CA1055951A - Process for preparing 1-ethyl-2-/2'-methoxy-5'-sulphonamidobenzoyl/-aminomethylpyrrolidine and its salts - Google Patents
Process for preparing 1-ethyl-2-/2'-methoxy-5'-sulphonamidobenzoyl/-aminomethylpyrrolidine and its saltsInfo
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- CA1055951A CA1055951A CA248,976A CA248976A CA1055951A CA 1055951 A CA1055951 A CA 1055951A CA 248976 A CA248976 A CA 248976A CA 1055951 A CA1055951 A CA 1055951A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/78—Halides of sulfonic acids
- C07C309/86—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/89—Halides of sulfonic acids having halosulfonyl groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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Abstract
ABSTRACT OF THE DISCLOSURE
1- Ethyl-2-(2'-methoxy-5'-sulphonamidobenzoyl)-amino-methyl-pyrrolidine of formula I
(I) and the acid-addition salts thereof are prepared by a) reacting an acid-amide derivative of formula II
(II) with a metal methoxide, or b) reacting a reactive derivative of 2-chloro-5-sulphonamidobenzoic acid with 1-ethyl-2-aminomethyl-pyrrolidine, and then reacting the obtained acid-amide derivative with a metal methoxide.
The obtained compound possesses a significant psycho-tropic and gastric ulcer inhibiting effect.
1- Ethyl-2-(2'-methoxy-5'-sulphonamidobenzoyl)-amino-methyl-pyrrolidine of formula I
(I) and the acid-addition salts thereof are prepared by a) reacting an acid-amide derivative of formula II
(II) with a metal methoxide, or b) reacting a reactive derivative of 2-chloro-5-sulphonamidobenzoic acid with 1-ethyl-2-aminomethyl-pyrrolidine, and then reacting the obtained acid-amide derivative with a metal methoxide.
The obtained compound possesses a significant psycho-tropic and gastric ulcer inhibiting effect.
Description
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) CONHCH2 ~ (I) 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 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
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) CONHCH2 ~ (I) 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 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 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) 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-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-~055951 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.
; 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 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 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 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 _ 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 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 ~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.
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) 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-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-~055951 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.
; 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 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 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 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 _ 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 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 ~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.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 1-ethyl-2-(2'-methoxy-5'-sulphonamido-benzoyl)-aminomethyl-pyrrolidine of formula I
(I) and of the acid-addition salts thereof, characterized in that a) an acid-amide derivative of formula II
(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, and 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 the addition of an acid.
(I) and of the acid-addition salts thereof, characterized in that a) an acid-amide derivative of formula II
(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, and 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 the addition of an acid.
2. A process as claimed in claim 1b, wherein an ester formed with an aliphatic acid, an acid halogenide or acid anhydride is used as the reactive derivative of 2-chloro-5-sulphonamidobenzoic acid.
3. A process as claimed in claim 2, wherein the reaction is per-formed in a neutral solvent and, if desired, in the presence of an alkaline additive.
4. A process as claimed in claim 1a or 1b, wherein an alkali metal methoxide, preferably sodium methoxide, is used as metal methoxide.
5. A process as claimed in claim 4, wherein the reaction is performed at a temperature between 60 °C and 160 °C, preferably between 125 °C and 130 °C and, if desired, in the presence of dimethyl formamide.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT202200011363A1 (en) * | 2022-05-30 | 2023-11-30 | Univ Degli Studi Di Torino | CRYSTALLINE COMPOUNDS OF SULPIRIDE |
-
1975
- 1975-03-28 HU HUGO001307 patent/HU169703B/hu unknown
-
1976
- 1976-03-23 DK DK128176A patent/DK128176A/en not_active Application Discontinuation
- 1976-03-24 AU AU12291/76A patent/AU501988B2/en not_active Expired
- 1976-03-25 DD DD19203476A patent/DD124418A1/xx unknown
- 1976-03-25 CS CS195276A patent/CS194754B2/en unknown
- 1976-03-26 FI FI760827A patent/FI61878C/en not_active IP Right Cessation
- 1976-03-26 CH CH380976A patent/CH619452A5/en not_active IP Right Cessation
- 1976-03-26 JP JP3345876A patent/JPS51125380A/en active Pending
- 1976-03-26 YU YU79676A patent/YU79676A/en unknown
- 1976-03-26 CA CA248,976A patent/CA1055951A/en not_active Expired
- 1976-03-26 GB GB1226476A patent/GB1492166A/en not_active Expired
- 1976-03-26 SU SU762338456A patent/SU626693A3/en active
- 1976-03-26 SE SE7603698A patent/SE410186B/en not_active Application Discontinuation
- 1976-03-26 BG BG032715A patent/BG26522A3/en unknown
- 1976-03-27 RO RO7685333A patent/RO68720A/en unknown
- 1976-03-27 ES ES446448A patent/ES446448A1/en not_active Expired
- 1976-03-29 DE DE19762613394 patent/DE2613394A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| SE410186B (en) | 1979-10-01 |
| FI61878C (en) | 1982-10-11 |
| JPS51125380A (en) | 1976-11-01 |
| CH619452A5 (en) | 1980-09-30 |
| ES446448A1 (en) | 1977-06-16 |
| RO68720A (en) | 1982-10-11 |
| DK128176A (en) | 1976-09-29 |
| DE2613394A1 (en) | 1976-10-07 |
| GB1492166A (en) | 1977-11-16 |
| SE7603698L (en) | 1976-09-29 |
| FI760827A (en) | 1976-09-29 |
| HU169703B (en) | 1977-02-28 |
| BG26522A3 (en) | 1979-04-12 |
| CS194754B2 (en) | 1979-12-31 |
| YU79676A (en) | 1982-06-30 |
| AU1229176A (en) | 1977-09-29 |
| FI61878B (en) | 1982-06-30 |
| SU626693A3 (en) | 1978-09-30 |
| AU501988B2 (en) | 1979-07-12 |
| DD124418A1 (en) | 1977-02-23 |
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