Note: Descriptions are shown in the official language in which they were submitted.
lOSS9S~
This invention relates to a novel process for preparing the
psychotropic and gastric ulcer inhibiting compound l-ethyl-2-(2'-methoxy-5'-
sulphonamidobenzoyl)-aminomethylpyrrolidine of the general formula (I)
OCH3
CONHCH2 ~ (I)
S2NH2 C2H5
called Sulpiride (Arch. Franc. Mal. Appar. Digest 59, 5O /1970/; Sem. Hop.
45, 3028 /1969/), as well as the salts thereof formed with therapeutically
acceptable acids.
Several methods are known from the literature for the preparation
of the compound of formula (I) and of the hydrochloric acid salt thereof.
According to Hungarian Patent Specification No. 153,310 the com-
pound of formula (I) is prepared by heating 2-methoxy-5-sulphonamidobenzoic
acid with excess thionyl chloride and condensing the formed acid chloride
with 1-ethyl-2-aminomethylpyrrolidine. The hydrochloric acid salt of the
compound of formula (I) crystallizes from the reaction mixture on the addi-
tion of water. The said specification refers only to the preparation of the
hydrochloric acid salt without giving any information about the yield. The
main drawback of this method of preparation is the small amount and the
impure nature of the hydrochloric acid salt obtained in course of the con-
densation of the acid chloride with 1-ethyl-2-aminomethylpyrrolidine;
besides, losses are involved in the purification and conversion of said salt
into the corresponding base. These drawbacks are particularly conspicuous
when the method is to be applied on a larger scale.
According to the United States Patent Specification No. 3,342,826
the compound of formula (I) is obtained in the following manner: the
carbonyl-diimidazole is prepared from imidazole and phosgene in dry benzene,
the imidazole hydrochloride is separated by filtration, the solution is
evaporated to dryness, the obtained residue is dissolved in anhydrous
tetrahydrofurane and reacted with 2-methoxy-5-sulphonamidobenzoic acid. The
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compound of the formula (I) is obtained by reacting the N-(2-methoxy-5-
sulphonamidobenzoyl)-imidazole obtained by the above reaction with 1-
ethyl-2-aminomethylpyrrolidine. There is no reference in the specification
concerning yields and the physical parameters of the base or of its hydro-
chloric acid salt. This method of preparation has a number of drawbacks.
On the one hand, dry solvents have to be used in every step; moreover, the
first reaction (preparation of carbonyl-diimidazole) has to be performed in
a dry nitrogen atmosphere. Moreover this step involves also the use of the
extremely poisonous phosgene. Besides, the solvents have to be removed by
evaporation under vacuum twice in course of the process, leading to unavoid-
able losses, thus to an uneconomic method. The process is highly sensitive
to both moisture and oxygen and therefore unsuited especially for the
preparation of larger batches.
According to the Belgian Patent Specification No. 787,180 compound
of formula (I) is prepared by first producing tris-(l-ethylpyrrolidyl-2-
methyl)-phosphorus amide from l-ethyl-2-aminomethyl-pyrrolidine and phos-
phorus oxychloride in pyridine solution and reacting this reaction product
with 2-methoxy-5-sulphonamidobenzoic acid. After evaporation the hydro-
chloric acid salt is formed which after purification gives the basic form of
the compound of formula (I). The yield, related to l-ethyl-aminomethyl-
pyrrolidine, amounts to 10.5 %, while related to the acid used as starting
material to 34.5 %. The main disadvantage of the method is its low yield,
further the fact that it requires materials (pyridine and phosphorus oxy-
chloride together) which, particularly in case of large batches, cause an
extremely intensive evolution of heat. Consequently, the method cannot be
recommended for production on commercial scale, and the low yields make it
anyhow uneconomical.
