A facile synthesis of bis-tacrine isosteres

Article abstract of DOI:10.1016/S0040-4039(00)00036-8

An efficient synthesis of highly potent and selective acetylcholinesterase (AChE) inhibitors, bis-tacrines and their isosteres 2-4, has been accomplished by bis-amination of 9-chloro-tetrahydroacridine (9a) and its analogs. The critical intermediates were concisely prepared in situ by heating the corresponding ortho-amino aromatic acids and cycloketones in the presence of phosphorus oxychloride. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00036-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1815–1818
A facile synthesis of bis-tacrine isosteres
∗
Ming-Kuan Hu and Chih-Feng Lu
School of Pharmacy, National Defense Medical Center, PO Box 90048-508, Taipei, Taiwan 100, Republic of China
Received 11 November 1999; accepted 24 December 1999
Abstract
An efficient synthesis of highly potent and selective acetylcholinesterase (AChE) inhibitors, bis-tacrines and
their isosteres 2–4, has been accomplished by bis-amination of 9-chloro-tetrahydroacridine (9a) and its analogs.
The critical intermediates were concisely prepared in situ by heating the corresponding ortho-amino aromatic acids
and cycloketones in the presence of phosphorus oxychloride. © 2000 Elsevier Science Ltd. All rights reserved.
Alzheimer’s disease is critical and may be life threatening for humans, especially the elderly. Demo-
1
graphic data indicate that the percentage of the elderly in the population is increasing. Therefore, much
attention has recently been paid to the treatment of Alzheimer’s disease. Tacrine (1, tetrahydroaminoacri-
2
dine or THA), is currently one of the major approved drugs for use in Alzheimer’s disease. It functions
as an acetylcholinesterase (AChE) inhibitor for treating the disease. However, there are considerable
debates over some drawbacks of tacrine due to its many actions in the CNS and its serious toxicity.3
Therefore, it is very important to design and develop more selective inhibitors of AChE as opposed to
4
tacrine.
Very recently, a series of bis-tacrines (e.g. 3b,c) were reported as highly potent and selective inhibitors
5
of AChE. These compounds were up to 10 000-fold more selective and 1000-fold more potent than
tacrine in inhibiting rat AChE. As a part of our program aimed at developing suitable prodrugs and
derivatives of tacrine, we are interested in the development of an efficient procedure for preparation of
9-chlorotetrahydroacridine (9a) and its isosteres as critical intermediates toward a series of bis-tacrine
analogs. In this paper, we report the results of our work in detail.
Sargent and others have reported the synthesis of 9a from chlorination of the corresponding tetrahy-
droacridone, which was obtained according to Tiedtke by treatment of anthranilic acid (6a) and cyclohex-
6
anone (7b) under Dean–Stark conditions. Here, we disclose that 9a could be concisely synthesized with
high efficiency (94% yield) by directly heating the mixture of 6a and 7b in POCl without isolation of
3
7
dehydrated adduct or tetrahydroacridone (Table 1). The method was applied to furnish the corresponding
chloride isosteres 8–10 by direct condensation of acids 6a–d and cycloketones 7a–c. When reacting with
cycloketones, acids 6a,c showed higher transformations to give 8a, 9a, and 9c whereas isosteric acid
∗
Corresponding author. E-mail: hmk@ndmctsgh.edu.tw (M.-K. Hu)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00036-8
tetl 16316

1
816
6b resulted in decreased yields (54–67%) of 8b, 9d, and 10b. The electron-withdrawing effect from
the pyridyl ring of 6b was supposed to be responsible for the reduced nucleophilicity of the amino
group and resulted in lower yields. The successful one-pot reactions were thought to proceed via rapid
dehydration followed by cyclization and chlorosubstitution in situ in the presence of the chlorinating
agent. Compared with the method previously described, this discovery provided a quite simple way
toward the synthesis of isosteres of chloride 9a, which could be economically utilized to prepare tacrine
6
c,8
and its related derivatives.
Table 1
Preparation of chlorides 8–10 from acids and cycloketones
Although Pang and co-workers reported the synthesis of bis-tacrines beginning with tacrine itself,5a
this method proved to be much less reproducible after numerous attempts by variation of the base,
reaction temperature, concentration, and solvent. In fact, Michalson and co-workers have reported similar
difficulties when preparing 9-(1-azetidinyl)-tetrahydroacridine by using tacrine and 1,3-diiodopropane.9
These results implied that the amino group of tacrine is apparently quite unreactive as a nucleophile. An
alternative method might be considered toward the synthesis of a series of bis-tacrine analogs.
It has been reported that most alkyl derivatives of tacrine can be made by heating 9a with appropriate
6
a,8
amines either in sealed tubes or in phenol.
The similar fashion was therefore optimized here to prepare
bis-tacrines and their isosteres. First, heating the mixture of 9a and 1,7-diaminoheptane (5b, 0.5 equiv.)
in the presence of phenol and catalytic amounts of sodium iodide at 100°C only gave the mono-aminated
product, 9-(7-aminoheptylamino)-tetrahydroacridine (11), in 38% yield accompanied by unreacted 9a
after silica gel chromatography. Extending the reaction time to 6 h or increasing the amount of sodium
iodide did not drive the second amination for 5b. These results proved the fact that the chlorine atom in 9a
1
0
is rather less reactive than that in corresponding fused aromatic ring systems such as 9-chloroacridine.
Noting the previous report for the preparation of alkyltacrines at high temperature in sealed tubes,6 we
a
therefore raised the reaction temperature of the bis-amination to 180°C under an argon atmosphere (Table
1
1
2
). As expected, bis-amination of 9a effectively occurred within 2 h to furnish the desired bis-tacrinyl
0
alkanes 3a–c in 47–56% yields. Bis-(6-fluoro)tacrinyl alkanes 3g–i and N,N -bis(cycloheptylquinolinyl)-
diamino alkanes 4a–c were obtained in lower yields (22–28%) together with undesired mono-aminated
products from the corresponding chlorides 9c and 10a. The lower transformations might attribute to the
electronic effects of the fluoro group and steric effects of the fused heptyl ring, respectively. The resulting

