Synthesis of steroid compounds containing a pyridazinone moiety

Article abstract of DOI:10.1007/s11172-018-2343-9

The reaction of 17-ketosteroids and glyoxylic acid followed by treatment with hydrazine affords steroid compounds condensed in the 16 and 17 positions with the pyridazin-3(2H)- one ring.

Full text of DOI:10.1007/s11172-018-2343-9

Russian Chemical Bulletin, International Edition, Vol. 67, No. 11, pp. 2144—2147, November, 2018
2144
Synthesis of steroid compounds containing a pyridazinone moiety
M. S. Cherkalin,a A. V. Kolobov,a E. I. Chernoburova,b M. A. Shchetinina,b and I. V. Zavarzinb
aYaroslavl State Technical University,
88 Moskovskii prosp., 150023 Yaroslavl, Russian Federation.
E-mail: cherkalinms@ystu.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninskii prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. E-mail: zavi@ioc.ac.ru
The reaction of 17-ketosteroids and glyoxylic acid followed by treatment with hydrazine
affords steroid compounds condensed in the 16 and 17 positions with the pyridazin-3(2H)-
one ring.
Key words: steroids, pyridazin-3(2H)-ones, glyoxylic acid, hydrazine hydrate.
The analogs of steroid hormones condensed in the 16
Earlier,13 we have proposed a convenient method for
the preparation of pyridazin-3(2H)-ones by condensation
of carbonyl compounds with glyoxylic acid followed by the
reaction with hydrazine in the presence of bases. We used
this protocol to obtain pyridazine-containing steroids.
Commercially available 3-methoxyestra-1,3,5(10)-
trien-17-one (1) and 3-hydroxyandrost-5-en-17-one (2)
were chosen as the starting compounds which were reacted
with glyoxylic acid and then were treated with hydrazine
hydrate. The reaction was performed in the presence of
both acids (acetic and p-toluene sulfonic acid) and bases
(potassium carbonate and hydroxide) (Scheme 1).
and 17 positions with nitrogen heterocycles are of interest
due to the biological activity (primarily, biocidal one)
intrinsic to these compounds in the absence of hormonal
action.1—3 For example, we have shown4 that steroidal
structures containing condensed heterocyclic fragments
exhibit high anticancer activity.
In continuation of our studies on steroid compounds
containing heterocyclic moieties,5—12 in the present work
we developed synthesis of steroids of the androstane
and estrone series condensed with the pyridazin-3(2H)-
one ring.
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2144—2147, November, 2018.
1066-5285/18/6711-2144 © 2018 Springer Science+Business Media, Inc.

Synthesis of pyridazinone-containing steroids
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
2145
The formation of target products, 3-methoxyestra-
1,3,5(10)-trieno[17,16-c]pyridazin-3´(2H)-6´-one (3) and
3-hydroxyandrost-5-eno[17,16-c]pyridazin-3´(2H)-6´-
one (4), may proceed through the formation of intermedi-
ates 5 and 6, respectively, followed by spontaneous
elimination of water (route A) or through crotonic con-
densation to result in products 7 and 8 (route B). In the
latter case, side addition of hydrazine hydrate to the acti-
vated double bond becomes possible. Since these products
were not detected, we assume that the reaction proceeds
through spontaneous elimination of water from com-
pounds 5 and 6 (route A) in accordance with the literature
data.14 Among the reaction products we detected azines
9 and 10 (Scheme 2). These by-products resulted from the
reaction of hydrazine with two molecules of carbonyl-
containing steroids 1 and 2.
this is due to a decrease in the electrophilicity of glyoxylic
acid as a result of the formation of its salt or insufficient
basicity of potassium carbonate. The replacement of the
solvent for acetonitrile and the use of p-toluene sulfonic
acid also did not result in the desired product.
Upon heating compound 1 for 8 h at 110 C in glacial
acetic acid in the three-fold molar excess of glyoxylic acid,
we succeeded in isolating the target product 3 in the total
yield of 10%. This result is due to a low conversion of the
starting steroid (which then reacts with hydrazine), which
is confirmed by detection of compound 9 among the reac-
tion products.
The reaction of substrate 2 under the same conditions
does not afford the target product. In this case, a product
of acylation at the hydroxyl group, 3-acetoxyandrost-5-
en-17-one (11), was isolated from the reaction mixture.