In the Belgian Patent Specification No. 787,794 the compound of
formula (I) is obtained in the following manner. First the ethyl ester of
2-methoxy-5-sulphonamidobenzoic acid is converted with hydrazine hydrate
into the acid hydrazide (yield: 86 %) from which the acid azide is prepared
with hydrochloric acid and sodium nitrite. Then the acid azide is directly
-- 2 --
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reacted with l-ethyl-2-aminomethyl-pyrrolidine in dioxane solution. After
treatment with hydrochloric acid the hydrochloric salt of the compound of
formula (I) is obtained which, when subjected to precipitation with ammonia,
gives the corresponding base. The yield of the end-product of formula (I)
related to 2-methoxy-5-sulphonamidobenzoic-hydrazide is 42.6 %, to 1-ethyl-
2-aminomethyl-pyrrolidine 21.3 %, and to the starting substance, 2-methoxy-
5-sulphonamidobenzoic acid ethyl ester 36.6 %. One of the main drawbacks of
this method is the overall low yield. In addition, the linking of the
finished acid component with the base component proceeds in four steps
(ester, hydrazide, azide, final product).
The object of this invention is to ensure, on eliminating the
drawbacks of the known procedures, a method by means of which the compound
of formula (I) can be prepared in a simple way and with good yields even on
commercial scales.
The invention is based on the following discoveries:
a) The chlorine atom in the compound of formula (II)
O~C~2- W (II)
C2H5
S2NH2
can be easily and with gOoa yield exchanged to the methoxy group.
b) The compound of general formula (II) is obtained simply and with
good yield by reacting 2-chlorobenzoic acid with chlorosulphonic acid,
amidating the obtained 2-chloro-5-chlorosulphonylbenzoic acid, and reacting
the reactive derivative of the thus-obtained 2-chloro-5-sulphonamidobenzoic
acid, e.g. its lower (Cl ~) alkyl ester or chloride with l-ethyl-2-amino-
methyl-pyrrolidine.
This discovery is surprising for more than one reason. Namely,
the halogen atoms linked to the benzene ring are known to be, as a rule,
only slightly reactive, provided they do not contain so-called loosening
groups. The sulphonamide and carboxylic acid groups in ortho- or para-
-- 3 --
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position to the halogen atom exert such a loosening effect (so-called
negative substituents). Thus, it would be logical to expect in course of
the reaction of the chlorine atom of compound of formula (Il) ~ith the
methoxide anion, particularly under relatively strong conditions, an inter-
action between said chlorine atom and the tertiary amine group too, thus
e.g. with the nitrogen atom of the ethyl pyrrolidine group in compounds of
formula (I) and (II), which might lead in both cases to the formation of
considerable quantities of quaternary-type by-products and this to the
deterioration of the yield and purity of the desired compound of formula
(I) during the conversion of compound of formula (II) into compound of for-
mula (I). However, by changing the chlorine atom to the methoxy group the
compound of formula (I) can be obtained in good yield and good degree of
purity from compound of formula (II), proving that no quaternary products
are formed in any significant amount, hence the exchange of the chlorine
atom to the methoxy group is a surprisingly selective process despite the
strong reaction conditions.
This discovery is further surprising since it would logically
follow that the reactive derivatives of 2-chloro-5-sulphonamidobenzoic acid
have the same reactivity as the chlorine atom in compound of formula (II).
Thus, it might be expected that during the preparation of the compound of
formula (II), when the reactive derivative of 2-chloro-5-sulphonamidobenzoic
acid is reacted with 1-ethyl-2-amino-methylpyrrolidine, the chlorine atom
in position 2 will react, particularly under relatively strong reaction con-
ditions, with the nitrogen atom of the ethylpyrrolidine group, again leading
to the formation of quaternary-type by-products and thus to the deterioration
of the yield and purity of the desired compound of formula (II). It is,
however, possible to obtain the compound of formula (II) in pure state and
good yields from the corresponding reactive derivatives of 2-chloro-5-
sulphonamidobenzoic acid and 1-ethyl-2-aminomethylpyrrolidine proving that
no significant amounts of the quaternary-type products are formed in course
of this reaction either. Hence the interaction between the reactive deriv-
atives of 2-chloro-5-sulphonamidobenzoic acid and 1-ethyl-2-aminomethyl-
-- 4 --
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pyrrolidine produces with surprising selectivity the compound of formula (II)
even under relatively strong reaction conditions.
