*3.1.4 Synthetic methods in preparing 2,4,5,6-Tera-substituted pyrimidines*

One main strategic approach employs the step-wise replacement of leaving groups that exist on the already constructed pyrimidine (like 2,4,6-trichloropyrimidine (109)). The selection of the substituted pyrimidine as starting material depends on the

**Figure 23.**

*Synthesis of* N*-2,4,6-trisubstituted pyrimidine derivatives as potent aurora a kinase inhibitor. Reagents and conditions: a) Et3N, EtOH, 0°C; b) TsOH.H2O, n-BuOH or 1,4-dioxane, 100–140°C; c) 1,4-dioxane, under microwave, 150–180°C.*

desired product i.e. in case of 2,4-disbustitited pyrimidine the synthesis starts with 2,4-dihalopyrimidine and in case of 2,4,6-trisubstitutedpyrimidine the 2,4,6-trichloropyrimidine (109) is picked. Additionally, the reaction conditions and reagents used in the chemical process is by virtue reliant on the type of chemical bond formed or the type reaction employed. The order of applying the sequential displacement of the leaving groups is contingent on the type and properties of the functional group and conditions that ensure better purity and higher yield of the intermediates, building blocks or the final products. A special attention will be devoted to recent reports related to synthesis of FDA approved drugs or in few cases such derivatives with high potential bio-activities.

Regioselectivity is mostly guaranteed by picking the proper starting material and the fitting sequence of substitution (**Figure 24**).

In a recent study Zhang and colleagues reported the synthesis of anisole containing 2,4,5,6-tetrasubstituted pyrimidines [92]. The team exploited the commercially available reagents like properly substituted malonic acid diesters (124) and guanidine hydrochloride (125) that were condensated in anhydrous methanol under slightly

**Figure 24.**

*Examples of 2,4,5,6-tetrasubstituted pyrimidines. R = H, methyl-, ethyl-, propyl-, isopropyl-, Propargyl-., R = allyl-, butyl-,* sec*-butyl-, phenyl-, benzyl-, Fluoro-.*

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

basic conditions (sodium methoxide) to produce the 5-substituted 4,6-dihydroxy-2 aminopyrimidine intermediate (126). (126) was converted to the 5-substituted 4,6 dichloro-2-aminopyrimidine derivative (127) upon treatment with Vilsmeier–Haack– Arnold (VHA) reagent [93]. Cations should be taken prior to treating 5-substituted 4,6-dichloro-2-aminopyrimidine derivatives with (chloromethylene) dimethyliminium chloride (VHA, 130) (**Figure 26**).

Using VHA reagent, drying of the starting materials and conducting the reaction under inert conditions helped in affording the final products in higher yields and purity compared to the previously reported reaction conditions (such as chloride donating mineral acids such as POCl3, PCl5, SOCl2, or COCl2 with diverse additives like DMF, pyridine, 2-methylpyridine, diphenylamine, or triethylamine) reported to end in less than 30% yields and complicated purification procedures [94]. Following the deprotection of the 2-(dimethylamino) methylene protecting group using hydrochloric acid the desired 4,6-dichloro-5-substituted-2-aminopyrimidines were isolated and purified. The 4,6-dichlorides were sequentially displaced under nucleophilic substitution conditions. The first 4-chloro was substituted by aniline derivatives in refluxing ethanol (see step c in **Figure 25**) while the second chloride was exchanged for anisole (4-methoxythiophenol) employing sodium tert-butoxide (1.33 mmol), under heating at 82°C (see step d in **Figure 25**, [92].
