IE45544B1 - Aptically active n-substituted pyrrolidines - Google Patents

Abstract

The optically active pyrrolidines of formula: are obtained from (R)- or (S)-glutamic acid, by formation of an aldimine with an aldehyde R''CHO, reduction of the imino group to an amino group, cyclisation by the action of an acid, esterification of the carboxyl, conversion of the ester to an amide and reduction. The compounds can be used in the synthesis of optically active benzamides, which have a therapeutic activity, of formula: To this end, they are condensed with a 2-methoxy-5-X-benzoic acid or one of its derivatives. None of the reactions affects the absolute configuration of the asymmetric carbon; thus, (S)-glutamic acid leads to an (S)-amine I and to an (S)-benzamide II. The symbols R', R'' and X are defined in Claims 1 and 8.

Description

The present invention relates to optically active Nsubstituted pyrrolidines, to a process for stereospecific synthesis thereof, and to the use of these pyrrolidines for the production of optically active benzamides carrying one pyrrolidinylmethyl substituent.

The invention provides an optically active pyrrolidine of the formula or an acid addition salt thereof, in which R represents either (ii 10 a CHjR^ radical of 1 to 5 carbon atoms (R^ being alkyl of from 1 to carbon atoms or being a hydrogen atom); or (ii) a radical of the formula in which A is a linear or branched chain of 1 to 4 carbon atoms and R2, R3 and R^' each represent, independently of one another, hydrogen, halogen (particularly chlorine or fluorine) trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl of 1 to 4 carbon atoms; or (iii) a radical of the formula (Cl S 5 4 4 in which A is as defined above and m is 2,3,4 or 5.

The compounds of the formula 1 may be used as intermediates in a process for the preparation of an optically substituted benzamide fo the formula in which R has the meaning given above and X represents chlorine, SO2R5 or SO2NRgR7, where Rg is alkyl of 1 to 4 carbon atoms and -Rg and Ry are identical or different and each represents hydrogen or alky of 1 to 4 carbon atoms, which process comprises reacting a pyrrolidine (I) as defined above with an acid of formula COOH Och3 or a reactive derivative thereof.

The benzamides (II) are compounds which possess therapeutic activity and have already been described, and the benzamides (II) of 15 pyrrolidines (I) in which R is an alkyl radical can be substituted by known methods to produce the following benzamides II': 3^44 in which R is an allcyl radical of 1 to 5 carbon atoms, B is a hydrogen atom, or an alkyl radical of 1 to 5 carbon atoms, and C, D and E independently represent a hydrogen atom, a halogen atom, an alkoxy radical of 1 to 5.carbon atoms, a nitro radical, an amino radical, an alkylamino radical, a dialkylamino radical or , an alkanoylamino radical, an acyl radical of 1 to 5 carbon atoms, the cyano radical, a sulphamoyl radical, an alkylsulphamoyl radical or a dialkylsulphamoyl radical, an alkylsulphonyl radical, a trihalogenomethyl radical, an alkylthio radical, a polyfluoroalkyl radical or a polyfluoroalkylsulphonyl radical.

The absolute configuration of the enantiomers of the formulae I(R) and I(S) has been established by continuous filiation between L-prolinol, of which the absolute configuration t Is known, and the (S) (-) laevorotatory enantiomer 1.

L-prolinol possesses an (S) (Sinistral) absolute configuration according to the rule of Cahn, Ingold and Prelog, since it derives from L-proline, of which the (S) configuration has been determined by an X-ray study (Buckingham et al.. Comm., 1S62. 583)/ ‘ The sequence of chemical reactions can therefore only lead to the (S) enantiomer Ί,which will itself lead to the (S) derivative II, since these reactions do not. affect the absolute configuration of the asymmetric carbon or its (R) or (S) nomenclature in the context of the Cahn, Ingold and Prelog rules.

We have perfected a process of stereospecific synthesis which permits the production of the (R) and ,(3) enantiomers of the formula (I). - 4 4 5 5 4 4 The process of the invention comprises subjecting (R)or (S)-glutamic acid or (R)- or (S)-proline, or a compound derived therefrom, to one or more condensation, esterification, saponification, amidation, cycliation and/or reduction reactions via an intermediate pyrrolidine which carries an asymmetric carbon in the α-position to an amino group.

