Preparation, Characterization and Crystal Structures of a Key Intermediate, and a Significant Impurity, in the Synthesis
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ORIGINAL PAPER
Preparation, Characterization and Crystal Structures of a Key Intermediate, and a Significant Impurity, in the Synthesis of Repaglinide Gui‑Mei Tang1 · Yong‑Tao Wang1 · Yu‑Song Wu1 Received: 21 September 2019 / Accepted: 31 October 2019 © Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract The crystal structure of 2-(3-ethoxy-4-(methoxycarbonyl)phenyl) acetic acid (RGA), an important intermediate in the preparation of Repaglinide, has been carried out. Hydrogen bonds between the carboxylate groups link the molecules into dimers while weak C–H···π interactions link these dimers into a one-dimensional chain lying along the crystallographic b axis. 4-(Carboxymethyl)-2-ethoxybenzoic acid (RGAA), an impurity observed in the preparation of Repaglinide, has been simply synthesized by the hydrolysis of RGAunder basic conditions. Hydrogen bonds between the carboxylate groups link the molecules into dimers while weak C–H···O interactions connect these dimers into a one-dimensional chain lying along the crystallographic c axis. The compound RGAAhas also been characterized by FT-IR and UV–Vis spectra, and by 1H NMR analysis. RGA: monoclinic, P21/n, a = 12.848(3) Å, b = 4.5539(10) Å, c = 22.328(5) Å, α = 90°, β = 101.703(5)°, γ = 90°, V = 1279.2(5) Å3. RGAA: monoclinic, P21/n, a = 14.0877(11) Å, b = 5.1814(3) Å, c = 14.5857(11) Å, α = 90°, β = 91.578(3)°, γ = 90°, V = 1064.26(13) Å3. The thermal behaviors and fluorescence properties of RGAAwere also investigated. Graphic Abstract The crystal structures of one key intermediate of Repaglinide and its derivative have been characterized, where their luminescence properties and thermal behavior have been investigated.
Keywords Repaglinide · Intermediate · Infrared spectra · UV–Vis and NMR spectra · X-ray diffraction · Crystal structures · Thermal behavior · Photoluminescence Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10870-019-00811-7) contains supplementary material, which is available to authorized users. Extended author information available on the last page of the article
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Journal of Chemical Crystallography
single-crystal X-ray structural analyses. Additionally, the fluorescence properties of both RGAand RGAA, and the thermal behavior of RGAA, have been investigated.
Experimental Scheme 1 The structure of the Repaglinide
Scheme 2 The structures of the RGAand RGAA
Introduction Repaglinide, (S)-2-ethoxy-4-(2-((3-methyl-1-(2(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethyl) benzoic acid (Scheme 1), is a new class of oral hypoglycemic agent for type-II non-insulindependent diabetes, which stimulates the secretion of insulin from pancreatic beta cells, acting via calcium channels [1–6]. Compared with other antidiabetic agents, Repaglinide gives a significantly better biological profile [7–10]. The 2-(3-ethoxy4-(methoxycarbonyl)phenyl) acetic acid (RGA) is one of the key intermediates for the synthesis of Repaglinide. A derivative of RGA, 4
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