4-hydroxy-2-quinolones. 108. N-R-amides of 9-fluoro-1-hydroxy-5-methyl-3- oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid and their antitubercular activity

Article abstract of DOI:10.1007/s10593-006-0228-6

The reaction of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline with triethylmethanetricarboxylate gives di(9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7- dihydro-3H,5H-pyrido[3,2,1-ij]quinolin-2-yl)methane and ethyl 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H

Full text of DOI:10.1007/s10593-006-0228-6

Chemistry of Heterocyclic Compounds, Vol. 42, No. 9, 2006
4-HYDROXY-2-QUINOLONES. 108*. N-R-AMIDES
OF 9-FLUORO-1-HYDROXY-5-METHYL-3-OXO-6,7-DIHYDRO-
3H,5H-PYRIDO[3,2,1-ij]QUINOLINE-2-CARBOXYLIC
ACID AND THEIR ANTITUBERCULAR ACTIVITY
I. V. Ukrainets1, L. V. Sidorenko1, O. V. Gorokhova1, O. V. Shishkin2, and A. V. Turov3
The reaction of 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline with triethylmethanetricarboxylate gives
di(9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinolin-2-yl)methane
and
ethyl 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate
from which alkyl-, dialkylaminoalkyl-, and hetarylamides as well as hydrazides were prepared. The
structure and antitubercular properties of the compounds synthesized are discussed.
Keywords: heterocyclic tricarbonylmethanes, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
esters and amides, antitubercular activity, X-ray structural analysis.
Fluoroquinolone preparations occupy an important place in the contemporary arsenal of antibacterial
chemotherapeutic agents and amongst these C(8)/N(1) annelated tricyclic derivatives of the general structure 1 can
be mentioned. They are noted for their high activity and good pharmacokinetic properties [2, 3]. Up to recent
times it was considered that the modification of the carboxyl group of fluoroquinolones leads to a marked
lowering of antimicrobial activity and carboxy derivatives can be active only in examples where they are readily
converted to the starting acids in vivo. However, this claim has gradually been disproved by many investigations.
As a result there have appeared the so called "double action" antibiotics which are esters of
O
F
COOH
R
N
X
Me
1a–e
1 a X = CH2, R = H (flumequine); b X = CH2, R = imidazol-1-yl (S-25932);
c X = CH2, R = 4-methylpiperazin-1-yl (vebufloxacin); d X = O, R = 4-methylpiperazin-1-yl (ofloxacin);
e X = S, R = 4-methylpiperazin-1-yl (rufloxacin)
_______
* For Communication 107 see [1].
__________________________________________________________________________________________
1
2
National Pharmaceutical University, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Institute of
Scintillation Materials, Ukraine National Academy of Sciences, Kharkiv 61001; e-mail:
3
shishkin@xray.isc.kharkov.com.
Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail:
nmrlab@univ.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1391-1407,
September, 2006. Original article submitted June 27, 2005.
1208
0009-3122/06/4209-1208©2006 Springer Science+Business Media, Inc.

fluoroquinolone carboxylic acids and cephalosporins [4]. In a number of cases 3-quinolinecarboxamides and
their cyclic analogs also show greater activity than the starting fluoroquinolones [3]. In addition, amidation has
led to the appearance of novel, useful properties including antiherpes [5], antiallergy [6], antitumor [7], and other
forms of biological activity.
OH
OH
F
F
N
O
N
O
Me
Me
F
5
OH
N
O
O
CH(COOEt)3
NH
Me
F
NH
Het
3
OH
N
2
COOEt
O
F
Me
10a–j
H2N–Het
Me
4
H2NNH2 . H2O
HCl, AcOH, H2O
H2N–R
O
OH
OH
O
O
OH
O
O
F
F
F
NH
OH
NHNH2
R
N
O
N
N
Me
Me
Me
7
8a–h
11
O
Het
220°C
– CO2
HCl
OH
O
O
OH
O
OH
F
F
F
NH
NH
N
. HCl
R
N
N
O
N
O
Het
Me
Me
12a–c
Me
6
9a–k
8 a R = 2-chlorobenzyl, b R = 2-(3,4-dimethoxyphenyl)ethyl, c R = 3-phenylpropyl,
d R = furfuryl, e R = tetrahydrofurfuryl, f R = 2-picolyl, g R = 3-picolyl,
h R = 4-picolyl; 9 a R = 2-dimethylaminoethyl, b R = 2-ethylaminoethyl, c R = 2-(2-hydroxyethylamino)ethyl,
d R = 2-diethylaminoethyl, e R = 3-dimethylaminopropyl, f R = 3-diethylaminopropyl, g R = 1-ethylpyrrolidin-2-ylmethyl,
h R = 2-piperazin-1-ylethyl, i R = 2-morpholin-4-ylethyl, j R = 3-morpholin-4-ylpropyl, k R = 3-piperidin-1-ylpropyl;
10 a Het = pyridin-4-yl, b Het = pyridin-3-yl, c Het = pyridin-2-yl, d Het = 3-methylpyridin-2-yl, e Het = 4-methylpyridin-2-yl,
f Het = 5-methylpyridin-2-yl, g Het = 6-methylpyridin-2-yl, h Het = 3-hydroxypyridin-2-yl, i Het = pyrimidin-2-yl,
j Het = pyrazin-2-yl; 12 a Het = pyridin-4-yl, b Het = pyridin-3-yl, c Het = pyridin-2-yl
1209

