Journal of Chemical Crystallography
single-crystal X-ray structural analyses. Additionally, the
ꢀ
uorescence properties of both RGA and RGAA, and the
thermal behavior of RGAA, have been investigated.
Experimental
Materials and Measurements
Scheme 1 The structure of the Repaglinide
2
-(3-Ethoxy-4-(methoxycarbonyl)phenyl) acetic acid (RGA
)
, sodium hydrate, and ethyl acetate were purchased from
Shandong Solar Power Material Limited Corporation. The
reagents and solvents employed were used as received with-
out further puriꢂcation.
Elemental analyses were performed on an Elemen-
tar vario EL III microanalyser. The FT-IR spectrum was
−
1
Scheme 2 The structures of the RGA and RGAA
recorded from KBr pellets in the range 400–4000 cm on
a Bruker spectrometer. The UV–Vis spectrum for RGAA
1
was recorded on Shimadzu UV-2600 spectrometer. The H
NMR spectra were recorded using a Bruker Advances 400 at
Introduction
4
00 MHz for sample held at room temperature and dissolved
in DMSO-d . Thermogravimetric analysis (TGA) data were
Repaglinide, (S)-2-ethoxy-4-(2-((3-methyl-1-(2-
6
collected with a TA SDT Q600 analyzer in N at a heating
(
piperidin-1-yl)phenyl)butyl)amino)-2-oxoethyl) benzoic
2
−
1
rate of 10 °C min from room temperature to 800 °C. At
room temperature, solid-state ꢀuorescent studies were con-
ducted on a HITACHI F-4500 system.
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 signifi-
cantly better biological proꢂle [7–10]. The 2-(3-ethoxy-
Crystallization of 2‑(3‑Ethoxy‑4‑(methoxycarbonyl)phenyl)
Acetic Acid (RGA)
4
-(methoxycarbonyl)phenyl) acetic acid (RGA) is one of
The solution of RGA (1 mmol, 0.252 g) and water (10 mL)
was stirred at 80 °C for 10 min. The solution was ꢂltered
and allowed to stand. The needle crystals suitable for sin-
gle-crystal diꢁraction were obtained after 1 week. Yield
the key intermediates for the synthesis of Repaglinide. A
derivative of RGA, 4-(carboxymethyl)-2-ethoxybenzoic
acid (RGAA) can be often observed during the prepara-
tion of Repaglinide, which is a crucial impurity aꢁected
the purity and the efficacy of the drug. Hydrolysis of
RGA under basic condition easily leads to the formation
of RGAA as a impurity [11]. To date there is still little
information about the relationship between the solid-state
structures and the properties of these compounds although
the synthesis and development of the Repaglinide motif
has been reported [12–20]. Thus, researching the solid-
state structural information and other properties of the key
intermediate of Repaglinide and its derivative still remains
a big challenge.
(
0.227 g, 90%).
Synthesis of 4‑(Carboxymethyl)‑2‑ethoxybenzoic Acid
(RGAA)
To a mixture solution of distilled water (10 mL) and NaOH
25 mmoL, 1.0 g), 2-(3-ethoxy-4-(methoxycarbonyl)phe-
(
nyl) acetic acid (10 mmol, 2.38 g) was added. The reaction
mixture was reꢀuxed on a steam bath for 4 h. After cool-
ing to room temperature, the pH value of the solution was
adjusted to 1 by adding concentrated HCl solution. The solid
formed was collected and washed with water. Yield (86.6%,
Herein, we present the preparation of a pivotal
intermediate of Repaglinide namely, 2-(3-ethoxy-
1
.9391 g). The compound was recrystallized in distilled
4
-(methoxycarbonyl)phenyl) acetic acid (RGA), and a
water. The colorless crystals suitable for single-crystal dif-
derivative of this latter compound, 4-(carboxymethyl)-
fraction were obtained after several days. M.p. 138–140 °C.
2
-ethoxybenzoic acid (RGAA) (Scheme 2), which has
Elemental analysis calcd (%) for C H O (224.21): C,
been easily obtained through the hydrolysis of RGA under
basic conditions. Both RGA and RGAA have both been
11 12
5
1
5
8.9; H, 5.4; N, 35.7; found: C, 58.7; H, 5.3; N, 35.8. H-
1
NMR (400 MHz, DMSO-d ) δ: 12.441 (s, 2H), 7.550 (d,
characterized by FT-IR, UV–Vis, H-NMR, MS and by
6
J=8 Hz, 1H), 7.000 (s, 1H), 6.861 (d, J=8 Hz, 1H), 4.059
1
3