Facile synthesis of novel tacrine analogues

Article abstract of DOI:10.3184/030823409X12511057064685

The synthesis of highly potent and selective acetylcholinesterase inhibitors, tacrine analogues with the structure of fused 4-aminoquinolines and 4-aminopyridines, has been accomplished by direct cyclocondensation of 1-aryl-4- cyano-5-aminopyrazoles with

Full text of DOI:10.3184/030823409X12511057064685

562 RESEARCH PAPER
SEPTEMBER, 562–564
JOURNAL OF CHEMICAL RESEARCH 2009
Facile synthesis of novel tacrine analogues
Huanan Hua*, Anjiang Zhangb and Lisheng Dingc
aCollege of Pharmaceutial and Chemical Engineering, Taizhou University, Linhai 317000, P.R. China
bNingbo Institute of Material Technology and Engineering, Chinese Academy of Sciences, Ningbo 315211, P.R. China
cChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P.R. China
The synthesis of highly potent and selective acetylcholinesterase inhibitors, tacrine analogues with the structure
of fused 4-aminoquinolines and 4-aminopyridines, has been accomplished by direct cyclocondensation of 1-aryl-4-
cyano-5-aminopyrazoles with cyclic ketones using tin(IV) chloride as catalyst.
Keywords: tacrine, pyrazoles, 4-aminoquinolines, 4-aminopyridines, tin(IV) chloride
Alzheimer's disease (AD), the most common form of
dementia among the elderly, is a progressive degenerative
disorder of the brain with loss of memory and cognition.1
The social and economic consequences of AD are alarming
due to the notable increase in life expectancy. Tacrine is a
reversible inhibitor of acetylcholinesterase (AChE) that was
launched in 1993 as the first drug for the treatment of AD.2
In the evaluation of the clinical effects of tacrine, it has shown
efficacy in delaying the deterioration of the symptoms of AD,
but the poor selectivity of this drug for AChE resulted in a
number of side effects, especially hepatotoxicity,3 and current
research is focused on developing new AChE inhibitors with
improved activity and reduced adverse side effects. Research
has therefore been concentrated on the development of novel
tacrine analogues.4–19
The main synthetic approach to tacrine analogues is through
the cyclocondensation of o-aminonitrile derivatives with cyclic
ketones using anhydrous AlCl3 as catalyst, but that method
leads to yields which are low to moderate. We report here the
cyclocondensation of 1-aryl-4-cyano-5-aminopyrazole with
cyclic ketones using SnCl4 as catalyst, whereby a series of
novel tacrine analogues 3 is generated, in good yields.
Table 1 Effect of the catalyst on the yieldsa
Entry
Catalyst
Yield/%b
1
2
3
4
5
6
CuCl
CuCl2
AlCl3
ZnCl2
TiCl4
0
0
30
21
32
82
SnCl4
aAll reactions were carried out using 1a (10 mmol), cyclo-
hexanone (10 mmol), catalyst (20 mmol) and toluene (20 mL),
refluxing for 3 h.
bIsolated yields.
After worked up, the product 3a was obtained in 82% yield
(Table 1). In contrast to the above results, we have found
that SnCl4 is the best effective catalyst for the preparation of
tacrine analogues 3a.
In addition, a profound solvent effect on the reaction was
observed. We initially studied the effect of non-polar solvents
in the reaction, such as DCM, DCE, THF and toluene, in
which SnCl4 is easy to dissolve. And then we went on to
study the polar solvent DMF. The results are summarised in
Table 2. These results suggested that the solvents used have
dramatic effects on the yields. Toluene was found to be the
best solvent.
Results and discussion
For the investigation of reaction conditions for
cyclocondensation of 1-aryl-4- cyano-5-aminopyrazole with
cycloketones, we chose the protocol of 1-phenyl-4-cyano-5-
aminopyrazole (1a) with cyclohexanone as a model reaction.
Because the choice of the catalyst played a crucial role,
we initially studied the effect of several catalysts on the
yields, and we found the use of anhydrous AlCl3, ZnCl2 and
TiCl4 was much less effective, and tacrine analogue 3a was
obtained in less than 35% yield, and the product 3a was not
obtained when we used CuCl and CuCl2 as catalysts. When
a mixture of 1-phenyl-4-cyano-5-aminopyrazole 1a and
cyclohexanone in toluene was stirred under reflux in the
presence of SnCl4, the reaction was completed within 3 h.
