DE2613394A1 - 1-AETHYL-2-ANGLE BRACKETS ON N- (2'-CHLORINE-5'-SULFONAMIDOBENZOYL) -AMINOMETHYL SQUARE BRACKETS FOR -PYRROLIDINE AND THE PROCESS FOR THE PRODUCTION OF THE SAME AND FROM 1-AETHYL-2-SQUARE -METHOXY-5'-SULFONAMIDOBENZOYL) -AMINOMETHYL SQUARE BRACKETS TO -PYRROLIDINE AND ITS SALT - Google Patents

Description

DR.STEPHAN G. BESZEDES PATENT ADVOCATE

806 DACHAU near MÖNCHEN

BOX 1168

AM HEIDEWEG 2

TELEPHONE: DACHAU 4371 Postal checking account Munich (BLZ 700 100 80)

Account no. 1368 71

Bank account No. 90 637 at the Kreis- und Stadtsparkasse Dachau-Indersdorf (bank code 700 515 40)

P 904

Description

for patent application

ALKA.L0IDA VEGYESZETI GYAR

Tiszavasvari, Hungary

concerning

_1-Äth> yl-2-CN- (2'-chloro-5'-sulfonamidobenzoyl) - -aminomethylj-pyrrolidine as well as methods for producing the same and 1-ethyl-2- [N- (2'-methoxy-5 '-sulfonamidobenzoyl) -aminomethyl- pyrrolidine and its salts

The invention relates to the new intermediate 1-ethyl -2-JN- (2'-chloro-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine and a new process for the preparation of the same and 1-ethyl-2, which has psychotropic and gastric ulcer-inhibiting effects - [N- (2 ^l -methoxy-5 '-sulfonamidobenzoyl) .aminomethylj-pyrrolidines of the formula

609841/1003

ORIGINAL INSPECTED

O - CH

(Arch. Franc. Mal. Appar. Diges ₍ t j> 9 [397 ⁰ Ji 5 ° ^and Sem. Hop. FfcS [j969]> 3 028), also called sulpiride, and of its salts with acids via the intermediate product mentioned.

Several processes for the preparation of the ^/ l-ethyl-2- [N- (2 ^l -methoxy-5'-sulfonamidobenzoyl) -aminomethyl] pyrrolidines of the formula I or its hydrochloride are known from the literature.

According to the Hungarian patent specification 153 310 this is 1-Ethyl-2- [n- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula I in the V / eise produced that by heating the 2-methoxy-5-sulfonamidobenzoic acid with an excess of thionyl chloride, the corresponding acid chloride 2-methoxy-5-sulfonamidobenzoyl chloride is formed and the latter with i-ethyl-2-aminomethylpyrrolidine is condensed. The hydrochloride of 1-ethyl-2-Qj- (2'- methoxy-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidines of the formula I crystallizes out after the addition of water

609 841/1003

the reaction mixture. In the description, only the production of the hydrochloric acid salt is given via the yield however, no information can be found.

The main disadvantage of this process is the formation of only small amounts of what is also impure hydrochloride of 1-ethyl-2- [N- (2 ^l -methoxy-5 ¹ -sulfonamidobenzoyl) -aminomethy Ij -pyrrolidines during the condensation of 2-methoxy -5-sulfonamidobenzoylchlorides with the i-ethyl-2-aminomethylpyrrolidine and the purification and conversion of the hydrochloride of 1-ethyl-2- [N- (2 ^l -methoxy-5'- -sulfonamidobenzoyl) -aminomethyl] -pyrrolidines to the corresponding Base 1-ethyl-2- [N- (2 · methoxy-5'-sulfonamidobenzoyl) -aminomethyl II -pyrrolidine is associated with considerable losses. All of these disadvantages are particularly pronounced when the process is to be carried out on a larger scale.

According to US Pat. No. 3,342,826, 1-ethyl--2- [n- (2'-methoxy-5 ¹ -sulfonamidobenzoyl) aminomethyl] - pyrrolidine of the formula I can be prepared as follows: From imidazole and phosgene becomes produced carbonyldiimidazole in dry benzene, the imidazole hydrochloride removed by filtration, the solution evaporated to dryness and the residue obtained dissolved in anhydrous tetrahydrofuran and reacted with 2-methoxy-5-sulfonamidobenzoic acid. The reaction of the N- (2-methoxy-5-sulfonamidobenzoyl) -imidazole obtained with i-ethyl-2-aminomethylpyrrolidine leads to 1-ethyl-2- [N- (2'-methoxy-5'-sulfonamidobenzoyl) -aminomethyl] pyrrolidine of the formula I. Data relating to the yield and the physical parameters of the base 1-ethyl -2- [V- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula I or its hydrochloride are not specified. This method also has many disadvantages

609841/1003

First, dry solvents must be used in each stage of the implementation, and in the first stage (preparation of the Carbonyldiimidazoles) even have a dry nitrogen atmosphere be used. Secondly, the extremely poisonous phosgene has to be used at this stage. Third During the process, the solvents have to be evaporated off under vacuum in 2 cases, which leads to inevitable losses leads and thus reduces profitability. The process is both against moisture and against the Atmospheric oxygen is extremely sensitive and that's why it is Process not suitable for large-scale production.

