(S)-spiro[1,3-diazacyclopent-1-ene)-5,2'-(7'-methyl-1',2',3',4'- tetrahydronaphthalene)]: Resolution, stereospecific synthesis, and preliminary pharmacological characterization as a partial α-adrenergic agonist

Article abstract of DOI:10.1021/jm970282m

Recently, we reported on the design, synthesis, and structure-activity relationships of a series of spiroimidazolines endowed with α-adrenergic agonist activities. Among the compounds described, (R,S)-spiro(1,3- diazacyclopent-1-ene)-[5,2'](7'-methyl-1',2

Full text of DOI:10.1021/jm970282m

J . Med. Chem. 1997, 40, 2931-2935
2931
(S)-Sp ir o[(1,3-d ia za cyclop en t-1-en e)-5,2′-(7′-m eth yl-1′,2′,3′,4′-
tetr a h yd r on a p h th a len e)]: Resolu tion , Ster eosp ecific Syn th esis, a n d
P r elim in a r y P h a r m a cologica l Ch a r a cter iza tion a s a P a r tia l r-Ad r en er gic
Agon ist
Alex A. Cordi,* J ean-Michel Lacoste, Fabrice Le Borgne,† Yolande Herve,† Lucile Vaysse-Ludot,†
J ean-J acques Descombes, Christine Courchay, Michel Laubie, and Tony J . Verbeuren
Institut de Recherches Servier, 11, rue des Moulineaux, 92150 Suresnes, France, and ORIL, 13,
rue Auguste Desgene´tais-B.P.17-76210 Bolbec, France
Received April 29, 1997X
Recently, we reported on the design, synthesis, and structure-activity relationships of a series
of spiroimidazolines endowed with R-adrenergic agonist activities. Among the compounds
described, (R,S)-spiro(1,3-diazacyclopent-1-ene)-[5,2′](7′-methyl-1′,2′,3′,4′-tetrahydronaphtha-
lene) fumarate (5RS) was chosen for further development as a venotonic agent. The resolution
of this compound, as well as the pharmacological characterization of the enantiomers,
stereospecific synthesis of eutomer (5S, S 18149), and determination of absolute configuration
by single-crystal X-ray diffraction analysis, are described.
In tr od u ction
methane extraction. The crude free base was combined
with an equimolecular amount of the D enantiomer of
dibenzoyltartaric acid and crystallized twice in ethanol
to afford the opposite enantiomer 5S in ee >96%.
Our approach toward the stereospecific synthesis of
5S was inspired by the work of Weinges et al.4 who
synthesized (R)-R-methylphenylalanine by a stereo-
specific Strecker synthesis using (1R)-phenylethylamine
as chiral inducer. Stereospecific Strecker synthesis5
have been successfully exemplified in recent years
starting mainly from aromatic aldehydes;6-13 however
comparatively little success has been achieved starting
from ketone substrates.14,15 In our case (Scheme 1) we
used the 7-methyl-2-tetralone as template, a ketone
with little difference between its two arms: a benzyl
residue and a phenylethyl residue. The reaction pro-
ceeded cleanly and in high yield to give a diastereo-
isomerically pure solid endowed with the desired 2S
configuration. As the Strecker reaction is a reversible
process, the complete diastereoselectivity observed dur-
ing this procedure is probably linked to the crystalliza-
tion of one pure diastereoisomer exhibiting much lower
solubility than the other and therefore displacing the
whole equilibrium in favor of the production of this sole
enantiomeric adduct. In this respect, it is worth men-
tioning that improvements of yield were obtained by
increasing the water content of the solvent mixture,
leading to better recovery of the poorly soluble product.
Attempts to characterize the presence of the other
diastereoisomer in the mother liquors failed. As ex-
pected, the mirror-image reaction starting from (1S)-
phenylethylamine led, in the same conditions, to 5R in
comparable yields (data not shown).
