NO812871L - PROCEDURE FOR PREPARATION OF N-SUBSTITUTED N-PYRROLIDINES - Google Patents

Description

The present invention relates to a method for the stereo-specific production of optically active N-substituted pyrrolidines suitable for use in the production of optically active benzamides bearing a pyrrol'idinylmethyl substituent.

The N-substituted pyrrolidines produced by the process according to the invention correspond to the following symmetrical formulas I (R) and I (S):

where R stands for

- either an alkyl radical CF^Rj with 1 to 5 carbon atoms

(R^ has 1 to 4 carbon atoms or stands for a hydrogen atom)

- or a radical with formula

wherein A is a straight or branched alkylene chain of 1 to 4 carbon atoms and

F*2, R, and R4 each stand for a hydrogen atom, a halogen atom, especially chlorine or fluorine, a trifluoromethyl radical, trifluoromethoxy, trifluoromethylthio, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms,

- or a radical with formula

in which a is a straight or branched alkylene chain with 1 to 4 carbon atoms and m is 2, 3, 4 or 5. The compounds of formula I are starting substances for the synthesis of substituted optically active benzamides of formula II

in which

R has the above meaning and X stands for a chlorine atom, a radical SC^R^ or SOgN RgRyihwhere R,- stands for an alkyl radical with 1 to 4 carbon atoms and Rg and Ry, which are the same or different, stand for a hydrogen atom or a alkyl radical with 1 to 4 carbon atoms.

The compounds of formula II are obtained by condensation of the amine

I with an o-methoxy-benzoic acid or one of its derivatives.

The benzamides II are compounds with therapeutic action and have previously been described in the literature.

The pyrrolidines .1 (r) and I (S) in which R is alkyl can lead to the following benzamides II'

wherein R is alkyl of 1 to 5 carbon atoms, B is a hydrogen atom or alkyl of 1 to 5 carbon atoms and C, D and E represent a hydrogen atom, a halogen atom, alkoxy of 1 to 5 carbon atoms, nitro, amino, alkylamino, dialkylamino or alkanoylamino,

acyl with 1.. to 5 carbon atoms, cyano, sulfamoyl, alkylsulfamoyl or dialkylsulfamoyl, alkylsulfonyl, trihalomethyl,

alkyl thio, polyfluoroalkyl or polyfluoroalkylsulfonyl.

The absolute configuration of the enantiomers of formula I (R) and

I (S) has been shown to be related to L-prolinol where the absolute configuration is known and the levorotatory enantiomer I

(S) (-). L-prolinol has an absolute configuration (S) (Sinister a counter-clockwise) according to the rules of Cahn, Ingold et Prélog, demonstrated on the basis of L-proline where the configuration (S) is determined by means of an X-ray analysis (Buckingham et al. Comm. 1969, 583)'.

The sequence of chemical reactions, which does not disturb the absolute configuration of the asymmetric carbon and its designation (R) or (S) in the rules of Cahn, Ingold and Prélog, can then only lead to the enantiomer I (S) which itself leads to the derivative ti (S).

<->i

The present invention thus relates to a stereospecific synthesis which allows obtaining the enantiomers (R) or (S)

with formulas I and II.

The method according to the invention consists in preparing the compounds I by stereospecific synthesis by starting from proline or glutamic acid (R) or (S) or a compound derived from these (pyroglutamic acid, prolinol) by introducing the starting product pyrrolidines which carry an asymmetrical carbon atom in the a-position to an aminated group, through a sequence of condensations, esterifications, amidations, ring closures and reductions.

The reaction forms are reproduced below.

In the reaction forms, the designations mean the following:

alk = CH3 or C2<H>5

X is halogen (preferred Cl)

tr

R<1>, take either R^(H or alkyl of 1 to 4 carbon atoms)

or

ell is

A' is a bond or alkylene with 1 to 3 carbon atoms.

The other meanings are as indicated earlier.

In the reaction scheme I, one starts from proline (S) to obtain the amine .I (S) .

The proline (R) leads in the same way to the amine I (R).

In the reaction scheme .2, the starting point is glutamic acid R for

obtaining the amine I (R) directly.

The glutamic acid (S) can similarly lead to the amine I (S).

