2,1-benzothiazine 2,2-dioxides. 3*. 4-hydroxy-1-methyl-2,2-dioxo-n- (1,3-thiazol-2-yl)-1H-2λ6,1-benzothiazine-3-carboxamides - A new group of potential analgetics

Article abstract of DOI:10.1007/s10593-014-1452-0

We have developed an effective synthetic method and prepared several 4-hydroxy-1-methyl-2,2-dioxo-N-(1,3-thiazol-2-yl)-1H-2λ⁶,1- benzothiazine-3-carboxamides and a few structurally related heterocyclic arylamides. The structural features of one of the substituted thiazolyl-2-amides obtained have been investigated. Compounds with a high analgesic activity have been identified within this group by pharmacological screening.

Full text of DOI:10.1007/s10593-014-1452-0

Chemistry of Heterocyclic Compounds, Vol. 50, No. 1, April, 2014 (Russian Original Vol. 50, No. 1, January, 2014)
2,1-BENZOTHIAZINE 2,2-DIOXIDES. 3*. 4-HYDROXY-
1-METHYL-2,2-DIOXO-N-(1,3-THIAZOL-2-YL)-
1Н-2λ6,1-BENZOTHIAZINE-3-CARBOXAMIDES –
A NEW GROUP OF POTENTIAL ANALGETICS
1
2
3
1**
I. V. Ukrainets , L. A. Petrushova , S. P. Dzyubenko , and G. Sim
We have developed an effective synthetic method and prepared several 4-hydroxy-1-methyl-2,2-dioxo-
N-(1,3-thiazol-2-yl)-1Н-2λ6,1-benzothiazine-3-carboxamides and a few structurally related heterocyclic
arylamides. The structural features of one of the substituted thiazolyl-2-amides obtained have been
investigated. Compounds with a high analgesic activity have been identified within this group by
pharmacological screening.
Keywords: amides, 2-aminothiazoles, 2,1-benzothiazines, esters, analgesic activity.
N-Hetaryl-4-hydroxy-2-methyl-1,1-dioxo-2Н-1λ6,2-benzothiazine-3-carboxamides, such as isoxicam
(1) and the widely used meloxicam (2) have been drugs of high importance for the suppression of pain and pain
syndromes of various etiology [2-6]. However, despite their value, these drugs (similarly to other analgetics
from different pharmacological groups) are not completely free of various drawbacks, which are the reason for
many contraindications and limitations to their use [7]. Therefore, the search for novel, highly active and, most
importantly, safe pain medications has never lost its importance.
O
O
N
OH
O
N
OH
Me
Me
S
N
H
N
H
N
N
S
Me
S
Me
O
O
O
O
Isoxicam (1)
Meloxicam (2)
_______
*For Communction 2, see [1].
**To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, 53 Pushkinska St., Kharkiv 61002, Ukraine.
2Vinnitsya National Pirogov Memorial Medical University, 56 Pirogova St., Vinnitsya 21018, Ukraine; e-mail:
ser800@mail.ru.
3Far-Eastern State Medical University, 35 Muravyeva-Amurskogo, Khabarovsk 680000, Russia; e-mail:
sim.hab@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 114-122, January, 2014. Original
article submitted November 14, 2013; revision submitted December 6, 2013.
0009-3122/14/5001-0103©2014 Springer Science+Business Media New York
103

From this perspective, N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carb-
oxamides are of great interest. On the one hand, these compounds are 2-sulfo analogs of strong analgesic agents –
N-R-amides of 4-hydroxy-1,2-dihydroquinoline-3-carboxylic acids [8-10], while on the other hand, they
represent isomers of the aforementioned drugs isoxicam (1) and meloxicam (2). It should be noted that the
seemingly trivial modifications of isoxicam (changing 2-С=О group to SO2 group) or meloxicam (switching
places the nitrogen and sulfur atoms in the thiazine ring) with the purpose of obtaining new target molecules
proved to be difficult synthetic challenges. N-hetaryl-4-hydroxy-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carb-
oxamides therefore remain hitherto unexplored both from the chemical and pharmacological aspects despite the
obvious value of such investigations.
