Fluoro-containing heterocycles: VI. New derivatives of 1,3,4-thiadiazino[6,5,4-i,j]quinoline

Article abstract of DOI:10.1023/A:1013152700659

A series of new tricyclic fluoroquinolones was prepared by replacing fluorine atoms in derivatives of 2-R-8-Y-7-oxo-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6- carboxylic acids. In acids and esters containing a hydrogen atom in position 8 occurred replacement of F¹⁰ by amine rests, and in compounds with a fluorine in position 8 was substituted either F⁸ or F¹⁰ and F⁸ depending on the amine character.

Full text of DOI:10.1023/A:1013152700659

Russian Journal of Organic Chemistry, Vol. 37, No. 8, 2001, pp. 1169 1176. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 8, 2001,
pp. 1228 1235.
Original Russian Text Copyright
2001 by Nosova, Lipunova, Sidorova, Charushin.
Fluoro-containing Heterocycles: VI.* New Derivatives
of 1,3,4-Thiadiazino[6,5,4-i,j]quinoline**
E. V. Nosova, G. N. Lipunova, L. P. Sidorova, and V. N. Charushin
Ural State Technical University, Yekaterinburg, 620002 Russia
Received May 5, 2000
Abstract A series of new tricyclic fluoroquinolones was prepared by replacing fluorine atoms in derivatives
of 2-R-8-Y-7-oxo-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxylic acids. In acids and
esters containing a hydrogen atom in position 8 occurred replacement of F10 by amine rests, and in com-
pounds with a fluorine in position 8 was substituted either F8 or F10 and F8 depending on the amine character.
We formerly described a synthesis of ethyl 2-R-8-
three doublets of doublets. Note the difference in the
3
Y-7-oxo-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]- vicinal coupling constants J(F,F) in the 19F spectra
3
3
of these compounds: J(F10, F9) = 23.2 Hz, J(F8,
quinoline-6-carboxylates [2]. These compounds may
be regarded as key intermediates for preparation of
new derivatives of tricyclic fluoroquinolones that
belong to an important class of antibacterial sub-
stances [3, 4]. The polycyclic fluoroquinolonecarb-
oxylic acids containing a cycloalkylamine moiety are
known to possess high antibacterial activity and also
the other types of biological activity (antiviral, anti-
tumor) [5 7].
F9) = 20.1 Hz.
The substitution of fluorine in acids Ia, c by amine
rests was carried out for 2 4 h in boiling pyridine or
at heating for 2 4 h in acetonitrile in the presence of
catalytic quantities of 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) (Scheme 1). The structure of aminoacids
1
IIa f obtained was confirmed by H and 19F NMR
spectra (Table 2) and also by mass spectra. In the
19F NMR spectra of acids IIa f appears a signal from
one fluorine atom in the 118.6 119.9 ppm region
Aiming to obtain new tricyclic fluoroquinolones
we prepared in this study 2-R-8-Y-7-oxo-9,10-di-
fluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-
carboxylic2-R-8-Y-7-oxo-9,10-difluoro-7H-1,3,4-
thiadiazino[6,5,4-i,j]quinoline-6-carboxylic2-R-8-Y-
7-oxo-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]-
quinoline-6-carboxylic acids Ia d and investigated the
fluorine substitution in the compounds. The acids
Ia d were obtained by hydrolysis of the correspond-
ing ethyl esters by boiling for 3 h in a mixture of
acetic and hydrochloric acids at 4: 1 ratio. The struc-
3
with the vicinal coupling constant J 11.5 12.2 Hz
that corresponds to the replacement of F10 atom by an
1
amine moiety. In the H NMR spectra of compounds
IIa f the signal of H8 atom is observed as a doublet
with a coupling constant 3J 11.5 12.5 Hz in the
region 7.55 7.70 ppm. In the mass spectra of sub-
stituted acids IIa, c, e, f the peak of maximum
intensity is [M CO2]+ , and in the mass spectrum of
ethoxycarbonyl derivative IId it is the peak
[M COOC2H4]+ (Table 3).
