FI61878C - PROCEDURE FOR FRAMSTATION OF AV 1-EECL-2- (2'-METOXY-5'-SULPHONAMIDOBENSOYL) -AMINOMETHYLPYRROLIDINE - Google Patents

Description

ESSr ^ l rBl f11 NOTICE OF PUBLICATION, * η τη o LBJ (11) utlAggnIngsskrift O I o / Ö c / 4S> Patent granted 11 10 1932

Patent aeddelat (51) Kv.ik? /Int.a.3 C 07 D 207/09 FINLAND-FINLAND (21) P * unttlh «k« mu · - PtMnttntöknlni 760827 (22) HtkamUpifvt - Aiutfknln | tdtf 26.03 * 76 ' "(23) AlkupUvt — Glttl | h« adtf 26.03.76 (41) Interpreters | ulklMkil - Bllvlt offwitllf 29.09.76 _ '/ 44)

Patent and registration authorities '' Antttkan utlagd och utUkrlftan publlcurad OO.uo.uc (32) (33) (31) Pyydetty «uoikwis — Bafird priorltet 28. 03.73

Hungary-Hungary (HU) GO-1307 (71) Alkaloid Chemical Plant, Tiszavasvari, Hungary-Hungary (HU) (72) Judit KosSry, Budapest, Endre Kasztreiner, Budapest, Lajos Farkas,

Budapest, Janos Borvendeg, Budapest, Judit Eggenhofer nee Sauer, Budapest, Veronika Pap, Budapest, Tibor Balogh, Budapest, György Somogyi,

Erno Orban, Budapest, iva Koczka nee Faita, Budapest,

Erzsebet Bursics nee Szekeres, Budapest, Hungary-Hungary (HU) (7 ^) Oy Kolster Ab () Method for the preparation of 1-ethyl-2- (2'-methoxy-5'-sulfonamido-benzoyl) -aminomethylpyrrolidine and its salts The present invention relates to a new process for the preparation of a compound for preventing the development of psychotropic ulcers and gastric ulcers, 1-ethyl-2- (2-methoxy-5, -sulfonamidobenzoyl) -amino-methylpyrrolidine and the like. For the preparation of J * -sulfonamidobenzoyl) -aminomethylpyrrolidine corresponding to the general formula (I) s OCH, I 5 Ir -COHHCHg- ^ sJ (I) I ° 2H5 SOgNHg and called Sulpiride (Arch. Franc. Mai. Appar. Digest 59 » 50 [1970]; Sem. Hop. 45 »3028 [1969]) as well as its salts formed with therapeutically acceptable acids.

Several methods are known in the literature for the preparation of a compound of formula (i) and its hydrochloride salt.

According to HU Patent Publication No. 153 * 310, a compound of formula (i) is prepared by heating 2-methoxy-5-eulfonamidobenzoic acid with an excess of thionyl chloride and condensing the acid chloride formed with 1-ethyl-2-aminomethylpyrrolidine. The hydrochloride salt of the compound of formula (i) crystallizes from the reaction mixture upon addition of water. Said patent specification relates only to the preparation of the hydrochloride salt without any indication of yield. The main disadvantage of this preparation method is the small amount of the hydrochloride salt obtained and the impurity when condensing the acid chloride with 1-ethyl-2-aminomethylpyrrolidine; in addition, waste is accumulated during purification and conversion of said salt to the corresponding base. These drawbacks are particularly noticeable when applying the method on a large scale.

According to U.S. Patent No. 3 * 342 * 826, the compound corresponding to handle (i) is obtained as follows: carbonyl diimidazole is prepared from imidazel and phosgene in dry benzene * imidazole hydrochloride is separated by filtration, the solution is evaporated to dryness, the residue obtained is dissolved in dry tetrahydrofur it is reacted with 2-methoxy-5-sulfonamidobenzoic acid. The compound of formula (i) is obtained by reacting N- (2-methoxy-5-sulfonlamido-benzoyl) -imidateol obtained in the above reaction with 1-ethyl-2-aminomethylpyrrolidine. There is no reference in the specification to the yields and physical parameters of the base or its hydrochloride salt. This manufacturing method has a number of drawbacks. On the other hand, dry solvents must be used at each stage; in addition, the first reaction (preparation of carbonyl-diimidazole) must be carried out under dry nitrogen protection. In addition, this step also involves the use of highly toxic phosgene. In addition, the solvents must be removed during the process by evaporation in vacuo twice, resulting in the inevitable waste, making the process uneconomical. The method is very sensitive to both moisture and acid and is therefore unsuitable, especially for the production of large batches.