As we have repeatedly demonstrated before, the reactions of lower alkyl esters of 4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids with primary and even secondary alkyl-, aryl-, and hetarylamines at
elevated temperature easily and rapidly produced the corresponding amides. It should be especially emphasized that
such syntheses often gave the best results in high-boiling inert solvents. The solvent volume, however, must not be
excessively high: the optimal amount was 0.5-2 ml per 0.01 mol of the starting ester, otherwise the reaction rate
dropped significantly, and the reaction completion required several hours instead of 3-5 minutes [11, 12].
According to our experiments, this scheme was also suitable for obtaining N-hetaryl-4-hydroxy-
1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxamides 3-5. For example, the methyl ester of 4-hydroxy-
1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxylic acid (6) reacted with equimolar amounts of thiazolyl-
2-amines or structurally related compounds in a dry xylene at 150°С, giving good yields of the respective target
hetarylamides 3-5. It should be noted, however, that the reactivity of their 2-sulfo analog 6 was considerably
lower than that of 4-hydroxyquinolin-2-one esters. The apparent reason was the strong effect of the sulfo group,
which increased the acidity of the 4-ОН group of ester 6 to such an extent that the desired course of the reaction
was impeded by salt formation. Nevertheless, the amide formation still occurred, even though it required much
longer time (approximately 1 h according to the reaction monitoring by 1Н NMR spectroscopy).
R
N
OH
O
OH
O
R
N
S
H2N
S
N
H
OMe
Xylene
150°С, 1 h
S
O
S
O
O
O
N
N
Me
O
Me
S
Me
N
COOMe
6
3a–d
Xylene
H2N
150°С, 1 h
Xylene
150°С, 1 h
NH2
O
N
OH
O
O
OH
O
O
S
Me
N
H
N
H
COOMe
S
S
N
N
O
O
Me
Me
5
4
3 a R = 5-Me, b R = 4-CH2COOEt, c R = 4-Ph, d R = 4-(adamant-1-yl)
All N-hetaryl-4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxamides 3-5 obtained
were white crystals with a yellowish tinge, with narrow melting ranges (in some cases with decomposition),
very well soluble at elevated temperatures in DMF, DMSO, and dioxane, sparingly soluble in alcohols, and
1
practically insoluble in water. The structures of these compounds were confirmed with elemental analysis, Н
and 13С NMR spectroscopy, as well as mass spectra.
Interestingly, aryl- and hetarylamides of 4-hydroxy-2-oxo-1,2-dihydroquinolin-3-carboxylic acids formed
molecular ions under the conditions of electron impact ionization that were prone to primary fragmentation
mainly by the cleavage of the acyclic amide bond, while their probability of fragmentation at the
104

С(3)CONHHet(Ar) bond was much lower, or even absent [13-15]. The situation was the opposite with 2-sulfo
analogs 3-5, the molecular ions of which fragmented mainly at the bond between the heterocycle and the
carbamide fragment (route A). This is shown in the scheme below, which uses the example of 5-methyl-
thiazolyl-2-amide 3а to explain the appearance of high intensity peaks with m/z 140 (76) and 211 (100), which
is typical in the mass spectra of the N-hetaryl-4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carb-
oxamides 3-5, and indicating a fragmentation that formed the isocyanate 7 and benzothiazine 8 ions,
respectively. It is important to note here that the molecular ion fragmentation according to the route A consists
not of one, but rather of two different processes, which represent rearrangements with hydrogen atom migration.
The charge during these rearrangements may be localized on either one of the fragments, but with different
probabilities. In other words, the fragmentation of the molecular radical cation 3а may produce either isocyanate
radical cation 7 with m/z 140 and simultaneously a neutral fragment with the mass of 211 au, or benzothiazine
radical cation 8 with m/z 211 by elimination of a neutral fragment with the mass of 140 au. The neutral
fragments are not detected in mass spectra and have been omitted from the scheme for clarity.