On the basis of the aforesaid the invention relates to a method
for the preparation of 1-ethyl-2-(2'-methoxy-5'-sulphonamidobenzyl)-amino-
methyl-pyrrolidine of formula (I) and the acid-addition salts thereof,
wherein
a) the acid amide derivative of formula (II) is reacted with a
metal methoxide, or
b) a reactive derivative of 2-chloro-5-sulphonamidobenzoic acid is
reacted with 1-ethyl-2-aminomethyl-pyrrolidine, the obtained acid-amide
derivative of formula (II) is reacted with a metal methoxide and, if desired,
the obtained compound of formula (I) is converted into a salt by means of
acids.
The 2-chloro-5-chlorosulphonylbenzoic acid is a compound known
from the literature (Swiss Patent ~o. 351,281); it is prepared by the reac-
tion of 2-chlorobenzoic acid with an excess of chlorosulphonic acid, pref-
erably by heating in the absence of solvent. Thereafter the excess of
chlorosulphonic acid is decomposed with water and the precipitate consisting
of crude 2-chloro-5-chlorosulphonylbenzoic acid is used in the next step.
The 2-chloro-5-sulphonamidobenzoic acid is a compound known from
the literature (J. Pharm. Pharmacol. 1~, 679 /1962/). It can be prepared by
reacting 2-chloro-5-chlorosulphonylbenzoic acid with a concentrated solution
of ammonia. As solvent a lower aliphatic alcohol, preferably isopropanol,
can be used. At the beginning of the reaction a low temperature of about
O C is chosen to maintain the ammonia concentration and the reaction is
finished at a higher, e.g. room temperature.
In order to convert 2-chloro-5-sulphonamidobenzoic acid into the
compound of formula (II), said acid is first converted into one of its more
reactive derivatives, preferably into an ester, acid halide or mixed
anhydride. From the esters those formed with aliphatic alcohols of 1 to 4
carbon atoms were found to be the most favourable. From the acid halides
the acid chloride can be preferably used.
-- 5 --
; lOSS9Sl
Though there is a literature reference concerning the methyl and
ethyl esters of 2-chloro-5-sulphonamidobenzoic acid (J. Pharm. Pharmacol.
14, 679 /1962/), neither the method of preparation nor the physical and
chemical parameters are given. The other esters of 2-chloro-5-sulphon-
amidobenzoic acid are not known from the literature. These esters can be
prepared e.g. by heating the acid with the appropriate alcohol in the pres-
ence of an acid-type catalyst, e.g. sulphuric or hydrochloric acid. It is
expedient to use an excess alcohol as solvent. The esterification reaction
can, however, be carried out by removing the water vapour formed during the
esterification with the vapour of the alcohol used as solvent.
The acid chloride can expediently be prepared by treating the acid
with thionyl chloride or a phosphorus-containing halogenating agent, e.g.
phosphorus trichloride, phosphorus oxichloride or phosphorus pentachloride.
It is preferable to carry out the reaction with thionyl chloride using excess
thionyl chloride as solvent at the boiling point of the mixture.
The 2-chloro-5-sulphonamidobenzoic ester can be reacted with 1-
ethyl-2-aminomethyl-pyrrolidine by heating the two components preferably in
a polar solvent, e.g. in a Cl 5 alcohol or alkane diol, preferably in
ethylene-glycol. It is further expedient to use in this reaction an additive
of an alkaline nature, e.g. the sodium compound of the appropriate alcohol
or of ethyleneglycol, or an organic base, e.g. an imidazole.
The reaction between 2-chloro-5-sulphonamidebenzoyl chloride and
l-ethyl-2-aminomethyl-pyrrolidine is expedlently carried out in a solvent,
which might be water or some neutral solvent or diluent medium, e.g. chlori-
nated hydrocarbon, such as chloroform. A basic substance might be added to
the reaction mixture to bind the hydrochloric acid formed in the reaction.
The excess of 1-ethyl-2-aminomethyl-pyrrolidine or of some other tertiary
amine, e.g. triethylamine or pyridine, or some inorganic acid-binding agent,
e.g. sodium or sodium carbonate, can be used to this purpose.