According to BB Patent Publication No. 787,180, a compound of formula (i) is prepared by first forming tris- (1-ethylpyrrolidinyl-2-methyl) -phosphoramide from 1-ethyl-2-aminomethyl-pyrrolidine and phosphorus oxychloride in pyridine solution and reacting this reaction product 2 -methoxy-5-eulfonamidobenzoic acid. After evaporation to dryness, 3 61 8 7 8 The hydrochloride salt is formed, from which, after purification, the base form of the compound of formula (i) is obtained. for 1-ethylaminomethyl-pyrrolidine the yield is 10 * 3 # * with respect to the starting acid 34 * 3%> · The main drawback of this method is the low yield * And also the fact * that it requires the use of materials (pyridine). din and phosphorus oxychloride together) * resulting in * very intense heat generation, especially in the case of large batches *.

Therefore, the method cannot be recommended for production on a technical scale, And low yields make it uneconomical in any case.

The compound of formula (i) of BE Patent No. 787,794 is obtained as follows. 2-Methoxy-5-sulfonamidobenteoic acid ethyl ester is first converted with hydrazine hydrate to the acid hydrate (yield: $ 86) * From which the acid azide is prepared with hydrochloric acid and sodium nitrite. The acid azide is then reacted directly with 1-ethyl-2-aminomethyl-pyrrolidine in dioxane solution. After treatment with hydrochloric acid, the yield of the final product of formula (i) with respect to 2-methoxy-3-sulfonylobenzoic acid hydrazide is 42 * 6% with respect to 1-ethyl-2-aminomethyl-pyrrolidine and 21.3% of the starting material, 2-methoxy-3 -sulfonamidobenzoic acid ethyl ester 36.6 One of the main aspects of this method is the low overall yield. In addition, the coupling of the final acid component to the base component takes place in four steps (ester * hydrazide * azide, final product).

It is an object of the present invention to provide * by eliminating the disadvantages of the known methods * a method by which a compound of formula (i) can be prepared in a simple manner and in good yields even on a technical scale.

The invention is based on the following findings: a) Formula (il)

Cl

• I I

-COTHCH. -L J (IX) I ° 2H5 eOjMj The chlorine atom of the corresponding compound can be easily converted to Methoxy in very good yields.

4 618 7 8 b) The compound corresponding to the general formula (II) is obtained in a simple manner and in very yields by reacting 2-chlorobenzoic acid with chlorosulfonic acid, amidating the obtained 2-chloro-5-chlorosulfonylbenzoic acid, and reacting the resulting 2-chloro-5-sulfonamide reacting a derivative, e.g. its lower (C 1-4) alkyl ester or chloride, with 1-ethyl-2-aminomethyl-pyrrolidine.

This invention is surprising for more than one reason. Namely, the halogen atoms attached to the benzene ring are known to be, in general, only weakly reactive, provided that they do not have so-called leaving groups. Sulfonamide and carboxylic acid groups ortho or para to the halogen atom have such a releasable effect (so-called negative substituents). Thus, it would be logical to expect that when a chlorine atom of a compound of formula (II) reacts with a methylate anion, especially under relatively stringent conditions, there is an interaction between said chlorine atom and a tertiary anine group, thus e.g. in either case results in the formation of considerable amounts of quaternary-type by-products and this reduces the yield and purity of the desired compound of formula (I) when converting a compound of formula (II) to a compound of formula (i). However, by converting a chlorine atom to a methoxy group, a compound of formula (i) can be obtained in good yields and purity from a compound of formula (II), indicating that no quaternary products are formed to a significant extent, so converting a chlorine atom to a methoxy group is a surprisingly selective process without severe reaction conditions.

