Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. III. Synthesis and antitumor activity of 3-phenylpiperazinyl-1-trans-propenes

Article abstract of DOI:10.1248/cpb.53.153

A series of novel 3-[4-phenyl-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)- 4-pyrazolyl]-1-trans-propenes and related compounds were synthesized and evaluated by their cytotoxic activity against several tumor cell lines in vitro and in vivo antitumor acti

Full text of DOI:10.1248/cpb.53.153

February 2005
Chem. Pharm. Bull. 53(2) 153—163 (2005)
153
Synthesis and Antitumor Activity of Novel Pyrimidinyl Pyrazole
Derivatives. III.1,2) Synthesis and Antitumor Activity of
3-Phenylpiperazinyl-1-trans-propenes
Hiroyuki NAITO,a Satoru OHSUKI,a Ryo ATSUMI,b Megumi MINAMI,c Mineko MOCHIZUKI,c
d
c
,a
*
Kenji HIROTANI, Eiji KUMAZAWA, and Akio EJIMA
a Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd.; b Drug Metabolism & Physicochemical
Property Research Laboratory, Daiichi Pharmaceutical Co. Ltd.; c New Product Research Laboratories III, Daiichi
Pharmaceutical Co. Ltd.; and d Discovery Research Laboratory, Daiichi Pharmaceutical Co. Ltd.; 1–16–13 Kita-kasai,
Edogawa-ku, Tokyo 134–8630, Japan. Received July 20, 2004: accepted November 6, 2004
A series of novel 3-[4-phenyl-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidinyl)-4-pyrazolyl]-1-trans-propenes and
related compounds were synthesized and evaluated by their cytotoxic activity against several tumor cell lines in
vitro and in vivo antitumor activity against some tumor models when administered both intraperitoneally and
orally. Compounds with the 3-chloropyridin-2-yl group (9g) and the 3-fluoro-5-substituted phenylpiperazinyl
group (29b, c, and e) showed significantly potent cytotoxicity by in vitro testing. Among them, the 3-cyano-5-fluo-
rophenyl derivative (29b) exhibited potent antitumor activity against several tumor cells including human carci-
noma without causing undesirable effects in mice.
Key words cytotoxic activity; antitumor activity; structure–activity relationship
In previous papers, we reported novel pyrimidinyl pyrazole Chemistry
derivatives (Fig. 1) that showed in vitro and in vivo antitumor
Syntheses of the 1-arylpyrazolyl compounds (9a—k) were
activity. These compounds were also found to inhibit tubulin carried out via the route shown in Chart 1. The hydrazine de-
polymerization as a mechanism of their action in cells.1,2) To rivatives (5a—j)3—7) were subjected to the construction of a
investigate the possibilities for modification of this scaffold, pyrazole ring with ethoxymethyleneacetylacetone8) to pro-
we divided the moieties into five parts from A to E as shown vide the 4-acetyl-1-heteroarylpyrazoles (6a—j). Phenylpyra-
in Fig. 1. So far, it has been reported that the length of the zole derivative (6k) was prepared by following the reported
three carbon chain on moiety C and the existence of piper-
azine on moiety D are important for the activity. In an effort
to improve the activity, we replaced the pyrimidine and pyra-
zole moieties of A and B with some heteroaryl moieties and
introduced various substituents to the phenyl ring of moiety
E. We describe here the modification of moieties A, B, and E
and the antitumor activities of the resulting compounds.
Fig. 1
Chart 1
∗ To whom correspondence should be addressed. e-mail: naitoxns@daiichipharm.co.jp
© 2005 Pharmaceutical Society of Japan

154
Vol. 53, No. 2
procedure.9,10) Mannich reaction of pyrazoles (6a—k) with pyrrol-3-yl)ethanone (14)14,15) was reacted with 2-chloropy-
1-(3-chlorophenyl)piperazine (7a), 1-(3,5-difluorophenyl)- rimidine to afford 2-methylpyrrole (15d). The derivatives
piperazine (7b), or 1-(3,5-dichlorophenyl)piperazine (7c) bearing a pyrazole ring (17a—c) and a pyrrole ring (17d)
gave 8a—k, respectively. Compounds (8a—k) were reduced were obtained from the 4-acetylpyrazole derivatives (15a—c)
with sodium borohydride to give the corresponding alcohols, and the pyrrole derivative (15d) with modified piperazines
which were dehydrated by p-toluenesulfonic acid (p-TsOH) (7a) and (7c) via the Mannich reaction and dehydration, re-
to afford 1-trans-propene derivatives 9a—k.
spectively (Chart 2).
Modification of the pyrazole moiety was carried out via
Furthermore, the imidazole derivative (23) having a nitro-
the route shown in Charts 2 and 3. Compound (11), which gen atom at 3-position of the pyrazole ring was also prepared
was prepared by iodination of 2-(1-pyrazolyl)pyrimidine by the procedure to construct this scaffold by employing re-
(10)11) with periodic acid, afforded 12 through a palladium- ductive amination instead of the Mannich reaction (Chart 3).
catalyzed cross-coupling reaction with vinyltributylstannum Ethyl 4-methyl-5-imidazolecarboxylate (18) was condensed
in the presence of lithium chloride.12) Compound (12) was with 2-chloropyrimidine to afford pyrimidinylimidazole (19).
treated with sulfuric acid and then oxidized with manganese Reduction of 19 with diisobutylaluminum hydride (DIBAL)
(IV) oxide to afford 5-demethylpyrazole (15a). Migration of gave aldehyde (20). The carbon–carbon bond formation of
the pyrimidinyl group of 131,2) to the 2-position from the 1- 20 with allyl bromide was performed with metallic stan-
position on the pyrazole ring was carried out by using diethyl num,16) followed by protection of the secondary alcohol with
carbonate and sodium hydride to produce 3-methylpyrazole triethylsilyl chloride to give 21. Oxidation of 21 with os-
(15b). Dimethylpyrazole (15c) was prepared following the mium tetraoxide (OsO4) and simultaneous oxidative cleavage
reported procedure.13) To investigate the possibility of replac- of the 1,2-diol with sodium periodate gave aldehyde (22).
ing the pyrazole ring with a pyrrole ring, 1-(2-methyl-1H- The reductive amination of 22 with 7b by treatment with
Chart 2
Chart 3

February 2005
155
Chart 4
sodium cyanoborohydride in acetic acid (AcOH)/EtOH gave
the corresponding adduct, followed by deprotection and si-
multaneous dehydration with hydrochloride to afford the 1-
trans-propene derivative (23).
Table 1. Cytotoxic Activity of 1-trans-Propene Derivatives
GI50 (ng/ml)a)
Compd. No.
PC-6
PC-12
On the other hand, some 3,5-disubstituted phenylpiper-
azine derivatives were synthesized via the route shown in
Chart 4, because 3,5-disubstitution of phenylpiperazine en-
hanced activity. As for the introduction of cyanide, 1-fluoro-
3-iode-5-nitrobenzene (24a) was reacted with copper(I)
cyanide to afford 1-cyano-3-fluoro-5-nitrobenzene (24b).
After reduction of the nitro group of compounds (24a, b), the
anilines (25a—d) were treated with bis(2-chloroethyl)amine
hydrochloride and potassium carbonate to give the
phenylpiperazines (27a—d). Compound (27e) was prepared
via a palladium(II)-catalyzed aromatic amination reaction17)
of 1-bromo-3-chloro-5-fluorobenzene (26) with piperazine.
Mannich reaction of 13 with 3,5-disubstituted phenylpiper-
azines (27a—e) gave 28a—e, respectively. Propene deriva-
tives (29a—e) were obtained from 28a—e by the same pro-
cedure as described in Chart 1.
