DE2331959A1 - METHOD FOR PREPARING HETEROCYCLIC BENZAMIDE COMPOUNDS - Google Patents

Description

DET.MATi'CHEMICALS LIMITJlD, ViHe LaSaHe (Quebec, Canada)

Process for the preparation of heterocyclic
Benzamide compounds

The invention relates to the manufacture of certain known ones biologically active htterocyclic bonuamide compounds of Formula (I)

(CH ₉ )

4 * X \

(D

^R 3

in all X a sulfamyl, N-lower alkyl-sulfamyl or
H, N-di (nitroalkyl) sulfamyl group, R is a lower alkyl group, R _{3 is} a lower alkyl group, η is zero, 1 or 2 and ml or 2.

309882/1394

BADORfQiNAL

These procedures are new and advantageous because eic has more than one lead new pre-bonding group, näralich heterocyclic ßen% -amidverbindungenon of formula (II)

Γ ^{2 m}

in which 11_, η and rn the meaning given in connection with formula (Ϊ) h £ - ». b :: n _r R, a Was & orritof fatora or eino. Low alkyl group and A represent a hydrogen atom or a chlorosulfonyl group. Representative compounds of the formula (II) are biologically active and can be easily converted into the heterocyclic eenzamides of the formula (I) without difficulty.

Heterocyclic benzamides of formula (I) are generally in the Canadian patent 801'04 3 and the French Patent (B.S.M.) 5916. These heterocyclic Bensamidverbindangen are in the patents mentioned are described as biologically active and are stated to be useful as antieinetics and psychopharmacas. Probably the best known of these compounds at present is 1-ethyl ~ 2 ~ (2-methoxy-5-sulf amylbenzamidomethyl) -pyrro- ' lidone, which is also known as N-- Ql ~ ethyl-2-pyrrolidinyl) -methylj ~ 5 · - ■ sulfamyl-o-anisamide can be referred to and generally Sulpiride is called, which is used in chemotherapy as an antidepressant, Antipyretic, anticmetic and generally used as a regulator of the digestive system.

Regarding the nomenclature used here, it should be noted that the sulfamoyl group designation of the definition referred to as "sulfamoyl" according to the IUPAC recommendation of nomenclature (C 641.8b)

309882 / 1,394 BATH ORIGINAL

of optionally mono- or disubstituted H-substituted Corresponds to sulfonamic groups.

In the above patents the preparation d '.- r is heterocyclic Benzamide compound of the formula (I) by reaction a corresponding preformed 2-alkoxy-5 ~ r; ubsti ~ Substitute benzoic acid in the form of a reactive derivative, e.g. heterocyclic amine described. This known ancestor is in the following form lroüss; ig shown:

NII - (CIl) 2 ^

(CH ₂ )

v; o :: in R, R, | X, υ and m have the meaning given in obeji. The prior art is presented as a specific example The above Angal ^ en about the production of 1-ethyl-2-- (2 ~ methoxy-5-nulfamylboiv. ^ - JiaJdonKithyl) ·· pyrrolidine, d. H. Sulpirid, 1-ethyl 2-aM.inoiae thy lpy.r roll din with 2-methoxy ~ 5-sulpharnylbenzo ^ lchloride implemented.

The Uerstellynij d :. r 2, 5 - ^disubstitu:; locate Uenzoesciureverbindungen, such as z-. B.? -M:.? Thoxy-5 * -sulf äinylbenzoüoäuro, is in the fran / .r,:; ir.chcn patent: jc: l) .r.if ten I ¹ 524'388 and .1'525 * 352 described. In the first-mentioned patent document, the connections are grounded in one!:. /v.lko;cybcnxol _; v; each methoxybenzene (anisole), in a

309882/1394 BAOOBIGINAL.