1
ture of compounds Ia d was confirmed by H and
1
19F NMR spectra (Table 1). In the H NMR spectra
In the similar reaction of trifluoro-containing acids
Ib, d two fluorine atoms F8 and F10 are substituted
by amines. This finding is consistent with the
published data on simultaneous substitution of F5
and F7 atoms by amine rests in the esters of
are present the signals from the protons of the
carboxy group, R substituent, and also a singlet from
H5 in the 8.5 8.6 ppm region; in the spectra of acids
Ia, c (Y = H) the signal of H8 appears as a doublet
of doublets in the 9.0 ppm region. In the 19F NMR
spectra of acids Ia, c appear two signals of fluorine
atoms in the form of doublet of doublets, and in the
19F NMR spectra of compounds Ib, d are present
N1-substituted
tetrafluoroquinolone-3-carboxylic
1
acids [8]. In the H NMR spectra of disubstituted
acids IV are observed proton signals from two cyclo-
alkylamine rests (Table 4), and in their 19F NMR
spectra the only fluorine atom appears as a singlet
in 131.0 132.0 ppm region. The mass spectra of
acids IV are also consistent with the assumed struc-
ture (Table 5).
*
For communication V, see [1].
The study was carried out under financial support of the Rus-
sian Foundation for Basic Research (grant no. 00-03-32785a).
**
1070-4280/01/3708-1169$25.00 2001 MAIK Nauka/Interperiodica

1170
NOSOVA et al.
Scheme 1.
I, R1 = pyrrolidin-1-yl (a, b), cyclohexylamino (c, d); Y = H (a, c), F (b, d); II, R1 = pyrrolidin-1-yl (a d),
cyclohexylamino (e, f); NR2R3 = pyrrolidin-1-yl (a, e), 4-methylpiperazin-1-yl (b), morpholino (c, f), 4-ethoxy-
carbonylpiperazin-1-yl (d); IIIa, R1 = pyrrolidin-1-yl, NR2R3 = morpholino; IV, R1 = pyrrolidin-1-yl (a d),
cyclohexylamino (e); NR2R3
Me$©2N(CH2)3NH (d).
=
pyrrolidin-1-yl (a, e), morpholino (b), 4-ethoxycarbonylpiperazin-1-yl (c),
Table 1. 1H and 19F NMR spectra of 7-oxo-2-R-9-fluoro-10-Y-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxylic
acids Ia d
Compd.
no.
1H NMR spectrum, , ppm, coupling constant, Hz
19F NMR spectrum, F, ppm,
d.d (coupling constant, Hz)
H5,
s
H8
COOH,
br.s
R
3
3
3
Ia
Ib
8.54 7.94 d.d J(H8, F9)
10.3, 4J(H8, F10)
8.6
14.45 1.99 m [4H, (CH2)2], 135.17 [F9, J(F9, F10) 21.4, J(F9, H8) 10.3],
3.58 m [4H, N(CH2)2] 129.03 [F10, 3J(F10, F9) 21.4, 4J(F10, H8)
8.6]
3
3
8.60
14.6 2.0 m [4H, (CH2)2], 159.86 [F9, J(F9, F10) 23.2, J(F9, F8) 20.1],
3.6 m [4H, N(CH2)2] 138.60 [F8, 3J(F8, F9] 20.1, 4J(F8, F10)
10.4], 126.66 [F10, 3J(F10, F9) 23.2,
4J(F10, F8) 10.4]
Ic
8.50 8.0 d.d 3J(H8, F9)
10.4, 4J(H8, F10)
7.9
14.7 1.2 m [4H, (CH2)2], 154.26 [F10, 3J(F10, F9) 22.0, 4J(F10, H8)
1.9 m [6H, (CH2)3], 7.9], 134.51 [F9, 3J(F9, F10) 22.0, 3J(F9,
3.81 m [1H, C_HNH], H8) 10.4]
7.8 d [1H, NH]
3
3
Id
8.54
14.56 1.15 m [4H, (CH2)2], 160.09 [F9, J(F9, F10) 23.2, J(F9, F8) 20.1]
20.1], 1.9
m
[6H,
139.34 [F8, 3J(F8, F9) 20.1, 4J(F8, F10)
(CH2)3], 3.77 m [1H, 9.8], 126.98 [F10, 3J(F10, F9) 23.2,
C_HNH], 8.03 d [1H, 4J(F10, F8) 9.8]
NH, 3J 7.0]
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

FLUORO-CONTAINING HETEROCYCLES: VI.