9a
9b
9c
9d
9e
9f
9g
9h
9i
306
127
113
NTb)
589
583
ꢀ1000
ꢀ1000
ꢀ1000
35
109
ꢀ1000
358
ꢀ1000
ꢀ1000
ꢀ1000
ꢀ1000
ꢀ1000
ꢀ1000
667
ꢀ1000
ꢀ1000
ꢀ1000
8.8
31
ꢀ1000
57
9j
9k
455
17a
17b
17c
17d
23
29a
29b
29c
29d
29e
2
ꢀ1000
ꢀ1000
461
691
ꢀ1000
104
4.8
5.4
40
2.5
34
6.4
6.3
0.3
27
75
370
22
208
63
205
33
Biological Activity and Discussion
The in vitro cytotoxic activity of these compounds was
measured by using the human lung cancer cell lines PC-6
and PC-12, and the concentrations producing a 50% growth
inhibitory effect (GI50) are listed in Table 1. Compounds (2—
4), VCR, and 5-fluorouracil (5-FU) were used as reference
compounds.
3
4
VCR
5-FU
460
30
PC-6, PC-12: Human non-small cell lung cancer cell lines. a) See Experimental.
b) NT: not tested.
Among a series of 1-arylpyrazole derivatives (9a—f) bear-
ing the 3-chlorophenylpiperazine moiety, the pyridine deriva-
tives (9a, b), and the pyrazine derivative (9c) showed weak compared with that of the pyrimidinylpyrazole compound
activity, while the other compounds (9d—f) were not active. (4). The pyrimidin-2-yl part and the 3-chloropyridin-2-yl part
On the other hand, in a series of 1-arylpyrazole compounds on moiety A are important for potent activity, because all the
(9g—j) bearing the 3,5-difluorophenylpiperazine moiety, the other derivatives showed decreased in vitro activity compared
3-chloropyridin-2-yl derivative (9g) showed similar activity with the corresponding pyrimidine derivatives.
and potency to that of the corresponding pyrimidin-2-yl de-
As for the modification of moiety B, compound (17c) hav-
rivative (3). The activities of compounds (9h—j) bearing a 3- ing methyl groups at both 3- and 5-positions of pyrazole
chloropyridin-4-yl, 3,5-dichloropyridin-4-yl, and 5-chloropy- showed weak in vitro cytotoxic activity, while the corre-
ridin-2-yl moiety, respectively, were moderate or inactive. sponding compounds (17a) without methyl group and (17b)
The phenylpyrazole compound (9k) had decreased activity with a methyl group at 3-position of pyrazole were not ac-

156
Vol. 53, No. 2
tive. The fact that compounds (2) and (17c) retained the cyto- strong in vitro cytotoxic activity, were tested in the in vivo
toxic activity, while no activity was observed with 17a and b, assay against murine fibrosarcoma Meth A as a solid tumor
indicates that a methyl group at 5-position of pyrazole plays model by intraperitoneal injection or oral administration.
a critical role for showing cytotoxic activity. Replacement of 5-FU was used as a reference compound.
the pyrazole ring with the pyrrole or imidazole ring caused a
As shown in Table 2, all compounds exhibited more potent
decrease of cytotoxic activity (17d, 23), even though these antitumor activity at the maximum tolerated dose (MTD)
compounds had a methyl group at the same position. It than that (26%) of 5-FU by intraperitoneal injection. Particu-
seemed to be very difficult to retain in vitro activity by larly, compound (29b) exhibited potent effect with the re-
changing the structure of moiety B.
spective inhibition rate (IR) value of 75% at the MTD, the
In the series of 3-fluoro-5-substituted phenyl derivatives antitumor activity of 29b was superior to those of 2 and 3
(29a—e) listed in Chart 4, compounds (29b, e) which bear a when administered intraperitoneally. The effect of 9g, 29c,
cyano or a chloro group at the same position of the phenyl and 29e, however, was moderate in spite of showing activity
ring, showed slightly enhanced activity compared with the almost equal to the in vitro cytotoxic activity of 29b. These
corresponding 3,5-difluorophenyl derivative (3) against PC-6 compounds also did not cause a decrease of body tempera-
and PC-12. The 3-bromo-5-fluorophenyl derivative (29c) ture as the side effect at the level of each MTD. Furthermore,
showed almost the same activity as 3, but the iodo substituent muscle relaxation and crouching posture were not observed
at 3-position dramatically decreased the in vitro activity for these compounds at the MTD in mice, although the lead
(29a). The activity of the corresponding compound (29d) compound (2) in this scaffold caused these visible symptoms.
bearing the trifluoromethyl group at the same position of the The tumor growth inhibition curves of 29b and 5-FU are
phenyl ring was moderate.
shown in Fig. 2.
Compounds (9g), (29b), (29c), and (29e), which showed
When administered orally, the effects of these compounds
Table 2. Antitumor Activity of 1-trans-Propene Derivatives against Murine Fibrosarcoma Meth Aa)
Antitumor activityb)
Compd. No.
i.p.
BWLmaxc) (%)
p.o.
Dose (mg/kg)
IR (%)
D/Ud)
Dose (mg/kg)
IR (%)
BWLmax (%)
D/U
9g
35.0ꢁ5
28.0ꢁ5
10.0ꢁ5
7.0ꢁ5
60.0ꢁ5
20.0ꢁ5
14.0ꢁ5
40.0ꢁ5
20.0ꢁ5
47*
34*
ꢂ0
ꢂ0
14.2
1.2
2.0
1.6
ꢂ0
27.0
9.2
0/7
0/7
0/7
0/7
0/7
0/7
0/7
6/7
0/7
60.0ꢁ5
35.0ꢁ5
10.0ꢁ5
7.0ꢁ5
89***
55**
86***
72**
15.0
ꢂ0
12.3
2.0
1/7
0/7
0/7
0/7
29b
75***
58**
43**
51**
43**
66
29c
29e
30.0ꢁ5
20.0ꢁ5
60.0ꢁ5
40.0ꢁ5
81***
57**
80
3.5
ꢂ0
25.4
14.5
0/7
0/7
3/7
0/7
5-FU1,2)
26
40**
Inhibition rate (IR) of VCR; 9.0% (1.6 mg/kg, i.v.), 2; 62% (43ꢁ5 mg/kg, i.p.) and 88% (60ꢁ5 mg/kg, p.o.), 3; 63% (7.4ꢁ5 mg/kg, i.p.) and 86% (12.5ꢁ5 mg/kg, p.o.).1,2) a)
Murine fibrosarcoma Meth A cells (1ꢁ106 cells/0.1 ml/head) were implanted into the right flank of BALB/c mice (day 0). Pyrimidinylpyrazole derivatives at the indicated doses
were administered intraperitoneally (i.p.) or per os (oral) administration (p.o.) on days 7—11, consecutively. b) See Experimental. c) Rate of body weight loss (BML). d)
Number of mice that died of toxicity/number of mice used. ∗∗∗ pꢂ0.001, ∗∗ pꢂ0.01, ∗ pꢂ0.05 vs. the control group.
Fig. 2. Tumor Growth Inhibition Curves of 29b and 5-FU1) against Meth A
Murine fibrosarcoma Meth A cells (1ꢁ106 cells/0.1 ml/head) were implanted into the right flank of BALB/c mice (day 0). Compound 29b and 5-FU at the indicated doses were
administered orally on days 7—11, consecutively.

