Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as a factor Xa inhibitor II. Substituent effect on biological activities

Article abstract of DOI:10.1248/cpb.50.1187

Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in

Full text of DOI:10.1248/cpb.50.1187

September 2002
Chem. Pharm. Bull. 50(9) 1187—1194 (2002)
1187
Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as
a Factor Xa Inhibitor1,2) II. Substituent Effect on Biological Activities
Hidemitsu NISHIDA,* Yutaka MIYAZAKI, Takafumi MUKAIHIRA, Fumihiko SAITOH, Miyuki FUKUI,
Kousuke HARADA, Manabu ITOH, Aki MURAOKA, Tomokazu MATSUSUE, Atsushi OKAMOTO,
Yoshitaka HOSAKA, Miwa MATSUMOTO, Shuhei OHNISHI, and Hidenori MOCHIZUKI
Chemistry Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-Uenohara, Gotemba,
Shizuoka 412–8524, Japan. Received February 25, 2002; accepted May 31, 2002
Intravascular clot formation is an important event in a number of cardiovascular diseases. The prevention
of blood coagulation has become a major target for new therapeutic agents. Factor Xa (FXa) is a trypsin-like ser-
ine protease that plays a key role in the blood coagulation cascade and represents an attractive target for antico-
agulant drug development. We have investigated substituents in the central part of a lead compound (3:
M55113), and discovered that compound M55551 (34: (R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-
pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid) is a potent inhibitor of FXa (IC50؍0.006 mM), with
high selectivity for FXa over trypsin and thrombin. The activity of this compound is ten times more powerful
than the lead compound.
Key words factor Xa inhibitor; 1-arylsulfonyl-3-piperazinone; structure–activity relationship; optical isomer; M55551
Factor Xa (FXa) is a serine protease which plays a critical Chemistry
role in the coagulation cascade, serving as the point of con-
vergence of intrinsic and extrinsic pathways.3—7) It represents ester hydrochloride, as illustrated in Chart 1. The compound
an attractive target for anticoagulant drug development.8—14)
5, obtained by the reaction of glycine ethyl ester hydrochlo-
A key intermediate 7 was prepared from glycine ethyl
Most nonpeptide FXa inhibitors reported in the literature ride (4) with bromoacetaldehyde diethyl acetal in the pres-
are dibasic compounds. Nagahara et al.15,16) have reported the ence of cesium carbonate (Cs2CO3)29,30) and sodium iodide,
synthesis and evaluation of a series of bis(amidino)-deriva- was treated with 6-chloro-2-naphthalenesulfonyl chloride
tives, and through investigation, DX-9065a (1)17—21) was under basic conditions, and the resulting sulfonamide 6 was
found to be a selective FXa inhibitor. Further, YM-60828 hydrolyzed with aqueous trifluoroacetic acid (TFA) to give
(2),22—27) which is closely related to 1 in terms of structure, the formyl compound 7.
was found to have a more potent inhibitory effect on FXa.
Synthetic routes of compounds 12 and 17 are shown in
On the other hand, as described in the preceding paper,1) Chart 2. Compound 9 was prepared by protection of the pri-
we have synthesized M55113 (3) as a potent inhibitor of FXa mary amino group with di-tert-butyl dicarbonate (Boc2O)
(IC50ϭ0.06 mM) with high selectivity for FXa over trypsin and subsequent debenzylation of a secondary amino group
and thrombin.
with H2 over Pd/C. Condensation of 9 with 4-chloropyridine
Compared with the structure of compound 3, the features 1-oxide under basic conditions gave the 4-piperidinopyridine
of compound 1 and compound 2 include a functional acid 1-oxide derivative 10. Hydrogenolysis of 10 over Raney Ni31)
group in the linker part of the molecule. According to the X- in methanol (MeOH), followed by treatment with HCl–
ray structure of the complex of compound 1 in des-Gla- MeOH, yielded compound 11. The final compound 12 was
FXa,28) it is clear that the nitrogen atom of Gln-192 forms a obtained smoothly by reductive condensation of 11 with the
weak hydrogen bond with the acid function of compound 1.
intermediate 7.32)
In order to obtain a compound which has powerful in-
Reaction conditions in the preparation of compound 17
hibitory activity on FXa, it is necessary to introduce a func- from compound 1333) were not much different from the con-
tional group into the position at which compound 3 and Gln- version of 8 to 12.
192 of FXa protein are expected to form a hydrogen bond.
Synthesis of 4-substituted piperidine derivatives contain-
In this paper, we wish to report the continuing search for ing another functional group (compound 18—20) in place of
potent compounds that have a substituent at the piperazine the hydroxyl group in 12 was accomplished as shown in
and piperidine rings of compound 3. Thus, the structure-ac- Chart 3.
tivity relationships of compound 3 derivatives were exam-
Swern oxidation34) of 17, followed by condensation of the
ined.
resulting aldehyde with hydroxylamine under traditional con-
To whom correspondence should be addressed. e-mail: hnishida@mochida.co.jp
© 2002 Pharmaceutical Society of Japan

1188
Vol. 50, No. 9
Chart 1. Synthesis of Intermediate 7
Chart 2. Synthesis of Compounds 12 and 17
sponding carboxylic acid (26) was obtained by the hydrolysis
of 24 with aqueous NaOH. Compound 27 was prepared by
heating 26 with methanolic ammonia in a sealed tube. Com-
pound 28 was yielded by the reduction of compound 25 with
lithium borohydride. Compound 29 was obtained by the
methylation of compound 28 with dimethyl sulfate. Com-
pound 28 was treated with phthalimide by Mitsunobu reac-
tion, and with hydrazine, successively, to give compound 30.
The oxidation of 28, followed by condensation of the result-
ing aldehyde with hydroxylamine under traditional condi-
tions, afforded 6-(hydroxyiminomethyl)-2-piperazinone (31).
Results and Discussion
Chart 3. Synthesis of 4-Substituted Piperidine Derivatives
The FXa inhibitory activity of the compounds synthesized
above was measured by a method similar to that described in
the preceding paper.1) The results are listed in Tables 1 and 2.
It is conceivable that the activity of compounds increases
when a substituent having hydrogen bond donating ability is
introduced into the molecule. In fact, 12 and 17 showed
slightly higher activity than lead compound 3, as listed in
Table 1. The carboxylic acid (19), however, showed very low
activity (1/10), contrary to our anticipation, while the activity
of the corresponding ester (20) is about same degree as that
of the original compound 3.
As described above, the substituent effect at the 4-position
of the piperidine ring on the activity is indistinct at present.
Accordingly, no further compounds with a substituent at the
4-position were synthesized.
Next, the activity of the compounds containing a sub-
stituent at the 6-position of the piperazine moiety was exam-
ined. As summarized in Table 2, all the compounds in this
series showed higher inhibitory activity than the lead com-
pound 3.
ditions, afforded 4-(hydroxyiminomethy)piperidine (18).
When the aldehyde was treated with NaClO2 and trimethyl-
silyldiazomethane, the carboxylic acid (19) and the corre-
sponding methyl ester (20) were obtained in good yields, re-
spectively.
Synthesis of piperazine derivatives containing a functional
carbon group on the 6-position of the piperazine ring was ac-
complished according to the route shown in Chart 4.