1171
1
Table 2. H NMR spectra of 2-R-7-oxo-10-Z-9-fluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxylic acids IIa f
Compd.
no.
Chemical shift, , ppm, coupling constant, Hz
H5,
s
H8, d
COOH,
br.s
R
Z
[3J(H8, F9)]
IIa
IIb
8.43
8.45
7.66 [12.2]
7.61 [11.9]
15.0
14.9
1.95 m [4H, (CH2)2],
3.53 m [4H, N(CH2)2]
2.02 m [4H, (CH2)2],
3.57 m [4H, N(CH2)2]
1.95 m [4H, (CH2)2],
3.22 m [4H, N(CH2)2]
2.85 s (3H, NCH3),
3.37 m [4H, N(CH2)2],
3.57 m [4H, N(CH2)2]
3.12 m [4H, N(CH2)2],
3.55 m [4H, O(CH2)2]
1.26 t (3H, CH3),
IIc
IId
8.45
8.38
7.68 [11.9]
7.55 [11.6]
14.9
14.4
1.96 m [4H, (CH2)2],
3.76 m [4H, N(CH2)2]
2.02 m [4H, (CH2)2],
3.55 m [4H, N(CH2)2]
3.07 m [4H, N(CH2)2],
3.55 m [4H, N(CH2)2],
4.10 q (2H, OCH2)
IIe
IIf
8.50
8.51
7.64 [12.2]
7.70 [12.2]
14.81
14.89
1.30 m [6H, (CH2)3],
1.76 m (2H, CH2),
1.95 m (2H, CH2),
3.81 m (1H, C_HNH),
7.59 m (1H, NH)
1.30 m [6H, (CH2)3],
1.74 m (2H, CH2),
1.99 m (2H, CH2),
3.75 m (1H, C_HNH),
7.84 d (1H, NH, 3J 7.0)
1.95 m [4H, (CH2)2],
3.25 m [4H, N(CH2)2]
3.27 m [4H, N(CH2)2],
3.75 m [4H, O(CH2)2]
Scheme 2.
V, R1 = pyrrolidin-1-yl (a, b), morpholino (c), hexamethyleneimino (d); Y = H (a), F (b d); VIa, VIIa, R1 =
NR2R3
= = = pyrrolidin-1-yl (a), morpholino (b),
pyrrolidin-1-yl; Y = H; VIII, NR2R3 morpholino, R1
hexamethyleneimino (c); IX, R1 = pyrrolidin-1-yl; NR2R3 = pyrrolidin-1-yl (a), Me2N(CH2)3NH (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

1172
NOSOVA et al.
Table 3. 19F NMR and mass spectra of
2-R-7-oxo-10-Z-9-fluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]-
quinoline-6-carboxylic acids IIa f
With morpholine is first replaced atom F8 to afford
derivative IIIa, and at prolonged process and amine
excess forms disubstituted quinolone IVa. The struc-
ture of 8-monosubstituted aminoacid IIIa was con-
1
Compd. F, ppm
no. [J(F9, H8),
Hz]
Mass spectrum,
m/z (Irel, %)
firmed by the data of H and 19F NMR and mass
spectra. In the 19F NMR spectrum of compound IIIa
the signals from two fluorine atoms appear as
3
doublets with J 22.0 22.5 Hz corresponding to a
IIa
IIb
118.61 d 402 (84), M+ , 358 (100), 325 (3),
[12.2] 288 (5), 261 (12), 234 (21)
119.73 d 431 (41), M+ , 417 (10), 387 (27),
vicinal coupling constant 3J(F9, F10). This pattern
indicates that F8 atom is substituted by an amine rest.
It should be noted that in bicyclic 5,6,7,8-tetra-
fluoro-containing esters of 4-oxo-1,4-dihydroquino-
line-3-carboxylic acids the amine replaces first of all
F5 atom. In this connection we decided to study the
substitution of fluorine atoms in esters V by amines
(Scheme 2).