This invention is further surprising because it would be logical for the reactivity of the reactive derivatives of 2'-chloro-5-8-sulfonlanidobenzoic acid to be the same as that of the chlorine atom of the compound of formula (II). Thus, it would be expected that in the preparation of a compound of formula (II) wherein a reactive derivative of 2-chloro-5-sulfonamidobenzoic acid is reacted with 1-ethyl-2-aminomethylpyrrolidine, the chlorine atom in position 2 will react, especially under relatively severe reaction conditions. with the nitrogen atom of the ethylpyrrolidine group, as a result of which quaternary-type by-products would still be formed and thus the yield and purity of the desired compound of formula (II) would be impaired. However, the compound of formula (II) can be obtained in pure form and in high yields from the corresponding reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid and 1-ethyl-2-aminomethylpyrrolidine, indicating that no significant amounts of quaternary type are formed during this reaction either. products. Thus, the interaction between the reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid and 1-ethyl-2-aminomethylpyrrolidine surprisingly selectively produces a compound of formula (II) even under relatively severe reaction conditions.

In view of the above, the invention relates to a process for the preparation of 1-ethyl-2- (2'-methoxy-5'-sulfonamidobenzyl) aminomethylpyrrolidine of the formula (I) and its acid addition salts, which process is characterized by reacting 2-chlorobenzoic acid with chlorosulfonic acid. 2-Chloro-5-chlorosulfonylbenzoic acid is amidated to 2-chloro-5-sulfonamidobenzoic acid, which is reacted with 1-ethyl-2-aminomethylpyrrolidine of formula II

^ conhch2- (II) K »s SO2m2, which is reacted with metal methoxide to give a compound of formula I, which is, if desired, converted into an acid addition salt.

The 2-chloro-5-chlorosulfonylbenzoic acid compound is known from the literature (CH Patent Publication No. 351,281); it is prepared by reacting 2-chloro-benzoic acid with excess chlorosulfonic acid, mainly by heating without solvent. The excess chlorosulfonic acid is then decomposed with water and the precipitate containing crude 2-chloro-5-chlorosulfonylbenzoic acid is used in the next step.

2-Chloro-5-sulfonamidobenzoic acid is a compound known from the literature (J. Pharm. Pharmacol. 14, 679 (1962)). It can be prepared by reacting 2-chloro-5-chlorosulfonylbenzoic acid with concentrated ammonia solution. A low molecular weight alcohol, mainly isopropanol, can be used as a solvent in the reaction. To maintain the ammonia concentration, the reaction temperature is initially selected to be a low temperature, about 0 ° C, and the reaction is terminated at a higher, e.g., room temperature.

To convert 2-chloro-5-sulfonamidobenzoic acid to a compound of formula (II), said acid is first converted to a more reactive derivative, mainly an ester, acid halide or mixed anhydride. Of the esters, esters formed with aliphatic alcohols having 1 to 4 carbon atoms were found to be the most preferred. Of the acid halides, mainly acid chlorides can be used.

Although there is a reference in the literature to methyl and ethyl esters of 2-chloro-5-sulfonamidobenzoic acid (J. Pharm. Pharmacol. 14, 679 (1962)), it does not disclose the method of preparation or the physical or chemical parameters of 6 618 7 3. Other esters of 2-chloro-5-sulfonamidobenzoic acid are not known in the literature. The wedding esters can be prepared, for example, by heating the acid with a suitable alcohol in the presence of an acid-type catalyst, e.g. sulfuric acid or hydrochloric acid. It is expedient for the excess alcohol to be used as solvent. However, the esterification reaction can be carried out by removing the water vapor formed during the esterification with the alcohol vapor used as a solvent.

The acid chloride is preferably prepared by treating the acid with thionyl chloride or a phosphorus-containing halogenating agent, e.g. phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride. It is preferred that the reaction with thionyl chloride be performed using excess thionyl chloride as the solvent and at the boiling point of the mixture.