The physicochemical parameters of compound 11 are
analogous to those obtained earlier.15
Scheme 2
In using compound 1 in the presence of potassium
hydroxide, product 3 was isolated in yield of 30%, as well
as the above-mentioned azine 9 and unidentified resinous
products were obtained. Under the same conditions,
compound 2 reacts with a considerably lower conversion.
As a result, product 10 was isolated in yield of 68% based
on the starting steroid. The target compound 4 was ob-
tained in yield of 20%.
Thus, we showed that the reaction of 17-ketosteroids
and glyoxylic acid followed by treatment with hydrazine
affords steroid compounds condensed in the 16 and 17
positions with pyridazin-3(2H)-one ring.
The solvents used, the synthesis conditions, and the
composition of isolated products are given in Table 1.
When the reaction was performed in the presence of
potassium carbonate in ethanol, no formation of interme-
diates 5 and 6 was observed after keeping the reaction
mixture for 16 h. After removal of the solvent, the starting
steroids 1 and 2 were isolated quantitatively. Obviously,
Table 1. Effect of conditions for the reaction of steroids 1 and
2 with glyoxylic acid on the product composition
Experimental
Mass spectra were recorded on a Kratos instrument with
direct sample injection (the energy of ionization was 70 eV) and
a MicrOTOF II instrument (Bruker Daltonics), electrospray
ionization (ESI), the ion polarity was positive (capillary voltage
of 4500 V) or negative (capillary voltage of 3200 V). Syringe
injection was used. The solvents were acetonitrile and methanol;
the solution flow rate was 3 μL min–1; the interface temperature
was 180 C, and the nebulizer gas was nitrogen (4.0 L min–1).
1H and 13C NMR spectra were recorded on a Bruker WM-300
spectrometer (300 and 75 MHz, respectively) at 303 K. The course
of processes and the individuality of synthesized compounds
were controlled by TLC on Kieselgel-G plates (Merck Si 254F)
using petroleum ether—ethyl acetate as the eluent. Column
chromatography was performed on a Мerck 60 silica gel
(40—63 mm).
Starting
steorid
Solvent
Acid or
base
t*/h
Isolated
products
1
1
1
1
2
2
2
2
AcOH
EtOH
EtOH
MeCN
AcOH
EtOH
EtOH
MeCN
—
K2CO3
KOH
р-TsOH
—
K2CO3
KOH
р-TsOH
08**
16
20**
20
08
16
20**
20
3, 9
1
3, 9
1
2, 11
2
4, 10
2
* The reaction time for step 1.
** The reaction with hydrazine hydrate was performed without
isolation of intermediates (2 h, 100 C).

2146
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
Cherkalin et al.
Reagents were commercially available and used as received.
Synthesis of compounds 3 and 4 in acetic acid (general proce-
dure 1). To a solution of the steroid 1 or 2 (1.76 mmol) in acetic
acid (5 mL), a 50% aqueous solution of glyoxylic acid (1.76 mmol)
was added. The mixture was heated to 110 C, kept for 8 h at this
temperature, cooled and diluted with water (5 mL). Aqueous
ammonia was added until pH 8. To the resulting mixture, hydrazine
hydrate (2.64 mmol) was added and refluxed for 2 h. Products
were isolated as precipitates formed upon cooling. The mixture
was separated by column chromatography (the eluent was petro-
leum ether—ethyl acetate).
Synthesis of compounds 3 and 4 in diethyl ether (general pro-
cedure 2). To a solution of the steroid 1 or 2 (1.76 mmol) in EtOH
(25 mL), a 50% aqueous solution of glyoxylic acid (1.76 mmol)
was added and potassium hydroxide (3.87 mmol) was added in
small portions. The mixture was refluxed for 10 h and cooled, yet
one portions of 50% glyoxylic acid (1.76 mmol) and potassium
hydroxide (1.76 mmol) were added, and refluxing was continued.
20 h after initiation of the reaction, the mixture was evaporated
by 1/3 of the volume and diluted with 3% HCl until pH 7, aque-
ous ammonia was added until pH 8, and then hydrazine hydrate
(2.64 mmol) was added. The reaction mixture was refluxed for
2 h and cooled. The precipitate formed was filtered off, washed
with water, and dried. The product mixture was separated by
column chromatography (the eluent was petroleum ether—ethyl
acetate).
