Synthesis of 6′-carbamoylmethylthio-5′-cyano-1′,4′- dihydro-3,4′-bipyridine-3′-carboxylic and 6′- carbamoylmethylthio-5′-cyano-1′,4′-dihydro-4, (...)

Article abstract of DOI:10.1007/s10593-007-0115-9

The stability of solutions of esters of 6′-carbamoylmethylthio- 5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bipyridine- 3′-carboxylic acids was investigated by HPLC. The corresponding esters of 6′-carbamoylmethylthio-5′-cyano-4,4′-bipyridine-3′- carboxylic acids,esters of 8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-2,3-dihydro-7H- thiazolo-[3,2-a]pyridine-6-carboxylic acids, methyl 3-amino-2-carbamoyl-6- methyl-4-(4-pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate, and methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-thieno[2,3-b]pyridine-5-carboxylate were synthesized as standard compounds (typical impurities). Analysis by HPLC was realized under the conditions of reverse-phase chromatography. It was established that solutions of the investigated compounds (with mixtures of acetonitrile with phosphate buffer, having pH values of not less than 3 and not more than 5, as solvents) are stable for one month when the solutions are stored in a place protected against light. It is also necessary to use chromatographic systems in which the aqueous components have pH 3-5 during determination of the purity of the esters of 6′-carbamoylmethylthio-5′-cyano-2′- methyl-1′,4′-dihydro-4, 4′-bipyridine-3′-carboxylic acid by HPLC in order to separate the analyzed sorbates and their typical impurities more completely.

Full text of DOI:10.1007/s10593-007-0115-9

Chemistry of Heterocyclic Compounds, Vol. 43, No. 6, 2007
SYNTHESIS OF 6'-CARBAMOYLMETHYLTHIO-
5'-CYANO-1',4'-DIHYDRO-3,4'-BIPYRIDINE-3'-CARBOXYLIC
AND 6'-CARBAMOYLMETHYLTHIO-5'-CYANO-1',4'-DIHYDRO-
4,4'-BIPYRIDINE-3'-CARBOXYLIC ESTERS AND INVESTIGATION
OF THEIR STABILITY. 2*. ESTERS OF 6'-CARBAMOYLMETHYL-
THIO-5'-CYANO-1',4'-DIHYDRO-4,4'-BIPYRIDINE-
3-CARBOXYLIC ACIDS
H. Kažoka, A. Krauze, M. Viļums, L. Černova, L. Sīle, and G. Duburs
The stability of solutions of esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bi-
pyridine-3′-carboxylic acids was investigated by HPLC. The corresponding esters of 6′-carbamoyl-
methylthio-5′-cyano-4,4′-bipyridine-3′-carboxylic acids, esters of 8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-
2,3-dihydro-7H-thiazolo-[3,2-a]pyridine-6-carboxylic acids, methyl 3-amino-2-carbamoyl-6-methyl-4-(4-
pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate, and methyl 3-amino-2-carbamoyl-6-methyl-4-(4-
pyridyl)-thieno[2,3-b]pyridine-5-carboxylate were synthesized as standard compounds (typical
impurities). Analysis by HPLC was realized under the conditions of reverse-phase chromatography. It
was established that solutions of the investigated compounds (with mixtures of acetonitrile with
phosphate buffer, having pH values of not less than 3 and not more than 5, as solvents) are stable for
one month when the solutions are stored in a place protected against light. It is also necessary to use
chromatographic systems in which the aqueous components have pH 3-5 during determination of the
purity of the esters of 6′-carbamoylmethylthio-5′-cyano-2′-methyl-1′,4′-dihydro-4,4′-bipyridine-
3′-carboxylic acid by HPLC in order to separate the analyzed sorbates and their typical impurities more
completely.
Keywords: 4,4′-bipyridines, 2,3-dihydro-7H-thiazolo[3,2-a]pyridines, thieno[2,3-b]pyridines, HPLC.
Earlier [2] we synthesized a series of esters of 6'-carbamoylmethylthio-5'-cyano-1',4'-dihydro-4,4'-bi-
pyridine-3'-carboxylic acids, which being regioisomers of the cardiotonic preparation milrinone [3] are of
interest as potential positively acting inotropic compounds. However, it is known [2] that hydrogenated
2-alkylthio-4,4'-bipyridines are unstable in acidic solutions.
