Note: Descriptions are shown in the official language in which they were submitted.
7~6;~
This invention relates to an optically active ben-
zamide, the process for its preparation, and therapeutic
compositions containing it.
; More precisely, the present invention relates to
levorotatory N-(ethyl-2~pyrrolidinomethyl)-2-methoxy-5-
sulphamoyl benzamide, the process for its preparation and
therapeutic compositions which contain it as their active
principle.
N-(L-ethyl-2-pyrrolidinomethyl)-2-methoxy-5-
sulphamoyl benzamide of formula
fEI2 l H2
CONH - CH - CH* CH
2 \ / 2
N
i~ ~ - OCH3 1~H5
H2NO2S - ~
has been known for some time, and has been available commer~
cially for some time under the common name of Sulpiride.
This compound has found widespread application in
` the neurological and psychiatric field, administered either
along or in association with other known tranquillisers.
As can be seen from the stated formula, Sulpiride
.
~ comprises one asymmetric carbon atom (indicated by an aster
~: :
isk), and is therefore a mixture of two optical antipodes.
It~has now been found that in reality the two opti-
- caL antipodes present in the raceme Sulpiride have very
:: :
different activity and toxicity values, such that they in
practice constitute t~o different therapeutic substances.
More eXactly, ~t~has been found that levarotatory
.: :
~ N~ ethyl-2-pyrrolidinomethyl)-2-methoxy-5 sulphamoyl ben-
. ~ :
zamide is much more active than the dextrorotatory isomer,
and ~ts toxicity is also much lower against all logical
expectancy.
Having determined the high therapeutic quality of
--1--
~7~6;~
levarotatory N~ ethyl-2-pyrrolidinomethyl)-2-me~hoxy-5-
sulphamol benzamide, the problem was posed of separating the
raceme Sulpiride containing it, by an economical industrial
process.
However, all attempts made to resolve the raceme
Sulpiride have either been totally negative or have at the
most led only to the isolation of small quantities of the
levarotatory isomer~
It was therefore absolutely impossible to base an
industrial process on these methods of resolution.
An industrial process has now been discovered, and
constitutes the object of the present invention, which star-
ting rom a raw material available commercially at low cost,
enables very pure levarotatory N-(l-ethyl-2-pyrrolidinomethyl)-
2-methoxy-5-sulphamoyl benzamide to be obtained at very high
yields, using a very simple and economical process.
The new process of the present invention is repre-
sented diagrammatically by the following reaction sequence~
1) ~ 1
acetylation ~ J -COOH
N N
H (levo) CO
CH3
20 2) reduction r~
-COOH ~ ~ J -CH2OH
N N
CO I 2
: CH3 ¦levo) CH3 (levo)
` ~ : -
3) r ¦ chlorination¦ NH~
-CH2OH ~ ~ ~ -CH2cl ~ ~ -CH2NH2
CH CH2 CH2
1 2 (levo) ¦ (levo) I tlevo)
CH3 -2- CH3 CH3
.
~76~i~
4 ) CO-OR
CH2 -NH2 + H2N2 ~J - ROH
1H3 ( levo)
CO - NH -- CH 2 ~ ~ , J
N
- OCH3 CH2
J ¦ (levo)
H2NO~S - ~ . CH3
It has in fact bsen surprisingly found that star-
ting with levarotatory proline, which is a natural product
available commercially at low cost, it is possible to subject
it to a series of chemical transformations to obtain levaro-
tatory N-ethyl-2-aminomethyl-pyrrolidine, without there
~ being any racemisation or inversion of optical activity of
: the product during the process steps.
The levorotatory N-ethyl-2-aminomethyl-pyrrolidine
obtained as the final product of these chemical transforma-
~`~ tions:of proline can be reacted with an ester of 2-methoxy-
S-sulphamoyl benzoic acid:under suitable conditions, to obtain
N~ ethyl-2-pyrrolidino-methyl~-2-methoxy-5-sulphamoyl ben-
~ zamide, thi5 being done under r~ther drastic:conditions of
.~; temperature, time and mechanical homogenization of the mass,
:
to obtain the final levarotatory pxoduct with nearly quanti-
tative yields.
