Preparation, Characterization and Crystal Structures of a Key Intermediate, and a Significant Impurity, in the Synthesis of Repaglinide

• Published in: Journal of chemical crystallography Vol. 50; no. 4; pp. 381 - 386
• Main Authors: Tang, Gui-Mei, Wang, Yong-Tao, Wu, Yu-Song
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2020; Springer Nature B.V
• Subjects: Acetic acid; Bonding strength; Chains; Chemistry; Chemistry and Materials Science; Crystal structure; Crystallography; Crystallography and Scattering Methods; Crystals; Dimers; Fluorescence; Hydrogen bonds; Impurities; Inorganic Chemistry; Ions; Luminescence; Monoclinic lattice; NMR; Nuclear magnetic resonance; Optical properties; Organometallic Chemistry; Original Paper; Physical Chemistry; Thermodynamic properties; Crystal structures; Intermediate; Thermal behavior; Photoluminescence; UV–Vis and NMR spectra; X-ray diffraction; Repaglinide; Infrared spectra
• ISSN: 1074-1542; 1572-8854
• DOI: 10.1007/s10870-019-00811-7

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 RGA under 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 RGAA has also been characterized by FT-IR and UV–Vis spectra, and by 1 H NMR analysis. RGA : monoclinic,  P 2 1 / 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) Å 3 . RGAA : monoclinic,  P 2 1 / 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) Å 3 . The thermal behaviors and fluorescence properties of RGAA were 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.