Elmer CHN Analyzer 2400.MS spectra were obtained on a VG-Analytical AutoSpec Q instrument.
Compounds 1, 1 6, 3 and 11, 4 were prepared as described in the literature.All other compounds were used without purification as obtained from commercial sources.

N-Benzoyl-(6-hydroxy[1,2,4]triazolo[4,3-b]pyridazin-3-yl)glycine (3).
A mixture of 180 mg (0.5 mmol) of 1 and 3.6 mL of 1 M NaOH was heated under reflux for 25 min.The reaction mixture was then cooled to room temperature and acidified with diluted HCl (pH=1).The separated solid was then collected by filtration to give 127 mg (81%) of 3, which was for analysis washed with chloroform; mp 259-262°C.(b) A suspension of 352 mg (1 mmol) of 8 in 6 mL of concentrated HCl was heated under reflux for 3 h.After cooling, the reaction mixture was diluted with 6 mL of water.The separated solid was collected by filtration to give 87 mg (52%) of phthalic acid.The remaining filtrate was evaporated under reduced pressure and the residue was treated with 6 mL of ethanol (96%).The separated solid was collected by filtration to give 120 mg (54%) of 5; mp over 360°C (ethanol/water).

1
Scheme 1 b]pyridazin-3-yl)methylamine hydrochloride (5).(a) A suspension of 500 mg (1.4 mmol) of 1 in 5 mL of diluted HCl (1:1) was heated under reflux for 4 h.The reaction mixture was then poured on ice and the white separated solid was collected by filtration to give 126 mg (80%) of benzoic acid.The remaining filtrate was evaporated under reduced pressure and the residue was treated with 6 mL of ethanol (96%).The separated solid was collected by filtration to give 227 mg (74%) of 5.
The reaction mixture was then heated on an oil bath at 120-130°C for 12 h, and poured into 90 mL of cold water.Upon cooling the separated solid was collected by filtration to give 547 mg (58%) of crude 8 which was for analysis purified by radial chromatography (chloroform); mp 264-266.5°C(chloroform/ethanol).