Preferred processes of the invention are those wherein: (1). (S>- or (R)-proline is esterified, the ester is then converted into the amide and the resulting 2-carbamolypyrrolidine is acylated at the nitrogen atom using a compound R'COOH or a derivative thereof to give a l-acyl-2-carbamoylpyrrolidine, Which is reduced to the (R) or (S)2-aminomethylpyrrolidine carrying the radical R on the nitrogen atom, R having the meaning given above and R* being either R·^ as defined in claim where A' is a valence bond, or an alkylene radical of 1 to 3 carbon atoms; (2). (R)- or (S)-glutamic acid is cyclised to l-R-2-oxopyrrol2o idine-5-carboxylic acid by sucessive treatment with an aldehyde R'CHO, where R is as defined above and R' is as defined above, and by reduction and acid cyclisation, the acid obtained is esterified, the ester obtained is converted into the amide and - 5 4 55 44 this amide is reduced to the (R) or (S) l-R-2-aminomethylpyrrolidine; (3) . natural (S)-glutamic acid is cyclised and racemised to pyroglutamic acid, the pyroglutamic acid is converted into a racemic alkyl ester, this ester is caused to react with a compound RX, R having the meaning given above and X being halogen, the resulting l-R-2-oxo-5-alkoxycarbonylpyrrolidine is saponified to give l-R-2-oxo-5-carboxypyrrol±dine which is resolved into the desired optical isomer, the optical isomer is esterified, the ester is then amidated, and finally the 1R-2-oxo-5-carbamoylpyrrolidine so obtained is reduced to the (R) or (S) l-R-2-aminomethylpyrrolidine I; and (4) . (R)-or (S)-prolinol is treated with an acid chloride R'COCl (R* having the meaning given above), the ester function of the amido-ester obtained is saponified, the l-acyl-2-hydroxymethylpyrrolidine obtained is converted into a halogenated derivative,, which is treated with sodium azide, and the azide obtained is reduced to the (R) or (S) l-R-2-aminomethylpyrrolidine, R having the meaning given above.

According to a further preferred embodiment of the present invention, the compounds of formula (I) are made by reducing a compound of the formula: wherein 2^ is-CO- or -CH2-; Zj is R or -CO-R' as hereinbefore 25 defined, and Z3 is -CONH2 or -CH2N3, with the proviso that, when 2.]. is -CO- then Z2 is R and Z3 is CONH2, and that when Zj^ is-CH2then Z2 is -COR1. The reaction schemes are represented below. - 6 4 5 5 4 4 l/Reaction scheme I H COOH S0Ci2 /alkOH 1st stage L-proline (S) (S) ~ 7 4 5 5 4 4 Reaction scheme 2 reduction 4th stage Reaotion scheme 3 cyclisation· and racemisation ,-5 racemisation - C2HSOit j-γ c L--5 ίRH --> I R 2LH COOH 0^XH'XX‘( HOOC » HgN COOH glutamic aeid (s> ·’ COOH u (R S) •cocc2hs r~LR resolution <· COOH L fR) (H S) (R S) CHjOH - 9 4 Β δ 44, Reaction scheme 4 ϊ. (Si (Si 3 5 4 4 In the reaction schemes, the meanings are as follows: alk a CHj or C2H,j X « halogen (preferably Cl) R’ « either R^ (H, or alkyl radical of 1 to 4 carbon atoms) A’ bond, or alkylene radical of 1 to 3 carbon atoms.

The other meanings are those given previously.

In reaction scheme 1, (S)-proline is used as the starting material to obtain the (S)-amine I.

(R)-Proline would lead to the (R)-amine I in the same manner.

In reaction scheme 2, (R)-glutamio acid is used as the starting material to obtain the (R)-amine I directly.

(S)-glutamio acid could lead to the (S)-amine I in the 15 ' same manner.

In reaction scheme 3, (S)-glutamic acid is used as the starting material, which, after cyclisation and racemisation, followed by resolution, also makes it possible- to obtain the (R)-araine I. 2o In reaction scheme 4, (S)-prolinol is used as the starting material to obtain the (S)-amine I.

(R)-Prolinol, obtained starting from (S)-glutamic acid by cyclisation and racemisation, followed by resolution into (R)-pyroglutamic acid and reduction of the latter, or by cycli25 ' sation and reduction of (R)-glutamic acid, would lead to the (R)-amine I in the same manner. - 11 48 5 44 Γ The reaction schemes are illustrated below in the examples.

The final reductions are carried out preferably by means of lithium aluminium hydride.

The resolution in reaction scheme 3 preferably carried out by means of L-tyrosine·hydrazide.

Example I (reaction scheme 1) (s) (-)-l-Cyclopropylmethyl-2-aminomethyl-pyrrolidine Stage 1,(S 2-Ethoxycarbonyl-pyrrolidine . io 34.8 g (0.3 mol) of L-proline (S) and 360 ml of ethanol • are introduced into an Erlenmeyer flask. 54.8 g (0.46 moi). of thionyl chloride are added dropwise, whilst cooling in an ice bath.' The mixture is stirred for one hour at ambient tempera15 ture and heated under reflux for three hours. The mixture is evaporated to dryness and -the residual oil is dissolved in chloroform and saturated·with ammonia. The ammonium chloride is filtered off and the organic phase is evaporated. An oil is recovered, which is distilled.

