Synthesis of new fluorinated derivatives of quinolinecarboxylic acids

Article abstract of DOI:10.1023/A:1020965312463

Ethyl esters of 1-(7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl-5-X-6,7, 8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acids (X = H, F; Z = pyrrolidino-, piperidino-, hexamethylenimino-, morpholino-, thiomorpholino-) have been synthesized by the interaction of quinolone-3-carboxylic acid hydrazides with ethyl esters of 3-ethoxy-2-(polyfluorobenzoyl)acrylic acid. It was shown possible to cyclize intramolecularly the esters obtained with the formation of 1,3,4-oxadiazino[6,5,4-i.j]quinoline derivatives.

Full text of DOI:10.1023/A:1020965312463

Chemistry of Heterocyclic Compounds, Vol. 38, No. 8, 2002
SYNTHESIS OF NEW FLUORINATED
DERIVATIVES OF QUINOLINECARBOXYLIC ACIDS
E. V. Nosova, L. P. Sidorova, G. N. Lipunova, N. N. Mochul'skaya, O. M. Chasovskikh,
and V. N. Charushin
Ethyl esters of 1-(7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl)-5-X-6,7,8-trifluoro-4-
oxo-1,4-dihydroquinoline-3-carboxylic acids (X
=
H, F;
Z
=
pyrrolidino-, piperidino-,
hexamethylenimino-, morpholino-, thiomorpholino-) have been synthesized by the interaction of
quinolone-3-carboxylic acid hydrazides with ethyl esters of 3-ethoxy-2-(polyfluorobenzoyl)acrylic acid .
It was shown possible to cyclize intramolecularly the esters obtained with the formation of
1,3,4-oxadiazino[6,5,4-i,j]quinoline derivatives.
Keywords: quinolone-3-carboxylic acid hydrazides, 1,3,4-oxadiazino[6,5,4-i,j]quinolines, reactivity,
spectral characteristics.
In previous publications [1,2] we have reported the synthesis of 1,3,4-oxadiazino[6,5,4-i,j]quinoline
derivatives by the cyclization of ethyl esters of 3-(2-acyl-1-hydrazino)-2-[tetra(penta)fluorobenzoyl]acrylic acid.
In the present communication the synthesis is described of new derivatives of this system, viz.
compounds 1, 2, containing a substituted quinolone residue in position 2 (see Scheme). The ethyl esters of
1-(7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl)-5-X-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-
3-carboxylic acids 6a-e and 7a-e were obtained in 78-95% yield by heating the ethyl esters of 3-ethoxy-2-
(polyfluorobenzoyl)acrylic acids 3 and 4 with the hydrazides of substituted quinolone-3-carboxylic acids 5a-e in
toluene (2-3 h). The initial hydrazides 5a-e were synthesized in 67-94% yield from the corresponding ethyl
esters of 7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acids and hydrazine hydrate. The
1H NMR spectra of compounds 5 are given in Table 1.
1
The H NMR spectra of esters 6 and 7, containing two quinolone residues (Table 2), are characterized
by the presence of singlet signals for the NH group proton at 13.0-13.2 and a singlet for 2-H at 8.4-8.5 ppm. A
characteristic multiplet for the 5-H proton with a center at 7.9-8.0 ppm was observed in the spectra of
compounds 6a-e. The chemical shifts of the protons in positions 2', 5', and 8' for esters 6 and 7 were close to
those for the initial hydrazides 5. The 19F NMR spectrum of compound 7a contains five signals for fluorine
atoms (see Experimental).
It might have been supposed that hydrolysis of compounds 6 and 7 would occur at both the ester and
amide groups. However on boiling esters 6a and 7b in an acidic medium (HCl–CH3COOH, 1:4) their amide
groups were retained and the corresponding acids 8 and 9 were obtained, the structures of which were
1
confirmed by data of H NMR spectra (Table 3). In the case of compound 8 replacement occurred of the 7-F
atom by a residue of cyclic amine (pyrrolidine, 4-methylpiperazine) and products 10a,b were obtained
(Table 3).