According to Belgian patent 787 180, the 1 -1thyl-2-JJH ^- -C2 · -ffiethoxy-5 '-sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula I is prepared in such a way that first from i-ethyl-2-aminomethylpyrrolidine and phosphorus oxychloride in a pyridine solution, the tris- (1-ethylpyrrolidyl- -2-methyl) -phosphoramide is prepared and the latter is reacted with 2-methoxy-5-sulfonamidobenzoic acid. After evaporation, the hydrochloride of 1-αϊ1 ^ 1-2-Γν- (2 · - -methoxy-5 ¹ -sulfonamidobenzoyl) -aminomethyIj-pyrrolidines is formed, from which the base 1-ethyl -2-ΓϊΓ after its purification - (2'-methoxy-5'-sulfonamidobenzoyl) -aminome thy IJ -pyrrolidine of the formula I is released. The yield is 10.5% based on the starting compound 1-ethyl-2-aminomethylpyrrolidine and 34.5% based on the starting material 2-methoxy-5-sulfonamidobenzoic acid. The disadvantages of this process consist primarily in the low yield and, secondly, in the fact that those substances (CPyridine and phosphorus oxychloride together) have to be used which, especially in the case of larger amounts, bring about an extremely strong development of heat. Accordingly, the process is not recommended for large-scale production and is also uneconomical because of the poor yields.

- 5 -609841/1003

According to Belgian patent 787 794-, the 1-ethyls- [n- (2'-methoxy-5 ¹ -sulfonamidobenzoyl) -aminomethyl] - -pyrrolidine of the formula I can be prepared as follows: First, ethyl 2-methoxy-5-sulfonamidobenzoate is prepared converted with the aid of hydrazine hydrazide into the corresponding acid hydrazide 2-methoxy-5-sulfonamidobenzhydrazide (yield 86%). The acid azide 2-methoxy-5-sulfonamidobenzazide is prepared from the latter by means of hydrochloric acid and sodium nitrite, which is reacted directly with 1-ethyl-2-aminomethylpyrrolidine in a dioxane solution. After treatment with hydrochloric acid, the hydrochloride of 1-ethyl-2 - [_ N- (2'-methoxy- -5'-sulfonamidobenzoyl) -aminomethy IJ -pyrrolidines of the formula I is obtained, from which the base is obtained by precipitation with ammonia The yield of 1-ethyl-2- [N- (2'-methoxy-5'-sulfonamidobenzoyl ) -aminomethyΐΊ-pyrrolidine of the formula I is 42.6%, based on the 2-methoxy-5-sulfonamidobenzoic acid hydrazide, 21.3% ^ based on the starting material i-ethyl-2-aminomethylpyrrolidine, and 36.6%, based on the starting material ethyl 2-methoxy-5-sulfonamidobenzoate. A major disadvantage of this process is the low yield. Another significant disadvantage is that 4 reaction stages (ester, hydrazide, azide, end product) are required to combine the acidic and basic components .

The invention is based on the object, while eliminating the disadvantages of the known processes, a process and an intermediate product through or via which the 1-ethyl-2- ^ N- (2'-methoxy-5 ¹ -sulfonamidobenzoyl) -aminomethy Ij- - pyrrolidine of the formula I can be produced in a simple manner and in good yield on an industrial or industrial scale.

The invention is based on the following findings: '

- 6 609841/1003

a) The chlorine atom in 1-ethyl-2- [N- (2'-clilor-5'- sulfonamidobenzoyl) aminomethyl pyrrolidine the formula

-H-

II

can be exchanged for a methoxy group easily and in good yield.

Ίύ) The above 1-ithyl-2- [k- (2 ^f ■■■ chloro-5 ^l - -sulfonamidobθnzoyl) -aminomethylJ-pyrrolidine of the formula II can be obtained in the same way in a simple manner and in good yield be that a reactive derivative, for example a lower alkyl ester or the chloride of 2-chloro-5-sulfonamidobenzoic acid, which may have been obtained by reacting 2-chlorobenzoic acid with chlorosulfonic acid and amidating the 2-chloro-5-chlorosulfonylbenzoic acid obtained, with 1 -Ethyl-2-aminomethylpyrrolidine is implemented.

