Synthesis and investigation of the stability of esters of 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-3, 4′- and -4,4′-bipyridine-3′-carboxylic acids 1. Esters of 6′-carbamoylmethylthio-5′-cyano-1′,4′-dihydro-3, 4′-bipyridine-3′-carboxylic acids

Article abstract of DOI:10.1007/s10593-007-0007-z

Esters of 6′-carbamoylmethylthio-5′-cyano-1′,4′- dihydro-3,4′-bipyridine-3′-carboxylic acids are obtained by the alkylation of piperidinium 3′-alkoxycarbonyl-5′-cyano-1′, 4′-dihydro-3,4′-bipyridine-6′-thiolates with iodoacetamide. For an HPLC study of the

Full text of DOI:10.1007/s10593-007-0007-z

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007
SYNTHESIS AND INVESTIGATION OF THE STABILITY
OF ESTERS OF 6'-CARBAMOYLMETHYLTHIO-5'-CYANO-
1',4'-DIHYDRO-3,4'- AND -4,4'-BIPYRIDINE-3'-CARBOXYLIC
ACIDS 1. ESTERS OF 6'-CARBAMOYLMETHYLTHIO-5'-CYANO-
1',4'-DIHYDRO-3,4'-BIPYRIDINE-3'-CARBOXYLIC ACIDS
H. Kažoka, A. Krauze, M. Viļums, L. Černova, L. Sīle, and G. Duburs
Esters of 6'-carbamoylmethylthio-5'-cyano-1',4'-dihydro-3,4'-bipyridine-3'-carboxylic acids are
obtained by the alkylation of piperidinium 3'-alkoxycarbonyl-5'-cyano-1',4'-dihydro-3,4'-bipyridine-6'-
thiolates with iodoacetamide. For an HPLC study of the stability of solutions of the abovementioned 1,4-
dihydrobipyridines (solution pH 2.3-9.0) the appropriate esters of 6'-carbamoylmethylthio-5'-cyano-
3,4'-bipyridine-3'-carboxylic acids and esters of 8-cyano-5-methyl(or phenyl)-3-oxo-7-pyridin-3-yl-2,3-
dihydro-7H-thiazolo[3,2-a]pyridine-6-carboxylic acids were synthesized as reference compounds.
Analysis by HPLC was carried out under conditions of reverse-phase chromatography. It was shown
that solutions of the investigated compounds in a mixture of acetonitrile and phosphate buffer (pH
3.0-5.0) were stable for 1 month on storage protected from light. Under the action of light in all the
solutions investigated irrespective of pH the formation occurs of the corresponding esters of
6'-carbamoylmethylthio-5'-cyano-3,4'-bipyridine-3'-carboxylic acids. The presence of esters of 8-cyano-
5-methyl(or phenyl)-3-oxo-7-pyridin-3-yl-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-6-carboxylic acids (no
more than 4%) was detected only in 0.1% solutions of phosphoric acid (pH 2.3) under conditions of
storage of the latter protected from light. A series of as yet unidentified products was detected in
solutions of pH 7.0-9.0.
Keywords: 3,4'-bipyridines, 2,3-dihydro-7H-thiazolo[3,2-a]piperidines, HPLC.
3.4'-Bipyridines have aroused considerable interest for more than 20 years since among them are
cardiotonic agents for the treatment of cardiac insufficiency. The preparations amrinone (5-amino-1H-3,4'-
bipyridin-6-one) and milrinone (2-methyl-6-oxo-1,6-dihydro-3,4'-bipyridine-5-carboxylic acid nitrile) show a
marked inotropic action on the heart, simultaneously displaying a vasodilating effect [1-6].
N
N
CN
NH2
O
N
N
H
Me
O
H
Amrinone
Milrinone
_______
* Dedicated to E. Lukevics on his 70th birthday
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga, LV-1006; e-mail: helena@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 1, pp. 59-68, January, 2007. Original article submitted March 6, 2006.
50
0009-3122/07/4301-0050©2007 Springer Science+Business Media, Inc.

