Synthetic studies connected with the preparation of 4-cyclopropyl-7-fluoro-6-(4-methylpiperazin-1-yl)-1,2,4,9-tetrahydrothiazolo[5, 4-b]quinoline-2,9-dione

Article abstract of DOI:10.1135/cccc19970791

Target 4-cyclopropyl-7-fluoro-6-(4-methylpiperazin-1-yl)-1,2,4,9-tetrahydrothiazolo[5, 4-b]quinoline-2,9-dione (5a) was obtained from 3-amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-mercaptoquinolin- 4(1H)-one (9b). This intermediate was obtained from 3-amino-1-cyclopropyl-6,7-difluoro-2-(methylsulfinyl)quinolin-4(1H)-one (9f) via 3-amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-(methylsulfinyl) quinolin-4(1H)-one (9c). Compound 9f was prepared from 2,4,5-trifluoroacetophenone (6a) in several steps. 4-Cyclopropyl-6,7-difluoro-2,3,4,9-tetrahydrothiazolo[5,4-b]quinoline-3,4-dione (5b) was prepared similarly as the target compound. Treatment of 5b with N-methylpiperazine did not afford 5a but 1-cyclopropyl-6,7-difluoro-2-mercapto-3-[(4-methylpiperazin-1-yl)carbonylamino] quinolin-4(1H)-one (11). Several unsuccessful attempts to prepare compound 5a and/or some useful intermediates of its synthesis are also described.

Full text of DOI:10.1135/cccc19970791

Synthetic Studies
791
SYNTHETIC STUDIES CONNECTED WITH THE PREPARATION OF
4-CYCLOPROPYL-7-FLUORO-6-(4-METHYLPIPERAZIN-1-YL)-
1,2,4,9-TETRAHYDROTHIAZOLO[5,4-b]QUINOLINE-2,9-DIONE
Stanislav RADL
Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3, Czech Republic;
e-mail: vufbchs@mbox.vol.cz
Received November 13, 1996
Accepted February 17, 1997
Target 4-cyclopropyl-7-fluoro-6-(4-methylpiperazin-1-yl)-1,2,4,9-tetrahydrothiazolo[5,4-b]quinoline-
2,9-dione (5a) was obtained from 3-amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-
mercaptoquinolin-4(1H)-one (9b). This intermediate was obtained from 3-amino-1-cyclopropyl-
6,7-difluoro-2-(methylsulfinyl)quinolin-4(1H)-one (9f) via 3-amino-1-cyclopropyl-6-fluoro-7-(4-
methylpiperazin-1-yl)-2-(methylsulfinyl)quinolin-4(1H)-one (9c). Compound 9f was prepared from
2,4,5-trifluoroacetophenone (6a) in several steps. 4-Cyclopropyl-6,7-difluoro-2,3,4,9-tetrahydrothia-
zolo[5,4-b]quinoline-3,4-dione (5b) was prepared similarly as the target compound. Treatment of 5b
with N-methylpiperazine did not afford 5a but 1-cyclopropyl-6,7-difluoro-2-mercapto-3-[(4-methyl-
piperazin-1-yl)carbonylamino]quinolin-4(1H)-one (11). Several unsuccessful attempts to prepare
compound 5a and/or some useful intermediates of its synthesis are also described.
Key words: Thiazolo[5,4-b]quinolines; Antibacterial quinolones.
Antibacterial quinolones of a general formula 1, which exert their activity by inhibiting
bacterial DNA gyrase, have attracted increasing attention as a source of clinically use-
ful drugs1,2. During our research into antibacterial quinolones we were also interested
in tricyclic compounds having annelated additional rings at positions 2 and 3 of the
quinoline moiety. Compounds of general formula 2, having an isothiazolone ring anne-
lated to the 2,3-position of the quinolone moiety, have been found to be extremely
active DNA gyrase inhibitors3. Since only compounds having an unsubstituted isothia-
zolone nitrogen were found to be active, we envisaged that involvement of the tau-
tomers 3 might be important for their biological action. This tautomer could be
involved in DNA gyrase-inhibitor complex with its carbonyl (hydrogen bond acceptor)
and hydroxy (hydrogen bond donor) groups in accordance with the model proposed by
Shen et al.4. Recently quite different type of DNA gyrase inhibitors of general formula 4
has been discovered5. In these compounds similar acceptor–donor pattern was sug-
gested to be involved in a biointeraction. In this case the hydrogen donor is represented
by an NH group. These findings inspired us to prepare new thiazolo[5,4-b]quinoline-
2,9-diones represented by compound 5a, which combine some features of both men-
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

792
Radl:
tioned groups of DNA gyrase inhibitors. For our initial study we chose a typical sub-
stitution pattern present in many potent quinolones, that is a cyclopropyl group as the N
substituent and a 4-methylpiperazin-1-yl group as the cyclic amine residue. Synthetic
studies connected with the preparation of the target compound 5a are presented in this
paper.
