Solid-Phase Synthesis Methodology Of N-Substituted-2-Aminothiazo (SPOS)

877 Words 4 Pages
A novel solid-phase synthesis methodology of N-substituted-2-aminothiazolo[4,5-b]pyrazine derivatives was developed. The key step in this synthesis strategy is tandem reaction of isothiocyanate terminated resin 2 with o-halo-2-aminopyrazine, affording cyclized 2-aminothiazolo[4,5-b]pyrazine resin 4. To increase the diversity of our library, Suzuki coupling reaction was performed at the position C6. Further functionalization of 2-aminothiazolo[4,5-b]pyrazine core skeleton with various electrophiles such as alkyl halides, acyl chlorides, and sulfonyl chlorides and cleavage from the resin with TFA in DCM generated N-alkyl-, N-acyl-, and N-sulfonyl-2-aminothiazolo[4,5-b]pyrazine derivatives. This synthetic strategy can efficiently provide a library …show more content…
In SPOS, an excess reagents are used to drive reaction to completion, and products can be easily isolated by simple filtration from solid support.1 Other benefits of solid-phase is the ease of automation and the ability of polymer to “fish out” low concentrations of product molecules from excess of starting material.2 Heterocyclic compounds usually serve as a backbone of hundreds of marketed drugs.3 In this respect, we have been interested in thiazolo[4,5-b]pyrazine core skeleton. Even though thiazolo[4,5-b]pyrazine has not been investigated in detail in the medicinal chemistry area, we have focused on it because of its structural similarity with thiazolopyrimidine (Figure 1). Thiazolopyrimidine core skeleton has shown various biological activities in the medicinal chemistry area such as kinase inhibitors,4 TRPV1 antagonists,5 E. coli and S. aureus SecA inhibitors,6 stearoyl-CoA desaturase (SCD) inhibitor.7 Figure 1 shows similar structural features of thiazolopyrimidine and thiazolopyrazine (Figure 1a, Energy minimized 3D structure). The only difference is the position of nitrogen atom equipped in each core skeleton, and this positional difference causes different polar surface area (Figure 1b). In drug discovery, polar surface area is considered as a key factor to interact with target protein by …show more content…
The synthesis route starts from the preparation of isothiocyanated terminated resin 2 from the 4-benzyloxy-2-methoxybenzylamine10 (BOMBA) resin 1 by the treatment with Et3N, CS2, and p-TsCl.11 The formation of the desired resin 2 was confirmed by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), showing typical isothiocyanate band at 2062 cm-1 (Figure S1(b), the Supporting Information). Next, the cyclization reaction of 2-aminothiazolo[4,5-b]pyrazine was performed. Before accomplishing cyclization reaction on solid phase, model study in solution phase was performed (Table S1, the Supporting Information). According to the results from the model study, resin 2 was reacted with 3,5-dibromo-2-amino-pyrazine 3a in the presence of NaOH in DMSO at room temperature (Table 1, Entry 1). Unfortunately, desired cyclized product 15a was obtained in trace amount because of low swelling property of DMSO into the lipophilic resin 2. To solve this problem, we changed the solvent to a 1:1 mixture of DMSO and THF to increase solvent system’s swelling properties. As a result, 15a was obtained in 56% overall yield after three steps (Table 1, Entry 2). Next, for better reactivity, further modification such as Suzuki coupling was attempted to replace bromine to iodine. From the result of the model study, resin 2 was reacted with

Related Documents