Synthesis of pyridine-containing derivatives of the alkaloids cytisine and d-pseudoephedrine

Article abstract of DOI:10.1007/s10600-010-9526-4

N-(5-Bromopyridyl-2)-2-N′-cytisino-and N′-d- pseudoephedrineoacetamides were synthesized by reaction of the alkaloids cytisine and d-pseudoephedrine with N-(5-bromopyridin-2-yl)-2-bromoacetamide hydrobromide. The compositions and structures of the product

Full text of DOI:10.1007/s10600-010-9526-4

Chemistry of Natural Compounds, Vol. 46, No. 1, 2010
SYNTHESIS OF PYRIDINE-CONTAINING DERIVATIVES
OF THE ALKALOIDS CYTISINE AND d-PSEUDOEPHEDRINE
I. V. Kulakov
UDC 547.94:547.822.5
N-(5-Bromopyridyl-2)-2-Nꢀ-cytisino- and Nꢀ-d-pseudoephedrineoacetamides were synthesized by reaction
of the alkaloids cytisine and d-pseudoephedrine with N-(5-bromopyridin-2-yl)-2-bromoacetamide
hydrobromide. The compositions and structures of the products were confirmed by IR and PMR spectroscopy
and mass spectrometry.
Keywords: alkaloids, cytisine, d-pseudoephedrine, 2-amino-5-bromopyridine, PMR spectroscopy.
The combination in a molecule of two and more pharmacophores is one of the principal approaches to the chemical
design of new biologically active compounds. Compounds with heterocyclic structural fragments, a special place among
which is occupied by pyridine derivatives, which comprise about 5% of all known drugs, are most numerous among all drugs.
Pyridine derivatives occur in essential vitamins (B and B ) and are widely used not only in medical practice as drugs with a
5
6
variety of therapeutic activity (antituberculosis, antibacterial, antihistamine, antidepressant, analgesic, nootropic, psychotropic,
and others) [1–3] but also in agriculture as effective fungicides, herbicides, and growth-stimulating compounds [4, 5]. More
effective and safer drugs based on pyridine are currently continuously sought in practically all areas of chemotherapy.
We chose 2-amino-5-bromopyridine as the starting synthon for preparing new derivatives of the alkaloids cytisine
and d-pseudoephedrine, which contain a pharmacologically active pyridine in their structures, and carried out the following
transformations.
First acylation of 2-amino-5-bromopyridine by bromoacetic acid bromide in anhydrous DMF with cooling to 5°C
produced N-(5-bromopyridin-2-yl)-2-bromoacetamide hydrobromide.
Br
Br
O
DMF
O
C
CH
C
Br
+
2
Br
5°C
N
N
H
CH Br
2
N
NH
2
.
HBr
1
Next, the resulting N-(5-bromopyridin-2-yl)-2-bromoacetamide hydrobromide (1) was used to alkylate the alkaloids
cytisine and d-pseudoephedrine with slight (to 60°C) heating of 1 hydrobromide and the alkaloids in anhydrous 1,4-dioxane in
the presence of a 3-fold excess of Et N according to the scheme:
3
15
Br
Br
O
14
O
C
1,4-dioxane, Et N
3
N
CH
C
2
16
N
N
H
CH Br
HN
N
+
2
HN
3 h, 60 °C
.
2, 3
HBr
1
13
5
7
N
OH
8
;
N
=
CH
CH
11
3
3
N
3
9
N
10
O
2
3
Institute of Organic Synthesis and Carbon Chemistry of the Republic of Kazakhstan, 100008, Karaganda, fax: (87212)
41 38 66, e-mail: kulakov_iv@mail.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 59–60, January–February,
2010. Original article submitted July 20, 2009.
©
66
0009-3130/10/4601-0066 2010 Springer Science+Business Media, Inc.