2-Chloro-5-sulfonamidobenzoic acid ester can be reacted with 1-ethyl-2-aminomethyl-pyrrolidine by heating both components in a predominantly polar solvent, e.g., a (β-alcohol or alkane-diol, mainly ethylene glycol). an alkaline additive, e.g. a sodium compound of a suitable alcohol or ethylene glycol, or an organic base, e.g. imidazole.

The reaction between 2-chloro-5-sulfonamide benzoyl chloride and 1-ethyl-2-aminomethylpyrrolidine is preferably carried out in a solvent which may be water or a neutral solvent or diluent, e.g. a chlorinated hydrocarbon such as eeim. chloroform. A basic substance can be added to the reaction mixture to bind the hydrochloric acid formed in the reaction. Excess 1-ethyl-2-aminomethylpyrrolidine or another tertiary amine, e.g. triethylamine or pyridine, or an inorganic acid scavenger, e.g. sodium or sodium carbonate, can be used for this purpose.

Conversion of a compound of formula (II) to a compound of formula (i) is carried out by reacting the former with a metal methylate in a suitable solvent. It is suitable to use methanol as the solvent, and alkali methylate, mainly sodium methylate, as the metal methylate. The reaction is carried out mainly at a temperature between the boiling point of methanol and 160 ° C, mainly at a temperature between 125 and 130 ° C. If it is desired to carry out the reaction at a temperature corresponding to the boiling point of methanol, that is, at normal pressure, it may be advantageous to add a few per cent of dimethylformamide to the reaction mixture, based on the amount of methanol.

Salts of a compound of formula (i) and therapeutically acceptable acids 7,61878 are preferably prepared by dissolving a base of formula (i) in a suitable organic solvent by heating and adding to this solution either the desired acid as such or a concentrated solution of the desired acid and water or the desired acid and organic solvent. The acid addition salts are doped at higher than normal temperatures or crystallize on cooling the solution, it is preferred to dissolve the fin in an aliphatic alcohol, mainly ethanol or isopropanol, and the acids in turn can be used as an 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: Using cheap 2-chlorobenzoic acid as a starting material, are sequentially listed at 95, 79, 88, 91 and 71.5? £).

The synthesis of a compound of formula (i) according to the process of claim 1 starts from the reaction between 2-chlorobenzoic acid and chlorosulfonic acid. Methods for the preparation of a compound of formula (I) known from the literature begin, as already mentioned, with 2-methoxy-5-sulfonamidobenzoic acid and, respectively, the ester of the latter. According to the corresponding literature, this acid can be prepared using salicylic acid (J.Chem.Soc.London, 1986 [1923]) or 2-nitrophenol (British Patent Specification No. 1,204,406) as a starting material, both of which have in common that the methoxy group-containing substance is administered react with chlorosulfonic acid or concentrated sulfuric acid (nebulizing sulfuric acid) to give the sulfonamide group in position 5: in the first case 2-methoxybenzoic acid must interact with the nebulizing sulfuric acid, and in the second case with chlorheulfonic acid of 2-nitroananol. However, methyl ether derivatives of phenols are known to be susceptible to decomposition by reaction with sulfuric acid or chlorosulfonic acid (J. Chem. Soc. London, 4963 [1961]; Berichte 98, 2070 [1965]; J. Or. Chem. 32, 1269 [1967]).

A particular advantage of the reaction according to the invention is that the reaction of the starting 2-chlorobenzoic acid with chlorosulfonic acid takes place in such a way that no by-products are formed and no decomposition takes place and the final products are obtained in excellent yields. The methoxy group at position 2 participates in the reaction only in the last step of the process by changing the chlorine atom to position 2. The method also has the advantage that the final step, namely the conversion of the compound of formula (II) to the compound of formula (i), is easy and the yield is good. As a result, the method is suitable for the production of large batches, that is, for use on a technical scale. The reaction is smooth and selective.

The method according to the invention is illustrated by the following examples.