With the above in mind it was of interest to extend the search for potential antitubercular agents and we
have carried out this for a series of amidated derivatives of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic
acid including the scope of structural analogs of flumequine 1a. 6-Fluoro-2-methyl-1,2,3,4-tetrahydroquinoline
(2) was condensed with triethylmethanetricarboxylate (3) according to a previous report [8] with a slight
modification. With steric hindrance at the NH group of quinoline 2 due to the neighboring methyl group in mind
the reaction was carried out not with an equivalent but with a 10% excess of the triester 3. The ethyl 9-fluoro-1-
hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (4) formed was separated
from the reaction mixture as the water soluble 4-O-sodium salt which was then acidified to give the target 4-OH
form.
According to X-ray analytical data (Fig. 1) two molecules (A and B) are found in the symmetrically
independent part of the crystal unit cell of this compound and they differ in the conformation of the partially
hydrogenated ring and the ester group. In molecule A the dihydropyridone ring is planar but in molecule B this
fragment is found to have the conformation of a strongly distorted chair. Atoms N(1) and C(12) deviated from the
plane of the remaining ring atoms by 0.08 and 0.12 Å respectively. Some differences are also seen in the
conformation of the tetrahydro ring N(1)C(1)···C(4)C(9). In molecule A this has a chair conformation (deviation of
atom C(2) = -0.69Å) and in B the chair is distorted to a half-chair (deviations of C(1) and C(2) 0.09 and -0.60 Å
respectively). In both molecules the methyl group C(16) is found in an axial position with torsional angles C(9)–
N(1)–C(1)–C(16) 92.7(5)° in A and 94.0(6)° in B.
The ester group has a transoid conformation (torsional angles C(11)–C(13)–O(4)–C(14) -178.5(5)° in A and
179.0(4)° in B and C(13)–O(4)–C(14)–C(15) 165.3(6)° in A and 173.9(5)° in B) and is somewhat rotated relative to
the plane of the quinolone fragment (torsional angles C(10)–C(11)–C(13)–O(3) -6.5(8)° in A and -7.3(7)° in B) but
this does not have a marked effect of the reactivity.
The formation of a 3D lattice by intra- and intermolecular hydrogen bonds O(1A)–H···O(3A) 2.05 Å, (angle
O(1A)–H···O 113°), O(1A)–H···O(3B) 2.43 Å (angle O–H···O 128°), O(1B)–H···O(3A) 2.46 Å (angle O–H···O 146°),
C(3A)–H···O(3B') (1 - x, -y, -z) 2.52 Å (angle C–H···O 144°), C(3B)–H···O(2A'') (-x, 1 - y, -z) 2.44 Å (angle C–H···O
170°) leads to a lengthening of the C(12A)=O(2A) 1.243(6) Å and C(13A)=O(3A) 1.256(6) Å bonds when compared
with the mean value of 1.210 Å [9].
It should also be noted that the separated compound 4 proved to be not the only reaction product of
quinoline 2 with the triester 3 since work up of the reaction mixture with aqueous sodium carbonate solution
gave a minor insoluble fraction. Bearing in mind previous similar work [1] it was logical to propose that the
Fig. 1. Structure and atomic numbering for the molecule of ester 4.
1210