O
OH
O
O
N
F
F
O
H
S
N
N
R
N
N
R
1
2
O
H
O
N
OH
N
O
F
F
N
N
S
N
N
R
N
R
3
4
Our strategy was based on annelation of the thiazole ring onto the quinolone moiety
constructed in previous steps. There are several methods for preparation of quinolones
bearing various substituents6. For this purpose we needed a 2-mercapto-3-aminoquino-
lone structure. We adopted method similar to that developed by Chu7 for preparation of
similar quinoline-3-carboxylates. We chose commercially available 2,4,5-trifluoro-
acetophenone (6a) as a suitable starting compound which can be easily transformed
into phthalimide derivative 6c via the corresponding bromoacetyl derivative 6b. Treat-
ment of a mixture of 6c and cyclopropyl isothiocyanate with one molar equivalent of
sodium hydride in DMF furnished intermediate 7a which, without isolation, was treated
with iodomethane at room temperature providing 7b as a main product. A small amount
1
of its N-methyl derivative 7c was also isolated. H NMR spectra of 7b and 7c do-
cumented that both compounds were present exclusively in one isomeric form (E or Z).
Since intramolecular nucleophilic cyclization of 7b, which was easily achieved by so-
dium hydride in THF at room temperature, yielded 8a, at least compound 7b is present
in its Z form.
Compound 8a seemed to be an ideal intermediate for the synthesis of 5 and we
proposed several ways of its preparation. First strategy was based on a reaction se-
quence which included introduction of the N-methylpiperazine substituent leading to
8b and deprotection of its 3-amino group which then could lead to 9a. We assumed that
the key intermediate 9b can be accessible either by a reduction of the 2-methylsulfanyl
group in 9a or via corresponding methylsulfinyl derivative 9c. Though this retrosyn-
thetic analysis was consistent with the current knowledge of the field, we were aware
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

Synthetic Studies
793
that there were some sources of potential troubles. For example, there are examples of
reduction of aromatic and heteroaromatic methylsulfanyl groups into mercapto groups
but none of them dealt with similar heterocycles. We also did not know if the methyl-
sulfanyl group in 9a would be preferentially oxidized to 9c without oxidation of the
piperazine nitrogen.
O
O
H
F
F
R
F
N
O
S
F
R
N
R
6
R
5
H
4MeP
F
a
b
c
a
b
Br
phthalimido
O
O
O
F
F
O
N
F
1
N
O
O
1
2
2
2
2
R N
SR
R
R
F
N
1
1
R
R
H
R
R
7
8
H
H
F
SMe
a
b
c
a
b
c
4MeP
F
Me
Me
SMe
Me
SOMe
In formulae 5, 8 and 9, 4MeP = 4-methylpiperazinyl
1
2
9
R
R
4MeP SMe
4MeP SH
4MeP SOMe
4MeP H
a
b
c
d
e
f
O
N
F
1
NH
2
2
R
R
F
F
F
SMe
SOMe
SH
g
A treatment of 8a with N-methylpiperazine under usual conditions really provided
compound 8b. Hydrazine hydrate was used for deprotection of the C-3 amino group in
this compound and 9a was obtained in high yield. Reduction of various aromatic and
heteroaromatic methylsulfanyl derivatives, e.g. 2-methylsulfanyl imidazoles, with so-
dium in liquid ammonia is known to provide corresponding mercapto derivatives8.
However, we applied this method to the reduction of 9a and obtained the corresponding
2-unsubstituted derivative 9d and not the required compound 9b. We have previously
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

794
Radl:
reported synthesis of 9d by catalytic hydrogenation of the corresponding 3-nitro deriva-
tive9,10. Attempts to oxidize 9a with 3-chloroperbenzoic acid (MCPBA) in dichloro-
methane or with hydrogen peroxide in acetic acid into the corresponding methylsulfinyl
derivative 9c were also unsuccessful. In both cases the N-oxide 10 was isolated. This
finding was surprising since similar S-oxidation of methyl 2-[2-chloro-5-fluoro-4-
(4-methylpiperazin-1-yl)phenyl]thioacetate with hydrogen peroxide was reported to
provide the corresponding S-oxide without N-oxidation11.