Route B
N
Route A
OH
+ ·
N
O
Me
O
O
+ ·
S
N
Me
7
S
N
H
m/z 140 (76%)
Route A
+ ·
+ ·
N
S
O
Route B
N
Me
S
H2N
O
OH
Me
3a [M]+
m/z 351 (8%)
9
m/z 114 (74%)
S
O
+ ·
O
+ ·
OH
N
O
–SO2
Me
8
S
O
N
m/z 211 (100%)
O
N
Me
m/z 147 (3%)
11
10
Me
m/z 237 (2%)
The primary fragmentation of the molecular radical cation similarly occurred at the carbamide bond
(route B). This direction was less characteristic for most of heterocyclic arylamides 3-5 despite the fairly high
intensity of the peaks due to the corresponding hetarylamines. For instance, amide 3а gave a mass spectrum
with 74% intensity of the characteristic peak (m/z 114) due to the liberation of 2-amino-5-methylthiazole (9). At
the same time, the associated peak of the bicyclic ketene 10, which was common to all the compounds studied,
had the intensity of only 2%. The ketene route of molecular ion fragmentation became more pronounced only in
the case of 5-methyl-1,2-oxazol-3-ylamide 4 when ketene 10 peak intensity was 69%. However, the strongest
peak in the mass spectrum was still that of benzothiazine 8 with m/z 211, thus the initial fragmentation in this
case also occurred at the benzothiazinecarbamide bond.
Remarkably, N-hetaryl-4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxamides 3-5 under
the conditions of mass spectrometry did not eliminate SO2. This typical high-temperature reaction of many
heterocycles containing a sulfo group [16-18] was quite insignificant in this case, and did not occur with the
molecular ion, but rather only during the fragmentation of the benzothiazine fragment ion 8. This was evidenced
by the very low intensity of the peaks produced by such fragmentation of hydroxyindole 11, which in none of
the examined cases reached even 10%.
According to our X-ray structural analysis data, the dihydrothiazine ring in the molecule of ethyl ({[(4-hydr-
oxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazin-3-yl)carbonyl]amino}-1,3-thiazol-4-yl)acetate (3b) was in an
intermediate conformation between a "twist-boat" and a "sofa" (the folding parameters [19]: S 0.64, Θ 48.9,
Ψ 17.3). The S(1) and С(8) atoms deviated from the least-squares plane of the remaining ring atoms by
-0.85 and -0.21 Å, respectively (Fig. 1).
105

The repulsion of the 1-N-methyl substituent and the aromatic ring (shortened intramolecular contact
Н(2)···С(17) 2.71 Å at the sum of the van der Waals radii equal to 2.87 Å [20]) resulted in the lengthening of
the C(1)N(1) bond to 1.408(3) Å, compared to its average length of 1.375 Å [21]. The carbamide group of the
substituent at the С(8) atom was practically coplanar with the endocyclic С(7)С(8) double bond (the dihedral
angle С(7)С(8)С(9)О(2) was 8.5(3)°), which was facilitated by the formation of intramolecular hydrogen
bonds O(1)H···O(2) (H···O 1.79 Å, OH···O 157°) and N(2)H···O(4) (H···O 1.99 Å, N–H···O 143°). This
conformation involved a redistribution of electron density as indicated by the lengthening of the С(9)О(2) and
С(7)С(8) bonds to 1.236(3) and 1.374(3) Å, respectively (with the average values 1.210 and 1.326 Å) and
shortening of the С(7)О(1) bond to 1.315(3) Å (the average value 1.362 Å).
Fig.1. The molecular structure of amide 3b with atoms represented by thermal vibration ellipsoids of 50%
probability.
The thiazole ring was in an antiperiplanar position relative to the С(8)С(9) bond and was coplanar with
the carbamide fragment (the torsion angles C(10)N(2)C(9)C(8) -175.5(2)°, C(9)N(2)C(10)S(2) 1.6(3)°).