February 2005
157
Table 3. Antitumor Effect of 3 and 29b on Human Carcinoma in Nude Micea)
Antitumor activityb)
29b
BWLmaxc) D/Ud)
3
VCR
Dose
(mg/kg)
IR
(%)
Dose
(mg/kg)
IR
(%)
BWLmaxc) D/Ud)
(%)
Dose
(mg/kg)
IR
(%)
BWLmaxc) D/Ud)
(%)
(%)
PC-12
PC-14
8.0ꢁ8
8.0ꢁ8
70***
38*
1.0
2.8
0/5
0/6
10.0ꢁ8
10.0ꢁ8
68***
53**
3.1
7.8
0/6
0/6
1.6ꢁ1
1.6ꢁ1
ꢄ10
53**
17.2
15.8
0/6
0/6
a) Human non-small cell lung cancer PC-12 and PC-14 blocks were inoculated s.c. into BALB/cAnNCrj-nu mice (day 0). Compounds 29b and 3 at the indicated doses were
administered per os (oral) administration (p.o.) from day 11 or 14. VCR was administrated i.v. on day 11 or 14, once. b) See Experimental. c) Rate of body weight loss. d)
Number of mice that died of toxicity/number of mice used. ∗∗∗ pꢂ0.001, ∗∗ pꢂ0.01, ∗ pꢂ0.05 vs. the control group.
Table 4. In Vitro Cytotoxicity against Multi-Drug Resistant Cell Linesa,b)
Ratec)
Compd.
No.
GI50 (ng/ml)
PC-6
PC-6/VCR29-9
PC-6/ADM2-1
PC-6/Tax1-1
PC-6/CDDP2-7
PC-6/FU26-23
29b
VCR
ADM
Taxol
Cisplatin
5-FU
4.8
0.101
12.6
0.31
203
0.97
842
27.9
580
0.54
0.85
1.63
691
18.7
365
1.17
1.09
1.34
398
8.65
299
0.66
0.78
2.17
2.58
1.02
1.08
28.6
0.72
1.87
1.60
0.46
1.02
0.11
24.8
420
a) See Experimental. b) PC-6/VCR29-9, PC-6/ADM2-1 and PC-6/Tax1-1 overexpress P-glycoprotein. PC-6/CDDP2-7 overexpresses GSH (glutathione) and GSSG. Mech-
anism of 5-FU resistance in the PC-6/FU26-23 cell line is unknown. c) (GI50 value against drug-resistant cell line)/(GI50 value against PC-6 cell line).
were superior to that by intraperitoneal injection (Table 2).
Compounds (29b) and (29e) showed potent antitumor activ-
ity with the respective IR values of 86% and 81% at the
MTD. The effects of 29b and 29e by oral administration were
superior to that (40%) of 5-FU and the same as that of 2 and
3, although the effect of 9g was moderate at the MTD
(IRꢃ55%). The oral absorption rates of compounds (9g) and
(29e) were evaluated by the intestinal loop method.18) As a
result, both compounds displayed high oral absorption rates
of 99.8% (9g) and 99.9% (29e) compared with 87.2% of 3
and 6.2%1) of 4. A fluoride atom of the phenyl ring on moi-
ety A was considered to be essential for good oral absorp-
tion.
Furthermore, the antitumor activity of 29b was evaluated
for oral administration by employing human lung carcinoma
PC-12 and PC-14 in nude mice. As shown in Table 3, com-
pound 29b exhibited significantly potent antitumor activity
against PC-12 with a respective IR value of 70% at the MTD
compared with that of vincristine (VCR) by intravenous in-
Fig. 3. Tumor Growth Inhibition Curves of 29b and 3 against PC-12
Human non-small cell lung cancer PC-12 block was inoculated s.c. into BALB/cAn-
NCrj-nu mice (day 0). Compounds 29b and 3 at the indicated doses were administered
orally on days 11—14 and 17—20, consecutively.
jection, and the effect was almost equal to that of 3. The
tumor growth inhibition curves of 29b and 3 are shown in
Fig. 3. While the antitumor activity of 29b against PC-14
was weak at the MTD (IRꢃ38%), compound 3 and VCR compared with those of compounds (2—4) (Table 5). Water
showed more potent activity with IR values of 53% at the solubility of both monohalogenated and dihalogenated com-
MTDs compared with that of 29b.
pounds (2—4) were low at pHꢃ6.8, whereas the appropriate
Consequently, compound (29b) was selected for further amount could be dissolved at pHꢃ1.1 because of the exis-
evaluation against various drug-resistant cell lines.19) As tence of piperazine. Especially, the dihalogenated compounds
shown in Table 4, compound (29b) did not show cross-resis- (3, 4) showed poor water solubility compared with the mono-
tance as indicated by the almost equal rates against all drug- halogenated compound (2). The logarithm of the distribution
resistant cell lines, while all reference drugs drastically de- coefficient (LogD) of compound (29b) in n-octanol/water
creased the in vitro activity against each drug resistant cell. system was 2.9 while those of the mono and dihalogenated
Compound (29b) possessed high activity against solid tu- compounds (2—4) were more than 3.5 at pHꢃ6.8. Introduc-
mors that were insensitive to some chemotherapeutic drugs.
tion of a cyano group on the phenyl ring improved water sol-
Physico-chemical properties of compound (29b) were ubility.

158
Vol. 53, No. 2
Table 5. Physico-chemical Properties of 1-trans-Propene Derivatives
(1H, s).
1
6i: Yield 28%, a pale yellow powder. H-NMR (CDCl3) d: 2.41 (3H, s),
2.53 (3H, s), 8.14 (1H, s), 8.7—8.8 (3H, m).
6j: Yield 64%, a pale yellow powder. H-NMR (CDCl3) d: 2.52 (3H, s),
2.97 (3H, s), 8.10 (1H, s), 8.79 (2H, s).
Water solubility (mg/ml)
LogDa) (pHꢃ6.8)
1
Compd. No.
pHꢃ1.1
pHꢃ6.8
3-[4-(3-Chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyridyl)-4-1H-
pyrazolyl]-1-propanone (8a) Paraformaldehyde (1.4 g, 46 mmol) and a
solution of 1 N HCl/EtOH (11 ml) were added to a mixture of 6a (2.3 g,
11 mmol) and 7a1,2) (2.6 g, 11 mmol) in EtOH (200 ml), and the mixture was
heated to reflux for 2 d. The mixture was diluted with CHCl3, successively
washed with saturated aqueous NaHCO3 and brine, and then dried. Evapora-
tion of the solvents afforded the crude mixture, which was chromatographed
on a silica gel column (CHCl3/MeOHꢃ50/1) to give 8a (2.3 g, 50%) as a
yellow amorphous solid. Compounds 6b—k and 7a—c were treated in the
same manner as described above to give 8b—k, respectively. The physical
data for these compounds and yields are shown in Table 6.
3-[4-(3-Chlorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyridyl)-4-1H-
pyrazolyl]-1-trans-propene Hydrochloride (9a) Sodium borohydride
(0.55 g, 15 mmol) was added in small portions to a solution of 8a (1.3 mg,
2.9 mmol) in anhydrous EtOH (70 ml) and THF (70 ml) at 0 °C, and the re-
action mixture was stirred at room temperature for 2 h. The reaction mixture
was quenched with a solution of 1 N HCl/EtOH. The mixture was diluted
with CHCl3, successively washed with saturated aqueous NaHCO3 and
brine, and dried. Evaporation of the solvents afforded the corresponding sec-
ondary alcohol. Next, p-TsOH·H2O (0.83 g, 4.4 mmol) was added to a solu-
tion of the above product in anhydrous 1,4-dioxane (50 ml) and THF (50 ml),
and the mixture was heated to reflux for 3.5 h. The reaction mixture was di-
luted with CHCl3, successively washed with saturated aqueous NaHCO3 and
2
3
4
86.0
244.2
77.7
16.9
5.1
1.6
ꢀ3.7
ꢀ3.6
ꢀ3.5
2.9
29b
307.1
107.4
a) The logarithm of the distribution coefficient (LogD) of compounds in n-
octanol/water system.