Me
O
N
O
N
H
N
N
F
NH
F
F
N
2
O
N
SMe
SH
Me
N
O
10
11
These results suggested that the introduction of the 4-methylpiperazin-1-yl group
into the structure in a later step can be necessary. However, this strategy has also some
risks. For example, relative reactivity of the C-7 fluorine and C-2 methylsulfinyl groups
in the prospective intermediate 9f toward the reaction with N-methylpiperazine was not
known. In case the isothiazolone species 5b is chosen as an intermediate, stability of
the thiazolone ring of the tricycle in the reaction with N-methylpiperazine was also
questionable. Therefore we decided to study these reactions. Compound 8a was easily
oxidized with MCPBA into 8c but we failed to deprotect this compound with hydrazine
hydrate to give 9f. At room temperature no reaction occurred and prolonged reflux in
ethanol provided a mixture of several compounds in which the starting material still
prevailed. On the other hand compound 8a was smoothly converted into 9e by treating
with hydrazine hydrate at room temperature. Oxidation of 9e with MCPBA then pro-
vided the intermediate 9f which treated with N-methylpiperazine at 70 °C for 5 days
provided the required intermediate 9c. This compound treated with sodium hydrogen-
sulfite in tetrahydrofuran provided mercapto derivative 9b which was, without isola-
tion, treated with triphosgene. Since only a small yield of the required compound 5a
was obtained by this way, the possibility to construct the thiazolo[5,4-b]quinolone
moiety first was also studied. Compound 9f was treated with sodium hydrogensulfite
followed by triphosgene in the same way as described above, yields about 60% of the
corresponding tetrahydrothiazolo[5,4-b]quinolone 5b were repeatedly obtained. At-
tempts to prepare 5a by a treatment of this compound with N-methylpiperazine failed
leading to compound 11, a product of a cleavage of the thiazole ring.
In conclusion, several potential routes to 5a have been studied and a small yield of
the compound has been obtained. The compound exerted no significant in vitro antibac-
terial activity.
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795
EXPERIMENTAL
Melting points were measured on Thomas Hoover capillary apparatus and are uncorrected. IR spectra
were taken on a Digilab FTS 15E spectrophotometer (wavenumbers in cm–1) and UV spectra on a
1
Cary 17D spectrometer. H NMR spectra were recorded on a Varian XL-200 instrument (200 MHz).
Chemical shifts are given in ppm (δ-scale), coupling constants (J) in Hz. Mass spectra were obtained
on a VG 7070 E-HF spectrometer. Flash and vacuum chromatography were done on silica gel 60
(230–400 mesh) and preparative TLC on pre-coated PLC plates (silica gel 60) from EM Science.
2-Bromo-1-(2,4,5-trifluorophenyl)ethanone (6b)
Bromine (4.6 g, 28.8 mmol) was added dropwise to a solution of 6a (5.0 g, 28.7 mmol) in dry ether
(7 ml) containing anhydrous aluminium chloride (0.05 g, 0.4 mmol) stirred in an ice bath. Then the
solution was evaporated and triturated with a mixture of hexane (2 ml) and water (2 ml), the inso-
luble portion was filtered off and washed with another portion of the hexane–water mixture and dried;
yield 6.3 g (87%). An analytical sample was purified by crystallization from ethanol, m.p. 56–57 °C. For
C8H4BrF3O (253.0) calculated: 37.98% C, 1.59% H, 31.58% Br, 22.53% F; found: 37.73% C, 1.49% H,
31.52% Br, 22.23% F. 1H NMR spectrum (CDCl3): 4.48 d, 2 H, J = 3 (CH2); 7.00–7.12 m, 1 H
(H-3); 7.72–7.88 m, 1 H (H-6). IR spectrum (CHCl3): 1 702, 1 687 (C=O). UV spectrum, λmax (log ε):
240 (3.94), 285 (3.47). Mass spectrum, m/z (%): 252 (M+, 3), 159 (100).
2-[2-Oxo-2-(2,4,5-trifluorophenyl)ethyl]-1H-isoindole-1,3(2H)-dione (6c)
A solution of 6b (2.5 g, 10 mmol) in N,N-dimethylformamide (5 ml) was added dropwise to a stirred
suspension of potassium phthalimide (2.05 g, 11.0 mmol) in N,N-dimethylformamide (15 ml) and the
mixture was stirred at room temperature for 2 h. Residue after evaporation of the mixture was tritur-
ated with water, the insoluble portion was filtered off, washed with water and dried. The crude pro-
duct was purified by flash chromatography (dichloromethane) and by crystallization from ethanol;
yield 2.5 g (78%) of 6c (white crystals), m.p. 168–169 °C. For C16H8F3NO3 (319.2) calculated:
1
60.20% C, 2.53% H, 4.39% N, 17.85% F; found: 60.05% C, 2.45% H, 4.33% N, 17.56% F. H NMR
spectrum (CDCl3): 5.03 d, 2 H, J = 4 (CH2); 7.02–7.18 m, 1 H (H-3); 7.72–7.96 m, 5 H (H-6, H of
phthalyl). IR spectrum (CHCl3): 1 777, 1 721 (C=O). UV spectrum, λmax (log ε): 217 (4.66), 231
(3.42), 239 (4.37), 285 (3.68), 290 (3.67). Mass spectrum, m/z (%): 319 (M+, 8), 160 (100).