Recently, we reported on the design, synthesis, and
structure-activity relationships of a series of spiro-
imidazolines endowed with R adrenergic agonist activi-
ties.1 Among the compounds described, (R,S)-spiro(1,3-
diazacyclopent-1-ene)-5,2′]-(7′-methyl-1′,2′,3′,4′-tetrahy-
dronaphthalene) fumarate (5RS) was chosen for further
development as a venotonic agent. Indeed, this com-
pound is the prototype of a venospecific constrictor as
it is able to constrict the saphenous vein of the dog
without noticeable effects on the mean arterial pressure.
As this compound contains an asymmetric center at
carbon 5-2′, it was important to assess the influence of
chirality on the pharmacological properties of compound
5RS. In fact, regulatory agencies are increasingly
concerned2 by the administration of racemic compounds
as drugs if no benefit can be related to the presence of
each of the enantiomers. In addition, it is preferential
to investigate whether the observed pharmacological
properties reside in one enantiomer, an eventuality
which could accelerate development.3
We now report on the resolution of this racemic
compound, describe the preliminary pharmacological
characterization of the most active enantiomer, and
document the determination of its absolute configura-
tion as well as its stereospecific synthesis.
Ch em istr y
The resolution of the two enantiomers of 5RS was
initially achieved by recrystallization of the dibenzoyl-
L-tartaric salt in ethanol. Resolution was monitored by
chiral HPLC. After three crystallizations the enantio-
meric purity exceeded the limit of detection of the
analytical method (ee >96%), the salt was decomposed
in strong basic media, and the free base was trans-
formed into the fumarate in 2-propanol to afford 5R.
The opposing enantiomer was obtained by evaporation
of the initial filtrates, followed by decomposition of the
salt by the addition of a strong base and dichloro-
Biology
The two enantiomers 5S and 5R as well as the
racemic 5RS described above were tested for their
biological activity in the pithed rat (in vivo) and on
contractibility of isolated canine saphenous veins and
femoral arteries (in vitro). The pithed rat assay allows
quantitative determination of the impact of the tested
† ORIL.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
S0022-2623(97)00282-3 CCC: $14.00 © 1997 American Chemical Society

2932 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Cordi et al.
Sch em e 1a
a
Reagents and conditions: (a) (R)-R-methylbenzylamine, NaCN, AcOH, EtOH, MeOH, H2O, 94% yield; (b) LiAlH4, THF, 93% yield; (c)
H2, 5% Pd/C, MeOH, 78% yield; (d) HC(dNH)NH2‚AcOH, EtOH, 87% yield; (e) dibenzoyl-D-tartaric acid or dibenzoyl-L-tartaric acid,
EtOH, 11 and 6% yield, respectively.
Ta ble 1. In Vitro and in Vivo R-Adrenergic Activity of Compounds 5
a
Concentration which increases the arterial pressure by 20 mmHg in the pithed rat, expressed in µg/kg iv (mean ( SEM, n ) 5).
b
Maximal pressure response (mean ( SEM) caused by the agonist, expressed in mmHg (the maximum obtained with phenylephrine is
150 mmHg). c Ratio of C20 obtained in the absence or presence of 0.1 mg of prazosin or 1 mg of yohimbine. EC50 value for the agonist
d
e
in the isolated blood vessel shown in µM (mean ( SEM, n ) 6-12). Emax ) maximal contractile response obtained with the agonist
expressed as percentage (mean ( SEM) of the maximal contraction to KCl (100 mM) in the blood vessel indicated.
compounds on the vascular tone defined by the dose (in
µg/kg iv) which increases the arterial blood pressure by
20 mmHg (C20 in Table 1). Additionally, the maximal
pressor response caused by the agonist (Max), expressed
in mmHg, is an indication of the efficacy of the tested
compounds. In the same assay, the use of selective R1-
and R2-adrenoceptor antagonists (prazosin and yohim-
bine) in the presence of the tested compounds allows
the definition of a C20 ratio (Praz and Yohim, respec-
tively), which are indicative of the contribution of R1-
and R2-adrenergic mechanisms to the pressor response.
