4956 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 25
Cecchetti et al.
at 90-100 °C for 8 h. After cooling, the mixture was poured
into ice water and the solid filtered, washed with water, and
dried to give 5 (0.7 g, 84%) as a white solid: mp 276-278 °C;
1H NMR (DMSO-d6) δ 1.20-1.40 (4 H, m, cyclopropyl CH2),
2.90 (3 H, d, J ) 3.2 Hz, CH3), 4.10-4.30 (1 H, m, cyclopropyl
CH), 7.80 (1 H, t, J ) 9.1 Hz, H-6), 8.45 (1 H, dd, J ) 6.3, 9.1
Hz, H-5), 8.65 (1 H, s, H-2). Anal. (C14H11BF3NO3) C, H, N.
In addition, it is well-known that the C-8 substituent
also contributes to toxicity of quinolone antibacterials.16
Since no data are reported about the role played by a
C-8 methyl group in such a context, dissecting this
question will represent an additional meaningful target
for further research.
Gen er a l P r oced u r e for Cou p lin g Rea ction . The mix-
ture of borine complex 5, appropiate heterocyclic amine (1.5
equiv), and Et3N (1.5 equiv) in dry DMSO was heated at 70-
120 °C until no starting material was present by TLC (usually
5-30 h). Occasionally, excess side chain was used as the base
instead of Et3N. The reaction mixture was then poured into
ice-water and extracted with CHCl3. The combined organic
layers were washed several times with water and dried. The
crude product is then purified as defined in footnote c in Table
1.
Exp er im en ta l Section
Thin layer chromatography (TLC) was performed on pre-
coated sheets of silica gel 60F254 (Merck) and visualized by
using UV. Column chromatography separations were carried
out on Merck silica gel 40 (mesh 70-230). Melting points were
determined in capillary tubes (Bu¨chi melting point apparatus)
and are uncorrected. Elemental analyses were performed on
a Carlo Erba elemental analyzer, Model 1106, and the data
for C, H, and N are within 0.4% of the theoretical values. 1H
NMR spectra were recorded at 200 MHz (Bruker AC-200) with
Me4Si as internal standard, and chemical shifts are given in
ppm (δ). The spectral data are consistent with the assigned
structures. Reagents and solvents were purchased from
common commercial suppliers and were used as received.
Organic solutions were dried over anhydrous Na2SO4 and
concentrated with a Bu¨chi rotary evaporator at low pressure.
Yields were of purified product and were not optimized. All
starting materials were commercially available unless other-
wise indicated. The physical properties of target acid deriva-
tive are summarized in Table 1.
Thiomorpholinyl derivative 6h was synthesized by a similar
procedure starting from the acid 4, instead of borine complex
5.
To prepare 3-aminopyrrolidinyl derivatives 6j and 6k , the
corresponding 3-acetamidopyrrolidine was employed as nu-
cleophile. The protective acetyl group was then removed by
basic hydrolysis as follows: a mixture of 3-acetamido deriva-
tive (0.1 g, 0.27 mmol), 20% NaOH (2 mL), and EtOH (1 mL)
was refluxed for 14 h. After cooling, the solution was acidified
to pH 4.5-6.5 with AcOH, and the precipitated solid was
filtered, washed with water and then with Et2O, and dried.
Further experimental details are given in Table 1, while
their spectral data are enumerated below.
Eth yl 2-(2-Ch lor o-4-flu or o-3-m eth ylben zoyl)-3-(dim eth -
yla m in o)a cr yla te (2). The mixture of 2-chloro-4-fluoro-3-
methylbenzoic acid 3 (1) (26 g, 0.13 mmol) and thionyl chloride
(20 g) was refluxed for 3 h. The excess thionyl chloride was
removed by distillation under reduced pressure to give a
mobile oil residue which was dissolved in dry toluene (50 mL)
Compound 6a : 1H NMR (CDCl3) δ 0.55-0.70 and 1.00-1.20
(each 2 H, m, cyclopropyl CH2), 2.50 (3 H, s, CH3), 3.10-3.40
(8 H, m, piperazine CH2), 3.95-4.10 (1 H, m, cyclopropyl CH),
6.85 (1 H, d, J ) 8.8 Hz, H-6), 7.45 (1 H, d, J ) 8.8 Hz, H-5),
8.50 (1 H, s, H-2). Anal. (C18H21N3O3‚HCl) C, H, N.