The crude carbaldehyde (22) which was obtained by
Swern oxidation of 1-(4-pyridinyl)-4-piperidinemethanol35)
(21) was treated with 3-(tert-butoxycarbonylamino)alanine
ethyl ester36) under reductive conditions to give compound
23. Compound 24 was yielded by the acylation of 23 with
chloroacetyl chloride in the presence of triethylborane (Et3B)
under basic conditions, followed by deprotection with
HCl–EtOH and then ring cyclization with Et3N in DMF.
The sulfonylation of compound 24 with 6-chloro-2-naph-
thalenesulfonyl chloride gave compound 25, and the corre-

September 2002
1189
Chart 4. Synthesis of 6-Substituted 2-Piperazinone Derivatives
Table 1. FXa Inhibitory Activity of Compounds 3, 12, 17—20
Table 3. Selectivity of M55551 for FXa over Thrombin and Trypsin
Selectivity
Enzyme
IC50 (mM)
(enzyme/FXa)
FXa
Thrombin
Trypsin
0.006
Ͼ100
Ͼ100
Ͼ16000
Ͼ16000
Compd.
R
IC50 (mM)
3
12
17
18
19
20
–H
–OH
–CH2OH
–CHNOH
–CO2H
CO2Me
0.060
0.031
0.038
0.048
0.683
0.065
Table 2. FXa Inhibitory Activity of Compounds 3, 25—31
At the final stage of the present investigation, the compari-
son of stereo isomers (R,S) of 6-substituted 2-piperazinones
on the inhibitory activity was carried out.
The activity of stereo isomers (R and S) of 25 was exam-
ined; (R)-isomer (32, 0.017 mM) had more powerful activity
than (S)-isomer (33, 0.070 mM). Then the (R and S)-isomer of
free carboxylic acid (26) was obtained by the hydrolysis of
32 and 33 under acidic conditions. The activity of the
stereoisomers (R and S) of 26 was examined; (R)-isomer (34,
0.006 mM) had more powerful activity than (S)-isomer (35,
0.079 mM).
Compd.
R
IC50 (mM)
3
25
26
27
28
29
30
31
–H
–CO2Et
–CO2H
–CONH2
–CH2OH
–CH2OMe
–CH2NH2
–CHNOH
0.060
0.030
0.010
0.017
0.012
0.031
0.012
0.013
The activity of this compound (34: M55551) is ten times
more powerful than the lead compound (3: M55113).
It should also be mentioned that M55551 (34) showed
When any substituent in which especially a hydrogen bond clear selectivity for FXa over related serine proteases; in par-
is possible was introduced into the molecule, the FXa in- ticular, the compound is 16000-fold more selective for FXa
hibitory activity of the compounds increased. Especially, the than for thrombin and trypsin, as shown in Table 3.
activity of compound 26 was six times more powerful than
the lead compound 3.
On the basis of these results described in the preceding
and present papers, M55551 (34) is evaluated to be the best

1190
Vol. 50, No. 9
(8) (7.5 g, 34 mmol) in 1,4-dioxane–H2O (66—34 ml), 1
N
aqueous NaOH
compound among all the derivatives in a series of 1-arylsul-
fonyl-3-piperazinones, not only in FXa inhibition activity but
also in selectivity between FXa and other serine proteases.
Crystallization of a complex of M55551 with FXa was at-
(34 ml) and Boc2O (8.16 g, 37.4 mmol) were added, successively. The reac-
tion mixture was stirred at 60 °C for 4 h. After cooling, the reaction mixture
was extracted with EtOAc. The organic layer was washed with water and
brine, dried over Na2SO4, and the solvent was evaporated under reduced
tempted in order to determine whether the carboxylic acid of pressure to give [[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methyl] car-
1
bamic acid 1,1-dimethylethyl ester (8.19 g, 75%) as a colorless crystal. H-
NMR (*CDCl3) d: 7.36—7.22 (5H, m), 4.98—4.82 (1H, m), 3.55 (2H, s),
3.15 (2H, d, Jϭ6.2 Hz), 2.69—2.56 (2H, m), 2.48—2.32 (2H, m), 1.71—
M55551 and Gln-192 of FXa protein form a hydrogen bond.
Experimental
Nuclear magnetic resonance (NMR) spectra were taken with JEOL JNM- 1.51 (4H, m), 1.44 (9H, s).
EX270 FT-NMR (JEOL, Ltd.) or JEOL JNM-LA300 (JEOL, Ltd.) in CDCl3
To the suspension of [[4-hydroxy-1-(phenylmethyl)-4-piperidinyl]methyl]
or dimethyl sulfoxide-d6 (DMSO-d6) using tetramethylsilane as the internal carbamic acid 1,1-dimethylethyl ester (8.19 g, 25.6 mmol) and 10% Pd–C
reference. Data measured by JEOL JNM-LA300 are marked with an aster- (800 mg) in MeOH (300 ml), ammonium formate (4.84 g, 76.8 mmol) was
isk. The following abbreviations were used: sϭsinglet, dϭdoublet, ddϭdou- added, and the reaction mixture was refluxed for 2 h. Then the catalyst was
ble doublet, dtϭdouble triplet, tϭtriplet, qϭquartet, mϭmultiplet and removed by filtration and the filtrate was condensed to afford 9 (6.03 g, 99%)
brϭbroad. High-resolution mass spectra (HR-MS) were taken with JEOL as a colorless crystal. 1H-NMR (*DMSO-d6) d: 6.62—6.52 (1H, m), 2.89
JMS-GCMATE (JEOL, Ltd.). Optical rotations were determined in the indi- (2H, d, Jϭ6.2 Hz), 2.79—2.55 (4H, m), 1.44—1.21 (4H, m), 1.38 (9H, s).
cated solvents on a JASCO DIP-1000 digital polarimeter (JASCO Corpora-
tion). Elemental analysis was performed on a CHNS-O EA1108 elemental Acid 1,1-Dimethylethyl Ester (10) To a suspension of compound 9
analyzer (Carlo Erba Instruments).
(2.00 g, 8.7 mmol) and 4-chloropyridine 1-oxide (1.12 g, 8.7 mmol) in
[[4-Hydroxy-1-(1-oxido-4-pyridinyl)-4-piperidinyl]methyl]carbamic
Measurement of Factor Xa, Thrombin and Trypsin Inhibition The isoamylalcohol (35 ml), NaHCO3 (1.75 g, 20.8 mmol) was added, and the re-
enzyme solution was mixed with a test compound dissolved at various con- action mixture was refluxed for 6 h. After cooling, water was added to the re-
centrations in dimethyl sulfoxide (DMSO). A synthetic substrate was added action mixture and the reaction mixture was extracted with CH2Cl2. The or-
and incubated in a 20 mM Tris–HCl buffer (pH 7.5) containing 0.13 M NaCl
ganic layer was washed with water and brine, dried over Na2SO4, and the
at 37 °C. The absorbance at 405 nm was measured continuously. The follow- solvent was evaporated under reduced pressure. The residue was purified by
ing enzymes and substrates were used: human factor Xa (Enzyme Research silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ9 : 1—4 : 1) to
Laboratories, Inc., 0.019 U/ml) and S-2222 (Chromogenix AB, 0.4 mM);
human thrombin (Sigma Co., 0.09 U/ml) and S-2238 (Chromogenix AB, m), 6.92—6.84 (2H, m), 6.78—6.70 (1H, m), 4.58 (1H, br s), 3.64—3.50
0.2 mM); human trypsin (Athens Research and Technology, Inc., 15 ng/ml)
(2H, m), 3.17—3.04 (2H, m), 2.92 (2H, d, Jϭ6Hz), 1.60—1.30 (4H, m),
and S-2222 (Chromogenix AB, 0.4 mM). To calculate the inhibitory activity 1.35 (9H, s).
give compound 10 (1.03 g, 37%). 1H-NMR (*DMSO-d6) d: 7.90—7.83 (2H,
of the test compound, the initial reaction velocity was compared with the
4-(Aminomethyl)-1-(4-pyridinyl)-4-piperidinol Hydrochloride (11)
value of a control containing no test compound. The inhibitory activity of To a solution of compound 10 (300 mg, 0.93 mmol) in MeOH (3 ml), Raney-
the test compound was expressed as IC50.