:
A description is gLven hereinafter in detail of the
:~ ~0 individual stag s of the process according to the present
~: invention: ;;
: 1. The levarotatory proline i6 acetylated in solution
with a suitable acetylating substance such as acetyl chloride
or acetic anhydride. The acetylation is:preferably carried
; -3-
~7~
out in an aqueous solution with a strong excess of acetic
anhydride.
The reaction is exothermic.
The levorotatory acetyl-proline precipitates by
cooling and is separated by filtration.
A very pure crystalline product is obtained in a
yield of around 90%.
2. The levorotatory acetyl-proline undergoes reduction
with a reducing system which acts simultaneously, under the
same conditions, on the acetyl and carboxyl groups. Good
results are obtained by using metal hydrides in an organic
solvent.
Particularly good yields, of around 60% are obtai-
; ned with LiAlH4 in tetrahydrofuran.
The reduction is carried out under reflux, and theproduct is separated b~ precipitating the unreacted acetyl-
proline from the reaction mixture by means of an alkaline
'~ base.
The levorotatory N--ethyl-2-pyrrolidino methanol is
,separated from the filtrate by dietillation under vacuum.
3. The levorotatory N-ethyl-2-pyrrolidino methanol is
transformed into the corresponding 2-methyl amine by firstlv
substltuting the hydroxyl with an active chlorine atom, and
then reacting~thechlorine atom, and then reacting the chloride
with ammonia~
The chlorine derivative of the alcohol can be pre-
pared using any suitabLe reactant system.
Preferably, the reaction is conducted with thionyl ----
chloride in an anhydrous chlorinated organic solvent such as
CHC13 , CC14 , CH2C12 , between ambient temperature and
60C.
The thionyl chloride can be used either in the
stoichiometric ratio or in slight excess.
-4-
..... ........... .....~ ,- , ~ ,
'''
~'a7~
When the reaction has terminated, the solvent is
eliminated and the residue is reacted with methanolic or
ethanolic ammonia at ambient temperature.
The levorotatory N-ethyl-2-aminomethyl-pyrrolidine
which has Eormed is separated, with yields of around 50%, by
eliminating the alcoholic solvent, dissolving it in an alka-
line aqueous solution and extracting it from the aqueous
solution by a suitable organic solvent, preferably ethyl ether.
4. The levorotatory N-ethyl-2-aminomethyl-pyrrolidine
is reacted with an ester of 2-methoxy-5-sulphamoyl benzoic
acid in the absence of solven~ at a temperature of 80-90C,
this temperature being maintained without adding external
heat because of the exothermic nature of the reaction, and
; using for mixing the reactants a Z mixer, this being criti-
cally necessary for carrying out the reaction (Spanish Patent
428,341).
Very pure levorotatory N-(l-ethyl-2-pyrrolidino
methyl)-2-methoxy-5-sulphamoyl benzamide i5 obtained by cry-
stallisation from the reaction mass using a suitable solvent,
preferably ethanol, giving yields of 90-95%.
Alternatively, stages 3 and 4 described above can
be carried out in succession in the same reactor, without
separating the intermediate amine. In this case, after ~li-
minating the alcohol and unreacted ammonia by evaporation,
~ the residue is mixed directly with the ester of 2-methoxy-5-
`~ sulphamoyl benzoic acid, in the absence of solvents, and
using a Z mixer for mixing purposes.
The levorotatory N-(l-ethyl-2-pyrrolidinomethyl)-
2-methoxy-5-sulphamoyl benzamide obtained by the process of
the present invention has the following characteristics:
M.P. - 186-188C (n.c.)
~C1D = -68.5 (C = 1% in DMF)
Purity = 99. 5%
-5-
. . .
7~62
IR See Fig. 1 which shows the superimposed spectra
for the product obtained by the process in four stages and by
the process in three stages.
TLC over silica gel 60 F 254
Eluent isopropanol : methano] : ammonia, conc. 8:1:1
Detector: UV 254 or Drayendorff
Rf = 0.40 approx.
