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Abstract:

Industrial synthesis process for, and crystalline form I of, the compound
of formula (I):
##STR00001##
and also crystalline form I of the associated free base.
Medicinal products containing the same which are useful in the treatment
of disorders of the histaminergic system.

Claims:

1. A process for the synthesis of a compound of formula (I):
##STR00010## wherein a compound of formula (II): ##STR00011## is
reacted with ammonia at a temperature greater than 100.degree. C. to form
a compound of formula (III): ##STR00012## which is reduced to yield a
bicyclic amine of formula (IV): ##STR00013## which latter compound is
subsequently subjected: either to a coupling reaction, under basic
conditions in a polar medium, with a compound of formula (V):
##STR00014## wherein Y represents --CH2-Hal wherein Hal is a
halogen, or a --CH2--OSO2--R group wherein R is an
(C1-C6)alkyl group or a --C6H4--CH3 group, or to
reductive amination, in an acid medium, with a compound of formula (V'):
##STR00015## wherein R' and R'' represent, each independently of the
other, a (C1-C6)alkyl group, or R' and R'' together form a
group --(CH2)n-- wherein n=2-3, or one of the groups R' and R''
represents a hydrogen atom and the other represents a
(C1-C6)alkyl group, or to reductive amination with a compound
of formula (V''): ##STR00016## to yield the free base of the compound
of formula (I), which is placed in the presence of HCl to form the
compound of formula (I), which is isolated in the form of a solid.

2. The process according to claim 1, wherein the reaction mixture
obtained at the end of the reaction of the compound of formula (II) with
ammonia is subjected to pyrolysis.

3. The process according to claim 2, wherein the pyrolysis is carried out
at a temperature greater than or equal to 200.degree. C.

4. The process according to claim 2, wherein the pyrolysis is carried out
at a temperature greater than or equal to 280.degree. C.

5. The process according to claim 1, wherein the conversion of the
compound of formula (III) into the compound of formula (IV) is carried
out in the presence of hydrogen and a metal or metal-containing catalyst.

6. The process according to claim 1, wherein the compound of formula (V)
is 4-(3-chloropropoxy)benzamide.

7. The process according to claim 1, wherein the coupling reaction of the
compound of formula (IV) with the compound of formula (V) is carried out
in the presence of a carbonate, an amine or a hydroxide.

8. The process according to claim 1, wherein the coupling reaction of the
compound of formula (IV) with the compound of formula (V) is carried out
in the presence of potassium carbonate or triethylamine.

9. The process according to claim 1, wherein the coupling reaction of the
compound of formula (IV) with the compound of formula (V) is carried out
in a polar medium composed of one or more polar solvents selected from
water, alcohols, ketones, ethers, amides, DMSO and acetonitrile.

10. The process according to claim 1, wherein the coupling reaction of
the compound of formula (IV) with the compound of formula (V) is carried
out in a water/acetonitrile mixture or a water/isopropanol mixture.

11. The process according to claim 1, wherein the salt formation step in
the presence of HCl takes place in a solvent selected from water, acetone
and an alcohol.

12. The process according to claim 1, wherein the salt formation step in
the presence of HCl takes place in acetone or isopropanol.

13. The process according to claim 1, wherein the compound of formula (I)
is subjected to recrystallisation.

14. A compound of formula (V) ##STR00017## wherein Y represents a
--CH2--OSO2--R group wherein R is an (C1-C6)alkyl
group or a --C6H4--CH3 group.6

15. A compound of formula (V') ##STR00018## wherein R' and R''
represent, each independently of the other, a (C1-C6)alkyl
group, or R' and R'' together form a group --(CH2)n-- wherein
n=2-3, or one of the groups R' and R'' represents a hydrogen atom and the
other represents a (C1-C6)alkyl group.

16. The compound according to claim 15 which is
4-(3,3-diethoxypropoxy)benzamide.

17. A crystalline form I of the compound of formula (I): ##STR00019##
having an X-ray powder diffraction diagram exhibiting the following
diffraction lines (Bragg's angle 2 theta, expressed in degrees
.+-.0.2.degree.): 16.97.degree., 17.84.degree., 18.90.degree.,
20.32.degree., 23.87.degree., 27.10.degree., 27.86.degree. and
30.34.degree..

19. The crystalline form I according to claim 17, having a Raman spectrum
exhibiting a significant peak at the location 1606 cm-1 or 1676
cm.sup.-1.