Ni (catalytic amount) was added, and the reaction mixture was stirred in an
N-(2,2-Diethoxyethyl)glycine Ethyl Ester (5) To the suspension of atmosphere of hydrogen for 3.5 h at ambient temperature. Then the catalyst
glycine ethyl ester hydrochloride 4 (1.00 g, 7.2 mmol) and bromoacetalde- was removed by filtration and the filtrate was condensed. The residue was
hyde diethyl acetal (1.08 ml, 7.0 mmol) in N,N-dimethylformamide (DMF) purified by silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ
(30 ml), cesium carbonate (4.67 g, 14.4 mmol) and sodium iodide (107 mg, 4 : 1) to give [[4-hydroxy-1-(4-pyridinyl)-4-piperidinyl]methyl]carbamic acid
0.7 mmol) were added. The reaction mixture was stirred for 4 h at 100 °C. 1,1-dimethylethyl ester (214 mg, 71%). 1H-NMR (DMSO-d6) d: 8.10 (2H, d,
After cooling, the reaction mixture was acidified with 1 N aqueous HCl to
Jϭ7 Hz), 6.87 (2H, d, Jϭ7 Hz), 6.76—6.68 (1H, m), 4.55 (1H, br s), 3.78—
pH 2 and was washed with AcOEt. Then the aqueous layer was made basic 3.65 (2H, m), 3.24—3.11 (2H, m), 2.92 (2H, d, Jϭ6 Hz), 1.58—1.30 (4H,
with 1 N aqueous NaOH to pH 11, and was extracted with CH2Cl2. The or-
ganic layer was washed with water and brine, dried over Na2SO4, and the
m), 1.35 (9H, s).
[[4-Hydroxy-1-(4-pyridinyl)-4-piperidinyl]methyl]carbamic acid 1,1-di-
solvent was evaporated under reduced pressure. Compound 5 was obtained methylethyl ester (175 mg, 0.57 mmol) was dissolved in 10% HCl–MeOH
1
(860 mg, 55%) as a pale yellow oil. H-NMR (CDCl3) d: 4.63—4.57 (1H, (2 ml), and the reaction mixture was stirred for 2 h at ambient temperature.
m), 4.24—4.14 (2H, m), 3.78—3.64 (2H, m), 3.61—3.48 (2H, m), 3.44 (2H, The solvent was removed under reduced pressure. The residue was triturated
s), 2.76 (2H, d, Jϭ6 Hz), 1.32—1.15 (9H, m).
with Et2O to give compound 11 (160 mg, 89%). 1H-NMR (DMSO-d6) d:
N-[(6-Chloro-2-naphthalenyl)sulfonyl]-N-(2,2-diethoxyethyl)glycine 13.68 (1H, br s), 8.20 (2H, d, Jϭ8 Hz),8.13 (2H, br s), 7.22 (2H, d, Jϭ8 Hz),
Ethyl Ester (6) To the suspension of compound 5 (504 mg, 2.3 mmol) in 5.43 (1H, s), 4.08—3.96 (2H, m), 3.52—3.32 (2H, m), 2.80 (2H, br s),
CH2Cl2 (20 ml), triethylamine (Et3N) (336 ml, 2.4 mmol) and 6-chloro-2- 1.77—1.46 (4H, m).
naphtalenesulfonyl chloride (600 mg, 2.3 mmol) were added at 0 °C. The re-
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[4-hydroxy-1-(4-pyridinyl)-
action mixture was stirred at ambient temperature overnight. Then brine was 4-piperidinyl]methyl]piperazinone (12) Acetic acid (0.02 ml) was added
added to the reaction mixture and the reaction mixture was extracted with to a suspension of compound 7 (58.4 mg, 0.16 mmol) and compound 11
CH2Cl2. The organic layer was washed with water and brine, dried over (50 mg, 0.16 mmol) in CH2Cl2 (3 ml) at 0 °C. The reaction mixture was
Na2SO4, and the solvent was evaporated under reduced pressure. The residue stirred for 1 h at ambient temperature. Then sodium triacetoxyborohydride
was purified by silica gel column chromatography (eluents; n-hexane : (NaBH(OAc)3) (67 mg, 0.32 mmol) was added to the reaction mixture at
AcOEtϭ20 : 1—4 : 1) to give compound
(*CDCl3) d: 8.40 (1H, s), 7.93—7.82 (4H, m), 7.55 (1H, dd, Jϭ2, 9 Hz),
4.68—4.63 (1H, m), 4.33 (2H, s), 3.96 (2H, q, Jϭ7 Hz), 3.77—3.64 (2H, and was extracted with CH2Cl2. The organic layer was washed with water
m), 3.60—3.47 (2H, m), 3.37 (2H, d, Jϭ6 Hz), 1.23—1.13 (6H, m), 1.12— and brine, dried over Na2SO4, and the solvent was evaporated under reduced
6
(750 mg, 74%). 1H-NMR 0 °C, and the reaction mixture was stirred at ambient temperature overnight.
Then the reaction mixture was made basic with 1 N aqueous NaOH to pH 9,
1.04 (3H, m).
pressure. The residue was purified by silica gel column chromatography
N-[(6-Chloro-2-naphthalenyl)sulfonyl]-N-(2-oxoethyl)glycine Ethyl (eluents; CH2Cl2 : MeOHϭ10 : 1), then another silica gel column chromatog-
Ester (7) To a mixture of trifluoroacetic acid (5 ml), CHCl3 (1.5 ml) and raphy (Chromatorex NHTM (Fuji Silysia Chemical, Ltd.) eluents; CH2Cl2 :
H2O (2.5 ml), the solution of compound 6 (560 mg, 1.3 mmol) in CHCl3 MeOHϭ20 : 1) to give compound 12 (23.3 mg, 29%). HR-MS m/z: Calcd
(1 ml) was added with vigorous stirring at 0 °C. After 1.5 h, the reaction for C25H27ClN4O4S: 514.1441. Found: 514.1448. 1H-NMR (CDCl3) d:
mixture was made basic with saturated sodium hydrogencarbonate 8.38—8.32 (1H, m), 8.21—8.13 (2H, m), 7.98—7.90 (3H, m), 7.82—7.75
(NaHCO3) aq. to pH 8, and was then extracted with diethyl ether (Et2O). The (1H, m), 7.65—7.58 (1H, m), 6.63—6.56 (2H, m), 3.83 (2H, s), 3.63—3.52
organic layer was washed with water and brine, dried over Na2SO4, and the (4H, m), 3.43—3.36 (2H, m), 3.39 (2H, s), 3.29—3.17 (2H, m), 2.02 (1H,
solvent was evaporated under reduced pressure. The residue was purified by br s), 1.59—1.44 (4H, m).
silica gel column chromatography (eluents; n-hexane : AcOEtϭ5 : 1—2 : 1)
to give compound 7 (240 mg, 51%). 1H-NMR (*CDCl3) d: 9.74—9.70 (1H,
m), 8.39 (1H, s), 7.98—7.85 (3H, m), 7.85—7.78 (1H, m), 7.62—7.53 (1H,
m), 4.24—4.03 (6H, m), 1.21—1.13 (3H, m).