[12.0]
307 (10), 271 (13), 235 (20), 221
(11), 220 (11), 207 (21), 114 (13),
106 (18), 97 (27), 96 (35), 95 (37),
85 (26), 83 (31), 78 (22), 72 (100),
57 (62)
IIc
119.73 d 419 (82), M+ , 375 (100), 317 (27),
The atom F10 in ethyl 2-(pyrrolidin-1-yl)-9,10-di-
fluoro-7-oxo-7H-1,3,4-thiadiazino[6,5,4-i,j]-quino-
line-6-carboxylate (Va) was substituted by pyrrolidine
at boiling in acetonitrile for 2 h in the presence of the
catalytic quantity of DBU. The structure of the sub-
[12.0]
279 (11), 248 (12), 220 (28), 192
(25)
IId
IIe
119.89 d 517 (1), M+ , 489 (96), 445 (100),
[11.5]
247 (26), 219 (31)
118.92 d 430 (81), M+ , 386 (100), 304 (31),
1
stituted ester VIa was confirmed by H and 19F NMR
[12.1]
271 (66), 261 (20), 258 (14), 234
(26)
and mass spectra (Table 6). From ester VIa was pre-
pared hydrazide VIIa whose structure was also
proved by the spectral data (Table 6). In the 1H NMR
spectrum are present the proton signals from groups
C(O)NHNH2, R , NR2R3, and singlet from H5 atom
at 8.43 ppm.
IIf
119.82 d 446 (58), M+ , 403 (25), 402 (100),
[12.0]
320 (63), 287 (16), 262 (52), 235
(15), 221 (18), 220 (58), 192 (37),
63 (82), 55 (95)
Table 4. 1H NMR spectra of 2-R-8,10-Z2-7-oxo-9-fluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxylic acids
IVa e
Compd.
no.
Chemical shift, , ppm
R
H5, s
8.33
8.42
8.69
COOH, br.s
15.55
Z
IVa
IVb
IVc
1.91 m [4H, (CH2)2],
3.47 m [4H, N(CH2)2]
1.96 m [4H, (CH2)2],
3.76 m [4H, N(CH2)2]
2.01 m [4H, (CH2)2],
3.65 m [4H, N(CH2)2]
1.91 m [8H, 2(CH2)2], 3.18 m [4H, N(CH2)2],
3.37 m [4H, N(CH2)2]
15.59
3.10 m [4H, N(CH2)2], 3.24 m [4H, N(CH2)2],
3.56 m [4H, O(CH2)2], 3.75 m [4H, O(CH2)2]
1.29 t (6H, 2CH3), 3.09 m [4H, N(CH2)2],
3.21 m [4H, N(CH2)2], 3.55 m [4H, N(CH2)2],
3.59 m [4H, N(CH2)2], 4.18 q (4H, 2OCH2)
1.79 m (2H, CH2), 1.82 m (2H, CH2),
2.23 s [6H, N(CH3)2], 2.29 s [6H, N(CH3)2],
2.38 m (2H, CH2), 2.48 m (2H, CH2),
3.45 m (2H, CH2), 3.60 m (2H, CH2),
5.93 br.s (1H, NH), 9.30 br.s (1H, NH)
1.97 m [8H, 2(CH2)2], 3.25 m [4H, N(CH2)2],
3.51 m [4H, N(CH2)2]
15.45
IVda
8.45
8.48
15.1
2.00 m [4H, (CH2)2],
3.51 m [4H, N(CH2)2]
IVe
15.57
1.28 m [4H, (CH2)2],
1.61 m [6H, (CH2)3],
3.82 m (1H, C_HNH),
3
8.1 d (1H, NH, J 7.0 Hz)
a
1H NMR spectrum was recorded in CDCl3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

FLUORO-CONTAINING HETEROCYCLES: VI.
1173
In the spectra of compounds VIa and VIIa the
Table 5. 19F NMR and mass spectra of 2 2-R-8,10-Z2-7-
oxo-9-fluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-
carboxylic acids IVa e
signal of H8 proton appears as a doublet at 7.6 ppm
3
with the coupling constant J(H8, F9) 12.5 Hz. In the
19F NMR spectra of ester VIa and hydrazide VIIa
the signal of F9 atom is a doublet in the region
120.8 ppm. The mass spectra of these compounds
contain characteristic peaks m/z 385 [M OC2H5]+ for
ester and [M NHNH2]+ for hydrazide.