20. The crystalline form I according to claim 17, having a Raman spectrum
exhibiting significant peaks at the locations 1676 cm-1, 1606
cm-1, 1564 cm-1, 1152 cm-1, 830 cm-1 and 296
cm.sup.-1.

21. A pharmaceutical composition comprising as active ingredient the
crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride according to claim 17, in combination with one or more
pharmaceutically acceptable, non-toxic, inert carriers.

22. A method of treating disorders of the histaminergic system, in a
subject in need thereof, comprising administration of an effective amount
of the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride according to claim 17.

23. A method of treating a condition selected from cognitive and
psycho-behavioural disorders associated with cerebral aging and with
neurodegenerative diseases, mood disorders, attention-deficit
hyperactivity syndrome, obesity and pain, in a subject in need thereof,
comprising administration of the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride according to claims 17.

24. A method of treating cognitive and psycho-behavioural disorders
associated with Alzheimer's disease, Parkinson's disease, Pick's disease,
Korsakoff's disease, Lewy body dementias, frontal and subcortical
dementias, frontotemporal dementias and vascular dementias, in a subject
in need thereof, comprising administration of the crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride according to claim 17.

25. A crystalline form I of the free base of the compound of formula (I):
##STR00020## having an X-ray powder diffraction diagram exhibiting the
following diffraction lines (Bragg's angle 2 theta, expressed in degrees
.+-.0.2.degree.): 6.25.degree., 12.55.degree., 17.74.degree.,
18.19.degree., 19.43.degree., 20.72.degree., 21.00.degree., 23.50.degree.
and 27.00.degree..

31. A pharmaceutical composition comprising as active ingredient the
crystalline form I of the free base of the compound of formula (I)
according to claim 25, in combination with one or more pharmaceutically
acceptable, non-toxic, inert carriers.

32. A method of treating disorders of the histaminergic system, in a
subject in need thereof, comprising administration of an effective amount
of the crystalline form I of the free base of the compound of formula (I)
according to claim 25.

33. A method of treating a condition selected from cognitive and
psycho-behavioural disorders associated with cerebral aging and with
neurodegenerative diseases, mood disorders, attention-deficit
hyperactivity syndrome, obesity and pain, in a subject in need to
thereof, comprising administration of the crystalline form I of the free
base of the compound of formula (I) according to claim 25.

34. A method of treating cognitive and psycho-behavioural disorders
associated with Alzheimer's disease, Parkinson's disease, Pick's disease,
Korsakoff's disease, Lewy body dementias, frontal and subcortical
dementias, frontotemporal dementias and vascular dementias, in a subject
in need thereof, comprising administration of the crystalline form I of
the free base of the compound of formula (I) according to claim 25.

Description:

[0001] The present invention relates to a process for the industrial
synthesis of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride of formula (I):

##STR00002##

[0002] The present invention relates also to crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-y]propoxy}benzamide
hydrochloride, to a process for its preparation and also to
pharmaceutical compositions containing it.

[0003] Crystalline form I of the free base of the compound of formula (I)
is, moreover, also obtained by the process of the invention and forms an
integral part of the invention, as do pharmaceutical compositions
containing it.

[0004] 4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
has the characteristic of interacting with central histaminergic systems
in vivo. These properties provide it with activity in the central nervous
system and, more especially, in the treatment of cognitive deficiencies
associated with cerebral aging and with neurodegenerative diseases.

[0005] 4-{3-[cis-Hexahydrocyclopenta[c]pyrrol-2(1H)-y]propoxy}benzamide,
its preparation in the form of an oxalate and its therapeutic use have
been described in Patent Application WO2005/089747.

[0006] In view of the pharmaceutical value of this compound it was
important to be able to obtain it by an effective synthesis process that
is readily transferable to the industrial scale, yielding
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride in a good yield and with excellent purity.

[0007] It was also important to be able to obtain
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride in a well-defined, perfectly reproducible crystalline form
having valuable filtration characteristics and ease of formulation.

[0008] The Patent Application WO2005/089747 describes obtaining
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide oxalate
in three steps starting from 4-hydroxybenzonitrile, which undergoes an
O-alkylation reaction before being coupled to an
octahydrocyclopenta[c]pyrrole-type ring system to form
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzonitrile. The
latter compound is finally subjected to basic hydrolysis in order to
yield 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide,
which is crystallised in the form of an oxalate. The yield for these
three steps is 46.6%.