Table 2 Effect of the solvent on the yieldsa
Entry
Solvent
Yield/%b
1
2
3
4
5
DCM
DCE
56
67
53
82
0
THF
Toluene
DMF
aAll reactions were carried out using 1a (10 mmol),
cyclohexanone (10 mmol), SnCl4 (20 mmol) and solvent
(20 mL), refluxing for 3 h.
bIsolated yields.
NH2
CN
O
N
N
SnCl4
NH2
N
N
N
n
+
toluene
n
R
R
2
3
1
Scheme 1
* Correspondent. E-mail: hhn12192000@yahoo.com.cn

JOURNAL OF CHEMICAL RESEARCH 2009 563
Typical procedure
Table
3
Cyclocondensation of 5-amino-1-arylpyrazole-4-
5-Amino-1-phenylpyrazole-4-carbonitrile 1 (10 mmol) and SnCl4
(2.3 mL, 20 mmol) were added to a stirred solution of cyclohexanone
or cyclopentanone (10 mmol) in dry toluene (20 mL). The mixture
was stirred under nitrogen at room temperature for 30 min and then
heated under reflux for 3 h. The reaction mixture was cooled and
dispersed into water and adjusted to pH 12–13 with saturated aqueous
Na2CO3. After filtration, the filtrate was extracted three times with
ethyl acetate, the organic layers were dried and evaporated under
reduced pressure to give the solid product. The product was purified
by silica gel column chromatography eluting with ethyl acetate/
petroleum (1:3 v:v) to give 3a–j.
1-Phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-4-amine
(3a): Colourless solid; m.p. 186–187°C. IR (KBr): nmax 3480, 3373,
2934, 2863, 1596, 1490, 1455, 1398, 1350 cm-1. NMR (CDCl3):
dH 8.29–8.32 (m, 2H), 7.98 (s, 1H), 7.44–7.50 (m, 2H), 7.21–7.26
(m, 1H), 4.60 (br, 2H), 2.98 (t, J = 6.4 Hz, 2H), 2.50 (t, J = 5.2 Hz,
2H), 1.89 (m, 4H); dC 158.5, 150.1, 144.8, 140.1, 130.4, 128.8,
125.2, 120.8, 107.6, 105.5, 34.2, 22.9, 22.8. MS-ESI (m/z, relative
intensity,%): 266 (M+ + 3) (1.8), 265 (M+ + 2) (18), 264 (M+ + 1)
(100). Anal. Calcd for C16H16N4: C, 72.70; H, 6.10; N, 21.20. Found:
C, 72.91; H, 6.28; N, 21.07%.
1-p-Tolyl-5, 6, 7, 8-tetrahydro-1H-pyrazolo[3, 4-b]quinolin-4-
amine (3b): Colourless solid; m.p. 177–178°C. IR (KBr): nmax 3480,
3377, 3250, 2975, 2933, 2864, 1596, 1494, 1453, 1390, 1352 cm-1.
NMR (CDCl3): dH 8.21 (d, J = 8.4 Hz, 2H), 7.98 (s, 1H), 7.29 (m,
2H), 4.55 (br, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H),
2.38 (s, 3H), 1.90 (m, 4H); dC 158.1, 149.5, 144.4, 137.2, 134.6,
129.6, 129.0, 120.6, 107.0, 104.9, 33.7, 22.5, 22.4, 20.6. MS-ESI
(m/z, relative intensity,%): 281 (M+ + 3) (3), 280 (M+ + 2) (20), 279
(M+ + 1) (100). Anal. Calcd for C17H18N4: C, 73.35; H, 6.52; N,
20.13. Found: C, 73.54; H, 6.39; N, 19.97%.
1-m-Tolyl-5, 6, 7, 8-tetrahydro-1H-pyrazolo[3, 4-b]quinolin-4-amine
(3c): Colourless solid; m.p. 171–172°C. IR (KBr): nmax 3480, 3375,
3246, 2973, 2936, 2862, 1595, 1490, 1457, 1393, 1350 cm-1. NMR
(CDCl3): dH 8.15 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.36 (t,
J = 7.8 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 4.56 (br, 2H), 2.98 (t, J = 5.1
Hz, 2H), 2.55 (t, J = 8.1 Hz, 2H), 2.44 (s, 3H), 1.90 (m, 4H); dC 158.4,
149.8, 144.5, 137.8, 134.6, 129.6, 129.5, 125.0, 120.6, 115.6, 107.0,
104.9, 34.0, 22.8, 22.6, 20.9. MS-ESI (m/z, relative intensity,%): 302
(7), 301 (32), 299 (M+ + 1) (100). MS-ESI (m/z, relative intensity,%):
281 (M+ + 3) (4), 280 (M+ + 2) (21), 279 (M+ + 1) (100). Anal. Calcd
for C17H18N4: C, 73.35; H, 6.52; N, 20.13. Found: C, 73.46; H, 6.72;
N, 19.96%.
