CH619452A5 - Process for the preparation of 1-ethyl-2-(2'-methoxy-5'-sulphonamidobenzoyl)aminomethylpyrrolidine and its acid addition salts - Google Patents

Description

The invention relates to a new process for the production of gastric ulcer inhibitory and psychotropic effects, called "Sulpiride" called l-ethyl-2- (2'-meth-

[Arch. Franc. Times. Appar. Digest 59, 50 (1970); Sem. Hop. 15 45, 3028 (1969)], as well as its salts formed with therapeutically acceptable acids.

Several methods are known from the literature for the preparation of the compound of the formula, or its hydrochloric acid salt.

20 According to Hungarian Patent No. 153310, the compound of formula I is prepared by heating the 2-methoxy-5-sulfonamidobenzoic acid with an excess of thionyl chloride to form the acid chloride and (II) condensing the latter with 1-ethylaminomethylpyrrolidine . The hydrochloric salt of the compound of formula I crystallizes from the reaction mixture after the addition of water. The description only gives the production of the hydrochloric acid salt, but gives no information about the yield.

30 The main disadvantage of this type of production is the formation of only small amounts of impure hydrochloric acid salt during the condensation of the acid chloride with 1 - ethyl-2-aminopyrrolidine; the cleaning and conversion of the hydrochloric acid salt into the corresponding base is associated with considerable loss. All these disadvantages appear in a particularly concise form if the process is to be used on a larger scale.

According to US Pat. No. 3,342,826, the compound of formula I can be obtained in the following manner: The carbonyl-diimidazole is prepared from 40 imidazole and phosgene in dry benzene, and the imidazole hydrochloride is removed by filtration, the The solution was evaporated to dryness, the residue obtained was dissolved in anhydrous tetrahydrofuran and reacted with 2-methoxy-5-sulfonamidobenzoic acid. The reaction of the N- (2-methoxy-5-sulfonamidoben-zoyl) imidazole obtained with l-ethyl-2-aminomethylpyrrolidine leads to the compound of the formula I. Data on the yield and the physical parameters of the base of the formula I or their hydrochloric salt is not shared in the description with -50. This type of production has many disadvantages. On the one hand, dry solvents must be used in each step of the reaction, and in the first step (production of the carbonyl-diimidazole) even a dry nitrogen atmosphere must be used. On the other hand, this step requires extremely toxic phosgene. 55 Third, during the process, the solvents must be concentrated in two cases under vacuum, which leads to inevitable losses and thus reduces economy. The process is extremely sensitive to both moisture and oxygen in the air and is therefore not suitable for the production of larger batches.

According to Belgian patent no. 787 180, the compound of the formula I is prepared in such a way that the tris (l-ethylpyrrolidyl-2-methyl) -65 -phosphoramide is first prepared from l-ethyl-2-aminomethylpyrrolidine and phosphorus oxychloride in a pyridine solution and the latter with 2-methoxy-5-sulfonamidobenzoic acid. After evaporation, the hydrochloric salt forms, from which the compound of formula I is obtained in basic form after purification. From-

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Prey is 10.5% based on the starting compound l-ethyl-2-amino-methylpyrrolidine, and 34.5% based on the acid used as starting material. The disadvantage of the process is primarily the low yield and secondly the fact that such substances have to be used (pyridine and phosphorus oxychloride together) which - especially in the case of larger batches - cause extremely strong heat generation. As a result, the process cannot be recommended for large-scale industrial production and is also uneconomical because of the poor yields.