2-[2-Cyclopropylamino-2-methylsulfanyl-1-[(2,4,5-trifluorobenzoyl)ethyl]-1H-isoindole-1,3(2H)-
dione (7b) and 2-[2-(N-Cyclopropyl-N-methyl)amino]-2-methylsulfanyl-1-[(2,4,5-trifluoro-
benzoyl)ethyl]-1H-isoindole-1,3(2H)-dione (7c)
Sodium hydride (80% suspension in mineral oil, 0.825 g, 27.8 mmol) was added during 30 min to a
solution of 6c (4.8 g, 15.0 mmol) and cyclopropyl isothiocyanate (1.65 g, 16.5 mmol) in N,N-di-
methylformamide (50 ml) stirred under argon at 0 °C. The temperature was allowed to raise to room
temperature and the stirring continued for additional 20 h. Then iodomethane (1.125 ml, 18 mmol)
was added and the mixture was stirred at room temperature for 5 h and then poured into a mixture
of water (200 ml) and acetic acid (2 ml). The insoluble portion was filtered off, washed with water,
dried and purified by flash chromatography (dichloromethane). The first isolated fraction was crystal-
lized from ether yielding 0.12 g (1.8%) of 7c (yellow crystals), m.p. 123–125 °C. For
C22H17F3N2O3S (446.5) calculated: 59.19% C, 3.84% H, 12.77% F, 6.27% N, 7.10% S; found:
1
59.26% C, 3.73% H, 12.87% F, 6.23% N, 7.38% S. H NMR spectrum (CDCl3): 0.72–1.03 m, 4 H
(2 × CH2); 2.14 s, 3 H (SCH3); 2.72 m, 1 H (CH); 3.24 s, 3 H (NCH3); 6.66–6.80 m, 1 H (H-3);
7.32–7.46 m, 1 H (H-6); 7.66–7.84 m, 4 H (H of phthalyl). IR spectrum (CHCl3): 1 784, 1 720, 1 660
Collect. Czech. Chem. Commun. (Vol. 62) (1997)

796
Radl:
(C=O). UV spectrum, λmax (log ε): 216 (4.65), 276 (4.09), 366 (4.11). Mass spectrum, m/z (%): 446
(M+, 11), 159 (100).
The following fraction isolated by flash chromatography was crystallized from methanol providing
3.45 g (53%) of 7b (white crystals), m.p. 178–179 °C. For C21H15F3N2O3S (432.4) calculated:
58.33% C, 3.50% H, 13.18% F, 6.48% N, 7.41% S; found: 58.30% C, 3.48% H, 13.14% F, 6.33% N,
1
7.55% S. H NMR spectrum (CDCl3): 0.90–1.06 m, 4 H (2 × CH2); 2.48 s, 3 H (SCH3); 3.12–3.22 m,
1 H (CH); 6.66–6.80 m, 1 H (H-3); 7.05–7.18 m, 1 H (H-6); 7.66–7.87 m, 4 H (H of phthalyl); 12.30 bs,
1 H (NH). IR spectrum (CHCl3): 1 784, 1 725 (C=O). UV spectrum, λmax (log ε): 217 (4.63), 262
(3.85), 346 (4.28). Mass spectrum, m/z (%): 432 (M+, 8), 159 (100).
