Synthetic study on novel immunosuppressant KF20444.

Article abstract of DOI:10.1016/S0968-0896(01)00238-3

The two new synthetic routes to 6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H- benzo[6,7]cyclohepta[1,2-b]-quinoline-8-carboxylic acid (1), a novel immunosuppressant KF20444, are described. The seven-membered ring construction from 2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-chloromethyl-6-fluoroquinoline (17c) was achieved by intramolecular Friedel-Crafts reaction under acidic conditions as the key step. Subsequently, the oxidation of 4-chloromethyl group followed by reduction of carbonyl group on the seven-membered ring afforded 1. This route provides a new method for the synthesis of 1.

Full text of DOI:10.1016/S0968-0896(01)00238-3

Bioorganic & Medicinal Chemistry 9 (2001) 3273–3286
Synthetic Study on Novel Immunosuppressant KF20444
Iwao Chujo,* Yoshiaki Masuda, Kenji Fujino, Sachiko Kato, Takehiro Ogasa,
Shin-ichiro Mohri and Masaji Kasai
Sakai Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., 1-1-53, Takasu-cho, Sakai, Osaka 590–8554, Japan
Received 12 April 2001; accepted 29 June 2001
Abstract—The two new synthetic routes to 6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H- benzo[6,7]cyclohepta[1,2-b]-quinoline-8-
carboxylic acid (1), a novel immunosuppressant KF20444, are described. The seven-membered ring construction from 2-[4-(2-
fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-chloromethyl-6-fluoroquinoline (17c) was achieved by intramolecular Friedel–Crafts
reaction under acidic conditions as the key step. Subsequently, the oxidation of 4-chloromethyl group followed by reduction of
carbonyl group on the seven-membered ring afforded 1. This route provides a new method for the synthesis of 1. # 2001 Elsevier
Science Ltd. All rights reserved.
Introduction
The structure–activity relationship (SAR) studies
revealed that the activity depended on the bridged ring
size between quinoline nucleus and biphenyl moiety.
The series of seven-membered ring compounds showed
high activities,6,7 and the most promising compound,
KF20444, was selected for further evaluation. It has
been reported on the construction of 6,7-dihydro-5H-
benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxylic acid
framework12,13 as well as 5,6-dihydro-3-benz[c]acridine-
7-carboxylic acid framework.12À19 They all utilized the
Pfitzinger reaction20 of the 1-benzosuberone or a-tetra-
lone derivatives with isatine to constitute these structure
(Scheme 1).
Immunosuppressive drugs have assumed a critical role
in the suppression of tissue rejection reaction, allowing
life-saving organ transplantation to become almost
routine.1 Brequinar sodium,2 undergoing clinical trials
for the prevention of organ transplant rejection,3 is a
inhibitor (Ki of 12nM) of dihydroorotate dehy-
drogenase (DHO-DH), which is the controlling step in
de novo pyrimidine nucleotide biosynthesis.4,5 6,7-
Dihydro-10-fluoro-3- (2-fluorophenyl)-5H-benzo[6,7]cy-
clohepta[1,2-b]quinoline-8-carboxylic
acid
(1;
KF20444), tetracyclic analogue of Brequinar with tri-
methylene bridge, has more potent inhibitory activity
(Ki of 4.6 nM) against DHO-DH.6À8 KF20444 has been
found to display a more potent immunosuppressive
effect than Brequinar sodium,8À11 and will be a useful
immunosuppressant.
The synthetic route of KF20444 also adapted the same
strategy to prepare the substrate for SAR studies.6,7
Therefore, 7-(2-fluorophenyl)-1-benzosuberone (2) was
chosen as a key intermediate and treatment of 2 with 5-
Figure 1.
*Corresponding author. Tel.: +81-722-23-5583; fax: +81-722-27-7214; e-mail: iwao.chujo@kyowa.co.jp
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00238-3

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I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
fluoroisatin (3) under Pfitzinger reaction conditions
produced KF20444 (Scheme 2).
Result and Discussion
The 4-quinolinecarboxylic acid derivative 5 was easily
synthesized from commercially available 2-fluorobiphenyl
(7). Friedel–Crafts reaction of 7 with methyl 5-chloro-5-
oxovalerate followed by Pfitzinger reaction with 5-
fluoroisatin (3)21À24 under the basic conditions afforded
4-quinolinecarboxylic acid derivative 5 in good yield.
First, we tried the cyclization reaction of 5 in acidic
conditions without protection of the carboxyl group at
the 4-position on the quinoline. However, the dec-
arboxylation and subsequent cyclization occurred, and
the undesirable product 10 was obtained exclusively.
The diester derivative 9 gave the same result (Scheme 4).
Taking into account the large-scale synthesis for the
further evaluation, there were several issues, for instance
use of heavy metal reagent and low temperature reac-
tion, low yield in several steps, and difficulties in isola-
tion and purification of some intermediates owing to
oily compounds included key intermediate 2. Therefore,
we decided to investigate alternative strategy for the
construction
of
6,7-dihydro-5H-benzo[6,7]cyclo-
hepta[1,2-b]quinoline-8-carboxylic acid framework. In
our strategy, the quinoline skeleton would be produced
before the construction of carbon seven-membered ring
to avoid the oily intermediate 2, then the ring closure by
intramolecular Friedel–Crafts reaction would afford the
6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-b]quinoline-8-
carboxylic acid framework. After that, the reduction of
the carbonyl group at seven-membered ring would
produce KF20444 (Scheme 3).
To avoid the decarboxylation, the carboxyl group at the
4-position was converted into the various amide groups.
The selective amidation of the carboxyl group at the 4-
position on the quinoline was achieved by taking
advantage of differences of reactivity between these two
Scheme 1.
Scheme 2.
Scheme 3. Synthetic strategy of KF20444.

I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
3275
carboxyl groups. Thus, without DMF, the monoester 11
was obtained exclusively by the treatment of dicar-
boxylic acid 5 with thionyl chloride (2.1 equiv) followed
by methanol. On the other hand, by the treatment with
thionyl chloride and catalytic amount of DMF after the
esterification of the side chain, the acid chloride at the 4-
position was obtained. Then the in situ treatment of the
acid chloride with adequate amine gave the amides. The
hydrolysis of the methyl ester on the side chain afforded
desired amide derivatives 12a–d (Scheme 5).
19%) compared with the piperidine amide 12a. In these
N-monosubstituted amides, the steric hindrance of N-
alkyl group did not affect the yield of the cyclization
reaction. Even though the yield of the product 13a was
not satisfactory (42%), the piperidine amide derivative
12a gave the best result.
Then, we tried to convert the octylamide derivative 13b
to KF20444 (Scheme 6). The attempts to reduce the
carbonyl group on the seven-membered ring with
hydrogenation, Wolff–Kishner reduction, or silane
reduction with triethylsilane were unsuccessful. Yet it
gave a hydroxy derivative mainly. These results pro-
moted us to reduce carbonyl group in stepwise. A
treatment of 13b with sodium borohydride, followed by
hydriodic acid and acetic anhydride25,26 gave the desired
product 15b successfully. Finally, KF20444 was
obtained by treating 15b with sodium nitrite and acetic
anhydride, followed by potassium hydroxide.27À29
The ring closure reaction of piperidine amide derivatives
12a with trifluoromethanesulfonic acid gave the desired
products 13a along with the dimer 14a and the dec-
arboxylation/cyclization product 10 (Table 1). When the
cyclization reaction was carried out with methane-
sulfonic acid or polyphosphoric acid (PPA), undesired
compound 10 was obtained exclusively. The seven-
membered ring closure reaction was promoted under
highly diluted conditions, and the yield of 13a increased
with suppression of the formation of 14a. On the other
hand, the reaction of N-monosubstituted amides 12b–d
gave more complex mixture and resulted low yield (16–
Although we obtained KF20444 by these procedures,
we made further efforts to improve the yield of seven-
membered ring closure reaction, in which the carboxyl
Scheme 4. Reagents: (i) MeO2C(CH2)3COCl, AlCl3, ClCH2CH2Cl, 5 ꢀC, 75%; (ii) 3, KOH, EtOH, dioxane, H2O, 55 ꢀC, 89%; (iii) SOCl2, DMF,
toluene, 50 ꢀC, then MeOH, Et3N, 46%; (iv) TfOH, 60 ꢀC, 71%; (v) TfOH, 70 ꢀC, 65%.
Table 1. Cyclization of 4-quinolinecarboxamide derivaitves 12a–d
Entry
Substrate
Conditions
13 Yield (%)b,c
Ratioc,d
Acid
Concd (g/L)a
Temp. (ꢀC)
Time (h)
13
14
10
1
2
3
4
5
6
7
12a
12a
12a
12a
12b
12c
12d
TfOH
TfOH
MsOH
PPA
TfOH
TfOH
TfOH
50
10
10
10
10
10
10
110
130
130
100
130
130
130
17
9
8
16
4
10
4
14
4261
N.D.
N.D.
16
25
13
N.D.
N.D.
19
22
2
N.D.
N.D.
122
2
60
87
7
16
18
not determined
not determined
aCalculated by weight of substrate (f)/volum of acid (mL).
bIsolated yield.
cN.D.; not detected.
dRatios of the reaction mixture were determined by HPLC (area %).