TABLE 1. Characteristics of the 9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-
dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid N-R-Amides
8-10
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
C
H
N
8a
8b
8c
8d
8e
8f
C21H18ClFN2O3
62.81
62.93
65.40
65.44
70.10
70.04
64.09
64.04
63.41
63.32
65.31
65.39
65.46
65.39
65.48
65.39
4.44
4.53
5.81
5.72
5.95
5.88
4.70
4.81
5.76
5.87
4.90
4.94
4.86
4.94
4.99
4.94
6.85
6.99
6.27
6.36
7.02
7.10
7.94
7.86
7.65
7.77
11.37
11.44
11.51
11.44
11.44
11.38
177-179
124-126
103-105
142-144
131-133
126-128
162-164
170-172
166-168
235-237
197-199
94
95
88
97
83
86
90
92
82
85
77
C24H25FN2O5
C23H23FN2O3
C19H17FN2O4
C19H21FN2O4
C20H18FN3O3
8g
8h
9a
9b
9c
C20H18FN3O3
C20H18FN3O3
C18H22FN3O3·HCl
C18H22FN3O3·HCl
C18H22FN3O4·HCl
56.44
56.32
56.30
56.32
54.14
54.06
6.15
6.04
6.00
6.04
5.72
5.80
10.88
10.95
10.91
10.95
10.43
10.51
9d
C20H26FN3O3·HCl
C19H24FN3O3·HCl
C21H28FN3O3·HCl
C21H26FN3O3·HCl
C20H25FN4O3·2HCl
C20H24FN3O4·HCl
C21H26FN3O4·HCl
C22H28FN3O3·HCl
C19H16FN3O3
58.40
58.32
57.27
57.36
59.34
59.22
59.41
59.50
52.00
52.07
56.50
56.40
57.46
57.34
60.30
60.34
64.69
64.58
64.71
64.58
64.50
64.58
65.47
65.39
65.50
65.39
65.52
65.39
65.30
65.39
61.67
61.79
6.70
6.61
6.39
6.33
6.96
6.86
6.53
6.42
5.77
5.90
5.83
5.92
6.28
6.19
6.57
6.67
4.68
4.56
4.65
4.56
4.49
4.56
4.99
4.94
4.85
4.94
5.03
4.94
4.88
4.94
4.48
4.37
10.14
10.20
10.67
10.56
9.98
9.87
9.82
9.91
12.01
12.14
9.97
9.86
9.50
9.55
9.67
9.59
11.77
11.89
11.95
11.89
11.80
11.89
11.37
11.44
11.48
11.44
11.37
11.44
11.51
11.44
11.47
11.38
240-242
214-216
177-179
205-207
238-240
181-183
215-217
237-239
213-215
206-208
238-240
180-182
251-253
256-258
222-224
225-227
264-266
246-248
84
80
76
88
83
89
84
75
86
85
80
77
88
83
90
75
73
86
9e
9f
9g
9h
9i
9j
9k
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
C19H16FN3O3
C19H16FN3O3
C20H18FN3O3
C20H18FN3O3
C20H18FN3O3
C20H18FN3O3
C19H16FN3O4
C18H15FN4O3
61.13
61.01
61.11
61.01
4.20
4.27
4.33
4.27
15.94
15.81
15.90
15.81
C18H15FN4O3
1211

fraction insoluble in base is the result of the amidation of compound 2 at one, two or all three ester groups of the
1
methanetricarboxylate 3. None the less, analysis of the H NMR spectrum shows that the given substance
contains at least one 2-substituted 9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]-
quinoline fragment (and not 6-fluoro-2-methyl-1,2,3,4-tetrahdroquinolylamide as proposed). The carbethoxy
groups are absent in the sample and the singlet with relative integrated intensity of one proton at 3.87 ppm is
unlikely to be identified as a CH group of a methanetricarboxylic acid since the mono-, di-, and triamides give a
signal at a much lower field (mean value 5.5 ppm [1]).
Chromato-mass spectrometric analysis has shown that the compound analyzed is a single substance with
molecular weight 478. Hence its composition must include not one but two pyridoquinoline rings combined with
one methylene unit since the primary decomposition of the molecular ion is accompanied by fission of the
HetCH2–Het bond to form two fragments with m/z 246 and 232 respectively. Thus combination of the 1H NMR
and mass spectrometric data shows that the side product of the condensation of compound 2 with triester 3 is
di(9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinolin-2-yl)methane (5).
The formation of analogous side products has not been noted in any of the previously reported reactions
of triethylmethanetricarboxylate with N-alkylamines [10], diphenylamine [11], indoline [1, 12],
1,2,3,4-tetrahydroquinoline, or azaheterylamines [13]. Only in the pyrolytic transformation of 1R-3-carbethoxy-
4-hydroxy-2-oxo-1,2-dihydroquinolines to 5,9-di-R-6,7,8-trioxodiquinolino[3,4-b;3',4'-e]-4H-pyrans have a
similarly structured di(1R-4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)ketones been proposed [14]. However, the
question of how, in this case, the reduction of the bridging carbonyl group arises and why this only occurs in the
reaction of triethylmethanetricarboxylate with 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline remains unclear. In
addition, it was experimentally confirmed ester 4 under pyrolytic conditions does not cyclize to the
corresponding diquinolinopyran but decomposes to 9-fluoro-1-hydroxy-5-methyl-6,7-dihydro-5H-pyrido-
[3,2,1-ij]quinolin-3-one (6). It follows that the dihetarylmethane 5 is apparently formed by an alternative
mechanism.
The ester 4 proved to be extremely stable towards basic hydrolysis. In addition, prolonged heating in
aqueous KOH solution is accompanied by decarboxylation and ultimately gives the 2H-derivative 6. Hence
9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (7) was
TABLE 2. Antitubercular Activity of the Compounds Synthesized
Inhibition
Inhibition
Compound
of M. Tuberculosis growth
at c = 6.25 µg/ml, %
Compound
of M. Tuberculosis growth
at c = 6.25 µg/ml, %
24
1
18
58
62
100
76
5
5
9i
7
9j
50
25
54
17
18
19
16
7
8a
8b
8c
8d
8e
8f
9k
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
11
100
20
17
17
14
20
82
21
1
8g
8h
9a
9b
9c
9d
9e
9f
8
0
26
42
0
12a
12b
12c
85
95
52
5
12
9g
9h
1212