2-[1-Cyclopropyl-6,7-difluoro-2-(methylsulfanyl)-4-oxo-1,4-dihydroquinolin-3-yl]-1H-isoindole-
1,3(2H)-dione (8a)
Sodium hydride (80% dispersion in mineral oil, 40 mg, 1.3 mmol) was added to a solution of 7b
(0.43 g, 1.0 mmol) in THF (5 ml) and the mixture was stirred at room temperature under nitrogen for
20 h. The mixture was evaporated, the residue was triturated with water and the insoluble portion
was filtered, washed with water and dried. Crystallization from ethanol yielded 0.28 g (68%) of 8a
(white crystals), m.p. 234–236 °C. For C21H14F2N2O3S (412.4) calculated: 61.16% C, 3.42% H,
9.21% F, 6.79% N, 7.77% S; found: 58.88% C, 3.29% H, 8.88% F, 6.37% N, 7.93% S. 1H NMR
spectrum (CDCl3): 1.05–1.56 m, 4 H (2 × CH2); 2.47 s, 3 H (SCH3); 3.32–3.46 m, 1 H (CH); 7.68–8.00 m,
5 H (H-8, H of phthalyl); 8.08 dd, 1 H, J = 7, J′ = 10 (H-5). IR spectrum (CHCl3): 1 787, 1 722
(C=O). UV spectrum, λmax (log ε): 218 (4.69), 250 (4.28), 247 (4.14), 330 (4.14), 338 (4.12); λinfl 303
(3.91). Mass spectrum, m/z (%): 412 (M+, 39), 218 (100).
2-[1-Cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-(methylsulfanyl)-4-oxo-1,4-dihydroquino-
lin-3-yl]-1H-isoindole-1,3(2H)-dione (8b)
A solution of 8a (2.06 g, 5.0 mmol) and N-methylpiperazine (1 ml, 9.0 mmol) in pyridine (25 ml)
was stirred at 110 °C for 12 h. The mixture was evaporated under reduced pressure and the residue
was triturated with water. The insoluble portion was filtered off, washed with cold water and dried,
the crude product was purified by flash chromatography (dichloromethane) and then by crystal-
lization from ethanol yielding 1.65 g (67%) of 8b (white crystals), m.p. 278–280 °C. For
C26H25FN4O3S (492.6) calculated: 63.40% C, 5.12% H, 3.86% F, 11.37% N, 6.51% S; found: 63.18% C,
5.01% H, 4.00% F, 11.04% N, 6.85% S. 1H NMR spectrum (CDCl3): 1.08–1.60 m, 4 H (2 × CH2); 2.47 s,
3 H (CH3); 2.49 s, 3 H (CH3); 2.46–2.78 m, 4 H (2 × CH2 of piperazine); 3.25–3.46 m, 5 H (CH, 2 × CH2
of piperazine); 7.65–8.06 m, 6 H (H-5, H-8, H of phthalyl). IR spectrum (CHCl3): 1 786, 1 720 (C=O).
UV spectrum, λmax (log ε): 218 (4.66), 270 (4.56) 335 (4.33). Mass spectrum, m/z (%): 492 (M+, 62),
43 (100).
2-[1-Cyclopropyl-6,7-difluoro-1,4-dihydro-2-(methylsulfinyl)-4-oxoquinolin-3-yl]-1H-isoindole-
1,3(2H)-dione (8c)
3-Chloroperbenzoic acid (80%, 0.22 g, 1.0 mmol) was added portionwise during 30 min to a solution
of 8a (0.41 g, 1.0 mmol) in dichloromethane (10 ml) stirred at 0 °C and the solution was stirred for
1 h at this temperature. The mixture was consecutively washed with dilute sodium hydrogen carbo-
nate and sodium bisulfide solutions, the dichloromethane solution was dried with magnesium sulfate
and purified by flash chromatography (dichloromethane–ethyl acetate 95 : 5). Crystallization from
ethanol gave 0.33 g (77%) of 8c (white crystals), m.p. 255–256 °C. For C21H14F2N2O4S (428.4) cal-
culated: 58.88% C, 3.29% H, 8.87% F, 6.54% N, 7.48% S; found: 58.92% C, 3.21% H, 9.08% F,
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797
1
6.52% N, 7.55% S. H NMR spectrum (CDCl3): 1.05–1.56 m, 4 H (2 × CH2); 3.14 s, 3 H (S(O)CH3);
3.32–3.44 m, 1 H (CH); 7.68–8.00 m, 5 H (H-8, H of phthalyl); 8.08 dd, 1 H, J = 7, J′ = 10 (H-5). IR
spectrum (CHCl3): 1 789, 1 722 (C=O). UV spectrum, λmax (log ε): 217 (4.76), 245 (4.37), 328
(4.09), , 339 (4.11). Mass spectrum, m/z (%): 429 (M+ + 1, 65).
