NO117127B

NO117127B -

Info

Publication number: NO117127B
Application number: NO16355266A
Authority: NO
Inventors: J Cavalla
Original assignee: Parke Davis & Co
Priority date: 1962-06-01
Filing date: 1966-06-20
Publication date: 1969-07-07

Description

Fremgangsmåte til fremstilling av nye, terapeutisk aktive, Process for the production of new, therapeutically active,

optisk aktive eller racemiske pyrrolidinforbindelser, optically active or racemic pyrrolidine compounds,

samt av syreaddisjonssalter av sådanne forbindelser. as well as of acid addition salts of such compounds.

Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av nye pyrrolidinforbindelser og syreaddisjonssalter av disse forbindelser, under anvendelse av utgangsmaterialer som likeledes er nye forbindelser. De nye pyrrolidinforbindelser som fåes ved fremgangsmåten ifolge oppfinnelsen har i form av frie ba- The present invention relates to a method for the production of new pyrrolidine compounds and acid addition salts of these compounds, using starting materials which are likewise new compounds. The new pyrrolidine compounds obtained by the process according to the invention have, in the form of free bases

ser folgende generelle formel: see the following general formula:

i hvilken R betegner et lavere alkylradikal, R1 betegner et alkylradikal med fra 2 til 4 carbonatomer, mens R^betegner hydrogen eller et alkylradikal med 1 eller 2 carbonatomer. in which R denotes a lower alkyl radical, R 1 denotes an alkyl radical with from 2 to 4 carbon atoms, while R 1 denotes hydrogen or an alkyl radical with 1 or 2 carbon atoms.

De frie baser såvel som syreaddisjonssaltene eksiste-rer i enantiomorfe former, og oppfinnelsen omfatter fremstilling av de adskilte optisk aktive isomere såvel som av de racemiske eller de ikke i optisk aktive isomere oppdelte stoffer. The free bases as well as the acid addition salts exist in enantiomorphic forms, and the invention encompasses the production of the separated optically active isomers as well as of the racemic or substances not divided into optically active isomers.

De forbindelser som fra synspunktet farmakologisk aktivitet kombinert med lettvint fremstillingsmetode fortrinnsvis skaf-fes ved fremgangsmåten ifolge oppfinnelsen, er dem i hvilke R er methylradikalet, R^er n-propylradikalet og R^ er hydrogen. The compounds which, from the point of view of pharmacological activity combined with an easy preparation method, are preferably obtained by the method according to the invention, are those in which R is the methyl radical, R is the n-propyl radical and R is hydrogen.

Pyrrolidinforbindelser som tilsvarer den ovenfor angitte generelle formel, altså i form av frie baser, reagerer med mange forskjellige organiske og anorganiske syrer under dannelse av addi-sjonssalter med vedkommende syre. Fremstillingen av saltene utfores hensiktsmessig ved å omsette de frie båser med en syre i et ikke re-aktivt opplosningsmiddel. På- den annen side kan syreaddisjonssaltene overfares til de frie baser ved omsetning med alkaliske stoffer Pyrrolidine compounds which correspond to the above general formula, i.e. in the form of free bases, react with many different organic and inorganic acids to form addition salts with the acid in question. The production of the salts is conveniently carried out by reacting the free cells with an acid in a non-reactive solvent. On the other hand, the acid addition salts can be converted to the free bases by reaction with alkaline substances

som natriumkarbonat, natriumhydroxyd og kaliumkarbonat. such as sodium carbonate, sodium hydroxide and potassium carbonate.

Nogen eksempler på addisjohssalter med syrer som kan anvendes for medisinske formål er hydrokloridene, hydr©bromidene, hydrojodidene, sulfatene» eitratene, acetåtene, tartratene, benzo-atené»sulfamatene, maleatene, malatene, gluconatene, ascorbatene og toluensulfonatene. Some examples of addition salts with acids that can be used for medicinal purposes are the hydrochlorides, hydrobromides, hydroiodides, sulfates, eitrates, acetates, tartrates, benzo-athenesulfamates, maleates, malates, gluconates, ascorbates and toluenesulfonates.

Forbindelsene som fåes ved<7>fremgangsmåten ifolge oppfinnelsen har en fordelaktig analgetisk aktivitet og er istand til å lindre sterke smerter uten å gi de tallrike bivirkninger som al-ka loi d-an alge tica forårsaker. I motsetning til alkaloider som morfin og codein forer forbindelsene som fremstilles ifolge oppfinnel sen ikke til narkomani. Oe kan anvendes oralt eller parenteralt. Det foretrekkes å anvende syreaddisjonssaltene når en relativ lett-opploselighet i vann er bnskelig. The compounds obtained by<7>the method according to the invention have a beneficial analgesic activity and are capable of relieving severe pain without producing the numerous side effects that al-kaloi d-an algetica cause. In contrast to alkaloids such as morphine and codeine, the compounds produced according to the invention do not lead to drug addiction. Oe can be used orally or parenterally. It is preferred to use the acid addition salts when relatively easy solubility in water is desired.