It was established that ethyl esters of 5'-cyano-1',4'-dihydro-3,4'-bipyridin-3'-carboxylic acids, depending
on the degree of hydrogenation, show a double inotropic action [7], and the nitrile of 3'-acetyl-6'-
carbamoylmethylthio-2'-hydroxy-2'-methyl-1',2',3',4'-tetrahydro-3,4'-bipyridine-5'-carboxylic acid (dose 0.1
mg/kg) increases blood flow in the femoral artery by 125%, but the effect is brief due to the instability of the
compound [8]. In addition the antioxidant activity of 6'-alkylthio-1',4'-dihydro-3,4'-bipyridines was shown by us
in [9], however it was established that some of them were unstable in dilute, especially acidic, solutions.
The 1,4-dihydropyridine ring of esters of 6'-carbamoylmethylthio-5'-cyano-1',4'-dihydro-3,4'-bipyridine-
3'-carboxylic acids 1 in dilute solution may be oxidized by oxygen of the air to a pyridine ring, since compounds
1 are antioxidants. In view of the potential practical value of 1',4'-dihydro-3,4'-bipyridines 1, in the present work
we have investigated their stability in aqueous solution (pH 2.3-9.0).
N
NH2
I
O
R1
O
CN
O
–
+
NH2
R
N
H
S
2a–c
N
N
NaNO2
AcOH
O
R
O
R
R1
R1
CN
S
CN
S
O
O
NH2
NH2
N
N
H
O
O
3a–c
1a–c
NH2
I
AcONa
AcOH
B
:
– NH3
N
O
N
O
O
R
R1
CN
CN
S
R1
O
O
R
N
N
S
H
4a–c
O
5a–c
a R = R1 = Me; b R = Me, R1 = Et; c R = Ph, R1 = Et
Compounds 1 were obtained by the alkylation of 3'-alkoxycarbonyl-5'-cyano-1',4'-dihydro-3,4'-bipyridine-6'-
thiolates 2 with iodoacetamide. The highest yields were achieved on carrying out these reactions under mild
conditions with gradual addition of iodoacetamide, which enables an excess of thiolate to be maintained.
Standard compounds were used in the study of the stability of aqueous solutions of the 1',4'-dihydro-3,4'-
bipyridines synthesized by us. These were esters of 6'-carbamoylmethylthio-5'-cyano-3,4'-bipyridine-
3'-carboxylic acids 3 obtained by the action of sodium nitrite on the corresponding 1',4'-dihydro-3,4'-bipyridines
1 in boiling acetic acid. It should be mentioned that in the presence of a carbamoylmethylthio substituent in
position 6 of the 1,4-dihydropyridine ring this simple method of oxidation [10] has a drawback, viz. elimination
of a molecule of ammonia occurs with the formation of a 7H-thiazolo[3,2-a]pyridine ring, which is stable to
oxidation. Bipyridines 3 were also obtained by the alkylation of pyridine-6(1H)-thiones 4 with iodoacetamide.
51