These findings are surprising for the following reasons

609841/1003

It is known that the halogen atoms bonded to the benzene ring are only slightly reactive if the compound in question has no so-called loosening groups. The sulfonamide and carboxylic acid groups (so-called negative substituents) attached to the halogen atom in the o- or p-position exert such a loosening effect. Accordingly, it would logically have been expected that if the chlorine atom in the 1-ethyl-2- | _N- (2 ^t -chlor-5 ^l -sulfonamidobenzoyl) -aminomethylj-pyrrolidine of the formula II with the methylate anion, especially under relatively energetic conditions, reacts, it interacts in the same way with tertiary amino groups, for example the nitrogen atom of the ethylpyrrolidine group of the compounds of the formulas I 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 of the desired 1- Ethyl-2- £ N- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula I and its purity in the reaction of 1-ethyl-2 - [_ N ~ C2'-chloro-5 ^l -sulfonamidobenzoyl) - -aminomethyIj -pyrrolidines of the formula II to the 1-Ä * thyl-2- - [N- (2'-methoxy-5'-sulfonamidobenzoyl) -aminomethyl] | - -pyrrolidine of the formula I would lead. In contrast, it is very surprising that 1-ethyl-2- [N- ( 2'-methoxy-5'-sulfonamidobenzoyl) -aminomethyll-pyrrolidine of the formula I can be obtained in good yield and pure by replacing the oxygen atom with the methoxy group, i.e. no quaternary products are formed in significant quantities. The exchange of the chlorine atom for the methoxy group is therefore a surprisingly selective process, despite the energetic reaction conditions.

The findings of the applicant are still well so surprising because it would have been to conclude logically that the reactive derivatives of

- 8. · 609841/1003

2-chloro-5-sulfonamidobenzoic acid have the reactivity of the chlorine atom of the I-ethyl ^ -JJET-C 2'-chloro-5'-sulfonamidobenzoyl) -aminome thy lj-pyrrolidines of the formula II. It would therefore have been expected that in the course of the preparation of the 1-ethyl-2- [N- ^ ¹ -chloro-5'-sulfonamidobenzoyl) - -aminomethyll-pyrrolidines of the formula II, in which the reactive derivative of the 2- Chlor-5-sulfonamidobenzoic acid is reacted with i-ethyl-2-aminomethylpyrrolidine, the chlorine atom in the 2-position, especially under relatively energetic reaction conditions, with the nitrogen atom of the ethylpyrrolidine group in reaction, which again leads to the formation of quaternary by-products and so on Deterioration in the yield of the desired 1-ethyl-2- -Γν- (2'-chloro-5'-sulfonamidobenzoyl) -aminome thy Ij -pyrrolidine of the formula II and the purity thereof would lead. In contrast, surprisingly, i-ethyl-2- [N- (2'-chloro-5'-sulfonamidobenzoyl) - can be obtained from the corresponding reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid by reacting them with i-ethyl-2-aminomethylpyrrolidine. -aminomethyl] pyrrolidine of the formula II can be obtained in good yield and pure, from which it follows that products of the quaternary type are not formed in any significant amount during this reaction either. The interaction between the reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid and the "i-ethyl-2-aminomethylpyrrolidine thus delivers the 1-ethyl-2- [N- (2 ^l -chlor- 5'- -sulfonamidobenzoyl) -aminomethy 1 ~ J-pyrrolidine of the formula II.

The invention therefore relates to 1-ethyl-2-JN- (2'-chloro- -5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula

609841/1003

Cl

-N-C

The invention also provides a method for
Preparation of the above 1-ethyl-2- [N- (2'-chloro-5'-sulfonamidobenzoyl) -aminomethylj-pyrrolidines, which is characterized in that a reactive derivative of 2-chloro-5-sulfonamidobenzoic acid with "i-ethyl -2-aminomethylpyrrolidine is implemented.

The invention also relates to a process for the preparation of 1-ethyl-2- [N- (2'-methoxy-5 ^l -sulfonamidobenzoyl) aminomethylj-pyrrolidine of the formula

0 - CH

609841/1003

and its salts, which is characterized in that

a) 1-ethyl-2- [k- (2'-chloro-5 ¹ -sulfonamidobenzoyl) - -aminomethyl-pyrrolidine of the formula

S-NH ₂

is reacted with a metal methylate

or

b) a reactive derivative of 2-chloro-5-sulfonamidobenzoic acid with 1-ethyl-2-aminomethylpyrrolidine is unused and then i-ethyl-2- Γν- (2 · -chlor- !? ¹ -sulfonumidobenzoyl) -aminomethyl -pyrrolidine of the formula

Cl

I. 0
Il H C - C ₂ H ₅ N - ^H 2

S-NH ₂

609841/1003

- Ή is reacted with a metal methylate

and optionally the 1-ethyl-2-rN- (2'- -methoxy-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine der Formula I is converted into a salt with an acid.

An ester, in particular an ester, is preferably used as the reactive derivative of 2-chloro-5-sulfonamidobenzoic acid those with aliphatic alcohols, an acid halide or an acid anhydride thereof are used.

The reactions are preferably carried out in an inert solvent, in the case of the reaction, the reactive solvent Derivatives of 2-chloro-5-sulfonamidobenzoic acid with the 1-ethyl-2-aminomethylpyrrolidine optionally in the presence an additive of an alkaline type.