__________________________________________________________________________________________
Urals State Technical University, Ekaterinburg 620002, Russia; e-mail: azine@htf.rcupi.e-burg.su.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1060-1066, August, 2002. Original article
submitted July 20, 1999; revision submitted June 5, 2000.
922
0009-3122/02/3808-0922$27.00©2002 Plenum Publishing Corporation

COOEt
3
O
2
1
N
O
O
X
F
O
F
O
O
4
5'
F
F
F
COOEt
OEt
4'
X
F
∆
3'
2'
F
NH
NH2
N
H
5
6'
+
PhMe
8
Z
N
Et
6
F
7'
N 1'
Et
Z
7
8'
3, 4
5a–e
F
6a–e, 7a–e
COOH
O
∆
X
O
6a, 7b
8
7
6
N
F
X
F
F
COOEt
HCl–AcOH,
1:4
9
5
10
4
F
N
N
1O
∆
F
6a,d,e, 7a
8, 9
PhMe
4'
COOH
O
K2CO3
2'
N 1'
O
5'
6'
∆
Et
N
F
8 +
YH
Py
8'
F
7'
F
Z
Y
10a,b
1a–c, 2
1a-c, 3, 6a-e, 8 X = H; 2, 4, 7a-e, 9 X = F; 1a, 2, 5a-7a, 8, 10a,b Z = pyrrolidino-;
5b-7b, 9 Z = piperidino-; 5c–7c Z = hexamethylenimino-; 1b, 5d-7d Z = morpholino-;
1c, 5e-7e Z = thiomorpholino-; 10 a Y = pyrrolidino-; b Y = 4-methylpiperazino-
TABLE 1. 1H NMR Spectra of Hydrazides 5a-e
Chemical shifts, δ, ppm, coupling constants (J), Hz
Com-
NH,
br. s
NH2,
NСH2,
СH2CH3,
pound
2-H, s
5'-H
8'-H, d
Z, m
br. s q, J = 7.2 t, J = 7.2
10.73 8.65 7.75,
6.57,
4.51
4.54
4.52
4.41
4.49
4.44
1.39
1.39
1.38
1.9-2.1
5a
3JHF = 14.8 4JHF = 7.6
(4H, 2CH2),
3.4-3.6
(4Н, N(CH2)2)
10.66 8.74 7.84,
7.06,
1.6-1.7
5b
5c
3JHF = 13.4 4JHF = 7.3
(6Н, 3CH2),
3.2-3.3
(4Н, N(CH2)2)
10.74 8.68 7.79,
6.79,
1.5-1.6
3JHF = 15.3 4JHF = 7.6
(4H, 2CH2),
1.8-1.9
(4H, 2CH2),
3.5-3.6
(4Н, N(CH2)2)
10.64 8.76 7.88,
7.09,
4.55
4.54
4.50
4.50
1.40
1.39
3.2-3.3
5d
5e
3JHF = 13.7 4JHF = 7.3
(4Н, N(CH2)2),
3.7-3.8
(4Н, O(CH2)2)
10.64 8.75 7.87,
7.13,
2.7-2.8
3JHF = 13.4 4JHF = 7.3
(4Н, S(CH2)2),
3.3-3.5
(4Н, N(CH2)2)
923

TABLE 2. 1H NMR Spectra of Hydrazides 5a-e
Com-
Chemical shifts, δ, ppm, coupling constants (J), Hz
pound
NH, s
13.18
2'-H, s 2-H, s
5-H
5'-H, d
8'-H, d
OCH2, q
CH2CH3, t
NСH2, q
СH2CH3, t
Z, m
8.76
8.85
8.76
8.85
7.96, ddd, 3J = 10.2,
7.75,
6.60,
4.20,
1.26,
4.45,
1.41,
1.8-2.0 (4Н, 2CH2),
6a