The spatial relationship between the С(9)=О(2) bond and the thiazole ring in combination with the distance
between the sulfur and oxygen atoms (2.76 Å, sum of van der Waals radii 3.13 Å) indicated σ-hole interaction
between them. The ester group of the substituent in the thiazole ring was in sp conformation relative to the
С(12)С(11) bond and was practically coplanar to the С(11)С(13) bond, with the torsion angles
С(12)С(11)С(13)С(14) 13.5(4)°, С(11)С(13)С(14)О(5) -6.6(4)°. The ethyl group was in ар
conformation relative to the С(13)С(14) bond, while the С(15)С(16) bond was practically orthogonal to the
СОО fragment plane, with the torsion angles С(15)О(6)С(14)С(13) -172.0(3)°, С(14)О(6)С(15)С(16)
-91.2(4)°. Weak intramolecular hydrogen bonds С(12)Н···О(5) (Н···О 2.40 Å, СН···О 116°),
С(17)Н(17а)···О(4) (Н···О 2.30 Å, С–Н···О 114°) were also identified in this molecule, and there was a
shortened intramolecular contact Н(5)···О(1) 2.41 Å (sum of van der Waals radii 2.46 Å).
The analgesic properties of hetarylamides 3-5 were studied with the standard thermal tail-flick test in
white rats, the procedure of which we have previously described in detail [22]. Each of the compounds studied
was tested in 7 animals. The experimental results obtained (Table 1) clearly demonstrated that the screening oral
dose of 20 mg/kg of the compounds studied and the reference drugs noticeably decreased the sensitivity of the
animals to pain. This was evidenced by the appropriate lengthening of the latent period of tail flick, as compared
to the control group of animals received only solvents.
Statistically significant analgesic activity (assuming the level of statistical significance at p ≤ 0.05) was
demonstrated for all N-hetaryl-4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxamides 3-5
described in this work. However, the magnitude of this analgesic effect varied quite widely and depended on the
structure of the amide fragment. First of all we should note that (5-methylthiazol-2-yl)amide 3а is an actual
isomer of meloxicam (2), and its higher activity confirms our approach in searching novel analgesic compounds.
Unfortunately, we were not able to directly compare two other isomers, isoxicam (the manufacture of which has
106

Table 1. The Analgesic Activity of Hetarylamides 3-5 and Reference
Drugs
The latent period after 1 h from
administering of the compounds, s
Change of the latent period,
compared to control, %
Compound
6.29 0.20
7.27 0.22
4.26 0.14
5.03 0.19
4.79 0.16
4.32 0.12
5.78 0.15
4.87 0.17
3.90 0.18
+61.5
+86.4
+9.4
+28.9
+22.9
+10.8
+48.2
+24.9
—
3a
3b
3c
3d
4
5
Meloxicam
Piroxicam
Control
been discontinued) and 5-methylisoxazol-3-ylamide 4. However, taking into account the very similar analgesic
properties of isoxicam and piroxicam [23], we may assume that the reversed positions of sulfur and nitrogen in
the benzothiazine ring had practically no effect on the activity in this case. Of particular interest among all the
compounds studied was ethyl ({[(4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazin-3-yl)carbonyl]amino}-
1,3-thiazol-4-yl)acetate (3b), which was much more effective than piroxicam and meloxicam in suppressing the
pain reaction caused by heat, and thus should be studied as a potential lead compound for further
pharmacological development of analgesic agents.
We conclude that the method proposed for the synthesis of N-hetaryl-substituted 4-hydroxy-1-methyl-
2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxamides has provided good yields and purity of the target
compounds, and thus can be recommended for a larger scale preparation of these compounds. The biological
testing has indicated that changing the molecular structure from 1,2-benzothiazines to the isomeric 2,1-analogs
is a promising approach that can successfully improve the analgesic properties of drug candidates.
EXPERIMENTAL
1Н and 13С NMR spectra of the compounds synthesized were acquired on a Varian Mercury 400
spectrometer (400 and 100 MHz, respectively) in DMSO-d6, with TMS as internal standard. Mass spectra were
recorded of a Varian 1200L instrument in full scan mode in the range of 35-700 m/z, with EI ionization (70 eV)
and direct sample introduction. Elemental analysis was performed on a EuroVector EA-3000 elemental
analyzer. Melting points were determined in a capillary by using an SMP10 Stuart digital melting point
apparatus. The starting methyl 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate (6) was
synthesized according to a literature procedure [22].
