*3.1.7 Synthesis of Minoxidil; (MNX); [(2,4-diamino-6-piperidinopyrimidine 3-oxide) (171)]*

Minoxidil (MNX) is a direct vasodilator introduced in the early 1970s for the treatment of hypertension [101]. Its first literature appearance was in 1968 and preliminary trials were first described in man in 1969 [102].

Coincidentally, physicians observed hair regrowth and generalized hypertrichosis in balding patients, which led to the development of a topical minoxidil formulation for treating androgenetic alopecia (AGA) first in male and then in female individuals [26, 103, 104].

An easy protocol for the synthesis of minoxidil drug in a two-step procedure is done, using magnetic nanoparticles of ferrites, which have been widely used as green and efficient heterogeneous catalysts in the synthesis of organic compounds, where these nano catalysts provide prominent advantages such as simple synthetic procedure, high catalytic activity, chemical reactivity and perfect reusability.

Magnetic nanoparticles (MNPs) of CoFe2O4 were prepared through a solid-state grinding procedure, in an agate mortar, where a mixture of CoCl2, Fe (NO3)39H2O, NaOH, and NaCl in a molar ratio of 1:2:8:2 was mixed, ground for 45 min at room temperature, then the excess amount of salt was removed from the reaction mixture, the obtained residue was dried in an oven at 80°C for 60 min, calcinated at 300, 500, 700, and 900°C within 80 min (20 min at each temperature) (**Figure 33**) [105].

*Synthetic Approaches for Pharmacologically Active Decorated Six-Membered Diazines DOI: http://dx.doi.org/10.5772/intechopen.109103*

**Figure 33.**

*Synthesis of Minoxidil (171). Reagents and conditions: a) Nano CoFe2O4 (5 Mol%), H2O2 (0.5 ml), ETOH, reflux, 60 min, 95%; b) Piperidine, reflux, 120 min, 80%.*

First step was carried out by N-oxidation of 6-chloro-2,4-diaminopyrimidine (168) using (30%, 0.5 mL) H2O2 in the presence of CoFe2O4 magnetic nanocatalyst (5 mol %) in 5 ml ethanol under reflux conditions for 60 min to get 2,6-diamino-4-chloropyrimidine N-oxide (169) in yield (95%).

A nucleophilic substitution reaction using boiling piperidine (106°C) under neat conditions with 2,6-diamino-4-chloro-pyrimidine N -oxide (169), for 120 min was then carried as step two, affording 2,4-diamino-6-piperidinopyrimidine 3-oxide (minoxidil, (171)) product in high yield (80%) and purity without requiring any further purification.