[0009] The present invention relates to a new industrial synthesis process
which yields
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-y]propoxy}benzamide
hydrochloride with satisfactory purity from the pharmaceutical point of
view and in an effective yield from the industrial point of view. By
virtue of this process it is possible to ensure a very low level of
genotoxic impurities, which is compatible with regulatory requirements.

[0010] The present invention relates, more specifically, to a process for
the industrial synthesis of the compound of formula (I):

##STR00003##

which process is characterised in that the compound of formula (II):

##STR00004##

is reacted with ammonia at a temperature greater than 100° C. to
form the compound of formula (III):

##STR00005##

which is reduced to yield the bicyclic amine of formula (IV):

##STR00006##

which latter compound is subsequently subjected:

[0011] either to a coupling reaction, under basic conditions in a polar
medium, with a compound of formula (V):

##STR00007##

wherein Y represents --CH2-Hal wherein Hal is a halogen, or a group
--CH2--OSO2--R wherein R is a (C1-C6)alkyl group or a
--C6H4--CH3 group,

[0012] or to reductive amination, in an acid medium, with a compound of
formula (V'):

##STR00008##

wherein R' and R'' represent, each independently of the other, a
(C1-C6)alkyl group, or R' and R'' together form a group
--(CH2)n-- wherein n=2-3, or one of the groups R' and R''
represents a hydrogen atom and the other represents a
(C1-C6)alkyl group,

[0013] or to reductive amination with the compound of formula (V''):

##STR00009##

to yield the free base of the compound of formula (I), which is placed in
the presence of HCl to form the compound of formula (I), which is
isolated in the form of a solid.

[0014] In a preferred embodiment of the invention, the reaction mixture
obtained at the end of the reaction of the compound of formula (II) with
ammonia is subjected to pyrolysis. The pyrolysis in question is carried
out preferably at a temperature greater than or equal to 200° C.,
and even more preferably at a temperature greater than or equal to
280° C.

[0015] Conversion of the compound of formula (III) into the compound of
formula (IV) is advantageously carried out in the presence of hydrogen
and a metal or metal-containing catalyst.

[0016] Preference is given to the compound of formula (V) being
4-(3-chloropropoxy)benzamide.

[0017] The coupling reaction of the compound of formula (IV) with the
compound of formula (V) is preferably carried out in the presence of a
carbonate, an amine or a hydroxide. Among the preferred carbonates,
amines and hydroxides there may be mentioned potassium carbonate, caesium
carbonate, triethylamine, pyridine, potassium hydroxide, sodium hydroxide
and lithium hydroxide. Even more preferably, the coupling reaction of the
compound of formula (IV) with the compound of formula (V) is carried out
in the presence of potassium carbonate or triethylamine. This reaction is
moreover advantageously performed in a polar medium composed of one or
more polar solvents selected from water, alcohols, ketones, ethers,
amides, DMSO and acetonitrile. Preferred alcohols are methanol, ethanol,
isopropanol and butanol. The preferred solvents also include acetone and
methyl ethyl ketone among the ketones, tetrahydrofuran,
methyltetrahydrofuran and cyclopentyl methyl ether among the ethers, and
also N-methyl-2-pyrrolidone among the amides. Even more preferably, the
coupling reaction of the compound of formula (IV) with the compound of
formula (V) is performed in a water/acetonitrile mixture or a
water/isopropanol mixture.

[0018] In the case of reductive amination, in an acid medium, of the
compound of formula (IV) with a compound of formula (V'), the latter is
preferably 4-(3,3-diethoxypropoxy)benzamide.

[0019] Furthermore, the step of forming a salt from the free base of the
compound of formula (I) in the presence of HCl preferably takes place in
a solvent selected from water, acetone and an alcohol. Preferred alcohols
are methanol, ethanol and isopropanol. Acetone and isopropanol are more
especially preferred for this salt formation step.

[0020] Optionally, the compound of formula (I) isolated at the end of the
salt formation step is subjected to recrystallisation.

[0021] It is important to emphasise that this synthesis process makes it
possible to obtain the compound
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-y]propoxy}benzamide,
exclusively, in a satisfactory yield on the industrial scale, and not its
trans homologue. Besides this advantage, it makes it possible to keep the
levels of genotoxic impurities (especially 4-(3-chloropropoxy)benzamide)
present in the batches well below the regulatory threshold.

