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Synlett
DOI: 10.1055/s-0043-1773516
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A Practical and Highly Efficient Procedure for the Synthesis of the Trifluoromethylpyrazol-Derived Canonical Transient Receptor ­Potential Channel (TRPC3) Inhibitor Pyr3 and Its Derivatives

Zhongzhi Wu∗
,
Wei Li  ∗
This work was supported by funds from the College of Pharmacy, Health Science Center, University of Tennessee. Additional partial support is from National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS, grant R41NS135658) to W.L. The contents of the article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH/NINDS.
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Abstract

Canonical transient receptor potential (TRPC) channels play a variety of diverse biological functions. Among the subgroups of the TRPC family (TRPC3, TRPC6, and TRPC7), TRPC3 has been implicated in several diseases, including neurological and cardiovascular diseases, cancer, and neurodegeneration. A pyrazole-based compound Pyr3 is a selective TRPC3 channel inhibitor which is now a standard tool compound to study conditions associated with TRPC3 dysregulation. However, the reported literature syntheses of Pyr3 either provided low yield or involved microwave reactions and harsh reaction conditions. We have developed a practical and highly efficient procedure for the synthesis of Pyr3 and its derivatives in high yields which is suitable for scale-up synthesis.

Key words

TRPC3 - ion channel inhibitor - Pyr3 - pyrazole synthesis - acylation

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1773517.
  • Supporting Information


Publication History

Received: 18 December 2024

Accepted after revision: 06 January 2025

Article published online:
29 January 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
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  • References and Notes

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  • 15 Synthesis of Compound N-Ethyl-1-[4-(2,3,3-trichloroacrylamido)phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (4) According to the similar procedure described for the synthesis of Pyr3 in ref. 12, 2,3,3-trichloroacryloyl chloride (0.50 g, 2.56 mmol) was added to the THF (20 mL) solution of intermediate 1-(4-aminophenyl)-N-ethyl-5-(trifluoroethyl)-1H-pyrazole-4-carboxamide (0.75 g, 2.51 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure, and the residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH = 9:1 v/v) to afford the desired product as a white solid (0.95 g, 82%). 1H NMR (400 MHz, DMSO-d 6): δ = 11.33 (s, 1 H), 8.56 (t, J = 5.2 Hz, 1 H), 8.10 (s, 1 H), 7.81 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.3 Hz, 2 H), 3.31–3.18 (m, 2 H), 1.11 (t, J = 7.1 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6): δ = 160.4, 159.3, 139.9, 139.3, 135.4, 130.0, 129.6, 127.4, 124.6, 123.8, 122.9, 122.0, 121.2, 120.5, 118.5, 34.3, 15.0. HRMS (ESI): m/z calcd for C16H13Cl3F3N4O2: 455.0051 [M + H]+; found: 455.0107. See the Supporting Information for complete synthetic procedures and spectral characterization.
  • 16 Byproduct 5 According to the literature reported procedures,8 intermediate1-(4-aminophenyl)-N-ethyl-5-(trifluoroethyl)-1H-pyrazole-4-carboxamide (0.57 g, 1.91 mmol) was dissolved in anhydrous THF under nitrogen. 2,3,3-Trichloroacrylic acid (0.34 g, 1.91 mmol), PyBOP (1.09 g, 2.10 mmol), and triethylamine (0.58 g, 5.73 mmol) were added to the above THF solution at room temperature. The resulting reaction mixture was stirred at room temperature for 5 h. Then, the solvent was removed under reduced pressure. The crude residue was subjected to flash column chromatography (silica gel, CH2Cl2/MeOH = 9:1 v/v) to give a brown solid product 5, 0.23 g, 32% yield. HNMR (400 MHz, DMSO-d 6: δ = 10.63 (s, 1 H), 8.55(t, J = 5.2 Hz, 1 H), 8.08 (s, 1 H), 7.77 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 4.31 (s, 2 H), 3.28–3.21 (m, 2 H), 1.10 (t, J = 7.2 Hz, 2 H). HRMS (ESI): m/z calcd for C15H15ClF3N4O2: 375.0836 [M + H]+; found: 375.0846.