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I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
Scheme 5. Reagents: (i) SOCl2, toluene, 50 ꢀC, then MeOH, 0 ꢀC, 99%; (ii) SOCl2, DMF, toluene, 60 ꢀC, then R1R2NH, Et3N, rt; (iii) aq NaOH,
MeOH, 50 ꢀC, 43–83%; (iv) (see Table 1).
of 16c with sodium borohydride in DMF produced the
4-methyl derivative 16d. Hydrolysis of the methyl ester
on 16a–d with aqueous sodium hydroxide or concd
hydrochloric acid gave the corresponding carboxylic
acids 17a–d (Scheme 7).
The cyclization reaction of 17a–d was investigated next
(Table 2). The reaction of chloromethyl derivative 17c
and methyl derivative 17d with trifluoromethanesulfonic
acid gave desired products in good yield. On the other
hand, the reaction of the hydroxymethyl compound 17a
resulted in low yield because the lactone 19 was formed
mainly, and the methoxymethyl compound 17b gave the
complex mixture. Although the cyclization reaction
proceeded under other conditions (PPA or methane-
sulfonic acid), the yields of the desired products were
not so good as with trifluoromethanesulfonic acid
(Scheme 8).
Figure 2.
group at the 4-position of quinoline ring was converted
into the other functional groups. The 4-hydroxymethyl
derivative 16a was synthesized by the treatment of the
monoester 11 with thionyl chloride, followed by reduc-
tion with sodium borohydride in THF. Reactions of 16a
with sodium hydride and iodomethane, or thionyl
chloride gave the 4-methoxymethyl derivative 16b or the
4-chloromethyl derivative 16c, respectively. A treatment
Then the chloromethyl derivative 18c was converted
into KF20444 (Scheme 9). The replacement of chlorine
to oxygen functionality proceeded successfully by the
substitution with sodium acetate in acetic acid. Under
basic conditions, however, decomposition of the sub-
strate occurred, and it resulted in the low yield of the
Scheme 6. Reagent: (i) NaBH, MeOH, 5 ꢀC; (ii) 57% HI, Ac2O, AcOH, 100 ꢀC, 96%; (iii) NaNO2, Ac2O, AcOH, rt; (iv) KOH, EtOH, 80 ꢀC, 74%.

I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
3277
replacement. The hydrolysis of the acetoxy group by
aqueous sodium hydroxide afforded the hydroxymethyl
derivative 18a. An oxidation of the hydroxymethyl
group into the carboxyl group proceeded directly with
chromium oxide under Jones oxidation condition and
Table 2. Investigation of cylization reaction of 17a–d
Entry Substrate
X
Conditionsa
18 Yield (%)b
Acid Time (h)
Figure 3.
1
2
3
4
5
6
7
17a
17b
17c
17c
17c
17d
17d
CH2OH TfOH
CH2OMe TfOH
5
13c
d
2Complex mixture
281
8
20
4
gave the carboxylic acid 4 in 86% yield. However, to
avoid the use of heavy metal reagents, we established
the stepwise oxidation method under mild reaction
conditions. The hydroxymethyl derivative 18a was oxi-
dized into the aldehyde 21 with acetic anhydride and
dimethylsulfoxide, then the treatment with sodium
chlorite30À32 afforded the carboxylic acid 4 in 88% yield.
Because of the low solubility of the carboxylic acid 4,
the carboxyl group was converted into the methyl ester
CH2Cl
CH2Cl
CH2Cl
Me
TfOH
MsOH
PPA
TfOH
PPA
No reaction
21
72
28
Me
11
aReaction was carried out at 130 ꢀC in 10 g/L concentration.
bIsolated yield.
cThe lactone 19 was main product.
dThe lactone 19 was obtained in 27% yield.
Scheme 7. Reagents: (i) SOCl2, DMF, toluene, 55 ꢀC, then NaBH4, THF, rt, 75%; (ii) MeI, NaH, DMF, 5 ꢀC, 94%; (iii) SOCl2, ClCH2CH2Cl, rt,
99%; (iv) NaBH4, DMF, rt, 91%; (v) aq NaOH, MeOH, 55 ꢀC, 99%; (vi) concd HCl, AcOH, 55 ꢀC, 98%.
Scheme 8.

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I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
Scheme 9. Reagents: (i) AcONa, AcOH, 110 ꢀC; (ii) aq NaOH, MeOH, rt, 97% from 18c; (iii) Ac2O, DMSO, rt, 90%; (iv) 87% NaClO2, NaH2PO4,
DMSO, H2O, rt, 98%; (v) MeI, K2CO3, acetone, 45 ꢀC, 77%; (vi) NaBH4, MeOH, rt; (vii) 57% HI, Ac2O, AcOH, 110 ꢀC, 73% from 21.
group by a treatment with iodomethane and potassium
carbonate to afford the methyl ester 22. Finally, the
reduction of the carbonyl group on the seven-membered
ring was accomplished by the same procedure already
established in the reduction of amide derivatives. Thus,
the treatment of 22 with sodium borohydride, followed
by hydriodic acid and acetic anhydride afforded
KF20444 in 73% yield from 22.
from commercial suppliers and used without further
purification. TLC analysis was carried out on silica gel
60 F-254 plates (0.1 mm, Merck) with iodine and/or UV
detection. Chromatographic separation was made on
silica gel columns (Wako-gel C-200, 75–150 mesh).
HPLC was carried out with Hitachi instrument (detec-
tor L-4000H, pump L-6000, oven L-5025, recorder
D-2500) and measured with 254 nm. Melting points
were measured on a Mettler FP61 melting point appa-
ratus and uncorrected. IR spectra were measured on a
1
Horiba FT-200 spectrophotometer. H NMR and 13C
Conclusions
NMR spectra were recorded using JEOL JNM-400
(400 MHz) and Bruker AC-300 (300 MHz) spectro-
meters using tetramethylsilane as an internal standard.
Mass spectra were recorded on a JEOL JMS-D300 and
micromass LCT spectrometers.
In conclusion, we have established two new synthetic
routes of KF20444 (1) in which the seven-membered ring
closure reaction of 4-N-octylcarbamoyl or 4-chloro-
methyl quinoline derivatives was the key step. In the
former route, the total yield from 7 is too poor (6.2%),
because of the low yield in seven-membered ring closure
reaction, to utilize it for the large scale synthesis. In the
latter route, the yields in every step are more than 70%
and the total yield was improved to 19%. Additionally,
according to this route, all intermediates are isolated as
crystals, and it does not need to use the heavy metal
reagent and the low temperature reaction. We expect
this route to provide a new method for the production
of 1 in large-scale. Further work is required to develop
this route, because our results are in early stage for the
improvement on the synthetic method of 1.
Methyl 4-[4-(2-fluorophenyl)benzoyl]butylate (8). Methyl
5-chloro-5-oxovalerate (21.0 g, 128 mmol) was added
dropwise to a mixture of 2-fluorobiphenyl (20.0 g, 116
mmol), AlCl3 (31.0 g, 232 mmol) and ClCH2CH2Cl (60
mL) at 5 ꢀC. The mixture was stirred at 5 ꢀC for 8 h and
then poured into 6 mol/L HCl (280 mL). The organic
layer was washed with 2mol/L HCl then brine, and
dried over MgSO4. After filtration and evaporation, the
resulting residue was crystallized from i-PrOH (140 mL)
to afford the ester 8 (26.2 g, 75%).
Mp 75–76 ꢀC (decomp); H NMR (CDCl3, 300 MHz) d
2.10 (2H, m), 2.49 (2H, t, J=7.2Hz), 3.09 (2H, t, J=7.2
Hz), 3.69 (3H, s), 7.14–7.27 (2H, m), 7.33–7.40 (1H, m),
7.45 (1H, dt, J=7.7, 1.8 Hz), 7.65 (1H, ddd, J=1.6, 1.8,
1
Experimental
5-Fluoroisatin was synthesized according to the descri-
bed methods.21À24 All other reagents were purchased