In reaction scheme 3, the starting point is glutamic acid (S) as

after cyclization, racemization and cleavage also allow obtaining the amine I (R)..

)

In reaction scheme 4, prolinol (S) is used as the starting point for obtaining

of the amine I (S) .

The prolinole R, obtained by starting from glutamic acid (S) by ring closure, racemization, then cleavage to pyroglutamic acid (R) and reduction of this, or by ring closure and reduction of glutamic acid (R), as this leads in the same way to the amine I (R).

The reaction schemes are exemplified in the following examples.

The final reductions are carried out preferably with the help of the double-hydride of lithium and aluminium.

The cleavage in reaction scheme 3 is carried out using L-tyrosine hydrazide.

Example 1 X reaction core 1)

l-cyclopropylmethyl-2-amihomethyl-pyrrolidine (S) (-)

Step_lJL2-ethoxy^arbony_l-£Yrrolidin_(S) .

In an Erlenmeyer flask, introduce 34.8 g (0.3 mol) L-proline (S)

and 360 ml of ethanol. During cooling in an ice bath, 54.8 g (0.46 mol) thionyl chloride are added dropwise.

It is stirred for 1 hour at ambient temperature and the mixture is heated under reflux for 3 hours. It is evaporated to dryness, the remaining oil is dissolved in chloroform and saturated with ammonia. The ammonium chloride is filtered off and the organic phase is evaporated.

An oil is obtained which is distilled.

Boiling point 2Q«<8>2°C

Step 2L ' 2-carbamoy^-gy_rrol idine (S) (-).

200 ml of methanol are introduced into an Erlenmeyer flask, which is saturated with ammonia while cooling. 17.2 g (0.12 mol) are introduced

of the ester obtained in step 1 in methanol. It is stirred for 2 hours and the mixture is set aside overnight.

It is evaporated to dryness and a solid is obtained which is recrystallized in benzene.

/Vp<5>-78° (c « 1, water)

Temp. b 101.5 - 102°C ?c

^ 365 " -258-5° (approx. 1twater)

Step 3_. 1-cyclopropylcarbonyl-2-carbamoyl-gyrrolidin_(_S) (-).

11.4 g (0.1 mol) of the prolinamide (S), 13.8 g (0.1 mol) potassium carbonate and anhydrous acetone are introduced into an Erlenmeyer flask.

It is cooled with an ice bath and 10.45 g (0.1 mol) of the chloride of cyclopropane carboxylic acid in acetone are added dropwise.

It is stirred for 1 hour at this temperature and the mixture is set aside overnight at ambient temperature. It is evaporated to dryness (T-S"30°C), it is extracted with chloroform and washed with a minimum amount of water. The organic phase is dried, over magnesium sulfate and evaporated. A solid is obtained which melts at 129 - 130°C ZV^g - 130.9° (c « 1, D.M.F.).

Trinn_4^l-Eykl2Er2Pviz2z2m^no!I!etyi_Pyrr2l:i'Éin_isi_iz2*

13.3 g (0.35 mol) of the double hydride of lithium and aluminum and 200 ml of anhydrous ether are introduced into an Erlenmeyer flask. 16 g (0.088 mol) of the above-mentioned diamide are added in small amounts and heated under reflux for 16 hours. It is hydrolysed with a solution of 10% sodium-potassium tartrate and the solid is filtered off. The solids are washed several times with ether and then the ether phases are combined and evaporated.

An oil is obtained which is distilled.

Boiling point 2Q« 88°C.

A7355-201.5° (cal, D.M.F.)

A7q° -68.5° (c a 1, D.M.F.)

Application of the pyrrolidine I (S): In the synthesis of N-/Tl-cyclopropylmethyl-2-pyrrolidinyl)-methyl7-2-methoxy-5-sulfamoyl-benzamide

(S) (-)

8.8 g (0.057 mol) of amine, 14.07 g (0.054 mol) of the ethyl ester of 2-methoxy-5-sulfamoyl-benzoic acid are introduced into an Erlenmeyer flask

and 18 ml of water. It is heated at 120°C for 10 hours. On cooling, a solid is formed. Ether and water are added and stirred. The solid is filtered off, dissolved in chloroform, dried over magnesium sulphate and evaporated. A solid is obtained which is recrystallized from ethyl acetate.

