Efficient solid-phase synthesis of 1,2,3-benzotriazin-4-ones with SynPhaseTM Lanterns

SHORT REPORT

Efficient solid-phase synthesis of 1,2,3-benzotriazin-4-ones with SynPhase^TM Lanterns

Shingo Makino^*; Eiji Nakanishi and Takashi Tsuji

Pharmaceutical Research Laboratories, Pharmaceutical Company, Ajinomoto Co., Inc. 1-1. Suzuki-cho. Kawasaki-ku. Kawasaki-shi. 210-8681 Japan

ABSTRACT

We have developed a solid-phase synthesis of 1,2,3-benzotriazin-4-ones through cyclization of 2-aminobenzamides via diazotization. The development of an efficient synthesis is important from the viewpoint of drug discovery, considering the various bioactivities of these derivatives. The precursors of 1,2,3-benzotriazin-4-ones, 2-aminobenzamides, were prepared from solid-supported amines and 2-nitrobenzoic acids. Various 1,2,3-benzotriazin-4-ones were obtained with high purity using SynPhase^TM Lanterns.

Keywords: solid-phase synthesis, drug, quinazoline, 1,2,3-benzotriazin-4-one, SynPhase^TM Lantern, diazotization

RESUMO

A síntese de 1,2,3-benzotriazin-4-onas em fase sólida através da ciclização de 2-aminobenzamidas é descrita. O desenvolvimento de um método de síntese eficiente é importante para o desenvolvimento de drogas em razão da atividade biológica variada desses compostos. Os precursores de 1,2,3-benzotriazin-4-onas, as 2-aminobenzamidas, foram preparadas a partir de aminas ligadas a suporte sólido e ácidos 2-nitrobenzóicos. Várias 1,2,3-benzotriazin-4-onas foram obtidas em alta pureza utilizando-se SynPhase^TM Lanterns."

Introduction

Solid-phase synthesis of small-sized, non-peptidic molecules has emerged as an important drug discovery tool.¹ The synthesis of heterocyclic compounds on solid-support, in particular, has been a focus of intensive study because of their applications toward a variety of drug targets.² Among various heterocycles, quinazolines are particularly attractive pharmacophores in view of their wide range of bioactivities.³ As a part of our project to develop an efficient synthetic protocol for quinazoline analogues on solid-support,⁴ we investigated the synthesis of 1,2,3-benzotriazin-4-ones. 1,2,3-Benzotriazin-4-ones have been known to possess various biological activities such as sedative,⁵ diuretic,⁶ anesthetic,⁷ antiarthritic⁸ and antitumor activity.⁹ In addition, numerous heterocycles such as quinazoline-2, 4-diones,^4,10 4-quinazolinones,^4,11 2-thioxoquinazolin-4-ones,⁴ 3-(sulfanyl)-1,2,4-benzothiadiazine 1,1-dioxide,⁴ 1,2,4-benzothiadiazin-3-one 1,1-dioxides,⁴ 2,1,3-benzothiadiazin-4-one 2-oxides,⁴ benzimidazole,¹² hydantoin¹³ and piperazinone¹⁴ have been prepared from the solid-supported amines. Therefore, the bioactivities of 1,2,3-benzotriazin-4-ones and these heterocycles can be efficiently compared if appropriate synthetic methods are developed. Here, we report the first solid-phase synthesis of 1,2,3-benzotriazin-4-ones.

