The synthesis of potential Neramexane metabolites: Cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2004.09.047

A seven step synthetic route toward potential Neramexane metabolites cis- and trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids, cis-1 and trans-1, has been developed from isophorone. The synthetic procedure represents a useful method for the preparation of γ-amino acids with both amino and carboxyl groups situated at tertiary carbon atoms.

Full text of DOI:10.1016/j.tetlet.2004.09.047

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8145–8147
The synthesis of potential Neramexane metabolites: cis- and
trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic acids
a
Dina Trifanova, Marija Trifonova, Aigars Jirgensons, Valerjans Kauss,
a
a,
a
*
a
a
Osvalds Pugovich, Ivars Kalvinsh and Guenter Quack
b
a
Latvian Institute of Organic Synthesis, 21 Aizkraukles str., 1006 Riga, Latvia
Merz Pharmaceuticals GmbH, Eckenheimer Landstrasse 100, D-60318 Frankfurt am Main, Germany
b
Received 22 June 2004; revised 1 September 2004; accepted 7 September 2004
Available online 22 September 2004
Abstract—A seven step synthetic route toward potential Neramexane metabolites cis- and trans-3-amino-1,3,5,5-tetramethylcyclo-
hexanecarboxylic acids, cis-1 and trans-1, has been developed from isophorone. The synthetic procedure represents a useful method
for the preparation of c-amino acids with both amino and carboxyl groups situated at tertiary carbon atoms.
Ó 2004 Elsevier Ltd. All rights reserved.
Neramexane is among NMDA receptor antagonists
undergoing phase II clinical trials for the treatment of
alcohol abuse. As part of a clinical investigation, we
H N
CH3
H N CH3
2
H N CH3
2
2
1
CO H
CH3
CH3
H C
CH3
CO H
H
3
C
2
H C
3
3
have undertaken studies of Neramexane metabolism in
living organisms. Among other metabolic pathways,
the complete oxidation of the C3-methyl group of Nera-
mexane by enzymes involved in drug metabolism can
be expected, leading to the formation of cis- and/or
trans-3-amino-1,3,5,5-tetramethylcyclohexanecarboxylic
H C
CH3
H C
H C
3
3
3
2
cis-1
trans-1
Neramexane
Figure 1.
2
acids cis-1 and trans-1 (Fig. 1). To prove the proposed
could not be applied to prepare amino acids cis-1 and
trans-1 due to difficulties in accessing starting materials.
metabolic pathway using analytical methods like GC/
MS or HPLC/MS, it was necessary to prepare potential
metabolites cis-1 and trans-1 as reference standards.
5
The Ritter reaction (reaction of an in situ generated
carbenium ion with nitriles) has been used to prepare
3-aminoadamantane-1-carboxylic acid derivatives from
3-hydroxyadamantane-1-carboxylic acid. Since 3-sub-
7
stituted-1-alkylcyclohexanols are readily available, this
seemed to be an attractive synthetic strategy for the syn-
thesis of aminocyclohexanecarboxylic acids cis-1 and
trans-1. We preferred to use a latent carboxyl group at
the desired position in cyclohexane because a carboxyl
group is known to retard the Ritter reaction consider-
c-Amino acids cis-1 and trans-1 are intriguing synthetic
targets since both amino and carboxyl groups are situ-
ated at a tertiary carbon atom. Commonly used meth-
ods for the synthesis of c-amino acids with the amino
group at a tertiary carbon atom involve conjugate addi-
tion of a,a-disubstituted nitro compounds to acrylates
and subsequent reduction of the nitro group in the addi-
6
3
tion product, or selective degradation of one carboxyl
to an amino group in pentanedicarboxylic acids and
6
ably. Moreover, 1-alkylcyclohexanecarboxylic acids
5b
4
masked dicarboxylic acids. These approaches, however,
can eliminate CO in strong acidic media. A phenyl
2
8
group was chosen as an appropriate latent carboxyl
group primarily due to its high chemical resistance,
and secondly, that it could facilitate the separation of
diastereomers at a later stage.
Keywords: Neramexane; Metabolites; The Ritter reaction; Latent
carboxyl group; Oxidation.
*
Corresponding author. Tel.: +371 7543503; fax: +371 7553142;
e-mail: aigars@osi.lv
A diastereomeric mixture of 3-phenylcyclohexanols 3
was prepared from isophorone 1 according to the
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.047