I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
3279
6.7 Hz), 8.04 (1H, ddd, J=1.8, 1.9, 6.7 Hz); 13C NMR
(CDCl3, 75 MHz) d 20.1, 33.9, 38.3, 52.3, 117.0 (J=22.6
Hz), 125.3 (J=3.8 Hz), 128.6 (J=13.1 Hz), 128.9, 129.9
(J=3.2Hz), 130.6 ( J=8.3 Hz), 131.3 (J=3.1 Hz),
136.5, 141.3 (J=0.8 Hz), 160.5 (J=248.8 Hz), 174.5,
199.7; MS m/z 300 (M+), 269, 241, 227, 214, 199, 171;
HR-MS [ESI(+)] calcd for C18H18FO3 (M+H):
301.1240, found 301.1240.
(J=3.6 Hz), 129.1 (J=13.2Hz), 129.3, 130.0 ( J=8.4
Hz), 130.1 (J=2.9 Hz), 130.2, 131.4 (J=3.3 Hz), 133.1
(J=9.4 Hz), 137.0, 139.7, 139.8, 144.4, 160.0 (J=2.9
Hz), 160.5 (J=248.4 Hz), 161.9 (J=249.7 Hz), 168.5,
173.0; MS m/z 461 (M+), 430, 402, 369, 342; HR-MS
[ESI(+)] calcd for C27H22F2NO4 (M+H): 462.1517,
found 462.1526.
4-[4-(2-Fluorophenyl)phenyl]-3-[(2-methoxycarbonyl)ethyl]-
6-fluoroquinoline-4-carboxylic acid (11). SOCl2 (4.04 g,
34.0 mmol) was added to a suspension of dicarboxylic
acid 5 (7.00 g, 16.2 mmol) in toluene (220 mL) at room
temperature. The mixture was stirred at 50 ꢀC for 3 h.
After cooling and adding MeOH (13 mL), the reaction
mixture was stirred at 0 ꢀC for 3 h. The precipitated
solid was filtered and dried under reduced pressure to
yield monoester 11 (7.20 g, 99%).
2-[4-(2-Fluorophenyl)phenyl]-3-(2-carboxyethyl)-6-fluoro-
quinoline-4-carboxylic acid (5). A solution of the ester 8
(10.1 g, 33.5 mmol) in EtOH (80 mL) and dioxane (40
mL) was added dropwise to a mixture of 5-fluoroisatin 3
(8.30 g, 50.3 mmol), KOH (13.3 g, 201 mmol) and water
(20 mL) at room temperature. The mixture was stirred
at 55 ꢀC for 13 h. After cooling and evaporation of
EtOH, water (150 mL) and Et2O (75 mL) were added to
the residue, then the aqueous layer was separated.
AcOH (40 mL) and water (50 mL) were added to the
aqueous layer, and the mixture was stirred at 5 ꢀC for 2
h. The precipitated solid was filtered and dried under
reduced pressure to yield 14.0 g of the crude product.
The crude product was recrystallized from AcOEt
(140 mL) to afford the dicarboxylic acid 5 (12.9 g,
89%).
Mp 243–244 ꢀC (decomp); 1H NMR (CD3OD,
300 MHz) d 2.51 (2H, brt, J=8.1 Hz), 3.21 (2H, brt,
J=8.1 Hz), 3.52 (3H, s), 7.14–7.29 (2H, m), 7.32–7.39
(1H, m), 7.50–7.78 (7H, m), 8.05(1H, dd, J=5.3, 9.2
Hz); 13C NMR (DMSO-d6, 75 MHz) d 25.6, 33.6, 50.5,
108.3 (J=23.2 Hz), 115.4 (J=23.0 Hz), 119.4 (J=26.4
Hz), 124.0 (J=3.4 Hz), 124.1 (J=9.3 Hz), 127.2, 127.8
(J=13.2 Hz), 128.3, 128.5 (J=3.0 Hz), 129.0 (J=8.4
Hz), 130.0 (J=9.1 Hz), 130.1 (J=3.1 Hz), 130.2, 136.1,
138.5, 142.5, 159.5 (J=247.0 Hz), 159.5, 160.6
(J=247.9 Hz), 170.8, 172.6; MS m/z 447 (M+), 402,
388, 342; HR-MS [ESI(+)] calcd for C26H20F2NO4
(M+H): 448.1360, found 448.1378.
Mp 220–221 ꢀC (decomp); 1H NMR (DMSO-d6,
300 MHz) d 2.28–2.34 (2H, m), 2.99–3.04 (2H, m), 7.28–
7.33 (2H, m), 7.38–7.42 (1H, m), 7.47 (1H, dd, J=2.8,
9.8 Hz), 7.56–7.73 (6H, m), 8.09 (1H, dd, J=5.5, 9.2
Hz); 13C NMR (DMSO-d6, 75 MHz) d 26.8, 35.2, 109.6
(J=22.9 Hz), 117.2 (J=22.5 Hz), 120.5 (J=25.8 Hz),
124.7 (J=10.2Hz), 162.1 ( J=3.4 Hz), 127.9, 128.7
(J=12.9 Hz), 129.5, 129.6 (J=2.7 Hz), 129.9, 130.8
(J=8.1 Hz), 131.8 (J=3.1 Hz), 132.9 (J=9.3 Hz),
135.9, 140.8, 144.1, 160.2( J=246.1 Hz), 160.5 (J=2.6
Hz), 161.0 (J=245.6 Hz), 170.5, 174.2; MS m/z 433
(M+), 388, 342; HR-MS [ESI(+)] calcd for
C25H18F2NO4 (M+H):434.1204, found 434.1199.
Typical procedure for the synthesis of 2-[4-(2-fluorophe-
nyl)phenyl]-3-(2-carboxyethyl)-quinoline-4-carboxamide
derivatives (12a–d) from monoester 11. DMF (0.1 equiv)
and SOCl2 (4.0 equiv) were added to a suspension of the
monoester 11 in toluene at room temperature. The
mixture was stirred at 60 ꢀC for 1 h. After cooling to
5 ꢀC, Et3N (15.0 equiv) and amine R1R2NH (4.0 equiv)
were added. The reaction mixture was allowed to warm
to room temperature and stirred for 4 h. After quench-
ing with water and 1 mol/L HCl, the reaction mixture
was extracted with AcOEt. The extract was washed with
water, brine, and dried over MgSO4. After filtration and
evaporation, the residue was dissolved in MeOH, and to
this solution was added 1 mol/L NaOH at room tem-
perature. The mixture was stirred at 50 ꢀC for 4 h. After
quenching with water and 1 mol/L HCl, the mixture
was extracted with AcOEt. The extract was washed with
brine, and dried over MgSO4. After filtration and eva-
poration, the amide derivatives (12a–d) were isolated by
silica gel column chromatography (toluene–AcOEt).
Methyl 2-[4-(2-fluorophenyl)phenyl]-3-[(2-methoxycarbo-
nyl)ethyl]-6-fluoroquinoline-4-carboxylate (9). DMF
(0.11 mL, 1.38 mmol) and SOCl2 (2.71 mL, 37.4 mmol)
were added to a suspension of dicarboxylic acid 5 (3.00
g, 6.92mmol) in toluene (90 mL) at room temperature.
The mixture was stirred at 50 ꢀC for 2h. After cooling,
MeOH (5.61 mL, 138.0 mmol) and Et3N (14.8 mL,
104.0 mmol) were added, and the resulting mixture was
stirred at room temperature for 30 min. After quenching
with water, the reaction mixture was extracted with
AcOEt. The extract was washed with 6 mol/L HCl,
brine, and dried over MgSO4. After filtration and eva-
poration, the residue was recrystallized from MeOH (10
mL) to afford the diester 9 (1.46 g, 46%).
Piperidino-2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-
6-fluoroquinoline-4-carboxamide (12a). Yield 43%. Mp
176–178 ꢀC (hexane/AcOEt=1:1, decomp); 1H NMR
(CDCl3, 300 MHz) d 1.48 (1H, brs), 1.72–1.77 (4H, m),
2.63 (1H, ddd, J=5.1, 11.8, 16.8 Hz), 2.93 (1H, ddd,
J=5.1, 11.8, 16.9 Hz) 2.94–3.04 (1H, m), 3.14–3.24 (4H,
m), 3.73–3.79 (1H, m), 4.01–4.05 (1H, m) 7.13–7.21 (1H,
m), 7.24 (1H, dd, J=1.3, 7.5 Hz), 7.30–7.38 (2H, m),
7.45–7.52 (2H, m), 7.57 (2H, dd, J=1.8, 6.5 Hz), 7.68
(2H, dd, J=1.5, 8.2Hz), 8.15 (1H, dd, J=5.4, 9.2Hz);
Mp 126–127 ꢀC (decomp); H NMR (CDCl3, 300 MHz)
1
d 2.42–2.48 (2H, m), 3.16–3.21 (2H, m), 3.59 (3H, s),
4.11 (3H, s), 7.15–7.22 (1H, m), 7.26 (1H, dd, J=1.3,
7.5 Hz), 7.32–7.49 (2H, m), 7.50–7.54 (2H, m), 7.59 (2H,
dd, J=1.8, 6.5 Hz), 7.70 (2H, dd, J=1.5, 8.3 Hz ), 8.15
(1H, dd, J=5.4, 9.2Hz); 13C NMR (CDCl3, 75 MHz) d
27.0, 35.1, 52.5, 53.7, 108.8 (J=23.7 Hz), 116.9 (J=22.7
Hz), 120.9 (J=25.8 Hz), 125.0 (J=10.3 Hz), 125.2