Boiling.point (20 mm) « 82°C.

Stage 2. (S) C-)-2-Carbamoyl-pyrrolidina 200 ml of methanol are introduced into an Erlenmeyer flask and saturated With ammonia whilst cooling. 17,2 g (0.12 mol) of the ester obtained in Stage 1 are introduced into the methanol. The mixture is stirred for two hours and allowed to stand for one night.

The mixture is evaporated to dryness and a solid is recovered, which is recrystallised from benzene.

S 3 4 4 Melting point « 101.5 - 102°C oC . o< “ -78° (o «= 1, water) D «=-258.5* (c = 1, water) 365 Stage 5, (S)(-l-l-cyclopropylcarbonyl-2-carbamoyl-pyrrolidine 11.4 g (0.1 mol) of (S)-prolinamide, 15.8 g (0.1 mol) of potassium carbonate and some anhydrous acetone are introduced into an Erlenmeyer flask.

The mixture is cooled with an ice bath and 10.45 g (0.1 mol) of cyclopropanecarboxylic. acid chloride in acetone are added dropwise·.

The mixture, is stirred for one hour at the same temperature and is allowed to stand for one night at ambient temperature. It i3 then evaporated to dryness (T<30°C) and extracted with chloroform,’ and the extract is washed with the minimum amount of water. Ihe organic phase is dried over magnesium sulphate and evaporated. A solid, which melts at 129-130°C, is recovered 436 =-130.9’ (c = 1, D.M.P.) Stage 4, (S)(-)-l-cycjLQpropyimathyl-2-aminomethyl-pyrrolidine 13«3 g (0.35 mol) of lithium aluminium hydride and 200 ml of anhydrous ether are introduced into an Erlenmeyer flask, 16 g (0.088 mol) of the preceding diamide are added in small amounts and the mixture is heated under reflux for 16 hours. It is then hydrolysed with a 10 % strength solution of sodium potassium tartrate and the solid is filtered off and washed several times with ether. The ether phases are -13 4SS44 mixed and evaporated.

An oil is recovered, which is distilled. Boiling point (20 mm) = 88°C. «* 20 «-201.5’ (c « 1, D.M.F.) I J 365 ^-68,30 iC “ 1# D·M·P·, Use of the (S)-pyrrolidine I: (s) (-)-N-£ (1-cyclopropylmethyl-2-pyrrolidihyl)methyl]-2-methoxy-5-*sulphamoyl- 8.8 g (0.057 mol) of amine, 14.07 g (0.054 mol) of 2-methoxy-5-sulphamoylben2oie acid ethyl ester and 18 ml of water are introduced into an Erlenmeyer flask. The mixture is heated at 120°C for 10 hours. A solid appears on cooling. Ether and water are added and the mixture is stirred. The solid is filtered off and dissolved in chloroform and the eolution is dried over magnesium sulphate and then evaporated.

A solid is recovered, which is recrystallised from ethyl acetate Melting point 134-134.5°C.

U J '77* (e β 1, D.M.F.) Example 2. (reaction scheme 2) (R) (+)-l-Cyclohexylmethyl-2-aminomethyl-pyrrolidine Stage 1, (R)(-) “l-GyclohexyImethyl-2-carboxy-5-oxo-pyrrolidine 58.8 g (0.4 mol) of (R)-glutamic acid and 400 ml of NaOH (2N) are introduced into an Erlenmeyer flask under a stream of · nitrogen and whilst cooling. 44.8 g (0.4 mol) of cyclohexane earbaldehyde in methanol are added dropwise. The reaction mixture is stirred for one hour and hydrogenated in the presence of Pd/C at ambient temperature and at atmospheric pressure.

When the theoretical volume of hydrogen has been absorbed, the catalyst is filtered off and the methanol is evaporated off.

The aqueous phase is recovered and extracted with ether. The pH ef the aqueous phase is adjusted to 2.5 with IN hydrochloric acid and the solution is heated at 100°C for two hours.

It is cooled and the white solid is filtered off and dissolved in chloroform. The solution is dried over magnesium sulphate and evaporated. A solid is recovered, which is triturated with cyclohexane.

Melting point=141.5-142°C ^355= -20.5° (c = 1. D.M.F.) Stage 2. (R)· (-)-l-Cyelohexylmethyl-2i-methoxycarbony-l-5-oxopyrrolldine 300 ml of methanol and 50 g (0.221 mol) of the compound obtained in Stage 1 are introduced into a one litre Erlenmeyer flask.' The mixture is heated to 40°C and 31.7 g (0.266 mol) of · thionyl chloride are introduced dropwise. The mixture is heated under reflux for four hours and evaporated to dryness. 19 β'5Ε»<1·4 An oil is recovered, which is distilled and which crystallises on cooling.