[[4-(Hydroxymethyl)-4-piperidinyl]methyl]carbamic Acid 1,1-Dimethyl
Ethyl Ester (14) To a solution of 4-(aminomethyl)-1-(phenylmethyl)-4-
piperidine-methanol 13 (16.4 g, 70.0 mmol) prepared by a documented
method33) in 1,4-dioxane–H2O (140–70 ml), 1 N aqueous NaOH (70 ml)
[(4-Hydroxy-4-piperidinyl)methyl]carbamic Acid 1,1-Dimethylethyl and Boc2O (16.8 g, 77.0 mmol) were added, successively. The reaction
Ester (9) To a solution of 4-(aminomethyl)-1-(phenylmethyl)-4-piperidinol
mixture was stirred at 60 °C for 1.5 h. After cooling, the reaction mixture

September 2002
1191
was extracted with EtOAc. The organic layer was washed with water and solved in EtOH–CHCl3 (6–1.2ml). Then sodium acetate (48 mg, 0.6 mmol)
brine, dried over Na2SO4, and the solvent was evaporated under reduced
pressure to give [[4-(hydroxymethyl)-1-(phenylmethyl)-4-piperidinyl]-
and hydroxylamine hydrochloride (38 mg, 0.6 mmol) were added to the reac-
tion mixture. The reaction mixture was stirred at ambient temperature
methyl]carbamic acid 1,1-dimethylethyl ester (21.4 g, 91%) as a colorless overnight. Water was added to the reaction mixture, and this mixture was
1
crystal. H-NMR (*DMSO-d6) d: 7.35—7.20 (5H, m), 6.75—6.60 (1H, m), made basic with saturated NaHCO3 aq. to pH 8, then extracted with CHCl3.
4.40—4.30 (1H, m), 3.42 (2H, s), 3.20—3.15 (2H, m), 2.95—2.90 (2H, m),
2.35—2.25 (4H, m), 1.37 (9H, s), 1.40—1.25 (4H, m).
The organic layer was washed with water and brine, dried over Na2SO4, and
the solvent was evaporated under reduced pressure. The residue was purified
To the suspension of [[4-(hydroxymethyl)-1-(phenylmethyl)-4-piperidinyl]-
by silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ20 : 1—
1
methyl]carbamic acid 1,1-dimethylethyl ester (0.81 g, 2.4 mmol) in EtOH– 5 : 1) to give compound 18 (100 mg, 54%). H-NMR (DMSO-d6) d: 10.73
CH2Cl2 (10–5ml), 10% Pd–C (80 mg) was added, and the reaction mixture (1H, s), 8.58 (1H, s), 8.32—8.24 (2H, m), 8.17 (1H, d, Jϭ9 Hz), 8.12—8.05
was stirred in an atmosphere of hydrogen for 2 d at ambient temperature. (2H, m), 7.90—7.84 (1H, m), 7.78—7.70 (1H, m), 7.15 (1H, s), 6.73—6.65
Then the catalyst was removed by filtration and the filtrate was condensed. (2H, m), 3.70 (2H, s), 3.60—3.20 (8H, m), 2.88—2.72 (2H, m), 1.60—1.44
The residue was purified by silica gel column chromatography (CH2Cl2 : (2H, m), 1.40—1.24 (2H, m).
1
MeOHϭ20 : 1—5 : 1) to give 14 (230 mg, 39%) as a colorless crystal. H-
4-[4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxopiperazinyl]methyl-1-
solution of DMSO
(23 ml) in CH2Cl2 (1.0 ml) was added to the solution of oxalyl chloride
(14 ml) in CH2Cl2 (1.0 ml) below Ϫ70 °C. A solution of compound 17
NMR (CDCl3) d: 4.92—4.83 (1H, m), 3.39 (2H, s), 3.09 (2H, d, Jϭ7 Hz), (4-pyridinyl)-4-piperidinecaboxylic Acid (19)
A
2.87—2.74 (4H, m), 1.60—1.20 (4H, m), 1.45 (9H, s).
[[4-(Hydroxymethyl)-1-(1-oxido-4-pyridinyl)-4-piperidinyl]methyl]-
carbamic Acid 1,1-Dimethylethyl Ester (15) To the suspension of com- (37 mg, 0.35 mmol) in DMSO–CH2Cl2 (0.4–0.4 ml) was added to the above
pound 14 (1.88 g, 7.7 mmol) and 4-chloropyridine 1-oxide (1.00 g, 7.7 solution below Ϫ70 °C. The reaction mixture was stirred for 1 h between
mmol) in isoamylalcohol (15 ml), NaHCO3 (1.55 g, 18.5 mmol) was added, Ϫ60 and Ϫ65 °C. Then Et3N (60 ml, 0.4 mmol) was added to the reaction
and reaction mixture was refluxed for 2 h. After cooling, water was added to mixture at Ϫ78 °C. After the temperature was raised to room temperature,
the reaction mixture, and the reaction mixture was extracted with CH2Cl2. water was added to the reaction mixture. This reaction mixture was extracted
The organic layer was washed with water and brine, dried over Na2SO4, and
with CH2Cl2 and washed with brine, then dried over Na2SO4. The solvent
the solvent was evaporated under reduced pressure. The residue was purified was removed under reduced pressure. Without purification, 2-methyl-2-
by silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ20 : 1— butene (56 ml, 0.5 mmol) was added to the solution of the residue in tert-bu-
13 : 2) to give compound 15 (1.11 g, 43%). 1H-NMR (CDCl3) d: 7.99 (2H, d, tanol–CHCl3 (0.5–0.1 ml). Then the solution of NaClO2 (11.7 mg, 0.1 mmol)
Jϭ7.9 Hz), 6.62 (2H, d, Jϭ7.9 Hz), 5.35—5.20 (1H, m), 4.35—4.10 (1H, and NaH2PO4–2H2O (16.1 mg, 0.1 mmol) in water (0.4 ml) was added to the
br s), 3.42 (2H, s), 3.40—3.22 (4H, m), 3.14 (2H, d, Jϭ6.9 Hz), 1.72—1.48 solution. The reaction mixture was vigorously stirred at ambient temperature
(4H, m), 1.45 (9H, s).
overnight. Saturated NH4Cl aq. was added to reaction mixture. Then CHCl3
4-(Aminomethyl)-1-(4-pyridinyl)-4-piperidinemethanol Hydrochloride and MeOH were added to the reaction mixture, successively. Na2SO4 was
(16) To a solution of compound 15 (250 mg, 0.7 mmol) in MeOH (1 ml), added to the reaction mixture, and the solvent was evaporated under reduced
Raney-Ni (catalytic amount) was added, and the reaction mixture was stirred pressure. The residue was triturated with THF to give compound 19 (40 mg,
1
in an atmosphere of hydrogen for 1 h at ambient temperature. Then the cata- 93%) as a white powder. H-NMR (DMSO-d6) d: 8.58 (1H, s), 8.32—8.10
lyst was removed by filtration. The filtrate was condensed to afford [[4-(hy- (5H, m), 7.90—7.84 (1H, m), 7.78—7.70 (1H, m), 6.96—6.88 (2H, m),
droxymethyl)-1-(4-pyridinyl)-4-piperidinyl]methyl]carbamic acid 1,1-di-
3.84—3.00 (8H, m), 3.72 (2H, s), 2.98—2.82 (2H, m), 1.88—1.72 (2H, m),
methylethyl ester (190 mg, 80%) as a colorless oil. 1H-NMR (CDCl3) d: 1.42—1.28 (2H, m).