1213

1214

1215

1216

prepared using a known method [10] by hydrolysis of ester 4 with an initially prepared solution of concentrated
hydrochloric acid in acetic anhydride i.e. essentially an HCl solution in acetic acid with a low water content.
On the other hand the amidation of ester 4 with alkylamines in ethanol occurs readily to give the amides
8 in high yields (Table 1). The basic dialkylaminoalkylamides formed under analogous conditions are very
readily soluble in the majority of organic solvents and have low melting points. For this reason they were
conveniently prepared and purified as the hydrochlorides 9. Hetarylamines do not react with ester 4 in refluxing
ethanol whereas the thermolysis of equimolar amounts of the reagents gives good yields of the 9-fluoro-1-
hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid amides 10 (Table 1).
Hydrazinolysis occurs quantitatively in alcohol medium even at room temperature and the hydrazide 11 then
gave rise to the isomeric pyridinemethylidenehydrazides 12 on this basis.
1
The H NMR spectra of all of the synthesized compounds (Table 3) showed signals for the aliphatic
protons of the 6,7-dihydropyridoquinolone ring but, at first sight, with an unexpected pattern for the spin-spin
interactions. Hence the signals for both methylene groups (7-CH2 and 6-CH2) were seen as a combination of a
doublet and triplet with a large (15-17 Hz) spin-spin coupling, each component of which underwent further
splitting. The appearance of these signals becomes understandable if one takes into account that each of them is
split by different couplings to the neighbouring methylene group protons. Thus one fragment of the signal for the
7-CH2 group at lower field (a triple doublet at 3.20 ppm) is due to an axial proton and the other (a double doublet
3
at 2.95 ppm) is due to an equatorial proton. The spin-spin coupling for the given signal is: J7He,6He = 3.5-5.5,
3
3
2
3J7He,6Ha = 3.5-5.5, J7Ha,6Ha = 12.4-13.2; J7Ha,6He = 5.2-6.2 Hz. The geminal coupling J7He,7Ha = 16.5-18.5 Hz.
The 6-CH2 signal has a component corresponding to an equatorial proton (dt at 2.15 ppm) and axial proton (tt
at 2.05 ppm). There are also observed vicinal spin-spin coupling with proton H-5: 3J5H,6Ha = 13-14; 3J5H,6He = 4.5-
5.5 Hz. The geminal coupling for the 6-CH2 signal 2J6He,6Ha = 14.0-16.0 Hz.
TABLE 4. Bond Lengths (l) in the Ester 4 Structure
Bond
(1A)–C(6A)
l, Å
Bond
N(1A)–C(9A)
l, Å
F
1.363(6)
1.406(6)
1.343(6)
1.256(6)
1.490(6)
1.517(6)
1.461(7)
1.398(7)
1.362(6)
1.398(6)
1.354(7)
1.466(7)
1.376(6)
1.398(6)
1.330(5)
1.213(5)
1.464(5)
1.514(7)
1.498(7)
1.420(6)
1.359(7)
1.403(6)
1.372(7)
1.488(6)
1.384(6)
1.502(6)
1.243(6)
1.282(6)
1.516(6)
1.547(8)
1.395(6)
1.383(7)
1.407(7)
1.445(6)
1.433(7)
1.453(9)
1.387(5)
1.485(6)
1.225(6)
1.300(6)
1.514(7)
1.517(7)
1.374(7)
1.356(7)
1.375(7)
1.452(6)
1.443(6)
1.512(7)
N(1A)–C(12A)
O(1A)–C(10A)
О(3A)–С(13A)
O(4A)–C(14A)
C(1A)–C(2A)
C(3A)–C(4A)
C(4A)–С(5A)
C(6A)–C(7A)
C(8A)–C(9A)
C(10A)–C(11A)
C(11A)–C(13A)
F(1B)–C(6B)
N(1B)–C(9B)
O(1B)–С(10B)
O(3B)–C(13B)
O(4B)–C(14B)
C(1B)–C(2B)
C(3B)–C(4B)
C(4B)–С(9B)
C(6B)–C(7B)
C(8B)–C(9B)
C(10B)–С(11B)
C(11B)–C(13B)
N(1A)–C(1A)
O(2A)–C(12A)
O(4A)–C(13A)
C(1A)–C(16A)
C(2A)–C(3A)
C(4A)–C(9A)
C(5A)–С(6A)
C(7A)–C(8A)
C(8A)–C(10A)
C(11A)–C(12A)
C(14A)–C(15A)
N(1B)–C(12B)
N(1B)–C(1B)
O(2B)–С(12B)
O(4B)–C(13B)
C(1B)–C(16B)
C(2B)–C(3B)
C(4B)–C(5B)
C(5B)–C(6B)
C(7B)–C(8B)
C(8B)–C(10B)
C(11B)–C(12B)
C(14B)–C(15B)
1217