The conversion of compound of formula (II) into the compound of
formula (I) is performed by the reaction of the first with a metal methoxide
in a suitable solvent. It is expedi~nt to use methanol as solvent, and an
-- 6 --
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alkali methoxide, preferably sodium methoxide, as metal methoxide. The
reaction is preferably carried out at a temperature between the boiling point
of methanol and 160 C, preferably between 125 C and 130 C. If it is
desired to carry out the reaction at the boiling point of methanol, that is
to say, under normal pressure, it might be expedient to add to the reaction
mixture a few per cent of dimethyl formamide related to the quantity of
methanol.
The salts of compound of formula (I) with therapeutically accept-
able acids are expediently prepared by dissolving the base of formula (I)
in an appropriate organic solvent under heating and adding to this solution
either the desired acid alone or the concentrated solution of the desired
acid in water or in an organic solvent. The acid-addition salts are
precipitated at elevated temperatures or crystallize when the solution is
cooled. The base is expediently dissolved in an aliphatic alcohol, pref-
erably in ethanol or isopropanol, while the acids can be used in ethanol or
isopropanol solution.
Compared to the methods described in the literature the main
advantages of the process according to the invention are as follows:
Starting from the commercially available, cheap 2-chlorobenzoic
acid the desired product of formula (I) is obtained in only five steps with
an overall yield of 42.9 % calculated for the starting 2-chlorobenzoic acid
(the yields of the steps are in succession: 95, 79, 88, 91 and 71.5 %).
According to the cIaimed method the synthesis of the compound of
formula (I) starts with the reaction of 2-chlorobenzoic acid withchloro-
sulphonic acid. ~he methods known from the literature for the preparation
of compound of formula (I) start, as already mentioned, from 2-methoxy-5-
sulphonamidobenzoic acid and, resp., from the ester of the latter. Accord-
ing to the pertaining literature, this acid can be prepared by starting from
salicylic acid (J. Chem. Soc. London, 1986 /1923/) or from 2-nitrophenol
(British Patent Specification ~o. 1,204,406), both methods having the common
feature of reacting a substance containing a methoxy-group with chloro-
sulphonic acid, or with concentrated sulphuric acid (oleum) in order to
-- 7 --
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produce a sulphonamide group in position 5: in the first case 2-methoxy-
benzoic acid must interact with oleum, and in the second case 2-nitroanisol
with chlorosulphonic acid. The methyl ether derivatives of phenols are,
however, known to suffer decomposition when reacted with sulphuric or
chlorosulphonic acid (J. Chem. Soc. London, 4963 /1961/j Berichte 98, 2070
/1965/; J. Org. Chem. 32, 1269 /1967/).
It is a particular advantage of the process according to the
invention that the reaction of 2-chlorobenzoic acid used as starting sub-
stance with chlorosulphonic acid proceeds without the formation of by-
products or decomposition and the end-product is obtained in an excellent
yield. The methoxy-group in position 2 is incorporated only in the last
step of the process by exchanging the chlorine atom in position 2. It is
a further advantage of the process that the last step, namely the con-
version of the compound of formula (II) into the compound of formula (I)
proceeds easily and gives a good yield. Consequently, the method is suit-
able for the preparation of large charges, that is for implementation on a
commerical scale. The reaction is uniform and selective.
The process according to the invention is further illustrated by
the aid of the following non-limiting Examples.
ExamPle 1
Step "A": 2-chloro-5-chlorosulphonylbenzoic acid
93.6 g. (o.o6 moles) of 2-chlorobenzoic acid is added in 90 min-
utes under constant stirring and cooling with ice-water to 360 ml. of
chlorosulphonic acid at a temperature between 5 C and 8 C. Thereafter the
reaction mixture is stirred first on an ice-water bath for one hour, then
at room temperature for another hour and finally at 96 C for 6 hours,
cooled to room temperature and poured over 1200 g. of ice. After one hour
the white precipitate is sucked, washed with water and dried under vacuum
in the presence of phosphorus pentoxide. Yield: 145 g. (95 ~) of 2-chloro-
5-chlorosulphonylbenzoic acidj m.p. 142-147 C.
