Synthesis of α-chloropyridine derivatives of γ-aminobutyric acid

Article abstract of DOI:10.1007/s10600-011-0057-4

The sodium salt of N-(6-chloronicotinoyl)-γ-aminobutyric acid, a structural analog of the known nootropic and vasidilating drug picamilon, was synthesized via Schotten-Baumann acylation of γ-aminobutyric acid with 6-chloronicotinoyl chloride and subsequent neutralization of the N-(6-chloronicotinoyl)-γ-aminobutyric acid that was obtained in >60% yield.

Full text of DOI:10.1007/s10600-011-0057-4

Chemistry of Natural Compounds, Vol. 47, No. 5, November, 2011 [Russian original No. 5, September-October, 2011]
SYNTHESIS OF ꢀ-CHLOROPYRIDINE DERIVATIVES
OF ꢁ-AMINOBUTYRIC ACID
*
N. V. Kovganko, S. N. Sokolov, and Yu. G. Chernov
UDC 547.466.3
The sodium salt of N-(6-chloronicotinoyl)-ꢁ-aminobutyric acid, a structural analog of the known nootropic
and vasidilating drug picamilon, was synthesized via Schotten–Baumann acylation of ꢁ-aminobutyric acid
with 6-chloronicotinoyl chloride and subsequent neutralization of the N-(6-chloronicotinoyl)- ꢁ-aminobutyric
acid that was obtained in >60% yield.
Keywords: ꢁ-aminobutyric acid, picamilon, analogs, synthesis.
ꢁ-Aminobutyric acid (1) is a natural compound that is well known as a nervous system mediator. The unique
physiological properties of 1 and several of its derivatives enable them to be used in medicine as nootropic drugs [1]. Our
attention was drawn to drugs that were derivatives of ꢁ-aminobutyric acid such as picamilon, the chemical structure of which
is the sodium salt of N-nicotinoyl-ꢁ-aminobutyric acid. Because the structure of picamilon includes portions of ꢁ-aminobutyric
acid and nicotinic acid, this drug in a pharmacological sense combines the properties of these two natural bioregulators.
We synthesized a close structural analog of picamilon. Its molecule includes ꢁ-aminobutyric acid and a portion of not
nicotinic but 6-chloronicotinic acid. We assumed that such substitution could produce compounds with unique biological
activity profiles because the chloropyridine moiety is largely responsible for the occurrence of biological activity in neonicotinoid
compounds, in particular, the natural analgesic epibatidine [2] and the insecticide imidacloprid, which is widely used in
O
agriculture [3, 4].
ONa
N
H
O
O
O
Cl
N
4
OH
O
NaOH
SOCl
Cl
N
H
NaOH
O
O
H N
2
+
O
OH
Cl
N
Cl
N
N
2
1
2
3
Cl
N
5
According to our plan, Schcotten–Baumann acylation of 1 by 6-chloronicotinoylchloride (2) in the presence of NaOH
synthesized in >60% yield N-(6-chloronicotinoyl)- ꢁ-aminobutyric acid (3). The structure of 3 was proved using spectral data.
Subsequent neutralization of 3 by methanolic NaOH produced in quantitative yield the sodium salt 4.
Compound 3 could also be used as a convenient intermediate in the synthesis of other ꢀ-chloropyridine-containing
derivatives of ꢁ-aminobutyric acid. Thus, reaction of 3 with thionylchloride in dioxane synthesized in about 85% yield
pyrrolidone 5, the formation of which was due to facile intramolecular cyclization to a five-membered ꢁ-lactam ring of the acid
chloride that was initially produced by the action of thionylchloride on 3.
EXPERIMENTAL
–1
IR spectra were recorded on a Bomem-Michelson 100 FTIR spectrometer in the range 700–3600 cm . PMR and
C NMR spectra were taken on a Bruker Avance 500 NMR spectrometer (operating frequency 500.13 MHz for H and
13
1
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, 220141, Belarus, Minsk, Ul. Akad.
Kuprevicha, 5/2, e-mail: kovganko@iboch.bas-net.by. Translated from Khimiya Prirodnykh Soedinenii, No. 5, September–
October, 2011, pp. 686–687. Original article submitted February 24, 2011.
©
0009-3130/11/4705-0781 2011 Springer Science+Business Media, Inc.
781