The in vitro evaluation allows the comparison in terms
of affinity (EC50) and efficacy (Emax) on two types of
vascular beds which might be responsible for either the
expected therapeutic efficacy (saphenous vein) or the
potential side effect (femoral artery).

Spiroimidazoline as R-Adrenergic Agonist
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2933
F igu r e 1. Effect of compounds 5 in the pithed rat. Dose-
response effect of 5RS (n ) 5) (9), 5R (n ) 5) (O), and 5S (n
) 8) (0) on mean arterial blood pressure (MBP) in the pithed
rat. Data are shown as means ( SEM.
F igu r e 2. Effect of compounds 5 on the dog saphenous vein
without Endothelium. Contractile activity of increasing con-
centrations of 5RS (9), 5R (0), and 5S (b) on the dog
saphenous vein without endothelium. Data are the means (
SEM of 6-12 experiments.
F igu r e 3. Single-crystal X-ray structure of 5S as a dibenzoyl-
D-tartaric acid salt.
less than 16% of the responses obtained with KCl (100
mM). In dog saphenous veins, compounds 5 evoked
concentration-dependent contractions (Figure 2); the
maximal response and the affinities of the three com-
pounds were in the following order of potency: 5S >
5RS . 5R, indicating that in this tissue also, 5S is the
active enantiomer of 5RS. A comparison of the maximal
effects of 5S in the dog saphenous vein (78.3 ( 9.1%)
and femoral artery (15.8 ( 3%) shows that the response
was significantly (p e 0.001) greater in the vein than
in the artery.
In our previous report,1 we discussed the use of an
empirical ratio between the C20 value in the pithed rat
and the EC50 value obtained in the vein as a discrimi-
nator in the search of venous specific compounds. When
the same calculations were made from the number
displayed in Table 1, the following order of venous
specificity is obtained 5S (26) > 5RS (19) > 5R (16),
confirming that all the favorable properties of the
racemic (potency and selectivity) are present in only one
enantiomer: 5S. As all the curves were parallel, one
can speculate that the residual activity of 5R in these
assays is linked to the likely presence of small amounts
of 5S (<2% according to the accuracy of the analytical
method) in “pure” R enantiomer samples.
Resu lts a n d Discu ssion
The results of the biological evaluations of compounds
5 are presented in Figures 1 and 2, as well as in Table
1. In the pithed rat (Figure 1), the three compounds
were administered in cumulative doses iv to three
groups of rats. These doses caused dose-related pressor
responses. The effect of 5S was comparable to that of
5RS. 5R was significantly less potent than 5RS and
5S but caused comparable increases in arterial blood
pressure at the highest doses used. The maximal
pressor response was reached with 5R at 4 mg/kg but
with 5RS and 5S at 1 mg/kg. The experiments were
repeated using the same cumulative doses after block-
ade of R1-adrenoceptors with prazosin (100 µg/kg iv 10
min before) and after blockade of R2-adrenoceptors with
yohimbine (1 mg/kg iv 10 min before). Both the R1- and
R2-adrenoceptor antagonists led to significant and com-
parable displacement of the dose-response curve to the
right (data not shown). Prasozin also decreased the
maximal pressor response induced by compounds 5. The
maximal responses were reached with 5RS and 5S at
1 mg/kg in the control group and at 4 mg/kg in both
prazosin- and yohimbine-treated animals. These ex-
periments offer in vivo evidence that 5S is the eutomer
of the racemic mixture 5RS and acts as a partial agonist
at both R1- and R2-adrenoceptors.
The absolute configuration of 5S was obtained through
single-crystal X-ray diffraction analysis performed on
the dibenzoyl-D-tartaric acid salt, by Dr. C. Pascard at
ICSN (Gif sur Yvette). The absolute configuration of
the tartaric acid being known, the configuration of
carbon 2 is S (Figure 3). One atom of hydrogen
appeared on each nitrogen atom, the two C-N bonds
In dog femoral arteries, compounds 5 evoked weak
concentration-dependent contractions (data not shown);
the maximal responses and the affinities of the three
compounds were not significantly different and averaged

2934 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Cordi et al.