In conclusion, the study on structural modifications of
moieties A, B, and E in this scaffold 1 has resulted in the dis-
covery of the 3-chloropyridin-2-yl compound (9g) and the
3-fluoro-5-substituted phenyl derivatives (29b, c, e), which
showed strong in vitro cytotoxic activity. Among them, com-
pound (29b) displayed potent antitumor activity in mice
without causing undesirable effects by means of both in-
traperitoneal injection and oral administration. The mecha-
nism of action for the cytotoxic activity of this scaffold was
reported to be inhibition of tubulin polymerization.20,21)
Therefore, the tubulin polymerization inhibitory activity of
29b was evaluated. As a result, compound (29b) displayed brine, and dried. After removal of the solvents, the crude mixture was chro-
matographed on a silica gel column (CHCl3/MeOHꢃ50/1) to afford the
propene. An appropriate volume of a solution of 1 N HCl/EtOH was added to
a solution of the propene in a small amount of EtOH, and the solvent was re-
moved. The residue was recrystallized from EtOH to give 9a (0.89 g, 70%)
inhibition concentration values (IC50) of 53 mM, suggesting
that inhibition of tubulin polymerization contributes to ex-
pression of the activity. Further work to improve the activity
and the mechanism of action in cells will be described else-
where.
as a pale yellow powder. Compounds 8b—k were treated in the same man-
ner as described above to give 9b—k, respectively. The physical data for
these compounds and yields are shown in Table 7.
4-Iodo-1-(2-pyrimidinyl)pyrazole (11) Periodic acid (2.1 g), iodine
(4.5 g), water (10 ml), and sulfuric acid (1.5 ml) were successively added to a
solution of 1011) (6.2 g, 42 mmol) in acetic acid (51 ml), and the mixture was
stirred at 65 °C for 2.5 h. The solvents were evaporated in vacuo, and water
(90 ml) and NaHCO3 (5.2 g) were added to the residue. The resulting precip-
itates were collected by filtration to give 11 (8.4 g, 73%) as a pale yellow
solid: 1H-NMR (CDCl3) d: 7.25 (1H, t, Jꢃ5 Hz), 7.83 (1H, s), 8.68 (1H, s),
8.76 (2H, d, Jꢃ5 Hz).
Experimental
Melting points were determined on a Yanaco MP-500D apparatus and are
uncorrected. Infrared (IR) spectra were recorded on a JEOL JIR-5300 or
Horiba FT-720 spectrometer. 1H-NMR spectra were recorded on a JEOL
JNM-EX400 (400 MHz) instrument, and the chemical shifts are given in d
values. Mass spectra (MS) were recorded on a JEOL JMS-HX110 or a JMS-
AX505W mass spectrometer. Elemental analyses were performed with a
Perkin-Elmer Series II CHNS/O 2400 instrument. Column chromatography
was performed with silica gel 60 F 254 (70—230 mesh) (Merck). Sodium
sulfate was employed as a drying agent.
4-Acetyl-5-methyl-1-(2-pyridyl)pyrazole (6a) A mixture of pyridin-2-
ylhydrazine (3.3 g, 30 mmol) and ethoxymethyleneacetylacetone8) (4.7 g,
30 mmol) in EtOH (40 ml) was stirred at 70 °C for 1 h. The reaction mixture
was cooled, and the precipitate obtained was filtered to give 6a (4.6 g, 74%)
as a pale yellow powder. Compounds 5b—k were treated in the same man-
ner as described above to give 6b—k, respectively.
1-(2-Pyrimidinyl)-4-vinylpyrazole (12) 2,6-Di-tert-butyl-4-methylphe-
nol (50 mg) was added to a mixture of 11 (2.0 g, 7.5 mmol), vinyltributyl-
stannum (2.4 ml, 8.0 mmol), lithium chloride (1.0 g, 23 mmol), and
tetrakis(triphenylphosphine)palladium (0) (0.18 g, 0.16 mmol) in 1,4-diox-
ane (38 ml), and the mixture was heated to reflux for 4 h. 10% Aqueous KF
(20 ml) was added to the reaction mixture, and the mixture was stirred for
8 h at room temperature. The resulting precipitates were removed by filtra-
tion. The filtrate was diluted with AcOEt, and the solution was successively
washed with water and brine, and then dried. Filtration and evaporation of
the solvent afforded the crude mixture, which was chromatographed on a sil-
ica gel column (AcOEt/hexaneꢃ3/1) to give 12 (0.87 g, 68%) as a pale
1
6a: Yield 74%, a pale yellow powder. H-NMR (CDCl3) d: 2.51 (3H, s),
2.92 (3H, s), 7.32 (1H, t, Jꢃ5 Hz), 7.80 (1H, d, Jꢃ8 Hz), 7.88 (1H, t,
Jꢃ8 Hz), 8.02 (1H, s), 8.53 (1H, d, Jꢃ5 Hz).
1
1
brown solid: H-NMR (CDCl3) d: 5.24 (1H, dd, Jꢃ11, 1 Hz), 5.64 (1H, dd,
6b: Yield 90%, a pale yellow powder. H-NMR (CDCl3) d: 2.51 (3H, s),
Jꢃ18, 1 Hz), 6.61 (1H, dd, Jꢃ18, 11 Hz), 7.20 (1H, t, Jꢃ5 Hz), 7.94 (1H, s),
8.55 (1H, s), 8.74 (2H, d, Jꢃ5 Hz).
2.72 (3H, s), 7.46 (2H, d, Jꢃ6 Hz), 8.06 (1H, s), 8.78 (2H, d, Jꢃ6 Hz).
6c: Yield 55%, a colorless powder. 1H-NMR (CDCl3) d: 2.52 (3H, s),
2.95 (3H, s), 8.06 (1H, s), 8.47 (1H, dd, Jꢃ3, 2 Hz), 8.59 (1H, d, Jꢃ3 Hz),
9.23 (1H, d, Jꢃ2 Hz).
4-Acetyl-1-(2-pyrimidinyl)pyrazole (15a) Compound 12 (0.50 g,
2.9 mmol) was added to 35% aqueous sulfuric acid (15 ml), and the mixture
was stirred for 24 h at room temperature. The reaction mixture was diluted
with ice-water and alkalized with NaHCO3, and the whole was extracted
with CHCl3/MeOH (9/1). The organic layer was washed with brine and
dried. After filtration and evaporation of the solvents, the crude mixture was
chromatographed on a silica gel column (AcOEt/hexaneꢃ3/1) to afford the
corresponding alcohol (0.12 g, 22%): 1H-NMR (CDCl3) d: 1.58 (3H, d,
Jꢃ7 Hz), 5.00 (1H, q, Jꢃ7 Hz), 7.21 (1H, t, Jꢃ5 Hz), 8.53 (1H, s), 7.93
(1H, s), 8.74 (2H, d, Jꢃ5 Hz).
The mixture of the above alcohol (0.12 g, 0.64 mmol) and manganese (IV)
oxide (0.80 g, 9.2 mmol) was stirred for 12 h at room temperature. The reac-
tion mixture was diluted with AcOEt, and the whole was filtered through a
Celite pad. Removal of the solvent afforded 15a (0.11 g, 92%) as a white
solid: 1H-NMR (CDCl3) d: 2.54 (3H, s), 7.33 (1H, t, Jꢃ5 Hz), 8.22 (1H, s),
8.81 (2H, d, Jꢃ5 Hz), 9.09 (1H, s).