8.35—8.07 (2H, m), 6.75—6.50 (2H, m), 5.12—4.95 (1H, m), 3.53—3.06
(9H, m), 1.70—1.33 (4H, m), 1.46 (9H, s).
4-[4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxopiperazinyl]methyl-1-
(4-pyridinyl)-4-piperidinecaboxylic Acid Methyl Ester (20) To the solu-
[[4-(Hydroxymethyl)-1-(4-pyridinyl)-4-piperidinyl]methyl]carbamic acid tion of compound 19 (10 mg, 0.02 mmol) in MeOH–CH2Cl2 (0.5–0.5 ml),
1,1-dimethylethyl ester (60 mg, 0.19 mmol) was dissolved in 10% HCl– trimethylsilyldiazomethane (12 ml, 0.02 mmol; 2.0 M in n-hexane) was added
MeOH (0.6 ml), and the reaction mixture was stirred for 10 min at 40 °C. at 0 °C. The reaction mixture was stirred at ambient temperature for 2 h. The
The solvent was removed under reduced pressure. Then Et2O was added to
solvent was evaporated under reduced pressure. The residue was purified
the residue, and it crystallized to afford compound 16 (46 mg, 75%) as a
by silica gel column chromatography (eluents; CH2Cl2 : MeOHϭ40 : 1—
white powder. 1H-NMR (DMSO-d6) d: 13.7—13.4 (1H, br), 8.25—8.16 8 : 1) to give compound 20 (4.5 mg, 44%). HR-MS m/z: Calcd for
(2H, m), 8.10—7.90 (2H, br), 7.23—7.12 (2H, m), 5.37—5.21 (1H, br), C27H29ClN4O5S: 556.1547. Found: 556.1543. 1H-NMR (CDCl3) d: 8.36—
3.80—3.30 (6H, m), 2.95—2.84 (2H, m), 1.65—1.51 (4H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[4-(hydroxymethyl)-1-(4- 7.65—7.59 (1H, m), 6.67—6.58 (2H, m), 3.79 (2H, s), 3.75—3.63 (2H, m),
pyridinyl)-4-piperidinyl]methyl]piperazinone (17) Acetic acid (28 ml) 3.73 (3H, s), 3.54 (2H, s), 3.37 (4H, s), 2.98—2.84 (2H, m), 2.17—2.05
was added to a suspension of compound 7 (100 mg, 0.27 mmol) and com- (2H, m), 1.60—1.48 (2H, m).
8.33 (1H, m), 8.28—8.16 (2H, m), 7.99—7.92 (3H, m), 7.82—7.77 (1H, m),
pound 16 (89 mg, 0.27 mmol) in CH2Cl2 (3 ml) at 0 °C. The reaction mixture
1-(4-Pyridinyl)-4-piperidinecarboxaldehyde (22) A solution of oxalyl
was stirred for 1 h at ambient temperature. Then NaBH(OAc)3 (114 mg, chloride (1.77 ml, 20 mmol) in CH2Cl2 (85 ml) was cooled to Ϫ78 °C under
0.54 mmol) was added to the reaction mixture at 0 °C, and the reaction mix- Ar. To the cooled solution, a solution of DMSO (3.25 ml, 42 mmol) in dry
ture was stirred at ambient temperature overnight. Then the reaction mixture CH2Cl2 (85 ml) was added dropwise for 20 min. Then, a solution of com-
was made basic with 1 N aqueous NaOH to pH 8, and was extracted with
pound 21 (3.0 g, 15.6 mmol) prepared by a documented method35) in dry
CHCl3. The organic layer was washed with water and brine, dried over CH2Cl2 (48 ml) and dry DMSO (48 ml) was added dropwise for another
Na2SO4, and the solvent was evaporated under reduced pressure. The residue 20 min. The reaction mixture was stirred at between Ϫ65 °C and Ϫ60 °C for
was purified by silica gel column chromatography (eluents; CH2Cl2 : 1 h, then cooled to Ϫ78 °C, and Et3N (8.31 ml, 60 mmol) was added. The re-
MeOHϭ20 : 1—5 : 1) to give compound 17 (43 mg, 30%). HR-MS m/z: action mixture was allowed to stand at room temperature, water (200 ml)
Calcd for C26H29ClN4O4S: 528.1598. Found: 528.1594. 1H-NMR (CDCl3) d: was added, and the mixture was extracted with CH2Cl2. The organic layer
8.39—8.35 (1H, m), 8.29—8.22 (2H, m), 7.99—7.93 (3H, m), 7.83—7.77
(1H, m), 7.65—7.60 (1H, m), 6.65—6.60 (2H, m), 3.86 (2H, s), 3.57—3.38
was washed with water and brine, dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The resulting aldehyde 22 was rather un-
(8H, m), 3.31 (2H, s), 3.26 (1H, br s), 3.29—3.06 (2H, m), 1.66—1.53 (2H, stable and should be used in the next reaction without purification. MS m/z:
1
m), 1.50—1.38 (2H, m).
190 (Mϩ). H-NMR (*CDCl3) d: 9.56 (1H, s), 8.16—7.99 (2H, m), 6.82—
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-1-[[4-(hydroxyiminomethyl)-1- 6.69 (2H, m), 3.83—3.71 (2H, m), 3.02—2.90 (2H, m), 2.61—2.45 (1H, m),
(4-pyridinyl)-4-piperidinyl]methyl]piperazinone (18) The solution of 1.90—1.78 (2H, m), 1.52—1.36 (2H, m).
DMSO (99 ml) in CH2Cl2 (4.5 ml) was added to the solution of oxalyl chlo-
3-(tert-Butoxycarbonylamino)-N-[[1-(4-pyridinyl)-4-piperidinyl]-
ride (61 ml) in CH2Cl2 (4.5 ml) below Ϫ70 °C. The solution of compound 17 methyl]alanine Ethyl Ester (23) Crude product 22 (0.56 g, 2.9 mmol),
(185 mg, 0.35 mmol) in DMSO–CH2Cl2 (2.2–2.2 ml) was added to the above obtained by Swern oxidation, was suspended in dry CH2Cl2 (16 ml). To the
solution below Ϫ70 °C. The reaction mixture was stirred for 1 h between suspension, b-(tert-butoxycarbonylamino)-alanine ethyl ester (0.70 g,
Ϫ60 and Ϫ65 °C. Then Et3N (292 ml, 2.1 mmol) was added to the reaction
3.0 mmol) obtained by a documented method36) and AcOH (0.37 ml) were
mixture at Ϫ78 °C. After the temperature was raised to room temperature, added in that order. After stirring the resulting mixture at room temperature
water was added to the reaction mixture. The reaction mixture was extracted for 30 min under Ar, NaBH(OAc)3 (1.6 g, 7.5 mmol) was added and the reac-
with CH2Cl2, washed with brine and dried over Na2SO4. The solvent was re-
tion mixture was stirred overnight at room temperature. Water (20 ml) was
moved under reduced pressure. Without purification, the residue was dis- added to the reaction mixture, then it was adjusted to pH 9 with 1 N sodium

1192
Vol. 50, No. 9
4.13—4.04 (2H, m), 3.96—3.80 (3H, m), 3.55 (1H, d, Jϭ17 Hz), 3.24 (1H,
dd, Jϭ4, 12 Hz), 2.86—2.69 (2H, m), 2.62 (1H, dd, Jϭ7, 14 Hz), 1.98—1.80
(1H, m), 1.75—1.50 (2H, m), 1.35—1.10 (2H, m).