Temp. o 134 - 134.5°C

Z"d7p° « -77° (c b 1,D.M.F.).

Example 2 (reaction core 2)

1-cyclohexylmethyl-2-aminomethyl-pyrrolidine (R) (+)

Step 1_. 1-CYclohexy^methyl^-2-carboxy^5-oxo-gyrrolidin_(R) (_) .

58.8 g (0.4 mol) glutamic acid (R) and 400 ml NaOH (C2N) are introduced into an Erlenmeyer flask under a stream of nitrogen and while cooling. 44.8 g (0.4 mol) cyclohexanecarbaldehyde is added dropwise

in methanol. It is stirred for 1 hour, the reaction mixture is hydrogenated in the presence of Pd/C at ambient temperature and atmospheric pressure. After the theoretical volume of hydrogen has been absorbed, the catalyst is filtered off and methanol is evaporated. The aqueous phase obtained is extracted with ether. The pH in the aqueous phase is adjusted to 2.5 with hydrochloric acid. They are heated at 100°C for 2 hours.

It is cooled and the white solid is filtered off and dissolved in chloroform, it is dried over magnesium sulfate and evaporated. A solid is obtained which is purified by trituration in cyclohexane.

Temp. 141.5 - 142°C ZV365-20-i>° (c lj D.M.F.)

i~2y!s12!2eksYlm?tyi~2~!iieioxyka£b22y1~5~0!£so~Eyr (R) (z).

™~ ~™ ~™" •

300 ml of methanol and 50 g (0.221 mol) of the compound obtained in step 1 are introduced into a 1 liter Erlenmeyer flask. It is heated to 40°C and 31.7 g (0.266 mol) of thionyl chloride is introduced dropwise. It is heated under reflux for 4 hours, evaporated to dryness and an oil is obtained which is distilled and which crystallizes on cooling.

Temp. a 87.5 - 88°C

Z0C7355 -6° (c a 1, D.M.F.) .

)

IN

Step 3_. 1-cyclohexyl-methyl-2-carbamoyl-5-oxo-pyrrolidine (R)(-).

400 ml of methanol are introduced into an Erlenmeyer flask and, while cooling, the solution is saturated with ammonia. 41.2 g (0.172 mol) of the ester obtained in step 2 are added, stirred for 2 hours and the mixture is set aside overnight.

It is evaporated to dryness, the solids are collected and recrystallized from ethyl acetate.

Temp. « 164.5 - 165°C.

fqj\ 6°5 -116° 1, D.M.F.)

Step 4. 1-cyclohexylmethyl-2-aminomethyl-pyrrolidine (R)(+).

13.6 g (0.356 mol) of the double hydride of lithium and aluminum and anhydrous ether are introduced into an Erlenmeyer flask. Under a stream of nitrogen, 20 g (0.089 mol) of the amide obtained in step 3 are added in small amounts. It is heated under reflux for 16 hours and hydrolyzed with a solution of sodium potassium tartrate. The solid is filtered off and the organic phase is evaporated. An oil is obtained which is distilled. • Boiling point^ «= 140°C.

^365+253° (c * 1>D.M.F.)

Use of the pyrrolidine I (R) for the synthesis of; N-((1-cyclohexylmethyl-2-pyrrolidinyl)-methyl7-2-methoxy-5-sulfamoyl-

12 g (0.061 mol) of the pyrrolidine obtained above, 8.44 g (0.061 mol) potassium carbonate and acetone are introduced into an Erlenmeyer flask.

At a temperature ^: 10°C and under a stream of nitrogen, 15.2 g (0.061 mol) of the chloride of 2-methoxy-5-sulfamoyl-benzoic acid in acetone are added dropwise.

It is stirred for 2 hours, evaporated to dryness and the residue subjected to a trituration in a mixture of water plus ether. The solid is filtered off and dissolved in chloroform, dried over magnesium sulphate and evaporated. A solid is obtained which is recrystallized from an ether/ethyl acetate mixture.

Temp. b 141.5 - 142°C

fa?* 0 + 96° (c b ,1, D.M.F.)

The methanesulfonate of this benzamide has a configuration (R)(-).

It melts at 164 - 165°C

JToJq° a -4.2° (c b 1, D.M.F.).