Example 1

Step "A": 2-Chloro-5-chlorosulfonyl-benzoic acid 95 * 6 g (0.06 mol) of 2-chlorobenzoic acid are added over a period of 90 minutes with continuous stirring and cooling with ice water to 360 ml of chlorosulfonic acid at a temperature between 5 and 8 ° C. The reaction mixture is then stirred first in 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 onto 1200 g of ice. After 1 hour, the white precipitate is filtered off with suction, washed with water and dried in vacuo in the presence of phosphorus pentoxide. Yield: 145 g (95-6) of 2-chloro-5-chlorosulfonylbenzoic acid | mp. 142-147 ° C.

Step "B": 2-k 1 o or i - 5 *> sul f on i ami dob en t ao ehoic acid 750 ml of isopropanol are saturated at 0-5 ° C with dry ammonia gas. 75 * 3 g (0.295 mol) of 2-chloro-5-chlorosulfonylbenzoic acid prepared in step nAw are then added over the course of continuous stirring at the same temperature, followed by the slow and continuous addition of ammonia gas, and stirring is continued first with ice-water under cooling for 1 hour and then at a temperature of 20 hours. The precipitate is filtered off with suction and the mother liquor is evaporated to dryness in vacuo at 45 [deg.] C. with a water bath. The residue is added to a filter cake, dissolved in 700 ml of water, purified on charcoal, filtered and the filtrate is acidified with concentrated hydrochloric acid. The mixture containing the precipitate is allowed to stand at 4 ° C until the next day, after which the precipitate is isolated by suction filtration, washed with water and dried. Yield 55 g (79%) of 2-chloro-5-sulfonamidobenzoic acid; mp. 220-222 ° C. The substance can be recrystallized from water without changing the melting point.

Step "C": 2-Chloro-5-sulfonamidobenzoic acid methyl ester

To a mixture of 4Θ g (0.22 moles) of 2-chloro-5-8-sulfonamidobenzoic acid prepared in step "B" and 480 ml of methanol is added dropwise 22 ml of concentrated sulfuric acid so that the temperature does not rise above 61 8 7 8 9 C. The mixture is then refluxed for 8 hours, purified hot on charcoal, filtered and the filtrate concentrated in vacuo. The 10% sodium hydroxide solution is then added dropwise until the pH reaches 7. The mixture containing the precipitate is kept at 4 ° C for a few hours, then filtered, washed with water and dried in vacuo in the presence of phosphorus pentoxide. Yield: 48.2 g ($ 94.5) of crude 2-chloro-5-sulfonic acid amidobenzoic acid ethyl ester. Recrystallization from 48 ml of methanol gives 44-6 g (88 #) of pure ester; mp. 127-128 ° C;

Step “D”: 1-Ethyl-2-N- (2'-chloro-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (II)

To a mixture of 43 * 7 g (0.175 moles) of 2-chloro-5-sulfonamidobenzoic acid methyl ester prepared in step nC "and 145 ml of dry ethylene glycol is added 11.6 g (0.17 moles) of imidazole, stirred for 30 minutes, then cooled. To 10. After adding 28.8 g (0.225 moles) of 1-ethyl-2-aminomethylpyrrolidine dropwise to the mixture, the mixture is stirred at 95 ° C for 8 hours and then kept at 4 ° C for 2 days. filtered off with suction, washed with 50% aqueous methanol and then with water and dried in vacuo in the presence of phosphorus pentoxide.

Yield 55 »1 g of (91 #) 1-ethyl-2-N- (2'-chloro-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (II); mp. 180 ° C. Recrystallization from methanol does not change the melting point.

Step "E": 1-Ethyl-2-N- (2, -methoxy-5-sulfonamidobenzoyl) aminomethylpyrrolidine (i)

Method 1 2.4 g (0.105 mol) of sodium are dissolved in 60 ml of methanol, and 10.38 g (0.03 mol) of the 1-ethyl-2-H- (2, -chloro- 5'-sulfonamidobenzoyl) aminomethyl-pyrrolidine (II) and 6.3 ml of dry dimethylformamide. The mixture is refluxed for 42 hours and then evaporated to dryness in vacuo at 40 ° C. The distillation residue is mixed with 150% absolute ethanol, which is acidified by adding 20% ethanolic hydrochloric acid solution until the pH reaches 5 °, mixed with 80 ml of acetone and kept at 4 ° C for 5-8 hours. The precipitate formed is filtered off, washed with acetone and dried. The resulting crystalline powder is dissolved in 160 g of hot water, added dropwise with 12 ml of concentrated aqueous ammonium hydroxide solution, and the mixture is kept overnight at 4 ° C. The precipitate is filtered off, washed with water and dried in vacuo in the presence of phosphorus pentokide. Yield: 7.4 g of (7115 #) 1-ethyl-2-H- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (i); mp. 176 ° C. Recrystallization from ethanol did not change its melting point.