Melting point = 87.5-88°C. (c Stage · 3. (R) (-) -l-Cyclohexylinethyl-2-carbamoyl-5-oxo-pyrrolldlne . 400 ml of methanol are introduced into an Erlenmeyer flask and the solution Is saturated with ammonia whilst cooling. 41.2 g (0.172 mol) of the ester obtained in Stage 2 are added and the mixture is stirred for two hours and allowed to stand for one night.

It is evaporated to dryness and a solid is recovered, whioh is recrystallised from ethyl acetate.

Melting point = 164.5-165°C.

Ct. «-116’ (c « 1, D.M.F.) 36S (R) (+) -l-Cyclohexylmettiyl-2raminomethyl-pyrrolidine 13.6 g (0.356 mol) of lithium aluminium hydride and some anhydrous ether are introduced into an Erlenmeyer flask. g (0.089 mol) of the amide obtained in Stage 3 are added in small amounts under a stream of nitrogen. The mixture is heated under reflux for 16 hours and hydrolysed with a 10 % strength solution of sodium potassium tartrate. The solid is filtered off and the organic phase is evaporated. An oil is recovered, which is distilled.

Boiling point (25 mm) = 14O°C. 365 +263° (c <= 1, D.M.F.) . — 16 Use of the (R)-pyrrolldlne I: synthesis of the Or) (+)-n-((1cyclohexylmethyl-2-pyrrolldinyl)methyl]-2-methoxy-5-sulphamoylbenzamide II g (0.061 mol) of the previously obtained pyrrolidine, 8.44 g (0.061 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask. .2 g (0.061 mol) of 2-methoxy-5-sulphamoylbenzoic acid chloride in acetone are added dropwise at a temperature of 4* 10°C and under a stream of nitrogen.

The mixture is stirred for two hours and evaporated to diyness and the residue is triturated with a mixture of water and ether. The solid is filtered off and dissolved in chloroform and the solution is dried over magnesium sulphate and evaporated. A solid is recovered, which is recrystallised from a mixture of ether and ethyl isoacetate.

Melting point « 141.5-142°C. » +96’ (c » 1, D.M.F.) D The methanesulphonate of this benzamide has a (R)(-) configuration and melts at 164-165°C.

T20 -4.2’ (c «1, D.M.F.) 'Example 3. (reaction scheme 3) (R)(+).-l-(p-Fluorobenzyl)-2-aminomethyl-pyrrolidine Stage 1; Racemic pyroglutamic acid 200 g (1.359 saols) of (S)-glutamic acid and 700 ml of water are introduced into a 1 1 autoclave. The temperature of the mixture is brought to 200° for 6 hours whilst stirring.

By cooling to ambient temperature, a'white solid crystallises • out from the resulting solution.

Melting point « 183-5°C Stage 2; Racemic ethyl pyroglutamate 200 g (1.549 mols) of racemic pyroglutamic acid, as a suspension in 1.5 1 of ethanol, are placed in a 2 1 roundbottomed flask, which is fitted with a reflux condenser and a is magnetic stirrer, and about 50 ml of Amberlite IR 120 (H) resin, (Amberlite is a Registered Trade Mark), previously washed with alcohol in order to remove water, are added to the suspension.

The mixture is brought to the reflux temperature and the insoluble solid dissolves.rapidly and completely. The'mixture is 2o allowed to reflux for about 12 hours and then the resin is filtered off and· the filtrate is evaporated. A colourless oil is obtained.

This oil is distilled under reduced pressure. After a very small head fraction, the product distils over as a colourless oil, which crystallises'spontaneously to give a white -solid. Ά brown residue remains, which cannot be distilled.

‘ After grinding the distilled crystalline compound, a white powder is obtained: Boiling point (0.005 mm) = 135-140°; - 18 Melting point = 61-62.5°C Stage 3: Racemic ethyl 1-(p-fluorobenzvl)-2-oxo-pyrrolldine-5carboxylate 4.8 g (0.1 mol) of a 50 % strength suspension of sodium hydride in oil is placed in an Erlenmeyer flask, which has a ground glass neck, under an atmosphere of nitrogen and the sodium hydride is washed three times with dry petroleum ether by decantation and then covered again with 100 ml of pure DMF. This suspension is cooled slightly in order to keep it at a io constant temperature of 20° during the subsequent operations.

A solution of 15.72 g (0.1 mol) of the preceding ester in 50 ml of DMF is then introduced dropwise into the suspension.

An abundant and regular evolution of gas is noticed from the start of this addition, indicating that the formation of the sodium derivative is taking place. The mixture is then allowed to stand for one night at ambient temperature in order to complete this reaction. It is then cooled in ice and a solution of 14.48 g (0-.1 mol) of £-fluorobenzyl chloride in 30 ml of DMF is added dropwise. The temperature of the mixture is then allowed to rise again progressively to 20°.