The new product can be administered orally mixed
with the normal pharmaceutical diluents such as lactose, mag-
nesium stearate etc., to form capsules or tablets.
It can also be administered parenterally in an aque-
ous solution in the form of a salt, for example a sulphate.
In order to facilitate the reproduction of the pro- -
cess according to the present invention, one practical embo-
diment is described hereinafter by way of non-limiting example
only.
EXAMPLE
; 1. Preparation of the levo N-acetyl-proline.
11.5 kg of levo-proline are dissolved in 30 1 of
water, and 21.5 kg of acetic anhydride are added to the
solution under agitation~
! The temperature rises spontaneously, and the mix-
ture is allowed to stand under agitation Eor a further 20-30
minutes.
The reactor is then cooled to a temperature of 0-
4C and is left to stand until the crystalline mass completely
separates (about 12 hours). It is filtered, the precipitate
is washed with iced water and dried. A further 10 kg of
product are recovered from the mother liquor after adding a
; 30 little isopropanol.
A total of 15 kg of levo N-acetyl-proline are
obtained, having a M.P. of 89C and a yield of 95~.
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t~
Percentage Anaylsis;
Calculated Found
C 53.49 53.35
H 7.06 7.00
N 8.90 8.95
2. Preparation of the levo N-ethyl-2-pyrrolidino
methanol.
15 kg of N-acetyl-proline are added to a solution
containing 14.25 kg of LiAlH4 in 500 litres of tetrahydro-
furan. The solution is heated under reflux for 24 hours.
After this time it is cooled to 0C, then 100 lit-
res of tetrahydrofuran containing about 4% of water and 12
litres of 20~ NaOH are added.
The precipitate formed is filtered, the tetrahydro-
furan is evaporated and the residue is distilled under vacuum.
9 kg of N-ethyl-2-pyrrolidino methanol are obtained,
having a B.P. of 80C/16 mm and a ~ield of 75~.
Percentage Anaylsis: -
Calculated Found
C 65.07 ~ 64.95
H 11.70 11.72
N 10.84 10.80
~ 3. Preparation of the levo N-(l-ethyl-2-pyrroli-
dinomethyl~-2-methoxy-5-sulphamoyl benzamide.
; 9 kg of levo~N-ethyl-2-pyrrolidinomethanol are
dissolved in 200 1 of CH~C12, and 6 kg of thionyl chloride
are dripped into this~solution under cold conditions. The
solution is agitated for 6 hours at ambient temperature and
then for Z hours under boiling, and is evaporated to dryness.
The Gily residue is taken up in ethanol saturated with ammo-
~, ,
nia, and the mixture is kept under agitation at ambient
temperature for one night. The alcohol and ammonia are then
evaporated under vacuum.
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,
~76~2
The residue is taken up in a little water, NaOH
is dripped in and the mixture extracted with ethyl ether.
The ether phase is dried and evaporated.
The residue from the evaporation (about 5 kg) to-
gether with 9 kg of ethyl-2-metho~y-5-sulphamoyl benzoate are
ed into a Z mixer and the mixture is heated to 85C.
After a certain time, a crystalline powder begins
to separate from the liquid mass. The reaction is exothermic
and the tempera-ture is maintained spontaneously at 80-85C
without any further addition of heat. The reaction is com-
plete in 8 hours.
The powder obtained is dissolved under cold condi-
tions in 400 litres of water containing 4 litres of concen-
trated hydrochloric acid, the solution is filtered and neu-
tralized with sodium bicarbonate.
The crystalline powder obtained is recrystallized
from ethanol.
11 kg of levo-N-(l-ethyl-2-pyrrolidinomethyl)-2-
methoxy-5-sulphamoyl benzamide are obtained having a purity
of 99.5% and a yield of 92% calculated on the ester.
The product obtained has the following characteris-
tics:
M.P. = 186-188C
[~]D = 68.5 (c - 1% in DMF)
Purity = 99.5%
Percentage Analysis:
- Calculated Found
C 52.77 52.65
H 6.79 6.72
:~ 3~ N 12.30 12.20
~ -8-
