KISELEV et al.
618
polyhedron, which the other no. One of the oxygen
atoms of the COOH group “remote” from the aromatic
ring coordinates to two calcium atoms, while the other
oxygen, only to one calcium atoms. At the same time,
in the “proximate” COOH group, one oxygen atom
coordinates to one calcium atom, while the other coor-
dinates to calcium and forms hydrogen bond with the
NH group. The phenolic OH group forms hydrogen bond
with the nitrogen atom in the aromatic ring (Fig. 2).
(3 × 500 mL), and dried at 55°С and a vacuum of
40 mmHg for 12 h to obtain 129 g (70%) of the target
product, purity by HPLC 99.61%, main substance
content by titration 80% (water 21%).
Calcium N-(5-hydroxynicotinoyl)-L-glutamate
(17). A suspension of 109 g was prepared Powdered
CaO, 16.7 g (0.297 mol), was added in portions to a
suspension of 109 g (main substance content 83.93 g,
0.313 mol) of acid 1 in 800 mL of water in a 2-L
beaker at room temperature. The suspension was
stirred for 20 min, and solid materials was filtered off
(Schott filter no. 4). The filtrate was transferred to a
4-L flask and stirred at 75–80°С for 1 h, after which
2400 mL of ethanol was added, and stirring was
continued for an additional 30 min at 50–60°С. The
reaction mixture was cooled to room temperature for
30 min, and the precipitate was filtered off (Schott
filter no. 3), and washed with ethanol (2 × 200 mL),
dried at 60°С in a vacuum of 20 mmHg for 12 h to
obtain 77 g (80%) of the target product.
EXPERIMENTAL
Reaction progress and purity of compounds were
controlled by HPLC−MS on a Thermo Acella 600 LC
system coupled with an LCQ Fleet mass spectrometer;
column Luna C18(2), 4.6 × 250 mm, was operated in a
gradient mode (phase А: 0.1% TFA in water; phase B:
0.1% TFA in acetonitrile).
Diethyl N-(5-hydroxynicotinoyl)-L-glutamate
(15). A suspension of 81 g (0.583 mol) of acid 4 and
89.1 g (0.550 mol) of CDI 13 in 600 mL of toluene
was prepared in a 2-L flask equipped with a
mechanical stirrer and reflux condenser stopped with
CaCl2 drying tube. The suspension was heated to
60–65°С (bath temperature) and stiired at this
temperature for 30 min and, after bath temperature was
elevated to 80–85°С, a solution of 176 g (0.867 mol)
of diethyl L-glutamate 14 in 200 mL of toluene
was added in one portion. The reaction mixture was
stirred at 80–85°С for 1 h and then concentrated at
60°С in a vacuum of 20 mmHg to obtain 345 g of a
raw product.
Single-crystal X-ray diffraction data for
compound 17, C11H14CaN2O8 (M 342.32): ortho-
rhombic, space group P212121 (no. 19), a 5.1174(9) Å,
b 8.0140(13) Å, c 33.969(6) Å, V 1393.1(4) Å3, Z 4,
T 100, μ(MoKα) 0.495 mm–1, Dcalc 1.632 g/mm3, 13909
measured reflection (2.4 = 2θ = 64.06), of which 4820
unique reflections (Rint 0.0670) were used in all
computations. Final divergence factors: R1 0.0437
[I > 2σ(I)] R2 0.1086.
1Н NMR spectrum (D2O), δ, ppm: 2.05–2.20 m
(4H, glut Hb2), 2.34 m (2H, glut Hg2), 4.37 m (1H, glut
Ha), 7.68 s (1H, pyr H4), 8.25 s (1H, pyr H6), 8.43 s
(1H, pyr H2), 8.64 s (1H, glut HN). 13С NMR spectrum
(D2O), δ, ppm: 31 (glut C9), 36.7 (glut C7), 58.9 (glut
C10), 126 (pyr C4), 133.7 (pyr C3), 139.9 (pyr С2), 142
(pyr C6), 156.6 (pyr C5), 170 (pyr C3=O), 178.5 (glut
C8), 182.1 (glut C11).
N-(5-Hydroxynicotinoyl)-L-glutamic acid (1). A
solution of 233 g (5.83 mol) of NaOH in 930 mL of
water was added to 345 g of the raw diethyl ester 15 in
a 3-L one-neck flask, and the mixture was stirred at
room temperature for 2 h, after which 30 g of activated
carbon was added, and stirring was continued for an
additional 30 min and filtered on a Buchner funnel to
remove the activated carbon. The filtrate was made
acidic (pH 4) by adding 545 mL of conc. HCl and
stirred for 1 h. The precipitate was filtered off (Schott
filter no. 3), washed with water (3 × 600 mL),
suspended in 750 mL of water, acidified to pH 4 with
65 mL of conc. HCl, and immediately neutralized to
pH 8 with 90 mL of 40% NaOH. Activated carbon,
13 g, was then added, and the mixture was stirred for
30 min, the activated carbon was removed by filtration,
and the filtrate was acidified to pH 4 with conc. HCl.
The precipitate was filtered off, washed with water
CONFLICT OF INTEREST
The authors declare no conflict of interest.
REFERENCES
1. Kuznetsova, E.A., Voronina, T.A., Khromova, I.V., Gari-
boca, T.L., Tosina, E.K., Stolyarova, L.G., Troitskaya, V.S.,
and Smirnov, L.D., Pharm. Chem. J., 1989, vol. 23, 943.
2. Voronina, T.A., Gariboa, T.L., Khromova, I.V.,
Kuznetsova, E.A., and Smirnov, L.D., Pharm. Toksikol.,
1990, vol. 53, p. 13.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 5 2019