After 3 hours, whilst stirring, the DMF is evaporated off at 35° under vacuum until the mixture is dry. The residue is extracted 3 times with ether in the presence of very slightly acidified water. The ether extracts are washed with water and then dried over magnesium sulphate in the presence of animal charcoal. A yellow oil remains after filtration of the extracts and evaporation of the solvent.

For the purpose of analysis, 0.9 g of the oil is -19 4S544 .

J ‘ · distilled in a bulb tube still (?), and a colourless oil is recovered: Boiling point (0.005 am) = 15O°C.

Stage 4: Rae emlo 1-(o-fluorobenzyl)-2-oxo--Dvrroli dine-5-carboxvlic acid A solution of 2.8 g (0.0697 mol) of sodium hydroxide in 10 ml. of water is added to a solution of 18.5 g (0.0697 mol) of the preceding crude ester (Stage 3) in 100 ml of ethanol, and the mixture is left for 2 hours whilst stirring. The solvent is then evaporated off under vacuum and the residue is taken up again between water and ether. After two extractions with ether, the alkaline aqueous phase is cooled in ice and acidified with concentrated hydrochloric aoid to a pH of about 1. The yellowish white solid which has crystallised out is filtered, washed with water and then with pentane and dried under reduced pressure in the presence of phosphorus pentoxide.

Melting point =131-132°C Stage 5i (R)(-)-1-(g-Fluorobenzyl)-2-oxo-(R)(-)-pyrrolidine-5carhoxylic acid 1· Preparation of the salt of .(S) L-tyrosine hydrazide 42.7.g (0.18 mol) of the preceding racemic acid (Stage 4) and 35.14 g (0.18 mol) of L-tyrosine hydrazide are placed In a 1 litre Erlenmeyer flask and 550 ml of ethyl alcohol are added to •idie mixture whioh is then brought to the reflux temperature.

A slight amount of insoluble material is filtered from the hot mixture and the solution is seeded, while still hot, with some of the salt which has already been resolved. A fine white solid gradually appears. The solution is allowed to stand - 20 /4 ίϊ S <ί d overnight, the crystalline material is broken up and the suspension is stirred for a further 10 hours. The white solid is filtered off, washed with a little cold alcohol and then with ether, and dried in an oven.

Melting point = 125-130°C A powder is obtained after recrystallisation from 200. ml of isopropanol and 150 ml of ethanol.

Melting point = 135-7°C 25 « -66.6° (c « 0.5 D.M.F.) 365 · 2. Production of the (R)(-)-acid 16.65 g (0.0385 mol) of the preceding salt are dissolved in a little water and about 200 ml of ether are added to the solution, which is acidified with excess concentrated HCl.

XS The aqueous phase is extracted three times with ether and the extracts are washed with water and then dried over magnesium sulphate. After evaporation of the solvent, a white crystalline compound remains, which is ground under pentane, filtered, washed and then dried at 60° under reduced pressure. 2o Melting point = 107-8°C » -120.87* Cc 2 i D.M.F.) 365 Stage 6; CR)(-)-Methyl-1-(p-fluorobenzyl)“2-oxo-pyrgplidine-5- . carboxylate g (0.16S mol) Of (R)(-)-1-(E-fluorobenzyl)-2-oxopyrrolidine-5-oarboxylic acid and 100 ml of methanol are introduced into an Erlenmeyer flask. The mixture is heated to 40° and 24 g (0.2 mol) of thionyl chloride are Introduced - 21 dropwise. The alcoholic solution is heated under reflux for .8 hours and evaporated to dryness, and an oily residue is recovered, which is distilled.

Boiling point (0.05 mm) = 144°C. & . “ - 56.86 (e « 2 { DMF) Stage 7: (R)(-)--1-(p-Fluorobenzyl)r2-oxo-pyrrplidine-5earboxamide 400 ml of methanol are introduced into a 1 litre Erlenmeyer flask and the solution is saturated with ammonia whilst cooling in ice. 22· g (0.087 mol) of methyl l-(p-fluorobenzyl) 2-cxo-(R)(“)~pyrrolidine-*5-carboxylate are thereafter introduced dropwise into the mixture, which is stirred for 8 hours at ambient temperature. The mixture Is evaporated to dryness and a solid is recovered, which is dried under reduced pressure over phosphorus pentoxide. The solid is recrystallised from the minimum amount of chloroform and it is a white powder.