3280
I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
13C NMR (CDCl3, 75 MHz) d 25.1, 26.4, 26.5, 27.2,
34.6, 43.3, 48.6, 108.6 (J=23.0 Hz), 117.0 (J=22.6 Hz),
121.0 (J=25.8 Hz), 125.1 (J=9.8 Hz), 125.2 (J=3.7
Hz), 128.9, 129.1 (J=13.1 Hz), 129.3, 130.0, 130.1
(J=3.0 Hz), 131.5 (J=3.3 Hz), 133.1 (J=9.3 Hz),
137.0, 139.8, 143.2( J=5.7 Hz), 144.3, 160.6 (J=248.3
Hz), 160.5 (J=2.8 Hz), 161.9 (J=249.9 Hz), 166.7,
177.2; MS m/z 500 (M+), 455, 372, 342; HR-MS
[ESI(+)] calcd for C30H27F2N2O3 (M+H): 501.1990,
found 501.1977.
AcOEt=16:1) gave the alcohol 16a (1.46 g, 75%).
ꢀ
1
Mp 189–192 C (AcOEt, decomp); H NMR (CDCl3,
300 MHz) d 2.46 (2H, t, J=7.2Hz), 3.26 (1H, t, J=5.8
Hz), 3.35, (2H, t, J=7.2Hz), 3.55 (3H, s), 5.18 (2H, d,
J=5.8 Hz), 7.15–7.27 (2H, m), 7.32–7.39 (1H, m), 7.43–
7.59 (4H, m), 7.64–7.71 (2H, m), 7.90 (1H, dd, J=2.7,
10.4 Hz), 8.11 (1H, dd, J=5.6, 9.2Hz); 13C NMR
(CDCl3, 75 MHz) d 24.0, 34.2, 51.9, 57.8, 108.1 (J=23.1
Hz), 116.2( J=22.6 Hz), 119.3 (J=25.7 Hz), 124.5
(J=3.7 Hz), 127.5 (J=9.7 Hz), 128.4 (J=14.7 Hz),
128.6, 129.2, 129.3 (J=2.9 Hz), 130.6, 130.7 (J=3.4
Hz), 132.3 (J=9.3 Hz), 135.9, 140.3, 143.1 (J=5.7 Hz),
143.8, 159.8 (J=248.2 Hz), 159.8 (J=2.8 Hz), 161.0
(J=247.9 Hz), 173.6; MS m/z 433 (M+), 401, 375, 356;
HR-MS [ESI(+)] calcd for C26H22F2NO3 (M+H):
434.1568, found 434.1559.
N-Octyl-2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-
6-fluoroquinoline-4-carboxamide (12b). Yield 76%. Mp
201–202 ꢀC (toluene, decomp); 1H NMR (CDCl3-
CD3OD, 300 MHz) d 0.90 (3H, t, J=6.8 Hz ), 1.20–1.43
(10H, m), 1.66–1.76 (2H, m), 2.44 (2H, brs), 3.19 (2H, t,
J=8.1 Hz), 3.54 (2H, t, J=7.1 Hz), 7.19 (1H, ddd,
J=1.2, 8.2, 10.8 Hz), 7.27 (1H, dt, J=1.3, 7.5 Hz),
7.34–7.41 (1H, m), 7.44–7.56 (3H, m), 7.60 (2H, d,
J=8.3 Hz), 7.72(2H, dd, J=1.5, 8.3 Hz), 8.09 (1H, dd,
J=5.3, 9.2Hz); MS m/z 544 (M+), 498, 371, 342; HR-
MS [ESI(+)] calcd for C33H35F2N2O3 (M+H):
545.2616, found 545.2626.
2-[4-(2-Fluorophenyl)phenyl]-3-(2-methoxycarbonylethyl)-
4-methoxymethyl-6-fluoroquinoline (16b). MeI (0.65 mL,
10.4 mmol) and NaH (62% dispersion in mineral oil,
121 mg, 3.12 mmol) were added to a solution of the
alcohol 16a (900 mg, 2.08 mmol) in DMF (18 mL) at
5 ꢀC, and the mixture was stirred for 2h. After quench-
ing with 1 mol/L HCl (4 mL) and water (60 mL), the
reaction mixture was extracted with AcOEt. The extract
was washed with water, brine, and dried over MgSO4.
After filtration and evaporation, chromatographic
separation of the residue (toluene/AcOEt=10:1) gave
the methyl ether 16b (876 mg, 94%).
N-Butyl-2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-
6-fluoroquinoline-4-carboxamide (12c). Yield 83%. Mp
238–240 ꢀC (AcOEt, decomp); 1H NMR (CDCl3,
300 MHz) d 0.97 (3H, t, J=7.3 Hz ), 1.40–1.50 (2H, m),
1.60–1.70 (2H, m), 2.44 (2H, brs), 3.19 (2H, t, J=7.7
Hz), 3.53–3.60 (2H, m), 6.53 (1H, brt, J=5.7 Hz), 7.14–
7.26 (2H, m), 7.32–7.39 (1H, m), 7.42–7.51 (3H, m), 7.56
(2H, d, J=8.3 Hz), 7.67 (2H, dd, J=1.5, 8.3 Hz), 8.11
(1H, dd, J=5.5, 9.0 Hz); MS m/z 488 (M+), 443, 371,
342; HR-MS [ESI(+)] calcd for C29H27F2N2O3 (M+H:
489.1990, found 489.1986.
Mp 203–204 ꢀC (toluene, decomp); H NMR (CDCl3,
1
300 MHz) d 2.48 (2H, brt, J=8.3 Hz), 3.29 (2H, brt,
J=8.3 Hz), 3.59 (3H, s), 3.62(3H, s), 4.91 (2H, s), 7.15–
7.27 (2H, m), 7.32–7.39 (1H, m), 7.43–7.57 (4H, m), 7.69
(2H, dd, J=1.5, 8.1 Hz), 7.75 (1H, dd, J=2.7, 10.5 Hz),
N-Methyl-2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-
6-fluoroquinoline-4-carboxamide (12d). Yield 77%. Mp
243–244 ꢀC (AcOEt, decomp); 1H NMR (CDCl3–
CD3OD, 300 MHz) d 2.41 (2H, brs), 3.11 (3H, s), 3.18
(2H, t, J=7.7 Hz), 7.19 (1H, ddd, J=1.2, 8.2, 10.8 Hz),
7.26 (1H, dt, J=1.2, 7.5 Hz), 7.35–7.41 (1H, m), 7.43–
7.55 (3H, m), 7.60 (2H, d, J=8.2Hz), 7.71 (2H, dd,
J=1.4, 8.2Hz), 8.10 (1H, dd, J=5.4, 9.2Hz); MS m/z
446 (M+), 399, 371, 342; HR-MS [ESI(+)] calcd for
C26H21F2N2O3 (M+H): 447.1520, found 447.1538.
8.12(1H, dd, J=5.7, 9.2Hz);
13C NMR (CDCl3,
75 MHz) d 24.9, 35.2, 51.7, 59.1, 67.4, 107.7 (J=23.1
Hz), 116.2( J=22.7 Hz), 119.3 (J=25.7 Hz), 124.4
(J=3.7 Hz), 127.8 (J=9.9 Hz), 128.5 (J=13.4 Hz), 128.6,
129.1, 129.2 (J=3.1 Hz), 130.8 (J=3.4 Hz), 132.0, 132.5
(J=9.3 Hz), 135.9, 140.2, 140.3, 143.8, 159.8 (J=248.1
Hz), 159.9 (J=2.8 Hz), 161.0 (J=247.6 Hz), 172.6; MS
m/z 447 (M+), 416, 360; HR-MS [ESI(+)] calcd for
C27H24F2NO3 (M+H): 448.1724, found 448.1706.
2-[4-(2-Fluorophenyl)phenyl]-3-(2-methoxycarbonylethyl)-
4-chloromethyl-6-fluoroquinoline (16c). SOCl2 (0.69 g,
5.83 mmol) was added dropwise to a solution of the
alcohol 16a (1.26 g, 2.91 mmol) in ClCH2CH2Cl (25
mL) at 0 ꢀC. The mixture was stirred at room tempera-
ture for 1 h. After quenching with water (20 mL), the
reaction mixture was neutralized with NaHCO3 and
separated. The organic layer was washed with brine and
dried over MgSO4. After filtration and evaporation,
chromatographic separation of the residue (CHCl3)
gave the chloride 16c (1.31 g, 99%).
2-[4-(2-Fluorophenyl)phenyl]-3-(2-methoxycarbonylethyl)-
4-hydroxymethyl-6-fluoroquinoline (16a). DMF (0.6
mL) and SOCl2 (2.12 g, 17.8 mmol) were added to a
suspension of monoester 11 (2.00 g, 4.47 mmol) in tol-
uene (60 mL) at room temperature. The mixture was
stirred at 55 ꢀC for 2h. After cooling, water (50 mL)
was added, and the organic layer was washed with brine
and dried over MgSO4. After filtration and evaporation,
the resulting residue was dissolved in THF (40 mL). To
this solution was added NaBH4 (0.34 g, 8.94 mmol) at
0 ꢀC and the mixture was stirred at room temperature
for 1.5 h. After quenching with water (40 mL) and 1
mol/L HCl (40 mL), the mixture was extracted with
CHCl3. The extract was washed with brine and dried
over MgSO4. After filtration and evaporation, chroma-
tographic separation of the residue (CHCl3/
ꢀ
1
Mp 129–131 C (CHCl3, decomp); H NMR (CDCl3,
300 MHz) d 2.49–2.55 (2H, m), 3.29–3.34 (2H, m), 3.62
(3H, s), 5.09 (2H, s), 7.15–7.28 (2H, m), 7.32–7.40 (1H,
m), 7.47–7.59 (4H, m), 7.68–7.76 (3H, m), 8.16 (1H, dd,
J=5.6, 9.2Hz); 13C NMR (CDCl3, 75 MHz) d 24.7,