8146
D. Trifanova et al. / Tetrahedron Letters 45 (2004) 8145–8147
O
H C
OH
Ph
H C NHCHO
3
3
H C NHCHO
3
a, b
CH3
H C
H C
c
3
H C
Ph
H C
Ph
H C
3
3
3
3
CH3
H C
CH3
H C
H C
3
3
CH3
3
cis - and trans -
3
cis - 4
trans - 4
2
Scheme 1. Reagents and conditions: (a) PhMgBr, CuCl, Et
0
2
O, À20°C, 2h, 76%; (b) MeLi, Et
2
O, 0°C to rt, 1h, 82%; (c) TMSCN, H
°C to rt, 20h, separation of isomers (light petroleum ether–ethyl acetate, 10:1, cis-4 eluted first followed by trans-4), cis-4 47%, trans-4 29%.
2 4
SO , AcOH,
H C NH3+
H C NHCHO
3
H C NHBoc
H C NBoc
3
3
3
a, b
a, b
c
d
CO2—
CH3
H C
Ph
H C
3
H C
3
H C
Ph
H C
O
3
3
H C
CH3
3
H C
H C
CH3
3
3
CH3
3
cis-4
cis-5
6
cis-1
H C NHCHO
H C NHBoc
H
3
C
NHBoc
CO
H C NH3+
3
3
3
c
e
CO2—
CH3
H C
Ph
H C
H C
Ph
CH3
H
H
3
3
C
2
H
H C
3
3
3
H C
CH3
C
CH3
H C
3
3
3
trans-4
trans-5
7
trans-1
Scheme 2. Reagents and conditions: (a) 20% aq H
two steps; (c) RuO , NaIO , H O, CCl , CH CN, rt, 3d, 6 40%, 7 68%; (d) 20% aq HCl, reflux, 31h, then aq NH
rt, 15min then aq NH OH, 78%.
2
SO
4
reflux 10h then NaOH until pH ꢀ 10; (b) Boc
2
O, Et
2
O, rt, 19h, cis-5 77%, trans-5 70% over
2
4
2
4
3
4
OH, 68%; (e) CF CO H, CH Cl
3
2
2
2
,
4
9
literature procedure (Scheme 1). The Ritter reaction of
Acknowledgements
1
0
cyclohexanol 3 with hydrogen cyanide (generated in
situ from TMSCN) gave a mixture of diastereomeric
formamides cis-4 and trans-4. Gratifyingly, at this point
diastereomers cis-4 and trans-4 were readily separable by
flash chromatography on silica gel. An initial attempt to
convert the phenyl to a carboxyl group in N-formyl ami-
nocyclohexanes 4 using the RuO –NaIO oxidizing sys-
1
3
We acknowledge J. Popelis for obtaining C NMR
spectra and E. Sarule for performing microanalyses.
We also wish to thank Dr. R. Zemribo for valuable
comments during the preparation of the manuscript.
2
4
8
a
References and notes
tem failed probably due to concomitant oxidation of
the formyl group. The formyl group was changed to a
tert-butoxycarbonyl (Boc) group that was expected to
be resistant to the oxidation conditions (Scheme 2).
Treatment of N-Boc protected 3-phenylcyclohexylamine
isomer cis-5 with RuO –NaIO gave N-Boc protected
1
. Danysz, W.; Parsons, C. G.; Jirgensons, A.; Kauss, V.;
Tillner, J. Curr. Pharm. Des. 2002, 8, 434–437.
. Williams, D. A. In Drug Metabolism. FoyeÕs Principles of
Medicinal Chemistry; Williams, D. A., Lemke, T. L., Eds.,
5th ed.; Lippincot Williams & Wilkins: Philadelphia, PA,
2002; pp 174–233.
2
2
4
1
1
bicyclic lactam 6 as the major product obviously
formed via cyclization of an intermediate N-Boc pro-
tected aminocyclohexanecarboxaldehyde. Acidic hydrolysis
3. (a) Kaji, E.; Igarashi, A.; Zen, S. Bull. Soc. Chem. Jpn.
976, 49, 3181–3184; (b) Hill, R. K.; Sawada, S.; Bock, M.
1
1
1
G.; Greene, J. R. Heterocycles 1987, 25, 515–520; (c)
Mimura, M.; Hayashida, M.; Nomiyama, K.; Ikegami, S.;
Iida, Y. Chem. Pharm. Bull. 1993, 41, 1971–1986; (d)
Newkome, G. R.; Moorefield, C. N.; Epperson, J. D.; Jon,
D. Eur. J. Org. Chem. 2003, 3666–3672.
. (a) Wilcox, C. F.; Leung, C., Jr. J. Org. Chem. 1968, 33,
877–880; (b) Petter, R. C.; Banarjee, S.; Englard, S. J. Org.
Chem. 1990, 55, 3088–3097.
of lactam 6 gave amino acid cis-1. The cis-configura-
tion of amino and carboxyl groups in amino acid cis-1
was defined by lactam 6 since no change of configura-
tion at C-1 and C-3 was possible during hydrolysis.
The oxidative degradation of the phenyl group in N-
Boc protected 3-phenylcyclohexylamine isomer trans-5
gave, as expected, N-Boc protected amino acid 7. The
Boc group in compound 7 was removed using
standard conditions to yield amino acid isomer
4
5. (a) Ritter, J. J.; Kalish, J. J. Am. Chem. Soc. 1948, 70,
4045; (b) Krimen, I.; Cota, D. J. Org. React. 1969, 17, 213;
1
1
(
c) Bishop, R. In Comprehensive Organic Synthesis; Trost,
B. M., Ed.; Pergamon: Oxford, 1991; Vol. 6, Chapter 1.9,
pp 261–300.
. Shokova, E.; Mousoulou, T.; Luzikov, Y.; Kovalev, V.
Synthesis 1997, 1034–1040.
. Jirgensons, A.; Kauss, V.; Kalvinsh, I.; Gold, M. R.;
Danysz, W.; Parsons, C. G.; Quack, G. Eur. J. Med.
Chem. 2000, 35, 555–565.
trans-1.
In summary, we have developed a seven step synthetic
route toward potential Neramexane metabolites cis-1
and trans-1 from isophorone in 6% and 7% overall
yields, respectively. The synthetic procedure represents
a useful method for the preparation of c-amino acids
with amino and carboxyl groups situated at tertiary car-
bon atoms.
6
7
8. (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless,
K. B. J. Org. Chem. 1981, 46, 3936–3938; (b) Chakraborti,