_ 4 -

ner six-step reaction sequence with the following Steps made:

Chlorosulfonation to produce a p-alkoxyber.zene: sulfonyl chloride, nitration to produce 3-nitro-4-alkoxybenzenesulfonyl chloride, amination to produce 2-nitro-4-sulfarnylalkoxybenzene, reduction of the trogroup to form the corresponding 2- Ara.ir; o-'i-sulfaiT'yla} koxybr; rizo.ls and conversion of the amino group into a carbc ;;. Acid group with formation of dr - r vjewünscht '-. N 2 ~ alkoxy ~ 5- -sulfamy! benzoic acid me a common two-stage Sandraoyer reaction, v / elciu; first the conversion of the amino group into a cyano group and then the hydrolysis of the. Cyano group umiasotc The total yield of 2-AlkOXy-S-GuIfany3.benzoic acid is according to the patent mentioned in the order of 14 %.

Geraäss French Patent ^I1 525'352 is the desired 2-alkoxy ~ 5 - sulfamy benzoic acid from an o - Kitro ~ phenol in a sixteenth :: · :; A step-by-step reaction that includes the following steps:

Alkylation to form the corresponding o-nitroalkoxyphc- nol, chlorosulfonation to form the 3-nitro-4-alkc>: ybenzenesulphonyl chloridec :: =, amination to the 2-nitro-4-sulfr.ray.lalk-oxybenzene, reduction the nitro group to form the corresponding 2 ~ 7i.mino ~ 4-sulfamylalkoxybenzene and conversion of the amino group into a carboxylic acid group with formation of the desired 2 ~ alkoxy ~ 5-sulfamylben: 2oic acid _/ again by a customary two-stage Sandmeyer reaction, which initially comprises converting the vmino group to a cyano group and then hydrolyzing the cyano group. The patent specification does not specify any extensions for the chlorosulionation of the second stage, but even if a 100% yield is assumed for this step, a total yield would result. ^r - booty in the order of magnitude of me 10 'b .

309882/139
BATH

In both cases, the 2-alkoxy / ~ 5-sulfamyl "benzoGSclure obtained in this way (as described in the above-mentioned Canadian patent specification and the French BSM patent specification) must be converted into the acid chloride (or another reactive derivative), which is then converted with of the preformed heterocyclic compound is reacted to form the desired heterocyclic benzamide compound. Although no yield values are given in the Canadian and French patents, the above explanations show that the total yield of the heterocyclic benzamide compounds after the two synthetic routes is not greater than 14'i and is probably less than 10 % .

In summary, it can be said that this is a well-known process ü for the production of heterocyclic benzamide compounds of formula (I) have the following essential characteristics: Education the appropriately substituted benzoic acid, such as 2-alkoxy-5-sulfamylbenzoic acid, Conversion into a reactive derivative, conveniently the acid chloride, and condensation of the reactive benzoic acid derivative, which all required Has substituents on the benzene ring, with the corresponding heterocyclic amine. Overall, these include well-known Process about eight individual reaction stages.

It has now been found that the known heterocyclic benzamide compounds of the formula (I) are extremely advantageous Processes can be made that compare to the eight process steps of the prior art comprise a total of only three or four individual reaction stages and good yields of the desired compounds, in particular 1- / iothyl ~ 2- {2-methoxy-5 "sulpho-amylbenzamidomethyl) pyrrolidine (Sulpiride).

309882/1394

BATH

The invention provides a method for making heterocyclic compounds Benzamide compounds of the formula (I)

X -

Nile - (CII ₉ ) 2 η

* ^(CII 2> m

R.

(D

by chlorosulfonation of compounds of the formula (

(CII

I- OR

(Ha)

to form the corresponding 5-chloronulfonyl compounds of Formula (Hb)

Nile - (CIL

^(ΑΐΙ 2> Γα

(lib)

R,

where R, R, Χ, η and m die. have the meaning given above. Then the 5-chlorosulfonyl compound of the formula (lib), which can optionally be processed either isolated or waiter without isolation, by ammonolysis with ammonia or by Aiuinolysis with primary arain or /. secondary £ onin in the 5-sulfarny3.-, 5-N-Niederalkylsulfamyl- or Ν, Ν-Di- (lowercilkyl) -sulfaraylverbindungen converted to formula (I).

The heterocyclic benzamide compounds of the formula (II) are new compounds which, together with processes for their preparation Are described in more detail in the simultaneously deposited patent application Kr.