I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
3281
34.3, 37.9, 51.8, 107.1 (J=23.3 Hz), 116.2 (J=22.7 Hz),
119.7 (J=25.7 Hz), 124.4 (J=3.7 Hz), 126.6 (J=9.6
Hz), 128.4 (J=12.5 Hz), 128.5, 129.2, 129.3 (J=3.1 Hz),
130.7 (J=3.3 Hz), 131.5, 133.0 (J=9.4 Hz), 136.1,
139.8, 139.9, 143.9, 159.8 (J=248.2 Hz), 160.0 (J=2.8
Hz), 161.2( J=249.2 Hz), 172.4; MS m/z 451 [M+
(Cl35)], 416, 392, 356; HR-MS [ESI(+)] calcd for
C26H21ClF2NO2 (M+H): 452.1229, found 452.1237.
4.89 (2H, s), 7.14–7.26 (2H, m), 7.31–7.38 (1H, m),
7.43–7.58 (4H, m), 7.67 (2H, dd, J=1.5, 8.3 Hz), 7.74
(1H, dd, J=2.7, 10.4 Hz), 8.12 (1H, dd, J=5.6, 9.2Hz);
MS m/z 433 (M+), 388, 360; HR-MS [ESI(+)] calcd for
C26H22F2NO3 (M+H): 434.1568, found 434.1560.
2-[4-(2-Fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-methyl-
6-fluoroquinoline (17d). Yield 99%. Mp 238–239 ꢀC
1
(AcOEt, decomp); H NMR (DMSO-d6, 300 MHz) d
2-[4- (2 - Fluorophenyl)phenyl] -3-(2-methoxycarbonyle-
thyl)-4-methyl-6-fluoroquinoline (16d). NaBH4 (92mg,
2.43 mmol) was added to a solution of the chloride 16c
(1.00 g, 2.21 mmol) in DMF (25 mL), and the mixture
was stirred at room temperature for 2h. After quench-
ing with 2mol/L HCl (4.9 mL), the reaction mixture
was extracted with AcOEt. The extract was washed with
brine and dried over MgSO4. After filtration and eva-
poration, chromatographic separation of the residue
(toluene/AcOEt=40:1) gave the 4-methyl derivative 16d
(0.84 g, 91%).
2.36 (2H, brt, J=8.2 Hz), 2.69 (3H, s), 3.09 (2H, brt,
J=8.2 Hz), 7.32–7.39 (2H, m), 7.43–7.49 (1H, m), 7.57–
7.69 (6H, m), 7.91 (1H, dd, J=2.4, 9.7 Hz), 8.01 (1H,
dd, J=5.8, 9.1 Hz); MS m/z 403 (M+), 358, 308; HR-
MS [ESI(+)] calcd for C25H20F2NO2 (M+H):
404.1462, found 404.1473.
2-[4-(2-Fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-chloro-
methyl-6-fluoroquinoline (17c). To a solution of the
methyl ester 16c (700 mg, 1.55 mmol) in AcOH (28.0
mL) was added concd HCl (7.0 mL) and the mixture
was stirred at 55 ꢀC for 2h. After cooling to room tem-
perature, water (200 mL) was added, and the mixture
was neutralized with NaHCO3. The mixture was
extracted with AcOEt. The extract was washed with
brine and dried over MgSO4. After filtration, the sol-
vent was removed under reduced pressure to afford the
carboxylic acid 17c (667 mg, 98%).
Mp 179–181 ꢀC (toluene, decomp); H NMR (CDCl3,
1
300 MHz) d 2.42–2.48 (2H, m), 2.71 (3H, s), 3.20–3.26
(2H, m), 3.62 (3H, s), 7.15–7.26 (2H, m), 7.31–7.38 (1H,
m), 7.41–7.45 (1H, m), 7.49 (1H, dd, J=2.1, 7.6 Hz),
7.53–7.56 (2H, m), 7.63 (1H, dd, J=2.8, 10.4 Hz), 7.68
(2H, dd, J=1.5, 8.1 Hz), 8.11 (1H, dd, J=5.7, 9.1 Hz);
13C NMR (CDCl3, 75 MHz) d 14.7, 25.3, 34.2, 51.7,
107. (J=22.6 Hz), 116.1 (J=23.6 Hz), 118.9 (J=25.7
Hz), 124.4 (J=3.6 Hz), 128.2 (J=9.3 Hz), 128.5, 128.6
(J=12.0 Hz), 129.1, 129.2 (J=3.0 Hz), 130.5, 130.7
(J=3.1 Hz), 132.6 (J=9.4 Hz), 135.7, 140.5, 141.7
(J=5.6 Hz), 143.1, 159.7 (J=2.7 Hz), 159.8 (J=248.3
Hz), 160.5 (J=247.1 Hz), 172.5; MS m/z 417 [M+
(Cl35)], 386, 358; HR-MS [ESI(+)] calcd for
C26H22F2NO2 (M+H): 418.1619, found 418.1603.
ꢀ
1
Mp 194–197 C (AcOEt, decomp); H NMR (CDCl3–
CD3OD, 300 MHz) d 2.51 (2H, brt, J=8.2Hz), 3.29
(2H, brt, J=8.2 Hz), 5.14 (2H, s), 7.17–7.29 (2H, m),
7.34–7.41 (1H, m), 7.52(2H, dd, J=1.7, 8.1 Hz ), 7.58
(2H, d, J=8.0 Hz), 7.73 (2H, dd, J=0.8, 7.6 Hz), 7.79
(1H, dd, J=2.6, 10.1 Hz ), 8.13 (1H, dd, J=5.6, 9.2
Hz); MS m/z 437 [M+ (Cl35)], 401, 356, 306; HR-MS
[ESI(+)] calcd for C25H19ClF2NO2 (M+H): 438.1072,
found 438.1082.
Typical procedure for the synthesis of carboxylic acid
(17a, 17b, 17d) from methyl ester (16a, 16b, 16d). To a
solution of the methyl ester 16 in MeOH (3.3%) was
added 1 mol/L aqueous NaOH (2.0 equiv), and the
mixture was stirred at 55 ꢀC for 2h. After cooling to
room temperature, the reaction mixture was con-
centrated under reduced pressure. Water and 1 mol/L
HCl (2.0 equiv) were added to the residue, and the
mixture was extracted with ethyl AcOEt. The extract
was washed with brine and dried over MgSO4. After
filtration, the solvent was removed under reduced pres-
sure to afford the carboxylic acid 17.
Reaction of dicarboxylic acid 5 with TfOH.{2,3-dihy-
dro-2-[4-(2-fluorophenyl)phenyl]-8-fluoro-1H-cyclopenta[c]
quinoline-1-one (10)}. The dicarboxylic acid 5 (100 mg,
0.23 mmol) was dissolved into TfOH (2.0 mL), and the
mixture was stirred at 60 ꢀC for 7 h. After cooling, the
resulting mixture was poured into water and neutralized
with Na2CO3, then extracted with AcOEt. The extract
was washed with water, brine, and dried over MgSO4.
After filtration and evaporation, chromatographic
separation of the residue (hexane/AcOEt=5:1) gave the
decarboxylated/cyclized product 10 (61 mg, 71%).
Mp 206–207 ꢀC (toluene, decomp); H NMR (CDCl3,
1
2-[4-(2-Fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-hydro-
xymethyl-6-fluoroquinoline (17a). Yield 99%. Mp 186–
189 ꢀC (AcOEt, decomp); 1H NMR (DMSO-d6,
300 MHz) d 2.41 (2H, brt, J=8.3 Hz), 3.14 (2H, brt,
J=8.3 Hz), 4.99 (2H, s), 7.33–7.39 (2H, m), 7.43–7.53
(1H, m), 7.60–7.72(6H, m), 7.91–8.07 (2H, m); MS m/z
419 (M+), 401, 356, 306; HR-MS [ESI(+)] calcd for
C25H20F2NO3 (M+H): 420.1411, found 420.1426.
400 MHz) d 2.88–2.90 (2H, m), 3.44–3.47 (2H, m), 7.19
(1H, ddd, J=1.2, 8.3, 10.7 Hz), 7.26 (1H, dt, J=1.2, 7.8
Hz), 7.34–7.40 (1H, m), 7.52(1H, dt, J=2.0, 7.8 Hz),
7.55 (1H, ddd, J=2.9, 8.2, 9.2 Hz), 7.75 (2H, dd, J=1.5,
8.6 Hz), 7.97 (2H, d, J=8.6 Hz), 8.25 (1H, dd, J=5.5,
9.2Hz), 8.69 (1H, dd, J=2.9, 9.5 Hz); 13C NMR
(CDCl3, 100 MHz) d 26.2, 36.8, 107.6 (J=24.0 Hz),
116.3 (J=22.3 Hz), 120.1 (J=25.6 Hz), 123.0 (J=11.6
Hz), 124.6 (J=3.3 Hz), 128.4 (J=13.2 Hz), 128.8, 129.4,
129.5 (J=9.9 Hz), 130.7 (J=3.3 Hz), 132.1 (J=9.9 Hz),
137.0, 137.8, 138.2( J=6.6 Hz), 145.1, 148.8, 156.7
(J=3.3 Hz), 159.9 (J=248.1 Hz), 162.6 (J=251.4 Hz),
2-[4-(2-Fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-meth-
oxymethyl-6-fluoroquinoline (17b). Yield 99%. Mp 224–
ꢀ
1
226 C (AcOEt, decomp); H NMR (CDCl3, 300 MHz)
d 2.46–2.52 (2H, m), 3.24–3.29 (2H, m), 3.56 (3H, s),