The ability of the synthesized compounds to inhibit the growth of Mycobacterium tuberculosis H37Rv
ATCC 27294 was studied in radiometric in vitro experiments [15]. The results of preliminary tests (Table 2)
show that compounds 7 does not have antitubercular activity. Contrary to expectations the hydrazide 11 and its
pyridinemethylidene derivatives 12 also proved inactive. Only some of the alkylamides 8 show modest
antimicrobial activity which generally agree with the biological structure–activity relationships seen earlier in a
series of 1R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid derivatives [16-18]. At the same time, the
9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid 1-ethyl-
pyrrolidin-2-ylmethylamide hydrochloride (9g) inhibited the growth of the tubercular micobacteria by 95% at a
concentration of 6.25 µg/ml even though this is not typical of water soluble compounds of the class studied. In
the group of hetarylamides the two substances pyridin-4-yl- and 3-methylpyridin-2-ylamides (10a and 10b) were
able to block the growth of Mycobacterium tuberculosis by 100% and show interest for further investigation.
TABLE 5. Valence Angles (ω) in the Ester 4 Structure
Valence angle
(9A)–N(1A)–C(12A)
ω, deg.
Valence angle
ω, deg.
C
123.5(4)
115.9(4)
109.4(4)
113.7(4)
108.1(4)
124.1(5)
122.2(5)
122.1(5)
116.9(5)
118.0(4)
119.6(4)
120.9(4)
113.1(5)
121.1(4)
121.8(5)
125.7(5)
120.1(5)
119.1(5)
122.7(4)
120.7(4)
109.6(4)
114.0(5)
109.2(4)
121.4(5)
122.1(5)
118.7(5)
116.8(5)
121.3(4)
121.0(4)
118.8(5)
116.0(5)
120.0(4)
122.5(5)
124.4(4)
122.5(4)
115.9(4)
C(9A)–N(1A)–C(1A)
120.5(4)
115.8(5)
109.2(4)
110.1(5)
116.4(4)
119.5(5)
118.9(5)
119.0(5)
121.6(4)
120.4(4)
119.5(4)
125.5(4)
121.4(4)
117.1(4)
117.9(5)
116.3(5)
120.7(5)
105.7(6)
116.6(4)
116.5(4)
109.4(5)
112.0(5)
116.9(5)
121.7(5)
123.0(6)
118.2(5)
122.4(5)
116.2(4)
120.2(5)
121.8(5)
122.2(4)
117.5(4)
118.4(4)
117.2(5)
121.6(5)
106.1(4)
C(12A)–N(1A)–C(1A)
N(1A)–C(1A)–C(16A)
С(16A)–C(1A)–C(2A)
C(4A)–C(3A)–C(2A)
C(9A)–C(4A)–C(3A)
C(6A)–C(5A)–C(4A)
C(7A)–C(6A)–C(5A)
C(6A)–C(7A)–C(8A)
C(9A)–C(8A)–C(10A)
N(1A)–C(9A)–C(4A)
C(4A)–C(9A)–C(8A)
O(1A)–C(10A)–C(8A)
С(10A)–C(11A)–С(12A)
C(12A)–C(11A)–C(13A)
O(2A)–C(12A)–C(11A)
O(3A)–C(13A)–O(4A)
O(4A)–C(13A)–C(11A)
C(12B)–N(1B)–C(9B)
C(9B)–N(1B)–C(1B)
N(1B)–C(1B)–C(16B)
C(16B)–C(1B)–C(2B)
C(4B)–C(3B)–C(2B)
С(5B)–C(4B)–С(3B)
C(6B)–C(5B)–C(4B)
C(5B)–C(6B)–F(1B)
C(6B)–C(7B)–C(8B)
C(7B)–C(8B)–C(10B)
N(1B)–C(9B)–C(8B)
C(8B)–C(9B)–C(4B)
O(1B)–C(10B)–C(8B)
C(10B)–C(11B)–C(12B)
C(12B)–C(11B)–C(13B)
O(2B)–C(12B)–C(11B)
O(3B)–C(13B)–O(4B)
O(4B)–C(13B)–C(11B)
C(13A)–O(4A)–C(14A)
N(1A)–C(1A)–C(2A)
C(1A)–C(2A)–C(3A)
C(9A)–C(4A)–C(5A)
C(5A)–C(4A)–C(3A)
C(7A)–C(6A)–F(1A)
F(1A)–C(6A)–C(5A)
C(9A)–C(8A)–C(7A)
C(7A)–C(8A)–C(10A)
N(1A)–C(9A)–C(8A)
O(1A)–C(10A)–C(11A)
C(11A)–C(10A)–C(8A)
C(10A)–C(11A)–C(13A)
O(2A)–C(12A)–N(1A)
N(1A)–C(12A)–C(11A)
O(3A)–C(13A)–C(11A)
C(15A)–C(14A)–O(4A)
C(12B)–N(1B)–C(1B)
C(13B)–O(4B)–C(14B)
N(1B)–C(1B)–C(2B)
C(1B)–C(2B)–C(3B)
C(5B)–C(4B)–C(9B)
C(9B)–C(4B)–C(3B)
C(5B)–C(6B)–C(7B)
C(7B)–C(6B)–F(1B)
C(7B)–C(8B)–C(9B)
C(9B)–C(8B)–C(10B)
N(1B)–C(9B)–C(4B)
O(1B)–C(10B)–C(11B)
C(11B)–C(10B)–C(8B)
C(10B)–C(11B)–C(13B)
O(2B)–C(12B)–N(1B)
N(1B)–C(12B)–C(11B)
O(3B)–C(13B)–C(11B)
O(4B)–C(14B)–C(15B)
1218