According to Belgian Patent No. 787 794, the compound of formula I can be obtained in the following manner. First, the ethyl ester of 2-methoxy-5-sulfonamidobenzoic acid is converted into the acid hydrazide using hydrazine hydrate (yield 86%). The latter is used to produce the acid azide using hydrochloric acid and sodium nitrite, which is immediately reacted with l-ethyl-2-aminomethyl-pyrrolidine in a dioxane solution. After treatment with hydrochloric acid, the hydrochloric acid salt of the compound of the formula I is obtained, from which the base is prepared by precipitation with ammonia. The yield of the compound of the formula I is 42.6% with respect to the 2-methoxy-5-sulfonamidobenzoic acid anhydride, 21.3% with respect to the l-ethyl-2-aminomethylpyrrolidine and 36.6% with respect to the starting material, i.e. of the ethyl ester of 2-methoxy-5-sulfonamidobenzoic acid. A major disadvantage of this process is the low yield. Another important disadvantage is that four reaction steps (ester, hydrazide, azide, end product) are required to combine the acidic and the basic components.

The object of the invention is to ensure, by eliminating the disadvantages of the known processes, a process which, in a simple manner and also on an industrial scale, enables the compound of the formula I to be prepared in a good yield.

The invention is based on the following findings: a) The chlorine atom in the compound of formula II

Gl can be easily exchanged with a methoxy group in good yield.

The compound of formula II can be obtained in a simple manner and in good yield if the 2-chloro-benzoic acid is reacted with chlorosulfonic acid, the 2-chloro-5-chlorosulfonylbenzoic acid obtained is amidated and a reactive derivative, e.g. a lower alkyl ester or the chloride of the 2-chloro-5-sulfonamidobenzoic acid obtained is reacted with 1-ethyl-2-aminomethylpyrrolidine.

The invention therefore relates to a process for the preparation of l-ethyl-2- (2'-methoxy-5'-sulfonamidoben-zoyl) aminomethylpyrrolidine according to claim. 1. The invention further relates to a process for the preparation of the compound of formula I according to the characterizing part of claim 2.

The success of the procedure according to the invention is surprising for the following reasons. It is known that the halogen atoms bonded to the benzene ring are only slightly reactive if the compound contains no so-called loosening groups. The sulfonamide and carboxylic acid groups (so-called negative substituents) which are in the ortho or para position to the halogen atom exert such a loosening effect. Accordingly, one could logically expect that if the chlorine atom in the compound of formula II reacts with the methoxide anion - especially under relatively energetic circumstances - it will interact in the same way with the tertiary amino group, e.g. with the nitrogen atom of the ethyl pyrrolidine group of the compounds of formeini and II, which in both cases leads to the formation of significant amounts of a quaternary by-product and thus to a deterioration in the yield and purity of the desired compound of formula I during the reaction of the compound of formula II into the compound that would lead formally.

From the compound of the formulas, however, the compound of the formula I can be obtained in good yield and in pure form by replacing the chlorine atom with the methoxy group, which proves that no quaternary products are formed in a considerable amount; consequently, the replacement of the chlorine atom by the methoxy group is a surprisingly selective process despite the vigorous reaction conditions.

The invention is also surprising in that

because it would logically follow that the reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid also have the reactivity of the chlorine atom in the compound of formula II. It would therefore be expected that in the course of the preparation of the compound of the formula II, if the reactive derivative of 2-chloro-5-sulfonamidobenzoic acid is reacted with 1-ethyl-2-aminomethyl-pyrrolidine, the chlorine atom in position 2 - especially below relatively vigorous reaction conditions - reacts with the nitrogen atom of the ethylpyrrolidine group, which in turn would lead to the formation of quaternary by-products and thus to a deterioration in the yield and purity of the desired compound of the formula II. However, the compound of formula II can be obtained in good yield and in a pure state from the corresponding reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid by reaction with l-ethyl-2-aminomethylpyrrolidine, and this proves that products of form quaternary type during this reaction in no significant amount, thus the interaction between the reactive derivatives of 2-chloro-5-sulfonamido-benzoic acid and l-ethyl-2-aminomethylpyrrolidine provides the compound of F with surprising selectivity despite the vigorous reaction conditions ormel II.

