Syntheses of compounds active toward glutamate receptors: I. New preparative synthesis of aminoindandicarboxylic acid (AIDA)

Article abstract of DOI:10.1023/A:1022515613414

A preparative procedure has been developed for the synhtesis of 1-aminoindan-1,5-dicarboxylic acid which is a new group I metabotropic glutamate receptor antagonist.

Full text of DOI:10.1023/A:1022515613414

Russian Journal of Organic Chemistry, Vol. 38, No. 12, 2002, pp. 1764 1768. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 12, 2002,
pp. 1825 1829.
Original Russian Text Copyright
2002 by Matveeva, Podrugina, Zefirova, Alekseev, Bachurin, Pellicciari, Zefirov.
Syntheses of Compounds Active
toward Glutamate Receptors: I. New Preparative Synthesis
of Aminoindandicarboxylic Acid (AIDA)*
E. D. Matveeva1, T. A. Podrugina1, O. N. Zefirova1, A. S. Alekseev1,
S. O. Bachurin2, R. Pellicciari3, and N. S. Zefirov1
1
Faculty of Chemistry, Moscow State University, Vorob’evy gory, Moscow, 119899 Russia
e-mail: edmatveeva@mail.ru
2
Institute of Physiologically Active Substances, Russian Academy of Sciences,
Chernogolovka, Moscow oblast, Russia
3
Universita degli studi di Perugia, via del Liceo, 1-06123 Perugia, Italy
Received February 20, 2002
Abstract A preparative procedure has been developed for the synhtesis of 1-aminoindan-1,5-dicarboxylic
acid which is a new group I metabotropic glutamate receptor antagonist.
In the last decade, the number of publications con-
cerning structural design and synthesis of compounds
selective for metabotropic glutamate receptors
(mGluR) considerably increased. Metabotropic gluta-
mate receptors are proteins partially immersed into
a cell membrane and having (S)-glutamic acid binding
sites. Activation of mGluR by glutamic acid launches
intracellular metabolic processes with participation of
several membrane proteins, which successively react
with each other. In the recent time it was shown that
disorder of the cellular mechanism for regulation of
the mGluR activation may be among factors respons-
ible for pathogenesis of various neurodegenerative
diseases, such as Alzheimer’s disease, Huntington’s
chorea, etc. Just realization of this fact gave an im-
petus to dramatically increased interest in chemical
compounds capable of acting as mGluR ligands [1 3].
The family of metabotropic glutamate receptors
includes at least 8 different subtypes which can be
divided into 3 groups with respect to their amino
acid sequence, signal transduction mechanism, and
sensitivity to some substances. Metabotropic gluta-
mate receptors of each subtype can be a biological
target in the therapic treatment of the above diseases.
____________
Here, potential neuroprotective activity should be
intrinsic to compounds which are antagonists at group
I metabotropic glutamate receptors or agonists at
groups II and III mGluR. It is important that the main
problem in the design of such structures is search
for compounds highly selective for a definite subtype
of metabotropic glutamate receptors [1].
Nonspecific antagonists at group I mGluR are
numerous derivatives of carboxyphenylglycine (I) [4].
Recent study of physiological activity of carboxy-
phenylglycine analogs with a limited conformational
mobility has shown that 1-aminoindan-1,5-dicar-
boxylic acid (II, AIDA) is not very active but (at low
concentrations) highly selective antagonist at mGluR1
subtype receptors which belong to group I metabo-
tropic glutamate receptors [5]. Due to its high selec-
tivity, dicarboxylic acid II is now widely used as
a
molecular tool for studying the corresponding
receptor subtype. In addition, extensive studies are
carried out on the synthesis of its analogs as potential
neuroprotecting agents.
*
This study was financially supported by the Russian Founda-
tion for Basic Research (project nos. 01-03-33085 and 00-
15-97454).
1070-4280/02/3812-1764$27.00 2002 MAIK Nauka/Interperiodica

SYNTHESES OF COMPOUNDS ACTIVE TOWARD GLUTAMATE RECEPTORS: I.