4J = 8.2, 5J = 1.8
3J = 14.7
4J = 7.6
J = 7.0
J = 7.0
J = 7.0
J = 7.0
3.5-3.7 (4H, N(CH2)2)
13.16
7.97, m
7.95, m
7.86,
7.09,
4.22,
1.27,
4.52,
1.44,
1.6-1.7 (2Н, CH2),
1.7-1.8 (4Н, 2CH2),
3.2-3.3 (4Н, N(CH2)2)
1.5-1.6 (4Н, 2CH2),
1.8-1.9 (4Н, 2CH2),
3.5-3.7 (4Н, N(CH2)2)
6b
3J = 13.4
4J = 7.0
J = 7.0
J = 7.0
J = 7.0
J = 7.0
13.15
8.80
8.80
7.75,
6.81,
4.21,
1.26,
4.46,
1.41,
6c
3J = 15.3
4J = 7.6
J = 7.0
J = 7.0
J = 7.0
J = 7.0
13.03
13.03
13.12
13.00
8.88
8.88
8.76
8.85
8.88
8.50
8.41
8.41
7.97, ddd, 3J = 10.3,
4J = 8.3, 5J = 1.8
7.88,
7.14,
4.21,
1.26,
4.52,
1.43,
3.3-3.4 (4Н, N(CH2)2),
6d
6e
7a
7b
3J = 13.7
4J = 7.3
J = 7.0
J = 7.0
J = 7.0
J = 7.0
3.8-3.9 (4Н, O(CH2)2)
7.97, m
7.86,
7.17,
4.21,
1.26,
4.53,
2.7-2.9 (4Н, S(CH2)2),
3.5-3.7 (4Н, N(CH2)2)
3J = 13.4
4J = 7.3
J = 7.0
J = 7.0
J = 7.0
7.75,
6.61,
4.20,
1.26,
4.45,
1.41,
1.8-2.0 (4Н, 2CH2),
—
3J = 14.2
4J = 7.7
J = 7.0
J = 7.0
J = 7.0
J = 7.0
3.5-3.6 (4Н, N(CH2)2)
7.85,
7.10,
4.21,
1.26,
4.52,
1.42,
1.6-1.7 (2Н, CH2),
1.7-1.8 (4Н, 2CH2),
3.2-3.3 (4Н, N(CH2)2)
—
3J = 13.6
4J = 7.3
J = 7.3
J = 7.3
J = 7.1
J = 7.1
13.09
8.79
8.40
7.77,
6.82,
4.21,
1.26,
4.48,
1.41,
1.5-1.6 (4Н, 2CH2),
1.8-1.9 (4Н, 2CH2),
3.5-3.7 (4Н, N(CH2)2)
7c
—
3J = 15.2
4J = 7.5
J = 7.0
J = 7.0
J = 7.0
J = 7.0
12.97
12.98
8.87
8.87
8.42
8.41
7.90,
7.14,
4.21,
1.26,
4.52,
1.43,
3.2-3.4 (4Н, N(CH2)2),
7d
7e
—
—
3J = 14.6
4J = 7.6
J = 7.1
J = 7.1
J = 7.0
J = 7.0
3.8-3.9 (4Н, O(CH2)2)
7.86,
7.18,
4.20,
1.26,
4.53,
1.43,
2.7-2.9 (4Н, S(CH2)2),
3.5-3.6 (4Н, N(CH2)2)
3J = 13.4
4J = 7.1
J= 7.1
J = 7.1
J = 7.0
J = 7.0

TABLE 3. 1H NMR Spectra of Quinolonecarboxylic Acids 8, 9, and 10a,b
Chemical shifts, δ, ppm, coupling constants (J), Hz
5'-H, d 8'-H, d
Com-
pound
COOH, s
13.93
NH, s
13.41
13.23
2'-H, s
8.80
2-H, s
8.77
5-H
8.12, m
—
Y
NСH2, q СH2CH3, t
Z, m
7.71,
6.60,
—
4.46,
1.41,
1.99 (4Н, 2CH2),
8
9
3J = 14.7
4J = 7.6
J = 7.0
J = 7.0
3.57 (4Н, N(CH2)2)
13.82
8.86
8.76
7.82,
7.10,
—
4.53,
1.42,
1.65 (2Н, CH2),
3J = 13.4
4J = 7.3
J = 7.0
J = 7.0
1.71 (4Н, 2CH2),
3.24 (4Н, N(CH2)2)
13.74