In the present work we investigated the stability of the above-mentioned esters in mixtures of acetonitrile
and a 0.1% solution of phosphoric acid (solutions with pH 2.3, Table 1) and an acetonitrile–phosphate buffer
(solutions with pH 3-9, Table 1).
_______
*For Communication 1, see [1].
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga, LV-1006; e-mail: helena@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 841-848, June, 2007. Original article submitted October 23, 2006.
708
0009-3122/07/4306-708©2007 Springer Science+Business Media, Inc.

Earlier [1] we studied the stability of esters of 6'-carbamoylmethylthio-5'-cyano-1',4'-dihydro-
3,4'-bipyridine-3'-carboxylic acids and showed that solutions of the investigated compounds in a mixture of
acetonitrile with phosphate buffer (pH 3-5) were stable for one month when the solutions were stored in a place
protected from light. Storage of the solutions in a place not protected from light (irrespective of the pH) led to
the formation of the corresponding esters of 6'-carbamoylmethylthio-5'-cyano-3,4'-bipyridine-3'-carboxylic
acids. The presence of esters of 8-cyano-5-methyl(phenyl)-3-oxo-7-(3-pyridyl)-2,3-dihydro-7H-thiazolo-
[3,2-a]pyridine-6-carboxylic acids (not more than 4%) was only detected in acetonitrile–phosphoric acid
solutions that had been stored in a place protected from light. A series of as yet unidentified products were found
in the solutions with pH 7-9.
O
Py
Py
O
CN
CN
–
R
R
I
NH2
O
O
O
NH2
Me
N
H
1, 2
S
Me
N
H
S
O
+
NH2
3, 4
NaNO2
AcOH
AcONa
AcOH
– NH3
Py
O
O
Py
N
R
CN
CN
S
R
O
O
NH2
Me
N
Me
S
O
5, 6
O
7, 8
KOH
Py
O
O
NH2
Me
CONH2
S
Me
N
10
O
Py
NH2
CONH2
Me
KOH
O
1
S
Me
N
H
9
1-10 Py = 4-(pyridine-4-yl); 1, 3, 5, 7 R = Me; 2, 4, 6, 8 R = Et
The subjects of the investigation in the present work esters of 6'-carbamoylmethylthio-5'-cyano-
2'-methyl-1',4'-dihydro-4,4'-bipyridine-3'-carboxylic acids 1 [2] and 2 [4] were prepared by alkylation of the
corresponding 3′-alkoxycarbonyl-5'-cyano-2'-methyl-1',4'-dihydro-4,4'-bipyridine-6′-thiolates 3 and 4 [5] with
iodoacetamide. As standard compounds (the supposed transformation products during storage of solutions of the
investigated esters) for study of the stability of the solutions of the esters 1 and 2 we used the corresponding
esters of 6'-carbamoylmethylthio-5'-cyano-2'-methyl-4,4'-bipyridine-3'-carboxylic acids 5 [2] and 6, esters of
8-cyano-5-methyl-3-oxo-7-(4-pyridyl)-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-6-carboxylic acids 7 [6] and 8,
methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate 9 [2], and
methyl 3-amino-2-carbamoyl-6-methyl-4-(4-pyridyl)thieno[2,3-b]pyridine-5-carboxylate 10 [2].
709

TABLE 1. Investigation of the Stability of Solutions of Compounds 1 and
2 by Reverse-Phase HPLC (Gradient Regime)*
Content of investigated compounds in analyzed solutions, %*2, at
Com-
pound
рН 2.3
Just after
dissolution
рН 3
рН 5
рН 7
рН 9
After one month (in the dark)
1
98.7
0.8
—
91.5
4.1
—
98.5
98.5
1
90.5
45
—
50
4
5+7
1
1
8
1А = 9
1C = 10
1X*3
—
—
0.5
—
—
—
—
—
0.5
0.5
4.4
0.5
1
2
98.7
1
91
4.7
—
98.4
1.3
—
98.4
1.3
—
93.5
1.3
5
81
–
6+8
2A
2C
2X*3
—
17
1.7
0.3
—
—
—
—
—
0.3
4.3
0.3
0.3
0.3
_______
* The conditions for chromatographic analysis are given in the
experimental section.