3282
I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
207.3; MS m/z 371 (M+), 342, 248; HR-MS [ESI(+)]
calcd for C24H16F2NO (M+H): 372.1200, found
372.1189.
cyclohepta[1,2-b]-quinoline-8-carboxamide (13b)}. The
carboxylic acid 12b (500 mg, 0.92mmol) was dissolved
into TfOH (50 mL), and the mixture was stirred at
130 ꢀC for 4 h. After cooling, the resulting mixture was
poured into water and neutralized with Na2CO3, then
extracted with AcOEt. The extract was washed with
water, brine, and dried over MgSO4. After filtration and
evaporation, chromatographic separation of the residue
(hexane/AcOEt=4:1) gave the cyclized product 13b (76
mg, 16%), dimer 14b (52mg, 12%) and decarboxylated/
cyclized product 10 (76 mg, 22%).
Reaction of diester 9 with TfOH. The diester 9 (50 mg,
0.11 mmol) was dissolved into TfOH (1.0 mL), and the
mixture was stirred at 70 ꢀC for 9 h. After cooling, the
resulting mixture was poured into water and neutralized
with Na2CO3, then extracted with AcOEt. The extract was
washed with water, brine and dried over MgSO4. After
filtration and evaporation, chromatographic separation of
the residue (hexane/AcOEt=5:1) gave the decarb-
oxylated/cyclized product 10 (26 mg, 65%).
Cyclized product 13b: mp 181–182 ꢀC (hexane/
1
AcOEt=4:1, decomp); H NMR (CDCl3, 300 MHz) d
0.89 (3H, brt, J=6.6 Hz), 1.23–1.43 (10H, m), 1.62–1.73
(2H, m), 3.09 (2H, brs), 3.22 (2H, brt, J=5.8 Hz), 3.62
(2H, q, J=6.6Hz), 6.08 (1H, brt, J=5.8 Hz), 7.17–7.29
(2H, m), 7.36–7.40 (1H, m), 7.44–7.56 (3H, m), 7.90
(1H, s), 7.92(1H, dd, J=1.7, 9.8 Hz), 8.10 (1H, d,
J=8.0 Hz), 8.16 (1H, dd, J=5.5, 9.1 Hz); 13C NMR
(CDCl3, 75 MHz) d 14.0, 22.6, 25.3, 27.0, 29.1, 29.2,
29.6, 31.7, 40.0, 45.6, 108.1 (J=23.2 Hz), 116.3 (J=22.5
Hz), 120.0 (J=25.8 Hz), 124.4 (J=10.0 Hz), 124.6
(J=3.7 Hz), 127.2 (J=13.0 Hz), 128.8 (J=2.7 Hz),
129.3, 129.9 (J=8.3 Hz), 130.5 (J=3.0 Hz), 130.9, 132.4
(J=9.3 Hz), 133.1 (J=3.3 Hz), 136.5, 137.5, 138.2,
140.9 (J=5.8 Hz), 144.5, 156.5 (J=2.8 Hz), 159.8
(J=248.8 Hz), 161.1 (J=250.3 Hz), 166.6, 204.3; MS
m/z 526 (M+), 398, 370, 342; HR-MS [ESI(+)] calcd
for C33H33F2N2O2 (M+H): 527.2510, found 527.2514.
Reaction of carboxylic acid 12a with TfOH.{Piper-
idino-6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-5H-
benzo[6,7]cyclohepta-[1,2-b]quinoline-8-carboxamide
(13a)}. The carboxylic acid 12a (100 mg, 0.20 mmol)
was dissolved into TfOH (10 mL), and the mixture was
stirred at 130 ꢀC for 9 h. After cooling, the resulting
mixture was poured into water and neutralized with
Na2CO3, then extracted with AcOEt. The extract
was washed with water, brine, and dried over MgSO4.
After filtration and evaporation, chromatographic separa-
tion of the residue (toluene/AcOEt=1:1) gave the cyclized
product 13a (40 mg, 42%), dimer 14a (12mg, 12%) and
decarboxylated/cyclized product 10 (2mg, 3%).
Cyclized product 13a: mp 228–229 ꢀC (hexane,
decomp); 1H NMR (CDCl3, 300 MHz) d 1.43–1.50 (2H,
m), 1.73–1.81 (4H, m), 2.95–3.13 (1H, m), 3.14–3.22
(5H, m), 3.86–4.02 (2H, m), 7.16–7.29 (2H, m), 7.32–
7.42 (2H, m), 7.46–7.56 (2H, m), 7.92–7.96 (2H, m), 8.13
(1H, d, J=8.6 Hz), 8.20 (1H, dd, J=5.4, 9.2Hz); 13C
NMR (CDCl3, 75 MHz) d 24.8, 26.0, 26.4, 27.2, 43.0,
45.7, 48.4, 108.5 (J=23.0 Hz), 116.8 (J=22.2 Hz), 120.7
(J=25.7 Hz), 124.8 (J=9.9 Hz), 125.1 (J=3.6 Hz),
127.9 (J=13.1 Hz), 128.7, 129.7, 130.4 (J=8.2Hz),
131.1 (J=3.1 Hz), 131.7, 133.3 (J=9.4 Hz), 133.7
(J=3.5 Hz), 137.3, 138.1, 138.7, 140.9 (J=5.9 Hz),
145.2, 157.3 (J=2.9 Hz), 160.3 (J=248.7 Hz), 161.9
(J=250.5 Hz), 166.1, 203.8; MS m/z 482(M +), 398,
368, 342; HR-MS [ESI(+)] calcd for C30H25F2N2O2
(M+H): 483.1884, found 483.1871.
1
Dimer 14b: H NMR (CDCl3, 300 MHz) d 0.90 (6H,
brt, J=6.4 Hz), 1.20–1.46 (20H, m), 1.65–1.75 (4H, m),
2.89–3.10 (4H, m), 3.25–3.62 (8H, m), 6.18 (2H, brt,
J=5.7 Hz), 7.20–7.33 (2H, m), 7.35–7.43 (4H, m), 7.51–
7.90 (12H, m), 8.16 (2H, dd, J=5.3, 9.1 Hz); 13C NMR
(CDCl3, 75 MHz) d 14.1, 22.4, 25.3, 27.2, 29.2, 29.3,
29.7, 38.5, 42.3, 46.6, 108.4 (J=22.9 Hz), 117.6 (J=23.9
Hz), 120.7 (J=25.6 Hz), 124.7 (J=9.8 Hz), 128.3
(J=13.5 Hz), 129.3, 129.5, 129.8, 130.6, 130.7 (J=4.9
Hz), 133.0 (J=9.3 Hz), 134.1 (J=3.3 Hz), 135.5, 140.6,
140.8, 143.0 (J=5.6 Hz), 143.1, 144.3, 159.6 (J=2.8
Hz), 161.9 (J=249.9 Hz), 163.2 (J=257.7 Hz), 168.3,
197.5; MS (SIMS) m/z 941 (M+H), 814, 784.
1
Dimer 14a: H NMR (acetone-d6, 300MHz) d 1.42–1.55
Reaction of carboxylic acid 12c with TfOH.{ N-Butyl-
6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-5H-benzo[6,7]-
cyclohepta[1,2-b]-quinoline-8-carboxamide (13c)}. The
carboxylic acid 12c (667 mg, 1.36 mmol) was dissolved
into TfOH (66 mL), and the mixture was stirred at
130 ꢀC for 10 h. After cooling, the resulting mixture was
poured into water and neutralized with Na2CO3, then
extracted with AcOEt. The extract was washed with
water, brine, and dried over MgSO4. After filtration and
evaporation, chromatographic separation of the residue
(toluene/AcOEt=10:1) gave the cyclized product 13c (121
mg, 16%). (We did not try to isolate the other product).
(4H, m), 1.68–1.85 (8H, m), 2.98–3.13 (4H, m), 3.29 (4H,
brt, J=4.5 Hz), 3.38–3.53 (4H, m), 3.88–4.02(4H, m), 7.32
(2H, dd, J=8.6, 10.8 Hz), 7.43 (2H, dd, J=2.6, 9.7 Hz),
7.62–7.69 (2H, m), 7.73–7.78 (6H, m), 7.85–7.91 (6H, m),
8.14 (2H, dd, J=5.5, 9.3 Hz); 13C NMR (CDCl3, 75MHz)
d 25.1, 25.3, 26.5, 27.2, 38.5, 43.2, 48.6, 108.6 (J=23.0 Hz),
117.6 (J=22.8 Hz), 120.8 (J=2 5.7 Hz), 12 4.9J(=10.0 Hz),
128.4 (J=13.5 Hz), 129.2, 129.6, 129.7, 130.1, 130.7 (J=4.6
Hz), 133.1 (J=9.2Hz), 134.3 ( J=3.3 Hz), 135.5, 140.7,
140.9, 143.2( J=5.7 Hz), 144.4, 144.5, 159.8 (J=2.7 Hz),
161.9 (J=249.9 Hz), 163.2 (J=257.5 Hz), 166.6, 197.6; MS
(SIMS) m/z 1053 (M+H), 926, 898.
Mp 243–244 ꢀC (hexane/AcOEt=4:1, decomp); 1H
NMR (CDCl3, 300 MHz) d 0.99 (3H, t, J=7.3 Hz),
1.42–1.51 (2H, m), 1.62–1.73 (2H, m), 3.05 (2H, brs),
3.18 (2H, brt, J=6.6 Hz), 3.59 (2H, q, J=6.5 Hz), 6.29
Reaction of carboxylic acid 12b with TfOH.{ N-Octyl-
6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-5H-benzo[6,7]-