The excess of Et N was necessary for conversion of 1 hydrobromide into the base and then as an acceptor for the HBr
3
released during the reaction. The selection of 1,4-dioxane was based on its solubilizing ability for the starting hydrobromide
of 1. Also, the products were isolated from the dioxane solution as the bases.
–1
IR spectra of products 2 and 3 contained a strong absorption band for the amide carbonyl at 1695 and 1706 cm
(1650 for the amide N–C=O of cytisine) and the hydroxyl at 3300–3410.
PMR spectra of 2 and 3 showed resonances for protons of the alkaloid fragments in their characteristic regions.
Aromatic protons of the 5-bromopyridine ring for 2 and 3 were recorded at weak field of 6.55-8.08 ppm as two doublets and
a singlet. Methylene protons near the carbonyl group were inequivalent and appeared as a doublet of doublets at 3.15 and 3.48
with SSCC 15.9 and 16.7 Hz.
EXPERIMENTAL
PMR spectra were recorded in DMSO-d on a Bruker DRX500 spectrometer at 500 MHz relative to TMS internal
6
standard. IR spectra were taken in KBr disks on an Avatar-320 Fourier-transform spectrometer (Nicolet). Mass spectra were
obtained in a Finnigan Mat.Incos 50 instrument by direct sample introduction with ionizing energy 70 eV. Melting points were
determined on a Boetius apparatus. TLC was performed on Sorbfil plates with development by iodine vapor. 2-Amino-5-
bromopyridine and bromoacetic acid bromide (98%) were obtained commercially (Aldrich) and used without further purification.
Elemental analyses of the products agreed with those calculated.
N-(5-Bromopyridin-2-yl)-2-bromoacetamide Hydrobromide (1). A stirred cooled (5°C) solution of 2-amino-5-
bromopyridine (1.73 g, 0.01 mol) in DMF (5 mL) was treated dropwise with bromoacetic acid bromide (2.42 g, 0.012 mol)
and stirred for 2 h at room temperature. The resulting finely crystalline light-beige precipitate was cooled, filtered off, and
washed several times with cold benzene to afford 1 (2.99 g, 80%), mp 230–232°C (dec.), C H Br N O.
7
7
3 2
N-(5-Bromopyridin-2-yl)-2-Nꢀ-cytisinoacetamide (2). A stirred suspension of N-(5-bromopyridin-2-yl)-2-
bromoacetamide hydrobromide (1.50 g, 4 mmol) in anhydrous 1,4-dioxane (10 mL) was treated with Et N (1.21 g, 12 mmol)
3
and cytisine (0.76 g, 4 mmol) and heated for 3 h at 60–70°C. The resulting precipitate of Et N4HBr was filtered off and
3
washed with warm dioxane. Solvent was distilled from the combined mother liquor. The resulting oily residue was ground
with hexane. The resulting powder was recrystallized from benzene:hexane (1:1) to afford 2 (1.14 g, 71%) as a white crystalline
+
+
compound, mp 171–173°C, C H BrN O . Mass spectrum (EI, 70 eV, m/z, I , %): 402 (16) [M] , 404 (12) [M] , 230 (31),
18 19
4
2
rel
203 (53), 160 (16), 146 (15), 58 (98), 42 (29).
PMR spectrum (500 MHz, DMSO-d , ꢁ, ppm, J/Hz): 1.72, 1.82 (2H, dd, J = 12.8, J = 12.9, H-8), 2.42 (1H, br.s,
6
8,7
8,9
H-9), 2.60 (2H, m, H-11), 2.84 (1H, br.d, J = 10.6, H-7), 3.00 (2H, m, H-13), 3.10, 3.19 (2H, dd, J = 15.9, N–CH ), 3.75 (1H,
a,b
2
dd, J
= 6.6, H-10a), 3.87 (1H, d, J
= 15.3, H-10e), 6.06 (1H, d, J = 6.8, H-5), 6.26 (1H, d, J = 9.0, H-3), 7.29
10a,9
10e,10a 5,4 3,4
(1H, dd, J = 6.8, 9.0, H-4), 7.96 (2H, d, J
= 8.9, H-14, H-15), 8.34 (1H, s, H-16), 9.65 (1H, s, N–H).
14,15
N-(5-Bromopyridin-2-yl)-2-Nꢀ-d-pseudoephedrinoacetamide (3) was synthesized analogously to 2 from N-(5-
bromopyridin-2-yl)-2-bromoacetamide hydrobromide (0.94 g, 2.5 mmol), d-pseudoephedrine (0.41 g, 2.5 mmol), and Et N
3
(0.76 g, 7.5 mmol). The oily residue that was obtained after removing solvent was ground with ice. The resulting powder was
filtered off to afford 3 (0.62 g, 66%) as white needle-like crystals, mp 68–70°C (30% EtOH), C H BrN O . Mass spectrum
17 20
3 2
(EI, 70 eV, m/z, I , %): 272 (9), 270 (9), 174 (15), 172 (15), 79 (15), 77 (25), 71 (100), 70 (22), 56 (45), 42 (47).
rel
PMR spectrum (500 MHz, DMSO-d , ꢁ, ppm, J/Hz): 0.67 (3H, d, J = 6.7, CH –CH), 2.33 (3H, s, N–CH ), 2.78 (1H,
6
3
3
m, CHN), 3.17, 3.48 (2H, dd, J = 16.7, N–CH ), 4.39 (1H, dd, J = 9.0, CH(OH)), 5.49 (1H, d, J = 3.2, OH), 7.28 (5H, m,
a,b
2
H
), 8.03 (1H, d, J
= 8.9, H-15), 8.12 (1H, d, J
= 8.9, H-14), 8.44 (1H, s, H-16), 10.53 (1H, s, N–H).
arom
15,14
14,15
REFERENCES
1.
A. T. Soldatenkov, N. M. Kolyadina, and I. V. Shendrik, Principles of the Organic Chemistry of Drugs [in Russian],
Khimiya, Moscow, 2001.
2.
3.
4.
5.
M. D. Mashkovskii, Drugs of the XXth Century [in Russian], OOO Izd. Novaya Volna, Moscow, 1998.
M. D. Mashkovskii, Drugs [in Russian], OOO RIA Novaya Volna, 15th Ed., Moscow, 2007.
N. N. Melꢀnikov, Pesticides. Chemistry, Technology and Application [in Russian], Khimiya, Moscow, 1987.
M. V. Shimanskaya and L. Ya. Leitis, Khim. Geterotsikl. Soedin., 5, 579 (1989).
67