*2 Quantitative analysis was performed by normalization of the areas
(λ = 254 nm) [7]. Solutions with pH 2.3: 5% acetonitrile in 0.3% solution
of phosphoric acid in water; pH 3: acetonitrile–0.01 M phosphate buffer
pH 3 (25:75); pH 5: acetonitrile–0.01 M phosphate buffer pH 5 (25:75); pH
7: acetonitrile–0.01 M phosphate buffer pH 7 (30:70); pH 9: acetonitrile–
0.01 M phosphate buffer pH 9 (30:70).
*3 The total content of unidentified impurities (number of unidentified
impurities not more than 3).
The bipyridines 5 and 6 were obtained by the action of sodium nitrite on the corresponding 1',4'-dihydro-
4,4′-bipyridines 1 and 2 in boiling acetic acid. The 2,3-dihydro-7H-thiazolo[3,2-a]pyridines 7 and 8 were
obtained by boiling compounds 1 and 2 in acetic acid with the addition of sodium acetate.
4,7-Dihydrothieno[2,3-b]pyridine 9 or thieno[2,3-b]pyridine was obtained by briefly heating a solution of
compound 1 or 5 respectively with a catalytic amount of potassium hydroxide.
The same gradient reverse-phase regime of HPLC as in [1] was used to investigate the stability of the
solutions of compounds 1 and 2 [1]. However, it was established that the given chromatographic system does not
make it possible to distinguish between such pairs of compounds as 5/7 and 6/8 [retention times, tr: 6.65 (5),
6.64 (7), and 7.45 (6), 7.49 min (8)]. The data for these compounds presented in Table 1 must therefore be
regarded as the total contents 5 + 7 and 6 + 8.
If the sample is introduced immediately after the compounds 1 and 2 have dissolved in the mobile phase
(solutions pH 2-3, Table 1), the peaks corresponding to the dihydrobipyridines 1 and 2 (the content of the latter
in the solutions being analyzed is 98.7%) predominate on the obtained chromatograms. On the chromatograms
of the same samples after one month the areas of the peaks corresponding to compounds 1 and 2 are reduced to
91-91.5%. At the same time there is an increase in the areas of the peaks corresponding to 5 + 7 and 6 + 8 (from
0.8 to 4.1% for solution 1, from 1 to 4.7% for solution 2). According to data obtained by means of a
spectrophotometric detector on a ProStar 330 diode matrix, immediately after dissolution of compounds 1 and 2
in the mobile phase the UV spectra of the peaks coinciding with the standards 5-8 in retention time coincide with
the UV spectra of the model compounds 5 and 6, while after one month they coincide with the UV spectra
710

of model compounds 7 and 8. This does not contradict the data we obtained earlier for esters of
6'-carbamoylmethylthio-5'-cyano-1',4'-dihydro-3,4'-bipyridine-3'-carboxylic acids. As demonstrated in [1], after
one month during storage of the solutions of the compounds with pH 2.3 in the dark the corresponding esters of
8-cyano-5-methyl(phenyl)-3-oxo-7-(3'-pyridyl)-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carboxylic
acids
were formed.
According to the data in Table 1, on the chromatograms of the solutions of compounds 1 and 2 with pH
3 and pH 5 there is only a slight increase in the area of the peaks corresponding to compounds 5 + 7 and 6 + 8
(not more than 0.3%), i.e., the solutions are stable for one month when stored in a place protected from light. It
was established (these data are not included in Table 1, since they are identical with the results obtained in [1])
that oxidation of the dihydrobipyridines 1 and 2 to the corresponding bipyridines 5 and 6 takes place under the
influence of light in all the investigated solutions irrespective of the pH value. Analysis of the solutions with pH
7 one month after dissolution of the investigated compounds showed a decrease in the content of the
dihydrobipyridines 1 and 2 (from 98.7 to 90.5% for solution of 1, from 98.7 to 93.5% for solution 2) and the
formation of products with characteristics close to those of the compounds of type A (content of 1A 8%, 2A 5%)
unidentified in [1]. In solutions with pH 9 after one month the content of the dihydrobipyridines 1 and 2 amounts
to only 81 for solution of 2 (R = Et) and 45% for solution of 1 (R = Me). At the same time the content of
compound 2A amounts to 17, while that of 1A amounts to 50%. In addition the formation of products close to
the unidentified compounds C [1] is observed (content of compound 1C 4, 2C 1.7%). Comparison of
compounds 1A and 1C with the model compounds 9 and 10 showed that compound 1A is identical with
compound 9 both in retention time and in UV spectrum while the model compound 10 corresponds to compound
1C. This can be explained by the fact that an intramolecular Thorpe cyclization of 1, leading to the
dihydrothienopyridine 9, takes place in the solution with pH 7, while oxidation of 1 and intramolecular
cyclization or intramolecular cyclization of 1 and oxidation with the formation of the thienopyridine 10 take
place in the solution with pH 9.