13.65
13.25
13.12
8.73
8.65
8.37
8.34
7.65, dd,
3J = 14.0;
5J = 1.5
8.00, dd,
3J = 13.7;
5J = 1.4
7.69,
6.57,
1.85 (4Н, m, 2CH2),
4.43,
1.44,
2.03 (4Н, 2CH2),
10a
10b
3J = 14.2
4J = 7.5
3.59 (4Н, m, N(CH2)2)
J = 7.0
J = 7.0
3.59 (4Н, N(CH2)2)
7.42,
6.84,
2.36 (3H, s, NCH3),
4.80,
1.53,
2.07 (4Н, 2CH2),
3J = 12.2
4J = 7.3
2.64 (4Н, m, N(CH2)2),
3.75 (4Н, m, N(CH2)2)
J = 6.7
J = 6.7
3.35 (4Н, N(CH2)2)
TABLE 4. 1H NMR Spectra and Mass Spectra of the Tricyclic Condensed Esters 1a-c and 2
Com-
Chemical shifts, δ, ppm, coupling constants (J), Hz
m/z (I, %)
pound
5-H, s 2'-H, s
8-H
5'-H, d
8'-H, d
NСH2, q
СH2CH3, t
OСH2, q
СH2CH3, t
Z, m
8.16
8.38
8.37
8.22
8.30
8.53
8.53
8.38
7.44, m
7.55,
6.46,
4.46,
1.58,
4.24,
1.32,
1.9-2.1 (4Н, 2CH2),
M+ 552 (85), 507 (9),
1а
1b
1c
2
3J = 11.6
4J = 7.2
J = 7.1
J = 7.1
J = 7.1
J = 7.1
3.4-3.6 (4Н, N(CH2)2)
480 (49), 284 (100), 240 (34),
223(19), 201 (14)
7.56, dd,
7.80,
7.05,
4.43,
1.44,
4.24,
1.30,
J = 7.0
3.2-3.3 (4Н, N(CH2)2), M+ 568 (31), 523 (5),
3J = 10.5; 3J = 13.4
4J = 7.0
J = 7.0
J = 7.0
J = 7.0
3.8-3.9 (4Н, O(CH2)2)
496 (37), 301 (27), 243 (100)
4J = 7.4
7.57, m
—
7.78,
7.08,
4.42,
1.44,
4.24,
1.30,
J = 7.0
2.7-2.9 (4Н, S(CH2)2),
3.5-3.7 (4Н, N(CH2)2)
M+ 584 (31), 539 (4),
512 (33), 438 (11), 317 (16),
243 (100)
3J = 13.4
4J = 7.0
J = 6.9
J = 6.9
J = 7.0
7.62,
6.44,
4.33,
1.42,
4.21,
1.29,
J = 7.0
1.9-2.0 (4Н, 2CH2),
M+ 570 (28), 525 (3),
498 (20), 285 (100)
3J = 12.3
4J = 7.1
J = 6.8
J = 6.8
J = 7.0
3.4-3.6 (4Н, N(CH2)2)

On boiling amides 6a,d,e and 7a in toluene in the presence of K2CO3 (3-4 h) an intramolecular
cyclization occurs with the participation of the amide group oxygen atom, leading to the formation of an
oxadiazine ring (yields of the corresponding products were 75-94%). The obtained ethyl esters of
2-(7-Z-1-ethyl-6-fluoro-4-oxo-3-quinolinyl)-8-X-9,10-difluoro-7-oxo-7H-1,3,4-oxadiazino[6,5,4-ij]quinoline-6-
carboxylic acids 1a-c and 2 may be considered as a new type of substituted tricyclic fluoroquinolone containing
a second quinolone fragment.