Melting point = 179.5-180°C £5)..(+)-l“(£-FmQKQhenzyl)-2-amln:omethvl-pyi:golidine 300 ml of anhydrous ether are introduced into an Erlenmeyer flask and 13 g (0.342 mol) of lithium aluminium hydride are added under a stream of dry nitrogen. The mixture is then heated to the reflux temperature of the ether, .2 g (0.085 mol) of the preceding amide are introduced in small amounts and the mixture is kept under reflux for 16 hours. It is then hydrolysed with a 10 % strength solution of sodium 4 5 5 4 4 potassium tartrate. The solid is filtered off and washed several times with ether. The ether phases are mixed and concentrated under reduced pressure. An oil is recovered, which is distilled and is a colourless liquid.

Bolling point (0.05 am) » 92°C + 8L8‘ (c ,- 0.5 Use of the (R)-amlne Ii preparation of (R) (+) -Ν-Γ(1-(p-fluorobenzvl) ~ 2 - pYrrolldlnyl)methvl1-2-methoxy-5-sulphamoylbenzamide lo g (O.OI9 mol) Of (R)(+)-2-aminomethyl-l-(g-fluorobenzyl-pyrrolidine and a suspension of 2.7 g (0.0196 mol) of potassium carbonate in acetone are introduced into an Erlenmeyer flask. A solution of 4.8 g (0.019 mol) of 2-methoxy-515 sulphamoylbenzoic acid chloride in acetone is added dropwise in the cold (T 4l0°C). The mixture is stirred at ambient temperature for 2 hours.

The reaction mixture is evaporated to dryness under reduced pressure at a temperature below 30°C. The residue is washed with a mixture of chloroform and water. The organic phase is separated, dried over magnesium sulphate and fevaporated; a solid is recovered.

The solid is recrystallised from a mixture of isopropyl ether and ethyl alcohol and it is a white solid: Melting point » 148-148.5°C 25 «= +92® (c=0.6 D.M.f} Q EXAMPLE 4 (reaction scheme 4) (S)-l-Ethyl-2-aminomethyl-pyrroli3ine X and its oxalate Stage 1. (S)(-) -.l-Acatyl-2-acetoxvroethvl-pyrrolidine g (0.435 mol) of (S)-prolinol and a suspension of g (0.435 mol) of potassium carbonate in 600 ml of acetone are introduced into a 1 litre Erlenmeyer flask. 78.5 g (l mol) of acetyl chloride are added dropwise in the cold whilst stirring, and then the mixture is heated at the reflux temperature for 8 hours. The suspension is then filtered and the inorganic solid is washed with the same solvent,· The filtrates are mixed and evaporated, and the residue is taken up again in ether and stirred in the presence of animal charcoal. After filtration, the solution is evaporated and the residue is distilled; the oil obtained then crystallises spontaneously. This is the diacetylated derivative (amido-ester).

Boiling point (0.1 mm) = 113-115°C Melting point = 44-6°C This produfct is sufficiently pure for the continuation ef the synthesis. - 53.2° 4 0 5 4 4 Stage 2 (Si .(.+.>-l-Acetvl-2-hvdroxymethyl-pvrrolidine 270 ml of IN alcoholic potassium hydroxide solution (0.27mol) are added dropwise to a cooled solution of 50 g (0.27 mol) of the preceding amido-ester in 50 ml of ethanol. The mixture is thereafter allowed to react for 24 hours af ordinary temperature and then evaporated to dryness, and the residue is taken up several times with ether whilst stirring. The ether phase is concentrated and the resulting oil is subjected to distillation under reduced pressure. The desired amido-alcohol is 10 obtained.

Boiling point (0.01 mm) = 95-6°C J*]q5 * + 51’ (C « 1, D.M.F.) I Stage 5 (S)(-)Tl-Acetvl-2-chloroinetAyl-pyrrQlidine 15 3. · Preparation of the hydrochloride A solution of 21.7 ml (0.3 mol) of thionyl chloride in ml of chloroform is added dropwise to a solution, cooled to below 10°, of 28.8 g (0.20 mol) of the preceding amido-alcohol in 200 ml of chloroform containing a few drops of pyridine. 2o This reaction mixture is stirred for 4 hours at a temperature below 10° and then concentrated under reduced pressure without heating. The residue is taken up again in chloroform and triethylamine Is then added until the solution ia neutral. The mixture is again concentrated to dryness and the residue is taken up again in ether in the presence of animal charcoal} the mixture is stirred and filtered and 'the filtrate is concentrated. The oily residue is distilled under reduced pressure. - 25 Boiling point (1 mm) = 90-4°C This oil is dissolved in anhydrous ether and the solution is treated with an excess of anhydrous hydrogen chloride gas and gives rise to a white solid, which is hygro5 scopic but well crystallised, namely l-acetyl-2-chloromethylpyrrolidine hydrochloride.

Melting point β 125-6°C.