ν
ν
52

Boiling 6'-carbamoylmethylthio-5'-cyano-1'.4'-dihydro-3,4'-bipyridine-3'-carboxylic acids 1 in acetic
acid with added sodium acetate gave esters of 8-cyano-5-methyl(or phenyl)-3-oxo-7-(3'-pyridyl)- 2,3-dihydro-
7H-thiazolo[3,2-a]pyridine-8-carboxylic acids 5, used later as standard compounds for studying the stability of
1',4'-dihydro-3,4'-bipyridines 1.
In the last decade high performance liquid chromatography (HPLC) has occupied a significant place in
the analytical chemistry of organic compounds. The reverse-phase variant has the widest application in
chromatographic practice, including the analysis of 1,4-dihydropyridines [11-13].
Investigation of the stability of compounds 1 in aqueous solution (pH 2.3 solution I; pH 3.0 solution II;
pH 5.0 solution III; pH 7.0 solution IV; pH 9.0 solution V; see EXPERIMENTAL) was carried out by reverse-
phase chromatography in gradient mode. The results obtained are given in Table 1.
On introducing a test sample of solution I to be analyzed (directly after solution of compound 1 in the mobile
phase) peaks corresponding to 1',4'-dihydro-3,4'-bipyridines 1 (97.7-98.5%) predominated, the peaks corresponding
to bipyridines 3 amounted to 0.3-2.3%, and the content of thiazolopyridines 5 in the solutions did not exceed 0.3%.
After 24 h (solutions I being analyzed were stored unprotected from light) a reduction was observed in
the area of peaks corresponding to 1',4'-dihydro-3,4'-bipyridine 1, and an increase was seen in the areas of peaks
corresponding to bipyridine 3. While the content of compounds 3a and 3b increased more than three times, the
area of the peak corresponding to compound 3c grew only from 2.3 to 2.9% in 24 h. Evidently the presence of a
phenyl substituent (R = Ph) in the compound 1c molecule makes the solution more stable towards oxidation of the
1,4-dihydropyridine ring to a pyridine ring compared with compounds 1a and 1b containing a methyl group as R.
One month after introducing the sample, chromatograms of solutions I-III (solutions stored unprotected
from light) were obtained in which peaks for 1',4'-dihydro-3,4'-bipyridines 1a and 1b were absent, but peaks
corresponding to bipyridine 3 amounted to 62-83% (see Table 1). It should be mentioned that apart from
bipyridines 3a and 3b there was also a whole series of unidentified contaminants on the chromatograms,
however the individual content of the latter did not exceed 5%. In solutions I (pH 2.3) and III (pH 5.0) of
compound 1c (R = Ph) the formation of bipyridine 3c occurs significantly more slowly (19.3% at pH 2.3, 36% at
pH 5.0), while in solution II (pH 3.0) of compound 1c the oxidation goes more rapidly and the area of the
bipyridine 3c peak amounted to 58.8%. The content of unidentified contaminants did not exceed 2.7%.
Solutions I-III stored in the dark for 1 month were in practice stable. On the corresponding
chromatograms only an insignificant increase was observed in the areas of peaks corresponding to
thiazolopyridine 5 (particularly in the value at pH 2.3 by 4%, see Table 1).
TABLE 2. Characteristics of Compounds A-C
UV spectrum,
λ, nm**
Com-
pound
Retention time,
Effect of light***
tr, min*
1аА
1bА
5.28
5.89
195; 218; 258; 295;
373
On storing solutions in the dark
194; 218; 258; 295;
374
1сА
7.17
192; 258; 382
On storing a solution both
in the dark and in the light (pH 9)
1aВ
1bВ
1aС
1bС
1сС
4.90
5.55
205
Under the action of light
205
7.15
203; 289
199; 288
199; 298
Both under the action of light
and in the dark
7.92
10.05
_______
*Conditions of chromatographic analysis, see EXPERIMENTAL.
**Data of spectrophotometric detector on a ProStar 330 diode matrix.
***Preparation of solutions, see in EXPERIMENTAL; pH 7.0; 9.0.
53