[0022] The compounds of formula (V) wherein Y represents a group
--CH2--OSO2--R wherein R is a (C1-C6)alkyl group or a
--C6H4--CH3 group and the compounds of formula (V') are
new and useful as intermediates in the synthesis of compound of formula
(I). The compound of formula (V'') is also useful as intermediate in the
synthesis of compound of formula (I).

[0023] The invention relates also to crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-y]propoxy}benzamide
hydrochloride obtained according to the process described above. This
crystalline form is well-defined, perfectly reproducible and consequently
has valuable characteristics of filtration, drying, stability and ease of
formulation.

[0024] Crystalline form I of the compound of formula (I) is characterised
by an X-ray powder diffraction diagram having the following diffraction
lines (Bragg's angle 2 theta, expressed in degrees ±0.2°):
16.97°, 17.84°, 18.90°, 20.32°,
23.87°, 27.10°, 27.86° and 30.34°.

[0025] More specifically, crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride is characterised further by the X-ray powder diffraction
diagram below, measured using a PANalytical X'Pert Pro MPD diffractometer
with an X'Celerator detector, and expressed in terms of line position
(Bragg's angle 2 theta, expressed in degrees ±0.2°) and
interplanar distance d (expressed in Å):

[0026] Besides that, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride has been characterised by Raman spectroscopy. Significant
peaks were observed in the following locations: 1676 cm-1, 1606
cm-1, 1564 cm-1, 1152 cm-1, 830 cm-1 and 296
cm-1.

[0027] Alternatively, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride may be characterised by the X-ray powder diffraction
diagram having the 8 significant lines given above and also by a Raman
spectrum having a significant peak at the location 1606 cm-1 or 1676
cm-1.

[0028] Obtaining this crystalline form has the advantage of allowing
especially rapid and efficient filtration and also the preparation of
pharmaceutical formulations having a consistent and reproducible
composition, which is especially advantageous when those formulations are
intended for oral administration. Furthermore, form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride has noteworthy properties of immediate dissolution.

[0029] The form thereby obtained is sufficiently stable to allow its
storage for an extended period without particular conditions for
temperature, light, humidity or oxygen levels. More specifically, form I
of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride has been found to be very stable over periods of up to 18
months under the following conditions: [0030] at 25° C. with a
humidity level of 60% in a double bag of polyethylene, [0031] at
30° C. with a humidity level of 65% in a double bag of
polyethylene, [0032] at 30° C. with a humidity level of 85% in a
double bag of polyethylene.

[0033] Another aspect of the invention relates to crystalline form I of
the free base of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2
(1H)-yl]propoxy}benzamide obtained according to the process described
above. This crystalline form is well-defined and perfectly reproducible.
Obtaining this form and isolating it in the course of the synthesis
process for the hydrochloride of formula (I) described above make it
possible to eliminate a large proportion of the genotoxic impurities
present in the batches.

[0034] Crystalline form I of the free base of the compound of formula (I)
is characterised by its X-ray powder diffraction diagram having the
following diffraction lines (Bragg's angle 2 theta, expressed in degrees
±0.2°): 6.25°, 12.55°, 17.74°,
18.19°, 19.43°, 20.72°, 21.00°, 23.50°
and 27.00°.

[0035] More specifically, crystalline form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-y]propoxy}benzamide is
characterised further by the X-ray powder diffraction diagram below,
measured using a PANalytical X'Pert Pro MPD diffractometer with an
X'Celerator detector, and expressed in terms of line position (Bragg's
angle 2 theta, expressed in degrees ±0.2°) and interplanar
distance d (expressed in Å):

[0036] In addition, form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has
been characterised by Raman spectroscopy. Significant peaks were observed
in the following locations: 292 cm-1, 618 cm-1, 1045 cm-1,
1483 cm-1, 1568 cm-1, 1683 cm-1.

[0037] Alternatively, form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide may be
characterised by the X-ray powder diffraction diagram having the 9
significant lines given above and also by a Raman spectrum having a
significant peak at the location 1683 cm-1.