minimum of diethyl ether was added until a haze appeared;
the system was cooled to 5 °C and left overnight. The desired
compound was obtained after filtration and drying, as colorless
crystals (0.46 g, 6%): mp 163-164 °C; 1H NMR (DMSO-d6) δ
8.5-11.5 (m exchanged with D2O), 8.25 (s, 1H), 7 (d, 1H), 6.95
(dd, 1H), 6.9 (d, 1H), 6.45 (s, 2H), 3.55 (AB system, 2H), 2.95
(AB system, 2H), 2.7-2.9 (m, 2H), 2.25 (s, 3H), 1.8-2.1 (m,
in the imidazoline are equal (1.29 Å), and the N1
nitrogen atom is in equatorial position as anticipated
in the design process.1 Additionally, two hydrogen
bonds joined each of the nitrogens to two oxygen atoms
belonging to different molecules N1-H-O (2.73 Å) and
N3-H-O (2.76 Å). It is worth mentioning that the
absolute configuration disclosed in the eutomer is the
same as that seen for SDZ-NVI 08516 and SK&F
l-89748,17 two other R-adrenoceptor agonists exhibiting
a comparable chiral center which is in fact absent in
the endogenous hormones adrenaline and noradren-
aline.
In conclusion, our quest for a potent and selective
R-adrenoceptor agonist endowed with a particular venous
selectivity has terminated with the selection of 5S. The
compound is currently under development as S 18149
to test the initial hypothesis that such compounds might
be useful in the treatment of venous disease and the
prevention of ulcers. Further characterization of the
pharmacological properties of 5S has already appeared
in abstract forms.18,19
2H); [R]20 ) +52° (c ) 1, ethanol 95%). Anal. (C13H16N2‚
D
C4H4O4) C, H, N.
(S)-Sp ir o[(1,3-d ia za cyclop en t -1-en e)-5,2′-(7′-m et h yl-
1′,2′,3′,4′-tetr a h yd r on a p h th a len e)], F u m a r a te (5S). The
compound was prepared as described for the R enantiomer.
(R,S)-Spiro[(1,3-diazacyclopent-1-ene)-5,2′-(7′-methyl-1′,2′,3′,4′-
tetrahydronaphthalene)] (5RS, 3 g, 15 mmol, ee: 50%) was
employed as starting material, resulting from the neutraliza-
tion with aqueous NaOH, of the mother liquors from the
resolution of the R enantiomer and using dibenzoyl-D-tartaric
acid (5.65 g, 15 mmol) as chiral agent. After three crystal-
lizations in ethanol (100 mL/g), the pure diastereoisomeric salt
was neutralized and the free base converted to the fumaric
acid salt. The title compound was isolated as colorless crystals
(0.51 g, 11%), mp 163-165 °C. Spectroscopic characteristics
were identical to those of the R enantiomer: [R]20 -53° (c )
D
1, ethanol 95%). Anal. (C13H16N2‚C4H4O4) C, H, N.
7-Meth yl-3,4-d ih yd r o-(1H)-n a p h th a len -2-on e (1). Step
a : m -Tolyla cetyl Ch lor id e. Thionyl chloride (984 g, 7.3 mol)
was added to a solution of m-tolylacetic acid (1, 1,000 g, 6.66
mol) in toluene (3 L), while the temperature was maintained
at 50 °C. At the end of the addition, the reaction mixture was
heated at 80-85 °C until the gas evolution ceased. The
solution was then cooled at 40 °C and the solvent carefully
removed under reduced pressure. The acid chloride was used
without further purification in the following step.