Analysis of solutions IV (pH 7.0) and solutions V (pH 9.0) (1 month storage in the dark) showed the
absence of the corresponding thiazolopyridines 5. In solutions IV the content of 1',4'-dihydro-3,4'-bipyridines 1
was 93-94%, but in solutions V it varied from 54 (solution of compound 1a) to 89% (solution of compound 1b),
the main contaminant was an unidentified compound, conditionally designated A (see Tables 1 and 2).
TABLE 3. Characteristics of the Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °С
C
H
N
S
1a
1b
C16H16N4O3S
C17H18N4O3S
55.52
55.80
56.77
56.97
51.77
51.71
62.77
62.84
4.59
4.68
4.97
5.06
4.97
4.85
4.97
4.79
16.09
16.27
15.39
15.63
14.39
14.19
13.39
13.32
9.19
9.31
8.89
8.95
8.12
8.12
7.63
7.63
192-194
196-197
72
34
53
79
1b·HCl C17H18N4O3S·HCl
181-182
1c
3a
C22H20N4O4S
C16H14N4O3S
183-185 [7]
185-186
56.13
56.13
4.12
4.12
16.36
16.36
9.37
9.37
67 (A)
23 (B)
3b
3c
5a
5b
5c
C17H16N4O3S
C22H18N4O3S
C16H13N3O3S
C17H15N3O3S
C22H17N3O3S
57.29
57.29
62.97
63.14
58.70
58.70
59.77
59.81
4.53
4.53
4.20
4.34
3.84
4.00
4.43
4.43
15.72
15.72
13.19
13.39
12.81
12.84
12.31
12.31
9.00
9.00
7.49
7.66
9.80
9.79
9.39
9.39
137-138
70 (A)
167-169 [7] 65 (A)
148-150
125-126
168-170
34
30
59
65.52
65.49
4.00
4.25
10.84
10.41
7.79
7.95
No 1',4'-dihydro-3,4'-bipyridines 1 were observed in solutions IV and V, stored unprotected from light.
The exceptions were solutions of compound 1c in which the content was 72.6% at pH 7.0 and 47.2% at pH 9.0
respectively. The formation of bipyridines 3 occurs under the action of light in all solutions. However the
content of bipyridines 3 in solutions V of compounds 1a and 1b did not exceed 25% and the content of
unidentified compounds B (see Tables 1 and 2) was more than 20%. In analogous solutions of compound 1c the
presence of compound 1cB was not detected, but on the chromatogram peaks were present for the conditionally
designated 1cA and 1cC (see Tables 1 and 2).
Under the action of light in all the investigated solutions irrespective of pH oxidation of the 1,4-
dihydropyridine ring occurs with the formation of the corresponding bipyridines 3. In solutions IV and V of
compounds 1a and 1b, together with bipyridines 3, the formation is also observed of as yet unidentified
compounds B (no more than 30%). The presence of a phenyl substituent (R = Ph) in the molecule of 1c gives
solutions that are more stable towards oxidation. The maximum (58.8%) formation of bipyridine 3c is observed
in solution II (pH 3.0) and the minimum (14%) in solution V (pH 9.0).
On storing the solutions of 1',4'-dihydro-3,4'-bipyridines 1 being investigated for 1 month protected from
light the most stable were solutions in II (pH 3.0) and III (pH 5.0). Solutions in I were less stable, after 1 month
the formation was observed of thiazolopyridines 5 (but no more than 4%). Solutions in IV and V were
characterized by the formation of as yet unidentified compounds, conditionally designated A (pH 7.0 no more
than 4.6%, pH 9.0 up to 41% for a solution of compound 1a) and C (pH 7.0 no more than 2.4%, pH 9.0 up to
17.6% for a solution of compound 1c).
The problem of the constitution of compounds A-C remains open and will become a subject of study in
our subsequent investigations.
54