The 2-chloro-5-chlorosulfonylbenzoic acid is a compound known from the literature (Swiss Patent No. 351 281). To produce them, 2-chlorobenzoic acid can be reacted with an excess of chlorosulfonic acid, preferably with heating and without a solvent, the excess of chlorosulfonic acid first being expediently decomposed with water and then the crude 2-chloro-5-chlorosulfonic acid obtained as a precipitate being used further becomes.

The 2-chloro-5-sulfonamidobenzoic acid is a compound known from the literature [J. Pharm. Pharmacol. 14, 679 (1962)]. It can be prepared by the reaction of 2-chloro-5-chloro-sulfonylbenzoic acid with concentrated ammonia solution. A lower aliphatic alcohol, preferably isopropanol, is expediently used as the solvent. At the beginning of the reaction, a low temperature (about 0 ° C.) is expediently used to maintain the ammonia concentration, and the reaction is then carried out at a higher temperature, for example. Room temperature, ended.

In order to convert the 2-chloro-5-sulfonamidobenzoic acid

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To produce a binding formula II, the acid must first be converted into a more reactive derivative, suitably into an ester, an acid halide or a mixed anhydride. Of the esters, the esters formed with aliphatic alcohols having 1-4 carbon atoms are the cheapest as starting materials for the process according to the invention. An acid chloride is preferably used as the acid halide.

The methyl and ethyl esters of 2-chloro-5-sulfonamido-benzoic acid are mentioned in one place in the literature [J. Pharm. Pharmacol. 14, 679 (1962)], but neither the method of preparation nor the physical and chemical properties of the compounds are disclosed. The other esters of 2-chloro-5-sulfonamidobenzoic acid are not known from the literature. These esters can e.g. by heating the acid with the corresponding alcohol in the presence of an acidic catalyst, e.g. Sulfuric acid and hydrochloric acid. An excess of the alcohol is expediently used as the solvent. However, the esterification reaction can also be carried out in such a way that the water vapors formed during the formation of the ester are removed by the vapors of the alcohol used as solvent.

The acid chloride is conveniently obtained by treating the acid with thionyl chloride or with a phosphorus-containing halogenating agent, e.g. Phosphorus trichloride, phosphorus oxychloride or phosphorus pentachloride. It is advantageous to carry out the reaction with thionyl chloride at the temperature of the boiling point of the mixture and to use the excess of thionyl chloride as the solvent.

The ester of 2-chloro-5-sulfonamidobenzoic acid and the l-ethyl-2-aminomethylpyrrolidine can also be heated, advantageously in a polar solvent, for example. in an alcohol or alkanediol having 1-5 carbon atoms, preferably in ethylene glycol. It is also advantageous to use an additive of an alkaline character, e.g. the sodium compound of the corresponding alcohol or ethylene glycol, or an organic base, e.g. Imid-azole.

The reaction of the 2-chloro-5-sulfonamidobenzoylchloride with l-ethyl-2-aminomethylpyrrolidine is advantageously carried out in a solvent. As a solvent, preferably water or a neutral solvent or diluent, e.g. a chlorinated hydrocarbon, e.g. Chloroform. You can also add a substance of basic character to the reaction mixture to form the hydrochloric acid formed. For this purpose, even the excess of 1-ethyl-2-aminomethylpyrro-lidin or another tertiary amine, e.g. Triethylamine or pyridine, or an inorganic acid binder such as e.g. Sodium or sodium carbonate can be used.

The reaction of the compound of formula II to the compound of formula I with metal methoxide is expediently carried out in a suitable solvent. Methanol is expediently used as the solvent and an alkaline methoxide, primarily sodium methoxide, is used as the metal methoxide. The reaction is expediently carried out at a temperature between the boiling point of the methanol and 160 ° C., preferably at 125 ° C. to 130 ° C. If it is desired to react at the boiling point of the methanol,

that is, under normal pressure, then it is advantageous to add a few percentages of dimethylformamide to the reaction mixture, based on the amount of methanol.

