*3.1.4.1 Synthesis of bay 41–4109 racemate [methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5 difluoropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (135)]*

The synthesis of Bay 41–4109 (135) (**Figures 27**) was initiated by allowing βketoacetate (133) to react with pyridine-2-carboximidamide salt and phenylacetaldehydes (134) via Biginelli cyclocondensation [95]. The reaction proceeded in isopropanol under microwave irradiation to produce the corresponding products (135) (**Figures 28** and **29**). On note, Bay 41–4109 (135) can be used for further derivatization. For example, the bromination of (140) using *N*-bromosuccinimide (NBS) can lead to the brominated intermediate (141), which can be easily substituted with nucleophiles like morpholine, *N*-methylpiperazine, methoxyethanol or

#### **Figure 25.**

*Conversion of 5-substituted-2-amino-4,6-dihydroxypyrimidines (126) to 5-substituted 2-amino-4,6 dichloropyrimidines (127) using (chloromethylene) dimethyliminium chloride (130).*

#### **Figure 26.**

*Synthesis of 2,4,5,6-tetrasubstituted pyrimidine derivatives. Reagents and conditions: a) EtONa/EtOH; b) (chloromethylene) dimethyliminium chloride/CHCl3; c) different anilines, ethanol, 100°C, 4 h; d) isopropanol, sodium* tert*-butoxide, 82°C, 6 h.*

#### **Figure 27.** *Bay 41–4109 racemate (135).*

#### **Figure 28.**

*Synthesis of bay 41–4109 (135). Method-1: One-pot three-component Biginelli condensation using aldehyde, β-ketoester and amidine. Reagents and conditions: a) piperidine, AcOH,* i*PrOH, 12 h, 11–36%.*

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

#### **Figure 29.**

*Synthesis of bay 41–4109 (135). Method-2: Reagents and conditions: a) NaH, DMF, 0°C* ! *rt., 1 h, 41–60%, b) pyridine-2-carboximidamide, Et3N, μW, 10 min, 14%; c) DDQ, toluene, rt., 1 h, 42–68%; d) NBS, 1,2-DCE, 50°C, 30 min, 80%; e) morpholine, Et3N, DMF, 0°C, 1 h, 29–72%.*

thiobenzene producing the corresponding derivatives (142a-d). Oxidation of these dihydropyrimidines using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) easily led to the desired pyrimidines (144).

#### *3.1.5 Synthesis of 2-amino-4,6-disubstituted pyrimidine*

Altenbach et al. initiated the synthesis of a group of 4-*tert*-butyl-6-substituted pyrimidin-2-ylamine derivatives (**Figure 30**) starting 2,4-dichloropyrimidine (38) that was alkylated with pivalic acid (151) via nucleophilic substitution of 4-chlorousing silver nitrate AgNO3 and ammonium persulfate. The 4-*tert*-butyl-6 chloropyrimidin-2-ylamine intermediate (151) was subjected to sequential nucleophilic amination to end in the desired group of compounds (154a-e). At the first step the displacement of the 2-chloro with N-Me-piperazine (155) afforded 4-*tert*-butyl-2 chloro-6-(4-methylpiperazin-1-yl) pyrimidine (152) as a mixture with second regioisomer 4-*tert*-butyl-6-chloro-2-(4-methylpiperazin-1-yl) pyrimidine (153). Following chromatography, (152) was treated with the second nucleophile to result in the desired group of compounds (154a-e) [94].

The same group also reported the synthesis of a group of 2-amino-4,5,6-trisubstituted pyrimidines (160a-m and 161a-o) starting from 2-amino-4,6-dichloro-5 substituted intermediate (156) (**Figure 31**). Evidently, 2-amino-4,6-dichoro-5 substituted intermediate (156) was treated with 1-methylpiperazine (155) under basic conditions (TEA or DIEA) while refluxed for 16 hours [94]. The second substitution was dependent on the type of connecting bond. In case of forming a C-C bond at C6 of the pyrimidine core, Suzuki conditions boronic acid derivatives (4-cyanophenylboronic acid or 4-methylphenylboronic acid), tetrakis (triphenylphosphine)-palladium (0) (Pd(PPh3)4) in 2-dimethoxyethane under basic (2 M Na2CO3) and inert

#### **Figure 30.**

*Synthesis of 2-amino-4,6-disubstituted pyrimidine derivative. Reagents and conditions: I): a) guanidine hydrochloride, EtONa, EtOH, Δ; b) POCl3, Δ; water; and c) amine, Δ, EtOH, Et3N; II) reagents and conditions: d) pivalic acid, AgNO3, ammonium persulfate, CH3CN/H2O; e) N-me-piperazine, Et3N, EtOH, Δ, chromatography; (154a): R = H): H2, Pd/C, MeOH; (154b): R = NHMe) 40% aqueous MeNH2, 2-MeOEtOH, Δ; (154c): R = NMe2): 40% aqueous Me2NH, 2-MeOEtOH, Δ; (154d): R = OH): 1 M HCl, 16 h, Δ; (154e): R = OMe): Excess NaOMe, MeOH, Δ.*

conditions. In the case of forming C-N bond at C6, Ullmann nucleophilic substitution conditions were applied. For example for synthesizing 4-(4-methylpiperazin-1-yl)- 6-(4-phenylimidazol-1-yl)pyrimidin-2-ylamine (160). The corresponding substituent 4-phenylimidazole (87 mg, 0.6 mmol) (159) was added to 4-(4-methylpiperazin-1 yl)- 6-chloropyrimidin-2-ylamine (157) in presence of catalytic copper iodide (CuI, 0.13 mmol ratio) under basic condition (K2CO3) in DMF that was heated to 135°C overnight. Generally, the yields reported for Suzuki conditions (C-C bond) were higher than those reported under Ullmann conditions.

2-Amino-4,6-dichloropyrimidines (156) were also used as starting materials for preparing 2-amino-4,5,6-trisubstituted derivatives (160a-m and 161a-o) (see **Figure 31**).