EXPERIMENTAL
1H NMR spectra for the synthesized compounds were obtained on a Bruker WM-260 (360 MHz)
instrument using DMSO-d6 with TMS as internal standard. The chromato-mass spectrum of the
dihetarylmethane 5 was recorded on a Finnigan MAT Incos 50 quadrupole spectrometer in the full scanning
mode in the range m/z 33-700, ionization 70 eV, direct introduction of the sample, and heating rate of about
5°C/min. Commercial 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline and triethylmethanetricarboxylate from
Aldrich and Fluka respectively were used in the synthesis of ester 4.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
Ethyl Ester (4). Quinoline 2 (16.52 g, 0.1 mol) was added in small portions with stirring to
triethylmethanetricarboxylate (3) (23.2 ml, 0.11 mol) heated to 220°C at such a rate that the reaction mixture
temperature did not vary by more than 5°C from the initial. The ethanol produced in the reaction process with
distilled off using a suitable fractionating column. After addition of all of the quinoline 2 the reaction mixture
was held for 10-15 min at the same temperature and then cooled. Aqueous sodium carbonate solution (10%,
300 ml) was added and the product was heated to 70-80°C and filtered. The residue on the filter was washed
with hot water. The solution obtained of the sodium salt of ester 4 was purified using carbon, cooled, and
acidified with dilute (1:1) HCl to pH 4.5-5. The precipitated ester 4 was filtered, washed with water, and dried.
1
Yield 23.2 g (76%); mp 131-133°C (hexane). H NMR spectrum, δ, ppm (J, Hz): 12.86 (1H, s, OH); 7.57 (1H,
dd, J = 9.1 and 3.0, H-10); 7.46 (1H, dd, J = 9.0 and 3.0, H-8); 5.00 (1H, m, 5-CH); 4.30 (2H, q, J = 7.0,
OCH2); 3.06 (1H, td, J = 17.1 and 5.3, Ha-7); 2.85 (1H, dd, J = 17.0 and 5.1, He-7); 2.02 (1H, dt, J = 13.4 and
5.0, He-6); 1.82 (1H, tt, J = 13.6 and 5.1, Ha-6); 1.28 (3H, t, J = 7.1, OCH2CH3); 1.14 (3H, d, J = 6.6, CH3).
Found, %: C 62.84; H 5.33; N 4.54. C16H16FNO4. Calculated, %: C 62.95; H 5.28; N 4.59.
X-Ray Analysis. Crystals of ester 4 were prepared from ethanol and are triclinic. At 20°C: a = 9.369(3),
b = 11.651(3), c = 13.521(5) Å; α = 99.43(3)°, β = 90.29(3)°, γ = 92.67(3)°; V = 1454.3(8) Å3; dcalc = 1.394
g/cm3; space group P1; Mr = 305.3; Z = 4; µ(MoKα) = 0.109 mm-1; F(000) = 640. The unit cell parameters and
intensities of 5146 reflections (4868 independent with Rint = 0.014) were measured on a Siemens P3/PC,
automatic four circle diffractometer (λMoKα, graphite monochromator, θ/2θ scanning to θ/2θmax = 50°).
The structure was solved by a direct method using the SHELX97 program package [19]. The positions
of the hydrogen atoms were revealed in electron density difference synthesis and refined using the "riding"
model with Uiso = nUeq for non-hydrogen atoms bound to the given hydrogen (n = 1.5 for a methyl group and 1.2
for the remaining hydrogen atoms). The structure was refined in F2 full-matrix least-squares analysis in the
anisotropic approximation for non-hydrogen atoms to wR2 = 0.252 for 4868 reflections (R1 = 0.067 for 1698
reflections with F > 4σ (F), S = 0.905). The full crystallographic information has been placed in the Cambridge
Structural Data Base (deposit No. CCDC 283292). The interatomic distances and valence angles are given in
Tables 4 and 5.
Di(9-fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinolin-2-yl)methane (5).
The residue on the filter (see the example of the preparation of ester 4) was crystallized from DMF to give 1.93 g
1
(8%) of the dihetarylmethane 5; mp 288-290°C. H NMR spectrum, δ, ppm (J, Hz): 12.70 (2H, s, 2OH); 7.56
(2H, dd, J = 8.9 and 2.6, 2H-10); 7.42 (2H, dd, J = 9.0 and 2.6, 2H-8); 5.16 (2H, d, two 5-CH); 3.87 (2H, s,
CH2); 3.13 (2H, td, J = 15.7 and 5.5, 2Ha-7); 2.92 (2H, dd, J = 16.8 and 3.6, 2He-7); 2.07 (2H, dt, J = 12.1 and
4.2, 2He-6); 1.91 (2H, tt, J = 13.7 and 4.6, 2Ha-6); 1.22 (6H, d, J = 7.0, 2CH3). Mass spectrum, m/z (Irel, %): 478
[M]+ (66), 246 [HetCH2]+ (12), 232 [Het]+ (42), 218 (68), 204 (69), 190 (57), 176 (100), 162 (29), 148 (43).
Found, %: C 67.68; H 5.12; N 5.92. C27H24F2N2O4. Calculated, %: C 67.77; H 5.06; N 5.85.
9-Fluoro-1-hydroxy-5-methyl-6,7-dihydro-5H-pyrido[3,2,1-ij]quinolin-3-one (6). A. A mixture of
ester 4 (3.05 g, 0.01 mol) and 20% aqueous KOH solution (50 ml) was refluxed for 40 h, cooled, and acidified
with HCl to pH 3. The precipitate was filtered, washed with water, and dried. Yield 1.93 g (83%);
1
mp 314-316°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 11.52 (1H, s, OH); 7.40 (1H, dd, J = 8.8 and 2.7,
H-10); 7.33 (1H, dd, J = 8.8 and 2.8, H-8); 5.86 (1H, s, H-2); 4.99 (1H, d, 5-CH); 3.06 (1H, td, J = 17.0 and 4.9,
1219