I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
3283
(1H, brt, J=5.7 Hz), 7.15–7.29 (2H, m), 7.34–7.60 (3H,
m), 7.69, (1H, dd, J=1.5, 8.2Hz), 7.86 (1H, brt, J=1.3
Hz), 7.91 (1H, dt, J=8.1, 1.8 Hz), 8.07 (1H, d, J=8.1 Hz),
8.13 (1H, dd, J=5.3, 9.0 Hz); 13C NMR (CDCl3, 75MHz)
d 13.7, 20.2, 25.4, 31.6, 39.8, 45.6, 108.1 (J=23.2 Hz ),
116.2( J=22.5 Hz), 120.1 (J=25.8 Hz), 124.5 (J=10.2
Hz), 124.6 (J=3.6 Hz), 127.3 (J=13.1 Hz), 128.4, 128.9
(J=2.7 Hz), 129.9 (J=8.3 Hz), 130.6 (J=3.1 Hz), 130.9,
132.5 (J=9.3 Hz), 133.1 (J=3.4 Hz), 136.6, 137.6, 138.3,
140.8 (J=5.8 Hz), 144.6, 156.6 (J=2.6 Hz), 159.8
(J=248.7 Hz), 161.2 (J=250.4 Hz), 166.6, 204.1; MS m/z
470 (M+), 398, 368, 342; HR-MS [ESI(+)] calcd for
C29H25F2N2O2 (M+H): 471.1884, found 471.1896.
5.21 (2H, s), 7.17–7.29 (2H, m), 7.35–7.42 (1H, m),
7.45–7.56 (2H, m), 7.82 (1H, dd, J=2.7, 10.3 Hz), 7.88
(1H, brt, J=1.5 Hz), 7.93 (1H, dt, J=8.1, 1.8 Hz), 8.12
(1H, d, J=8.0 Hz), 8.17 (1H, dd, J=5.6, 9.2Hz); 13C
NMR (DMSO-d6, 75 MHz) d 23.8, 45.8, 55.8, 108.5
(J=23.1 Hz), 116.3 (J=22.3 Hz), 119.1 (J=26.0 Hz),
125.2 (J=3.5 Hz), 126.7 (J=12.8 Hz), 127.1 (J=9.9
Hz), 127.8 (J=3.0 Hz), 130.4 (J=8.2Hz), 130.7 ( J=2.9
Hz), 130.8, 132.2 (J=2.8 Hz), 132.4, 132.5, 136.3,
137.1, 138.6, 142.8 (J=5.8 Hz), 144.2, 156.6 (J=2.6
Hz), 159.2( J=246.7 Hz), 160.2 (J=245.1 Hz), 204.7;
MS m/z 401 (M+), 384, 370, 306, 276; HR-MS
[ESI(+)] calcd for C25H18F2NO2 (M+H): 402.1306,
found 402.1313.
1
Reaction of carboxylic acid 12d with TfOH.{ N-Methyl-
6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-5H-benzo[6,7]-
cyclohepta-[1,2-b]quinoline-8-carboxamide (13d)}. The
carboxylic acid 12d (100 mg, 0.22 mmol) was dissolved
into TfOH (10 mL), and the mixture was stirred at
130 ꢀC for 4h. After cooling, the resulting mixture was
poured into water and neutralized with Na2CO3, then
extracted with AcOEt. The extract was washed with
water, brine, and dried over MgSO4. After filtration and
evaporation, chromatographic separation of the residue
(hexane/AcOEt=3:2) gave the cyclized product 13d
(18 mg, 18%). (We did not try to isolate the other
product).
Lactone 19: H NMR (CDCl3, 300 MHz) d 3.09–3.14
(2H, m), 3.32 (2H, brt, J=6.7 Hz), 5.80 (2H, s), 7.16–
7.29 (2H, m), 7.33–7.41 (1H, m), 7.46–7.58 (4H, m), 7.63
(1H, dd, J=2.6, 10.4 Hz), 7.70 (2H, dd, J=1.6, 8.2Hz),
8.19 (1H, dd, J=5.7, 9.2Hz); MS m/z 401 (M+), 372,
356, 306; HR-MS [ESI(+)] calcd for C25H18F2NO2
(M+H): 402.1306, found 402.1298.
Reaction of carboxylic acid 17b with TfOH. The car-
boxylic acid 17b (140 mg, 0.32mmol) was dissolved into
TfOH (14 mL), and the mixture was stirred at 130 ꢀC
for 2h. After cooling, the resulting mixture was poured
into water and neutralized with Na2CO3, then extracted
with AcOEt. The extract was washed with water, brine,
and dried over MgSO4. After filtration and evaporation,
chromatographic separation of the residue (toluene/
AcOEt=3:1) gave the lactone 19 (35 mg, 27%) as the
only isolable product.
Mp 240–241 ꢀC (hexane/AcOEt=1:2, decomp); 1H
NMR (DMSO-d6, 400 MHz) d 2.95 (3H, d, J=4.6 Hz),
3.08 (4H, brs), 7.36–7.54 (4H, m), 7.67 (1H, dt, J=1.7,
7.8 Hz), 7.75 (1H, dt, J=2.9, 8.5 Hz), 7.79 (1H, brt,
J=1.5 Hz), 8.00 (1H, dt, J=8.1, 1.7 Hz), 8.10 (1H, d,
J=8.1 Hz), 8.21 (1H, dd, J=5.4, 9.3 Hz), 8.81 (1H, brq,
J=4.6 Hz); 13C NMR (DMSO-d6, 100 MHz) d 25.1,
25.8, 45.2, 108.3 (J=22.3 Hz ), 116.3 (J=22.3 Hz),
119.9 (J=25.6 Hz), 124.4 (J=9.9 Hz), 125.2 (J=3.3
Hz), 126.7 (J=13.2Hz), 128.2( J=3.3 Hz), 129.3, 130.4
(J=8.3 Hz), 130.7 (J=2.5 Hz), 130.9, 132.4 (J=9.1
Hz), 132.4, 136.2, 136.5, 138.5, 142.0 (J=5.0 Hz), 144.0,
156.3 (J=2.5 Hz), 159.1 (J=246.5 Hz), 160.4 (J=247.3
Hz), 166.1, 204.0; MS m/z 428 (M+), 413, 398, 370; HR-
MS [ESI(+)] calcd for C26H19F2N2O2 (M+H):
429.1415, found 429.1431.
Reaction of carboxylic acid 17c with TfOH.{6,7-dihy-
dro-10-fluoro-3-(2-fluorophenyl)- 5-oxo-8-chloromethyl-
5H-benzo[6,7]cyclohepta-[1,2-b]quinoline (18c)}. The
carboxylic acid 17c (2.00 g, 4.57 mmol) was dissolved
into TfOH (200 mL), and the mixture was stirred at
130 ꢀC for 2h. After cooling, the resulting mixture was
poured into water and neutralized with Na2CO3, then
extracted with AcOEt. The extract was washed with
water, brine, and dried over MgSO4. After filtration and
evaporation, chromatographic separation of the residue
(CHCl3) gave the cyclized product 18c (1.55 g, 81%).
Reaction of carboxylic acid 17a with TfOH.{6,7-Dihy-
dro-10-fluoro-3-(2-fluorophenyl)- 5-oxo-8-chloromethyl-
5H-benzo[6,7]cyclohepta-[1,2-b]quinoline (18a)}. The car-
boxylic acid 17a (610 mg, 1.45 mmol) was dissolved into
TfOH (61 mL), and the mixture was stirred at 130 ꢀC
for 5h. After cooling, the resulting mixture was poured
into water and neutralized with Na2CO3, then extracted
with AcOEt. The extract was washed with water, brine,
and dried over MgSO4. After filtration and evaporation,
chromatographic separation of the residue (toluene/
AcOEt=5/1) gave the cyclized product 18a (61 mg,
10%) and lactone 19 (210 mg, 36%).
Mp 214–216 ꢀC (toluene/AcOEt=10:1, decomp); 1H
NMR (CDCl3, 300 MHz) d 3.11–3.15 (2H, m), 3.36–
3.40 (2H, m), 5.05 (2H, s), 7.16–7.29 (2H, m), 7.35–7.42
(1H, m), 7.49–7.56 (2H, m), 7.72 (1H, dd, J=2.6, 10.0
Hz), 7.91–7.93 (1H, m), 7.94 (1H, dt, J=8.1, 1.8 Hz),
8.12(1H, d, J=8.0 Hz), 8.20 (1H, dd, J=5.6, 9.2Hz);
13C NMR (CDCl3, 75 MHz) d 24.3, 37.4, 45.3, 107.0
(J=23.5 Hz ), 116.3 (J=22.5 Hz), 119.7 (J=25.8 Hz),
124.6 (J=3.7 Hz), 126.3 (J=9.6 Hz), 127.4 (J=13.3
Hz), 128.9 (J=2.7 Hz), 129.8 (J=8.3 Hz), 130.6 (J=3.1
Hz), 130.9, 132.6, 133.1, 133.3 (J=9.5 Hz), 137.2, 137.6,
137.7 (J=6.0 Hz), 138.2, 144.8, 156.9 (J=3.0 Hz), 159.8
(J=248.9 Hz), 161.4 (J=249.8 Hz), 203.8; MS m/z 419
(M+ (Cl35)), 384, 290; HR-MS [ESI(+)] calcd for
C25H17ClF2NO (M+H): 420.0967, found 420.0971.
Cyclized product 18a: mp 208–211 ꢀC (hexane/
1
AcOEt=2:1, decomp); H NMR (CDCl3, 300 MHz) d
2.02 (1H, brs), 3.06–3.10 (2H, m), 3.38–3.42 (2H, m),

3284
I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
Reaction of carboxylic acid 17d with TfOH.{6,7-
(J=7.8 Hz), 129.8, 130.7 (J=3.3 Hz), 132.3 (J=9.2
Hz), 137.1, 138.9, 139.0, 140.8 (J=5.5 Hz), 144.1, 144.1,
159.6 (J=2.8 Hz), 159.8 (J=248.1 Hz), 160.9 (J=248.7
Hz), 167.1; MS m/z 512(M +), 384, 356; HR-MS
[ESI(+)] calcd for C33H35F2N2O (M+H): 513.2717,
found 513.2705.
Dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-8-methyl-5H-
benzo[6,7]cyclohepta[1,2-b]-quinoline (18d)}. The car-
boxylic acid 17d (2.00 g, 4.96 mmol) was dissolved into
TfOH (200 mL), and the mixture was stirred at 130 ꢀC
for 4 h. After cooling, the resulting mixture was poured
into water and neutralized with Na2CO3, then extracted
with AcOEt. The extract was washed with water, brine,
and dried over MgSO4. After filtration and evaporation,
chromatographic separation of the residue (toluene/
AcOEt=10:1) gave the cyclized product 18d (1.38 g,
72%).
6,7-Dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-8-
hydroxymethyl-5H-benzo[6,7]cyclo-hepta[1,2-b]quinoline
(18a). AcONa (527 mg, 6.42 mmol) was added to a
solution of the chloride 18c (350 mg, 0.83 mmol) in
AcOH (17.5 mL). The mixture was stirred at 110 ꢀC for
22 h. After cooling and quenching with water (100 mL),
the reaction mixture was neutralized with NaHCO3,
then extracted with AcOEt. The extract was washed
with water, brine and dried over MgSO4. After filtration
and evaporation, MeOH (16 mL) and 1 mol/L NaOH
(0.85 mL) were added to the residue. The resulting
mixture was stirred at room temperature for 2h. Then
water (100 mL) was added, and the mixture was
extracted with AcOEt. The extract was washed with
water, brine, and dried over MgSO4. After filtration and
evaporation, chromatographic separation of the residue
(toluene/AcOEt=1:1) gave the alcohol 18a (323 mg,
97%).
Mp 241–242 ꢀC (hexane/AcOEt=3:1, decomp); 1H
NMR (CDCl3, 300 MHz) d 2.71 (3H, s), 3.02–3.06 (2H,
m), 3.29–3.33 (2H, m), 7.16–7.27 (2H, m), 7.33–7.40
(1H, m), 7.43–7.55 (2H, m), 7.64 (1H, dd, J=2.7, 10.4
Hz), 7.88 (1H, brs), 7.92(1H, dt, J=8.2, 1.6 Hz ), 8.12
(1H, d, J=8.1 Hz), 8.13 (1H, dd, J=5.6, 9.2Hz); 13C
NMR (CDCl3, 75 MHz) d 14.4, 24.4, 45.2, 107.6
(J=22.7 Hz ), 116.2 (J=22.5 Hz), 118.9 (J=25.6 Hz),
124.5 (J=3.8 Hz), 127.5 (J=13.1 Hz), 128.2 (J=9.3
Hz), 128.6 (J=2.6 Hz), 129.7 (J=8.2Hz), 130.6 ( J=3.1
Hz), 130.7, 131.4, 132.8 (J=9.3 Hz), 133.0 (J=3.4 Hz),
137.2, 137.9, 138.3, 139.5 (J=5.7 Hz), 144.2, 156.5
(J=2.8 Hz), 159.8 (J=248.6 Hz), 160.8 (J=247.6 Hz),
204.5; MS m/z 385 (M+), 357, 290; HR-MS [ESI(+)]
calcd for C25H18F2NO (M+H): 386.1356, found
386.1342.
6,7-Dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-8-for-
myl-5H-benzo[6,7]cyclohepta[1,2-b]-quinoline (21). Ac2O
(0.24 mL, 2.49 mmol) was added to a solution of the alco-
hol 18a (200 mg, 0.50 mmol) in DMSO (6.0 mL) at room
temperature. The mixture was stirred at room temperature
for 17 h. After cooling to 0 ꢀC, MeOH (1 mL) was added,
and the mixture was stirred for 2h. Water (20 mL) was
added to the mixture, and the mixture was extracted with
AcOEt. The extract was washed with water, brine, and
dried over MgSO4. After filtration and evaporation, chro-
matographic separation of the residue (toluene/
AcOEt=10:1) gave the aldehyde 21 (180 mg, 90%).
N-Octyl-6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H-
benzo[6,7]cyclohepta[1,2-b]-quinoline-8-carboxamide (15b).
NaBH4 (9.0 mg, 0.22 mmol) was added to a solution of
the ketone 13b (117 mg, 0.22 mmol) in MeOH (12 mL)
at 5 ꢀC. The mixture was stirred at room temperature for
1 h. After quenching with acetone (1.0 mL), the reaction
mixture was concentrated under reduced pressure, and
water was added to the residue. The mixture was
extracted with AcOEt, and the extract was washed with
brine and dried over Na2SO4. After filtration and eva-
poration, the residue was dissolved in AcOH (2.0 mL).
Then Ac2O (2.0 mL) and HI (57%, 4.0 mL) were added
to this solution at room temperature, and the mixture
was stirred at 100 ꢀC for 3 h. After cooling and quench-
ing with 10% aqueous Na2S2O5 (10 mL), the mixture
was neutralized with NaHCO3, then extracted with
AcOEt. The extract was washed with brine and dried
over Na2SO4. After filtration and evaporation, chroma-
tographic separation of the residue (toluene/
AcOEt=20:1) gave the carboxamide 15b (108 mg, 96%).
ꢀ
1
Mp 185–189 C (toluene, decomp); H NMR (CDCl3,
300 MHz) d 3.15–3.19 (2H, m), 3.49–3.58 (2H, m), 7.17–
7.30 (2H, m), 7.34–7.43 (1H, m), 7.51–7.60 (2H, m), 7.92
(1H, brt, J=1.5 Hz), 7.96 (1H, dt, J=8.1, 1.8 Hz), 8.15
(1H, d, J=8.1 Hz), 8.23 (1H, dd, J=5.5, 9.2Hz), 8.26
(1H, dd, J=2.8, 10.5 Hz), 11.02 (1H, s); 13C NMR
(CDCl3, 75 MHz) d 23.1, 45.4, 107.6 (J=24.6 Hz), 116.3
(J=22.5 Hz), 120.2 (J=25.9 Hz), 124.4 (J=10.8 Hz),
124.6 (J=3.7 Hz), 127.3 (J=13.1 Hz), 128.9 (J=2.7
Hz), 129.9 (J=8.4 Hz), 130.6 (J=3.0 Hz), 131.0, 132.9
(J=9.6 Hz), 133.2( J=3.6 Hz), 134.4 (J=6.1 Hz),
134.8, 136.3, 137.9, 138.3, 145.2, 157.7 (J=3.0 Hz),
159.8 (J=248.8 Hz), 162.3 (J=251.1 Hz), 192.6, 203.5;
MS m/z 399 (M+), 370, 276; HR-MS [ESI(+)] calcd for
C25H16F2NO2 (M+H): 400.1149, found 400.1157.
Mp 149–150 ꢀC (toluene, decomp); H NMR (CDCl3,
1
300 MHz) d 0.87–0.91 (3H, m), 1.15–1.52(10H, m),
1.58–1.73 (2H, m), 2.24–2.31 (2H, m), 2.64–2.76 (4H,
m), 3.59 (2H, brq, J=6.9 Hz), 6.01 (1H, brt, J=5.7 Hz),
7.15–7.27 (2H, m), 7.31–7.38 (1H, m), 7.44–7.53 (4H,
m), 7.63 (1H, dt, J=7.9, 1.4 Hz), 7.87 (1H, d, J=7.9
Hz), 8.16 (1H, dd, J=5.4, 10.1 Hz); 13C NMR (CDCl3,
75 MHz) d 14.1, 22.6, 27.0, 27.6, 29.1, 29.2, 29.7, 31.0,
31.5, 31.7, 40.1, 108.1 (J=23.2 Hz ), 116.2 (J=22.8 Hz),
119.4 (J=25.7 Hz), 124.4 (J=3.7 Hz), 124.6, 127.8
(J=2.7 Hz), 128.2, 128.6 (J=13.4 Hz), 129.0, 129.2
6,7-Dihydro-10-fluoro-3-(2-fluorophenyl)-5-oxo-5H-
benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxylic
acid
.
(4). A solution of NaH2PO4 H2O (72mg, 0.46 mmol) in
water (1.0 mL) was added to a suspension of the alde-
hyde 21 (80 mg, 0.20 mmol) in DMSO (8.0 mL) at room