309882/1394

BADORlGiNAt

«. * 7 -

The 5-unsubstituted compound of the formula (IIa) can ζ. B. expediently by amidation of a benzoic acid compound of Formula (III) ·. "

(III)

produced vrcrdcn, v; as by reaction of the benzoic acid compound or a reactive derivative thereof with a heterocyclic amine of the formula (IV)

(CH ₂ ) "—Η ^(< r ⁿ 2 ^} m (IV)

j (CH

* 3

'where R, R, η and m have the meaning given above, in Presence of a condensation agent such as silicon tetrachloride and N, N - dicyclohexylcarbodiimide. The corresponding 5-chlorosulfonyl compounds of the formula (Ub) can obtained by chlorosulfonation of the 5-unsubstituted compounds.

An embodiment of the method according to the invention for The preparation of the desired heterocyclic benzamides of the formula (I) therefore comprises the following steps:

(Λ) Amidation of a 2-alkoxy-benzoic acid compound of the formula (III) by reaction with a heterocyclic amine of formula (IV) to form a heterocyclic Ben? - araid compound of the formula (Ha),> ■

(B) chlorosulfonation of the heterocyclic benzamide compound to form the corresponding 5-chlorosulfonyl compound of formula (^ Ib) , and.

309882/1394

PJA

(C) Ammonolysis or aminolysis of the 5-chlorosulfonyl compound by reaction with ammonia or a primary amine or a secondary amine to form the corresponding 5-sulfamyl, N-lower alkylsulfamyl, or N _f N-di (nicderalkyl) - sulfamy! compounds of the formula (I).

To prepare the 5-unsubstituted compounds of the formula (II), a benzoic acid compound of the formula (III ¹ ) can also be used.

(Ill ¹ )

in the form of the free acid or a reactive derivative thereof with a heterocyclic amine of the formula (IV)

^NII 2 - ^(CH 2 '"-F" J (IV)

to the heterocyclic benzamide compound of the formula (II'a)

(CIL,)

- 2 m

(Il'a)

implemented v / earth, which is then in 2-position;: ur corresponding 2-Lower alkoxy compound of the formula (Ha) is alkylated.

309882/1394

Another embodiment of the method according to the invention for the preparation of the desired heterocyclic benzamides

the formula (I) therefore comprises the following steps: ι

(Λ) Amidation of 2-hydroxybenzoic acid of the formula (III ¹ ) by reaction of the free acid or a reactive derivative thereof with heterocyclic! Amine of formula (IV) to form a heterocyclic benzamide compound of formula (II'a),

(B) alkylation of the compound of formula (II'a) with conversion the hydroxy group in a lower alkoxy group to BiI-

- formation of a compound of the formula (Ha),

(C) Chlorosulfonation of the heterocyclic benzamide compound of formula (Ha) to form the corresponding 5-chlorosulfonyl compound the formula (lib), and

(D) Aminolysis or aminolysis of the 5-chlorosu.lfonyl compound by reaction with ammonia or .einem primary amine or a secondary amine to form the corresponding 5-sulfamyl, N-lower alkylsulfamyl or N, N-di (lower alkyl) sulfamyl compounds of formula (I).

The 5-unsubstituted heterocyclic benzamide starting compound of formula (Ha) for the chlorosulfonation reaction can be in the form of the free base or as a salt, e.g. B. as an acid addition salt with a mineral acid such as hydrochloric acid. Conveniently, it is in shape an acid addition salt is used.

The chlorosulfonation reaction can be effected by any conventional method. An appropriate way of working is based ensure that excess chlorosulfonic acid is substituted with the 5-unsubstituted brought into contact heterocyclic benzamide compound of the formula (Ha) and the mixture is heated, preferably

309882/7394

se- at temperatures in the range of 50-15 ° C until the reaction is practically complete.