TABLE 4. Spectral Characteristics of Compounds 1, 3, and 5
Com-
pound
IR spectrum, ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)*
1a
1628, 1668, 1702 (C=O); 2.36 (3H, s, 6-CH3); 3.55 (3H, s, OCH3); 3.64 and 3.80 (2Н, d
and d, J = 16, SCH2); 4.50 (1H, s, H-4); 7.32-8.55 (4H, m,
C5H4N), 7.64 and 7.94 (2H, br. s and br. s, CONH2);
10.54 (1H, s, NH)
2200 (C≡N); 3120,
3300 (NH, NH2)
1b
1646, 1680, 1702 (C=O); 1.07 and 3.97 (5H, t and q, J = 7.0, ОC2H5); 2.32 (3H, s,
6-CH3); 3.67 and 3.78 (2Н, d and d, J = 16, SCH2);
4.58 (1H, s, H-4); 7.30-8.52 (4Н, m, C5H4N);
2196 (C≡N);
3164, 3332 (NH, NH2)
7.67 and 7.93 (2H, br. s and br. s, CONH2); 10.52 (1H, s, NH)
3a
3b
1672, 1728 (C=O);
2225 (C≡N); 3130,
3340 (NH2)
2.66 (3H, s, 6-CH3); 3.57 (3H, s, OCH3); 3.96 (2H, s, SCH2);
5.90 and 6.53 (2H, br. s and br. s, NH2);
7.40-7.84 and 8.58-8.84 (4H, m and m, C5H4N)
1673, 1718 (C=O);
2222 (C≡N); 3330 (NH2)
0.96 and 4.08 (5H, t and q, J = 7.0, ОC2H5);
2.67 (3H, s, 6-CH3); 3.97 (2Н, s, SCH2);
5.86 and 6.55 (2H, br. s and br. s, CONH2);
7.42-8.80 (4Н, m, C5H4N)
3c [7] 1674, 1728 (C=O);
2224 (C≡N); 3120,
3312 (NH2)
0.70 and 3.84 (5H, t and q, J = 7.0, ОC2H5);
4.06 (2Н, s, SCH2); 7.26 and 7.56 (2H, br. s and br. s, CONH2);
7.40-8.78 (9Н, m, C6H5 and C5H4N)
5a
5b
5c
1654, 1722, 1736 (C=O), 2.68 (3H, s, 6-CH3); 3.64 (3H, s, OCH3); 3.98 (2Н, s, 2-CH2);
4.80 (1Н, s, Н-7); 7.30-7.70 and
8.38-8.74 (4H, m and m, C5H4N)
2198 (C≡N)
1673, 1720, 1743 (C=O), 1.12 and 4.06 (5H, t and q, J = 7.0, ОEt); 2.66 (3H, s, 6-CH3);
3.97 (2Н, s, 2-CH2); 4.76 (1H, s, Н-7);
7.30-8.60 (4Н, m, C5H4N)
2200, 2006 (C≡N)
1672, 1757 (C=O),
2206 (C≡N)
0.69 and 3.68 (5H, t and q, J = 7.0, ОC2H5);
3.89 (2Н, s, 2-CH2); 4.86, (s, Н-7); 7.14-7.50,
7.68-7.77, 8.54-8.68 (9Н, m, C6H5 and C5H4N)
_______
*1H NMR spectra were taken in DMSO-D6 (compounds 1a,b, 3a,c, and 5a,c)
and CDCl3 (compounds 3b and 5b).
EXPERIMENTAL
1
The IR spectra were taken on a Perkin-Elmer 580B spectrometer in nujol. The H NMR spectra were
recorded on a WH 90/DC (90 MHz) spectrometer. Internal standard was HMDS (δ 0.05 ppm). A check on the
progress of reactions and the purity of substances was effected by TLC on Silufol 254 plates, eluent was
chloroform–hexane–acetone, 2 : 1 : 1. Compounds were recrystallized from ethanol. The synthesis of compound
1c is described in [7].
Esters of 6'-Carbamoylmethylthio-5'-cyano-2'-methyl(or phenyl)-1',4'-dihydro-3,4'-bipyridine-3'-
carboxylic Acids 1 (general procedure). A mixture of 3'-alkoxycarbonyl-5'-cyano-1',4'-dihydro-3,4'-
bipyridine-6'-thiolate 2 [15] (10 mmol) and iodoacetamide (10 mmol) in ethanol (20-40 ml) was stirred at 40-
50°C for 15-30 min. The resulting solid was filtered off, washed with ethanol (5-10 ml) cooled to 0°C, and with
water (10 ml).
Esters of 6'-carbamoylmethylthio-5'-cyano-2'-methyl(or phenyl)-3,4'-bipyridine-3'-carboxylic Acids 3.
A. A mixture of 6'-carbamoylmethylthio-5'-cyano-2'-methyl(or phenyl)-1',4'-dihydro-3,4'-bipyridine-3'-carboxylic
acid (1) (10 mmol) in acetic acid (20 ml) was heated to boiling and sodium nitrite (30 mmol) was added. After the
end of NO2 evolution the reaction mixture was poured into water (20 ml), and neutralized with ammonia. The
solid was filtered off, washed with water (10 ml), and compounds 3a-c were obtained.
55