The data of the 1H NMR spectra of compounds 1 and 2 (Table 4) indicate the closing of the oxadiazine
ring. The signal for the NH group proton is absent, the signals of the protons in positions 5 and 2' are displaced
towards high field by 0.3-0.4 ppm, and the signal of the 8-H proton is displayed as a doublet of doublets
(3J = 10.5, 4J = 7.4 Hz), in difference to the initial esters 6 and 7 in which this signal has the shape of a doublet
of doublets of doublets.
TABLE 5. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С
Yield, %
C
H
N
59.34
58.95
4.42
4.42
9.80
9.82
>250
>250
94
80
75
82
91
94
73
69
67
78
89
87
89
87
95
91
93
91
89
83
70
64
78
1а
1b
1c
2
C28H23F3N4O5·H2O
C28H23F3N4O6·H2O
57.70
4.30
9.38
57.34
4.30
9.55
C28H23F3N4O5S·H2O
C28H22F4N4O5·H2O
C16H19FN4O2
55.17
55.81
4.15
4.18
8.78
9.30
>250
56.46
3.89
10.02
>250
57.15
4.11
9.52
60.15
60.37
6.07
6.02
17.64
17.60
259-261
255-257
226-228
250-252
246-248
178-180
179-182
>250
5а
5b
5c
5d
5e
6а
6b
6c
6d
6e
7а
7b
7c
7d
7e
8
C17H21FN4O2
61.33
6.27
17.03
61.43
6.37
16.86
C18H23FN4O2
62.29
62.41
6.57
6.69
16.00
16.17
C16H19FN4O3
57.42
5.74
16.68
57.48
5.73
16.76
C16H19FN4O2S
54.78
54.84
5.45
5.47
16.33
15.99
C28H24F4N4O5
58.31
4.53
10.06
58.74
4.23
9.79
C29H26F4N4O5·H2O
C30H28F4N4O5·H2O
C28H24F4N4O6·H2O
C28H24F4N4O5S·H2O
C28H23F5N4O5
57.30
57.62
4.73
4.67
9.34
9.27
58.18
4.93
9.16
58.25
4.89
9.06
55.05
55.45
4.38
4.32
9.20
9.24
178-179
172-174
197-200
178-179
267-268
198-200
>250
54.28
4.16
9.16
54.02
4.21
9.00
57.46
56.95
3.76
3.93
9.26
9.49
C29H25F5N4O5
57.56
4.37
9.21
57.62
4.17
9.27
C30H27F5N4O5·H2O
C28H23F5N4O6·2H2O
C28H23F5N4O5S
56.76
56.60
4.72
4.59
8.90
8.80
51.75
4.19
9.18
52.34
4.24
8.72
54.68
54.02
4.01
3.72
9.00
9.00
C26H20F4N4O5·0.5H2O
C27H21F5N4O5·H2O
C30H28F3N5O5·H2O
C31H31F3N6O5·2H2O
56.46
3.89
10.02
>250
56.44
3.82
10.13
53.78
54.55
3.71
3.90
9.06
9.42
>250
9
59.18
4.79
11.36
>250
10a
10b
58.72
4.93
11.41
55.79
56.36
5.22
5.34
12.59
12.72
>250
926

The chemical shifts of the 5'-H and 8'-H protons and of the protons of the cyclic amine residue were
changed insignificantly. The mass spectra of compounds 1 and 2 were characterized by the presence of intense
peaks for the molecular ions. The presence of [M-45]+ and [M-72]+ peaks is caused by fission of ethoxy and
carbethoxy groups. Further fragmentation occurs with breaking of the oxadiazine ring.