3-Amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-(methylsulfanyl)quinolin-4(1H)-one (9a)
A suspension of 8b (0.49 g, 1.0 mmol) in a mixture of 85% hydrazine hydrate (65 µl, 2.8 mmol) and
ethanol (20 ml) was refluxed for 4 h and then evaporated to dryness. The residue was triturated with
ethyl acetate, the insoluble phthalyl hydrazide was filtered off, the filtrate was evaporated and crys-
tallized from toluene yielding 0.34 g (94%) of 9a (yellow crystals), m.p. 176–179 °C. For
C18H23FN4OS (362.5) calculated: 59.65% C, 6.40% H, 5.24% F, 15.46% N, 8.84% S; found: 59.73% C,
6.40% H, 5.32% F, 15.50% N, 8.67% S. 1H NMR spectrum (CDCl3): 0.84–0.92 m, 2 H (CH2); 1.36–1.46 m,
2 H (CH2); 2.38 s, 3 H (CH3); 2.44 s, 3 H (CH3); 2.60–2.75 m, 4 H (2 × CH2 of piperazine); 3.22–3.44 m,
5 H (CH, 2 × CH2 of piperazine); 4.44 s, 2 H (NH2); 7.18 d, 1 H, J = 7 (H-8); 7.94 d, 1 H, J = 12
(H-5). IR spectrum (CHCl3): 3 297 (NH2), 1 630 (C=O). UV spectrum, λmax (log ε): 245 (4.15), 284
(4.47), 343 (4.12), 385 (3.96); λinfl 210 (4.24). Mass spectrum, m/z (%): 362 (M+, 100).
3-Amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)quinolin-4(1H)-one (9d)
Compound 9a (0.10 g, 0.28 mmol) was added to a stirred liquid ammonia (300 ml) and the mixture
was stirred until all the compound dissolved. Sodium (0.03 g, 1.3 mmol) was then added portionwise
to the solution and the mixture was stirred under a stream of nitrogen till all ammonia evaporated.
Ice (10 g) was added, the mixture was acidified with acetic acid and the suspension was extracted
with dichloromethane. Purification by preparative TLC (chloroform–methanol 9 : 1) provided after
crystallization from toluene 0.04 g (45%) of 9d (yellow crystals), m.p. 207–209 °C. The compound
was found to be identical (TLC, 1H NMR, IR) with the sample prepared by a different method10.
3-Amino-1-cyclopropyl-6,7-difluoro-2-(methylsulfanyl)quinolin-4(1H)-one (9e)
A mixture of 8a (0.41 g, 1.0 mmol), 85% hydrazine hydrate (65 µl, 2.8 mmol) and ethanol (25 ml)
was stirred at room temperature for 48 h and then evaporated to dryness. The residue was triturated
with ethyl acetate and the insoluble phthalyl hydrazide was filtered off. The filtrate was evaporated
and crystallized from toluene yielding 0.25 g (87%) of 9e (yellow crystals), m.p. 125–128 °C. For
C13H12F2N2OS (282.3) calculated: 55.31% C, 4.28% H, 13.46% F, 9.92% N, 11.36% S; found:
1
55.39% C, 4.16% H, 13.45% F, 9.97% N, 11.56% S. H NMR spectrum (CDCl3): 0.84–0.96 m, 2 H
(CH2); 1.36–1.46 m, 2 H (CH2); 2.42 s, 3 H (SCH3); 3.26–3.38 m, 1 H (CH); 4.46 s, 2 H (NH2);
7.60 dd, 1 H, J = 7 (H-8); 8.12 dd, 1 H, J = 8, J′ = 11 (H-5). IR spectrum (CHCl3): 3 445, 3 355
(NH2), 1 638 (C=O). UV spectrum, λmax (log ε): 269 (3.97), 323 (4.35), 491 (3.94); λinfl 235 (3.97).
Mass spectrum, m/z (%): 282 (M+, 100).
3-Amino-1-cyclopropyl-6,7-difluoro-2-(methylsulfinyl)quinolin-4(1H)-one (9f)
3-Chloroperbenzoic acid (80%, 0.22 g, 1.0 mmol) was added portionwise during 30 min to a solution
of 9e (0.28 g, 1.0 mmol) in dichloromethane (10 ml) stirred at 0 °C, and the solution was stirred for
2 h at this temperature. The mixture was consecutively washed with dillute sodium hydrogencarbo-
nate and sodium bisulfide solutions. The dichloromethane solution was dried with magnesium sulfate
and purified by flash chromatography (dichloromethane–ethyl acetate 95 : 5). Crystallization from
ethanol gave 0.22 g (74%) of 9f (white crystals), m.p. 218–219 °C. For C13H12F2N2O2S (298.3) cal-
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798
Radl:
culated: 52.34% C, 4.05% H, 12.74% F, 9.39% N, 10.75% S; found: 52.40% C, 3.94% H, 13.06% F,
9.37% N, 10.78% S. 1H NMR spectrum (CDCl3): 0.82–1.54 m, 4 H (2 × CH2); 3.18 s, 3 H
(S(O)CH3); 3.22–3.38 m, 1 H (CH); 5.15 s, 1 H (NH2); 7.65 dd, 1 H, J = 8, J′ = 11 (H-8); 8.11 dd, 1 H,
J = 8, J′ = 11 (H-5). IR spectrum (CHCl3): 3 438, 3 338 (NH2), 1 608 (C=O). UV spectrum, λmax
(log ε): 210 (4.17), 271 (4.36), 308 (3.26), 324 (3.18), 393 (3.90). Mass spectrum, m/z (%): 298 (M+, 100).