Example 3 (reaction core 3)

1-p-fluorobenzyl-2-aminomethyl-pyrrolidine (R)(+)

Step 1: Rscemic pyroglutamic acid.

200 g (1,359 mol) of glutamic acid are introduced into a 1 liter autoclave

S and 700 ml of water. The mixture is brought to 200°C for 6 hours with stirring. On cooling to ambient temperature, a white solid crystallizes from the resulting solution.

M.p. Tb 183 - 185°C.

Racemic ethyl gyroglutamate.

In a 2 liter flask with reflux cooling and magnetic stirring, 200 g (1.549 mol) of racemic pyroglutamic acid are placed in suspension in 1.5 liters of ethanol and approximately 50 ml of resin "Amberlite" IR 120 (H) previously washed with alcohol to remove vwater is added . The mixture is brought to reflux and the insoluble solid dissolves quickly and completely. It is boiled under reflux for about 12 hours and then the resin is sucked off on a filter and the filtrate is evaporated. A colorless oi>je is obtained.

This oil is distilled under reduced pressure. After a small initial fraction, the product distills to a colorless oil which crystallizes spontaneously and gives a white solid. A non-distillable brown residue remains.

After crushing the distilled crystallized compound, a white powder is obtained:

Boiling points 0 '<1>35 - 140°C. mp 61 - 62.5°C

^ 0.005 mmrT

Step Racemic ethyl 1-p-fluorobenzyl-2-oxo-joyrrolidin-5-carboxylate.

4.8 g (0.1 mol) of sodium hydride 50% in oil are placed in an Erlenmeyer flask with a ground neck under nitrogen atmosphere and washed by decantation three times with dry petroleum ether, after which the mixture is poured over with 100 ml of pure DMF. This suspension is cooled slightly to keep the temperature constant at 20°C during all these operations. A solution of 15.72 g (0.1 mol) of the above-mentioned ester in 50 ml of DMF is then introduced dropwise. One notes at the beginning of this . in addition, an abundant and steady evolution of gas shows that sodium is being introduced. The mixture is allowed to stand overnight at ambient temperature to complete this reaction. It is then cooled in an ice bath and a solution of 14.48 g (0.1 mol) of p-fluorobenzyl chloride in 30 ml of DMF is added dropwise, after which the temperature is allowed to rise gradually to 20°C: After 3 hours with stirring, the DMF is evaporated to dryness at 35 °C under vacuum. The residue is extracted with ether three times in the presence of very weakly acidified water. The ether extract is washed with water and then dried over magnesium sulfate in the presence of animal charcoal. After filtering and evaporating the solvent, a yellow oil remains.

By distillation for analysis of 0.9 g in a ball column is obtained

a colorless oil:

Boiling point - no. c ' a 150°C

K 0.005 mm

Step 4: Racemic 1-p-fluorobenzyl-2-oxo-pyrrolidine-5-■ carboxylic acid.

To a solution of 18.5 g (0.0697 mol) of the crude ester from step 3 in 100 ml of ethanol is added as a solution of 2.8 g (0.0697 mol) of sodium hydroxide in 10 ml of water and the mixture is stirred for 2 hours. The solvent is then evaporated under vacuum and the residue is shaken between water and ether. After 2 extractions with ether, the alkaline aqueous phase is cooled in ice and acidified with concentrated hydrochloric acid, to approximately pH 1. The yellowish-white solid that crystallizes is filtered off with suction, washed with water and then with pentane and dried under reduced pressure in the presence of phosphoric anhydride.

M.p. T131 - 132°C.

Step 5: 1-p-fluorobenzyl-2-oxo-pyrrolidine-5-carboxylic acid

1°) Prepare Ung from the salt of L-tyrosine hydrazide (S)

42.7 g (0.18 mol) of

the previous racemic acid (step 4) and 35.14 g (0.18 mol) L-tyrosine hydrazide and 550 ml of ethyl alcohol are added, after which the mixture is boiled under reflux. A small amount of insoluble substance is sucked off the filter and the solution is inoculated while warm

with already split salt. Little by little, a fine white solid appears. The mixture is set aside overnight,

the crystalline mass is crushed and the suspension is stirred for a further 10 hours. The white solid is sucked off on a filter,

washed with a little cold alcohol and then with ether and dried in a drying cabinet.