1765
Scheme 1.
The present communication opens a series of our
reports on the synthetic program aimed at developing
new methods for preparation of compound II and its
analogs and studying their pharmacological properties.
The known procedure for preparation of amino acid II
[5] allowed us to obtain only small amounts of the
target compound. Therefore, the goal of this study
was to develop a new preparative procedure for the
synthesis of 1-aminoindan-1,5-dicarboxylic acid (II)
and isomeric 1-aminoindan-1,6-dicarboxylic acid (XI)
(Scheme 1). As starting compound we used indan
(III). Its acylation with acetyl chloride (4 h) gave
5-acetylindan (IV) in quantitative yield. Ketone IV
was brought into haloform reaction to obtain 5-indan-
carboxylic acid (V). The optimal conditions at that
stage (yield of V 99%) were heating of the reaction
mixture for 5 h at 55 C.
Methyl 5-indancarboxylate (VI) was prepared by
a standard procedure, from the corresponding acyl
chloride and sodium methoxide. The subsequent
oxidation of ester VI with chromium(VI) oxide led to
formation of two isomeric products, methyl 1-oxo-
indan-5- and -6-carboxylates VII and VIII, which
were separated by recrystallization from ethyl acetate
petroleum ether, followed by column chromatography
on silica gel. As a result, we isolated isomeric esters
VII and VIII in 20 and 25% yield, respectively. The
structure of compounds VII and VIII was proved by
1
1
the data of H and 13C NMR spectroscopy. The H
NMR spectrum of methyl 1-oxoindan-5-carboxylate
(VII) contained a doublet at 7.76 ppm (1H, 7-H,
Harom), a doublet at 8.00 ppm (1H, 6-H, Harom), and
1
a singlet at 8.12 ppm (1H, 4-H, Harom). In the H
NMR spectrum of 6-methoxycarbonyl analog VIII,
the doublet signal corresponding to 4-H appeared at
7.56 ppm, the doublet from 5-H was observed at
8.24 ppm, and the singlet from 7-H was located
at
8.36 ppm. We thus unambiguously identified
isomers VII and VIII. The purity of each isomer was
checked by GLC.
Ketones VII and VIII were converted into the
corresponding hydantoins. A known [5, 6] procedure
for the synthesis of hydantoins from ketones by the
action of sodium cyanide and ammonium carbonate
requires severe conditions (increased pressure). We
have found that this procedure cannot be applied to
the synthesis of ketone VII, for the reaction is accom-
panied by strong tarring and the yield of the target
product is very poor. We have proposed a procedure
for preparation of hydantoins under milder conditions
(under atmospheric pressure), which has not been
applied previously for indan systems. The reactions
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1766
MATVEEVA et al.
were carried out in aqueous DMF at 90 100 C (reac-
tion time 36 h). As a result, we isolated 2 ,4 -dioxo-
indan-1-spiro-5 -imidazolidine-5-carboxylic acid (IX)
and methyl 2 ,4 -dioxoindan-1-spiro-5 -imidazolidine-
6-carboxylate (X) in 65 and 75% yield, respectively.
internal reference. The IR spectra were obtained on
a UR-20 instrument from solutions in carbon tetra-
chloride. GLC analysis was performed on a Chrom-
5M gas chromatograph equipped with a flame-ioniza-
tion detector and a BP-1 25-m 0.25-mm capillary
column (carrier gas helium, flow rate of 1.5 ml/min).
The progress of reactions was monitored by thin-layer
chromatography on Silufol plates. Merck 60 silica gel
(70 230 mesh ASTM) was used for column chromato-
graphy.
1
The H NMR spectra of hydantoins IX and X con-
tained characteristic signals from the amide protons
in the regions 8.03 8.55 and 9.02 10.9 ppm. In the
IR spectra of IX and X we observed absorption bands
1
from the amide carbonyl groups at 1600 1620 cm .