D. Trifanova et al. / Tetrahedron Letters 45 (2004) 8145–8147
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2
and 0.78 (total 6H, both s, 5,5-CH
3
1.21 (3H, s, 3-CH ); 0.99 (1H, d, J = 14Hz, ring proton);
1.12 (1H, d, J = 15Hz, ring proton); 1.26 (1H, d,
J = 15Hz, ring proton); 1.60 (1H, d, J = 15Hz, ring
proton); 1.84 (1H, d, J = 14Hz, ring 13 proton),
and 2.18ppm (1H, d, J = 15Hz, ring proton); C NMR
3
); 0.98 (3H, s, 1-CH
3
605–2610; (c) Banik, B. K. Synth. Commun. 1997, 27,
637–3656.
3
9
. Shapiro, B. L.; Johnston, M. D., Jr.; Shapiro, M. J. J. Org.
Chem. 1974, 39, 796–804.
0. Chen, H. G.; Goel, O. P.; Kesten, S.; Knobelsdorf, J.
1
Tetrahedron Lett. 1996, 37, 8129–8132.
1. N-tert-Butoxycarbonyl-1,3,3,5-tetramethyl-6-azabicyclo [3.2.1]
(50MHz, CDCl ): d 27.15, 32.74, 32.98, 36.44, 45.29,
3
1
45.71, 49.90, 50.21, 55.76, 190.16. t-3-Amino-1,3,5,5-
tetramethylcyclohexane-r-1-carboxylic acid (trans-1):
1
octan-7-one 6: H NMR (200MHz, CDCl
3
): d 0.89 (3H, s,
1
3
-CH ); 0.97 (3H, s, 3-CH ); 1.10 (3H, s, 1-CH ); 1.24 and
3
H NMR (200MHz, D O): d 0.80 (6H, s, 5,5-CH ); 0.85
3
3
2
3
3
3
1
.26 (total 2H, both d, J = 14Hz, ring protons); 1.40–1.60
); 1.52 (9H, s, t-
Bu); 1.69 (1H, dt, J = 12Hz and 2Hz, ring proton), and
(1H, d, J = 14Hz, ring proton); 0.97 (3H, s, 1-CH
(1H, d, J = 13Hz, ring proton); 1.28 (3H, s, 3-CH
); 1.06
); 1.13
(
2H, m, ring protons); 1.45 (3H, s, 5-CH
3
(1H, d, J = 13Hz, ring proton); 1.51 (1H, d, J =
13Hz, ring proton); 2.00 (1H, d, J = 14Hz, ring
proton), and 2.37ppm (1H, d, J = 13Hz, ring
1
3
2
(
3
1
.10ppm (1H, d, J = 14Hz, ring proton); C NMR
50MHz, CDCl ): d 21.28, 25.69, 28.05, 30.36. 30.48,
5.87, 43.07, 44.37, 47.37, 49.04, 60.66, 82.38, 150.35,
78.41. c-3-Amino-1,3,5,5-tetramethylcyclohexane-r-1-
3
1
3
3
proton); CNMR (50MHz, CDCl ): d 27.70, 29.13,
33.34, 34.32, 37.05, 45.72, 48.75, 50.24, 58.18,
187.34.
1
carboxylic acid (cis-1): H NMR (200MHz, D O): d 0.76
2