The salts of the compound of the formula I formed with therapeutically compatible acids are expediently prepared in such a way that the base of the formula I is dissolved warm in a suitable solvent and the solution is the desired one

Acid itself, or the concentrated aqueous solution of the desired acid or its solution in an organic solvent. The acid addition salts precipitate out in the heat and crystallize when the solution cools down. An aliphatic alcohol, primarily ethanol or isopropanol, is expediently used to dissolve the base; the acids are used in their ethanol or isopropanol solution.

The most important advantages of the method according to the invention in relation to the methods described in the literature are as follows:

Starting from the commercially available cheap 2-chlorobenzoic acid, the target product of the formula I is obtained in no more than five steps in a total yield of 42.9% 15 with respect to the 2-chlorobenzoic acid (the yields of the individual steps are 95.79, 88 in sequence , 91 and 71.5%).

In this consideration, the synthesis of the compound of formula I is initiated with the reaction between 2-chlorobenzoic acid and chlorosulfonic acid. As already mentioned, the starting compound of the processes described in the literature for the preparation of the compound of the formula I is 2-methoxy-5-sulfonamidobenzoic acid or its ester. According to the literature, this acid can be derived from salicylic acid [J. 25 Chem. Soc. London, 1986 (1923)] or starting from 2-nitrophenol (British Patent No. 1 204 406); However, both processes have the common feature that a compound containing the methoxy group has to be reacted with chlorosulfonic acid or with oleum in order to form the sulfonamide group in position 5; in the first case 2-methoxybenzoic acid must interact with oleum, in the second 2-nitroanisole should react with chlorosulfonic acid. However, it is known that the methyl ether derivatives of the phenols can be decomposed by sulfuric acid or 35 by chlorosulfonic acid [J. Chem. Soc., London, 4963 (1961); Reports, 98, 2070 (1965); J. Org. Chem. 32,1269 (1967)].

These disadvantages of the known processes are avoided according to the invention by providing for the introduction of the 40 methoxy group in the 2-position as the last process step.

Another advantage of the process is the simple procedure and good yield in the reaction of the compound of the formula II to the compound of the formula I. The process is therefore suitable for the production of large amounts, ie also for industrial implementation. The response is uniform and selective.

The method according to the invention is explained in more detail using the exemplary embodiments below.

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example 1

Step «A»: 2-chloro-5-chlorosulfonylbenzoic acid

93.6 g (0.06 mol) of 2-chlorobenzoic acid are added to 360 ml of chlorosulfonic acid with cooling with ice water and stirring at 5-6 ° C. within 90 minutes. The reaction mixture is subsequently stirred on the ice-water bath for one hour, at room temperature for one hour and at 96 ° C. for 6 hours, cooled to room temperature and poured onto 1200 g of ice. After standing for one hour, the white precipitate which has separated out is filtered off with suction, washed with water and dried under vacuum in the presence of phosphorus pentoxide. Yield: 145 g (95%) 2-chloro-5-chlorosulfonylbenzoic acid; Mp: 142-147 ° C.

65 Step «B»: 2-chloro-5-sulfonamidobenzoic acid

750 ml of isopropanol are saturated with dry ammonia gas at 0 to 5 ° C, 75.3 g (0.295 mol) of that in step «A»

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prepared 2-chloro-5-chlorosulfonylbenzoic acid added with stirring in one hour, and then stirred with slow continuous ammonia supply for one hour with ice water cooling and then for 20 minutes at room temperature. The precipitate which has separated out is filtered off with suction and the mother liquor is concentrated to dryness in a water bath at 45 ° C. The residue is added to the precipitate which had previously been suctioned off, dissolved in 700 ml of water, clarified with charcoal and, after filtering, the solution is acidified with concentrated hydrochloric acid. The mixture containing the precipitate is left to stand at 4 ° C. the next day, suction filtered, the precipitate washed with water and dried. Yield: 55 g (79%) 2-chloro-5-sulfamidobenzoic acid; Mp 220-222 ° C. After recrystallization from water, the melting point of the substance does not change.