Thus, the esters of 2-chloro-5-sulfonamidobenzoic acid and 1-ethyl-2-aminomethylpyrrolidine can, in particular, by heating in a polar solvent, for example an alcohol or alkanedioja having 1 to 5 carbon atoms, preferably Ethylene glycol. It is also advantageous to use an additive of an alkaline type, for example the sodium compound of an appropriate alcohol or ethylene glycol or an organic base such as imidazole use"

The reaction of the 2-chloro-5-sulfonamidobenzoyl chloride with 1-ethyl-2-aminomethylpyrrolidine is also preferred carried out in a solvent. As a solvent is preferably water or an inert solvent or diluent, for example a chlorinated hydrocarbon, such as chloroform, is used. A substance of a basic type can also be used in the reaction mixture to bind the hydrochloric acid formed can be added. To this end

- 12 • 609841/1003

can be an excess of 1-ethyl-2-aminomethylpyrrolidines or another tertiary 1min, such as triethylamine or pyridine, or an inorganic acid terminating agent, such as Sodium or sodium carbonate, can be used.

The reaction of the 1-ethyl-2- [K- (2 ^l -chloro-5 ^l - -sulfonamidobenzoyl) aminomethyl] pyrrolidines of the formula II with the metal methylate to give 1-ethyl-2- [N- (2'- methoxy-5'- sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula I is preferably carried out in a suitable solvent. In particular, methanol is used as the solvent. It is preferred to use an alkali metal methylate, in particular sodium methylate, as the metal methylate. It is also preferred, the reaction of 1-ethyl-2 - {_ N- (2 ^l -ch.lor- -5'-sulfonamidobenzoyl) -aminomethylj-pyrrolidines of the formula II with the Metallmethylat at a temperature of 60 to 160 ⁰ G , in particular 125 "to 130 ^° C., optionally in the presence of dimethylformamide. In particular, it is advantageous to add a few percent of dimethylformamide, based on the amount of methanol, to the reaction mixture if it is desired to carry out the reaction at the boiling point of the methanol, ie under normal pressure.

The salts of 1-ethyl-2- [N- (2 ^l -methoxy-5 ¹ -sulfonamidobenzoyl ^ aminomethyl] -pyrrolidines of the formula I with acids are expediently prepared in such a way that the base 1-ethyl-2-fj! T- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine of the formula I is dissolved warm in a suitable solvent and the desired acid itself or a concentrated solution of the desired acid in water or an organic solvent is added to the solution The acid addition salts precipitate in the heat and crystallize on cooling the solution. 1-Ethyl-2-ΓN- (2'-methoxy-5'-sulfonamidobenzoyl,) aminomethyl] pyrrolidine is expedient for dissolving the base an aliphatic alcohol, in

- 13 609841/1003

primarily ethanol or isopropanol. The acids can advantageously be ethanolic or isopropanolic Solution can be used.

2-chloro-5-chlorosulfonylbenzoic acid is a compound known from literature (Swiss patent 351 281). It may have been obtained as follows. 2-chlorobenzoic acid is reacted with an excess of chlorosulfonic acid, preferably with heating and without a solvent. Then the excess chlorosulfonic acid is decomposed with water and the crude 2-chloro obtained as a precipitate -5-chlorosulfonylbenzoic acid is used in the next stage.

2-chloro-5-sulfonamidobenzoic acid is also a compound known from literature (J. Pharm. Pharmacol. 14 £ 19623 ₅ 679) It can be obtained as follows. 2-Chloro-5-chlorosulfonylbenzoic acid is reacted 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 around ⁰ ° C. is expediently used to maintain the ammonia concentration and then the reaction is ended at a higher temperature, for example room temperature.

According to the invention for the reaction with 1-ethyl-2-aminomethylpyrrolidine to 1-ethyl-2- [N- (2'-chloro-5'-sulfonamidobenzoyl) -aminomethy \\ -pyrrolidine of the formula II used reactive derivatives of the 2-chloro 5-sulfonamidobenzoic acid can have been obtained from this in a manner known per se. Of the esters of the same which can be used as reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid, the aliphatic alcohols having 1 to 4 carbon atoms have proven to be the most favorable

609841/1003

proven. Of the acid halides which can also be used as reactive derivatives of 2-chloro-5-sulfonamidobenzoic acid of these, the acid chlorides are preferred. The also as reactive derivatives of the 2-chloro-5- -sulfonamidobenzoic acid usable acid anhydrides thereof can be mixed anhydrides.

The methyl and ethyl esters of 2-chloro-5-sulfonamidobenzoic acid are mentioned in a single place in the literature (J. Pharm. Pharmacol. j14 JJ962J, 679), but neither a process for their preparation and the physical and chemical properties of the same are given. the other esters of 2-chloro-5-sulfonamidobenzoic acid are not known from the literature. These esters can for example by heating the 2-chloro-5-sulfonamidobenzoic acid with the appropriate alcohol in the presence of an acidic catalyst such as sulfuric acid and hydrochloric acid have been. An excess of the alcohol has expediently been used as the solvent. The esterification reaction but can also have been carried out in such a way that the water vapors formed during the formation of the ester by the Vapors of the alcohol used as solvent are removed.