The 5-chlorosulfonyl compound thus formed does not have to be isolated but can be entered directly into the corresponding 5-sulfamyl, 'N-lower alkyl sulfarayl or N, N-di (lower alkyl) aulfamyl compound being transformed. The 5-Sul £ amylverbindungen is conveniently made by reacting the S-chlorosulfonyl compound with concentrated ammonia, while the 5 ~ N ~ lower alkylsulfamyl or the 5-N, N-di (lower alkyl) sulfamyl compounds appropriately by Umr, ei; zimg with appropriately substituted primary or secondary amine can be formed.

In the Forme Is cheina I is an advantageous three-stage example Procedure for the preparation of a representative heterocyclic ben / amide compound, namely sulpiride, according to the inventive method shown. An inventive The method of operation is shown in Formula II, where this way of working comprises four steps and is therefore less economically attractive than the other one explained Way of working. For comparison purposes, in formula scheme III the procedure for making the same compound is given below the French patent specification 1'524'388 and (in connection with the last two steps) of the French patent specification B.S.M. 5916 shown.

309882/1394

8AO ORIGINAL

FORMELSC in IA I (according to the invention)

(Ilia)

COOH

OCH.

STEP h (Amidation) "N ^ S ^H 5

C-KH-CIL

OCH.

(Il'a)

STEP B (chlorosulfonation)

ClO ₂ S

- NH -

(Il'b)

NH

STEP C (AmmonolysG)

H ₉ NO

(Sulpiride) 309882/1394

^C 2 ^H 5

BAD ORIOiNAL.

(he f indungsyenviss)

f ^ V-COCl

+ NIJ.

-OH

CIL.

(ΙΧΪ ¹ )

^ £ Ι3ϋΠί..Ιΐ (amination) ν

Il

C-KH-

OH

(II ¹ α) C ₂ H ₅

TTJB (Hethylation)

z. B. (CH ₃ )

C - NIi "CIL

OCH,

STEP C (chlorosulfo-

"' ^η 2

OCH.

(Il'b)

^C 2 ^H 5

STEP D (Aminonolysis)

NH · - CH.-1

iL-OCH.

• I \ T

C ₂ H ₅

(I ¹ )

(SulpJa'id)

2..J: _(ΐν «)

BATH ORIGINAL

FORH ELSCHEMA III (state of the art)

(Chlorosulfonation)

OCH.

ClO,

STEP 2 (nitration) _Λ

ENT.

STEP 3 (Formation of the

Sulfamyl group)

2 ^CO 3

STEP TT 4 (reduction.

the nitro group)

(1) ENT ₂

(2) NaCN

309882/1394

(Continuation)

(Conversion of the amino group into the cyano group)

ΪΤ- CN

bcii.

SCHRXT_Tj5 _T (hydrolysis of

H ₂ SO ₄

OCIL

STEPJ7; (Acidchlorld * - "" education)

H ₂ NO ₂ S

STEP 8 (amidation)

·. ■. - O I. 3 (Sulpiride) j Il NH - CH ₂ - ^ _n H ₂ NO ₂ S - ^ \ -OH C ₂ H ₅

^C 2 ^H 5

30888 2 / \ 3 94

BAD ORiQfNAi:

~ 15 ~

The comparison of the process shown in the formal scheme shows that the working methods of the process according to the invention are based on the easily accessible and technically obtainable 2-ilethoxy or 2-hydroxybenzoic acid and comprise only three or four process stages, ie. four or five steps less than in the prior art method based on an equally accessible starting material, namely Ansiol. The advantages in terms of process economy and overall expediency that result from this impressive reduction in process steps from eight according to the prior art to three or four according to the invention are readily apparent. These process advantages are immediately apparent from the concept of introducing the 5-chlorosulfonyl group into a preformed heterocyclic. Benzouiiclverbindimg depends on what. avoids the laborious and complicated substitutions for building up the benzoic acid group. In addition, the three-stage embodiment of the process of the invention gives excellent total yields of the order of magnitude of 70-80% of sulpiride (high purity), while the yields according to the prior art, as evidenced by four prior publications mentioned, do not exceed 14 % . According to French patent 1,524,308, the yield up to the end of stage 6, ie the preformed 2-methoxy-S-sulfamylbenzoic acid, is only 13.5 liters ,

The invention is illustrated by the following examples.