[0038] Finally, form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has
also been characterised by solid-state NMR spectroscopy. Significant
peaks were observed at 112.2 ppm, 119.2 ppm, 127.2 ppm, 128.6 ppm, 132.4
ppm, 162.2 ppm and 173.2 ppm. More precisely, the 13C CP/MAS (Cross
Polarization Magic Angle Spinning) spectra have the following peaks
(expressed in ppm±0.2 ppm):

[0039] Pharmacological study of form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride and also that of form I of its free base have shown
substantial activity on the central nervous system which makes it
possible to establish its usefulness in the treatment of cognitive and
psycho-behavioural disorders associated with cerebral aging and with
neurodegenerative diseases, and also in the treatment of mood disorders,
attention-deficit hyperactivity syndrome, obesity and pain.
Neurodegenerative diseases more especially targeted are Alzheimer's
disease, Parkinson's disease, Pick's disease, Korsakoff's disease, Lewy
body dementias, frontal and subcortical dementias, frontotemporal
dementias and vascular dementias.

[0040] The invention relates also to pharmaceutical compositions
comprising as active ingredient crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide
hydrochloride, or crystalline form I of its free base, together with one
or more appropriate, non-toxic, inert excipients. Among the
pharmaceutical compositions according to the invention there may be more
especially mentioned those that are suitable for oral, parenteral
(intravenous or subcutaneous) or nasal administration, tablets or
dragees, granules, sublingual tablets, capsules, lozenges, suppositories,
creams, ointments, dermal gels, injectable preparations, drinkable
suspensions and chewing gums.

[0041] The useful dosage can be varied according to the nature and
severity of the disorder, the administration route and also the age and
weight of the patient. The useful dosage varies from 1 mg to 100 mg per
day, in one or more administrations. Preferably, crystalline form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride is administered at daily doses (expressed as free base
equivalent) of 2 mg, 5 mg and 20 mg (or, that is to say, 2.25 mg, 5.63 mg
and 22.52 mg of the hydrochloride).

[0042] The Examples hereinbelow illustrate the invention.

Preparation 1: 4-(3-Chloropropoxy)benzamide

[0043] 10.5 kg of 4-hydroxybenzamide, 10.58 kg of potassium carbonate and
83 kg of acetonitrile are introduced into a reactor. The mixture is
stirred and then there are added 24.14 kg of a solution of
1-bromo-3-chloropropane. The reaction mixture is heated at reflux for 4
hours. Water (105 L) is added in the hot state, the mixture is then
cooled to 5° C. and filtered. The filter cake is washed with water
and then with acetonitrile. The title product is obtained in the form of
a powder in a yield of 82%.

[0044] Melting point: 144° C.

Preparation 2: 4-(3-Oxopropoxy)benzamide

Step A: 4-(3,3-Diethoxypropoxy)benzamide

[0045] 500 mg of 4-hydroxybenzamide, 1.51 g of potassium carbonate, 10 mL
of DMF and 730 mg of 3-chloro-1,1-diethoxypropane are added to a flask.
The reaction mixture is stirred at 100° C. for 18 hours and then 5
mL of water are added. The aqueous phase is extracted with ethyl acetate,
and then the organic phases are collected, washed with water and
concentrated under reduced pressure. The product is obtained in the form
of a powder in a yield of 89% and with a chemical purity of 95%.

[0046] Melting point: 108° C.

Step B: 4-(3-Oxopropoxy)benzamide

[0047] 5 g of the product obtained in Step A, 100 ml of THF and 94 mL of
1N hydrochloric acid solution are added to a flask. The mixture is
stirred at ambient temperature for 1 hour. The aqueous phase is extracted
with dichloromethane, and then the organic phases are concentrated under
reduced pressure. The product is obtained in the form of a solid in a
yield of 96% and with a chemical purity of 93%.

[0048] Load 1 kg of diethyl 1,2-cyclopentanedicarboxylate and 1.02 kg of
27% ammonia into an autoclave. The reaction mixture is heated in the
autoclave at a temperature of 130° C. for a minimum of 4 hours.
After cooling to 60° C. and depressurisation, evaporation of the
solvent is carried out. The residue is then subjected to pyrolysis at
280° C. for 1 hour. The imide is purified by distillation in vacuo
(4-12 mbars) at a temperature of 200° C. After isolation, the
title product is obtained in a yield of 96%.

[0049] Melting point: 89° C.