1-Aminoindan-1,5-dicarboxylic acid (II). A mix-
ture of 0.31 g (0.0012 mol) of compound IX and
0.38 g (0.0012 mol) of Ba(OH)2 8H2O in 10 ml of
water was heated for 10 h under reflux. It was then
cooled to room temperature, 0.58 g (0.006 mol) of
ammonium carbonate was added, and the mixture was
refluxed for 2.5 h. The precipitate was filtered off, the
filtrate was evaporated, and the residue was subjected
to cation-exchange chromatography on Dowex 50
200 using a 10% solution of pyridine in water as
eluent. Yield 0.2 g (71%), yellowish crystals, mp
By hydrolysis of compounds IX and X we obtained
the corresponding -amino acids II and XI. The
general procedure for hydrolysis under pressure [7]
turned out to be inapplicable for the preparation of
amino acids of the indan series. Also, there were
difficulties in the isolation of the amino acids from
the reaction mixtures. We have studied the hydrolysis
of IX and X in various solvents (H2O, ethanol, DMF)
using such bases as NaOH and Ba(OH)2 with varia-
tion of the other parameters. The best results were
obtained in water with Ba(OH)2 as a base at a reactant
ratio (hydantoin base ammonium carbonate) of
1:1:2.5 at 100 C (reaction time 12.5 h). These condi-
tions ensured synthesis of amino acids II and XI in
70% yield. The structure of the products was con-
1
>300 C (cf. [5]). H NMR spectrum (DMSO-d6), ,
ppm: 2.42 m (1H, CH2), 2.65 m (1H, CH2), 3.18 t
(2H, CH2), 7.52 d (1H, Harom), 7.88 d (1H, Harom),
7.98 s (1H, Harom).
1
firmed by the H and 13C NMR spectra. Amino acid
5-Acetylindan (IV). Aluminum chloride, 21.8 g
(0.16 mol), was added in portions to a solution of
19.3 g (0.16 mol) of indan and 16.1 g (0.20 mol) of
acetyl chloride in 100 ml of benzene, which was
stirred at 0 C under argon. The mixture was allowed
to warm up to room temperature, stirred for 4 h, and
poured into 30 ml of water containing ice. It was
acidified with 10% hydrochloric acid and extracted
with ethyl acetate (3 20 ml). The combined extracts
were washed with 50 ml of a saturated solution of
sodium chloride, dried over calcined sodium sulfate,
and evaporated. Yield of IV 25 g (98%), yellow oily
II shows in the 1H NMR spectrum a singlet at
5.5 ppm, which belongs to the NH2 protons, while
those assignable to amide NH protons are absent.
A characteristic signal in the 13C NMR spectrum is
that from the quaternary C1 carbon atom, which is
displaced to
88 ppm.
C
Thus we have developed a preparative procedure
for the synthesis of aminoindandicarboxylic acids.
Our preliminary results on docking of several AIDA
analogs (in particular, of those containing various
substituents instead of the terminal carboxy group)
into a computer-simulated mGluR1 model (which was
built up on the basis of the X-ray diffraction data [8])
showed the possibiliy for some compounds to exhibit
a higher activity and/or selectivity for mGluR1, as
compared to AIDA. The proposed procedure opens
the way to substituted -amino acids of the indan
series, which could considerably increase the number
of available AIDA analogs.
1
substance. IR spectrum: (C O) 1680 cm . The
product had a purity of 100% (according to GLC).
5-Indancarboxylic acid (V). Bromine, 48.9 g
(0.3 mol), was quickly added to a solution of 56 g
(1 mol) of KOH in 200 ml of water while stirring at
0 C. 5-Acetylindane (IV), 12.3 g (0.076 mol), was
slowly added to the resulting solution, the mixture
was heated for 3 h at 55 C, 11.4 g (0.06 mol) of
Na2S2O5 was added, and the mixture was acidified to
pH 3 with concentrated hydrochloric acid. The precip-
itate was filtered off and dried in air. Yield 11.8 g
(95%), colorless crystals, mp 165 C; published data
[5]: mp 165 166 C. 1H NMR spectrum, , ppm:
2.5 m and 3.3 m (CH2), 7.8 d (1H, 7-H), 8.4 d (1H,
4-H), 8.0 s (1-H, 6-H).