Table 2 shows the dependence of the retention time of compounds 1, 2, and 5-8 on the pH of the
phosphate buffer and the concentration of acetonitrile in the mobile phase (an isocratic regime of HPLC). As
expected, in reverse-phase chromatography the retention time of the sorbate decreases with increase in the
concentration of acetonitrile. It is seen that there is a significant change in the retention time of the bipyridines 5
and 6 with change in the pH of the mobile phase from 3 to 5.
The main disadvantage of the described gradient regime (Table 1) was the unsatisfactory separation of
the pairs of compounds 7/5 and 8/6. On the basis of the data in Table 2 the selectivity or the relative retention (α)
was calculated for the following pairs of compounds: 5/1, 7/1, 7/5, 6/2, 8/2, 8/6. It is known that good
TABLE 2. The Dependence of the Retention Time of Compounds 1, 2, and
5-8 on the pH of the Phosphate Buffer and the Concentration of
Acetonitrile in the Mobile Phase (Isocratic Regime)*
Retention time, tr, min, at
Com-
pound
pH 3
pH 5
pH 7
pH 9
30%
20%
25%
5.65
30%
40%
25%
35%
30%
35%
40%
1
5
7
2
6
8
15.33
—
3.33
14.82
14.84
6.44
1.93
3.56
4.99
2.41
5.16
8.49
4.13
9.27
2.34
3.38
7.07
3.18
4.62
11.91
3.32
3.70
9.52
5.25
5.61
2.85
3.09
7.08
3.73
4.06
11.10
3.45
3.83
9.80
5.13
5.45
2.20
2.36
4.39
2.75
2.92
33.49
25.30
13.39
—
—
20.55
7.71
41.25
—
31.15
35.65
15.38
42.20
—
—
17.18
16.71 6.27
_______
* For the conditions of chromatographic analysis, see the experimental section.
711

chromatographic separation of two substances is possible with selectivity α > 1.5. It follows from the data
presented in Table 3 that the chromatographic system in which the mobile phase has pH 3-5 meets this
requirement. If the chromatographic system in which the aqueous component of the mobile phase has pH > 5 is
used, a problem can arise in the separation of the dihydrobipyridines 1 and 2 with the corresponding bipyridines
5 and 6 (α < 1.4). It is seen that the selectivity of separation of the pairs of compounds 7/5 and 8/6 deteriorates in
more acidic systems. It is not therefore surprising that the separation of the bipyridines 5 and 6 with the
corresponding thiazolopyridines 7 and 8 is unsatisfactory (α < 1.1) under the conditions of the gradient regime,
where a 0.1% solution of phosphoric acid (pH 2.3) was used as aqueous component of the mobile phase.
An isocratic chromatographic system with a mobile phase consisting of 35% acetonitrile and 65% of a
0.01 M phosphate buffer (pH 5) was used to confirm the formation of the thiazolopyridines 7 and 8 in the
solutions of compounds 1 and 2 with pH 2.3 that had been stored in the dark for one month. It was established
that immediately after dissolution of compounds 1 and 2 in the mobile phase apart from the dihydrobipyridine 1
or 2 the chromatogram only contained the respective bipyridine 5 or 6, while analysis of the solutions (pH 2.3)
of compounds 1 and 2 that had been stored in the dark for one month showed that the content of the bipyridine 5
or 6 had not changed, whereas the corresponding thiazolopyridine 7 or 8 had formed.