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

22 ml of concentrated sulfuric acid are added dropwise at a temperature not exceeding 40 ° C. to a mixture of 48 g (0.22 mol) of the 2-chloro-5-sulfonamidobenzoic acid prepared in step “B” and 480 ml of methanol, with constant stirring. The mixture is boiled under reflux condenser for 8 hours, hot clarified with charcoal, and the solution obtained after filtration is greatly concentrated in vacuo. Then a 10% sodium carbonate solution is added dropwise to the solution until a pH of 7 is reached. The mixture containing the precipitate is left for a few hours at a temperature of 4 ° C, then suction filtered, the precipitate washed with water and dried under vacuum in the presence of phosphorus pentoxide. Yield: 48.2 g (94.5%) of unpurified methyl ester of 2-chloro-5-sulfonamidobenzoic acid, which gives 44.6 g (88%) of pure ester recrystallized from 48 ml of methanol; Mp: 127-128 ° C.

Step «D»: 1-ethyl-2-N- (2'-chloro-5'-sulfonamidobenzoyl) - aminomethylpyrrolidine (II)

11.6 g (0.17 mol) of imidazole are added to a mixture of 43.7 g (0.175 mol) of methyl 2-chloro-5-sulfonamidobenzoate prepared in step “C” and 145 ml of absolute ethylene glycol. The mixture is stirred for half an hour, then cooled to 10 ° C and, after the dropwise addition of 28.8 g (0.225 mol) of l-ethyl-2-aminomethylpyrrolidine, is stirred for 8 hours at 95 ° C, and then at 4 ° C left for two days. The precipitate is filtered off, washed first with 50% aqueous methanol and then with water, and dried under vacuum in the presence of phosphorus pentoxide. Yield: 55.1 g (91%) of l-ethyl-2-N- (2'-chloro-5-sulfonamidobenzoyl) aminomethylpyrrolidine (II); Mp: 180 ° C. Recrystallized from methanol, the melting point of the substance does not change.

Step «E >>: l-ethyl-2-N- (2'-methoxy-5'-sulfonamido-benzoyl) aminomethylpyrrolidine (I)

Method 1

2.4 g (0.105 atom) of sodium are dissolved in 60 ml of methanol, and 10.38 g (0.03 mol) of the 1-ethyl-2-N- (2'-chloro- 5'-sulfonamidobenzoyl) aminomethylpyrrolidins (II) and 6.3 ml of anhydrous dimethylformamide were added. The mixture is refluxed for 42 hours and then concentrated to dryness in vacuo at a temperature of 40 ° C. The distillation residue is mixed with 150 ml of anhydrous ethanol and acidified to a pH of 5 with a 20% hydrochloric acid solution in ethanol. 80 ml of acetone are added and the mixture is kept at a temperature of 4 ° C. for 5-6 hours. The precipitate is filtered off, washed with acetone and dried. The crystal powder thus obtained is in 160 ml

Dissolved water, added dropwise with 12 ml of concentrated aqueous ammonium hydroxide solution and left to stand at 4 ° C. over N eight. The precipitate which has separated out is filtered off with suction, washed with water and dried under reduced pressure in the presence of phosphorus pentoxide. Yield: 7.4 g (71.5%) of l-ethyl-2-N- (2'-methoxy-5'-sulfonamidobenzoyl) -amino-methylpyrrolidine (I). Mp: 178 ° C. After recrystallization from ethanol, the melting point of the substance remains unchanged.