Results and Discussion

Wang-type SynPhase^TM Lantern (1a)¹⁵ bearing a 3-aminobenzoic acid ester⁴ was reacted with 2-nitrobenzoyl chloride (2a)/2,6-lutidine to give 3a (Scheme 1). The derivatized Lantern 3a was treated with SnCl₂ • 2H₂O/EtOH /NMP to give 2-aminobenzamide (4a) with high purity. Next, the cyclization of 4a through diazotization was attempted. Diazotization of arylamines has been often performed with NaNO₂ in highly acidic solvents such as TFA¹⁶ or concentrated HCl.⁵ However, compounds on Wang-type solid-supports are cleaved off when treated with these solvents. Therefore, numerous solvents were tested for the diazotization and AcOH/H₂O (1/1) was found as the best solvent to give 6a with high purity (Table 1). Other 1,2,3-benzotriazin-4-ones (6b-d) were also synthesized using the solid-supported arylamines and 2-nitrobenzoyl chloride. This synthetic method was found to work with a solid-supported alkylamine and phenylalanine ester (6e). 1,2,3-Benzotriazin-4-ones with substitutions on the aromatic ring were also synthesized using substituted 2-nitrobenzoic acids. 2-Nitrobenzoic acids were coupled with 3-aminobenzoic acid ester using N,N'-diisopropylcarbodiimide (DIC)/1-hydroxy-7-azabenzotriazole (HOAt) to give 3f-h. The usage of HOAt was important as the acylation was not completed with HOBt. Following a similar reaction sequence, substituted 1,2,3-benzotriazin-4-ones (6f-h) were successfully synthesized with high purity. Yields of products ranged from 46 - 83% based on the theoretical loading weights of the target molecules.¹⁷ The structures of all the products in this manuscript were confirmed by ¹H NMR and LC-MAS (ESI mass spectrometry).

In conclusion, the solid-phase synthesis of 1,2,3-benzotriazin-4-ones has been accomplished by cyclization of 2-aminobenzamides via diazotization from various solid-supported amines and 2-nitrobenzoic acids. Although the size of the library is not large due to the limited diversity points (two diversity points), the same solid-supported amines can be derivatized into various heterocycles as described above, making this library an addition to the larger heterocycle library.

Experimental

General

Commercial reagents were used without further purification. ¹H NMR spectra were recorded on Varian VXR-300S (300 MHz) spectrometers using tetramethylsilane as an internal standard. Liquid chromatography was performed using symmetry C₁₈ column with ESI/PDA detection on Micromass platform.

Representative procedure: synthesis of 3-(6-chloro-4-oxo-4H-benzo[d][1,2,3]triazin-3-yl)-benzoic acid (6f)

SynPhase^TM Lanterns bearing a 3-aminobenzoic acid ester (1f) were prepared according to the previous report.⁴ The Lantern was treated with 5-chloro-2-nitrobenzoic acid /HOAt/DIC/NMP (1.0 mg/1.0mg/25 mL/2 mL) for 16 h at 60 °C to give 3f. The Lanterns were washed with DMF (2 mL x 3) and CH₂Cl₂ (2 mL x 3) and dried under vacuum. After reduction of the nitro group with SnCl₂ • 2H₂O/NMP/EtOH (1.0 g/2.0 mL/0.1 mL) for 16 h, the lantern was washed with DMF (2 mL x 3) and CH₂Cl₂ (2 mL x 3), and dried under vacuum for 1h to give 4f. Acetic acid (1.0 mL) and H₂O (1.0 mL) were added to the Lantern in a 2.5 mL syringe with a cap¹⁷, and immediately after adding solid NaNO₂ (100 mg), the syringe was sealed and put into a 50 mL Falcon tube¹⁸ to prevent the syringe from opening. After shaking the tube for 16 h, the tube and the syringe cap were carefully removed and the lantern was washed with DMF (2 mL x 3) and CH₂Cl₂ (2 mL x 3) and dried under vacuum to give 5f. The lantern was treated with 95% TFA/H₂O for 1 h and the solution was concentrated with a Genevac evaporater.¹⁹ The residue was dissolved with 50% CH₃CN/H₂O and lyophilized to give the product 6f (Entry f in Table 1) in 79% yield based on the theoretical loading weight of the target molecule.

3-(4-Oxo-4H-benzo[d][1,2,3]triazin-3-yl)-benzoic acid (6a).¹H NMR (DMSO-d₆) d 7.73 (dd, 1H, J 7.8, 7.8 Hz), 7.94 (ddd, 1H, J 1.2, 2.4, 8.1 Hz), 7.7-8.03 (m, 1H), 8.08-8.18 (m, 2H), 8.24 (dd, 1H, J 1.7, 1.8 Hz), 8.28-8.36 (m, 2H). MS m/z 268 (M + 1)⁺.