I. Chujo et al. / Bioorg. Med. Chem. 9 (2001) 3273–3286
3285
temperature. Then 87% NaClO2 (83 mg, 0.80 mmol) was
added dropwise to the mixture for 5 min. The resulting
mixture was stirred at room temperature for 2h, and
water (20 mL) and 1 mol/L HCl (1 mL) were added. The
mixture was extracted with AcOEt, and the extract was
washed with water, brine, and dried over MgSO4. After
filtration, the solvent was removed under reduced pres-
sure to afford the carboxylic acid 4 (81 mg, 98%).
EtOH was removed under reduced pressure. Water (60
mL) and Et2O (40 mL) were added to the residue, and
the mixture was stirred at room temperature, then
separated. The aqueous layer was adjusted to pH 2.0
with 2mol/L HCl and extracted with AcOEt. The
extract was washed with water, brine, and dried over
MgSO4. After filtration and evaporation, CHCl3 (3.0
mL) was added to the residue and stirred at 5 ꢀC. The
precipitated solid was filtered and dried under reduced
pressure to afford KF20444 (33 mg, 74%).
Mp 285–290 ꢀC (AcOEt, decomp); 1H NMR (DMSO-d6,
300 MHz) d 3.07–3.16 (4H, m), 7.34–7.42(H2 , m),
7.47–7.52(1H, m), 7.57 (1H, dd, J=2.8, 9.8 Hz), 7.67
(1H, dt, J=1.7, 7.9 Hz), 7.73–7.80 (2H, m), 7.99 (1H,
dt, J=8.2, 1.7 Hz), 8.10 (1H, d, J=8.2Hz), 8.21 (1H,
dd, J=5.6, 9.2Hz); MS m/z 415 (M+), 370, 320; HR-
MS [ESI(+)] calcd for C25H16F2NO3 (M+H):
416.1098, found 416.1087.
From the methyl ester 22: NaBH4 (13 mg, 0.35 mmol)
was added to a suspension of the methyl ester 22 (70 mg,
0.16 mmol) in MeOH (7.0 mL) at 5 ꢀC. The mixture was
stirred at room temperature for 2.5 h. After quenching
with acetone (2.0 mL) and evaporation, to the residue
were added water (15 mL) and 1 mol/L HCl (2mL).
The mixture was extracted with AcOEt and the extract
was washed with water, brine, and dried over MgSO4.
After filtration and evaporation, the residue was dis-
solved in AcOH (4.0 mL), then Ac2O (4.0 mL) and HI
(57%, 4.0 mL) were added to this solution at room
temperature. The mixture was stirred at 110 ꢀC for 5 h.
After cooling and quenching with 5% aqueous Na2S2O5
(50 mL), the mixture was extracted with AcOEt. The
organic layer was washed with water, brine and dried
over Na2SO4. After filtration and evaporation, CH2Cl2
(7.0 mL) was added to the residue and stirred at room
temperature. The precipitated solid was filtered and
dried under reduced pressure to afford KF20444 (47 mg,
73%).
Methyl
6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5-
oxo-5H-benzo[6,7]cyclohepta[1,2-b]-quinoline-8-carbox-
ylate (22). Na2CO3 (40 mg, 0.29 mmol) and MeI (82 mg,
0.59 mmol) were added to a suspension of the car-
boxylic acid 4 (81 mg, 0.20 mmol) in acetone (8.1 mL) at
room temperature. The mixture was stirred at 45 ꢀC for
5 h. After cooling, water (30 mL) and 1 mol/L HCl (1
mL) were added to the reaction mixture. The mixture
was extracted with AcOEt, and the extract was washed
with water, brine, and dried over MgSO4. After filtra-
tion and evaporation, chromatographic separation of
the residue (toluene/AcOEt=20:1) gave the methyl ester
22 (64 mg, 77%).
Mp 230–234 ꢀC (CH2Cl2, decomp); H NMR (DMSO-
1
Mp 209–212 ꢀC (toluene, decomp); H NMR (CDCl3,
d6, 300 MHz) d 2.20–2.27 (2H, m), 2.56–2.68 (4H, m),
7.33–7.40 (2H, m), 7.43–7.51 (1H, m), 7.56–7.66 (4H,
m), 7.75 (1H, dt, J=2.8, 8.8 Hz), 7.86 (1H, d, J=7.9
Hz), 8.21 (1H, dd, J=5.6, 9.2Hz); MS m/z 401 (M+),
356, 306, 259; HR-MS [ESI(+)] calcd for C25H18F2NO2
(M+H): 402.1306, found 402.1307.
1
300 MHz) d 3.12–3.21 (4H, m), 4.13 (3H, s), 7.17–7.29
(2H, m), 7.35–7.42 (1H, m), 7.45 (1H, dd, J=2.7, 9.5
Hz), 7.50–7.57 (2H, m), 7.92–7.96 (2H, m), 8.14 (1H,
dd, J=0.4, 7.9 Hz), 8.20 (1H, dd, J=5.5, 9.2Hz); 13C
NMR (CDCl3, 75 MHz) d 26.3, 45.3, 53.0, 108.3
(J=23.7 Hz), 116.3 (J=22.5 Hz), 120.2 (J=25.8 Hz),
124.3 (J=10.3 Hz), 124.6 (J=3.6 Hz), 127.4 (J=13.1
Hz), 129.0 (J=2.7 Hz), 129.9 (J=8.4 Hz), 130.4, 130.6
(J=3.0 Hz), 130.9, 132.7 (J=9.5 Hz), 133.2( J=3.5
Hz), 136.5, 136.8 (J=5.8 Hz), 137.7, 138.4, 144.7, 156.7
(J=3.0 Hz), 159.8 (J=248.7 Hz), 161.4 (J=250.3 Hz),
167.4, 203.7; MS m/z 429 (M+), 414, 398, 370, 334; HR-
MS [ESI(+)] calcd for C26H17F2NO3 (M+H):
430.1255, found 430.1268.
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