carbonitriles and cyclic ketones (Scheme 1)
R
n
Product
Yield/%a
H
1
1
1
1
1
0
0
0
0
0
3a
3b
3c
3d
3e
3f
82
80
76
81
78
80
77
73
79
75
4-CH3
3-CH3
4-Cl
3-Cl
H
4-CH3
3-CH3
4-Cl
3-Cl
3g
3h
3i
3j
aIsolated yields.
Under the optimised reaction conditions, with SnCl4 as catalyst
and anhydrous toluene as solvent, reflux for 3 h, a series of
5-amino-1-arylpyrazole-4-carbonitriles and cyclic ketones
were tested and a series of tacrine analogues 3 was thereby
prepared in good yields regardless of whether the R group was
attached at the 3- or the 4-position in the aryl group. Possibly
cyclohexanone is sterically more flexible than cyclopentanone,
so the yields of 3a–e were higher than those of 3f–j when
cyclohexanone was used instead of cyclopentanone for the
reaction. The results are summarised in Table 3.
The mechanism of formation of the tacrine analogues 3 can
be explained by Scheme 2. The attack of the amino group of
1 onto the carbonyl carbon atom of 2 gave intermediate 4, and
product 3 was obtained through Friedlander reaction.
In conclusion: we have developed an efficient catalyst
system for the condensation of pyrazole o-aminonitriles with
cycloketones using SnCl4 in anhydrous toluene. A facile
synthesis of highly potent and selective acetylcholinesterase
(AChE) inhibitors, tacrine analogues 3a–j, was thereby
accomplished. In contrast to previous reports, this method
requires simple manipulation and provides good yields in
short reaction times.
1-(4-Chlorophenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-
4-amine (3d): Colourless solid; m.p. 189–190°C. IR (KBr): nmax 3480,
3376, 3248, 2936, 2866, 1596, 1495, 1454, 1398, 1353 cm-1. NMR
(CDCl3): dH 8.35 (d, J = 4.8 Hz, 2H), 7.99 (s, 1H), 7.44 (m, 2H), 4.57
(br, 2H), 2.98 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.3 Hz, 2H), 1.91 (m, 4H);
dC 158.7, 150.1, 144.7, 140.8, 130.8, 129.8, 125.0, 120.4, 108.0, 105.5,
34.2, 22.8, 22.7. MS-ESI (m/z, relative intensity,%): 302 (7), 301 (31),
299 (M+ + 1) (100). Anal. Calcd for C16H15ClN4: C, 64.32; H, 5.06; N,
18.75. Found: C, 64.25; H, 5.21; N, 19.20%.
1-(3-Chlorophenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolin-
4-amine(3e):Colourlesssolid;m.p. 196–197cm-1. IR(KBr):nmax 3480,
3376, 3247, 2935, 2864, 1596, 1495, 1454, 1398, 1353 cm-1. NMR
(CDCl3): dH 8.45 (d, J = 2.1 Hz, 1H), 8.33 (m, 1H), 8.00 (s, 1H), 7.39
Experimental
All melting points were determined on an XT-4A apparatus. TLC
was performed using precoated silica gel GF254 (0.25 mm), and
column chromatography using silica gel (200–300 mesh). The 1H
and 13C NMR spectra were measured at 25°C at 300 and 75 MHz,
respectively, on a Bruker Avance 300 spectrometer, using TMS as
internal standard. J values are given in Hz, chemical shifts (d values)
in ppm. The MS spectra were recorded on a Finnigan DECAX-30000
LCQ DecaXP plus instrument. The IR spectra were taken on a Bruker
Vector 55 spectrometer. Elemental analyses were obtained using an
EA 1112 elemental analyser. 5-Amino-1-arylpyrazole-4-carbonitriles
1 were prepared according to the procedures reported.20
CN
CN
CN
O
HO
..
NH2
N
N
N
N
N
N
H
N
N
Ar
1
Ar
Ar
SnCl4
2
4
N:SnCl4
NH
NH2
C
H
N
..
