Quaternary salts of alkaloids

Article abstract of DOI:10.1007/s10600-006-0183-6

New biologically active quaternary salts of the alkaloids ajmaline, quinine, hyoscyamine, codeine, and strychnine were synthesized. So-called separable conformers were observed among the ajmaline derivatives.

Full text of DOI:10.1007/s10600-006-0183-6

Chemistry of Natural Compounds, Vol. 42, No. 4, 2006
QUATERNARY SALTS OF ALKALOIDS
I. F. Makarevich and Yu. I. Gubin
UDC 543.51+547.944/945
New biologically active quaternary salts of the alkaloids ajmaline, quinine, hyoscyamine, codeine, and
strychnine were synthesized. So-called separable conformerswere observed among the ajmaline derivatives.
Key words:
alkaloids, ajmaline, hyoscyamine, quinine, codeine, strychnine, N-quaternarysalts, separableconformers,
antiarrhythmic activity.
We reported previously [1] on the preparation of several quaternary salts of the alkaloid ajmaline. The present article
contains both information from the previous study [1] and new results on the preparation of biologically active derivatives of
ajmaline and other alkaloids.
Quaternary salts of ajmaline were first prepared by Keck [2]. It was also found that conversion of ajmaline to certain
quaternary salts increases significantly its antiarrhythmic activity. Thus, N(b)-propylajmaline bromide was 8-10 times more
active than ajmaline and was proposed by us as a medicinal preparation called "propajmaline."
1 36
Compounds - (Table 1) were synthesized in one step bydirect reaction of the appropriate alkaloid and alkyl halide.
The reaction occurred selectively at the N(b)-atom for ajmaline.
R
_
−
OH
OH
X
+
X
N
−
O
C
HC
X
H
C
+
+
R
R
N CH
3
O
N
OH
H CO
3
N
CH=CH
2
H
HOH C
2
CH
C H
3
2
5
N
28 - 32
H
1 - 23
24 - 27
R
where:
O
+
H CO
3
−
N
X
H C
2
O
O
CH
11: R = CH
C O CH
3
3
2
N
N
O
+
−
R
X
O
23: R =
CH CH CH
2
O
2
35, 36
O
33, 34
Low-molecular-weight alkyl halides react with alkaloids at room temperature whereas bulky reagents require heating
and in some instances for a rather long time. All quinine derivatives were prepared with heating.
Wesynthesizedpreviouslyalkaloidcardenolides[3-10] that had cardiotonic and antiarrhythmic activitywith relatively
low toxicity. The synthesis was based on quaternary salts of the alkaloids. However, these syntheses were carried out in two
steps. The first was preparation of the cardenolide halide derivatives; the second, reaction of the alkaloids with the cardenolide
halides. The course of the reactions was monitored using paper chromatography and MEK:m-xylene (1:1)/formamide and
n-butanol:toluene (1:2)/water.
During the investigations of N(b)-alkyl ajmaline derivatives, so-called separable conformers were observed. This is
a rather rare observation in stereochemistry. This happens mainly in compounds with a long alkyl chain. The occurrence of
separable conformers is due to hindered rotation around the N–C bond of the alkyl chain.
1
National Pharmaceutical University, Ukraine, 61002, Khar′kov, ul. Pushkinskaya,53, e-mail:x123@ua.fm. Translated
from Khimiya Prirodnykh Soedinenii, No. 4, pp. 381-383, July-August, 2006. Original article submitted September 12, 2005.
0009-3130/06/4204-0473 ©2006 Springer Science+Business Media, Inc.
473