Method 2 1.38 g (0.06 mol) of sodium are dissolved in 50 ml of methanol and 3.46 g (0.01 mol) of the 1-ethyl-2-N- (2'-chlorine) prepared in step "D" are added to the mixture. -5'-sulfonamidobenzoyl) aminomethyl-pyrrolidine (II), which mixture is then heated in a bomb tube in a 140 ° C oil bath for 12 hours. After cooling and charcoal purification, the solution is evaporated to dryness in vacuo at 40 ° C, the residue is dissolved in 50% absolute ethanol, acidified by adding 20% ethanolic hydrochloric acid solution until the pH is 5 »and the mixture is kept after adding 50 ml of acetone, 4 At ° C for 5-6 hours. The precipitate is filtered off, washed with acetone and dried. The obtained crystalline powder is dissolved in 50 ml of hot water, 4 ml of concentrated aqueous ammonium hydroxide solution are added dropwise, and the mixture is kept overnight at 4 ° C. The mixture is filtered, the precipitate is washed with water and dried in vacuo in the presence of phosphorus pentokide. Yield: 2.36 g of (69 #) -1-ethyl-2-N- (2, -methoxy-5, -sulfonamidobenzoyl) aminomethylpyrrolidine (i); mp. 178 ° C.

Example 2

Step "A": 2-Chloro-5-sulfonamidobenzoyl chloride

A mixture of 23.68 g (0.1 mol) of 2-chloro-5-sulphonamidobenzoic acid in 140 ml of thionyl chloride is refluxed for 1.5 hours * The resulting clear solution is kept overnight at 4 ° C, filtered , the precipitate is washed with benzene and dried in vacuo at room temperature in the presence of phosphorus pentoxide. Yield: 22.45 β (88.5%) of 2-chloro-5-sulfonamido-benzoyl chloride; mp. 141-143 ° C.

An additional 5-6% of the acid chloride can be obtained by carefully evaporating the mother liquor to dryness.

Step "B": 1-Ethyl-2-N- (2'-chloro-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (II)

Method 1

To a mixture of 5-59 g (0.044 mol) of 1-stylyl-2-aminomethyl-pyrrolidine and 80 ml of water is added, with stirring and ice-water at 4-7 ° C under cooling, 5 * 08 g (0.02 mol) in step 61878 u-2-chloro-5-sulfonamidobenzoyl chloride prepared in "A". The mixture is then stirred at the same temperature for a further 2 hours, filtered, the precipitate is washed with water and dried at 40 [deg.] C. Yield: 6.08 g (87.9 l) -ethyl 2-N- (2'-chloro-5, -sulfonamidobenzoyl) aminomethylpyrrolidine (II) and mp 178-180 [deg.] C. After recrystallization from methanol, the substance has a melting point of 180 [deg.] C.

Method 2

To a mixture of 1.54 g (0.012 mol) of 1-ethyl-2-aminomethyl-pyrrolidine, 1.2 g (0.012 mol) of triethylamine and 50 ml of water is added, with constant stirring and ice water at 4-7 ° C under cooling, 2 .54 g (0.01 mol) of 2-chloro-5-eulfonamidobenzoyl chloride. Thereafter, the process proceeds in the same manner as in Step "A" of Method 1 of Example 2. Yield: 2.90 g (85.610) of 1-ethyl-2-N- (2'-chloro-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (II); mp. 178 ° C.