10 Method 2

1.38 g (0.06 atom) of sodium are dissolved in 50 ml of methanol, 3.46 g (0.01 mol) of the 1-ethyl-2-N- (2'-chloro- 5'-sulfonamidobenzoyl) aminomethyl-15 pyrrolidine (II) is added to the solution and the mixture is heated in a bomb tube on a 140 ° C oil bath for 12 hours. After cooling and clarifying with charcoal, the solution is concentrated in vacuo at a temperature of 40 ° C., the residue is mixed with 20 ml of ethanol 20 and concentrated under the same circumstances as first. The distillation residue is mixed with 50 ml of anhydrous ethanol, acidified with a 20% hydrochloric acid solution in ethanol until a pH of 5 is reached, and kept at 4 ° C. for 5 to 6 hours after the addition of 50 ml of acetone precipitated precipitate is filtered off, washed with acetone and dried. The crystal powder obtained in this way is dissolved in 50 ml of hot water, 4 ml of an aqueous concentrated ammonium hydroxide solution are added dropwise and the mixture is left to stand at a temperature of 4 ° C. until the next day. The precipitate is filtered off, washed with water and dried under vacuum in the presence of phosphorus pentoxide. Yield: 2.36 g (69%)

1-ethyl-2-N- (2'-methoxy-5'-sulfonamidobenzoyl) amino-methylpyrrolidine (I); Mp: 178 ° C.

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Example 2

Step «A»: 2-chloro-5-sulfonamidobenzoyl chloride

A mixture of 23.68 g (0.1 mol) of 2-chloro-5-sulfonamido-40-benzoic acid and 140 ml of thionyl chloride is boiled under the reflux condenser for 1.5 hours, the pure solution is left to stand at 4 ° C. overnight and suction filtered , washed with benzene and dried under vacuum at room temperature in the presence of phosphorus pentoxide. Yield: 22.45 g (88.5%) 2-45 chloro-5-sulfonamidobenzoyl chloride; Mp: 141-143 ° C. A further 3 to 6% of the acid chloride is obtained by carefully concentrating the mother liquor.

Step «B»: l-ethyl-2-N- (2'-chloro-5'-sulfonamidobenzoyl) -m -aminomethylpyrrolidin (II)

Method 1

A mixture of 5.59 g (0.044 mol) of l-ethyl-2-aminomethylpyrrolidine and 80 ml of water is mixed with constant stirring and cooling with ice water at a temperature of 4 55 to 7 ° C. to 5.08 g (0.02 Mol) of the 2-chloro-5-sulfonamidobenzoyl chloride prepared in step “A” was added. The mixture is stirred at the same temperature for a further 2 hours, suction filtered, washed with water and dried at 40 ° C. Yield: 6.08 g (87.9%) of l-ethyl-2-N- (2'-chloro-5'-sulfonami-60 dobenzoyl) aminomethylpyrrolidine (II); Mp: 178-180 ° C. After recrystallization from methanol: mp: 180 ° C.

Method 2

A mixture of 1.54 g (0.012 mol) of l-ethyl-2-amino-65 methylpyrrolidine, 1.2 g (0.012 mol) of triethylamine and 50 ml of water are stirred and cooled with ice water at a temperature of 4 to 7 ° C 2.54 g (0.01 mol)

2-Chloro-5-sulfonamidobenzoyl chloride added. After that

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proceed as in method 1, step «A» of example 2. Yield: 2.90 g (85.6%) of l-ethyl-2-N- (2'-chloro-5-sulfonamidobenzoyl) aminomethylpyrrolidine (II): mp: 178 ° C.

Step «C»: 1-ethyl-2-N- (2'-methoxy-5'-sulfonamido

benzoyl) aminomethylpyrrolidine (I) (sulpiride)

Corresponds to step «E» in example 1.

Example 3

1-ethyl-2 -N- (2'-methoxy-5 '-sulfonamidobenzoyl) amino-methylpyrrolidine (I) hydrochloride

A hot solution of 43.95 g (0.13 mol) of 1-ethyl-2-N- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (I) in 770 ml of anhydrous ethanol is added dropwise 103 ml (0.29 mol) of a 10.28% hydrogen chloride gas solution in anhydrous ethanol, the mixture containing the precipitate boils for 10 minutes with constant stirring and then stands at a temperature of 4 ° C overnight. The next day, the crystalline hydrochloric acid salt is suctioned off, the precipitate is washed with acetone and dried under vacuum in the presence of phosphorus pentoxide. Yield: 44.8 g (92.6%) hydrochloride salt: mp: 233 to 237 ° C.

