Natural Products Chemistry & Research

Natural Products such as terpenoids, alkaloids etc., properties play a significant role in the discovery and development of new drugs. Quinazolines and quinazolinones are proven to be considerably bioactive and shown to possess antitumor, anti-inflammatory, antidiabetic, etc. Quinazolinone moiety is present in many commercialized drugs such as Albaconazole 1, Gifitinib 2 (Figure 1) etc. [1,2]. Besides several quinazoline derived clinical candidates are in various stages of development [2,3].

Figure 1: Albaconazole and Gifitinib

The quinazolinone based natural product 4 (Figure 2) was isolated by Zihong Zhu, et al. in 2011 from marine species Bacillus cereous [1]. They also have confirmed the structure by the synthesis of the same from 2-aminobenzamide. The present communication is to report a simple formal synthesis of the quinazolinone from readily available anthranilic acid and 2-ethylhexanoic acid.

Figure 2: Quinazolinone and 2-aminobenzamide.

The quinazolinone 3 upon reduction furnishes the marine natural product 4, the dihydro quinazolinone. These compounds show significant anti-fungal and anti-viral activity. Hence viable alternative synthetic routes are needed.

The marine natural product dihydroquinazolinone 4 was isolated from marine species Bacillus cereous and synthesized from 2-aminobenzamide [1]. Herein we report a short formal synthesis of quinazolinone 3 from readily available anthranilic acid and 2-ethylhexanoic acid as shown in the following scheme (Figure 3).

Figure 3: Reaction of anthranilic acid with 2-ethylhexanoyl chloride.

Since the synthesis of 4 from 3 is already reported, we report here the convenient synthesis of 3 only. The synthesis starts with reaction of anthranilic acid with 2-ethylhexanoyl chloride (obtained by reaction of 2-ethylhexanoic acid with thionyl chloride under reflux) in dimethylformamide (DMF) solvent at room temperature under stirring for 2 hrs followed by usual workup to provide the compound 5 as shown in the following scheme. The compound 5 is then heated in acetic anhydride at 120°C for four hours followed evaporation to provide the compound 6, which without purification treated with ammonium acetate in dimethyl formamide (DMF) at 120°C for two hours followed by usual workup furnished the quinazolinone 3 which is purified by silica gel chromatography using dichloromethane and methanol as eluent. The pure quinazolinone 3 is obtained as a white solid which was characterized by ¹HNMR (Table 1), ¹³CNMR (Table 2), DEPT135 and Mass. The ¹HNMR was recorded in CDCl₃ as solvent by 400 MHz. The aromatic protons with expected multiplicity appeared between 7 and 9 ppm, NH at 11 ppm, two methyl groups as triplets at 1 ppm, and remaining protons between 1.3 and 2.2 ppm. The ¹³CNMR showed 15 peaks while DEPT showed 11 peaks corresponding to CH, CH₂ and CH₃. The mass spectrum showed M+1 at 245. Also a strong peak at 246. By using this information, it is confirmed beyond any doubt that the product 3 indeed is the desired quinazolinone which can be converted into 4 using the reported procedure [4-10].

Table 1: Proton Chemical Shifts of compound 3.

All the reagents were purchased from Sigma-Aldrich or Merck and used as such without purification. All solvents were obtained from standard sources and used as such without drying. 1HNMR and ¹³CNMR were recorded on Bruker 400 MHz and Mass on Agilent1100LC/MSD. Chromatographic purification is carried out using silica gel (Figure 4).

Figure 4: Silica gel.

In a clean and dry round bottom flask, anthranilic acid (1 g, 0.0073 moles) was taken in DMF (10 ml). To the contents of the flask 1.2 eq of 2-ethylhexanoyl chloride (obtained from 2-ethylhexanoic acid and thionyl s chloride) was added and stirred vigorously for 2 h at room temperature. The reaction mixture was poured into water and extracted with DCM (2×15 ml), separated the DCM layer, dried over anhydrous Sodium sulfate and concentrated. The crude product was used as such in the next reaction (Figure 5).

Figure 5: Anthranilic acid.

To the crude product obtained from the above reaction acetic anhydride (4 ml) was added and stirred under reflux for 4 hrs, followed by distilling off the acetic anhydride. To the product obtained after distillation dimethyl formamide (10 ml) was added and 2 eq of ammonium acetate and heated under stirring at 120°C for 2 hrs. The reaction mixture was poured into water, extracted with dichloromethane (3×15 ml). The DCM layers were collected, washed with water, dried over anhydrous Sodium sulfate, concentrated and subjected to purification by column chromatography on silica gel using a mixture of dichloromethane and methanol as eluent to obtain pure quinazolinone 3 (400 mg) in about 30% overall yield. The compound was characterized by ¹HNMR, ¹³CNMR, DEPT135 and M/S [11,12].

We summarize that in the present communication, a simple and formal synthetically viable route to the quinazolinone 3 is reported which in turn can easily be converted to 4 using the reported procedure.