Temp. T125 130°C.

After recrystallization from 200 ml of isopropanol and -150 ml of ethanol. a powder is obtained.

Mp.T o 135 - 137°C.

^365-66*6° (° a °' 5 D.M.F.)

2°) Production of the acid ( R)(-)

Dissolve 16.6b g (0.0385 mol) of the salt from the previous step in a little water, add approximately 200 ml of ether and acidify with concentrated HCl in excess. The aqueous phase is extracted three times with ether, the extracts are washed with water and then dried over magnesium sulphate. After evaporation of the solvent, a white crystalline compound remains which is treated under pentane, filtered off with suction and washed and then dried under reduced pressure at 60°C.

Temp. b 107 - 108°C.

</07>3g5« -120.87° (c 2, D.M.F.)

Step 6£ Methyl-1-p-fluorobenzyl-2-oxo-pyrrolidine-5-

carboxylate (R)(-).

j

40 g (0.168 mol.) of 1-p-fluoro-benzyl-2-oxo-pyrrolidine-5-carboxylic acid (R)(-) and 100 ml of methanol are introduced into an Erlenmeyer flask. It is heated at 40°C and 24g (0.2 mol) thionyl chloride is added dropwise. It is heated under reflux for 8 hours and the alcoholic solution is evaporated to dryness and an oily residue is recovered which is distilled.

Boiling pointn>05mm<«>144°C

^7.365-56*85° (c 83 2>D.M.F O

Step_7: 1-g-Fluorobenz^1^-oxo-pyrrolidine-5-carboxamide (r)(-)

400 ml of methanol are introduced into a 1 liter Erlenmeyer flask and the solution is saturated with ammonia while cooling on ice.• 22 g (0.087 mol) of methyl-l-p-fluorobenzyl-2-oxo-pyrrolidine-carboxylate (R)(-) are then introduced dropwise. and it is stirred for 8 hours at ambient temperature. It is evaporated to dryness bg a solid is obtained which is dried under reduced pressure over phosphoric anhydride. One recrystallizes from the smallest possible amount in kl.QDof orm. The compound is a white powder.

Smp.' 179.5 - 180°C

ZtS?355«-305.6° (c. = 0.7, D.M.F.)

Step 8: 1-p-fluorobenzyl-2-aminomethyl-1-pyrrolidine (R)( + )

300 ml of anhydrous ether are introduced into an Erlenmeyer flask and 13 g (0.342 mol) of the double hydride of lithium and aluminum are added under a stream of dry nitrogen. The ether is then heated to reflux and 20.2 g (0.085 mol) of the preceding amide are introduced in small portions and the mixture is kept under reflux for 16 hours. It is hydrolysed with a solution of the double tartrate of sodium and potassium. The solids are filtered and washed several times with ether. The ether phases are combined and concentrated under reduced pressure. An oil is obtained which is distilled.

This is a colorless liquid.

Boiling point0>05mm 92°C.

A/q<5>+81.8° (c b 0.5, D.M.F.).

Use of the amine I .( R) for the preparation of N-/"-( l-p-fluorobenzyl-2-pyrrolidinyl)- methyl7- 2- methoxy-5- sulphamoyl-benzamide ( R)(+)

In an Erlenmeyer flask. 4 g (0.019 mol) of 2-amino-methyl-1-p-fluorobenzyl-pyrrolidine (R)(+) and further 2.7 g (0.0196 mol) of potassium carbonate in suspension in acetone are introduced. In the cold (T 5j<»>10°C) a solution of 4.8 g (0.019 mol) of the chloride of 2-methoxy-5-sulfamoyl-benzoic acid in acetone is added dropwise. It is stirred at ambient temperature for 2 hours.

The reaction mixture is evaporated to dryness under reduced pressure at a temperature lower than 30°C. The residue is washed with a chloroform-water mixture. The organic phase is separated and dried over magnesium sulphate, it is evaporated and a solid substance is obtained.

The solid is recrystallized from an isopropyl ether-ethyl alcohol mixture and is a white solid.

SMP. Take 148 - 148.5°C.

£qj^ b +92° (c b 0.6 D.M.F.).

Example 4 (Reaction nucleus 4)

1-ethyl-2-aminomethyl-pyrrolidine I (S) and its oxalate.