Compd. F, ppm
no.
(1F, F9)
Mass spectrum, m/z (Irel, %)
IVa 131.36 s 471 (18), M+ , 375 (85), 358 (70), 347
(60), 306 (20), 288 (25), 262 (100),
234 (54)
In reactions with esters V (Y = F) as with acids
Ib, d the amines replace both F8 and F10 providing
diamino derivatives IX. Using morpholine we
succeeded in isolating 8-monosubstituted derivatives
VIII. The structure of compounds VIII, IX was
IVb 132.02 s 503 (23), M+ , 485 (14), 444 (13), 390
(44), 389 (88), 374 (53), 348 (49),
343 (21), 304 (31), 286 (15), 243 (29),
220 (100), 192 (27)
1
confirmed by H and 19F NMR and mass spectra
IVc 131.11 s 645 (11), M+ , 601 (11), 556 (12), 543
(16), 517 (18), 505 (28), 499 (26),
473 (28), 460 (86), 447 (68), 421 (36),
403 (21), 235 (21), 96 (29), 56 (100)
IVd 151.76 s 533 (3), M+ , 475 (9), 457 (22), 86 (13),
85 (27), 84 (79), 72 (30), 70 (13),
59 (16), 58 (100)
(Table 6). In the 19F NMR spectra of monosubstituted
esters VIII are observed two fluorine signals as
doublets in the region 149 and 132 ppm with the
coupling constants 3J(F9,F10) 23.0 23.4 Hz. It is
interesting that 8-morpholino-substituted compounds
VIIIa, b, IIIa in the mass spectra have a peak of
maximum intensity m/z 322 corresponding to
[M COOC2H4 R]+ for esters VIII, and [M CO2 R]+
for acid IIIa. Compounds II IV, VI IX synthesized
in the course of this investigation are potential bio-
logically active substances.
IVe 131.11 s 499 (3), M+ , 375 (66), 358 (28), 347
(24), 332 (27), 329 (22), 306 (31),
288 (18), 262 (100), 234 (37)
encies 250.135 MHz for protons and 75.38 MHz
for fluorine from solutions in DMSO-d6; internal
reference for protons was TMS, for fluorine hexa-
fluorobenzene. Mass spectra were measured on
Finnigan MAT-8200 instrument.
EXPERIMENTAL
1H and 19F were registered on spectrometers Bruker
WP-250 and Bruker WP-80-SY at operating frequ-
1
Table 6. H and 19F NMR spectra and mass spectra of compounds VI IX
Compd.
no.
Chemical shift, , ppm in 1H NMR spectra
R, m (4H)
8.30 1.97 [CH2)2], 3.49 [N(CH2)2] 1.97 m [4H, (CH2)2], 3.16 m [4H, N(CH2)2]
OCH2CH3 (NHNH2) H5, s
Z
VIa 1.33 t (3H, CH3)
4.22 q (2H, OCH2)
VIIa 4.40 br.s (2H, NH2) 8.43 1.98 [CH2)2], 3.52 [N(CH2)2] 1.98 m [4H, (CH2)2], 3.17 m [4H, N(CH2)2]
10.48 s (1H, CONH)
VIIIa 1.31 t (3H, CH3),
4.21 q (2H, OCH2)
VIIIb 1.32 t (3H, CH3),
4.22 q (2H, OCH2)
8.21 1.97 [CH2)2, 3.72 [N(CH2)2] 3.17 m [4H, N(CH2)2], 3.53 m [4H, O(CH2)2]
8.24 3.52 [N(CH2)2], 3.71 [O(CH2)2] 3.18 m [4H, N(CH2)2], 3.69 m [4H, O(CH2)2]
VIIIc 1.33 t (3H, (CH3),
4.22 q (2H, OCH2)
8.20 1.58 [CH2)2], 1.79 [(CH2)2], 3.18 m [4H, N(CH2)2], 3.62 m [4H, O(CH2)2]
3.73 [N(CH2)2]
IXa 1.35 t (3H, CH3),
4.33 q (2H, OCH2)
8.36 1.97 [CH2)2], 3.54 [N(CH2)2] 1.97 m [8H, 2(CH2)2], 3.21 m [4H, N(CH2)2],
3.54 · [4H, N(CH2)2]
IXb 1.31 t (3H, CH3),
4.19 q (2H, OCH2)
8.11 1.97 [CH2)2], 3.52 [N(CH2)2] 1.69 m (2H, CH2), 1.72 m (2H, CH2),
2.15 s (6H, NMe2), 2.20 s (6H, NMe2),
2.30 m (2H, CH2), 2.37 m (2H, CH2),
3.28 m (2H, CH2), 3.39 m (2H, CH2),
5.65 br.s (1H, NH), 10.05 br.s (1H, NH)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

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NOSOVA et al.