Step "B": 2-chloro-5-sulphonamidobenzoic acid
750 ml. of isopropanol are saturated at 0-5 C with dry ammonia
-- 8 --
lOS5951
gas. Then 75.3 g. (0.295 moles) of the 2-chloro-5-chlorosulphonylbenzoic
acid prepared in step "A" are added at the same temperature under constant
stirring in one hour, followed by the slow continuous addition of ammonia
gas and stirring first under ice-water cooling for 1 hour and then at room
temperature for 20 hours. The precipitate is sucked and the mother liquor
is evaporated to dryness in vacuum on a 45 C water-bath. The residue is
added to the sucked precipitate, dissolved in 700 ml of water, purified on
charcoal, filtered and the filtrate acidified with concentrated hydrochloric
acid. The mixture containing the precipitate is allowed to stand at 4 C
till next day, then the precipitate is separated by sucking, washed with
water and dried. Yield: 55 g (79 %) of 2-chloro-5-sulphonamidobenzoic
acid; m.p.: 220-222 C. The substance can be recrystallized from water
without a change in its melting point.
Step "C": 2-chloro-5-sulphonamidobenzoic acid methyl ester
To the mixture of 48 g. (0.22 moles) of the 2-chloro-5-sulphon-
amidobenzoic acid prepared in step "B" and of 480 ml. of methanol 22 ml. of
concentrated sulphuric acid are added dropwise at a temperature not exceed-
ing 40 C. Thereafter the mixture is boiled under reflux for 8 hours,
purified while hot with charcoal, filtered and the filtrate is concentrated
in vacuum. Then a 10 % soda solution is added dropwise till the pH reaches
a value of 7. The mixture containing the precipitate is kept at 4 C for
some hours, then sucked, washed with water and dried in vacuum in the pres-
ence of phosphorus pentoxide. Yield: 48.2 g. (94.5 %) of crude 2-chloro-
5-sulphonamidobenzoic acid ethyl ester. Recrystallization from 48 ml. of
methanol gives 44.6 g. (88 %) of the pure ester; m.p.: 127-128 C.
Step "D": 1-ethyl-2-N-(2'-chloro-5'-sulphonamidobenzoyl)-
aminomethylpyrrolidine (II)
To a mixture of 43.7 g. (0.175 moles) of the 2-chloro-5-sulphon-
amidobenzoic acid methyl ester prepared in step "C" and of 145 ml. of
anhydrous ethyleneglycol 11.6 g. (0.17 moles) of imidazole are added,
stirred for 30 minutes, then cooled to 10 C. After the dropwise addition
of 28.8 g. (0.225 moles) of 1-ethyl-2-aminomethyl-pyrrolidine the mixture
_ 9 _
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is stirred at 95 C for 8 hours, and then kept at 4C for 2 days. The
precipitate is sucked, washed with 50 % aqueous methanol and then with water
and dried in vacuo in the presence of phosphorus pentoxide. Yield 55.1 g.
(91 %) of 1-ethyl-2-N-(2'-chloro-5'-sulphonamidobenzoyl)-aminomethyl-
pyrrolidine (II); mp.: 180 C. After recrystallization from methanol no
change in its melting point.
Step "E": 1-ethyl-2-~-(2'-methoxy-5-sulphonamidobenzoyl)-
aminomethyl-pyrrolidine (I)
Method 1
2.4 g. (0.105 atoms) of sodium are dissolved in 60 ml. of
methanol, and 10.38 g. (0.03 moles) of the 1-ethyl-2-N-(2'-chloro-5'-
sulphonamidobenzoyl)-aminomethyl-pyrrolidine (II) prepared in step "D" and
6.3 ml. of anhydrous dimethyl formamide are added to the solution. The
mixture is boiled under reflux for 42 hours and then evaporated to dryness
in vacuum at a temperature of 40 C. The distillation residue is mixed with
150 ml. of absolute ethanol, acidified with 20 % hydrochloric acid in
ethanol until the pH reaches a value of 5, mixed with 80 ml. of acetone and
kept at 4 C for 5 to 6 hours. The formed precipitate is sucked, washed
with acetone and dried. The obtained crystalline powder is dissolved in
160 ml. of hot water, 12 ml. of concentrated aqueous ammonium hydroxide
solution are added dropwise, and the mixture is kept overnight at 4 C.