N
N
N
N
H
N
N
N
N
Ar
Ar
Ar
3
Scheme 2 Proposed mechanism for tacrine analogue synthesis

564 JOURNAL OF CHEMICAL RESEARCH 2009
(t, J = 8.1 Hz, 1H), 7.18 (m, 1H), 4.58 (br, 2H), 2.99 (t, J = 5.7 Hz, 2H),
2.55 (d, J = 6.0 Hz, 2H), 1.91 (m, 4H); dC 158.8, 150.3, 144.8, 141.2,
134.5, 130.8, 129.8, 124.9, 120.4, 118.3, 108.0, 105.6, 34.1, 22.8, 22.7.
MS-ESI (m/z, relative intensity,%): 302 (6), 301 (30), 299 (M+ + 1)
(100). Anal. Calcd for C16H15ClN4: C, 64.32; H, 5.06; N, 18.75. Found:
C, 65.13; H, 5.19; N, 18.67%.
1-Phenyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[3,4-e]pyridin-
4-amine (3f): Colourless solid; m.p. 201–202°C. IR (KBr): nmax
3480, 3375, 3248, 2935, 1591, 1495, 1452, 1398, 1352 cm-1. NMR
(CDCl3): dH 8.24 (d, J = 7.8 Hz, 2H), 7.99 (s, 1H), 7.48 (t, J = 7.8
Hz, 2H), 7.27(m, 1H), 4.53 (br, 2H), 3.06 (t, J = 7.5 Hz, 2H), 2.78 (t,
J = 7.5 Hz, 2H), 2.20 (m, 2H); dC 167.9, 152.5, 142.6, 139.9, 130.5,
128.9, 125.5, 121.3, 112.3, 105.9, 34.9, 26.3, 23.1. MS-ESI (m/z,
relative intensity,%): 252 (M+ + 3) (1.5), 251 (17) (18), 250 (M+ + 1)
(100). Anal. Calcd for C15H14N4: C, 71.98; H, 5.64; N, 22.38. Found:
C, 72.20; H, 5.77; N, 22.15%.
1-p-Tolyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[3,4-e]pyridin-
4-amine (3g): Colourless solid; m.p. 268–270°C. IR (KBr): nmax
3480, 3375, 3246, 2975, 2934, 1590, 1495, 1454, 1397, 1353 m-1.
NMR (CDCl3): dH 8.10 (d, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.33 (m,
2H), 4.55 (br, 2H), 3.05 (t, J = 7.5 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H),
2.38 (s, 3H), 2.20 (m, 2H); dC 167.9, 152.5, 142.6, 139.9, 130.5,
128.9, 125.5, 121.3, 112.3, 105.9, 34.9, 26.3, 23.1, 21.1. MS-ESI
(m/z, relative intensity,%): 267 (M+ + 3) (1.5), 266 (M+ + 2) (18),
265 (M+ + 1) (100). Anal. Calcd for C16H16N4: C, 72.70; H, 6.10; N,
21.20. Found: C, 72.53; H, 6.21; N, 21.09%.
1-m-Tolyl-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[3,4-e]pyridin-
4-amine (3h): Colourless solid; m.p. 225–227°C. IR (KBr):
nmax 3480, 3376, 3241, 2972, 2930, 1596, 1492, 1450, 1396, 1353
cm-1. NMR (CDCl3): dH 8.06 (d, J = 6.0 Hz, 2H), 7.99 (s, 1H), 7.37 (t,
J=8.4Hz, 1H), 7.08(t, J=7.5Hz, 1H), 4.50(br, 2H), 3.07(t, J=7.5Hz,
2H), 2.77 (t, J = 7.5 Hz, 2H), 2.44 (s, 3H), 2.21 (m, 2H); dC 167.8,
142.5, 138.7, 131.4, 130.2, 129.5, 128.7, 126.4, 121.9, 118.1, 112.4,
106.7, 34.8, 26.3, 23.1, 21.2. MS-ESI (m/z, relative intensity,%): 267
(M+ + 3) (1.5), 266 (M+ + 2) (20), 265 (M+ + 1) (100). Anal. Calcd
for C16H16N4: C, 72.70; H, 6.10; N, 21.20. Found: C, 72.64; H, 6.22;
N, 21.17%.
134.5, 130.9, 129.9, 125.3, 120.9, 118.8, 112.9, 106.0, 34.9, 26.3,
23.1. MS-ESI (m/z, relative intensity,%): 288 (5), 287 (34), 285
(M+ + 1) (100). Anal. Calcd for C15H13ClN4: C, 63.27; H, 4.60; N,
19.68. Found: C, 63.37; H, 4.74; N, 19.62%.
Received 24 March 2009; accepted 17 August 2009
Paper 09/0508 doi: 10.3184/030823409X12511057064685
Published online: 8 September 2009
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