6d: Yield 64%, a red amorphous solid. 1H-NMR (DMSO-d6) d: 2.51 (3H,
s), 2.66 (3H, s), 7.77 (1H, br s), 8.24 (2H, br s).
1
6e: Yield 82%, a pale yellow powder. H-NMR (CDCl3) d: 2.52 (3H, s),
3.18 (3H, s), 7.40 (1H, t, Jꢃ8 Hz), 7.50 (1H, t, Jꢃ8 Hz), 7.86 (1H, d,
Jꢃ8 Hz), 7.96 (1H, d, Jꢃ8 Hz), 8.03 (1H, s).
1
6f: Yield 63%, a pale yellow powder. H-NMR (CDCl3) d: 2.53 (3H, s),
3.10 (3H, s), 7.60 (1H, t, Jꢃ7 Hz), 7.77 (1H, t, Jꢃ8 Hz), 7.88 (1H, d,
Jꢃ8 Hz), 8.02 (1H, d, Jꢃ9 Hz), 8.06 (1H, s), 8.07 (1H, d, Jꢃ6 Hz), 8.32
(1H, d, Jꢃ7 Hz).
1
6g: Yield 65%, a pale yellow powder. H-NMR (CDCl3) d: 2.50 (3H, s),
2.52 (3H, s), 7.47 (1H, dd, Jꢃ8, 5 Hz), 7.97 (1H, dd, Jꢃ8, 2 Hz), 8.08 (1H,
s), 8.56 (1H, dd, Jꢃ5, 2 Hz).
6h: Yield 74%, a pale yellow powder. H-NMR (CDCl3) d: 2.47 (3H, s),
2.52 (3H, s), 7.37 (1H, d, Jꢃ5 Hz), 8.08 (1H, s), 8.70 (1H, d, Jꢃ5 Hz), 8.84
1

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159
Table 6. Physical Data for Propanone Derivatives
Compd. Yield
1H-NMR (CDCl3) d
No.
8a
8b
8c
(%)
50
31
79
14
37
2.84 (3H, s), 3.1—3.3 (4H, m), 4—3.6 (4H, m), 3.6—3.7 (2H, m), 3.9—4.0 (2H, m), 6.88 (1H, d, Jꢃ8 Hz), 6.98 (1H, d, Jꢃ8 Hz),
7.08 (1H, s), 7.27 (1H, t, Jꢃ8 Hz), 7.51 (1H, t, Jꢃ5 Hz), 8.4 (1H, d, Jꢃ8 Hz), 8.08 (1H, t, Jꢃ8 Hz), 8.40 (1H, s), 8.58 (1H, d, Jꢃ5 Hz)
2.73 (3H, s), 3.1—3.3 (4H, m), 3.5—4.0 (8H, m), 6.88 (1H, dd, Jꢃ8, 2 Hz), 6.99 (1H, dd, Jꢃ8, 2 Hz), 7.08 (1H, s), 7.27 (1H, t, Jꢃ8 Hz),
7.88 (2H, d, Jꢃ6 Hz), 8.52 (1H, s), 8.87 (2H, d, Jꢃ6 Hz)
2.85 (3H, s), 3.1—3.4 (6H, m), 3.5—3.7 (4H, m), 3.8—4.0 (2H, m), 6.87 (1H, dd, Jꢃ8, 2 Hz), 6.98 (1H, dd, Jꢃ8, 2 Hz),
7.08 (1H, t, Jꢃ2 Hz), 7.27 (1H, dt, Jꢃ8, 2 Hz), 8.50 (1H, s), 8.66 (1H, dd, Jꢃ3, 2 Hz), 8.76 (1H, d, Jꢃ3 Hz), 9.16 (2H, d, Jꢃ2 Hz)
2.53 (3H, s), 3.0—3.2 (4H, m), 3.2—3.4 (4H, m), 3.5—3.6 (2H, m), 3.6—3.8 (2H, m), 6.88 (2H, d, Jꢃ8 Hz), 6.98 (2H, d, Jꢃ8 Hz),
7.08 (1H, s), 7.27 (1H, t, Jꢃ8 Hz), 7.75 (1H, d, Jꢃ4 Hz), 8.25 (1H, d, Jꢃ4 Hz)
2.67 (4H, t, Jꢃ5 Hz), 2.89 (2H, t, Jꢃ7 Hz), 3.08 (2H, t, Jꢃ7 Hz), 3.19 (3H, s), 3.22 (4H, t, Jꢃ5 Hz), 6.80 (2H, dt, Jꢃ8, 2 Hz),
6.88 (1H, t, Jꢃ2 Hz), 7.16 (1H, t, Jꢃ8 Hz), 7.41 (1H, t, Jꢃ8 Hz), 7.51 (1H, t, Jꢃ8 Hz), 8.87 (1H, d, Jꢃ8 Hz), 7.96 (1H, d, Jꢃ8 Hz),
8.09 (1H, s)
8d
8e
8f
49
3.04 (3H, s), 3.1—3.3 (4H, m), 3.5—3.6 (4H, m), 3.6—3.7 (2H, m), 3.9—4.0 (2H, m), 6.88 (1H, d, Jꢃ8 Hz), 7.00 (1H, d, Jꢃ8 Hz),
7.09 (1H, s), 7.27 (1H, t, Jꢃ8 Hz), 7.70 (1H, t, Jꢃ8 Hz), 7.87 (1H, t, Jꢃ8 Hz), 8.04 (1H, d, Jꢃ8 Hz), 8.06 (1H, d, Jꢃ9 Hz),
8.10 (1H, d, Jꢃ8 Hz), 8.49 (1H, s), 8.64 (1H, d, Jꢃ9 Hz)
8g
8h
53
36
24
24
62
58
36
32
48
26
20
32
30
32
2.51 (3H, s), 2.66 (4H, t, Jꢃ5 Hz), 2.89 (2H, t, Jꢃ7 Hz), 3.08 (2H, t, Jꢃ7 Hz), 3.21 (4H, t, Jꢃ5 Hz), 6.3—6.4 (1H, m), 6.4—6.5 (2 H, m),
7.48 (1H, dd, Jꢃ8, 5 Hz), 7.97 (1H, dd, Jꢃ8, 2 Hz), 8.12 (1H, s), 8.56 (1H, dd, Jꢃ5, 2 Hz)
2.47 (3H, s), 2.67 (4H, t, Jꢃ5 Hz), 2.90 (2H, t, Jꢃ7 Hz), 3.09 (2H, t, Jꢃ7 Hz), 3.22 (4H, t, Jꢃ5 Hz), 6.25 (1H, tt, Jꢃ9, 2 Hz),
6.36 (2H, dd, Jꢃ9, 2 Hz), 7.37 (1H, d, Jꢃ5 Hz), 8.13 (1H, s), 8.70 (1H, d, Jꢃ5 Hz), 8.84 (1H, s)
2.37 (3H, s), 3.2—3.3 (4H, m), 3.5—3.6 (4H, m), 3.6—3.7 (2H, m), 3.9—4.1 (2H, m), 6.5—6.6 (1H, m), 6.7—6.8 (2H, m), 8.51 (1H, s),
8.99 (2H, s)
2.84 (3H, s), 3.1—3.3 (4H, m), 3.3—3.6 (4H, m), 3.6—3.7 (2H, m), 3.9—4.1 (2H, m), 6.5—6.6 (1H, m), 6.74 (2H, d, Jꢃ9 Hz),
7.89 (1H, d, Jꢃ9 Hz), 8.19 (1H, dd, Jꢃ9, 3 Hz), 8.42 (1H, s), 8.63 (1H, d, Jꢃ3 Hz)
2.54 (3H, s), 3.1—3.3 (4H, m), 3.4—3.5 (4H, m), 3.5—3.7 (2H, m), 3.9—4.1 (2H, m), 6.96 (1H, s), 7.08 (2H, s), 7.5—7.6 (5H, m),