hydroxide solution, followed by extraction with CH2Cl2. The organic layer
was washed with water and brine, dried over Na2SO4, and the solvent was
evaporated at reduced pressure. The residue was purified by silica gel col-
umn chromatography (eluents; CH2Cl2 : MeOHϭ99 : 1—80 : 20) to give
compound 23 (0.62 g, 52%). 1H-NMR (CDCl3) d: 8.24 (2H, d, Jϭ5 Hz),
6.65 (2H, d, Jϭ5 Hz), 5.03—4.90 (1H, m), 4.20 (2H, q, Jϭ7 Hz), 3.95—
3.83 (2H, m), 3.58—3.17 (3H, m), 2.90—2.77 (2H, m), 2.58 (1H, dd, Jϭ7,
11 Hz), 2.44—2.34 (1H, m), 1.94—1.59 (3H, m), 1.44 (9H, s), 1.29 (3H, t,
Jϭ7 Hz), 1.37—1.19 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-(hydroxymethyl)-1-[[1-(4-
pyridinyl)-4-piperidinyl]methyl]piperazinone (28) Compound 25 (0.15
g, 0.26 mmol) was dissolved in MeOH (10 ml). To the solution, lithium
borohydride (0.60 g, 27.5 mmol) was added in three portions at 30-min inter-
vals. To the reaction mixture, 10% HCl–MeOH was added under cooling
with ice to make it acidic, and the mixture was then concentrated to dryness.
Water was added to the residue, then saturated NaHCO3 aq. was added to
make the residue alkaline, and the mixture was extracted with CH2Cl2. The
organic layer was washed with brine, dried over Na2SO4, and the solvent was
evaporated under reduced pressure. The residue was purified by silica gel
column chromatography [Chromatorex NHTM] (eluents; EtOAc) to give
compound 28 (60 mg, 43%). HR-MS m/z: Calcd for C26H29ClN4O4S:
6-Oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic
Acid Ethyl Ester (24) To the solution of the compound 23 (2.9 g,
7.1 mmol) in dry CH2Cl2 (12 ml), triethylborane (Et3B, 8.4 ml, 8.4 mmol;
1.0 M in THF) was added at 0 °C. The mixture was cooled to Ϫ78 °C. To the
cooled solution, a solution of chloroacetyl chloride (0.68 ml, 8.4 mmol) in
dry CH2Cl2 (2 ml) and Et3N (1.2 ml, 8.4 mmol) were added in that order, and
the mixture was stirred at Ϫ78 °C for 1 h. The reaction mixture was allowed
to stand at room temperature for 5 h. After cooling the reaction mixture with
ice, water was added, and it was extracted with CH2Cl2. The organic layer
was washed with water and brine, dried over Na2SO4, and the solvent was
evaporated under reduced pressure. To the solution of residue (5.1 g) in
EtOH (38 ml), 20 wt% HCl–EtOH (38 ml) was added at 0 °C for 5 min and
stirred at 0 °C. The mixture was allowed to stand at room temperature with
stirring for 2 h. The solvent was evaporated under reduced pressure and the
residue was used in the next reaction without purification. A solution of the
residue in anhydrous dimethylformamide (DMF) (6.7 ml) was cooled with
ice. To the cooled solution, Et3N (14.8 ml, 0.11 mol) was added, and the
mixture was stirred at room temperature for 3 h. The reaction mixture was
concentrated under reduced pressure. The residue was purified by silica gel
column chromatography [Chromatorex NHTM] (eluents; CH2Cl2 : MeOHϭ
1
528.1598. Found: 528.1636. H-NMR (CDCl3) d: 8.36 (1H, s), 8.21 (2H, d,
Jϭ7 Hz), 8.00—7.90 (3H, m), 7.84—7.76 (1H, m), 7.62 (1H, dd, Jϭ2,
9 Hz), 6.58 (2H, d, Jϭ7 Hz), 4.28—4.12 (2H, m), 3.95—3.72 (5H, m),
3.48—3.35 (2H, m), 2.84—2.63 (4H, m), 2.05—1.46 (3H, m), 1.34—1.13
(2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-(methoxymethyl)-1-[[1-(4-
pyridinyl)-4-piperidinyl]methyl]piperazinone (29) Compound 28 (43
mg, 0.08 mmol) was suspended in CH2Cl2 (1 ml). To the stirred suspension,
50% NaOH solution (0.3 ml) was added under cooling with ice. Then, ben-
zyltriethylammonium chloride (3 mg, 0.013 mmol) and dimethyl sulfate
(9 ml, 0.09 mmol) were added, and the mixture was stirred for 2 h under
cooling with ice. Ice water was added to the reaction mixture to quench the
reaction, and the mixture was extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column chromatog-
raphy (eluents; CH2Cl2 : MeOHϭ9 : 1) to give compound 29 (16 mg, 36%).
HR-MS m/z: Calcd for C27H31ClN4O4S: 542.1754. Found: 542.1739. 1H-
NMR (*CDCl3) d: 8.36 (1H, s), 8.26—8.19 (2H, m), 7.98—7.92 (3H, m),
7.80 (1H, dd, Jϭ2, 9 Hz), 7.61 (1H, dd, Jϭ2, 9 Hz), 6.62—6.55 (2H, m),
4.17 (1H, d, Jϭ17 Hz), 4.05 (1H, d, Jϭ12 Hz), 3.94—3.70 (3H, m), 3.70—
3.43 (3H, m), 3.38 (3H, s), 3.38 (1H, d, Jϭ17 Hz), 2.88—2.66 (4H, m),
2.08—1.90 (1H, m), 1.71—1.54 (2H, m), 1.38—1.07 (2H, m).
1
95 : 5—90 : 10) to give compound 24 (1.04 g, 43%). H-NMR (*CDCl3) d:
8.13 (2H, d, Jϭ7 Hz), 6.97 (2H, d, Jϭ7 Hz), 4.27 (2H, q, Jϭ7 Hz), 4.23—
4.17 (3H, m), 3.94 (1H, dd, Jϭ8.14 Hz), 3.57 (2H, s), 3.43—3.11 (4H, m),
2.66 (1H, dd, Jϭ7, 14 Hz), 2.20—2.03 (1H, m), 1.98—1.81 (2H, m), 1.44—
1.24 (2H, m), 1.32 (3H, t, Jϭ7 Hz).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxylic Acid Ethyl Ester (25) Com-
pound 24 (52 mg, 0.15 mmol) was dissolved in CH2Cl2 (5 ml). To the solu-
tion, Et3N (0.1 ml, 0.7 mmol) and 6-chloro-2-naphthalenesulfonyl chloride
(39.1 mg, 0.15 mmol) were added, in that order, and the mixture was stirred
overnight at room temperature. Water was added to the reaction mixture,
which was extracted with CH2Cl2. The organic layer was washed with water
and brine, dried over Na2SO4, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column chromatography
(eluents; CH2Cl2 : MeOHϭ99 : 1—9 : 1) to give compound 25 (48 mg, 56%).