1
817
1
bis-tacrines and their isosteres were characterized by their satisfactory spectra ( H NMR, MS, and HR-
FABMS). The 6-fluoro and 6-chloro group on the aromatic ring of chlorides 9c, 9d proved to be stable
under the bis-amination conditions.
Table 2
Synthesis of bis-tacrines and their isosteres
In brief, direct POCl -mediated cyclocondensation as well as chlorination in situ proves to be
3
applicable to the preparation of the critical chloride 9a and its analogs. This method allows the efficient
synthesis of the target bis-tacrines and their isosteres.
Acknowledgements
This work was supported in part by the National Science Council of the Republic of China (NSC
88-2314-B-016-048). Elemental analyses and high-resolution mass spectra performed by the National
Science Council Regional Instruments Center at National Taiwan University and National Tsing Hua
University are also gratefully appreciated.
References
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3
4
5
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. (a) Pang, Y. P.; Quiram, P.; Jelacic, T.; Hong, F.; Brimijoin, S. J. Biol. Chem. 1996, 271, 23646. (b) Pang, Y. P.; Brimijoin,
S. US Patent 5 783 584.

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6
. (a) Sargent, L. J.; Small, L. J. Org. Chem. 1946, 11, 359. (b) Tiedtke, H. Chem. Ber. 1909, 42, 621. (c) Cheng, X.-M.; Lee,
C.; Klutchko, S.; Winters, T.; Reynolds, E. E.; Welch, K. M.; Flynn, M. A.; Doherty, A. M. Bioorg. Med. Chem. Lett. 1996,
6
, 2999.
. Typical procedure (for the preparation of 9a): To a mixture of 6a (7.4 g, 53.9 mmol) and 7b (5.36 mL, 51.7 mmol) was
carefully added 50 mL of POCl in an ice bath. The mixture was heated under reflux for 2 h, then cooled at room temperature,
and concentrated to give a slurry. The residue was diluted with EtOAc, neutralized with aqueous K CO , and washed with
brine. The organic layer was dried over anhydrous K CO and concentrated in vacuo to furnish a pale brown solid. It was
recrystallized from acetone to give 9a (11.4 g, 94%): mp 68–70°C (lit. mp 66–68°C); H NMR (300 MHz, CDCl
7
3
2
3
2
3
6
a
1
3
) δ 8.13
d, J=7.5 Hz, 1H, ArH), 8.00 (d, J=8.3 Hz, 1H, ArH), 7.63 (dd, J=9.2, 7.5 Hz, 1H, ArH), 7.51 (dd, J=9.2, 8.3 Hz, 1H, ArH),
(
3
1
1
3
.10 (t, J=6.3 Hz, 2H, CH
2 2 2 2 3
), 2.97 (t, J=4.8 Hz, 2H, CH ), 1.91 (s br, 4H, CH -CH ); C NMR (75 MHz, CDCl ) δ 160.1,
+
+
47.2, 129.9, 129.5, 129.1, 127.1, 124.3, 34.7, 28.1, 23.2, 23.0; EIMS: 217 (M , 100), 219 (M+2 , 33); HR-EIMS: exact
+
mass calcd for C13H12NCl: [M] 217.0659, found: 217.0648.
8
9
. Brian, W. P.; Souther, B. L. J. Med. Chem. 1965, 8, 143.
. Michalson, E. T.; D’andrea, S.; Freeman, J. P.; Szmuszkovicz, J. Heterocycles 1990, 30, 415.
1
1
0. von Braun, J.; Heymons, A.; Manz, G. Chem. Ber. 1931, 64, 227.
1. Typical procedure (for the preparation of 3a): A mixture of 9a (0.75 g, 3.5 mmol), 5a (0.25 g, 1.75 mmol), phenol (1.5
g), and NaI (0.07 g) were carefully heated at 180°C under an inert system for 2 h and then cooled at room temperature.
The mixture was diluted with EtOAc and made basic with 10% KOH solution. The organic layer was washed with water
and brine, and then dried over anhydrous MgSO
chromatography (CH Cl to CH Cl :MeOH=10:1) to give 3a (0.47 g, 56%) as amber glass foam: mp 94–96°C; R
CH Cl :MeOH:NH OH=10:1:1); H NMR (300 MHz, CDCl
Ar-H), 7.54 (t, J=7.0 Hz, 2H, Ar-H), 7.32 (t, J=7.0 Hz, 2H, Ar-H), 4.00 (s br, 2H, 2 NH), 3.47 (t, J=7.1 Hz, 4H, 2 N-
4
. After concentration, the resulting residue was purified on silica gel
0.42
) δ 7.94 (d, J=4.1 Hz, 2H, Ar-H), 7.91 (d, J=4.1 Hz, 2H,
2
2
2
2
f
1
(
2
2
4
3
CH
CH
2
), 3.06 (s br, 4H, 2 CH CH
2
), 2.68 (s br, 4H, 2 CH
2
), 1.89 (s br, 8H, 2 CH
2
CH
2
), 1.65 (s br, 4H, CH
2
2
), 1.41 (s br, 4H,
+
2
CH ); FABMS (NBA as matrix): m/z [M+H] 479.2; HR-FABMS: exact mass calcd for C32H N : [M+H]+479.3173,
2
39 4
found: 479.3187.