8.36 (1H, s)
8i
8j
8k
16a
16b
16c
16d
28a
28b
28c
28d
28e
2.67 (4H, t, Jꢃ5 Hz), 2.90 (2H, t, Jꢃ7 Hz), 3.10 (2H, t, Jꢃ7 Hz), 3.21 (4H, t, Jꢃ5 Hz), 6.7—6.8 (2H, m), 6.87 (1H, t, Jꢃ2 Hz),
7.16 (1H, t, Jꢃ8 Hz), 7.33 (1H, t, Jꢃ5 Hz), 8.24 (1H, s), 8.81 (2H, d, Jꢃ5 Hz), 9.13 (1H, s)
2.63 (3H, s), 2.67 (4H, t, Jꢃ5 Hz), 2.89 (2H, t, Jꢃ7 Hz), 3.08 (2H, t, Jꢃ7 Hz), 3.21 (4H, t, Jꢃ5 Hz), 6.79 (2H, dt, Jꢃ8, 2 Hz),
6.87 (1H, t, Jꢃ2 Hz), 7.16 (1H, t, Jꢃ8 Hz), 7.28 (1H, t, Jꢃ5 Hz), 8.78 (2H, d, Jꢃ5 Hz), 9.08 (1H, s)
2.58 (2H, t, Jꢃ5 Hz), 2.61 (3H, s), 2.66 (2H, t, Jꢃ5 Hz), 2.8—3.0 (1H, m), 2.91 (3H, s), 3.06 (1H, t, Jꢃ7 Hz), 3.1—3.3 (4H, m),
6.78 (1H, d, Jꢃ8 Hz), 6.81 (1H, d, Jꢃ8 Hz), 6.87 (1H, s), 7.16 (1H, t, Jꢃ8 Hz), 7.30 (1H, t, Jꢃ5 Hz), 8.84 (2H, d, Jꢃ5 Hz)
2.88 (3H, s), 3.2—3.3 (4H, t, Jꢃ5 Hz), 3.4—3.5 (4H, m), 3.6—3.7 (2H, m), 4.0—4.1 (2H, m), 6.85 (1H, d, Jꢃ3 Hz), 6.94 (1H, s),
7.06 (2H, s), 7.52 (1H, t, Jꢃ5 Hz), 7.60 (1H, d, Jꢃ3 Hz), 8.91 (2H, d, Jꢃ5 Hz)
2.83 (3H, s), 3.1—3.2 (4H, m), 3.5—3.6 (4H, m), 3.6—3.7 (2H, m), 3.9—4.0 (2H, m), 6.91 (1H, d, Jꢃ12 Hz), 7.02 (1H, d, Jꢃ8 Hz),
7.1—7.2 (1H, m), 7.66 (1H, t, Jꢃ5 Hz), 8.41 (1H, s), 9.00 (2H, d, Jꢃ5 Hz), 10.1—10.2 (1H, m)
2.83 (3H, s), 3.1—3.3 (4H, m), 3.4—3.6 (4H, m), 3.65 (2H, d, Jꢃ11 Hz), 4.07 (2H, d, Jꢃ13 Hz), 7.1—7.2 (1H, m),
7.26 (1H, dt, Jꢃ13, 2 Hz), 7.3—7.4 (1H, m), 7.66 (1H, t, Jꢃ5 Hz), 8.42 (1H, s), 9.00 (2H, d, Jꢃ5 Hz), 10.7—10.8 (1H, m)
2.5—2.6 (4H, m), 2.99 (3H, s), 3.0—3.2 (2H, t, Jꢃ7 Hz), 3.5—3.8 (4H, m), 6.55 (1H, dt, Jꢃ9, 2 Hz), 6.8—6.9 (2H, m),
7.39 (1H, t, Jꢃ5 Hz), 8.32 (1H, s), 8.88 (2H, d, Jꢃ5 Hz)
2.6—2.7 (4H, m), 2.89 (2H, t, Jꢃ7 Hz), 3.00 (3H, s), 3.09 (2H, t, Jꢃ7 Hz), 3.2—3.3 (4H, m), 6.7—6.8 (1H, m), 6.8—6.9 (1H, m),
6.88 (1H, s), 7.35 (1H, t, Jꢃ5 Hz), 8.15 (1H, s), 8.86 (2H, d, Jꢃ5 Hz)
2.6—2.6 (4H, m), 2.88 (2H, t, Jꢃ7 Hz), 3.00 (3H, s), 3.08 (2H, t, Jꢃ7 Hz), 3.2—3.3 (2H, m), 6.46 (1H, dt, Jꢃ12, 2 Hz),
6.53 (1H, dt, Jꢃ8, 2 Hz), 6.64 (1H, s), 7.35 (1H, t, Jꢃ5 Hz), 8.14 (1H, s), 8.86 (2H, d, Jꢃ5 Hz)
4-Acetyl-3-methyl-1-(2-pyrimidinyl)pyrazole (15b) The mixture of
131,2) (0.40 g, 2.0 mmol), diethyl carbonate (0.40 ml), and NaH (0.16 g of
60% in mineral oil, 4.0 mmol) in toluene (180 ml) was heated to reflux for
3 h. The reaction mixture was poured into 10% hydrochloric acid, and the
whole was extracted with AcOEt. The organic layer was washed with brine
and dried. After filtration and evaporation of the solvents, the residue was re-
crystallized from ether to give 15b (0.31 g, 78%) as a colorless powder: 1H-
NMR (CDCl3) d: 2.52 (3H, s), 2.63 (3H, s), 7.28 (1H, t, Jꢃ5 Hz), 8.78 (2H,
d, Jꢃ5 Hz), 9.02 (1H, s).
3-[4-(3-Chlorophenyl)-1-piperazinyl]-1-[1-(2-pyrimidinyl)-4-1H-pyra-
zolyl]-1-propene Hydrochloride (17a) Synthesis of 17a—d from 16a—d
was performed as described for the synthesis of 9a. The physical data for
17a—d are shown in Table 7.
4-Ethoxycarbonyl-5-methyl-1-(2-pyrimidinyl)imidazole
(19) The
mixture of ethyl 4-methyl-5-imidazolecarboxylate (18, 20 g, 0.13 mmol),
K2CO3 (18 g, 0.13 mol), and 2-chloropyrimidine (15 g, 0.13 mmol) in DMF
(132 ml) was stirred at 100 °C for 6 h. The reaction mixture was
filtered through a Celite pad, and the filtrate was evaporated to afford the
crude mixture, which was chromatographed on a silica gel column
(CHCl3/MeOHꢃ98/2) to give 19 (22 g, 73%) as a brown amorphous solid:
1H-NMR (CDCl3) d: 1.43 (3H, t, Jꢃ7 Hz), 2.93 (3H, s), 4.41 (2H, q,
Jꢃ7 Hz), 7.31 (1H, t, Jꢃ5 Hz), 8.50 (1H, s), 8.77 (2H, d, Jꢃ5 Hz).