. The preceding hydrochloride is treated with a solution io of triethylamine in excess ether. The triethylamine hydrochloride is filtered off and the filtrate is evaporated and distilled carefully. Liquid l-acetyl-2-chloromethyl-pyrrolidine is recovered.

Boiling point (1 mm) = 9O-1°C. [ct] « “61.8* (c « 0.5, CME) Stage 4 (S)-l-Acstyl-2-azidomethyl-gvcrolidine A suspension of 14.3 g (0.0885 mol) of the compound obtained In Stage 3, 11.5 g (0.177 mol) of sodium azide and 1.5 g (0.009 mol).of potassium iodide in 200 ml of dimethyl2o formaaide is heated for 8 hours at 110°.

As much of the BMP as possible is then evaporated off under reduced pressure, the residue is taken up again in chloroform, the insoluble material is filtered off and the •filtrate is concentrated to dryness. An oil remains, which is not purified. This is the desired azido derivative.

Stage 5 (5):.(.-1)-l-Ethyl-2-amj.nom.ethylpyrrolidine and 1+s oxalafeJL 1. Diamine - 26 4 5 4 4 .2 g (Ο.532 mol) of lithium aluminium hydride in 500 ml of dry ether are introduced into a 3-necked, round-bottomed flask, fitted with a stirrer, a dropping funnel and a reflux condenser and placed under a stream of nitrogen. The mixture is cooled and 14.9 g (0.0886 mol) of the preceding azide are poured in dropwise whilst stirring well. The mixture is thereafter heated for 8 hours at the reflux temperature and then hydrolysed in the cold by the slow addition of 38.2 ml of a 10 % strength aqueous solution of sodium potassium tartrate.

After an additional1 hour of stirring, in order to complete the hydrolysis, the suspension is filtered and the inorganic solid Is washed 3 times, each time with 200 ml of ether. The ether phases are mixed and concentrated and lead to a residue which is distilled under reduced pressure. The l-ethyl-215 aminomethylpyrrolidine obtained is a colourless liquid.

Boiling point (25 mm) «= 78-80°C “ ~ 86.1’ (c= 0.6, d.m.f.) 2. Oxalate The oxalate is prepared by reaction of 0.256 g of this diamine with 0.18 g of oxalic acid in methanol. The salt crystallises out rapidly; it is filtered off, washed with boiling methanol, filtered off and dried.

Melting point = 174-5°G. [<*] β “ 36.3* (c « 0.6, BgO) Application of the (S)(-)-.pyrrolidine X By condensation with 2-methoxy-5-sulphamoylbenzoic acid •488 44 chloride, preferably in an acetone medium which has been made alkaline with a basic carbonate,(S)(-)-l-ethyl-2-aminomethylpyrrolidine I leads to the 2-methoxy-5-sulphamoylbenzamide (II) with a (S)(-) structure.

The (S)(-)-N-£l-ethyl-2-pyrrolidineJmathyl-2-inethoxy5-sulphamoylbenzamide obtained melts at 185-186°C.

The compounds I obtained according to the invention are shown in Table I below.

In each case, analyses’, IR spectra and NMR spectra have confirmed the structure of the compounds obtained.

The melting points have been determined by means of a Tottoli apparatus.

Claims (5)

1. CLAIMS:1. An optically active pyrrolidine of the formula Ck Γ CH 2 NH 2 R cv I ch 2 nh 2 R (I) or an acid addition salt thereof, in which R represents either (i) a radical CHjR^ of 1 to 5 carbon atoms, (R^ being hydrogen or alkyl of 1 to 4 carbon atoms): or (ii) a radical of the formula in which A is a linear or branched alkylene chain of 1 to 4 1q carbon atoms and R 2 , R and R^ each represent, independently of one another, hydrogen, halogen, trifluoromethyl,trifluoromethoxy trifluoromethylthio, alkyl of 1 to 4 carbon atoms, or alkoxy of 1 to 4 carbon atoms: or (iii) a radical of the formula: A in which A is as defined above, and m is 2,3,4 or 5. 2. Stage 4, Example 3 stage 8, or Example 4 stage 5. 22. A pyrrolidine according to claim 1 when prepared by a process according to any of claims 11 to 21. 23. A process for the preparation of an optically active 15 benzamide of the formula: X in which R is as defined in claim 1 and X represents chlorine, -SO 2 Rg or -SO 2 NRgR 7 , where Rg is alkyl of 1 to 4 carbon atoms and Rg and Ry are identical or different and each represent 20 hydrogen or alkyl of 1 to 4 carbon atoms, which comprises reacting a pyrrolidine according to any of claims 1 to 10 and 22 with an acid of formula: 35 4-5SA4 V* or a reactive derivative thereof. 24. A process according to claim 23, substantially as described in any one of the foregoing Examples 1 to 4. 25. A benzamide of the formula (II) as defined in claim 23,