Step B: cis-Octahydrocyclopenta[c]pyrrole

[0050] 1 kg of the imide of Step A, 250 g of copper chromite and 2 L of
dioxane are loaded into a reactor. The reaction mixture is stirred at a
temperature of 265° C. and under a hydrogen pressure of 205 bars
until the absorption of hydrogen is complete. After cooling of the
reactor, the catalyst is filtered off.

[0051] The hydrogenation liquors are loaded into a separator and then 0.37
L of water is added.

[0052] The pH is adjusted to a pH of less than 3 by adding sulphuric acid
96%. The lower, aqueous phase is drawn off. After adding 2.5 L of water,
the residual dioxane is removed by azeotropic distillation with
monitoring of the refractive index. The pH is then brought to 13 by
adding 30% sodium hydroxide solution. The title product is purified by
azeotropic distillation with water to obtain a 30% solution by weight in
a yield of 83%.

[0053] 13.35 kg of 4-(3-chloropropoxy)benzamide obtained according to
Preparation 1, 10.33 kg of potassium carbonate and 168 kg of acetonitrile
are introduced into a reactor. The mixture is stirred. There are then
loaded 34.74 kg of cis-octahydrocyclopenta[c]pyrrole in a 30% aqueous
solution, 26.7 L of water. The reaction mixture is heated at reflux until
all the starting material has been consumed. Then water (13.3 L) is
added. The mixture is cooled to 5° C., before being filtered and
washed with water. The title product is obtained in the form of a solid
in a yield of 81% and with a chemical purity of 96%.

[0057] 14.69 kg of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and 122
L of water are introduced into a reactor. A solution of 6.81 kg of 37%
hydrochloric acid in 11.54 L of water is also prepared. 13.75 kg of this
acid solution are added to the reactor. The mixture is stirred for 1 hour
at ambient temperature, and then for 1 hour 30 minutes at 60° C.
The suspension is filtered in the hot state and the filter is then rinsed
with water. A solvent change is then carried out on the filtrate, keeping
the volume constant, in order to obtain an isopropanol/water ratio of
9/1. The product is isolated at 0° C. and the precipitate obtained
is washed with isopropanol. The title product is finally obtained in a
yield of 89% and with a chemical purity greater than 99%.

[0058] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the crystalline
form I of the hydrochloride was obtained.

[0059] The hydrochloride salt obtained in Step D is recrystallised from a
mixture of isopropanol (264 kg) and water (37.4 L). The mixture is heated
at reflux for 45 minutes. The solution is filtered in the hot state and
then rinsed with isopropanol. Crystallisation is then initiated at
55° C. The mixture is maintained at that temperature for 40
minutes before being cooled to 0° C. After several hours, the
product is isolated by filtration. After washing with isopropanol, the
title product is obtained in the form of a powder in a yield of 93% and
with a chemical purity greater than 99%.

[0060] Melting point: 213-215° C.

[0061] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the crystalline
form I of the hydrochloride was obtained.

[0064] 15.2 kg of 4-(3-chloropropoxy)benzamide, 40.28 kg of
cis-octahydrocyclopenta[c]pyrrole in 30% aqueous solution, 63.84 kg of
water, 21.48 kg of isopropanol and 14.39 kg of triethylamine are
introduced into a reactor. The reaction mixture is stirred and heated at
reflux until all the starting material has been consumed. The reaction
mixture is then cooled to 20° C., before being filtered and washed
with a mixture of isopropanol and water. The product is obtained in the
form of a powder in a yield of 83% and with a chemical purity of 97%.

[0068] 16.49 kg of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide, 16.36
kg of acetone, 6.76 kg of concentrated aqueous hydrochloric acid and
18.96 kg of water are introduced into a reactor. The mixture is stirred
and heated at 50° C. for 1 hour. The mixture is then filtered in
the hot state into a second reactor containing 57.67 kg of acetone and
1.65 kg of water. The mixture is then brought to reflux and 73.32 kg of
acetone are added. Reflux is maintained for 10 minutes and then cooling
to 0° C. is carried out. The product is filtered off and the solid
obtained is washed with acetone. The product is obtained in the form of a
powder in a yield of 85% and with a chemical purity greater than 99%.

[0069] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the crystalline
form I of the hydrochloride was obtained.

[0070] The procedure is the same as that described in Step A of Example 1.

Step B: cis-Octahydrocyclopenta[c]pyrrole

[0071] The procedure is the same as that described in Step B of Example 1.