HR-MS m/z: Calcd for C28H31ClN4O5S: 570.1703. Found: 570.1681. 1H-
NMR (CDCl3) d: 8.34 (1H, s), 8.25—8.18 (2H, m), 7.98—7.90 (3H, m),
7.77 (1H, dd, Jϭ2, 9 Hz), 7.64—7.58 (1H, m), 6.64—6.57 (2H, m), 4.38—
4.04 (5H, m), 3.96—3.75 (3H, m), 3.46 (1H, d, Jϭ17 Hz), 3.07—2.96 (1H,
m), 2.88—2.68 (2H, m), 2.66—2.55 (1H, m), 1.93—1.75 (1H, m), 1.73—
1.55 (2H, m), 1.32 (3H, t, Jϭ7 Hz), 1.32—1.14 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxylic Acid (26) To a solution of
the compound 25 (18 mg, 0.03 mmol) in MeOH (0.5 ml), 2 N NaOH solution
(63 ml) was added, and the mixture was stirred at 40 °C for 30 min. The reac-
tion mixture was concentrated under reduced pressure and the resulting
residue was dissolved in water and rendered weakly acidic with 0.1 N HCl.
The supernatant was removed by decantation, and the residue was dissolved
in MeOH, dried over Na2SO4, and the solvent was evaporated under reduced
pressure to give compound 26 (9 mg, 53%). 1H-NMR (*CD3OD) d: 8.47
(1H, s), 8.16—7.99 (5H, m), 7.90—7.83 (1H, m), 7.64 (1H, dd, Jϭ2, 9 Hz),
7.02 (2H, d, Jϭ8 Hz), 4.18—3.91 (5H, m), 3.81 (1H, dd, Jϭ8, 14 Hz), 3.58
(1H, d, Jϭ16 Hz), 3.30—3.20 (1H, m), 3.12—2.93 (2H, m), 2.72 (1H, dd,
Jϭ7, 14 Hz), 2.08—1.92 (1H, m), 1.82—1.71 (1H, m), 1.62—1.52 (1H, m),
1.31—1.04 (2H, m).
6-(Aminomethyl)-4-[(6-chloro-2-naphthalenyl)sulfonyl]-1-[[1-(4-
pyridinyl)-4-piperidinyl]methyl]piperazinone (30) Azodicarboxylic acid
diethyl ester (as 40% toluene solution) (1.71 ml, 3.78 mmol) was added to a
solution of triphenylphosphine (0.99 g, 3.78 mmol) and phthalimide (0.56 g,
3.78 mmol) in CH2Cl2 (30 ml) under cooling with ice. After stirring the mix-
ture at the same temperature for 10 min, compound 28 (0.50 g, 0.95 mmol)
was added, and the mixture was stirred at room temperature for 30 min. Sat-
urated NaHCO3 aq. was added to the reaction mixture under cooling with
ice, and the mixture was extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column chromatog-
raphy (eluents; CH2Cl2 : MeOHϭ9 : 1) to give 4-[(6-chloro-2-naphthalenyl)-
sulfonyl]-6-phthaliminomethyl-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-
1
piperazinone (0.61 g, 98%). H-NMR (*CDCl3) d: 8.42 (1H, s), 8.24—8.19
(2H, m), 7.97—7.87 (6H, m), 7.83—7.75 (2H, m), 7.63—7.51 (1H, m).
6.62—6.56 (2H, m), 4.33—4.20 (1H, m), 4.11 (1H, d, Jϭ17 Hz), 4.04—
3.93 (2H, m), 3.87—3.68 (4H, m), 3.43 (1H, d, Jϭ17 Hz), 2.96—2.68 (4H,
m), 2.08—1.87 (1H, m), 1.73—1.57 (2H, m), 1.42—1.17 (2H, m).
A portion (0.61 g, 0.93 mmol) of 4-[(6-chloro-2-naphthalenyl)sulfonyl]-6-
phthaliminomethyl-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]piperazinone
was suspended in EtOH (15 ml). Hydrazine monohydrate (54 ml, 1.11 mmol)
was added to the suspension at room temperature, followed by stirring at
room temperature for 20 h. The suspension was then allowed to reflux for
4 h. After leaving the suspension to cool, the insolubles were filtered off and
the filtrate was concentrated. The residue was purified by silica gel column
chromatography (eluents; CH2Cl2 : MeOHϭ9 : 1) to give compound 30
(0.36 g, 77%). HR-MS m/z: Calcd for C26H30ClN5O3S: 527.1758. Found:
527.1780. 1H-NMR (*CDCl3) d: 8.36 (1H, d, Jϭ1 Hz), 8.22—8.19 (2H, m),
7.97—7.94 (3H, m), 7.82—7.78 (1H, m), 7.61 (1H, dd, Jϭ2, 9 Hz), 6.59—
6.57 (2H, m), 4.25—4.16 (2H, m), 3.89—3.76 (3H, m), 3.36 (1H, d,
Jϭ17 Hz), 3.30—3.22 (1H, m), 3.07 (1H, dd, Jϭ10, 13 Hz), 2.96 (1H, dd,
Jϭ4, 13 Hz), 2.79—2.68 (3H, m), 2.63 (1H, dd, Jϭ8, 14 Hz), 2.05—1.87
(1H, m), 1.73—1.57 (2H, m), 1.35—1.14 (2H, m).
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxamide (27) Ammonia gas was
blown into a solution of compound 26 (0.20 g, 0.35 mmol) in 2 N ammo-
nia–MeOH (5 ml), and the solution was stirred in a sealed tube at 80—90 °C
for 8 h. The reaction mixture was concentrated under reduced pressure, and
the residue was purified by silica gel column chromatography (eluents;
CH2Cl2 : MeOHϭ9 : 1) to give compound 27 (0.14 g, 74%). HR-MS m/z:
4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxaldehyde 2-Oxime (31) A solu-
tion of oxalyl chloride (33 ml, 0.38 mmol) in CH2Cl2 (1 ml) was cooled to
Ϫ78 °C under Ar. To the cooled solution, a solution of DMSO (60 ml,
1
Calcd for C26H28ClN5O4S: 541.1550. Found: 541.1509. H-NMR (CDCl3ϩ
CD3OD) d: 8.48—8.44 (1H, m), 8.14—8.00 (5H, m), 7.85 (1H, dd, Jϭ2,
9 Hz), 7.65 (1H, dd, Jϭ2, 9 Hz), 6.72 (2H, d, Jϭ6 Hz), 4.19 (1H, t, Jϭ3 Hz),

September 2002
1193
3.01 (1H, m), 2.81—2.67 (2H, m), 2.60—2.47 (1H, m), 1.89—1.73 (1H, m),
1.65—1.54 (1H, m), 1.49—1.38 (1H, m), 1.17—0.85 (2H, m). Anal. Calcd
for C26H27ClN4O5S–H2O: C, 55.66; H, 5.21; N, 9.99. Found: C, 55.54; H,
5.04; N, 10.05.