In conclusion, new derivatives of bi- and tricyclic fluoroquinolones have been obtained. Acids 8 are not
only intermediates for the synthesis of new tricyclic fluoroquinolones but are of separate interest, since under
defined conditions two reactive fluoroquinolone fragments may be released, which may possibly lead to a
change in the spectrum of biological activity.
EXPERIMENTAL
The 1H NMR spectra were obtained on a Bruker WP-250 (250 MHz) instrument, solvent was DMSO-d6,
internal standard TMS. The 19F NMR spectra were taken on a Bruker WP-80 (80 MHz) instrument, solvent was
DMSO-d6, internal standard hexafluorobenzene. The mass spectra were recorded on a Varian MAT 311A
spectrometer. Plotting conditions: accelerating voltage 3 kV, cathode emission current 300 µA, energy of
ionizing electrons 70 eV, samples were inserted directly into the ion source.
Hydrazides of 7-Z-1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acids (5a-e). A
suspension of 7-Z-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid ethyl ester (6 mmol) and
hydrazine hydrate (4.5 ml) in pyridine (10 ml) was maintained for 1 h at 80°C. The reaction mixture was cooled
to room temperature, dissolved in distilled water (40 ml), and acetic acid added to pH 5-6. The precipitated solid
was filtered off, washed with water, with ethanol, and with ether.
Ethyl Esters of 1-(7-Z-1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl)-5-X-6,7,8-
trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic Acids (6a-e, 7a-e). Ethyl ester 3 or 4 (0.95 mmol) was
added to a suspension of hydrazide 5a-e (0.94 mmol) in absolute toluene (8 ml). The reaction mixture was
boiled for 2 h, then cooled. The precipitate of 6 or 7 was filtered off and recrystallized from acetonitrile.
19F NMR spectrum of compound 7a, , ppm: 161.41 (1F, m); 155.29 (1F, m); 149.80 (1F, m); 143.69 (1F, m);
δ
128.31 (1F, m).
Ethyl Esters of 2-(7-Z-1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinolinyl)-8-X-9,10-difluoro-7-oxo-7H-
1,3,4-oxadiazino[6,5,4-i,j]quinoline-6-carboxylic Acids (1a-c, 2). Calcined potassium carbonate (1.1 mmol)
was added to a suspension of amide 6a,d,e or 7a (0.85 mmol) in absolute toluene (15 ml). The reaction mixture
was boiled for 3-4 h and cooled. The solid product 1 or 2 was filtered off, washed with water, and recrystallized
from DMSO.
1-(7-Z-1-Ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbamoyl)-5-X-6,7,8-trifluoro-4-oxo-1,4-
dihydroquinoline-3-carboxylic Acids (8, 9). A solution of compound 6a or 7b (1 mmol) in a mixture (25 ml)
of hydrochloric and acetic acids (1:4) was boiled for 3 h. The reaction mixture was cooled, diluted with water,
the solid product 8 or 9 was filtered off, and recrystallized from DMSO.
1-(1-Ethyl-6-fluoro-4-oxo-7-pyrrolidino-1,4-dihydroquinoline-3-carbamoyl)-7-Y-6,8-difluoro-4-oxo-
1,4-dihydroquinoline-3-carboxylic Acids (10a,b). Pyrrolidine or 4-methylpiperazine (6 mmol) was added to a
solution of acid 8 (0.55 g, 1.05 mmol) in pyridine (6 ml). The reaction mixture was boiled for 4 h, then cooled.
The solid product 10a or 10b was filtered off, and recrystallized from DMSO.
The work was carried out with the financial support of the Federal scientific-technical program
"Investigations and development on priority directions on progress of science and technology for civil
purposes", direction "Fundamental problems of contemporary chemistry", project 9.1.06.
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G. N. Lipunova, E. V. Nosova, V. N. Charushin, L. P. Sidorova, and O. M. Chasovskikh, Mendeleev
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