3-Amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-(methylsulfinyl)quinolin-4(1H)-one (9c)
A mixture of 9f (1.49 g, 5.0 mmol), N-methylpiperazine (3.0 ml, 27.0 mmol) and acetonitrile (50 ml)
was stirred under nitrogen at 70 °C for 5 days. Then the mixture was evaporated to dryness and the
residue was triturated with water. The insoluble portion was filtered off, washed with water and dried
yielding 1.65 g (87%) of 9c (yellow crystals), not melting up to 300 °C. For C19H23FN4O2S (378.5)
calculated: 57.13% C, 6.13% H, 5.02% F, 14.80% N, 8.47% S; found: 56.88% C, 6.04% H, 4.65% F,
15.04% N, 8.11% S. 1H NMR spectrum (CD3SOCD3): 0.76–1.52 m, 4 H (2 × CH2); 2.54 s, 3 H
(NCH3); 2.80–3.00 m, 4 H (2 × CH2 of piperazine); 3.19 s, 3 H (S(O)CH3); 3.24–3.46 m, 5 H (CH, 2 × CH2
of piperazine); 5.42 s, 2 H (NH2); 7.08 d, 1 H, J = 7 (H-8); 7.92 d, 1 H, J = 12 (H-5); 12.15 bs, 1 H
(NH). IR spectrum (KBr): 3 412, 3 316 (NH2), 16 277 (C=O). UV spectrum, λmax (log ε): 258 (4.25),
292 (4.42), 350 (4.10), 385 (3.98). Mass spectrum, m/z (%): 378 (M+, 100).
3-Amino-1-cyclopropyl-6-fluoro-7-(4-methylpiperazin-1-yl)-2-(methylsulfanyl)quinolin-4(1H)-one
N-Oxide (10)
A solution of 3-chloroperbenzoic acid (80%, 0.05 g, 0.23 mmol) in dichloromethane (1 ml) was
added dropwise to a cold solution (0 °C) of 9a (0.11 g, 0.3 mmol) in dichloromethane (4 ml) and the
mixture was stirred for 30 min at 0 °C. Then the solution was washed with a solution of sodium
hydrogencarbonate (0.1 g) in water (3 ml) and the dichloromethane solution was dried with magne-
sium sulfate. The residue after evaporation of the solvent was purified by preparative TLC (chloro-
form–methanol 8 : 2) yielding after crystallization from toluene 42 mg (36%) of 10 (yellow crystals),
m.p. 220–225 °C (decomposition). For C18H23FN4OS.H2O (396.5) calculated: 54.53% C, 6.36% H,
4.79% F, 14.13% N, 8.09% S; found: 54.30% C, 6.01% H, 4.67% F, 13.47% N, 7.46% S. 1H NMR
spectrum (CDCl3): 0.86–0.94 m, 2 H (CH2); 1.38–1.48 m, 2 H (CH2); 2.44 s, 3 H (SCH3); 3.26–3.94 m,
10 H (CH, 2 × CH2 of piperazine, N(O)CH3); 4.46 s, 2 H (NH2); 7.32 d, 1 H, J = 6 (H-8); 7.94 d, 1 H,
J = 11 (H-5). IR spectrum (CHCl3): 3 297 (NH2), 1 630 (C=O). UV spectrum, λmax (log ε): 242
(4.07), 284 (4.45), 340 (4.02), 386 (3.89). Mass spectrum, m/z (%): 379 (M+ + H, 38).