Step b: 7-Meth yl-3,4-d ih yd r o-(1H)-n a p h th a len -2-on e
(1). m-Tolylacetyl chloride (1.000 g, 5.9 mol) in CH2Cl2 (3.5
L) was added dropwise to a stirred solution of AlCl3 (925 g,
6.95 mol) in CH2Cl2 (7.5 L) at 0 °C. At the end of the addition,
the reaction mixture was maintained at 0 °C for 15 min and
then lowered to -40 °C. Ethylene (468 g, 16.7 mol) was
bubbled slowly (430 g/h) into the mixture while the temper-
ature was kept below -30 °C. Reaction progress was followed
by gas chromatography. When starting material concentration
was below 5%, the reaction mixture was poured over a mixture
of water and ice (50/50, 18 kg) while the temperature was kept
in the 15-20 °C range. The mixture was diluted with CH2Cl2
(4.5 L). The phases were separated, the aqueous solution was
extracted with more CH2Cl2, and the pooled organic phases
were washed with aqueous NaHCO3 until neutrality. The
organic phase was dried over MgSO4 and evaporated under
reduced pressure. The solid residue was washed with diiso-
propyl ether to remove the isomeric 1,2,3,4-tetrahydro-5-
methyl-2(1H)-naphthalenone and dried under reduced pres-
sure (445 g, 47%), mp 61 °C with decomposition.
7-Met h yl-2(S)-[[1(R)-p h en ylet h yl]a m in o]-1,2,3,4-t et -
r a h yd r on a p h th a len e-2-ca r bon itr ile (2). 1(R)-Phenylethyl-
amine (757 g, 6.24 mol) was added dropwise, followed by acetic
acid (375 g, 6.24 mol) to a solution of 7-methyl-3,4-dihydro-
(1H)-naphthalen-2-one (1) (1000 g, 6.24 mol) in a mixture of
ethanol, methanol, and water (6 L, 4/1/1), at such a rate that
the temperature did not exceed 35 °C. A solution of sodium
cyanide (337 g, 6.86 mol) in water (1.5 L) was then added
dropwise and the reaction mixture heated to 40 °C for 1 h
during which the suspension became difficult to stirr. Water
(4.5 L) was added, and the mixture was stirred for 2.5 h at 40
°C, followed by 24 h at room temperature. Water (3 L) was
added again, and the suspension was cooled at -15 °C for 1
h, filtered, rinsed with ice cold ethanol, and dried under
reduced pressure to afford a white solid (1700 g, 94.5%): mp
112 °C; 1H NMR (CDCl3) δ 7.1-7.4 (m, 5H), 7 (d, 1H), 6.9 (dd,
1H), 6.4 (d, 1H), 4.25 (q, 1H), 3 (m, 2H), 2.6 (AB system, 2H),
2.2 (s, 3H), 2-2.3 (m, 2H), 1.65 (m exchanged with D2O), 1.45
(d, 3H).
Exp er im en ta l Section
Biology. Methods (pithed rat and isolated blood vessels)
described in ref 1 were used without changes.
Ch em istr y. Reagents were commercially available and of
synthetic grade. 1H NMR spectra relative to TMS were
recorded on Bruker 200 or 400 MHz spectrometers. Infrared
spectra were obtained as Nujol emulsion, on a Bruker Fourier
transform spectrometer. All new substances were homoge-
neous in TLC and exhibited spectroscopic data consistent with
the assigned structures. Elemental analyses (C, H, N) were
performed on a Carlo Erba 1108 instrument and agree with
the calculated values within the (0.4% range. Melting points
were obtained on a Reichert hot stage microscope and are
uncorrected. Silica gel 60, Merck 230-400 mesh, was used
for both flash and medium-pressure chromatography. TLC
were performed on precoated 5 × 10 cm, Merck silica gel 60
F254 plates (layer thickness 0.25 mm). Gas chromatography
was performed on a 5890 Hewlett-Packard instrument with a
CP Sil 5 CB column (50 m × 0.32 mm), on column injection
(150 °C), FID detection (280 °C), t° raising from 100 to 250 °C
at the rate of 15 °C/min and then holding this t° for 20 mn.
Chiral HPLC were performed on a Hewlett-Packard series
1050 instrument equipped with a UV variable detector set at
220 nm and a DAICEL Chiralpack AS column eluted with a
mixture of n-heptane/2-propanol/diethylamine (920/80/0.5).