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
1
a Varian VXR-400 spectrometer (400 MHz for H) in
CDCl3 and DMSO-d6 using tetramethylsilane as
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

SYNTHESES OF COMPOUNDS ACTIVE TOWARD GLUTAMATE RECEPTORS: I.
1767
Methyl 5-indancarboxylate (VI). Thionyl
acetate was added, and the mixture was washed with
chloride, 6 ml, was added on cooling to a solu- 60 ml of water. The product was extracted into 30%
tion of 10 g (0.06 mol) of 5-indancarboxylic acid (V)
in 10 ml of dry benzene. The mixture was heated for
2 h under reflux until gaseous products no longer
evolved and was then heated for 1 h under reduced
pressure to remove excess thionyl chloride. 5-Indan-
carbonyl chloride thus obtained, 11.14 g (0.06 mol),
was added dropwise at 0 C under argon to a solution
of 3.24 g (0.065 mol) of sodium methoxide in 20 ml
of anhydrous methanol. The mixture was stirred for
3 h, poured ino ice water, and extracted with diethyl
ether (3 50 ml). The combined extracts were dried
over calcined sodium sulfate and evaporated, and the
remaining dark brown oily material was subjected to
flash chromatography on silica gel using petroleum
ether as eluent. Yield 9.64 g (90%), yellow oily sub-
stance (purity 99%, GLC).
aqueous NaOH (60 ml). The aqueous phase was
separated and acidified to pH 5 with hydrochloric
acid. Acid IX was extracted into ether (3 50 ml), the
combined extracts were dried over calcined sodium
sulfate and evaporated, and the residue was recrystal-
lized from benzene. Yield 0.28 g (65%), light brown
1
crystals, mp 252 C. H NMR spectrum (DMSO-d6),
, ppm: 2.43 m (1H, CH2), 2.54 m (1H, CH2), 3.10 d
(2H, CH2), 7.69 d (1H, Harom), 7.87 d (1H, Harom),
7.94 s (1H, Harom), 8.10 s (1H, NH), 8.43 s (1H, NH).
Methyl 2 ,4 -dioxoindan-1-spiro-5 -imidazoli-
dine-6-carboxylate (X). A solution of 0.83 g
(0.01 mol) in 3 ml of water was added to a solution
of 4.5 g (0.047 mol) of ammonium carbonate and
2 g (0.01 mol) of methyl 1-oxoindan-6-carboxylate
in 20 ml of DMF. The mixture was heated for 36 h at
90 C and cooled, 100 ml of ethyl acetate was added,
and the mixture was washed with 100 ml of water
and extracted with 100 ml of a 30% solution of
sodium hydroxide. The aqueous phase was separated
and acidified to pH 5 with hydrochloric acid. Ester
X was extracted into ether (3 50 ml), the combined
extracts were dried over calcined sodium sulfate and
evaporated, and the residue was recrystallized from
benzene. Yield 2 g (75%), light brown crystals,
Oxidation of methyl 5-indancarboxylate. A solu-
tion of 7 g (0.07 mol) of CrO3 in a mixture of 27 ml
of acetic acid and 11.6 ml of water was added over
a period of 30 min to a solution of 5 g (0.028 mol)
of methyl 5-indancarboxylate in 13.5 ml of glacial
acetic acid, which was stirred at room temperature.
The mixture was stirred for 12 h, diluted with 60 ml
of water, and extracted with ethyl acetate (4 50 ml).
The combined extracts were washed with a 10% solu-
tion of Na2CO3 (3 30 ml) and a concentrated solu-
tion of sodium chloride (30 ml), dried over calcined
sodium sulfate, and evaporated under reduced pres-
sure. The residue, a dark yellow oily substance, was
recrystallized from ethyl acetate petroleum ether and
was then purified by flash chromatography on silica
gel using petroleum ether ethyl acetate (85:15) as
eluent. We isolated 1.15 g (20%) of methyl 1-oxo-
indan-5-carboxylate (VII) and 1.44 g (25%) of
methyl 1-oxoindan-6-carboxylate (VIII) as colorless
crystalline substances with mp 111 C (for both
isomers); published data [5]: mp 111 112 C. 1H NMR
spectrum (CDCl3), , ppm: compound VII: 2.76 t
(2H, CH2), 3.20 t (2H, CH2), 3.95 s (3H, CH3), 7.56 d
(1H, Harom), 8.24 d (1H, Harom), 8.36 s (1H, Harom);
VIII: 2.76 t (2H, CH2), 3.20 t (2H, CH2), 3.95 s
(3H, CH3), 7.76 d (1H, Harom, 8.12 s (1H, Harom).