3-Acetyl-2-methyl-1-(2-pyrimidinyl)pyrrole (15d) Compound 1414,15)
(0.92 g, 7.5 mmol) was added to a suspension of KOH (2.0 g, 30 mmol) in
DMSO (15 ml), and the reaction mixture was stirred at room temperature for
1 h. 2-Chloropyrimidine (1.0 g, 9.0 mmol) was added to the above reaction
mixture, and the mixture was stirred for 20 h at room temperature. The reac-
tion mixture was diluted with ice-water and the whole was extracted with
4-Formyl-5-methyl-1-(2-pyrimidinyl)imidazole (20)
A solution of
DIBAL (31 ml of a 1.0 M solution in hexane, 31 mmol) was added dropwise
AcOEt. The organic layer was washed with brine and dried. After filtration to a solution of 19 (4.7 g, 20 mmol) in anhydrous CH2Cl2 (50 ml) and THF
and evaporation of the solvents, the crude mixture was chromatographed on
(50 ml) at ꢄ78 °C, and the mixture was stirred for 2.5 h at ꢄ78 °C. The reac-
a silica gel column (hexane/AcOEtꢃ2/1) to afford 15d (1.2 g, 80%) as a col-
orless powder: H-NMR (CDCl3) d: 2.47 (3H, s), 2.96 (3H, s), 6.62 (1H, d, was extracted with CHCl3. The organic layer was washed with brine and
Jꢃ3 Hz), 7.20 (1H, t, Jꢃ5 Hz), 7.58 (1H, d, Jꢃ3 Hz), 8.73 (2H, d, Jꢃ5 Hz).
3-[4-(3-Chlorophenyl)-1-piperazinyl]-1-[1-(2-pyrimidinyl)-4-1H-pyra- tallized from ether to give 20 (3.0 g, 80%) as a colorless powder: H-NMR
zolyl]-1-propanone (16a) Mannich reaction of 16a—d from 15a—d with (CDCl3) d: 2.99 (3H, s), 7.34 (1H, t, Jꢃ5 Hz), 8.57 (1H, s), 8.79 (2H, d,
7a, c was performed as described for the synthesis of 8a. The physical data Jꢃ5 Hz), 10.08 (1H, s).
tion mixture was poured into 1 N aqueous hydrochloric acid, and the whole
1
dried. After filtration and evaporation of the solvents, the residue was crys-
1
for 16a—d are shown in Table 6.
2-[5-Methyl-4-[1-[(triethylsilyl)oxy]-3-butenyl]-1-1H-imidazolyl]-

160
Vol. 53, No. 2
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February 2005
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d

162
Vol. 53, No. 2
pyrimidine (21) Allyl bromide (4.9 ml, 57 mmol) and metallic tin (2.2 g,
19 mmol) were added to a solution of 20 (3.0 g, 16 mmol) in THF (50 ml)
and water (50 ml), and the mixture was sonicated for 2.5 h in an ultrasonic
cleaning bath (Pasolina USC-1). The reaction mixture was carefully
quenched with 1 N aqueous HCl (200 ml) at 0 °C, diluted with CHCl3/MeOH
6.0 mmol) and bis(2-chloroethyl)amine hydrochloride (1.1 g, 6.1 mmol) in n-
BuOH (15 ml) was refluxed for 45 h. Anhydrous sodium carbonate (0.83 g,
6.0 mmol) was added to the mixture. After being stirred for 26 h, the reac-
tion mixture was diluted with CHCl3, successively washed with 1 N aqueous
NaOH, water, and brine, and then dried. Evaporation of the solvents afforded
(95/5), washed with brine, and dried. After removal of the solvents, the the crude mixture, which was chromatographed on a silica gel column
residue was chromatographed on a silica gel column (CHCl3/MeOHꢃ98/2) (CHCl3/MeOHꢃ20/1) to give 27a (0.53 g, 28%) as an orange oil. Com-
1
to give the alcohol (2.8 g, 77%) as a colorless amorphous solid: H-NMR pounds 25b—d were treated in the same manner as described above to give
(CDCl3) d: 2.5—2.8 (2H, m), 2.59 (3H, s), 4.75 (1H, dd, Jꢃ13, 7 Hz), 5.09
(1H, dd, Jꢃ10, 1 Hz), 5.16 (1H, dd, Jꢃ16, 1 Hz), 5.83 (1H, ddt, Jꢃ16, 10,
7 Hz), 7.21 (1H, t, Jꢃ5 Hz), 8.51 (1H, s), 8.71 (2H, d, Jꢃ5 Hz).
27b—d, respectively.
27a: Yield 28%, an orange oil. H-NMR (CDCl3) d: 3.0—3.1 (4H, m),
3.1—3.2 (4H, m), 6.52 (1H, dd, Jꢃ12, 2 Hz), 6.87 (1H, dd, Jꢃ7, 2 Hz),
1
Imidazole (1.5 g, 22 mmol) and chlorotetraethylsilane (3.7 ml, 22 mmol) 6.9—7.0 (1H, m).
were added successively to a solution of the above alcohol (1.7 g, 7.3 mmol)
in anhydrous DMF (10 ml) at 0 °C, and the mixture was stirred for 3.5 h at
room temperature. Water (30 ml) was added to the mixture, and the whole
was extracted with AcOEt. The organic layer was washed with brine and
dried. After removal of the solvents, the residue was chromatographed on a
27b: Yield 23%, a pale yellow oil. 1H-NMR (CDCl3) d: 3.0—3.1 (4H, m),
3.1—3.2 (4H, m), 6.75 (1H, d, Jꢃ2 Hz), 6.7—6.8 (1H, m), 6.9—7.0 (1H,
m).
27c: Yield 19%, a pale yellow powder. 1H-NMR (CDCl3) d: 3.00 (4H, dd,
Jꢃ5, 3 Hz), 3.14 (4H, dd, Jꢃ5, 3 Hz), 6.50 (1H, dt, Jꢃ12, 2 Hz), 6.68 (1H,
silica gel column (CHCl3/MeOHꢃ99/1) to afford 13 (2.9 g, quantitative dt, Jꢃ8, 2 Hz), 6.79 (1H, s).
yield) as a pale yellow oil: 1H-NMR (CDCl3) d: 0.5—0.6 (6H, m), 0.8—1.0
(9H, m), 2.5—2.7 (2H, m), 2.62 (3H, s),4.79 (1H, t, Jꢃ7 Hz), 4.99 (1H, dt,
Jꢃ10 Hz), 5.06 (1H, d, Jꢃ17 Hz), 5.79 (1H, ddt, Jꢃ17, 10, 7 Hz), 7.19 (1H,
t, Jꢃ5 Hz), 8.46 (1H, s), 8.70 (2H, d, Jꢃ5 Hz).
27d: Yield 30%, a pale yellow oil. 1H-NMR (CDCl3) d: 3.0—3.1 (4H, m),
3.2—3.3 (4H, m), 6.71 (1H, dd, Jꢃ12, 2 Hz), 6.74 (1H, dd, Jꢃ10, 2 Hz),
6.8—6.9 (1H, m).
1-(3-Chloro-5-fluorophenyl)piperazine (27e) Piperazine (25 g, 0.29
3-[5-Methyl-1-(2-pyrimidinyl)-4-1H-imidazolyl]-3-[(triethyl- mol), dichlorobis(tri-o-tolylphosphine)palladium (1.7 g, 2.2 mmol), and
silyl)oxy]propanal (22) 4-Methylmorpholine N-oxide (NMO, 1.3 g, 11 sodium tert-butoxide (9.6 g, 0.10 mol) were added to a solution of 1-bromo-
mmol) and a catalytic amount of osmium tetraoxide were added to a 3-chloro-5-fluorobenzene (26, 15 g, 72 mmol) in toluene (350 ml), and the
solution of 21 (1.9 g, 5.6 mmol) in THF (25 ml) and water (3.0 ml), and the
mixture was stirred at room temperature for 4 h. A suspension of sodium pe-
riodate (5.9 g, 28 mmol) in water (25 ml) was added to the above mixture at
room temperature, and the mixture was stirred at the same temperature for to afford 27e (5.7 g, 37%) as a pale yellow oil: H-NMR (CDCl3) d: 2.8—
2 h. The mixture was diluted with CHCl3, washed with brine, and dried.