4-Hydroxy-1-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carboxamide
(3a). A mixture of ester 6 (2.69 g, 0.01 mol), 2-amino-5-methylthiazole (1.14 g, 0.01 mol), and absolute xylene
(2 ml) was kept for 1 h at 150°С on a liquid metal bath using a suitable air-cooled distilling column that allowed
to distill off the methanol formed without removing the xylene solvent. The reaction mixture was cooled, EtOH
(5 ml) was added, and the mixture was left for several hours at room temperature. The crystalline amide 3a
precipitated was filtered off, washed with cold EtOH, and dried. Yield 3.12 g (89%), yellowish crystals; mp
1
277-279°С (decomp., DMF–EtOH, 1:5). H NMR spectrum, δ, ppm (J, Hz): 15.09 (1H, s, ОН); 8.82 (1Н, s,
NH); 8.00 (1Н, d, J = 7.7, Н-5); 7.50 (1Н, t, J = 7.6, Н-7); 7.18-7.11 (2Н, m, Н-6,8); 6.93 (1Н, s, Н-4 thiazole);
3.27 (3Н, s, NCH3); 2.37 (3Н, s, 5'-CH3). 13C NMR spectrum, δ, ppm: 169.9 (C-4); 162.3 (С=О); 159.9 (C-2
thiazole); 141.1 (С-8а); 133.1 (С-5); 128.9 (C-4 thiazole); 127.7 (C-5 thiazole); 125.5 (С-7); 123.5 (С-6); 122.8
(С-8); 117.2 (С-4а); 104.4 (C-3); 30.5 (NCH3); 12.1 (5'-CH3). Mass spectrum, m/z (Irel, %): 351 [М]+ (8), 237
107

(2), 211 (100), 147 (3), 140 (76), 114 (74), 105 (35), 91 (53), 72 (50). Found, %: C 47.76; H 3.65; N 12.03;
S 18.11. C14H13N3O4S2. Calculated, %: C 47.85; H 3.73; N 11.96; S 18.25.
Hetarylamides 3b-d, 4, and 5 were obtained similarly as white crystals with a yellowish tinge.
Ethyl
({[(4-Hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazin-3-yl)carbonyl]amino}-1,3-thiazol-
4-yl)acetate (3b). Yield 83%; mp 144-146°С (DMF–EtOH, 1:8). 1H NMR spectrum, δ, ppm (J, Hz): 16.08 (1H,
s, ОН); 9.67 (1Н, s, NH); 8.01 (1Н, d, J = 7.8, Н-5); 7.58 (1Н, t, J = 7.8, Н-7); 7.25-7.18 (2Н, m, Н-6,8); 7.04
(1Н, s, Н-5 thiazole); 4.17 (2Н, q, J = 7.2, ОСН2СН3); 3.79 (2Н, s, CH2СООEt); 3.32 (3Н, s, NCH3); 1.29 (3Н,
t, J = 7.2, ОCH2CH3). 13C NMR spectrum, δ, ppm: 172.6 (COOEt); 169.6 (C-4); 162.8 (С=О); 162.6 (C-2
thiazole); 141.2 (С-8а); 135.0 (C-4 thiazole); 133.7 (С-5); 127.6 (С-7); 123.3 (С-6); 123.1 (С-8); 117.5 (С-4а);
111.5 (C-5 thiazole); 105.0 (C-3); 61.6 (OCH2CH3); 34.3 (CH2COOEt); 30.7 (NCH3); 14.7 (OCH2CH3). Mass
spectrum, m/z (Irel, %): 423 [М]+ (14), 237 (2), 212 (47), 211 (89), 186 (58), 147 (5), 139 (100), 118 (21), 105
(35), 91 (54), 71 (31). Found, %: C 48.15; H 3.96; N 9.98; S 15.02. C17H17N3O6S2. Calculated, %: C 48.22;
H 4.05; N 9.92; S 15.14.
