Intensified Microwave-Assisted N-Acylation Procedure – Synthesis and Activity Evaluation of TRPC3 Channel Agonists with a 1,3-Dihydro-2H-benzo[d]imidazol-2-one Core

 

 Permissions and Reprints All articles of this category

Abstract

Upon controlled microwave heating and using cyanuric chloride as a coupling reagent, an efficient amidation procedure for the synthesis of 1,3-dihydro-2H-benzo[d]imidazol-2-one-based agonists of TRPC3/6 ion channels has been developed. Compared to the few conventional protocols, a drastic reduction in processing time from ca. 2 days down to 10 minutes was achieved accompanied by significantly improved product yields. The robustness of the method was confirmed by 18 additional examples including aromatic, aliphatic, and heterocyclic amines and acids. The obtained agonists were screened for biological activity at 1 μM concentration and few structure–activity relations have been established.

• References and Notes

• 1a Lichtenegger M In Mammalian Transient Receptor Potential (TRP) Cation Channels . Vol. 1; Nilius B, Flockerzi V. Springer; Berlin/Heidelberg: 2014: 67-84
  CrossrefGoogle Scholar
• 1b Dietrich A In Mammalian Transient Receptor Potential (TRP) Cation Channels . Vol. 1; Nilius B, Flockerzi V. Springer; Berlin/Heidelberg: 2014: 157-188
  CrossrefGoogle Scholar
• 1c Pathologies of Calcium Channels . Weiss N, Koschak A. Springer; Berlin/Heidelberg: 2014
  CrossrefGoogle Scholar
• 2a Harteneck C, Gollasch M. Curr. Pharm. Biotechnol. 2011; 12: 35
  CrossrefPubMed
• 2b Bon RS, Beech DJ. Br. J. Pharmacol. 2013; 170: 459
  CrossrefPubMed
• 2c Gautier M, Dhennin-Duthille I, Ay AS, Rybarczyk P, Korichneva I, Ouadid-Ahidouch H. Br. J. Pharmacol. 2014; 171: 2582
  CrossrefPubMed
• 3 Xu X, Lozinskaya I, Costell M, Lin Z, Ball JA, Bernard R, Behm DJ, Marion JP, Schnackenberg CG. Biophys. J. 2013; 104: 454a; Suppl. 1
• 4 Doleschal B, Primessnig U, Wölkart G, Wolf S, Schernthaner M, Lichtenegger M, Glasnov T, Kappe CO, Mayer B, Antoons G, Heinzel F, Poteser M, Groschner K. Cardiovasc. Res. 2015; 106: 163
  CrossrefPubMed
• 5a Colombo M, Bossolo S, Aramini A. J. Comb. Chem. 2009; 11: 335
  CrossrefPubMed
• 5b Glasnov TN, Groschner K, Kappe CO. ChemMedChem 2009; 4: 1816
  CrossrefPubMed
• 6 Rad MN. S, Behrouz S, Arari Z, Khalafi-Nezhad A. Monatsh. Chem. 2014; 145: 1933
  Crossref

Selected references:
• 7a Rayle HL, Fellmeth L. Org. Process Res. Dev. 1999; 3: 172
  Crossref
• 7b Montalbetti CA. G. N, Falque V. Tetrahedron 2005; 61: 10827
  Crossref
• 7c Blotny G. Tetrahedron 2006; 62: 9507
  Crossref
• 7d Bergman K, Elvingson C, Hilborn J, Svensk G, Bowden T. Biomacromolecules 2007; 8: 2190
  CrossrefPubMed
• 7e Chen C.-Y, Frey LF, Shultz S, Wallace DJ, Marcantonio K, Payack JF, Vazquez E, Springfield SA, Zhou G, Liu P, Kieczykowski GR, Chen AM, Phenix BD, Singh U, Strine J, Izzo B, Krska SW. Org. Process Res. Dev. 2007; 11: 616
  Crossref
• 7f Prasad KV. S. R. G, Bharthi K, Haseena BB. Int. J. Pharm. Sci. Rev. Res. 2011; 8: 108
• 7g El-Faham A, Albericio F. Chem. Rev. 2011; 111: 6557
  CrossrefPubMed
• 7h Duangkamol C, Jaita S, Wangnagae S, Phakhodee W, Pattarawarapan M. RSC Adv. 2015; 5: 52624
  Crossref
• 7i Dunetz JR, Magano J, Weisenburger GA. Org. Process Res. Dev. 2016; 20: 140
  Crossref