B. A mixture of pyridine-6(1H)-thione 4a (0.285 g, 1 mmol), piperidine (0.1 ml, 1 mmol), and
iodoacetamide (0.19 g, 1 mmol) in ethanol (2 ml) was heated to boiling, cooled to 0oC, and the solid filtered off.
The solid was washed with ethanol (2 ml) and with water (5 ml). Compound 3a (0.08 g, 23%) was obtained.
Esters of 8-Cyano-5-methyl(or phenyl)-3-oxo-7-(3'-pyridyl)-2,3-dihydro-7H-thiazolo[3,2-a]pyri-
dine-8-carboxylic Acids 5. A mixture of 6-carbamoylmethylthio-5-cyano-2-methyl(or phenyl)-1,4-dihydro-4,3'-
bipyridine-3'-carboxylic acid ester 1 (10 mmol) and sodium acetate (5 mmol) in acetic acid (20 ml) was boiled
for 1-4 h. After cooling, the reaction mixture was poured into water (20 ml), and neutralized with ammonia. The
solid was filtered off, and washed with water (10 ml).
The characteristics of the synthesized compounds are given in Tables 3 and 4.
The chromatographic investigation was carried out on a Varian “Prostar” chromatograph consisting of a
Prostar 240 gradient pump, a Prostar 330 spectro-photometric detector on a diode matrix (λ = 254 nm), and a
Prostar 410 autosampler. The column (150 x 4.6 mm) (Agilent) was packed with Zorbax SB-C18 sorbent.
Mobile phase was acetonitrile–0.1% phosphoric acid solution in water (pH 2.3). The linear gradient was 15 min
from 5 to 95% acetonitrile. Consumption of mobile phase was 1.0 ml/min. The test sample (10 µl, concentration
0.5 µg/ml in mobile phase) was introduced by the autosampler.
Retention times, tr, min: 1a) 5.54; 3a) 7.32; 5a) 6.90; 1b) 6.17; 3b) 8.13; 5b) 7.84; 1c) 7.60; 3c) 9.98;
5c) 9.42 min. Retention time t0 of an apparently unabsorbed substance (uracil) was 1.55 min.
Solutions of 0.01 M phosphate buffer (pH 3.0; 5.0; 7.0; 9.0) were obtained by titration of 0.01 M
phosphoric acid with 1 M potassium hydroxide to the desired pH value [16].
Solutions for Analysis. Solution I. Compound 1a (5 mg) was dissolved in a 5% solution (10 ml)
of acetonitrile in 0.1% phosphoric acid solution in water. The obtained solution (about 1 ml) was placed in four
autosampler bottles of volume 1.5 ml (three bottles were of ordinary glass and one was of dark glass) which
were tightly closed with appropriate caps. One of the three bottles of ordinary glass was placed in the
autosampler and was analyzed directly after preparation of the solution to be analyzed. The second and third
bottles were stored unprotected from light, in the first case for 1day and in the second for 1 month, and only then
was HPLC analysis of the solutions carried out. The solution in the fourth bottle of dark glass was also stored
for 1 month and then analyzed by HPLC.
Solutions of compounds 1b and 1c were prepared for analysis analogously.
Solution II. Compound 1a (5 mg) was dissolved in a solution (10 ml) of 25% acetonitrile in 0.01 M
phosphate buffer (pH 3.0). The solution obtained (about 1 ml) was placed in one bottle of ordinary glass and in
one of dark glass (the bottleswere tightly closed with appropriate caps). The solutions were stored unprotected
from light for 1 month and then analyzed by HPLC.
Solutions of compounds 1b and 1c were prepared for analysis analogously.
Solution III. Compound 1a (5 mg) was dissolved in a solution (10 ml) of 25% acetonitrile in 0.01 M
phosphate buffer (pH 5.0). The solution obtained (about 1 ml) was placed in one bottle of ordinary glass and one
of dark glass (the bottles were tightly closed with appropriate caps). The solutions were stored unprotected from
light for 1 month and then analyzed by HPLC.
Solutions of compounds 1b and 1c were prepared for analysis analogously.
Solution IV. Compound 1a (5 mg) was dissolved in a solution (10 ml) of 30% acetonitrile in 0.01 M
phosphate buffer (pH 7.0). The solution obtained (about 1 ml) was placed in one bottle of ordinary glass and one
of dark glass (the bottles were tightly closed with appropriate caps). The solutions were stored unprotected from
light for 1 month and then analyzed by HPLC.
Solutions of compounds 1b and 1c were prepared for analysis analogously.
Solution V. Compound 1a (5 mg) was dissolved in a solution (10 ml) of 30% acetonitrile in 0.01 M
phosphate buffer (pH 9.0).The solution obtained (about 1 ml) was placed in one bottle of ordinary glass and one
of dark glass (the bottles were tightly closed with appropriate caps). The solutions were stored unprotected from
light for 1 month and then analyzed by HPLC.
Solutions of compounds 1b and 1c were prepared for analysis analogously.
56

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