SÍNTESIS DE POSIBLES AGONISTAS NICOTÍNICOS CON POTENCIAL ACTIVIDAD INSECTICIDA

Ethyl N-benzylpyridine-3-carboximidoate7 was prepared by reacting N-benzylnicotinamide and ethyl chloroformate, the other ethyl imidatehydrochloride, ethyl N-(2-phenylethyl) pyridine-3-carboximidoate8, was prepared with the same method. Compound6 was obtained by synthesis of N-benzyl-N-(2-cyanoethyl) nicotinamide4, the latter was used as a starting material to obtain N-(3-aminopropyl)-N-benzylnicotinamide5 by reduction with Ni-Raney in good yield. Cyclization reaction was obtained by p-toluenesulfonic acid of compound5. Finally, compound (5,6-dihydro-2-(pyridin-3-yl)pyrimidin-1(4H)-yl)(2,4-dimethoxyphenyl) methanone9 was prepared by direct benzoylation of 1,4,5,6-tetrahydro-2-(pyridin-3-yl) pyrimidine.


INTRODUCTION
One of the most promising areas in insecticide development is the identification and synthesis of new compounds that act on the two main points of insecticide action: nicotinic acetylcholine receptors (nAChRs) that are activated by endogenous neurotransmitter acetylcholine and neonicotinoid agonists and acetylcholinesterase (AChE) which are inhibited by organophosphorus and methylcarbamate, which compounds to generate and maintain toxic ACh levels 1,2 localized. Neonicotinoid insecticides (NNSs), which interact with nAChR, have a higher affinity for insect receptors than for mammalian receptors [2][3][4] , and have attracted the attention of several research groups, because of their interesting insecticidal activity [5][6][7] .
We have recently reported the synthesis of novel 1,4,5,6-tetrahydro-2-(pyridin-3-yl) pyrimidine analogues 8 (figure 1) and we now have decided to extend our synthetic strategy to prepare novel tetrahydropyrimidines (THPs) and analogue compounds. In this investigation, the design and synthesis of some new compounds that bind to nicotinic acetylcholine receptors are described (figure 2), however, their biological properties remain unexplored.

Synthesis of compounds
Solvents and chemicals were purchased from Merck (Darmstadt, Germany) and Sigma-  Nicotinoyl chloride (1). SOCl 2 (60 mL, 813.0 mmol) was added to a solution of nicotinic acid (10 g, 81.3 mmol) in CH 2 Cl 2 . The mixture was stirred at room temperature for 5 minutes and then at reflux temperature for 4 more hours. After that, the solvent was evaporated to dryness, the product was crystallizing in a minimum volume of CH 2 Cl 2 and the product was used immediately for the next step. (10.2 g, yield 89%) N-benzylnicotinamide (2). K 2 CO 3 (4.5 g, 46 mmol) was added to a benzylamine (5 mL, 46 mmol) in acetone (50 mL) solution and kept at room temperature, and stored under nitrogen for 15 minutes. After this time a constant stirring nicotinoyl chloride (6.5 g, 46 mmol) dissolved in acetone was added while stirring for 2 hours. Then the solvent was evaporated to dryness, the residue was washed (undiluted) with a 25% NaOH solution (1 x 100 mL) and extracted with CH 2 Cl 2 (3 x 100 mL). The organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in a vacuum. The oily residue was purified by chromatography on silica gel (MeOH / EtOAc 1:1) and allowed to crystallize in CH 2 (5). N-benzyl-N-(2-cyanoethyl) nicotinamide (0.80 g, 3.0mmol), methanolic ammonia (7 N, 100 mL), and Raney nickel (5 mL, washed three times with MeOH) were added to a 500 mL hydrogenation flask. The flask was transferred to a stainless Steel Parr shaker hydrogenation apparatus, charged with hydrogen (50 psi), and shaken (for 1 minute). The flask was evacuated under aspiration in vacuum (1 min) and then charged with hydrogen (50 psi,1 min) three times, the resultant slurry/solution was shaken under hydrogen at 50 psi for 24 h. The catalyst was removed by filtration through a Celite (washed with methanol) pad, and the solution was concentrated in vacuum. The material that was obtained (a green-blue solid) was dissolved in 95% EtOH (100 mL), and Dowex monosphere 300A (-OH) anion exchange resin (21.5 mL, 25.8 mmol -OH) was added to the obtained solution. The slurry was refluxed for 24 h, cooled to rt, and the resin was removed by gravity filtration. The resin was then washed with 95% EtOH (2 x 50 mL), and the combined filtrate was concentrated in vacuum to obtain the nickel free title compound

RESULTS AND DISCUSSIONS
This research's goal was to develop a new synthetic strategy for tetrahydropyrimidinic systems and also to structurally prepare related compounds by having new nicotinic agonists with insecticidal activity. In a previous article, the synthesis of 2-(pyridin-3-yl)-1,4,5,6tetrahydropyrimidines derivatives by the one pot method using boric acid as the main catalyst (scheme 1) was reported.
Although the reaction is an easy strategy for these types of compounds, the low reactivity observed of the pyrimidine system from acid chlorides, make it difficult to obtain benzylated and benzoylated systems in good yield, only the use of a strong base such as BuLi allowed to obtain 9 in a yield of 21%. The synthesis of 6 using this method was only possible in a yield which is not higher than 2% (not shown data). As an alternative for the synthesis of 6, all pertaining to the route described in 1966 by Oedigeret, all 3 steps were performed. Compound 3's formation had more than 90% efficiency and did not require chromatographic purification. We tried to obtain 3-(phenethylamino)propanenitrile using this methodology. However, the formation of 3,3'-[(2-phenylethyl)azanediyl]dipropanenitrile was in a yield of 78% (unpublished data).

CONCLUSION
In conclusion, we have described an efficient protocol for obtaining compounds with potential insecticide activity. Generally speaking, a high maintenance sythntesis is shown with a low reaction time, and also soft reaction conditions.