Step lj_ l-acetyl-2-acetoxy_methyl_l-pyrrolidine (S) (-)_•'

44 g (0.435 mol) prolinol (S) and 60 g (0.435 mol) potassium carbonate are introduced into a 1 liter Erlenmeyer flask in suspension in 600 ml acetone. 78.5 g (1 mol) of acetyl chloride are added dropwise in the cold while stirring, then heated at reflux temperature for 8 hours. The suspension is then filtered and the inorganic solid is washed with the same solvent. The combined filtrates are evaporated and the residue taken up in ether and stirred in the presence of animal charcoal. After filtration, the solution is evaporated and the residue is distilled. The obtained oil then crystallizes spontaneously. It consists of the diacetyl derivative (the amido ester).

Boiling point Q 1 113 - 115°C.

Temp. Te 44 - 46°C.

This product is sufficiently pure for further synthesis.

fj^ -53.2° (c 4.65, D.M.F.).

Step 2:. 1-acety_l-2-hydroxymethyl-gyrrolidin_).£S).( + )^

To a cooled solution of 50 g (0.27 mol) of the above-mentioned amido ester in 50 ml of ethanol, 270 ml of alcoholic KOH IN (0.27 mol) are added dropwise. The mixture is allowed to react for 24 hours at ordinary temperature and is then evaporated to dryness and the residue is extracted several times with ether while stirring. The ether phase is concentrated and the resulting oil is subjected to a distillation under reduced pressure. The intended amino alcohol is obtained.

Boiling pointQ Q1 = 95 - 96°C.

CvJ^ 2 ,+51° <c = X>D.M.F. ).

Step_3: l-acetyl-2-chloromethyl-gyrrolidin_(S)(-2* •

1) Preparation of the hydrochloride.

To a solution cooled to at least 10°C of 28.8 g (0.20 mol). of the above-mentioned amido alcohol in 200 ml of chloroform containing a few drops of pyridine, a solution of 21.7 ml (0.3 moi) of thionyl chloride in 50 ml of chloroform is added dropwise. The reaction mixture is stirred for 4 hours at a temperature lower than 10°C and then concentrated under reduced pressure without heating.

The residue is taken up in chloroform, after which triethylamine is added

to neutral reaction. It is again concentrated to dryness, the residue is taken up in ether in the presence of animal charcoal, stirred, filtered and the filtrate concentrated. The oily residue is distilled under reduced pressure.

Boiling point 90 - 94°C.

This oil is dissolved in anhydrous ether and treated with an excess of anhydrous hydrogen chloride gas and leads to a white hydroscopic solid which is well crystallized, namely the hydrochloride of 1-acetyl-2-chloromethyl-pyrrolidine. • - Smp.,J,. , 125 - 126°C.•

2) Preparation of l-acetyl-2-chloromethyl-pyrrolidine (S)(-).

The above hydrochloride is treated with a solution of triethylamine in ether in excess. The hydrochloride of triethylamine

is suctioned off on a filter and the filtrate is evaporated and carefully distilled. 1-acetyl-2-chloromethyl-pyrrlididine is obtained in liquid form.

Boiling point^ « 90 - 91°C

£a/^ 5 -61.8° (c 0.5, D.M.F.)

v

IN

Step 4: 1-acetyl-2-azidomethyl-pyrrolidine ( S )_

For 8 hours at 110°C, a suspension of 14.3 g (0.0885 mol) of the compound obtained in step 1, 11.5 g (0.177 mol) of sodium azide and 1.5 g (0.009 mol) of potassium iodide is heated in 200 ml of dimethyl-

formamide.

One then evaporates under reduced pressure as much as possible of DMF, the residue is taken up in chloroform, insoluble matter is filtered off and the filtrate is concentrated to dryness. What remains is an oil that has not been purified and is made up of the desired azido derivative.

Step_5: 1-Ethy^-2-aminomethyl-pyrrolidine and its oxalate I (S_2(-)_-1) Diamine.