Thus, the chromatographic behavior of compounds 1, 2, and 5-8 under various conditions of reverse-
phase chromatography was studied in the present work. It was established that the bipyridines 5 and 6 are
formed under the influence of light in all the investigated solutions irrespective of the pH value. It was shown
that the formation of thiazolopyridines 7 and 8 is observed in the solutions with pH < 3 when the solutions are
stored in the dark, while the formation of the corresponding 4,7-dihydrothieno[2,3-b]pyridines A and/or
thieno[2,3-b]pyridines C is observed in the solutions with pH > 5. It was established that solutions of the
investigated compounds (when mixtures of acetonitrile with the phosphate buffer with pH not less than 3 and not
greater than 5 are used as solvents) are stable for one month provided that the solutions are stored in a place
protected from light. Moreover, it is also necessary to use chromatographic systems in which the aqueous
component of the mobile phase has pH 3-5 during determination of the purity of the dihydrobipyridines 1 and 2
by HPLC (determination of the content of the typical impurities 5-8) in order to obtain more complete separation
of the sorbates being analyzed.
TABLE 3. The Selectivity of the Chromatographic System* in Relation to
the pH of the Mobile Phase
Selectivity*2, α
Two separated
compounds
AN – PB
(40 : 60),
рН 3
AN – PB
(35 : 65),
рН 5
AN – PB
(35 : 65),
рН 7
AN – PB
(40 : 60),
рН 9
5/1
7/1
7/5
6/2
8/2
8/6
5.33
9.17
1.72
4.28
8.22
1.92
2.34
6.70
3.02
1.88
6.38
3.38
1.18
4.26
3.60
1.37
5.28
3.83
1.24
4.41
3.55
1.15
3.97
3.47
_______
* Isocratic regime. For the conditions of chromatographic analysis, see the
experimental section.
*2 The selectivity or the relative retention of the separated compounds:
αij = tri − t0/trj − t0 = ki/kj, where tri and trj are the retention times of the
corresponding i-th and j-th components of the separated pair;
t0 − {uracil} = 1.56 min.
712

EXPERIMENTAL
1
The IR spectra were recorded in vaseline oil on a Perkin-Elmer 580B instrument. The H NMR spectra
were recorded on a WH 90/DC spectrometer (90 MHz) with HMDS as internal standard (δ 0.05 ppm). The
reactions and the individuality of the substances were monitored by TLC on Silufol UV-254 plates with 2:1:5
chloroform–hexane–acetone as eluent. The compounds were recrystallized from ethanol.
The synthesis and the characteristics of compounds 1, 5, 9, and 10 were described in [2], compound 2 in
[4], and compound 7 in [6].
Ethyl 6'-Carbamoylmethylthio-5'-cyano-2'-methyl-4,4'-bipyridine-3'-carboxylate (6). A solution of
ethyl 6'-carbamoylmethylthio-5'-cyano-2'-methyl-1',4'-dihydro-4,4'-bipyridine-3'-carboxylate (2) (0.36 g,
1 mmol) in acetic acid (3 ml) was heated to boiling, and sodium nitrite (0.11 g, 1.5 mmol) was added. When the
release of NO2 had stopped the reaction mixture was poured into water (10 ml) and neutralized with ammonia.
The precipitate was filtered off and washed with water (10 ml). We obtained 0.20 g (58%) of compound 6; mp
1
162-164°C. IR spectrum, ν, cm-1: 1684, 1728 (С=0); 2224 (C≡N); 3164, 3312 (NH2). H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 0.95 and 4.03 (5Н, t and q, J = 7, ОС2Н5); 2.68 (3Н, s, 6-СН3); 3.97 (2Н, s, SCH2);
6.06 and 6.53 (2Н, br. s and br. s, CONH2); 7.32 and 8.30 (4Н, dd and dd, J = 5, C5H4N). Found, %: С 57.26;
Н 4.28; N 15.86; S 9.00. C17H16N4O3S. Calculated, %: С 57.29; Н 4.53; N 15.72; S 9.00.