2-R-10-Z-7-Oxo-9-fluoro-7H-1,3,4-thiadiazino-
Table 6. (Contd.)
[6,5,4-i,j]quinoline-6-carboxylic acids II. (a) To a
solution of 0.7 g (2 mmol) of 7-oxo-2-(pyrrolidin-1-
yl)-9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quino-
line-6-carboxylic acid (Ia) in 8 ml of pyridine was
added 0.6 ml )8 mmol) of pyrrolidine, and the mix-
ture was boiled for 3 h. After cooling the precipitate
was filtered off and washed with ether. To the
precipitate was added 4 ml of 2 N HCl and 4 ml of
Compd. Chemical shift
no. in 19F NMR spectra,
F, ppm (J, Hz)
Mass spectrum, m/z
(Irel, %)
VIaa 120.78 d [1F, F9, 430 (48), M+ , 385 (5), 358
3J(F9, H8) 12.4]
(100), 261 (11), 234 (16),
70 (11)
VIIab 120.78 d [1F, F9, 416 (56), M+ , 386 (32), 385 methanol, the mixture was boiled for 30 min, the
3J(F9, H8) 12.4]
(100), 289 (28), 243 (19),
192 (11)
precipitate of compound IIa was filtered off and re-
crystallized from DMSO. Yield 0.4 g (50%). Similar-
ly was prepared compound IIc. (b) To a dispersion
of 0.85 g (2.42 mmol) of acid Ia in 15 ml of an-
hydrous acetonitrile was added 1,15 ml (7.26 mmol)
of ethoxycarbonylpiperazine and 4 drops of DBU.
The mixture was boiled for 3 h, on cooling the
precipitate of compound IId was filtered off and
recrystallized from ethanol. Yield 0.65 g (55%).
VIIIa 149.27 d [1F, F9, 464 (5), M+ , 369 (12),
3J(F9, F10) 23.4], 368 (60), 323 (25), 322
132.55 d [1F, F10, (100), 307 (26), 294 (28),
3J(F10, F9) 23.4]
VIIIb 149.45 d [1F, F9,
3J(F9, F10) 22.9],
238 (19), 209 (13)
132.56 d [1F, F10,
3J(F10, F9) 23.4]
Compounds IIb, c, e, f were prepared similarly
and recrystallized from DMSO.
VIIIc 149.19 d [1F, F9, 492 (3), M+ , 369 (12), 368
3J(F9, F10) 23.4], (62), 335 (12), 323 (27),
132.34 d [1F, F10, 322 (100), 294 (24), 238
8-Morpholino-7-oxo-2-(pyrrolidin-1-yl)-9,10-
difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-
carboxylic acid (IIIa). To 0.45 g (1.2 mmol) of acid
Ib in 15 ml of anhydrous acetonitrile was added
0.21 ml (2.4 mmol) of morpholine and 3 drops of
DBU. The reaction mixture was boiled for 1 h,
cooled, the precipitate was filtered off and recrystal-
3J(F10, F9) 23.3]
(16), 223 (12)
IXa 134.79 s (1F, F9)
499 (5), M+ , 403 (46), 386
(14), 375 (28), 374 (48),
360 (20), 358 (26), 346
(14), 334 (26), 306 (19),
263 (17), 262 (100)
1
IXb 148.82 d.d [1F, F9, 561 (1), M+ , 503 (14), 457
lized from DMSO. Yield 0.35 g (67%). H NMR
4J(F9, NH) 1.0]
(26), 375 (10), 266 (11),
85 (13), 84 (72), 72 (27),
59 (15), 58 (100)
spectrum (DMSO-d6, , ppm): 1.95 m [4H, (CH2)2],
3.27 m [4H, N(CH2)2], 3.52 m [4H, O(CH2)2], 3.75
m [4H, N(CH2)2], 8.42 s (1H, H5), 15.28 br.s
(1H, COOH). 19F NMR spectrum (DMSO-d6,
,
F
3
ppm): 147.73 d [F9, J(F9, F10) 22.5 Hz], 129.14 d
(H8): a 7.56 d [J(H8, F9) 12.5 Hz], 7.57 d [J(H8, F9) 12.6 Hz].