1
mp 250 C. H NMR spectrum (DMSO-d6), , ppm:
2.20 m (1H, CH2), 2.48 m (1H, CH2), 3.05 m (2H,
CH2), 3.85 s (CH3), 7.42 d (1H, Harom), 7.62 s (1H,
Harom), 7.95 d (1H, Harom), 8.55 s (1H, NH), 10.90 s
(1H, NH).
1-Aminoindan-1,6-dicarboxylic acid (XI). A mix-
ture of 0.5 g (0.0019 mol) of compound X and 0.61 g
(0.0019 mol) of Ba(OH)2 8H2O in 10 ml of water
was heated for 10 h under reflux. The mixture was
cooled to room temperature, 0.46 g (0.005 mol) of
ammonium carbonate was added, and the mixture was
refluxed for 2.5 h. The precipitate was filtered off,
and the filtrate was evaporated. The residue was
purified by cation-exchange chromatography on
Dowex 50 200 using a 10% solution of pyridine in
water as eluent. Yield 0.3 g (72%), yellowish crystals,
1
mp >300 C (cf. [5]). H NMR spectrum (D2O),
,
ppm: 2.22 m (1H, CH2), 2.55 m (1H, CH2), 2.96 t
(2H, CH2), 7.22 d (1H, Harom), 7.56 s (1H, Harom),
7.76 d (1H, Harom).
2 ,4 -Dioxoindan-1-spiro-5 -imidazolidine-5-car-
boxylic acid (IX). A solution of 0.13 g (0.0026 mol)
of sodium cyanide in 2 ml of water was added to
a solution of 0.73 g (0.0076 mol) of ammonium car-
bonate and 0.32 g (0.0017 mol) of methyl 1-oxoindan-
5-carboxylate in 3 ml of DMF. The mixture was
heated for 36 h at 90 C and cooled, 50 ml of ethyl
REFERENCES
1. Zefirova, O.N. and Zefirov, N.S., Russ. J. Org. Chem.,
2000, vol. 36, no. 9, pp. 1231 1258.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1768
MATVEEVA et al.
2. Brauner-Osborne, H., Egebjerg, J., Nielsen, E.,
Madsen, U., and Krogsgaard-Larsen, P., J. Med.
Chem., 2000, vol. 43, no. 14, pp. 2609 2645.
6. Sarges, R., Schnur, R.C., Belletire, J.L., and Peter-
son, M.J., J. Med. Chem., 1988, vol. 31, no. 1,
pp. 230 243.
3. Knopfel, T., Kuhn, R., and Allgeier, H., J. Med.
Chem., 1995, vol. 8, no. 9, pp. 1417 1426.
7. Coker, J., Kohlhase, W., and Martens, T., J. Org.
Chem., 1962, vol. 27, no. 9, pp. 3201 3204.
4. Schoepp, D.D., Jane, D.E., and Monn, J.A., Neuro-
pharmacology, 1999, vol. 38, no. 10, pp. 1431 1476.
8. Rogers, A.O., Allan, G.G., Kunishima, N.,
Shimada, Y., Tsuji, Y., Sato, T., Yamamoto, M.,
Kumasaka, T., Nakanishi, S., Jingami, N., and
Morikawa, K., Nature, 2000, vol. 407, pp. 971 977.
5. Pellicciari, R., Luncia, R., Costantino, G., and
Marinozzi, M., J. Med. Chem., 1995, vol. 38, no. 19,
pp. 3717 3719.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002