Ha-7); 2.85 (1H, dd, J = 17.1 and 4.2, He-7); 2.00 (1H, dt, J = 13.8 and 5.1, He-6); 1.81 (1H, tt, J = 13.7 and 4.9,
Ha-6); 1.12 (3H, d, J = 6.7, CH3). Found, %: C 66.85; H 5.14; N 6.09. C13H12FNO2. Calculated, %: C 66.94;
H 5.19; N 6.01.
B. Acid 7 (2.77 g, 0.01 mol) was held for 10 min at 220°C. Vigorous evolution of carbon dioxide
occurred at the conclusion of which the reaction product was cooled and crystallized from aqueous ethanol Yield
2.09 g (90%).
C. Ester 4 (3.05 g, 0.01 mol) was held for 20 min at 250°C, cooled, and the residue was crystallized from
aqueous ethanol. Yield 1.083 g (79%).
Mixed samples of the quinolin-3-one 6 prepared by the different methods did not give a depression of
melting point. The 1H NMR spectra of these compounds were identical.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
(7). Ester 4 (3.05 g, 0.01 mol) was added to a solution of HCl in acetic acid (30 ml, prepared as in the method
[10]) and held for 5 h at 60°C. The product was cooled and the crystals of acid 7 were filtered off, washed with
1
alcohol and then water, and dried. Yield 2.38 g (86%); mp 183-185°C (ethanol). H NMR spectrum, δ, ppm
(J, Hz): 14.10 (1H, s, OH); 7.68 (2H, d, J = 8.9 and 8, H-10); 5.07 (1H, m, 5-CH); 3.05 (1H, td, J = 17.0 and
5.1, Ha-7); 2.90 (1H, dd, J = 17.1 and 5.0, He-7); 2.05 (1H, dt, J = 13.6 and 5.2, He-6); 1.87 (1H, tt, J = 13.4 and
5.0, Ha-6); 1.20 (3H, d, J = 6.7, CH3). Found, %: C 60.77; H 4.45; N 5.12. C14H12FNO4. Calculated, %: C 60.65;
H 4.36; N 5.05.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
2-Chlorobenzylamide (8a). 2-Chlorobenzylamine (1.33 ml, 0.011 mol) was added to a solution of ester 4
(3.05 g, 0.01 mol) in ethanol (30 ml) and refluxed for 3 h. The product was cooled, cold water (100 ml) added,
and it was then acidified with HCl to pH 4. The precipitated amide 8a was filtered, washed with water, and
dried.
Alkylamides 8b-e were prepared similarly. In the preparation of the picolylamides 8f-h the reaction
mixture was acidified with acetic acid.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
2-Dimethylaminoethylamide Hydrochloride (9a). 2-Dimethylaminoethylamine (1.1 ml, 0.01 mol) was added
to a solution of ester 4 (3.05 g, 0.01 mol) in ethanol (15 ml) and refluxed for 3 h. The product was cooled to
room temperature and saturated gaseous HCl in ethanol was added to pH 3 after which the reaction mixture was
held for 7-8 h at 5°C. The separated hydrochloride 9a was filtered, washed with ether, and dried.
Alkylamides 9b-k were prepared similarly.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
Pyridin-4-ylamide (10a). A mixture of ester 4 (3.05 g, 0.01 mol), 4-aminopyridine (0.94 g, 0.01 mol), and DMF
(0.5 ml) was held for 2-3 min at 170°C. The product was cooled, ethanol (15 ml) was added, and thoroughly
triturated. The precipitated amide 10a was filtered off, washed with alcohol, dried, and crystallized from DMF.
Hetarylamides 10b-j were prepared similarly.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
Hydrazide (11). Hydrazine hydrate (0.011 mol, calculated on the actual content) was added to a solution of ester
4 (3.05 g, 0.01 mol) in ethanol (15 ml). After 2 h the reaction mixture was diluted with cold water. The
precipitated hydrazide 11 was filtered off, washed with water, and dried. Yield 2.90 g (quantitative);
mp 169-171°C (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 16.22 (1H, s, OH); 11.09 (1H, s, CONH); 7.59 (1H,
dd, J = 8.9 and 2.8, H-10); 7.47 (1H, dd, J = 8.9 and 2.6, H-8); 5.11 (1H, m, 5-CH); 4.81 (2H, br. s, NNH2);
3.08 (1H, td, J = 17.0 and 4.7, Ha-7); 2.84 (1H, dd, J = 12.8 and 3.5, He-7); 2.07 (1H, dt, J = 13.7 and 5.5, He-6);
1.90 (1H, tt, J = 13.4 and 4.9, Ha-6); 1.21 (3H, d, J = 6.5, CH3). Found, %: C 57.60; H 4.71; N 14.56. C-
14H14FN3O3. Calculated, %: C 57.73; H 4.84; N 14.43.
1220