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

Example 4

1-ethyl-2-N- (2'-methoxy-5 '-sulfonamidobenzoyl) - aminomethylpyrrolidine (I) - hydrogen sulfate

A hot solution of 3.41 g (0.01 mol) of l-ethyl-2-N - (2'-methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (I) in 100 ml of anhydrous ethanol is added dropwise with

0.6 ml (0.012 mol) of concentrated sulfuric acid are added. The mixture containing the precipitate is left to stand at 4 ° C. until the next day, then suction filtered, washed with anhydrous ethanol and dried under vacuum in the presence of phosphorus pentoxide. Yield: 4.35 g (99%) sulfuric acid salt; After recrystallization from ethanol: 198 ° C.

Example 5

10 1 -ethyl-2 -N- (2'-methoxy-5'-sulfonamidobenzoyl) -

aminomethylpyrrolidine (I) hydrogen maleate A hot solution of 3.41 g (0.01 mol) of l-ethyl-2-N - (2-methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (I) in 150 ml of isopropanol 1.3 g (0.011 mol) of maleic acid was added. The mixture is left to stand at 4 ° C. until the next day, then suction filtered, the precipitate washed with isopropanol and dried under vacuum in the presence of phosphorus pentoxide. Yield: 3.34 g (73%) mal-acid salt; Mp after recrystallization from isopropyl

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panol: 132 ° C.

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Example 6

l-ethyl-2-N- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (I) hydrogen fluoride

A solution of 1.13 g (0.0033 mol) of l-ethyl-2-N- (2 '- methoxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine (I) in 35 ml of isopropanol is 0.5 ml (0.029 mol ) a 50% aqueous hydrogen fluoride solution. The mixture 30 is left at 4 ° C. until the next day, the precipitate is filtered off with suction, washed with isopropanol and dried under vacuum in the presence of phosphorus pentoxide. Yield: 1.05 g (88%) of hydrofluoric acid salt; Mp after recrystallization from ethanol: 129-130 ° C.

Claims (6)

619452 2nd PATENT CLAIMS I. Process for the preparation of l-ethyl-2- (2'-methoxy - 5'-sulfonamidobenzoyl) aminomethylpyrrolidine of formula I. oxy-5'-sulfonamidobenzoyl) aminomethylpyrrolidine of the formula I. OCH- OCH- - CONHCH ~ - 0) 10th - CONHCH2 - 0) g, H ( S02NfI2 so2nh2 and its acid addition salts, characterized in that the acid amide of the formula II - conuch2 - S02NH2 C., H J> reacted with a metal methoxide and the compound of the formula I obtained in this way is optionally converted into an acid addition salt with an acid. 2. Process for the preparation of l-ethyl-2- (2'-methoxy - 5'-sulfonamidobenzoyl} aminomethylpyrrolidine of formula I and its acid addition salts, characterized in that a reactive functional derivative of 2-chloro-5- sulfonamidobenzoic acid reacted with l-ethyl-2-aminomethylpyrro-lidine and the acid amide of the formula II obtained in this way is converted into the compound of the formula I by the process of claim 1. 3. The method according to claim 1, characterized in that an alkali metal methoxide, preferably sodium methoxide, is used as the metal methoxide. 4. The method according to claim 1, characterized in that the reaction is carried out at a temperature between 60 ° C and 160 ° C, preferably between 125 ° C and 130 ° C, optionally in the presence of dimethylformamide. 5. The method according to claim 2, characterized in that as a reactive functional derivative of 2-chloro-5 - sulfonamidobenzoic acid, their esters with aliphatic alcohols, the acid halides or acid anhydrides are used. 6. The method according to claim 2, characterized in that the reaction is carried out in a neutral solvent, optionally in the presence of an additive with an alkaline character.