3-Methoxyestra-1,3,5(10)-trieno[17,16-c]pyridazin-3´(2H)-
6´-one (3) was obtained in yield of 10% (method 1) and 32%
(method 2), m.p. 223 С (dec.). Found (%): C, 74.82; H, 7.33;
N, 8.44. C21H24N2O2. Calculated (%): C, 74.97; H, 7.19;
N, 8.33. 1H NMR (DMSO-d6), : 1.05 (s, 3 H, C(18)H3); 1.40—1.43
(m, 1 H, H(7)); 1.53—1.55 (m, 1 H, H(11)); 1.66—1.67 (m, 2 H,
H(8), H(12)); 1.68—1.70 (m, 1 H, H(14)); 1.81—1.83 (m, 1 H,
H(12)); 1.93—1.95 (m, 1 H, H(7)); 2.23—2.25 (m, 1 H, H(9));
2.33—2.35 (m, 1 H, H(11)); 2.44—2.46 (m, 2 H, H(6)); 2.75—2.78
(m, 1 H, H(15)); 2.95—1.97 (m, 1 H, H(15)); 3.47—3.54 (m, 3 H,
C(3)OCH3); 6.54—6.57 (m, 1 H, CH (pyridazine)); 6.59—6.61
(m, 1 H, CH arom.); 6.64—6.66 (m, 1 H, CH arom.); 7.13—7.15
(m, 1 H, CH arom.); 10.69 (s, 1 H, NH). 13C NMR (DMSO-d6),
: 16.6 (C(18)), 24.9 (C(11)), 29.6 (C(7)), 30.7 (C(6)), 32.3
(C(12)), 34.5 (C(8)), 35.9 (C(15)), 41.9 (C(9)), 44.9 (C(13)),
53.8 (C(14)), 56.7 (C(OCH3)), 111.3 (C(2)), 113.1 (C(4)), 122.4
(C (pyridazine)), 127.2. (C(1)), 129.9 (C(10)), 139.6 (C(5)), 148.3
(C(16)), 158.4 (C(3)), 159.3 (C=O), 172.1 (C(17)). HRMS, found:
m/z 336.4352 [M + H]+. Calculated for C21H24N2O2: M + H =
= 336.4271.
3β-Hydroxyandrost-5-eno[17,16-c]pyridazin-3´(2H)-6´-one
(4) was obtained in yield of 0% (method 1) and 20% (method 2),
m.p. 215—217 C. Found (%): C, 73.93; H, 8.41; N, 8.34.
C21H28N2O2. Calculated (%): C, 74.08; H, 8.29; N, 8.23.
1H NMR (DMSO-d6), : 0.79—0.81 (m, 1 H, H(9)); 0.85 (s, 3 H,
C(18)H3); 0.87 (s, 3 H, C(19)H3); 0.89—0.91 (m, 1 H, H(12));
0.97—1.08 (m, 2 H, H(1), H(12)); 1.21—1.50 (m, 4 H, C(11)H2,
H(8), H(2)); 1.53—1.68 (m, 4 H, H(1), H(2), H(7), H(15));
1.76—1.95 (m, 3 H, H(7), H(14), H(15)); 2.03—2.15 (m, 2 H,
C(4)H2); 3.48—3.51 (m, 1 H, OH); 3.53—3.55 (m, 1 H, H(3));
5.33—5.36 (m, 1 H, H(6)); 6.54—6.57 (m, 1 H, CH (pyridazine));
10.73 (s, 1 H, NH). 13C NMR (DMSO-d6), : 18.3 (C(18)), 19.1
(C(19)), 19.9 (C(11)), 30.6 (C(7)), 30.7 (C(8)), 31.3 (C(2)), 33.7
(C(15)), 34.3 (C(12)), 36.3 (C(10)), 36.6 (C(1)), 40.6 (C(13)),
42.2 (C(4)), 49.9 (C(9)), 60.4 (C(14)), 69.9 (C(3)), 119.7 (C(6)),
121.9 (C (pyridazine)), 141.6 (C(5)), 148.8 (C(16)), 160.1 (C=O),
171.3 (C(17)). HRMS, found: m/z 341.4659 [M + H]+. Calculated
for C21H28N2O2: M + H = 341.4581.