Selected references:
• 8a Alterman M, Andersson HO, Garg N, Ahlsén G, Lövgren SB, Classon B, Danielson UH, Kvarnström I, Vrang L, Unge T, Samuelsson BA, Hallberg A. J. Med. Chem. 1999; 42: 3835
  CrossrefPubMed
• 8b Varma RS. Green. Chem. 1999; 1: 43
  Crossref
• 8c Nöteberg D, Schaal W, Hamelink E, Vrang L, Larhed M. J. Comb. Chem. 2003; 5: 456
  CrossrefPubMed
• 8d Microwaves in Organic Synthesis . 3rd ed., Vol. 1; de la Hoz A, Loupy A. Wiley-VCH; Weinheim: 2012
  CrossrefGoogle Scholar
• 8e Microwaves in Organic Synthesis . 3rd ed., Vol. 2; de la Hoz A, Loupy A. Wiley-VCH; Weinheim: 2012
  CrossrefGoogle Scholar
• 9 Schnyder A, Beller M, Mehltretter G, Nsenda T, Studer M, Indolese AF. J. Org. Chem. 2001; 66: 4311
  CrossrefPubMed
• 10 General Experimental Procedure for Microwave-Assisted TCT-Acylation To a stirred mixture of a corresponding acid (0.819 mmol, 1 equiv), cyanuric chloride (90.5 mg, 0.491 mmol, 0.6 equiv), dry pyridine (99.1 mg, 1.23 mmol, 1.5 equiv), and dry MeCN (4.5 mL) in a 5 mL Pyrex microwave vial, equipped with a magnetic stir bar, the corresponding amine (0.983 mmol, 1.2 equiv) was added after initial stirring at r.t. for 5 min. The reaction mixture was then crimped with a Teflon septum, stirred for 10 s, and subjected to microwave heating for 5 min (fixed hold time) at 140 °C and subsequently cooled down to 40 °C. The resulting reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography (with CHCl₃ or a gradient of 0–10% MeOH in CHCl₃) to afford amides 1a–g. For pharmacological experiments, analytical-grade samples of compounds 1a–g were additionally purified by the means of a semipreparative HPLC (see the provided Supporting Information). 1-(1-Octanoylpiperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (1a) Transparent oil; yield 177 mg (63%). ¹H NMR (300 MHz, CDCl₃): δ = 10.05 (br s, 1 H), 7.15–7.04 (m, 4 H), 4.90 (d, J = 13.1 Hz, 1 H), 4.60–4.52 (m, 1 H), 4.07 (d, J = 13.1 Hz, 1 H), 3.20 (t, J = 12.9 Hz, 1 H), 2.68 (t, J = 13.5 Hz, 1 H), 2.43–2.26 (m, 4 H), 1.93–1.88 (m, 2 H), 1.73–1.64 (m, 2 H), 1.40–1.25 (m, 8 H), 0.88 (t, J = 6.8 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 171.9, 155.1, 129.0, 128.2, 121.6, 121.3, 110.1, 109.4, 50.9, 45.4, 41.5, 33.6, 31.9, 29.6, 29.3, 25.6, 22.8, 14.2. HRMS (APCI): m/z calcd for C₂₀H₃₀N₃O₂ [M + H]⁺: 344.2332; found: 344.2334.

• Supplementary Material