17
and added to ethyl 3-(dimethylamino)acrylate (18.6 g, 0.13
mmol) and dry Et3N (28 g, 0.27 mmol). The resulting solution
was heated at 90° C for 2 h. After cooling and filtration of
the insoluble material, the solvent was washed several times
with water, dried, and evaporated to dryness. The obtained
thick residue, after treatment with cyclohexane, gave a solid
which was washed with Et2O and dried to give 2 (23 g, 56%):
Compound 6b: 1H NMR (CDCl3) δ 0.90-1.00 and 1.20-1.30
(each 2 H, m, cyclopropyl CH2), 2.35-2.85 (10H, m, piperazine
CH2, NCH3, and CH3), 3.10-3.30 (4 H, m, piperazine CH2),
4.05-4.20 (1 H, m, cyclopropyl CH), 7.20 (1 H, d, J ) 8.8 Hz,
H-6), 8.30 (1 H, d, J ) 8.8 Hz, H-5), 8.90 (1 H, s, H-2), 14.95
(1 H, bs, CO2H). Anal. (C19H23N3O3) C, H, N.
Compound 6c: 1H NMR (CDCl3) δ 0.80-0.95 and 1.10-1.25
(each 2 H, m, cyclopropyl CH2), 1.50-1.85 (6 H, m, piperidine
CH2), 2.65 (3 H, s, CH3), 2.95-3.10 (4 H, m, piperidine CH2),
3.95-4.15 (1 H, m, cyclopropyl CH), 7.10 (1 H, d, J ) 8.8 Hz,
H-6), 8.20 (1 H, d, J ) 8.8 Hz, H-5), 8.80 (1 H, s, H-2), 15.00
(1 H, bs, CO2H). Anal. (C19H22N2O3) C, H, N.
Compound 6d : 1H NMR (CDCl3) δ 0.90-1.05 and 1.20-
1.35 (each 2 H, m, cyclopropyl CH2), 1.60-1.95 (3 H, m,
piperidine CH2 and OH), 2.05-2.20 (2 H, m, piperidine CH2),
2.75 (3 H, s, CH3), 2.95-3.13 and 3.30-3.50 (each 2 H, m,
piperidine CH2), 3.90-4.20 (2 H, m, cyclopropyl CH and
piperidine CH), 7.20 (1 H, d, J ) 8.8 Hz, H-6), 8.25 (1 H, d, J
) 8.8 Hz, H-5), 8.95 (1 H, s, H-2), 15.00 (1 H, bs, CO2H). Anal.
(C19H22N2O4) C, H, N.
Compound 6e: 1H NMR (CDCl3) δ 0.85-0.95 (2 H, m,
cyclopropyl CH2), 1.05 (3 H, d, J ) 5.5 Hz, piperidine CH3),
1.20-1.30 (2 H, m, cyclopropyl CH2), 1.40-1.90 (5 H, m,
piperidine CH and CH2), 2.70 (3 H, s, CH3), 2.90-3.00 and
3.25-3.40 (each 2 H, m, piperidine CH2), 4.05-4.20 (1 H, m,
cyclopropyl CH), 7.20 (1 H, d, J ) 8.8 Hz, H-6), 8.25 (1 H, d,
J ) 8.8 Hz, H-5), 8.80 (1 H, s, H-2), 15.00 (1 H, bs, CO2H).
Anal. (C20H24N2O3) C, H, N.