0.76 mmol) in CH2Cl2 (1 ml) was added dropwise over 20 min. Then, a solu-
tion of compound 28 (10 mg, 0.019 mmol) in CH2Cl2 (1 ml) was added drop-
wise over another 20 min. The reaction mixture was stirred at between
Ϫ65 °C and Ϫ60 °C for 1 h, the mixture was cooled to Ϫ78 °C, and Et3N
(0.16 ml, 1.14 mmol) was added. The reaction mixture was allowed to stand
at room temperature, water (4 ml) was added, and the mixture was extracted
with CH2Cl2. The organic layer was washed with water and brine, dried over
Na2SO4, and the solvent was evaporated under reduced pressure. The result-
ing crude aldehyde was dissolved in EtOH (1 ml). Hydroxylamine hy-
drochloride (2.5 mg, 0.038 mmol) and sodium acetate (3 mg, 0.038 mmol)
were added to the solution. AcOH was added to the reaction mixture to ad-
just its pH to about 4, then the mixture was stirred overnight at room tem-
perature. The reaction mixture was rendered alkaline by the addition of satu-
rated NaHCO3 aq., then extracted with CH2Cl2. The organic layer was
washed with brine, dried over Na2SO4, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column chromatog-
raphy [Chromatorex NHTM] (eluents; CH2Cl2 : MeOHϭ97 : 3) to give com-
pound 31 (1.9 mg, 19%). 1H-NMR (*CDCl3) d: 8.37—8.35 (1H, m), 8.17
(2H, d, Jϭ6 Hz), 7.98—7.92 (3H, m), 7.83—7.77 (1H, m), 7.65—7.58 (1H,
m), 7.46 (0.7H, d, Jϭ8 Hz), 6.84 (0.3H, d, Jϭ7 Hz), 6.59 (2H, d, Jϭ6 Hz),
4.96—4.87 (0.3H, m), 4.18—4.00 (1.7H, m), 3.95—3.48 (5H, m), 3.19—
3.05 (1H, m), 2.90—2.64 (3H, m), 2.15—1.95 (1H, m), 1.70—1.45 (2H, m),
1.35—1.10 (2H, m).
(R)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxylic Acid Ethyl Ester (32)
Using (R)-b-(tert-butoxycarbonylamino)alanine ethyl ester, the method used
to synthesize compound 25 was repeated to give compound 32. The optical
purity of this compound was measured by HPLC [CHIRALPAKTM AS (Dai-
cel Chemical Industries, Ltd.); methanol : diethylamineϭ100 : 0.1], and it
was found to be 98.3% e.e. HR-MS m/z: Calcd for C28H31ClN4O5S:
570.1703. Found: 570.1664. [a]D29 Ϫ49.9° (cϭ1.00, EtOH). 1H-NMR
(CDCl3) d: 8.34 (1H, s), 8.25—8.18 (2H, m), 7.98—7.90 (3H, m), 7.77 (1H,
dd, Jϭ2, 9 Hz), 7.64—7.58 (1H, m), 6.64—6.57 (2H, m), 4.38—4.04 (5H,
m), 3.96—3.75 (3H, m), 3.46 (1H, d, Jϭ17 Hz), 3.07—2.96 (1H, m), 2.88—
2.68 (2H, m), 2.66—2.55 (1H, m), 1.93—1.75 (1H, m), 1.73—1.55 (2H, m),
1.32 (3H, t, Jϭ7 Hz), 1.32—1.14 (2H, m).
(S)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxylic Acid Monohydrate (35)
A
solution of compound 33 (50 mg, 0.088 mmol) in 1 N HCl (5 ml) was heated
under reflux for 12 h. The reaction mixture was concentrated under reduced
pressure. The residue was dissolved in MeOH (5 ml), and 1 N aqueous
NaOH was added to make it alkaline. To the solution, MuromacTM MSC-1
(Hϩ form, 1 g, Muromachi Kagaku Kogyo Kaisha, Ltd.) was added, and the
resulting suspension was stirred at room temperature for 30 min. The ion ex-
change resin was collected with suction, then washed with water and MeOH.
To the resin, 10% (w/w) NH3–MeOH (5 ml) was added. After stirring for
30 min, the resin was filtered off and the filtrate was concentrated under re-
duced pressure. The residue was purified by silica gel column chromatogra-
phy (Chromatorex NHTM (Fuji Silysia Chemical, Ltd.) eluents; AcOEt :
MeOHϭ3 : 1—1 : 2) to give (S)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-
oxo-1-[[1-(4-pyridinyl)-4-piperidinyl]methyl]-2-piperazinecarboxylic acid
ammonium salt (33 mg, 65%). To a solution of the ammonium salt (33 mg,
0.058 mmol), 0.1 M H2SO4 aq. (0.27 ml) was added, and the resulting precipi-
tate was collected to give compound 35 (30 mg, 91%). The optical purity of
this compound was measured by HPLC [CHIRALPAKTM WH (Daicel
Chemical Industries, Ltd.); 0.5 mM CuSO4 aq. : acetonitrileϭ1 : 1], and it was
1
found to be 91.3% e.e. H-NMR (*DMSO-d6) d: 8.58 (1H, s), 8.29 (1H, d,
Jϭ9 Hz), 8.26 (1H, d, Jϭ2 Hz), 8.17 (1H, d, Jϭ9 Hz), 8.10 (2H, d, Jϭ7 Hz),
7.87 (1H, dd, Jϭ2, 9 Hz), 7.72 (1H, dd, Jϭ2, 9 Hz), 6.82 (2H, d, Jϭ7 Hz),
4.17—4.04 (2H, m), 3.96—3.62 (3H, m), 3.81 (1H, d, Jϭ16 Hz), 3.39 (1H,
d, Jϭ16 Hz), 3.10—3.01 (1H, m), 2.81—2.67 (2H, m), 2.60—2.47 (1H, m),
1.89—1.73 (1H, m), 1.65—1.54 (1H, m), 1.49—1.38 (1H, m), 1.17—0.85
(2H, m).
Acknowledgments The authors thank Emeritus Professor Hiroshi Ya-
manaka of Tohoku University for his encouragement and helpful discussion
throughout this study.
References and Notes
(S)-4-[(6-Chloro-2-naphthalenyl)sulfonyl]-6-oxo-1-[[1-(4-pyridinyl)-4-
piperidinyl]methyl]-2-piperazinecarboxylic Acid Ethyl Ester (33)
Using (S)-b-(tert-butoxycarbonylamino)alanine ethyl ester, the method used
to synthesize compound 25 was repeated to give compound 33. The optical
purity of this compound was measured by HPLC [CHIRALPAKTM AS (Dai-
cel Chemical Industries, Ltd.); methanol : diethylamineϭ100 : 0.1], and it
was found to be 96.7% e.e. HR-MS m/z: Calcd for C28H31ClN4O5S:
570.1703. Found: 570.1689. [a]D30 ϩ42.1° (cϭ1.00, EtOH). 1H-NMR
(CDCl3) d: 8.34 (1H, s), 8.25—8.18 (2H, m), 7.98—7.90 (3H, m), 7.77 (1H,
dd, Jϭ2, 9 Hz), 7.64—7.58 (1H, m), 6.64—6.57 (2H, m), 4.38—4.04 (5H,
m), 3.96—3.75 (3H, m), 3.46 (1H, d, Jϭ17 Hz), 3.07—2.96 (1H, m), 2.88—
2.68 (2H, m), 2.66—2.55 (1H, m), 1.93—1.75 (1H, m), 1.73—1.55 (2H, m),
1.32 (3H, t, Jϭ7 Hz), 1.32—1.14 (2H, m).
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