b
3
[F10, J(F10, F9) 22.0 Hz]. Mass spectrum [m/z (Irel,
%)]: 436 (5), M+ , 340 (48), 322 (100), 307 (11), 294
Yields, melting points and elemental analyses of
compounds I IV, VI IX are listed in Table 7.
(25), 238 (15).
2-R-8,10-Z2-7-Oxo-9-fluoro-7H-1,3,4-thiadi-
azino[6,5,4-i,j]quinoline-6-carboxylic acids IV. (a)
To a dispersion of 0.8 g (2.2 mmol) of acid Ib in
10 ml of anhydrous acetonitrile was added 0.6 ml
(9 mmol) of pyrrolidine and 5 drops of DBU. The
reaction mixture was boiled for 2 h, cooled, the
precipitate was filtered off. To the precipitate was
added 5 ml of 2 N HCl, the mixture was boiled for
30 min, the precipitate was filtered off and recrystal-
lized from DMSO, Yield 0.7 g (68%).
2-R-8-Y-Ethyl 7-oxo-2,10-bis(pyrrolidin-1-yl)-9-
fluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-
carboxylate-7-oxo-9,10-difluoro-7H-1,3,4-thiadi-
azino[6,5,4-i,j]quinoline-6-carboxylic acids I. To
1.1 g (2.9 mmol) of ethyl 7-oxo-2-(pyrrolidin-1-yl)-
9,10-difluoro-7H-1,3,4-thiadiazino[6,5,4-i,j]quino-
line-6-carboxylate (Va) was added 25 ml of a mixture
HCl AcOH (1: 4). The reaction mixture was boiled
for 3 h, cooled, diluted with water, the precipitate of
acid Ia was filtered off and recrystallized from
DMSO. Yield 0.75 g (74%).
Similarly were prepared derivatives IVb e;
compounds IVc, d were recrystallized from ethanol.
In the synthesis of compound IVb the reaction time
was prolonged to 6 h. (b) To 0.5 g (1.15 mmol) of
acid IIIa in 12 ml of anhydrous acetonitrile was
In a similar way were prepared acids Ib d. Mass
spectrum of compound Ib [m/z (Irel, %]: 369 (100),
M+ , 325 (93), 256 (12), 226 (16), 201 (22), 178 (17),
157 (14).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

FLUORO-CONTAINING HETEROCYCLES: VI.
1175
Table 7. Yields, melting pointsa, and elemental analyses of compounds synthesized
Compd.
no.