3-[2-(4-Oxo-4H-benzo[d][1,2,3]triazin-3-yl)-phenyl] -acrylic acid(6b).¹H NMR (DMSO-d₆) d 6.61 (d, 1H, J 16.0 Hz), 7.67 (d, 1H, J 16.0 Hz), 7.62-7.73 (m, 2H), 7.84-7.89 (m, 1H), 7.98-8.04 (m, 2H), 8.13-8.19 (m, 1H), 8.29-8.36 (m, 2H). MS m/z 294 (M + 1)⁺.

3-[3-(4-Oxo-4H-benzo[d][1,2,3]triazin-3-yl)-phenyl] -acrylic acid (6c).¹H NMR (DMSO-d₆) d 6.59 (d, 1H, J 15.9 Hz), 7.22 (d, 1H, J 15.9 Hz), 7.64-7.69 (m, 3H), 8.01-8.10 (m, 2H), 8.18-8.23 (m, 1H), 8.34 (d, 1H, J 1.5 Hz), 8.37 (d, 1H, J 1.2 Hz). MS m/z 294 (M + 1)⁺.

3-[4-(4-Oxo-4H-benzo[d][1,2,3]triazin-3-yl)-phenyl] -acrylic acid (6d).¹H NMR (DMSO-d₆) d 6.65 (d, 1H, J 1.6 Hz), 7.69 (d, 1H, J 1.6 Hz), 7.72 (d, 2H, J 8.7 Hz), 7.92 (d, 2H, J 8.7 Hz), 7.98-8.03 (m, 1H), 8.13-8.19 (m, 1H), 8.28-8.29 (m, 1H), 8.31-8.36 (m, 1H). MS m/z 294 (M + 1)⁺.

2-(4-Oxo-4H-benzo[d][1,2,3]triazin-3-yl)-3-phenyl -propionic acid(6e).¹H NMR (DMSO-d₆) d 3.53 (dd, 1H, J 11.0, 14.2 Hz), 3.65 (dd, 1H, J 5.1, 14.2 Hz), 7.08-7.16 (m, 5H), 7.91-7.96 (m, 1H), 8.07-8.13 (m, 1H), 8.17-8.23 (m, 2H). MS m/z 296 (M + 1)⁺.

3-(6-Chloro-4-oxo-4H-benzo[d][1,2,3]triazin-3-yl) -benzoic acid (6f).¹H NMR (DMSO-d₆) d 7.72-7.77 (m, 1H), 7.91-7.95 (m, 1H), 8.09-8.12 (m, 1H), 8.18-8.25 (m, 2H), 8.31-8.36 (m, 2H). MS m/z 302, 603 (M + 1)⁺.

3-(4-Oxo-7-trifluoromethyl-4H-benzo[d][1,2,3]triazin -3-yl)-benzoic acid (6g).¹H NMR (DMSO-d₆) d 7.76 (dd, 1H, J 7.8, 7.8 Hz), 7.95 (ddd, 1H, J 1.3, 2.2, 7.8 Hz), 8.12 (ddd, 1H, J 1.3, 1.4, 7.8 Hz), 8.26 (dd, 1H, J 2.2, 2.2 Hz), 8.30 (dd, 1H, J 1.4, 8.2 Hz), 8.53 (d, 1H, J 8.2 Hz), 8.73 (s, 1H). MS m/z 336 (M + 1)⁺.

3-(8-Methyl-4-oxo-4H-benzo[d][1,2,3]triazin-3-yl) -benzoic acid (6h).¹H NMR (DMSO-d₆) d 7.73 (dd, 1H, J 7.8, 7.8 Hz), 7.87 (dd, 1H, J 7.8, 7.8 Hz), 7.92-7.95 (m, 1H), 7.96-8.01 (m, 1H), 8.07-8.11 (m, 1H), 8.17 (dd, 1H, J 0.9, 7.5 Hz), 8.23 (dd, 1H, J 1.8 Hz). MS m/z 282 (M + 1)⁺.

Acknowledgment

We would like to thank Dr. Andrew Bray, at Mimotopes Pty.Ltd., for proof reading this manuscript.

References

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Received: December 11, 2001

Published on the web: April 7, 2003

Publication Dates

• Publication in this collection
  18 June 2003
• Date of issue
  May 2003

History

• Accepted
  07 Apr 2003
• Received
  11 Dec 2001