The precipitate is sucked, washed with water and dried in vacuo in the pres-
ence of phosphorus pentoxide. Yield: 7.4 g. (71.5 %) of 1-ethyl-2-~-(2'-
methoxy-5-sulphonamidobenzoyl)~aminomethyl-pyrrolidine (I); mp.: 176 C.
After recrystallization from ethanol no change in its melting point.
Method 2
1.38 g. (0. o6 atoms) of sodium are dissolved in 50 ml. of
methanol, and 3.46 g. (0.01 moles) of the 1-ethyl-2-~-(2'-chloro-5'-sul-
phonamidobenzoyl)-aminomethyl-pyrrolidine (II) prepared in step "D" are
added to the mixture which is then heated in a bomb tube on a 140 C oil
bath for 12 hours. After cooling and purification with charcoal the solu-
tion is evaporated in vacuum at 40 C, the residue is taken up in 50 ml. of
-- 10 --
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absolute ethanol, acidified to pH 5 with a 20 % hydrochloric acid solut~on
in ethanol, and kept after the addition of 50 ml. of acetone at 4 C for
5-6 hours. The precipitate is sucked, washed with acetone and dried. The
obtained crystalline powder is dissolved in 50 ml. of hot water, 4 ml. of
a concentrated aqueous ammonium hydroxide solution are added dropwise, and
the mixture is kept overnight at 4 C. The mixture is sucked, the precip-
itate washed with water and dried in vacuo in the presence of phosphorus
pentoxide. Yield: 2.36 g. (69 %) of 1-ethyl-2-N-(2'-methoxy-5'-sulphon-
amidobenzoyl)-aminomethyl-pyrrolidine (I); m.p.: 178 C.
ExamPle 2
Step "A": 2-chloro-5-sulphonamidobenzoyl chloride
The mixture of 23.68 g. (0.1 moles) of 2-chloro-5-sulphon-
amidobenzoic acid with 140 ml. of thionyl chloride is boiled under reflux
for 1.5 hours. The obtained clear solution is kept overnight at 4 C,
sucked, the precipitate washed with benzene and dried in vacuo at room
temperature in the presence of phosphorus pentoxide. Yield: 22.45 g.
(88.5 ~) of 2-chloro-5-sulphonamidobenzoyl chloride; m.p.: 141-143 C
A further 3 to 6 per cent of acid chloride can be obtained by the
careful evaporation of the mother liquor.
Step "B": 1-ethyl-2-N-(2'-chloro-5'-sulphonamidobenzoyl)-
aminomethyl-pyrrolidine (II)
Method 1
To the mixture of 5.59 g. (0.044 moles) of 1-ethyl-2-aminomethyl-
pyrrolidine and 80 ml. of water 5.08 g. (0.02 moles) of 2-chloro-5-sulphon-
amidobenzoyl chloride prepared in step "A" are added under constant stirring
and cooling with ice-water to 4 to 7 C. Then the mixture is stirred at the
same temperature for further 2 hours, sucked, the precipitate washed with
water and dried at 40 C. Yield: 6.o8 g. (87.9 %) of 1-ethyl-2-N-(2'-
chloro-5'-sulphonamidobenzoyl)-aminomethyl-pyrrolidine (II); m.p.: 178-
180 C. After recrystallization from methanol the melting point of the
substance is 180 C.