Compound 6f: 1H NMR (CDCl3) δ 0.90-1.00 and 1.15-1.35
(each 2 H, m, cyclopropyl CH2), 1.60-2.00 (5 H, m, piperidine
CH and CH2), 2.50 (1 H, m, OH), 2.70-3.60 (9 H, m, piperidine
CH2 and CH3), 4.10-4.30 (1 H, m, cyclopropyl CH), 7.20 (1 H,
d, J ) 8.8 Hz, H-6), 8.20 (1 H, d, J ) 8.8 Hz, H-5), 8.90 (1 H,
s, H-2), 15.00 (1 H, bs, CO2H). Anal. (C20H24N2O4) C, H, N
Compound 6g: 1H NMR (CDCl3) δ 0.80-1.00 (8 H, m,
cyclopropyl CH2 and piperidine CH3), 1.20-1.30 (2 H, m,
cyclopropyl CH2), 1.80-2.00 (4 H, m, piperidine CH2), 2.30-
2.50 (2 H, m, piperidine CH2), 2.70 (3 H, s, CH3), 3.15-3.30 (2
H, m, piperidine CH2), 4.00-4.20 (1 H, m, cyclopropyl CH),
1
mp 110-114 °C; H NMR (CDCl3) δ 0.90 (3 H, t, J ) 7 Hz,
CH2CH3), 2.30 (3 H, d, J ) 3 Hz, CH3), 2.95 and 3.35 (each 3
H, bs, NCH3), 3.95 (2 H, q, J ) 7 Hz, CH2CH3), 6.95 (1 H, t, J
) 8.9 Hz, H-5), 7.20 (1 H, dd, J ) 6.7 and 8.9 Hz, H-6), 7.80
(1 H, s,vinyl H). Anal. (C15H17ClFNO3) C, H, N.
Eth yl 1-Cyclop r op yl-7-flu or o-8-m eth yl-4-oxo-1,4-d ih y-
d r oqu in olin e-3-ca r boxyla te (3). A stirred solution of 2 (20
g, 64 mmol) in EtOH/Et2O (1:2) (350 mL) was treated dropwise
with cyclopropylamine (3.65 mL, 64 mmol). After 15 min at
room temperature the solvent was evaporated to dryness and
the residue dissolved in dry DMF (50 mL) and treated with
K2CO3 (8.82 g, 63.9 mmol). The resulting mixture was heated
at 100 °C for 3 h and, after cooling, poured into ice water. The
solid so obtained was filtered, washed with water, and dried
to give 3 (15 g, 81%): mp 164-166 °C; 1H NMR (CDCl3) δ
0.90-1.05 and 1.15-1.30 (each 2 H, m, cyclopropyl CH2), 1.40
(3 H, t, J ) 7.1 Hz, CH2CH3), 2.72 (3 H, d, J ) 2.7 Hz, CH3),
3.90-4.05 (1 H, m, cycloproyl CH), 4.40 (2 H, q, J ) 7.1 Hz,
CH2CH3), 7.12 (1 H, t, J ) 8.9 Hz, H-6), 8.35 (1 H, dd, J ) 6.7
and 8.9 Hz, H-5), 8.65 (1 H, s, H-2). Anal. (C16H16FNO3) C,
H, N.
1-Cyclopr opyl-7-flu or o-8-m eth yl-4-oxo-1,4-dih ydr oqu in -
olin e-3-ca r boxylic Acid (4). The mixture of 3 (2 g, 6.9 mmol)
and 6 N HCl (10 mL) was refluxed for 2 h. After cooling, the
crystalline-precipitate solid was filtered off, washed with
1
water, and dried to give 4 (1.4 g, 80%): mp 236-237 °C; H
NMR (DMSO-d6) δ 1.05-1.35 (4 H, m, cyclopropyl CH2), 2.80
(3 H, d, J ) 3.2 Hz, CH3), 4.30-4.50 (1 H, m, cyclopropyl CH),
7.50 (1 H, t, J ) 9 Hz, H-6), 8.25 (1 H, dd, J ) 6.3, 9 Hz, H-5),
8.85 (1 H, s, H-2), 14.80 (1 H, bs, CO2H). Anal. (C14H12FNO3)
C, H, N.
1-Cyclopr opyl-7-flu or o-8-m eth yl-4-oxo-1,4-dih ydr oqu in -
olin e-3-ca r boxylic Acid BF 2 Ch ela te (5). The mixture of 3
(0.8 g, 2.7 mmol) and 48% HBF4 in water (10 mL) was heated