Step C: cis-Octahydrocyclopenta[c]pyrrole hydrochloride

[0072] 2 g of cis-octahydrocyclopenta[c]pyrrole are dissolved in 10 mL of
ethanol in a flask. The solution is cooled to 0° C., and there are
then added 1.64 mL of concentrated hydrochloric acid solution (11M). The
reaction mixture is stirred at 20° C. for 30 minutes before being
concentrated under reduced pressure. The reaction mixture is stirred in
methyl tert-butyl ether at 0° C. The product is isolated by
filtration in the form of a solid in a yield of 83% and with a chemical
purity of 99%.

[0074] 915 mg of the product obtained in Step C, 1.65 g of sodium
triacetoxyborohydride, 45 mL of THF and 7.5 mL of trimethyl orthoformate
are added into a reactor. There are then added 1 g of the compound
obtained in Preparation 2. The reaction mixture is heated at 40°
C. for 50 minutes and then cooled to ambient temperature. There are then
added a saturated NaHCO3 solution. The aqueous phase is extracted
with ethyl acetate, and then the organic phases are combined and washed
with water. The organic phase is dried over MgSO4, filtered and
concentrated under reduced pressure. The residue is suspended in an
isopropanol/water mixture in the presence of hydrochloric acid. The
reaction mixture is heated at 40° C. then cooled to 5° C.
The product is isolated by filtration in the form of a solid in a yield
of 33% and with a chemical purity of 98%.

[0075] Characterisation of the product thereby formed, using the
techniques given in Examples 4 to 5, demonstrated that the crystalline
form I of the hydrochloride was obtained.

EXAMPLE 4

Crystalline Form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride

[0076] Prior to recording the X-ray diffraction diagram, the samples
obtained according to the procedure described in one of Examples 1 to 3
were milled for 30 seconds at 30 Hz in the presence of 100 μL of
anhydrous ethanol per 200 mg of active ingredient in a 25-ml
stainless-steel jar containing 2 stainless-steel balls.

[0086] The X-ray powder diffraction diagram of form I of the
4-{3-[cis-hexahydrocyclopenta-[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride thereby obtained is expressed in terms of line position
(Bragg's angle 2 theta, expressed in degrees ±0.2°),
interplanar distance (expressed in Å) and relative intensity
(expressed as a percentage relative to the most intense line). The
significant lines are collated in the following table:

Crystalline Form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride

[0094] Form I of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
hydrochloride was characterised by Raman spectroscopy. The spectra were
recorded in reflection mode (PerkinElmer) and transmission mode (Cobalt)
with laser focalisation of 785 nm and 830 nm respectively, using a CCD
detector. The wavelength shift depends on the material and is
characteristic of that material, which allows analysis of the chemical
composition and of the molecular arrangement of the sample studied. The
spectra are acquired:

[0095] in reflection mode with a laser power of 400 mW, a spot size of 100
μm, five exposures of five seconds and a spectral resolution of 2
cm-1,

[0096] in transmission mode with a laser power of 650 mW, a spot size of 4
mm, twenty exposures of 3 seconds and a spectral resolution of 2
cm-1.

[0097] The spectral range explored ranges from 0 to 3278 cm-1 in
reflection mode and from 37 to 2400 cm-1 in transmission mode.

[0108] The X-ray powder diffraction diagram of form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide
obtained according to the process of one of Examples 1 to 3 is expressed
in terms of line position (Bragg's angle 2 theta, expressed in degrees
±0.2°), interplanar distance (expressed in Å) and relative
intensity (expressed as a percentage relative to the most intense line).
The significant lines are collated in the following table:

Crystalline Form I of the Free Base of
4-{3-[cis-hexahydrocyclopenta[c]-pyrrol-2(1H)-yl]propoxy}benzamide

[0109] Form I of the free base of
4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}-benzamide was
characterised by Raman spectroscopy. The spectra were recorded in
transmission mode (Cobalt) with laser focalisation of 830 nm using a CCD
detector. The wavelength shift depends on the material and is
characteristic of that material, which allows analysis of the chemical
composition and of the molecular arrangement of the sample studied. The
spectra are acquired with a laser power of 650 mW, a spot size of 4 mm,
twenty exposures of 0.9 second and a spectral resolution of 2 cm-1.
The spectral range explored ranges from 37 to 2400 cm-1.