Guanfacine hydrochloride is a selective alpha-2A adrenergic receptor agonist for the treatment of moderate to severe hypertension. It can also be used for the treatment of attention deficit hyperactivity disorder (ADHD). It is suitable for children and for adolescent that stimulant is not suitable, or invalid.

Here we describe several methods for the synthesis of guanfacine hydrochloride and compare them.

(1) Dissolve 2, 6-dichlorobenzene acetonitrile in methanol, add concentrated sulfuric acid slowly, alcoholysis at 80 °C, and incubate for 12 hours. Slowly add the reaction mixture to methanol containing a small amount of water and stir for 30 minutes. After distilling methanol to recover, water is added and the mixture is extracted with ethyl acetate. The organic layer is rotatory distilled to remove ethyl acetate to obtain methyl 2, 6-dichlorobenzeneacetate, which is then dissolved in isopropyl alcohol, and then added to the guanidine isopropanol solution, stir at room temperature for 10 hours, vacuum filtration to obtain guanfacine hydrochloride crude product. The next step is to add isopropyl alcohol to the crude product, adjust the pH to about 1~2 with hydrochloric acid ethanol, and vacuum filter to remove insoluble matter. The filtrate is concentrated to give the final product. One drawback of this method is that concentrated sulfuric acid tends to remain.

(2) After stirring guanidine hydrochloride, sodium isopropoxide and isopropanol at room temperature for 24 hours, remove sodium chloride by vacuum filtration, and add 2, 6-dichlorobenzeneacetic acid methyl ester isopropanol solution to the filtrate. After stirring at room temperature for 15 minutes, recover solvent and cool to precipitate solid product. After adding isopropanol to the solid, pH value was adjusted to 1~2 with hydrogen chloride ethanol solution, vacuum-filtered to remove insoluble chemicals, and the filtrate was concentrated. Needle-like white crystals were precipitated with suitable amount of ether. Filtration under vacuum condition, crude guanfacine hydrochloride was obtained. The hydrogen chloride ethanol solution used in this method is not easy to purchase and store. The ether itself is a controlled product.

(3) Guanidine hydrochloride, potassium carbonate and acetonitrile were added to the reactor, and then 2, 6-dichlorobenzene acetyl chloride acetonitrile solution was added under stirring at room temperature. After the above operation was completed, the reagents were react at room temperature for 3~4 hours. The solvent acetonitrile was distilled off while reaction completed, and water was added to make them slurry with stirring. The filter cake was washed with water to obtain a guanfacine, which was completely dissolved in ethanol with a concentration of 95%. The filtrate obtained is then added to a hydrochloric acid with a concentration of 35 to 37%, the pH is adjusted to 1~2. The reaction was carried out at room temperature for 30 to 40 minutes with stirring. The ethanol is removed after the reaction is completed, cool to obtain crystal at room temperature for 2 to 3 hours. Crude guanfacine hydrochloride was obtained through suction filter; further purify to obtain the final product. The operation is simple in this method, low in production cost, little in pollutant discharge in the preparation process, and is conducive to environmental protection [1].

Among the above three guanfacine hydrochlorides synthesis methods, considering the production cost, environmental protection, and operation process, the feasibility of the third synthetic method is superior to the other two.

References

[1] Zhang Baoguo, Zhu Zanmei et al., Preparation of guanfacine hydrochloride, CN103058890A