4-Cyclopropyl-7-fluoro-6-(4-methylpiperazin-1-yl)-1,2,4,9-tetrahydrothiazolo[5,4-b]quinoline-2,9-
dione (5a)
A solution of sodium hydrosulfide hydrate (0.9 g, 12.2 mmol) in water (5 ml) was added to a stirred
solution of 9c (1.2 g, 3.2 mmol) in THF (75 ml) and the mixture was stirred under nitrogen over-
night. The mixture was evaporated to dryness, then water (50 ml) was added to the residue and the
mixture was acidified with acetic acid and extracted with dichloromethane. Triethylamine (3 ml) was
added to the water portion from the previous extraction and then triphosgene (0.60 g, 2.0 mmol) was
added in several portions and the mixture was stirred at room temperature overnight. The formed
solid was filtered off, washed with water and dried; yield 0.2 g (17%) of 5a (yellow solid), decom-
posing without melting at 310–315 °C. For C18H19FN4O2S (374.4) calculated: 57.74% C, 5.11% H,
5.07% F, 14.96% N, 8.56% S; found: 57.36% C, 5.29% H, 5.01% F, 14.74% N, 8.33% S. 1H NMR
spectrum (CD3SOCD3): 1.14–1.46 m, 4 H (2 × CH2); 2.22 s, 3 H (CH3); 3.10–3.40 m, 8 H (H of
piperazine); 3.50–3.62 m, 1 H (CH); 7.40 d, 1 H, J = 8 (H-8); 7.76 d, 1 H, J = 12 (H-5); 11.6 bs, 1 H
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Synthetic Studies
799
(NH). IR spectrum (KBr): 1 710 (C=O). UV spectrum, λmax (log ε): 213 (4.23), 252 (4.31), 261
(3.30), 284 (3.45), 337 (4.24), 357 (4.01); λinfl 324 (4.13). Mass spectrum, m/z (%): 386 (M+, 80).
9-Cyclopropyl-6,7-difluoro-2,3,4,9-tetrahydrothiazolo[5,4-b]quinoline-3,4-dione (5b)
A solution of sodium hydrosulfide hydrate (0.3 g, 4.1 mmol) in water (3 ml) was added to a stirred
solution of 9f (0.30 g, 1.0 mmol) in THF (25 ml) and the mixture was stirred under nitrogen over-
night. Then water (25 ml) was added and the mixture was extracted with ether (25 ml), the water
layer was acidified with dilluted hydrochloric acid and extracted with dichloromethane (6 × 50 ml).
Triethylamine (0.5 ml) was added to the collected dichloromethane extracts and then triphosgene
(0.15 g, 0.50 mmol) was added in several portions and the mixture was stirred at room temperature
for 1 h. The solution was washed with water, dried with magnesium sulfate, evaporated and the
residue was purified by flash chromatography (chloroform–methanol 95 : 5) yielding after crystal-
lization from ethanol 0.18 g (61%) of 5b (white crystals), decomposing without melting at 235–240 °C.
For C13H8F2N2O2S (294.3) calculated: 53.06% C, 2.74% H, 12.91% F, 9.52% N, 10.89% S; found:
1
52.85% C, 3.04% H, 13.17% F, 9.74% N, 10.55% S. H NMR spectrum (CD3SOCD3): 1.14–1.46 m,
4 H (2 × CH2); 3.52–3.66 m, 1 H (CH); 7.98–8.18 m, 2 H (H-5, H-8); 12.15 bs, 1 H (NH). IR
spectrum (KBr): 1 708 (C=O). UV spectrum, λmax (log ε): 222 (4.27), 268 (4.55), 307 (3.52), 312
(3.54), 345 (3.98), 350 (3.97). Mass spectrum, m/z (%): 294 (M+, 80), 279 (100).
1-Cyclopropyl-6,7-difluoro-2-mercapto-3-[(4-methylpiperazin-1-yl)carbonylamino]quinolin-4(1H)-
one (11)
A mixture of 5b (0.05 g, 0.17 mmol), N-methylpiperazine (0.1 ml, 0.9 mmol), triethylamine (0.3 ml)
and acetonitrile (10 ml) was stirred at 50 °C under argon for 3 days. The mixture was evaporated to
dryness and the residue was purified by preparative TLC (toluene–hexane 9 : 1) providing the main
product which after crystallization from methanol yielded 0.03 g (45%) of 11 (yellowish crystals),
decomposing without melting over 300 °C. For C18H20F2N4O2S (394.4) calculated: 54.81% C, 5.11% H,
9.63% F, 14.20% N, 8.13% S; found: 54.58% C, 4.98% H, 9.69% F, 14.44% N, 7.77% S. 1H NMR
spectrum (CDCl3): 0.98–1.12 m, 2 H (CH2); 1.48–1.64 m, 2 H (CH2); 2.55 s, 3 H (CH3); 2.80–3.00 m,
4 H (2 × CH2 of piperazine); 3.35–3.46 m, 1 H (CH); 3.85–4.04 m, 4 H (2 × CH2 of piperazine);
7.76–8.04 m, 2 H (H-5, H-8); 9.84 bs, 1 H (NH); 13.90 bs, 1 H (SH). Mass spectrum, m/z (%): 395
(M+ + H, 18), 217 (100).
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