mp,
C
Yield,
%
Found, %
H
Calculated, %
H
Formula
C
N
C
N
11.96
Ia
Ib
Ic
Id
IIa
IIb
IIc
IId
>260
74
78
69
71
50
24
68
55
72
74
67
62
76
80
43
57
61
92
65
52
49
72
77
51.14
47.96
53.62
51.19
56.70
55.90
54.33
53.87
58.21
55.80
52.03
58.18
54.33
53.70
55.78
59.80
58.41
54.61
54.13
52.21
58.85
59.64
57.61
3.10
2.78
4.16
3.76
4.77
4.98
4.90
4.79
5.12
4.99
4.31
5.63
4.9
5.86
6.56
6.27
5.29
4.99
4.59
4.49
5.15
6.09
7.02
11.88
11.34
11.08
9.76
13.55
16.11
13.0
14.02
12.86
12.71
13.02
14.80
13.73
15.16
18.58
13.86
12.97
20.00
12.28
11.85
11.51
13.76
17.61
C15H11F2N3O3S
C15H10F3N3O3S
C17H15F2N3O3S
C17H14F3N3O3S
C19H19FN4O3S
C20H22FN5O3S
C19H19FN4O3S
C22H24FN5O5S
C21H23FN4O3S
C21H23FN4O4S
C19H18F2N4O4S
C23H26FN5O3S
C23H26FN5O5S
C29H36FN7O7S
C25H36FN7O3S
C25H30FN5O3S
C21H23FN4O3S
C19H21FN6O2S
C21H22F2N4O4S
C21H22F2N4O4S
C23H26F2N4O4S
C25H30FN5O3S
C27H40FN7O3S
51.28
48.78
53.82
51.38
56.71
55.67
54.54
53.98
58.59
56.49
52.29
58.58
54.86
53.94
56.27
60.10
58.59
54.79
54.30
52.49
56.09
60.10
57.73
3.16
2.73
3.99
3.55
4.76
5.14
4.58
4.94
5.38
5.19
4.16
5.56
5.20
5.62
6.80
6.05
5.38
5.08
4.77
4.62
5.32
6.05
7.18
240 242
258 260
>260
230 232
246 248
>260
254 256
>260
>260
251 253
245 247
279 281
216 218
121 123
>260
235 237
246 248
166 168
218 220
188 190
240 242
206 208
11.38
11.08
10.57
13.92
16.23
13.39
14.31
13.02
12.55
12.84
14.85
13.91
15.18
18.37
14.02
13.01
20.18
12.06
11.66
11.38
14.02
17.45
IIe
IIf
IIIa
IVa
IVb
IVcb
IVdb
IVe
VIa
VIIa
VIIIab
VIIIbb
VIIIcb
IXa
IXbb
a
b
Solvent for crystallization: DMSO,
ethanol.
added 1 ml (11.5 mmol) of morpholine and 8 drops
of DBU. The reaction mixture was boiled for 6 h, on
cooling the precipitate of compound IVb was filtered
off and recrystallized from DMSO. Yield 0.45 g
(83%).
off and recrystallized from DMSO. Yield 0.18 g
(92%).
Ethyl 2-R-8-(morpholin-1-yl)-7-oxo-9,10-di-
7fluoro-H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-
carboxyates VIII. To 0.2 g (0.5 mmol) of ester Vb
in 8 ml of anhydrous acetonitrile was added 0.2 ml
(2 mmol) of morpholine and 3 drops of DBU. The
reaction mixture was boiled for 2 h. On cooling the
precipitate of compound VIIIb was filtered off and
recrystallized from ethanol. Yield 0.12 g (52%).
Compounds VIIIa, c were obtained by the similar
procedure.
Ethyl 7-oxo-2,10-bis(pyrrolidin-1-yl)-9-fluoro-
7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carb-
oxylate (VIa). To 0.65 g (1.72 mmol) of ethyl ester
Va in 8 ml of anhydrous acetonitrile was added
0.37 ml (5.1 mmol) of pyrrolidine and 3 drops of
DBU. The reaction mixture was boiled for 2 h. On
cooling the precipitate of compound VIa was filtered
off and recrystallized from DMSO. Yield 0.45 g
(61%).
Ethyl 7-oxo-2-(pyrrolidin-1-yl)-8,10-Z2-9-fluoro-
7H-1,3,4-thiadiazino[6,5,4-i,j]quinoline-6-carboxy-
lates IX. To 0.4 g (1 mmol) of ester Vb in 5 ml of
anhydrous acetonitrile was added 0.15 ml (2.2 mmol)
of pyrrolidine and 3 drops of DBU. The reaction
mixture was boiled for 2 h. On cooling the precipitate
of compound IXa was filtered off and recrystallized
from ethanol. Yield 0.4 g (80%).
Hydrazide of 2-(pyrrolidin-1-yl)-7-oxo-10-(pyr-
rolidin-1-yl)-9-fluoro-7H-1,3,4-thiadiazino[6,5,4-
i,j]quinoline-6-carboxylic acid (VIIa). To 0,2 g
(0.47 mmol) of ethyl ester VIa in 3 ml of pyridine
was added 1.2 ml of 70% hydrazine hydrate. The
reaction mixture was heated to 80 C for 1.5 h. On
cooling the hydrazide VIIa precipitate was filtered
Compound IXb was obtained similarly.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001

1176
NOSOVA et al.
Khim. Farm. Zh., 1995, no. 9, pp. 5 19.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 8 2001