4-Hydroxy-1-methyl-2,2-dioxo-N-(4-phenyl-1,3-thiazol-2-yl)-1Н-2λ6,1-benzothiazine-3-carbox-
1
amide (3с). Yield 90%; mp 256-258°С (DMF–EtOH, 1:5). H NMR spectrum, δ, ppm (J, Hz): 15.12 (1H, s,
ОН); 9.97 (1Н, s, NH); 8.05 (1Н, d, J = 7.8, Н-5); 7.84 (2Н, d, J = 7.5, Н-2,6 Ph); 7.60 (1Н, t, J = 7.5, Н-4 Ph);
7.51 (1Н, s, Н-5 thiazole); 7.46 (2Н, t, J = 7.5, Н-3,5 Ph); 7.39 (1Н, t, J = 7.7, Н-7); 7.27-7.21 (2Н, m, Н-6,8);
3.35 (3Н, s, NCH3). 13C NMR spectrum, δ, ppm: 169.7 (С-4); 162.5 (С=О); 161.8 (C-2 thiazole); 143.7 (C-4
thiazole); 141.2 (С-8а); 133.4 (С-5); 132.2 (C-i Ph); 129.6 (C-3,5 Ph); 129.3 (C-4 Ph); 127.7 (С-7); 126.5
(C-2,6 Ph); 123.9 (С-6); 123.0 (С-8); 117.5 (С-4а); 108.5 (C-5 thiazole); 105.1 (C-3); 30.7 (NCH3). Mass
spectrum, m/z (Irel, %): 413 [М]+ (25), 237 (8), 211 (55), 202 (100), 176 (74), 147 (4), 134 (51), 118 (12), 105
(21), 91 (29), 77 (25). Found, %: C 55.28; H 3.75; N 10.23; S 15.42. C19H15N3O4S2. Calculated, %: C 55.19;
H 3.66; N 10.16; S 15.51.
N-[4-(Adamant-1-yl)-1,3-thiazol-2-yl]-4-hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carb-
oxamide (3d). Yield 96%; mp 251-253°С (DMF–EtOH, 1:5). 1H NMR spectrum, δ, ppm (J, Hz): 16.04 (1H, s,
ОН); 9.54 (1Н, s, NH); 8.02 (1Н, d, J = 7.5, Н-5); 7.55 (1Н, t, J = 7.3, Н-7); 7.24-7.17 (2Н, m, Н-6,8); 6.68
(1Н, s, Н-5 thiazole); 3.31 (3Н, s, NCH3); 2.11 (3Н, s, 3,5,7-CH adamantane); 1.94 (6Н, s, 2,8,9-CH2
adamantane); 1.78 (6Н, s, 4,6,10-CH2 adamantane). 13C NMR spectrum, δ, ppm: 173.1 (С-4); 162.4 (С=О);
152.4 (C-2 thiazole); 141.3 (С-8а); 137.3 (C-4 thiazole); 133.5 (С-5); 127.6 (С-7); 124.2 (С-6); 123.0 (С-8);
117.5 (С-4а); 105.7 (C-5 thiazole); 105.0 (C-3); 43.2 (2,8,9-CH2 adamantane); 36.6 (4,6,10-CH2 adamantane);
35.4 (C-1 adamantane); 30.7 (NCH3); 28.6 (3,5,7-CH adamantane). Mass spectrum, m/z (Irel, %): 471 [М]+ (12),
260 (59), 237 (4), 234 (100), 211 (30), 203 (18), 177 (13), 147 (4), 105 (12), 91 (25), 77 (20). Found, %:
C 58.69; H 5.45; N 9.03; S 13.53. C23H25N3O4S2. Calculated, %: C 58.58; H 5.34; N 8.91; S 13.60.
4-Hydroxy-1-methyl-N-(5-methyl-1,2-oxazol-3-yl)-2,2-dioxo-1Н-2λ6,1-benzothiazine-3-carbox-
1
amide (4). Yield 84%; mp 178-180°С (DMF–EtOH, 1:5). H NMR spectrum, δ, ppm (J, Hz): 15.43 (1H, s,
ОН); 10.06 (1Н, s, NH); 8.08 (1Н, d, J = 7.6, Н-5); 7.77 (1Н, t, J = 7.7, Н-7); 7.48 (1Н, d, J = 8.3, Н-8); 7.37
(1Н, t, J = 7.4, Н-6); 6.68 (1Н, s, Н-4 oxazole); 3.49 (3Н, s, NCH3); 2.45 (3Н, s, 5'-CH3). 13C NMR spectrum,
δ, ppm: 170.3 (С-4); 162.3 (С=О); 158.4 (C-3 oxazole); 137.3 (С-8а); 133.9 (С-5); 128.8 (C-5 oxazole); 124.2
(С-7); 123.7 (С-6); 122.6 (С-8); 119.4 (C-4 oxazole); 118.2 (С-4а); 106.2 (C-3); 31.5 (NCH3); 12.9 (5'-CH3).