309882/139 /,

BATH ORIGINARY Example 1

l-Aethyl- 2_- (2j2neJ ^ hjDxyj ^ 5j ^ u ^^

4.8 g (0.016 mol) of 1-ethyl-2- (2-methoxybenz'amidomethyl) -pyrrolidine hydrochloride were added to 46.6 g (0.40 mol) of chlorosulfonic acid in small merges 0-5 C had cooled. The mixture was then warmed to -75 ° C. for 6 hours, cooled to 30 ° C. and then poured into a mixture of 60 g of ground ice and 40 g of concentrated ammonium hydroxide (as a jellyfish for ammonia). The resulting solution was stirred for 6 hours at 0-5 ° C., after which the solids were filtered off and, after drying at 60 ^° C., gave 5.0 g (yield 92 %) whitish solid. .

A sample of the free base was converted to uniquely the hydrochloride salt and the analytical sample was converted from methanol to a tailed, mp 233-234 ° C. '' -

Analysis calculated, "*

for C ₁₁ -H ₀₄ N ₃ O ₄ VSCl: C 47.67%, H 6.40%, N 11.12%, S 8.48%, Cl 9.3t found: C 47.88%, H 6 , 52%, - N 11.95%, S 8.60%, Cl 9, IS

For example ^

l ~ Aeth yl-2 · - (2 ~ m ^ tj ^ thy 1) ~ jpyrroli.dirt

A solution of 7.9 g (0.03 mol) of 1-ethyl-2- (2-methoxybenzamidomethyl) pyrrolidine in 18 ml of methylene chloride was acidified with hydrogen chloride gas (pH 1) and the solution was then added to 87.4 g (0 , 75 mol) chlorosulfonic acid given. The resulting solution was heated to 75 ° C. for 6 hours and the methylene chloride was distilled off during this period. The chilled mixture was slowly eaten into a mixture of cracked ice and ammonium hydroxide, maintaining a basic pH throughout. The resulting suspension was extracted with chloroform. The extracts were washed with water and dried over sodium sulfate. The target product was obtained in good yield by Abdestilliercn the chloroform "A Aualy-

3.09882 / 1394

BATH

sen sample was recrystallized from chloroform, pp 177-179 ° C <

A sample was converted to the hydrochloride salt by treatment with hydrogen chloride in ethanol and used for analysis crystallized from methanol, Pp 233-234 ° '

Analysis calculated "

for C ₁₅ II ₂ ^ CIN ₇ O ₂ JS: C 47.67 ^, H 6, Ko%, N 11.12 ^, Cl $ 9.385, S $ 8.48 found:. C 47.98 ^, H 6.52%, N 11.45 ^, Cl 9.19 / ', S 8.60%

The 1-ethyl-2- (2-methoxybenz-

amidomethyl) pyrrolidine was prepared by one of the following methods:

Verfa lead A

2.27 g of NjN'-dicyclohexylcarbodiimide (o, oll mol) became one Solution given, the 1.52 g (o, ol mol) of 2-methoxybenzoic acid and

1.28 g (o, ol mol) of 1-methyl-2-arninoethylpyrrolidine in 10 ml of acetonitrile contained; The resulting solution was stirred for 4 hours at room temperature. The precipitated N, N ^f -bicyclohexyl urea was filtered off. The mother liquors were evaporated to dryness. The residue was dissolved in chloroform, the solution was washed well with water and the chloroform was dried , and evaporated, whereupon 2.J) K g (yield 90 $) of the -Zi egg product remained in the form of a beige oil.This product was proven by thin-layer chromatography and comparison of the IR spectra in solution to be identical to an authentic sample .