After removal of the solvents, the residue was chromatographed on a silica
mixture was stirred at 100 °C for 38 h. The reaction mixture was washed
with water and brine, and dried. After removal of the solvents, the crude
mixture was chromatographed on a silica gel column (CHCl3/MeOHꢃ93/7)
1
3.2 (4H, m), 3.0—3.3 (4H, m), 6.46 (1H, dt, Jꢃ12, 2 Hz), 6.53 (1H, dt, Jꢃ8,
2 Hz), 6.6—6.7 (1H, m).
gel column (CHCl3/MeOHꢃ99/1) to give 22 (0.23 g, 12%) as a pale yellow
oil: H-NMR (CDCl3) d: 0.5—0.6 (6H, m), 0.9—1.0 (9H, m), 2.64 (3H, s), idinyl)-4-(1H)-pyrazolyl]-1-propanone (28a) Synthesis of 28a—e from
2.87 (1H, ddd, Jꢃ16, 5, 2 Hz), 3.07 (1H, ddd, Jꢃ16, 8, 2 Hz), 5.31 (1H, dd, 27a—e with 13 was performed as described for the synthesis of 8a. The
3-[4-(3-Fluoro-5-iodophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrim-
1
Jꢃ8, 5 Hz), 7.22 (1H, t, Jꢃ5 Hz), 8.48 (1H, s), 8.71 (2H, d, Jꢃ5 Hz), 9.86
(1H, t, Jꢃ2 Hz).
3-[4-(3,5-Difluorophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrimidin-
physical data for 28a—e are shown in Table 6.
3-[4-(3-Fluoro-5-iodophenyl)-1-piperazinyl]-1-[5-methyl-1-(2-pyrim-
idinyl)-4-(1H)-pyrazolyl]-1-trans-propene Hydrochloride (29a) Synthe-
yl)-4-1H-imidazolyl]-1-trans-propene Hydrochloride (23) AcOH (15 ml, sis of 29a—e from 28a—e was performed as described for the synthesis of
1.3 mmol) and sodium cyanoborohydride (82 mg, 1.3 mmol) were added
successively to a solution of 22 (89 mg, 0.26 mmol) and 7b (0.25 g,
1.3 mmol) in EtOH (10 ml), and the mixture was stirred at room temperature
9a. The physical data for 29a—e are shown in Table 7.
In Vitro Cytotoxicity To examine the direct growth-inhibitory effects of
the test compounds against PC-6 and PC-12 human non-small cell lung can-
for 0.5 h. The reaction mixture was diluted with CHCl3, washed with satu- cer cell lines and resistant cell lines,19) the 3-(4,5-dimethylthiazol-2-yl)-2,5-
rated aqueous NaHCO3 and brine, and dried. After removal of the solvents, diphenyltetrazolium bromide (MTT) assay was performed, and the concen-
the crude mixture was chromatographed on
a
silica gel column
tration giving a growth inhibition of 50% (GI50) was calculated according to
(CHCl3/MeOHꢃ100/3) to afford the propene. An appropriate volume of a a published procedure.22)
solution of 1 N HCl/EtOH was added to a solution of the propene in a small
amount of EtOH, and the solvent was removed. The residue was recrystal-
Evaluation of Therapeutic Effect in Vivo Meth A murine fibrosar-
coma cells (1ꢁ106) were implanted into the right flank of BALB/c mice
lized from EtOH to give 23 (28 mg, 27%) as a colorless powder. The physi- (day 0). Compounds were administered p.o. on days 7—11, consecutively.
cal data for 23 are shown in Table 7. Tumor weights were measured on day 17. Human non-small cell lung cancer
1-Cyano-3-fluoro-5-nitrobenzene (24b) CuCN (5.0 g, 56 mmol) was PC-12 and PC-14 blocks were inoculated s.c. into BALB/cAnNCrj-nu mice
added to a solution of 1-fluoro-3-iodo-5-nitrobenzene (24a, 15 g, 56 mmol)
in DMF (120 ml), and the mixture was heated to reflux for 3 h. The mixture
was diluted with ether, successively washed with 1 N aqueous HCl, water,
and brine, and then dried. Evaporation of the solvents afforded the crude
(day 0). Compounds at the indicated doses were administered per os (oral)
administration (p.o.) on days 11—14 and 17—20, or on days 14—17 and
21—24. VCR was administrated i.v. on day 11 or 14, once. The tumor
growth-inhibition rate (IR) was calculated by the formula: IR
(%)ꢃ(1ꢄTWt/TWc)ꢁ100 (%), where TWt represents the mean tumor
weight of a treated group, and TWc represents that of the control group. To
evaluate the intensity of the side effects of the compounds, the rate of body
weight loss (BWL) was utilized as a parameter of toxicity. The maximum
value of BWL was designated as BWLmax, and a BWLmax of less than
zero indicates no body weight loss.
mixture, which was chromatographed on
a
silica gel column
1
(hexane/AcOEtꢃ50/3) to give 24b (8.0 g, 86%) as a pale yellow oil: H-
NMR (CDCl3) d: 7.73 (1H, dd, Jꢃ7, 2 Hz), 8.21 (1H, dt, Jꢃ8, 2 Hz), 8.3—
8.4 (1H, m).
3-Fluoro-5-iodoaniline (25a) The suspension of 1-fluoro-3-iodo-5-ni-
trobenzene (24a, 2.0 g, 7.5 mmol) and SnCl2·2H2O (6.0 g, 26 mmol) in
EtOH (30 ml) was heated to reflux for 1.5 h. After removal of the solvent,
the crude mixture was diluted with ether, washed with 4 N aqueous NaOH
and brine, and dried. Evaporation of the solvents afforded the crude mixture,
which was chromatographed on a silica gel column (hexane/AcOEtꢃ9/1) to
References and Notes
1) Naito H., Sugimori M., Mitsui I., Nakamura Y., Ishii M., Iwahana M.,
Hirotani K., Kumazawa E., Ejima A., Chem. Pharm. Bull., 47, 1679—
1684 (1999).
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3) Compounds 5a, b, e, f, g, and i were commercially available.
4) The synthesis of 5c; Spingarn N. E., Sartorelli A. C., J. Med. Chem.,
22, 1314—1316 (1979).
5) The synthesis of 5d; Lee A. L., Mackay D., Manery E. L., Can. J.
Chem., 48, 3554—3562 (1970).
1
give 25a (8.0 g, 86%) as an orange oil: H-NMR (CDCl3) d: 3.7—3.8 (2H,
m), 6.32 (1H, dt, Jꢃ11, 2Hz), 6.7—6.9 (1H, m), 6.9—7.0 (1H, m).
3-Cyano-5-fluoroaniline (25b) Compound 24b (14 g, 85 mmol) was
dissolved in EtOH (850 ml) and hydrogenated with 10% Pd/C (5.0 g) under
H2 atmosphere for 2 h at room temperature. The reaction mixture was fil-
tered through a Celite pad and the filtrate was evaporated to afford the
crude mixture, which was chromatographed on a silica gel column
(hexane/AcOEtꢃ4/1) to give 25b (8.5 g, 74%) as a pale yellow oil: 1H-NMR
(CDCl3) d: 4.0—4.1 (2H, m), 6.56 (1H, dt, Jꢃ10, 2 Hz), 6.6—6.7 (2H, m).
1-(3-Fluoro-5-iodophenyl)piperazine (27a) A mixture of 25a (1.4 g,
6) The synthesis of 5h; Fleet G. W. J., Fleming I., J. Chem. Soc. C, 1969,

February 2005
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163
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