The acid chlorides of 2-chloro-5-sulfonamidobenzoic acid are expedient by treating the 2-chloro-5-sulfonamidobenzoic acid with thionyl chloride or a phosphorus-containing halogenating agents, for example phosphorus trichloride, Phosphorus oxychloride or phosphorus pentachloride. It is beneficial to implement with Carry out thionyl chloride at the temperature of the boiling point of the mixture and use an excess of thionyl chloride as the solvent to use.

The main advantages of the invention over the

- 15 -609841/1003

- 15 state of the art are as follows:

Calculated from the commercially available, cheap 2-chlorobenzoic acid the end product is 1-ethyl-2-rN- (2'-methoxy-5'- -sulfonamidobenzoyl) -aminomethylj-pyrrolidine of the formula I. in 5 stages with a total yield of 42.9%? based on 2-chlorobenzoic acid (the yields of the individual stages are 95%, 79%, 88%, 91% and 71.5% in sequence).

As already mentioned, the preparation of one of the starting materials used according to the invention is initiated with the reaction between 2-chlorobenzoic acid and chlorosulfonic acid. The starting compounds of the process described in the literature for the preparation of the 1-ethyl-2- [N- (2 ^l - -methoxy-5'-sulfonamidobenzoyl) -aminomethyll-pyrrolidines of the formula I are, as already mentioned, the 2-methoxy-5- sulfonamidobenzoic acid or its ester. According to the literature, this acid can be prepared from salicylic acid (J. Chem. Soc. London [1923 ^ j, 1986) or from 2-nitrophenol (British patent 1 204 406). However, both processes have the common feature that a compound containing the methoxy group must be reacted with chlorosulfonic acid or oleum in order to form the sulfonamide group in the 5-position; in the first case 2-methoxybenzoic acid has to be reacted with oleum and in the second case 2-nitroanisole has to be reacted with chlorosulfonic acid. It is known, however, that the methyl ether derivatives of phenols can be decomposed by sulfuric acid or chlorosulfonic acid "(J. Chem. Soc, London, 1961, 4 963; Reports 98 [1965], 2 070; J. Org. Chem. *> 2 ( 1967 ^, 1 269) · In contrast, it is a particular advantage of the invention that the 2-chlorobenzoic acid used for the production of one of the starting materials used according to the invention without by-products and decomposition and in excellent yield with

- 16 609841/1003

the chlorosulfonic acid reacts. The methoxy group in the The 2-position only becomes the end product 1-ethyl-2- | lj- (2'-methoxy-5'-sulfonamidobenzoyl) aminomethyl] - pyrrolidine of the formula I incorporated by exchanging the chlorine atom in the 2-position for them.

Another advantage of the invention is the simplicity and good yield of the implementation of the 1-ethyl-2- - [ϊΓ- (2'-chloro-5 '-sulfonamidobenzoyl) -aminomethylj -pyrrolidines of formula II to 1-ethyl-2- [N- (2'-methoxy-5'-sulfonamidobenzoyl) -aminomethy] J -pyrrolidine of the formula I. That's how it is Process for the production of larger quantities, also for technical or industrial implementation suitable. The reaction is clear or uniform and selective.

The invention is not intended to be limiting in light of the following Examples to be understood are explained in more detail.

example 1

1-1thyl-2- [k- (2'-chloro-5'-sulfonamidobenzoyl) - -aminomethylj -pyrrolidine (Formula II)

It was a mixture of 43.7 g (0.175 mol) of 2-chloro

7th

-5-sulfonamidobenzoic acid methyl ester and 145 cnr of absolute ethylene glycol were added to 11.6 g (0.17 mol) of imidazole. The mixture was stirred or shaken for 4 hours, then cooled to 10 ° 0 and, after the dropwise addition of 28.8 g (0.225 mol) of 1-ethyl-2-aminomethylpyrrolidine, stirred or shaken for 8 hours at 95 ° O and then for 2 days left to stand ^{at 4 ° C.} Of the

- 17 -

609841/100 3

Precipitate was filtered off with suction, washed first with 50% strength aqueous methanol and then with water and dried under vacuum in the presence of phosphorus pentoxide. Yield: 55.1 g (91% of theory) of 1-ethyl-2- [N- (2'-chloro-5 ^l - -sulfonamidobenzoyl) -aminomethyl] -pyrrolidine (formula II). Melting point: 180 ^° C. When recrystallizing from methanol, the melting point of the substance did not change.

II

1-ethyl-2-JN- (2'-methoxy-5-sulfonamidobenzoyl) aminomethyl] pyrrolidine (Formula I)

Procedure 1

2.4 g (0.105 gram atom) of sodium were dissolved in 60 cnr of methanol and 10.38 g (0.03 mol) of the 1-ethyl-2- [N- (2'-chloro-5) prepared in Part I of this example '-sulfonamidobenzoyl) aminomethyl] pyrrolidines (formula II) and 6.3 cur of anhydrous dimethylformamide were added. The mixture was heated for 42 hours to boiling under reflux and then evaporated under vacuum at a temperature of 40 ⁰ C to dryness. The distillation residue was mixed with 150 cnr anhydrous ethanol and with a 20% ethanolic hydrogen chloride solution until one was reached