Procedure B

2.8 g of silicon tetrachloride (ο, οίβ5 mol) were slowly added to a well-stirred solution containing 6 g of 2-methoxybenzoic acid (0.0396 mol), 6.7 g of triethylamine (0.066 mol) and 4.22 g of N-ethyl -2-aminomethylpyrrolidine (0.033 mol) in 225 ml of toluene. The resulting mixture was refluxed for 3 hours, after which the precipitated solids were filtered off and washed with toluene. The combined toluene filtrate and washing liquid were washed with 100 ml of 2% aqueous sodium hydroxide solution and then with 100 ml of water, dried

■ - 18 3.09882 / 1394

and the toluene is distilled off under reduced pressure. There were 7.9 g (yield $ 91) of the desired product as brownish oil preserved.

A sample was treated with hydrogen chloride in methyl. ethyl ketone converted into the hydrochloride salt and this recrystallized from the same solvent for analysis, Pp 174 ~ 176 ° C.

Analysis calculated

for C ₁₅ H ₂₅ ClN ₂ O ₂ : C $ 60.29, H $ 7.75, N 9.31%, Cl 11, found: C $ 60.52, H $ 7.65, N $ 9.56 , Cl 12,

Procedure C
Section (a)

1-Aethyl- _i 2- (2-hydroxybqn7, a.nildornethyl) pyrrolidine 25 g of thionyl chloride (0.21 mol) were added to a suspension of 28 g of salicylic acid (0.21; 5 mol) in 150 ml of petroleum ether (150 ml -6o °), which contained 0.1 g of pyridine. The mixture was heated to 40 ° C. for 2.5 hours, cooled to room temperature, filtered and distilled to remove the solvent. The product thus obtained was a pale yellow oil which, by distillation, gave a colorless oil in good yields, boiling point 55-60 ° C./1 mm Hg.

A solution of 6.2 g of salicylic acid chloride (0.059 moles) in yy ml of chloroform was slowly converted at 0-5 ° C. into a solution of 5 S l-ethyl-2-aminomethylpyrrolidine (0.09 moles) in 5 nil Chloroform. Given. The resulting solution was stirred for 15 minutes at room temperature and then made basic (pH 10 -11) with concentrated ammonium hydroxide / water. The organic layer was washed with water, dried over sodium sulfate and the chloroform was distilled off to give the product as a beige oil in quantitative (100 $) yield.

Section (b)

1-ethyl-2- (2-methoxybenzamidomethyl) -pyrrolidin 5.5 g of dimethyl sulfate (0.04 mol) were slowly at room temperature to form a suspension of 9.7 S, ethyl-2- (2-hydroxybenzamidomethyl ) -pyrrolidine (prepared according to section (a) of

Method C) and lo, 9 g of anhydrous potassium carbonate (0.078 mol)

309882/1394 _ _19th ..

* BAD ORiGfNAL

given in 150 ml of acetone. The mixture was refluxed for 18 hours and the acetone was distilled off as completely as possible. The residue was taken up between methylene chloride and water, the organic phase was separated off and, after washing with water, dried over sodium sulfate. After the riethylene chloride had been distilled off, the product was obtained as a pale yellow oil (yield 78 %) .

Kino by treatment with hydrochloric acid in methanol in the hydrochloride salt converted sample was used for analysis recrystallized from methyl ethyl ketone: mp 176-179 ° C.

Analysis calculated

for C ₁₅ H ₂₃ ClN ₂ O _2: C 60.29%, H 7,75i, N 9.37%, Cl 11.86% found: C 60.53%, H 7.652, N 9.56%, Cl 12.05%.

309882/139 /,

BATH ORIGINAL

Y 3

Claims (11)