Ethyl 8-Cyano-5-methyl-3-oxo-7-(4'-pyridyl)-2,3-dihydro-7H-thiazolo[3,2-a]pyridine-8-carboxy-
late (8). A mixture of the ester 2 (0.36 g, 1 mmol) and sodium acetate (0.02 g, 0.25 mmol) in acetic acid (3 ml)
was heated for 3 h. After cooling ethanol (5 ml) was added to the reaction mixture. The mixture was then
neutralized with ammonia, and the precipitate was filtered off and washed with water (5 ml). The filtrate was
poured into water (10 ml), and the precipitate was filtered off and recrystallized from ethanol. We obtained 0.18
1
g (53%) of compound 8; mp 162-164°C. IR spectrum, ν, cm-1: 1667, 1718 (С=0); 2202 (C≡N). H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.12 and 4.07 (5Н, t and q, J = 7, ОС2Н5); 2.68 (3Н, s, 6-СН3); 3.94 (2Н, s,
2-СН2); 4.72 (1H, s, 7-Н); 7.16 and 8.60 (4Н, dd and dd, C5H4N). Found, %: С 59.58; Н 4.23; N 12.30; S 9.24.
C17H15N303S. Calculated, %: С 59.81; H 4.43; N 12.31; S 9.39.
Conditions of HPLC. Gradient Regime. The measurements were made on a Varian ProStar 240 liquid
chromatograph consisting of a ProStar 240 gradient pump, a spectrophotometric detector based on a ProStar 330
diode matrix (λ = 254 nm), and a ProStar 410 autosampler. The Agilent column (150×4.6 mm) was packed with
Zorbax SB-C18. The mobile phase was acetonitrile–0.1% phosphoric acid solution in water (pH 2.3) with linear
gradient (15 min) from 5 to 95% acetonitrile. The consumption rate of the mobile phase was 1.0 ml/min. The
samples (10 µl, in the mobile phase 0.5 mg/ml) were introduced by means of the autosampler. Retention times,
tr: 5.54 (1); 6.65 (5); 6.64 (7); 5.28 (1А = 9); 6.70 (1С = 10); 6.11 (2); 7.45 (6); 7.49 (8); 5.95 (2А); 7.52 min
(2С). The retention time of the conditionally unsorbed substance (uracil) was t0 1.55 min.
The preparation of the analyzed solutions was described in [1].
Isocratic Regime. The measurements were made on a chromatographic system consisting of a Waters
510 pump, a Du Pont Instruments UV Spectrophotometer detector (λ = 254 nm), and a Hewlett Packard HP
3395 integrator. The Agilent column (150×4.6 mm) was packed with Zorbax Extend-C18. The mobile phase was
acetonitrile (AN)–phosphate buffer (PB). The solutions of 0.01 M PB (pH 3, 5, 7, 9) were prepared by titration
of 0.01 M phosphoric acid with potassium hydroxide to the required pH value [1]. The consumption rate of the
mobile phase was 1.0 ml/min. The samples (50 µl, in the mobile phase c = 0.05 mg/ml) were introduced without
stopping the flow by means of a Rheodyne 7125 loop tap dispenser. For the ratio of the components of the
mobile phase and the retention time, see Table 2.
713

REFERENCES
1.
H. Kažoka, A. Krauze, M. Viļums, L. Černova, L. Sīle, and G. Duburs, Khim. Geterotsikl. Soedin., 59
(2007). [Chem. Heterocycl. Сотр., 43, 50 (2007)].
2.
3.
4.
A. Krauze and G. Duburs, Latv. J. Chem., 92 (1994).
A. A. Alausi and D. С Johnson, Circulation, 73, 10 (1986).
A. A. Krauze, E. E. Liepin'sh, Yu. E. Pelcher, Z. A. Kalme, and G. Ya. Dubur, Khim. Geterotsikl. Soedin.,
75 (1987). [Chem. Heterocycl. Сотр., 23, 61 (1987)].
5.
6.
7.
A. A. Krauze, E. E. Liepinsh, Yu. E. Pelcher, Z. A. Kalme, and G. Ya. Dubur, Khim. Geterotsikl.
Soedin., 630 (1986). [Chem. Heterocycl. Сотр., 22, 517 (1986)].
A. Krauze and G. Dubur, Khim. Geterotsikl. Soedin., 1134 (1996). [Chem. Heterocycl. Сотр., 32, 982
(1996)].
V. D. Shatts and O. V. Sakhartova, High Performance Liquid Chromatography: Basic Theory.
Methodology. Application in Medicinal Chemistry [in Russian], Zinatne, Riga (1988), p. 255.
714