2. A pyrrolidine according to claim 1, in which R is the said radical of formula: - 31 (C H A

3. A pyrrolidine according to claim 1, in which R is the said radical of formula: R 4

4. (S)(-)-l-Cyclopropylmethyl-2-aminomethylpyrrolidine and its acid addition salts. 5. (R)(+)-l-Cyclohexylmethyl-2-aminomethylpyrrolidine and its acid addition salts. 6. (R)(+)-1-(p-Fluorobenzyl)-2-aminomethylpyrrolidine and its acid addition salts. 7. (Ξ)(-)-l-Ethyl-2-aminomethyl-pyrrolidine and its acid addition salts. 8. (Sj(-)-l-Cyclobutylmethyl-2-aminomethylpyrrolidine and its acid addition Salts. 9. (S)(-)-l-Cyclopentylmethyl-2-aminomethylpyrrolidine and its acid addition salts. 10. (S)(-)-1-(p-Fluorobenzyl)-2-aminomethylpyrrolidine and its acid addition salts. 11. A process for the stereospecific synthesis of a pyrrolidine according to any of claims 1 to 10, which process comprises subjecting (R)- or (S)-glutamic acid or (RJ- or (S)-proline, or a oompound derived therefrom, to one or more condensation, esterification, saponification, amidation, cyclisation and/or reduction, reactions via an intermediate pyrrolidine which carries an asymmetric carbon in the α-position to an amino group - 32 4 0 5 4 4 12. A process according to claim 11, in which (S)- or (R)proline is esterified, the ester is then converted into the amide and the resulting 2-carbamoyl-pyrrolidine is acylated at the nitrogen atom using a compound R'COOH or a derivative thereof to give a l-acyl-2-carbamoylpyrrolidine, which is reduced to the (R) or (S) 2-aminomethylpyrrolidine carrying the radical R in the nitrogen atom, R having the meaning given in claim 1 and R' being either as defined in claim 1, or or (c €T.> ” a '~ where A' is a valence bond, or an alkylene radical of 1 to 3 carbon atoms. 13. A process according to claim 11, in which (R)- or (S)~ glutamic acid is cyclised to l-R-2-oxopyrrolidine-5-carboxylic 15 acid by successive treatment with an aldehyde R'CHO, where R is as defined in claim 1 and R 1 is as defined in claim 12, and by reduction and acid cyclisation, the acid obtained is esterified, the ester obtained is converted into the amide and this amide is reduced to the (R) or (S) l-R-2-aminomethylpyrrolidine. 20 14. A proeess according to claim 11, In which natural (S)glutamic acid is cyclised and racemised to pyroglutamic acid, the pyroglutamic acid is converted into a racemic alkyl ester, this ester is caused to react with a compound RX, R having ths meaning given in claim land X being halogen, the resulting 1R-2-oxo-5-alkpxycarbonylpyrrolidiiie is saponified to give 1-R5 2-ox0-5-carboxypyrrolidine which is resolved into the desired optical isomer, the optical isomer is esterified, the ester is then amidated, and finally the l-R-2-oxo-5-carbamoylpyrrolidine so obtained is reduced to the (R) or (S) l-R-2-aminomethylpyrrolidine I. 10 15. A process according-to claim 11, in which (R)- or (S)prolinol is treated with an acid chloride R'COCl (R 1 having the meaning given in claim 12), the ester function of the amidoester obtained is saponified, the l-acyl-2-hydroxymethylpyrrolidine obtained is converted into a halogenated derivative, 15 which is treated with sodium azide, and the azide obtained is reduced to the (R) or (S) l-R-2-aminomethylpyrrclidine, R having the meaning given in claim 1. 16. A process according to any one of claims 11 to 15, in which the final reduction is carried out with lithium 2o aluminium hydride. 17. A process according to claim 14, in which the resolution is carried out by means of L-tyrosine hydrazide. 18. A process for the preparation of an optically active pyrrolidine according to any one of claims 1 to 10, which 25 comprises reducing a compound of the formulas or '3 - 34 4 5 5 4 4 wherein is-CO- or -CH 2 - ; z 2 is R or ~ C0 “ R '> where R' is as defined in claim 12; and Z 3 is -CONH^ or with the proviso that, when Z^ is -CO-then Z 2 is R and Z 3 is -CONH 2 , and that when Z^ is -CH,,- then Z 2 is -COR. 5 19. A process according to claim 18, in which the reduction is effected with lithium aluminium hydride. 20. A process according to claim 11, substantially as described in any one of the foregoing Examples 1 to 4. 21. A process according to claim 18, substantially as des10 cribed in any one of the foregoing Example 1 stage 4, Example

5. When prepared by the process claimed in claim 23 or 24.