Mass spectrum, m/z (Irel, %): 335 [М]+ (23), 237 (69), 211 (100), 146 (28), 133 (25), 124 (53), 105 (63), 98 (64),
91 (79), 77 (62). Found, %: C 50.03; H 3.99; N 12.44; S 9.47. C14H13N3O5S. Calculated, %: C 50.14; H 3.91;
N 12.53; S 9.56.
Methyl
3-{[(4-Hydroxy-1-methyl-2,2-dioxo-1Н-2λ6,1-benzothiazin-3-yl)carbonyl]amino}thiophene-
1
2-carboxylate (5). Yield 80%; mp 222-224°С (DMF–EtOH, 1:8). H NMR spectrum, δ, ppm (J, Hz): 15.57
(1H, s, ОН); 11.40 (1H, s, NН); 8.10 (1Н, d, J = 7.8, Н-5); 8.06 (1Н, d, J = 5.5, Н-5 thiophene); 7.82 (1Н, d,
J = 5.5, Н-4 thiophene); 7.77 (1Н, t, J = 7.5, Н-7); 7.48 (1Н, d, J = 8.3, Н-8); 7.39 (1Н, t, J = 7.5, Н-6); 3.93
(3Н, s, ОCH3); 3.51 (3Н, s, NCH3). 13C NMR spectrum, δ, ppm: 170.6 (СOOMe); 164.7 (С-4); 163.3 (С=О);
155.9 (C-3 thiophene); 137.3 (С-8а); 133.6 (С-5); 133.0 (C-2 thiophene); 128.8 (C-5 thiophene); 124.4 (С-7);
108

123.9 (С-6); 121.0 (С-8); 119.3 (C-4 thiophene); 118.9 (С-4а); 104.8 (C-3); 52.9 (ОСН3); 32.3 (NCH3). Mass
spectrum, m/z (Irel, %): 394 [М]+ (32), 237 (3), 211 (3), 157 (100), 125 (30), 105 (5), 91 (6), 77 (11). Found, %:
C 48.64; H 3.67; N 7.18; S 16.16. C16H14N2O6S2. Calculated, %: C 48.72; H 3.58; N 7.10; S 16.26.
X-ray Structural Study of Compound 3b. Compound 3b (C17H17N3O6S2, М 423.47) formed
monoclinic crystals (DMF), at 20°С: a 10.7511(7), b 7.2105(5), c 23.998(1) Å; β 97.665(5)°; V 1843.7(2) Å3;
Z 4; space group P21/с; dcalc 1.526 g/cm3; (MoKα) 0.331 mm-1; F(000) 880. Unit cell parameters and intensities
of 18008 reflections (5367 independent, Rint 0.034) were measured on an Xcalibur-3 diffractometer (MoKα-
radiation, ССD detector, graphite monochromator, ω-scanning, 2θmax 60°).
The structure was solved directly with the SHELXTL software package [24]. The structure was refined
with the constrained bond length in the ethyl group (1.54 Å). The hydrogen atom positions were identified by
differential synthesis of electron density and refined with the "rider" model with Uiso = nUeq for each non-
hydrogen atom linked to the corresponding hydrogen atom (n = 1.5 for methyl groups and n = 1.2 for the rest of
the hydrogen atoms). The hydrogen atoms involved in hydrogen bonding were refined in isotropic
approximation. The structure was solved by F2 full-matrix method of least squares in anisotropic approximation
for the non-hydrogen atoms to wR2 0.172 using 5257 reflections (R1 0.056 using 3391 reflections with
F > 4σ(F), S 1.017). The complete crystallographic data set was deposited at the Cambridge Crystallographic
Data Center (deposit CCDC 969536).
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