(R)-Sp ir o[(1,3-d ia za cyclop en t -1-en e)-5,2′-(7′-m et h yl-
1′,2′,3′,4′-tetr ah ydr on aph th alen e)], Fu m ar ate (5R). Reso-
lu tion by F or m a tion of Dia ster eoisom er ic Sa lts.
A
solution of dibenzoyl-L-tartaric acid (9.41 g, 25 mmol) in
ethanol (200 mL) was added to a stirred solution of (R,S)-spiro-
[(1,3-diazacyclopent-1-ene)-5,:2′-(7′-methyl-1′,2′,3′,4′-tetrahy-
dronaphthalene)]1 (5RS, 5 g, 25 mmol) in ethanol (170 mL).
The solution was filtered and concentrated under reduced
pressure to provide an amorphous residue which was dissolved
in boiling ethanol (550 mL). After cooling at 20 °C for 2 h
and then at 5 °C overnight, crystals formed which were
filtered, washed with a small amount of cold ethanol, and dried
under reduced pressure (4.7 g, ee: 76%). This crystallization
procedure was repeated three times under the same conditions
(minimum amount of ethanol to ensure the complete dissolu-
tion = 100 mL/g) until enantiomeric purity was superior to
98%, as indicated by chiral HPLC. The pure diastereoisomeric
salt (1.3 g, ee: .96%) was taken up in water (10 mL) and
treated with concentrated aqueous NaOH (5 mL); the free base
was extracted with CH2Cl2 (3 × 15 mL). The combined organic
phases were dried over MgSO4, filtered, and evaporated to
yield a white solid (0.44 g, 2.2 mmole). The solid was dissolved
in boiling 2-propanol (20 mL) in the presence of fumaric acid
(0.255 g, 2.2 mmol) and the resulting solution filtered hot. A
[2(S)-(Am in om eth yl)-7-m eth yl-1,2,3,4-tetr a h yd r on a p h -
t h a len -2-yl][1(R)-p h en ylet h yl]a m in e, Dih yd r och lor id e
(3). A solution of 7-methyl-2(S)-[1(R)-phenylethyl]amino]-
1,2,3,4-tetrahydronaphthalene-2-carbonitrile (2, 1000 g, 3.44

Spiroimidazoline as R-Adrenergic Agonist
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2935
mol) in THF (7 L) was added dropwise to a suspension of
LiAlH4 (304 g, 8 mol) in THF (13 L) at such a rate that gas
evolution remained controlable and the temperature did not
exceed 20 °C. The suspension was stirred at 20 °C for 3 h
until the starting material had disappeared on TLC (methanol/
acetone, 80/20). The reaction mixture was hydrolyzed by
careful and succesive additions of water (0.3 L), 2 N NaOH
(0.35 L), and water (0.575 L) while the temperature was
maintained below 20 °C. The solid was filtered and washed
with THF (2 × 1 L), and the pooled organic solutions were
evaporated under reduced pressure. The residue was taken
up in ethyl acetate (6.5 L), and the hydrochloride salt was
formed by addition of 3.5 N HCl in ethyl acetate (2 L) at 0 °C.
The solid was filtered, washed with ethyl acetate, and dried
under reduced pressure to afford a white solid (1180 g, 93%):
mp 190 °C; 1H NMR (DMSO-d6) δ 10.15 (br s exchanged with
D2O, 2H), 8.74 (br s exchanged with D2O, 3H), 7.80 (br s, 2H),
7.46 (br s, 3H), 6.96 (AB system, 2H), 6.50 (s, 1H), 3.61-3.32
(m, 2H), 3.13-2.61 (m, 4H), 2.39-1.92 (m, 3H), 2.17 (s, 3H),
1.77 (d, 3H).
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(16) Nozulak, J .; Vigouret, J . M.; J aton, A. L; Hofmann, A.; Dravid,
A. R.; Weber, H. P.; Kalkman,H. O.; Walkinshaw, M. D.
Centrally Acting R1-Adrenoceptor Agonist Based on Hexahy-
dronapht[2,3-b]-1,4-oxazines and Octahydrobenzo[g]quinolines.
J . Med. Chem. 1992, 35, 480-489.