20.2 g (0.532 mol) of the double hydride of lithium and aluminum are placed in 500 ml of dry ether in a tr<e>ha-1 flask equipped with a stirrer, dropping funnel and reflux cooler. It is cooled and, with good stirring, 14.9 g are added dropwise

(0.0886 mol) of the above azide. It is then heated for 8 hours at the reflux temperature and then hydrolyzed in the cold by the careful addition of 38.2 ml of an aqueous solution of the 10% double tartrate of sodium and potassium. After 1 hour of further stirring to complete the hydrolysis, the suspension is filtered and the inorganic solid is washed three times

with 200 ml of ether each time. The ether phases are combined and concentrated and lead to a residue which is distilled under reduced pressure. The 1-ethyl-2-aminomethyl-pyrrolidine obtained is a colorless liquid.

Boiling point 2578 - 80°C

A7d<5>= -86.1°; (c » 0.6, D.M.F.).

2) The oxalate.

The oxalate is produced via the influence of 0.256 g of this

diamine of 0.18 g of oxalic acid in methanol. The salt crystallizes quickly, is filtered off with suction and washed with boiling methanol, filtered off with suction and dried.

Mp-T ' * 174 - 175°C.

C&l5-36.3°.(c b 0.6, H2O)

Use of the pyrrolidine I (S)(-) l-ethyl-2-aminomethyl-pyrrolidine I (S)(-), leads by condensation with the chloride of the 2-methoxy-5-sulfamoyl-benzoic acid, preferably in an acetone environment which has been made alkaline with a basic carbonate,

to 2-methoxy-5-sulfamoyl-benzamide II of structure (S)(-).

The N-[I-ethyl-2-pyrrolidinyl-7-methyl-2-methoxy-5-sulfamoyl-benzamide (S)(-) obtained melts at 185-186°C.

Zo7d5 a -66.8° (c b 0.5, D.M.F.)

The following table shows compounds I obtained by the method according to the invention.

Analyzes and IR and NMR have confirmed the structure in each case

of the compounds obtained.

The melting points are determined using a Tottoli apparatus.

Claims (6)

1. Procedure for the stereospecific synthesis of optically active, N-substituted pyrrolidines with the following symmetrical general formulas I(R) and I(S) wherein R' <1> either means an alkyl group with 1 to 4 carbon atoms or a hydrogen atom, or a group of the general formula wherein A means a straight-chain or branched alkylene chain with 1 to 4 carbon atoms and R 2 , R 2 and R 4 independently of each other mean hydrogen atoms, halogen atoms, trifluoromethyl groups, trimethylfluoromethoxy groups, trifluoromethylthio groups, alkyl groups with ct to 4 carbon atoms. or alkoxy groups with 1 to 4 carbon atoms, and m means the number 2,3,4 or 5, characterized in that an oralin with formula is esterified with SO2 C1 under alkaline conditions to form a compound of the general formula in which alk stands for methyl or ethyl, the ester thus obtained is reacted with ammonia to form an amide of formula this amide is acylated with an acid of the general formula R''COOH, R'* in this and in the following formulas having the above meaning, or with the chloride or hydride of this acid, forming a compound of the general formula and the latter compounds are reduced to a compound of formula I(R) or I(S). 2. Procedure as stated in claim 1, grade! Ls ert in that 1-proline (S) is used as starting compound. 3. Process as stated in claim 1 or 2 for the preparation of compounds of general formula I(R) and I(S), in which R' <1> means a group of the general formula in which A, R 2 , R 3 and R 4 have the meanings stated in claim 1, characterized in that an acid of the general formula R''COOH is used for acylation in which R' <1> has the above meaning, or its chloride or anhydride . 4. Method as stated in claim 1 or 2, for the preparation of compounds with the general formulas I(R) and R (S) in which R<1>' stands for a group with the general formula in which A and m have the meanings stated in claim 1, characterized in that an acid of the general formula R''COOH is used for acylation, in which R'' has the above-mentioned meaning, or its chloride' or anhydride. 5. Process as stated in claim 4, for the preparation of compounds of formula I(S), in which R<1>' stands for cyclopropyl, characterized in that an acid with the general formula R''COOH is used for acylation in which R'' means cyclopropyl, or its chloride or anhydride. 6. Process as stated in claim 1 or 2 for the preparation of compounds with the general formulas I(R) and I(S) in which R'' stands for an alkyl group with 1 to 4 carbon atoms or a hydrogen atom, characterized in that an acid of the general formula R''COOH is used for acylation in which R' <1> has the above meaning, or its chloride or anhydride.