1,2-Bis(3-methoxyestra-1,3,5(10)trien-17-ylidene)hydrazone
(9) was obtained in yield of 15%, m.p. 231—233 C. Found (%):
C, 80.65; H, 8.71. C38H48N2O2. Calculated (%): C, 80.81; H, 8.57.
1H NMR (DMSO-d6), : 1.03 (s, 6 H, 2 C(18)H3); 1.24—1.47
(m, 4 H, 2 H(7), 2 H(12)); 1.61—1.71 (m, 2 H, 2 H(8)); 1.72—1.99
(m, 6 H, 2 H(7), 2 H(11), 2 H(12)); 2.05—2.13 (m, 4 H, 2 H(11),
2 H(15)); 2.37—2.49 (m, 2 H, 2 H(15)); 2.52—2.68 (m, 6 H,
2 H(9), 2 C(16)H2); 2.73—2.85 (m, 6 H, 2 C(6)H2, 2 H(14));
3.52—3.57 (m, 6 H, 2 C(3)OCH3); 6.61—6.65 (m, 2 H, 2 CH
arom.); 6.68—6.72 (m, 2 H, 2 CH arom.); 7.25—7.29 (m, 2 H,
2 CH arom.). 13C NMR (DMSO-d6), : 16.5 (2 C(18)), 24.9
(2 C(15)), 25.9 (2 C(7)), 26.1 (2 C(11)), 28.1 (2 C(16)), 29.9
(2 C(6)), 34.1 (2 C(12)), 36.5 (2 C(8)), 42.9 (2 C(9)), 44.7 (2 C(13)),
52.5 (2 C(14)), 56.1 (2 C(OCH3)), 111.6 (2 C(2)), 113.5 (2 C(4)),
126.2 (2 C(1)), 131.9 (2 C(10)), 138.9 (2 C(5)), 157.6 (2 C(3)),
173.7 (2 C(C=N)). HRMS, found: m/z 564.7889 [M + H]+.
Calculated for C38H48N2O2: M + H = 564.7805.
1,2-Bis(3β-hydroxyandrost-5-en-17-ylidene)hydrazine (10)
was obtained in yield of 68%, m.p. 241—243 C. Found (%):
C, 79.62; H, 9.99. C38H56N2O2. Calculated (%): C, 79.67; H, 9.85.
1H NMR (DMSO-d6), : 1.01 (s, 6 H, 2 C(18)H3); 1.03 (s, 6 H,
2 C(19)H3); 1.09—1.26 (m, 6 H, 2 H(1), 2 H(9), 2 H(12));
1.54—1.76 (m, 10 H, 2 H(2), 2 H(7), 2 H(8), 2 H(11), 2 H(12));
1.86—1.95 (m, 6 H, 2 H(1), 2 H(2), 2 H(11)); 2.09—2.25 (m, 8 H,
2 C(4)H2, 2 H(7), 2 H(15)); 2.51—2.78 (m, 8 H, 2 H(14), 2 H(15),
2 C(16)H2); 3.48—3.51 (m, 2 H, 2 OH); 3.52—3.54 (m, 2 H,
2 H(3)); 5.33—5.36 (m, 2 H, 2 H(6)). 13C NMR (DMSO-d6),
: 17.1 (2 C(18)), 18.1 (2 C(15)), 19.0 (2 C(19)), 19.9 (2 C(11)),
29.1 (2 C(16)), 30.7 (2 C(8)), 31.5 (2 C(12)), 31.6 (2 C(2)), 32.0
(2 C(7)), 36.3 (2 C(10)), 37.1 (2 C(1)), 42.2 (2 C(4)), 44.6
(2 C(13)), 48.9 (2 C(9)), 52.9 (2 C(14)), 70.9 (2 C(3)), 120.7
(2 C(6)), 141.6 (2 C(5)), 174.1 (2 C=N). HRMS, found: m/z
573.4413 [M + H]+. Calculated for C38H56N2O2: M + H =
= 573.4481.
This work was financially supported by the Russian
Science Foundation (Project No. 14-50-00126).
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Received June 21, 2018;
in revised form September 27, 2018;
accepted October 12, 2018