7th

acidified pH value of 5. Then 80 cnr acetone was added and the whole was kept at a temperature of 4 ° C for 5 to 6 hours. The deposited precipitate was filtered off with suction, washed with acetone and dried. The crystalline powder thus obtained was dissolved in 160 cnr v / ater, treated dropwise with a concentrated aqueous ammonium hydroxide solution 12 cur and allowed to stand overnight at 4 ^0C. The deposited precipitate was filtered off with suction, washed with water and under vacuum in the presence of

- 18 6 0 9841/1003

Dried phosphorus pentoxide. Yield: 7> 4- S (71.5% of theory) 1-ethyl-2- [N- (2'-methoxy-5-sulfonamidobenzoyl) -aminomethyl] pyrrolidine (formula I). Melting point: 178 ^° C. When recrystallizing from ethanol, the melting point of the substance remained unchanged.

Procedure 2

1.38 g (0.06 gram atom) of sodium were dissolved in 50 cur of methanol, and 3> 46 g (0.01 mol) of the 1-ethyl-2-jJT- (2 '-chloro-5' sulfonamidobenzoyl) -aminomethylj-pyrrolidines (formula II added) and the mixture was for 12 hours in a sealed tube on a 14-0 ⁰ C hot oil bath heated. After cooling and clearing with charcoal, the solution was ^{evaporated under vacuum at a temperature of 4-0 0} G, the residue was mixed with 20 cnr ethanol and evaporated under the same conditions as before. The distillation residue was mixed with 50 cnr anhydrous ethanol, with a 20% ethanolic hydrogen chloride solution was acidified until a pH of 5 and maintained by the addition of 50 cur acetone for 5 to 6 hours at 4 ⁰ C. The deposited precipitate was filtered off with suction, washed with acetone and dried. The crystal powder thus obtained was dissolved in 50 cubic meters of hot water, 4 cubic centimeters of an aqueous concentrated ammonium hydroxide solution was added dropwise, and the mixture was allowed to stand at a temperature of 4 C. over a fold. The precipitate was filtered off with suction, washed with water and dried under vacuum in the presence of phosphorus pentoxide. Yield: 2.36 g (69% of theory) of 1-ethyl-2- [N- (2'-methoxy-5 ^f -sulfonamidobenzoyl) aminomethyl] pyrrolidine (formula I); Melting point: 178 ^° C.

The methyl 2-chloro-5-sulfonamidobenzoate used as the starting substance (Formula II) is as follows

- 19 609841/1003

- 19 described have been obtained:

2-chloro-5-chlorosulfonylbenzoic acid

Were added under cooling with ice water and stirring or shaking at 5 "to 6 ⁰ G for 90 minutes 93" 6 g (0.06 mol) of 2-chlorobenzoic acid to 360 cnr of chlorosulfonic acid. After the reaction mixture was for 1 hour on an ice water bath, Stirred or shaken for 1 hour at room temperature and 6 hours at 96 ° C. and then cooled to room temperature and poured onto 1,200 g of ice . dried to give 145 g (95% of theory) 2-0hlor-5-chlorosulfonyl benzoic acid. melting point: ⁰ to

B.
2-chloro-5-sulfonamidobenzoic acid

⁵ S ο

There were 750 cur isopropanol at 0 to 5 C with

Saturated dry ammonia gas, then 75 »3 g (0.295 moles) of that prepared in Part A of this example 2-chloro-5-chlorosulfonylbenzoic acid was added with stirring or shaking for 1 hour and then was slowly and continuously bubbling in ammonia for 1 hour while cooling with ice water and then Stirred or shaken for 20 minutes at room temperature. The precipitate which separated out was filtered off with suction and the mother liquor to dryness on a 45 ° C water bath evaporated. The residue was sucked off with the previously

- 20 - • 6 09841/100 3

The precipitate was combined and the resulting mass was dissolved in 700 cnr v / water and clarified with charcoal and, after filtering, the solution was acidified with concentrated hydrochloric acid. The precipitate-containing mixture was allowed to stand monitored at 4 ⁰ C and the precipitate was filtered off with suction, washed with water and dried. Yield: 55 g (79% of theory) of 2-chloro-5-sulfonamidobenzoic acid. Melting point: 220 to 222 ^° C. When recrystallizing from water, the melting point of the substance did not change.

Methyl 2-chloro-5-sulfonamidobenzoate

There were a mixture of 48 g (0.22 mol) of the im

Part B of this example prepared 2-chloro-5-sulfone

7th
amido benzoic acid and 480 cur methanol was added dropwise 22 cnr concentrated sulfuric acid at a temperature not exceeding 40 ⁰ C with continuous stirring or shaking. The mixture was heated to boiling under reflux for 8 hours and clarified hot with bone charcoal and the solution obtained after filtration was strongly concentrated in vacuo. A 10% soda solution was then added dropwise to the solution until a pH of 7 was reached. The mixture containing a precipitate was allowed to stand for several hours at a temperature of 4 ⁰ C and then the precipitate was filtered off with suction, / ater washed with V and dried under vacuum in the presence of phosphorus pentoxide. Yield: 48.2 g (94.5% of theory) of crude methyl 2-chloro-5-sulfonamidobenzoate, the recrystallization of which from 48 cnr ⁵ methanol gave 44.6 g (88% of theory) of pure methyl 2-chloro-5-sulfonamidobenzoate. Melting point: 127 to 128 ⁰ C.