9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
Pyridin-4-ylmethylidenehydrazide (12a). Isonicotinic aldehyde (1.04 ml, 0.011 mol) was added to a solution
of hydrazide 11 (2.91 g, 0.01 mol) in hot ethanol (20 ml) and refluxed for 1 h. The product was cooled and the
precipitated crystals of pyridin-4-ylmethylidenehydrazide 12a were filtered off, washed with alcohol, and dried.
1
Yield 3.65 g (96%); mp 292-294°C (DMF–ethanol). H NMR spectrum, δ, ppm (J, Hz): 16.31 (1H, s, OH);
13.52 (1H, s, CONH); 8.66 (2H, d, J = 5.4, H-2',6'); 8.53 (1H, s, CH=N); 7.70-7.60 (3H, m, H-10 + H-3',5');
7.52 (1H, dd, J = 8.7 and 2.4, H-8); 5.16 (1H, m, 5-CH); 3.11 (1H, td, J = 17.1 and 5.4, Ha-7); 2.84 (1H, dd,
J = 12.9 and 3.8, He-7); 2.11 (1H, dt, J = 13.9 and 5.4, He-6); 1.94 (1H, tt, J = 13.6 and 5.0, Ha-6), 1.27 (3H, d,
J = 6.8, CH3). Found, %: C 63.23; H 4.61; N 14.80. C20H17FN4O3. Calculated, %: C 63.15; H 4.50; N 14.73.
Compounds 12b,c were prepared by a similar method.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
1
Pyridin-3-ylmethylidenehydrazide (12b) Yield 95%; mp 210-212°C (DMF–ethanol). H NMR spectrum,
δ, ppm (J, Hz): 16.47 (1H, s, OH); 13.46 (1H, s, CONH); 8.89 (1H, d, J = 1.9, H-2'); 8.62 (1H, dd, J = 4.9 and
1.6, H-6'); 8.57 (1H, s, CH=N); 8.14 (1H, dt, J = 8.0 and 2.1, H-4'); 7.64 (1H, dd, J = 8.7 and 2.8, H-10);
7.56-7.43 (2H, m, H-8 + H-5'); 5.16 (1H, m, 5-CH); 3.14 (1H, td, J = 17.3 and 5.4, Ha-7); 2.93 (1H, dd, J = 17.5
and 4.2, He-7); 2.11 (1H, dt, J = 13.5 and 5.3, He-6); 1.95 (1H, tt, J = 13.7 and 4.9, Ha-6); 1.27 (3H, d, J = 6.5,
CH3). Found, %: C 63.26; H 4.58; N 14.85. C20H17FN4O3. Calculated, %: C 63.15; H 4.50; N 14.73.
9-Fluoro-1-hydroxy-5-methyl-3-oxo-6,7-dihydro-3H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic Acid
1
Pyridin-2-ylmethylidenehydrazide (12c). Yield 90%; mp 266-268°C (DMF–ethanol). H NMR spectrum,
δ, ppm (J, Hz): 16.40 (1H, s, OH); 13.44 (1H, s, CONH); 8.64 (1H, d, J = 4.5, H-6'); 8.42 (1H, s, CH=N); 7.98
(1H, d, J = 7.8, H-3'); 7.88 (1H, td, J = 7.4 and 1.5, H-4'); 7.63 (1H, dd, J = 8.8 and 2.9, H-10); 7.51 (1H, dd,
J = 8.8 and 2.6, H-8); 7.43 (1H, td, J = 5.9 and 1.4, H-5'); 5.17 (1H, d, 5-CH); 3.14 (1H, td, J = 17.4 and 5.4,
Ha-7); 2.92 (1H, dd, J = 17.2 and 4.0, He-7); 2.10 (1H, dt, J = 13.8 and 5.4, He-6); 1.94 (1H, tt, J = 13.5 and 4.7,
Ha-6), 1.26 (3H, d, J = 6.5, CH3); Found, %: C 63.11; H 4.67; N 14.64. C20H17FN4O3. Calculated, %: C 63.15;
H 4.50; N 14.73.
The authors thank the National Institute for Allergic and Infectious Illnesses (USA) for carrying out the
study of the antitubercular properties of the compounds synthesized by us (contract No. 01-A1-45246) under the
TAACF program (Tuberculosis Antimicrobial Acquisition & Coordinating Facility).
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