13
125.75 MHz for C). Chemical shifts are given relative to TMS as an internal standard. Mass spectra were measured on an
Accela HPLC system with an LCQ-Fleet mass detector (three-dimensional ion trap) using chemical ionization at atmospheric
pressure (APCI) (detection of positive and negative ions). The reactive gas was N . The m/z values are given for the strongest
2
peaks. The course of reactions and purity of products were monitored using Kieselgel 60F plates (Merck). Melting points
254
were determined on a Kofler block.
N-(6-Chloronicotinoyl)-ꢁ-aminobutyric Acid (3). A solution of 1 (2.89 g, 0.028 mol) in aqueous NaOH (10%,
12.3 mL, 0.034 mol) and H O (20 mL) was cooled in a salted ice-bath to –7–(–5)°Ñ, stirred, and treated simultaneously with
2
solutions of aqueous NaOH (10%, 12.3 mL, 0.034 mol) and 6-chloronicotinoylchloride (2, 5.00 g, 0.028 mol) (prepared by the
literature method [5]) in THF (9 mL). The solutions of NaOH and 6-chloronicotinoylchloride were added simultaneously in
equal portions of 2 mL at 5–7 min intervals, keeping the temperature of the reaction mixture at –7–(–5)°C. When the addition
of the solutions was finished, the reaction mixture was stirred for another 30 min, treated dropwise with HCl solution (23 mL,
2N) until the pH was ~1–2, and stirred at –7–(–5)°C for another hour. The resulting precipitate was filtered off, washed with
cold water (3 ꢂ 15 mL), and dried in air to afford crude N-(6-chloronicotinoyl)- ꢁ-aminobutyric acid (3, 4.92 g). The aqueous
filtrate was extracted with dichloroethane (5 ꢂ 20 mL). The combined organic extract was dried over MgSO . The desiccant
4
was removed. The dichloroethane was evaporated in vacuo to produce another portion of crude 3 (0.82 g). The combined
portions of the product were recrystallized from EtOAc to afford 3 (4.2 g). Yield 61%, mp 133–134°C. IR spectrum (KBr, ꢃ,
–1
+
cm ): 3317 (NH), 1706 (COOH), 1642 (CO–NH). Mass spectrum (m/z): 243, 245 [M + H] .
PMR spectrum (DMSO-d , ꢄꢅ, ppm, J/Hz): 1.76 (2H, q, J = 7, H-3), 2.30 (2H, t, J = 7, H-2), 3.30 (2H, dt, J = 7,
6
1
J = 5.5, H-4), 7.65 (1H, d, J = 8, H-5 ), 8.23 (1H, dd, J = 8, J = 2.5, H-4 ), 8.75 (1H, t, J = 5.5, CO–NH), 8.82 (1H,
2
Py
1
2
Py
d, J = 2.5, H-2 ), 12.12 (1H, br.s, COOH).
Py
13
C NMR spectrum (DMSO-d , ꢅ, ppm): 24.3 (C-3), 31.0 (C-2), 38.7 (C-4), 124.0 (C-5 ), 129.4 (C-3 ), 138.5
6
Py
Py
(C-4 ), 148.8 (C-2 ), 152.3 (C-6 ), 163.7 (Py–CO–NH), 174.1 (C-1).
Py
Py
Py
N-(6-Chloronicotinoyl)-ꢁ-aminobutyric Acid, Sodium Salt (4). A solution of NaOH (0.082 g, 2.06 mmol) in
anhydrous MeOH (5 mL) was treated in several portions with 3 (0.5 g, 2.06 mmol). The MeOH was evaporated in vacuo. The
solid was dried in vacuo (0.5 mm Hg) to constant mass to afford 4 (0.54 g, 99%), double mp 220–222 and 228–229°C
(MeOH).
PMR spectrum (DMSO-d , ꢅ, ppm, J/Hz): 1.72 (2H, q, J = 6.5,H-3), 2.12 (2H, t, J = 6.5, H-2), 3.26 (2H, dt, J = 6.5,
6
1
J = 4.0, H-4), 7.61 (1H, d, J = 8, H-5 ), 8.28 (1H, dd, J = 8, J = 2.5, H-4 ), 8.85 (1H, d, J = 2.5, H-2 ), 10.00 (1H, br.s,
2
Py
1
2
Py
Py
CO–NH).
13
C NMR spectrum (DMSO-d , ꢅ, ppm): 24.7 (C-3), 35.7 (C-2), 40.6 (C-4), 123.9 (C-5 ), 129.5 (C-3 ), 138.3
6
Py
Py
(C-4 ), 148.9 (C-2 ), 152.1 (C-6 ), 163.0 (Py–CO–NH), 176.7 (C-1).
Py
Py
Py
–
Mass spectrum (m/z): 241, 243 [M – Na] .
1-(6-Chloronicotinoyl)pyrrolidone-2 (5). A suspension of 3 (0.5 g, 2.06 mmol) in dichloroethane (1 mL) was
treated with thionylchloride (0.17 mL, 2.27 mmol), heated for 5 h at 50–55°C, evaporated in vacuo, and co-evaporated with
dichloroethane (2 ꢂ 3 mL). The solid was crystallized from petroleum ether:EtOAc (3:1, 4 mL) to afford 5 (0.39 g, 1.74 mmol,
–1
85%), mp 106–108°C (petroleum ether:EtOAc, 80–90°C). IR spectrum (KBr, ꢃ, cm ): 1747 (CO–N), 1673 (Py–CO). Mass
+
spectrum (m/z): 225, 227 [M] , C H ClN O .
10
9
2 2
PMR spectrum (DMSO-d , ꢅ, ppm, J/Hz): 2.05 (2H, q, J = 8, H-4), 2.55 (2H, t, J = 8, H-3), 3.83 (2H, t, J = 8, H-5),
6
7.61 (1H, d, J = 8, H-5 ), 8.00 (1H, dd, J = 8, J = 2.5, H-4 ), 8.56 (1H, d, J = 2.5, H-2 ).
Py
1
2
Py
Py
13
C NMR spectrum (DMSO-d , ꢅ, ppm): 16.9 (C-4), 32.6 (C-3), 45.8 (C-5), 123.4 (C-5 ), 130.3 (C-3 ), 139.5
6
Py
Py
(C-4 ), 149.4 (C-2 ), 152.0 (C-6 ), 166.6 (Py–CO–N), 175.1 (C-2).
Py
Py
Py
REFERENCES
1.
2.
M. D. Mashkovskii, Drugs [in Russian], Vol. 1, Novaya Volna, Moscow, 2002, pp. 110–117.
T. F. Spande, H. M. Garraffo, M. W. Edwards, H. J. C. Yeh, L. Panel, and J. W. Daly, J. Am. Chem. Soc., 114,
3475 (1992).
3.
4.
5.
N. V. Kovganko and Zh. N. Kashkan, Zh. Org. Khim., 40, No. 12, 1759 (2004).
P. Jeschke and R. Nauen, Pest Manage. Sci., 64, No. 11, 1084 (2008).
N. V. Kovganko, Yu. G. Chernov, S. N. Sokolov, Zh. N. Kashkan, and V. L. Survilo, Khim. Prir. Soedin.,
175 (2009).
782