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Example 2

1-ethyl-2- [IT- (2'-clilor-5'-sulfonamidobenzoyl) -aminomethylj-pyrrolidine (formula II)

Procedure 1

It was a mixture of 5) 59 g (0.04-4 mol) 1-1thy1- -2-aminomethylpyrrolidine and 80 cnr v / water with constant stirring or shaking and cooling with ice water at a temperature of 4 to 7 ° C 5 0.8 g (0.02 mol) of 2-chloro-5-sulfonamidobenzoyl chloride was added. The mixture was stirred for 2 hours at the same temperature or shaken and the precipitate was filtered off with suction, washed with water and dried at 40 ⁰ C. Yield: 6.08 g (87.9% of theory) of 1-ethyl-2- [N- (2'-chloro-5'-sulfonamidobenzoyl) -aminomethyIj-pyrrolidine (formula II), melting point: 178-180 ⁰ C; Melting point after recrystallization from methanol: 180 ^° C.

Procedure 2

There were a mixture of 1.54 g (0.012 mol) of 1-ethyl -2-aminomethylpyrrolidine, 1.2 g (0.012 mol) of triethylamine and 50 cm. Water 2-chloro-5-sulfonamidobenzoylchlorid added under constant Kühren or shaking and cooling with ice water at a temperature of 4 to 7 ⁰ C 2.54 g (0.01 mol). Thereafter, the procedure described in procedure 1 of this example was followed. Yield: 2.90 g (85.6% of theory) 1-ethyl- -2- [N- (2'-chloro-5 ^! -Sulfonamidobenzoyl) -aminomethyl- pyrrolidine (formula II). Melting point: 178 ° C.

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1-ethyl-2- [ν- (2 · methoxy-5 ¹ -sulfonamidobenzoyl) - -aminomethylj-pyrrolidine (formula I)

Corresponded to Part II of Example 1.

The 2-chloro-5-sulfonamidobenzoyl chloride used as the starting substance has been obtained as follows:

2-chloro-5-sulfonamidobenzoyl chloride

A mixture of 23.68 g (0.1 mol) of 2-chloro-5-sulfonamidobenzoic acid obtained as described in Example 1, parts A and B and 140 cm of thionyl chloride was refluxed for 1.5 hours, then the pure solution ^{was left to stand overnight at 4- 0} G and the precipitate was filtered off with suction, washed with benzene and dried at room temperature under vacuum in the presence of phosphorus pentoxide. Yield: 22.45 g (88.5% of theory) of 2-chloro-5-sulfonamidobenzoyl chloride. Melting point: 141 to 143 ° C. Careful concentration of the mother liquor gave a yield of 3 to 6% of theory of 2-chloro-5-sulfonamidobenzoyl chloride.

Example 3

1-ethyl-2- [n- (2'-methoxy-5 ¹ -sulfonamidobenzoyl) -

-aminomethylj-pyrrolidine hydrochloride

(Formula I, hydrochloride salt)

There were a hot solution of 43.95 S (0.13 mol) of 1-ethyl-2- [n- (2 '-methoxy-5' -sulfonamidobenzoyl) -aminomethylj -pyrrolidine (Formula I) in 770 cnr anhydrous ethanol

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103 cur 10.28% hydrogen chloride (0.29 mol) was added dropwise into solution containing anhydrous ethanol and the mixture containing a precipitate was added 10 minutes siedengelassen with constant stirring or shaking and then allowed to stand at a temperature of 4 ⁰ G overnight. The following day the crystalline hydrochloric acid salt was suction filtered, washed with acetone and dried under vacuum in the presence of phosphorus pentoxide. Yield: 44.8 g (92.6% of theory) 1-ethyl-2- [N- (2'- methoxy-5'-sulfonamidobenzoyl) -aminomethyl-pyrrolidine hydrochloride. Melting point: 233 to 237 ° 0. After recrystallization from aqueous isopropanol containing hydrochloric acid, the melting point was 238 to 239 ° 0.

Example 4

1-ethyl-2- [N- (2'-methoxy-5'-sulfonamidobenzoyl) - -aminome thyl]] - pyrr ο lidinhydr ogen sulfate (Formula I, sulfuric acid salt)

It was a hot solution of 3 »4-1 g (0.01 mol) of 1-ethyl-2- [N- (2 · methoxy-5'-sulfonamidobenzoyl) aminomethyl ~] · pyrrolidine (formula I) in 100 cnr anhydrous ethanol 0.6 cnr (0.012 mol) concentrated sulfuric acid was added dropwise. The mixture containing a precipitate was left to stand overnight at 4 ° C. and then the precipitate was filtered off with suction, washed with anhydrous ethanol and dried under vacuum in the presence of phosphorus pentoxide. Yield: 4.35 g (99% of theory) ethyl-2- [N- (2'-methoxy -5 · -sulf onamidobenzoyl) -aminome thy l]] - melting point olidinhydrogensulfat pyrr after recrystallization from ethanol: 198 ⁰ C..