Step "C": 1-Ethyl-2-N- (2, -methoxy-5-sulfonamidobenzoyl) aminomethyl-pyrrolidine (i) (Sulpiride)

Method same as step "E" of Example 1

Example 5 1-Ethyl-2-N- (2, -methoxy-5'-sulfonlamidobenteoyl) aminomethyl-pyrrolidine (i) hydrochloride

To a hot solution of 45-95 g (0.13 moles) of 1-ethyl-2-N- (2'-methoxy-5'-8-sulfonamidobenzoyl) aminomethyl-pyrrolidine (i) in 770 ml of absolute ethanol is added dropwise 105 ml (0.29 moles of absolute ethanol with $ 10.28 of hydrogen chloride gas). The mixture containing the precipitate is boiled with stirring for 10 minutes and then allowed to stand overnight at 4 [deg.] C. The crystalline hydrochloride salt is filtered off, washed with acetone and dried in vacuo. in the presence of phosphorus pentoxide Yield: 44.8 g (92.6 l) of the hydrochloride salt, mp 233-237 ° C.

After recrystallization from aqueous isopropanol containing hydrochloric acid, the melting point of the substance is 238-239 ° C.

Example 4 1-#-Style-2-N- (2, -methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (I) hydrogen sulfate

To a hot solution of 3 * 41 g (0.01 mol) of 1-ethyl-2-H- (2'-methoxy-5,5-sulfonamidobenzoyl) aminomethylpyrrolidine (i) and 100 ml of absolute ethanol is added dropwise 0 .6 ml (0.012 mol) of concentrated sulfuric acid. The mixture containing the precipitate is allowed to stand at 4 ° C overnight. The precipitate is then isolated by filtration, washed with absolute ethanol and dried in vacuo in the presence of phosphorus pentoxide. Yield: 4.35 g (99 #) of sulfuric acid salt; mp. after recrystallization from ethanol: 198 ° C.

Example 5 1-Ethyl 2-N- (2, -methoxy-5, -sulfonamidobenzoyl) aminomethylpyrrolidine (i) hydrogen maleate 1 * 3 g (0.11 moles) of maleic acid are added to a hot solution of 3 * 41 g (0.01 mol) of 1-ethyl-2-K- (2, -methoxy-5'-sulphenamidobenzoyl) aminomethylpyrrolidine (i) in 150 ml of isopropanol and the mixture is allowed to stand at 4 ° C overnight: in. The precipitate is then isolated by filtration, washed with isopropanol and dried in vacuo in the presence of phosphorus pentoxide. Yield: 3 * 34 g (73 g) of the maleic acid salt; ep. after recrystallization from isopropanol: 132 ° C.

Example 6 1-Ethyl-2-H- (2, -methoxy-5, -sulfonamidobenzoyl) aminomethylpyrrolidine (i) Hydrofluoride 0.5 ml (0.029 mol) of hydrogen fluoride is added as a 50% aqueous solution to a solution of 1.13 g (0.0033 mol) of 1-ethyl-2 - N- (2, -methoxy-5'-8-sulfonamidobenzoyl) aminomethylpyrrolidine (i) in 33 ml of isopropanol. The mixture is allowed to stand at 40 ° C overnight. The precipitate is isolated by filtration, washed with isopropanol and continued in vacuo in the presence of phosphorus pentoxide. Yield: 1 * 03 g (Θ8 j6) of hydrogen fluoride salt; mp. after recrystallization from ethanol: 129-130 ° C.

Claims (1)

A new process for the preparation of 1-ethyl-2- (2, -methoxy-5, -sulfonamidobenzoyl) aminomethylpyrrolidine of the formula I OOH-^ (J) / = 2Η5 so2 »h2 and its acid addition salts characterized in that 2-chlorobenzoic acid is reacted with chlorosulfonic acid, the resulting 2-chloro-5-chlorosulfonylbenzoic acid is amidated to 2-chloro-5-sulfonamidobenzoic acid, which is reacted with 1-ethyl-2-aminomethylpyrrolidine of formula II Cl - i II) | <^ \ pCOHHCH2 y \ I C2B5 so2nh2, which is reacted with metal methoxide to give a compound of formula I, which is, if desired, converted into an acid addition salt.