TABLE 1. Physicochemical Properties of 1-36
Compound
R
X
Formula
mp, °C
[α]D in MeOH
N(b)-Alkylated ajmaline
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH3(CH2)10-
Br
Br
J
Br
Br
Br
J
C31H49N2O2Br
C34H55N2O2Br
C27H41N2O2J
C23H30N3O2Br
C26H37N2O3Br
C29H45N2O2Br
C28H43N2O2J
C26H39N2O2Br
C26H37N2O2J
C23H32N2O2Br2
C27H33N2O5Br
C24H34N2O2Br2
C27H33N2O2Br
C30H47N2O2Br
C22H31N2O2Br
C23H33N2O2Br
C24H35N2O2Br
C23H31N2O2Br
C24H35N2O2J
C21H29N2O2J
C22H30N2O2Br2
C22H31N2O2J
C23H31N2O3Br
222-224
Amorf.
+111±2°
+92±2°
+123±2°
+148±2°
+98±2°
+105±2°
+85.5±2°
+123±2°
+99±2°
+121±2°
+103±3°
+110±3°
+100±2°
+89±2°
+115±2°
+112±3°
+124±2°
+117±2°
+99.5±2°
+119.2±2°
+118±2°
+113.6±3°
+97.7±2°
CH3(CH2)13-
CH3(CH2)6-
N C-CH2-CH2-
see the formula
CH3(CH2)8-
CH3(CH2)7-
CH3(CH2)5-
(CH3)2C=CH-CH2-CH2-
Br-CH2-(CH2)2-
see the formula
Br-CH2-(CH2)3-
Bz
212-215
257-260
266-268
230-233
215-218
264-267
235-238
360
172-175
261-263
187-189
215-217
272-275
311-314
283-286
268-272
Br
J
Br
Br
Br
Br
Br
Br
Br
Br
Br
J
CH3(CH2)9-
CH3CH2-
CH3(CH2)2-
CH3(CH2)3-
CH2=CH-CH2-
CH3(CH2)3-
CH3-
Br(CH2)2-
CH3CH2-
see the formula
J
Br
J
238-240/257-260
247-249/265-268
200-203
Br
N(b)-Alkylated quinine
24
25
26
27
CH3-
J
C21H27N2O2J
C25H29N2O2Br
C24H32N2O2Br2
C24H33N2O2J
182-185/215-220
155-158
193-196/215-217
144-147
-128.8±2°
-113.6±3°
-69.8±2°
-55.7±3°
CH3-CH2-
Br-CH2-(CH2)3-
CH3-(CH2)3-
Br
Br
J
N-Alkylated hyoscyamine
28
29
30
31
32
CH3-
J
C18H26NO3J
C21H31NO3Br2
C21H32NO3Br
C19H28NO3Br
C24H32NO3J
128-130/151-153
248-252/285-290
105-109
204-206/210-211
128-130/151-153
-12.7±2°
-8.7±2°
-9.4±2°
-10.2±2°
-12.7±2°
Br-CH2-(CH2)3-
CH3-(CH2)3-
CH3-CH2-
Br
Br
Br
J
CH3-(CH2)3-
N-Alkylated codeine
33
34
CH3-
CH3-CH2-
J
Br
C19H24NO3J
C29H26NO3Br
254-256
172-175
-63.3±4°
-127±4°
N-Alkylated strychnine
35
36
CH3-
CH3-CH2-
J
Br
C21H24N2O2J
C22H26N2O2Br
304-307
312-314
0
0
Thus, compounds with a C -C and higher alkyl chain form two separable conformers (Figs. 1 and 2) for 6 with a C
9
5
14
alkyl chain. Paper chromatography showed two compounds of similar polarity that gave clearly distinct spots.
Computer modeling of the stereochemistry showed that only two conformations can be constructed with retention of
the bond angles and the minimum free energy. In one of these the hydrocarbon chain is directed toward the methyl on the
N(α)-atom; in the other, toward the ethyl group.
474

Fig. 1. Conformer 1 of 6.
Fig. 2. Conformer 2 of 6.
The biological activity has been determined for individual ajmaline derivatives (1, 15, 16). Compared with ajmaline,
the antiarrhythmic activity of 15 and 16 was 7-10 times greater whereas that for 1 with a long hydrocarbon chain was about the
same as for ajmaline.
EXPERIMENTAL
The course of reactions and purity of products were monitored using TLC on Silufol UV-254 plates with
CHCl :CH OH:H O (85:15:0.7) eluent. Ajmaline and its derivatives were developed on chromatograms byspraying with conc.
3
3
2
HNO to form strongly colored red spots. Chromatograms were thoroughlydried beforehand to remove formamide in a drying
3
chamber at 105-110°C. Quinine, hyoscyamine, codeine, strychnine, and their derivatives were developed on chromatograms
byirradiation with unfiltered UV light. Elemental analyses were performed on a Model 1106 automated C-H-N-S analyzer and
agreed for all compounds with those calculated.
N(b)-Nonylajmaline Bromide (6). A solution of ajmaline (1.7 g) in CH CN:CHCl (1.5:1, 25 mL) was treated with
3
3
nonylbromide (2.4 g), refluxed for 8 h, concentrated to a volume of ~7 mL, and left overnight at room temperature. The
resulting crystals were separated on a Buchner funnel and washed with CH CN (4 mL) and hexane (20 mL).
3
The crystals were recrystallized by dissolving in boiling CH CN (40 mL). The hot solution was filtered, concentrated
3
to a volume of ~5 mL, and left for 5 h at room temperature. The crystals were separated and washed with CH CN (3 mL) to
3
afford 6 (1.2 g), C H N O Br.
29 45
2 2
N(b)-Methylquinine Iodide (24). Quinine (2 g) was dissolved in CHCl (10 mL) and treated with methyliodide
3
(3 mL). The solution was sealed in a glass ampul and held in a thermostat at -40°C for 17 h. The resulting crystals were
separated on a Buchner funnel and washed with CHCl (5 mL) and hexane (2 mL) toafford crystals (2.4 g) of the crude product.
3
The crystals were recrystallized by dissolving in CH OH (30 mL) with heating. The solution was concentrated to a
3
volume of ~5 mL, treated with CH CN (15 mL), and evaporated to a volume of ~7 mL. The resulting golden yellow crystals
3
were separated and washed with CH CN (5 mL) to afford 24 (1.7 g), C H N O I.
3
21 27 2 2
N-Bromobutylhyoscyamine Bromide (29). Hyoscyamine (1.5 g) was dissolved with heating in CH CN (15 mL) and
3
treated with 1,4-dibromobutane (3.7 mL). The solution was held at room temperature for 3 d. The product precipitated upon
addition of hexane (45 mL). The resulting thick solid was triturated four times with hexane until it turned into a powder. The
solvent was decanted. The amorphous powder was dried in vacuo.
The crude product was recrystallized by dissolving in CH CN (50 mL) with heating. The solution was concentrated
3
to a volume of ~7 mL and left overnight. The resulting crystals were washed with CH CN (5 mL) to afford 29 (1.3 g),
3
C H NO Br .
21 31
3
2
The remaining quaternary salts of the alkaloids were synthesized analogously.
475

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