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Example 5

1-ethyl-2- [N- (2'-methoxy-5 '-sulfonamidobenzoyl) -aminomethylj-pyrrolidine hydrogen maleate (Formula I, maleic acid salt)

There were a hot solution of 3 »41 g (0.01 mol) of 1-ethyl-2- [N- (2 ^! -Methoxy-5 '-sulfonamidobenzoyl) aminomethyr] pyrrolidine (formula I) in 150 1.3 g (0.011 mol) of maleic acid were added to isopropanol. The mixture was left to stand overnight at 4 ° C. and then the precipitate was filtered off with suction, washed with isopropanol and dried under vacuum in the presence of phosphorus pentoxide. Yield: 3.34 g (73% of theory) of 1-ethyl-2- [N- (2'-methoxy- -5 '-sulfonamidobenzoyl) -aminome thy 1 ~ | -pyrrolidine hydrogen maleate. Melting point after recrystallization from isopropanol: 132 ⁰ O.

Example 6

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

aminomethyl ^ pyrrolidine hydrofluoride

(Formula I, hydrofluoride salt)

It was a solution of 1.13 g (0.0033 mol) of 1-ethyl- -2- £ N- (2'-methoxy-5 ¹ -sulfonaiaidobenzoyl) aminomethyl]] - pyrrolidine (formula I) in 35 cm Isopropanol 0.5 (0.029 mol) was added to a 50% strength aqueous hydrogen fluoride solution. The mixture was allowed to stand overnight at 4 ⁰ C and the precipitate was suction filtered, washed with isopropanol and dried under vacuum in the presence of phosphorus pentoxide. Yield: 1.05 g (88% of theory) 1-Ethy1-2- £ n- (2'-methoxy-5 ¹ -sulfonamidobenzoyI) -

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-aminome thyl ~] pyrrolidine hydrofluoride. Melting point after recrystallization from ethanol: 129 to 150 ^° C.

Claims 609841/1003

Claims (1)

Claims 1-ethyl-2- {IT- (2'-chloro-5 ¹ -sulfonamidobenzoyl) aminomethyl]] pyrrolidine of the formula 0 H G-N-C S-NH, II 2.) Process for the preparation of 1-ethyl-2- [N- (2 ^l - -chloro-5 ¹ -sulfonamidobenzoyl) -aminomethylj-pyrrolidines according to claim 1, characterized in that a reactive derivative of 2-chloro-5 -sulfonamidobenzoic acid is reacted with i-ethyl-2-aminomethylpyrrolidine. $.) Process for the preparation of 1-ethyl-2- [N- (2 ^l -methoxy- -5'-sulfonamidobenzoyl) -aminomethyl] -pyrrolidine of lOrmel 609841/1003 H
N - C ₂ H ₅ S-NH and its salts, characterized in that one a) i-ethyl ^ -pT- ^ ¹ -chlor-5 ¹ -sulfonamidobenzoyl) -aminomethy! j-pyrrolidine of the formula Cl C ₂ H ₅ II reacts with a metal methylate a reactive derivative of 2-chloro-5- - 28 - 609841/1003 -sulfonamidobenzoic acid is reacted with 1-ithyl-2-aminomethylpyrrolidine and the i-ethyl-2-JN- (2 ^f -chloro-5'-sulfonamidobenzoyl) aminomethyl] pyrrolidine obtained has the formula C-N-C II reacts with a metal methylate and optionally the 1-ethyl-2- [N- (2 · - -methoxy-5'-sulfonamidobenzoyl) -aminome thy lj- -pyrrolidine of the formula I converted into a salt with an acid. 4-.) Method according to claim 2 or 3 b), characterized in that that the reactive derivative of 2-chloro-5-sulfonamidobenzoic acid is an ester, in particular one with aliphatic alcohols, an acid halide or an acid anhydride thereof used. 5.) Process according to Claim 2 to 4, characterized in that the reactions are carried out in an inert Solvent, in the case of the implementation of the reaction - 29 - B09841 / 1003 due derivative of 2-chloro-5-sulfonamidobenzoic acid with 1-ethyl-2-aminomethylpyrrolidium, if appropriate in the presence of an additive of an alkaline type. 6.) Process according to claim 3 "to 3 ·> characterized in that an alkali metal methylate, in particular sodium methylate, is used as the metal methylate. 7.) Process according to Claim 3 to 6, characterized in that the reaction of the 1-ethyl-2- | jN'- (2'-chloro-5 '-sulfonamidobenzoyl) aminomethyl]] - -pyrrolidines of the formula II with the Metallmethylat at a temperature of 60 to 160 ⁰ C, in particular 125 to 130 ° C, optionally in the presence of dimethylformamide performs. 609841/1003 ORIGINAL INSPECTED