~055951
Method 2
To the mixture of 1.54 g. (0.012 moles) of 1-ethyl-2-aminomethyl-
pyrrolidine, 1.2 g. (0.012 moles) of triethylamine and 50 ml. of water,
2.54 g. (0.01 moles) of 2-chloro-5-sulphonamidobenzoyl chloride are added
under constant stirring and cooling with ice-water at a temperature of 4 to
7 C. Subsequently the procedure is the same as in Step "A" of Method 1 in
Example 2. Yield: 2.90 g. (85.6 %) of l-ethyl-2-N-(2~-chloro-5t-sulphon
amidobenzoyl)-aminomethyl-pyrrolidine (II); m.p.: 178 C.
Step "C": 1-ethyl-2-N-(2'-methoxy-5-sulphonamidobenzoyl)-
aminomethyl-pyrrolidine (I) (Sulpiride)
The same as Step "E" in Example 1.
Example 3
l-Ethyl-2-N-(2'-methoxy-5'-sulphonamidobenzoyl)-aminomethyl-
pyrrolidine (I) hydrochloride.
To the hot solution of 43.95 g. (0.13 moles) of 1-ethyl-2-N-(2'-
methoxy-5'-sulphonamidobenzoyl)-aminomethyl-pyrrolidine (I) in 770 ml. of
absolute ethanol 103 ml. (0.29 moles) of absolute ethanol containing 10.28 %
of hydrogen chloride gas are added dropwise. The mixture containing the
precipitate is boiled under stirring for 10 minutes and then allowed to stand
overnight at 4 C. The crystalline hydrochloric acid salt is separated by
sucking, washed with acetone and dried in vacuo in the presence of phosphorus
pentoxide. Yield: 44.8 g. (92.6 %) of the hydrochloride salt; m.p.: 233-
237 C.
After recrystallization from aqueous isopropanol containing hydro-
chloric acidthe melting point of the substance is 238-239 C.
Example 4
1-Ethyl-2-N-(2'-methoxy-5'-sulphonamidobenzoyl)-aminomethyl-
pyrrolidine (I) hydrogen sulphate
To the hot solution of 3.41 g. (0.01 moles) of 1-ethyl-2-N-(2'-
methoxy-5'-sulphonamidobenzoyl)-aminomethyl-pyrrolidine (I) and 100 ml. of
absolute ethanol o.6 ml. (0.012 moles) of concentrated sulphuric acid are
added dropwise. The mixture containing the precipitate is allowed to stand
- 12 -
~OS595~
overnight at 4 C. Then the precipitate is separated by sucking, washedwith absolute ethanol and dried in vacuo in the presence of phosphorus
pentoxide. Yield: 4.35 g. (99 %) of sulphuric acid salt; m.p. after re-
crystallization from ethanol: 198 C.
Example 5
l-Ethyl-2-N-(2'-methoxy-5'-sulphonamidobenzoyl)-aminomethyl-
pyrrolidine (I) hydrogen maleate
1.3 g. (0.11 moles) of maleic acid are added to the hot solution
of 3.41 g. (0.01 moles) of 1-ethyl-2-~-(2'-methoxy-5'-sulphonamidobenzoyl)-
aminomethyl-pyrrolidine (I) in 150 ml. of isopropanol, and the mixture is
allowed to stand overnight at 4 C. Then the precipitate is separated by
sucking, washed with isopropanol and dried in vacuo in the presence of
phosphorus pentoxide. Yield: 3.34 g. (73 %) of maleic acid salt; m.p.
after recrystallization from isopropanol: 132 C.
Example 6
1-Ethyl-2-~-(2'-methoxy-5'-sulphonamidobenzoyl)-aminomethyl-
pyrrolidine (I) hydrofluoride
0.5 ml. (0.029 moles) of hydrogen fluoride in the form of a 50 %
aqueous solution are added to the solution of 1.13 g. (0.0033 moles) of 1-
ethyl-2-~-(2'-methoxy-5'-sulphonamidobenzoyl)-aminomethyl-pyrrolidine (I)
in 35 ml. of isopropanol. The mixture is allowed to stand overnight at
4 C. Then the precipitate is separated by sucking, washed with isopropanol
and dried in vacuo in the presence of phosphorus pentoxide. Yield: 1.05 g.
(88 %) of hydrogen fluoride salt, m.p. after recrystallization from ethanol:
129-130 C.