(17) De Marinis, R. M.; Hieble, J . P. l-1,2,3,4-Tetrahydro-8-
methoxy-5-(methylthio)-2-naphthalenamine: A Potent and Se-
lective Agonist at R1-Adrenoceptors. J . Med Chem. 1983, 26,
1215-1218.
(18) Verbeuren, T. J .; Vayssettes-Courchay, C.; Descombes, J .-J .;
Simonet, S.; Lacoste, J .-M.; Cordi, A. A.; Laubie, M. S 18149 is
a Partial Agonist at R-Adrenoceptors: Studies in Pithed Rats
and isolated Canine and Human Blood Vessels. Br. J . Pharma-
col. 1996, 117, 277P.
2(S)-(Am in om eth yl)-7-m eth yl-1,2,3,4-tetr a h yd r on a p h -
th a len -2-yla m in e, Dih yd r och lor id e (4). A solution of [2(S)-
aminomethyl-7-methyl-1,2,3,4-tetrahydronaphthalen-2-yl][1(R)-
phenylethyl]amine, dihydrochloride (3) (1000 g, 2.74 mol) in
methanol (12 L) was hydrogenated at 20 °C under 1 bar of
hydrogen and in the presence of Pd (5% Pd/C, 50% humidity,
100 g). Each time the flow of hydrogen decreased (twice), the
suspension was filtered and a new batch of catalyst (5% Pd/C,
50% humidity, 100 g) was added to the reactor. At the end of
the theoretical absorption (68 L), the catalyst was filtered off
and the solution was concentrated under reduced pressure.
The residue was stirred with hot acetone (5 L), cooled at 0 °C,
and filtered to afford, after drying under reduced pressure, a
1
white solid (559 g, 78%): mp 250 °C; H NMR (DMSO-d6) δ
8.87 (br s exchanged with D2O, 6H), 6.97 (dd, 2H), 6.9 (s, 1H),
3.21 (AB system, 2H), 3.03 (br s, 2H), 2.66 (AB system, 2H),
2.21 (s, 3H), 2.06 (t, 2H).
(S)-Sp ir o[(1,3-d ia za cyclop en t -1-en e)-5,2′-(7′-m et h yl-
1′,2′,3′,4′-tetr ah ydr on aph th alen e)], Fu m ar ate (5S). NaOH
pellets (353 g, 8.83 mol) were added to a suspension of 2(S)-
(aminomethyl)-7-methyl-1,2,3,4-tetrahydronaphthalen-2-yl-
amine, dihydrochloride (4, 1000 g, 3.8 mol), and formamidine
acetate (491 g, 4.75 mol) in ethanol (15.7 L). The reaction
mixture was stirred for 1 h at 20 °C, concentrated under
reduced pressure, and then taken up in 1.5 N HCl (14 L) and
extracted with ethyl acetate (2 × 2 L). The aqueous phase
was brought to pH 12.5 by the slow addition of 10 N NaOH
while the temperature was kept at 20 °C. The solid was
filtered, washed with water, and dried under reduced pressure
to afford a white powder (661 g, 87%), mp 182-183 °C. The
fumarate salt was prepared quantitatively in ethanol or
2-propanol at the concentration of 1/15: mp 162-165 °C.
Spectroscopic characteristics were identical to those of the
compound obtained by the other route.
Ack n ow led gm en t . The authors thank Michele
Hipeaux, Pascal Vrillaud, Yvette Menant, Elisabeth
Adnet, and Veronique Barou for their expert technical
assistance, and Angela D. Morris is thanked for help in
preparation of the manuscript.
(19) Vayssettes-Courchay, C.; Lacoste, J .-M.; Cordi, A. A.; Laubie,
M.; Verbeuren, T. J . In vivo Cardiovascular Effects of the
R-Adrenoceptor Agonist S 18149 in the Anaesthetized Dog. Br.
J . Pharmacol. 1996, 117, 255P.
Su p p or tin g In for m a tion Ava ila ble: X-ray analysis data
(5 pages). Ordering information is given on any current
masthead page.
J M970282M