Claims Process for the preparation of heterocyclic benzyl compounds the formula. (I) c - m - (CH ₂ ) - CO in which X is a sulfamyl, a 5-N-lower alkyl sulfainyl or an N ₁ -N-di (lower alkyl) sulfarnyl group, "R and R. each represent a lower alkyl group, η is zero, 1 odor 2 and m is 1 or 2, characterized in that _f a compound of formula (IXa) - <CH ₂ > _n -Γ (Ha) by Chlorosulphonation into the corresponding 5 ~ ^Chlorsuli: ony compound of Forrctol (Hb) ClO ₂ S rc - NH - (CH ₂ ) (CH ₉ J _n ~ TJ
^ N - ^ (lib) is converted ^un ^ that the 5-Chlorimlfonylgruppo der Fojrir.el (Hb) then by amonolysis with ammonia or .Ai.iinolyso with a primary or secondary amine to the corresponding 5-sulfamyl-, N-nicderalkylsulfamyl- or N, W-- D: L- (lower alkyl sulfamyl compound of formula (I) is converted 309882/1394 bath 2. The method according to claim 1, characterized in that the 5-chlorosulfonyl compound directly without isolation in the corresponding 5-sulfamyl, 5-N-lower al] -ylsu3famyl- or 5-N, K-di- (lower-alkyl) -sulfamy! compound will. 3. The method according to claim 1 or 2, characterized in that the as. Starting compound for the chlorosulfonation reaction The heterocyclic benzamide compound of the formula (Ha) used is in the form of the acid addition salt. 4..Verfahren according to any one of the preceding claims, characterized characterized, dar.s the chlorosulfonation reaction by heating a mixture of the 5-unsubstituted benzamide compound of the formula (Ha) with excess chlorosulfonic acid is achieved. 5. The method according to claim 4, characterized in that the chlorosulfonation ^{reaction is carried out by Ει-heating the mixture to 50-150 0} C until the practical completion of the reaction. 6. The method according to any one of the preceding claims, characterized in that the heterocyclic benzene obtained - amide compound into a corresponding N-oxide, quaternary Ammonium or acid addition salt is converted. 7. The method according to any one of the preceding claims, characterized characterized in that the 5-unsubstituted compound of the formula (Ha) by amidation of a 2-alkoxybenzoic acid compound of formula (III) 309882/1394 BAt? (III) in the form of the free acid or a reactive derivative of which with a heterocyclic amine of the formula (IV) (IV) ^R 3
is obtained, wherein R and R- each represent a lower alkyl group represent pe, η is zero, 1 or 2 and m is 1 or 2. 8 «Method according to one of claims 1 ~ 6, characterized in that the 5-unsubstituted compound of the formula (Ha) by junction of a 2-hydroxybenzoic acid compound of the formula (III ¹ ) (III ¹ ) in the form of the free acid or a reactive derivative thereof with a heterocyclic amine of the formula (IV) NH ₂ - (CB ₂ ). {CHJ _m 2 m R. (IV) to form a heterocyclic benzamide compound of BAD ORlQJNAL ^J Formula (II ¹ a) CJ - NH - (CH) \ ~ J * ^m (II ¹ a) OH and subsequent alkylation of this compound in the 2-position to the corresponding 2-alkoxy compound is prepared, wherein R ^ is a lower alkyl group, η zero, 1 or 2 and m 1 or 2 are. 9. The method according to claim 1 for the preparation of l-ethyl-2- (2-methoxy-5-sulfamylbenzamidornethyl) -pyrrolidine, characterized by chlorosulfonation of 1 ~ ethyl-2- (2-methoxybenz ~ amidomethyl) pyrrolidine to 1-ethyl-2- (2-methoxy-5-chloro sulfonyl benzamidoinethyl) pyrrolidine, used for conversion dor 5-chlorosulfony! group into a 5-sulfamy! group with Ammonia is treated. 10. The method according to claim 9, characterized in that the l-Ethyl-2- (2-mGthoxybenzamido-methy1) -pyrrolidine in the form an acid addition salt of this compound is used. 11. The method according to claim 9 or 10, characterized in that, that the l-ethyl - 2- (2-methoj: ybenzamidomethyl) -pyrrolidine by reacting 2-methoxybenzoic acid or a reactive one Derivatives thereof with 1-ethyl-2-aminomethylpyjrrolldin manufactured in the manner of a condensing agent iüt. 309882/1394 BADORIQiNAL 12, method according to claim 11, characterized in that the Kcndensationsmitte - Sil.ior'.iri-fe'si'.raro; ^: .cri5, '. 5t- ₄ 13 »Method according to claim,,., I, aaaiirch geiven-zexchnac, das; das Kcndensationamitt.il exn '; arbcaiimj.ddc: ri. "£, t is" BATH ORIGINAL