Fra praktisk synspunkt anvendes fortrinnsvis racematet, men i alminnelighet har den venstredreiende isomer en sterkere aktivitet enn den tilsvarende hoyredreiende isomer eller racematet. From a practical point of view, the racemate is preferably used, but in general the levorotatory isomer has a stronger activity than the corresponding dextrorotatory isomer or the racemate.

Der er tidligere foreslått å anvende som analgetica andre pyrrolidinderivater enn dem som fremstilles ifolge foreliggende oppfinnelse. Således angis der i belgisk patentskrift nr. 570.359 at 1,2-diaryl-substituerte 3,5-pyrrolidindioner, eventuelt substituert også i 4-stillingen med visse grupper, har en ikke nær-mere presisert analgetisk virkning. Disse forbindelser fremstilles ved en cycliseringsreaksjon som er beskrevet i patentskriftet. Ifolge B. Helwig "Moderne Arzneimittel" 2. Aufl. (1961), side 9, har d-2,2-difenyl-3-methyl-4-morfolino-butyryl-pyrrolidin ("Dextromoramide") en fremtredende analgetisk virkning. Det er imid-lertid påvist at denne forbindelse er beheftet med samme ulempe som opium-alkaloider (morfin, codein etc), nemlig at dens anvendelse er forbundet med faren for narkomani. It has previously been proposed to use other pyrrolidine derivatives than those produced according to the present invention as analgesics. Thus, it is stated in Belgian patent document no. 570,359 that 1,2-diaryl-substituted 3,5-pyrrolidinediones, optionally also substituted in the 4-position with certain groups, have an analgesic effect that is not further specified. These compounds are produced by a cyclization reaction which is described in the patent document. According to B. Helwig "Moderne Arzneimittel" 2. Aufl. (1961), page 9, d-2,2-diphenyl-3-methyl-4-morpholino-butyryl-pyrrolidine ("Dextromoramide") has a prominent analgesic effect. However, it has been shown that this compound is affected by the same disadvantage as opium alkaloids (morphine, codeine etc), namely that its use is associated with the risk of drug addiction.

I overensstemmelse med oppfinnelsen fremstilles pyrro-lidinf orbindelser som tilsvarer den foran angitte generelle formel ved å oppvarme et 4-pyrrolidinderivat med den generelle formel: In accordance with the invention, pyrrolidine derivatives corresponding to the above general formula are prepared by heating a 4-pyrrolidine derivative with the general formula:

i hvilken Z betegner hydrogen eller radikalet -CQNH^»mens R, R^og R3har de foran angitte betydninger, med en alkalisk katalysator. in which Z denotes hydrogen or the radical -CQNH^» while R, R^ and R 3 have the above meanings, with an alkaline catalyst.

Som alkaliske katalysatorer kan der anvendes alkali-metallhydroxyder, alkaliaetallalkoholater eller alkalimetaller. Alkali metal hydroxides, alkali metal alcoholates or alkali metals can be used as alkaline catalysts.

Reaksjonen utfdres hensiktsmessig i et hdytkokende organisk oppldsningsmiddel (kokepunkt 150°C eller hoyere) somdiethylen- glycol, octylalkohol, triethanolamin, ethere av diethylenglycol eller lignende. Laverekokende organiske opplbsningsmidler som ethanol og n-propanol kan også anvendes, men reaksjonstemperaturen nødvendig-gjor da anvendelse av et lukket kar. Reaksjonen utfores ved en temperatur fra 150 til 210°C. The reaction is suitably carried out in a high-boiling organic solvent (boiling point 150°C or higher) such as diethylene glycol, octyl alcohol, triethanolamine, ethers of diethylene glycol or the like. Low-boiling organic solvents such as ethanol and n-propanol can also be used, but the reaction temperature necessitates the use of a closed vessel. The reaction is carried out at a temperature from 150 to 210°C.

Om bnskes kan hydrazon- eller semicarbazonutgangsmate-rialene dannes in situ fra hydrazin eller, semicarbazid og den tilsvarende 4-ketopyrrolidinforbindelse. If desired, the hydrazone or semicarbazone starting materials can be formed in situ from hydrazine or, semicarbazide and the corresponding 4-ketopyrrolidine compound.

En annen modifikasjon omfatter enkel oppvarmning av Another modification involves simple heating of

en blanding av 4-ketopyrrolidinforbindelsen, hydrazinet og den alkaliske katalysator til reaksjonstemperaturen, fremfor forst å anvende en lavere temperatur for å danne hydrazonet og derpå den hoye reaksjonstemperatur. a mixture of the 4-ketopyrrolidine compound, the hydrazine and the alkaline catalyst to the reaction temperature, rather than first using a lower temperature to form the hydrazone and then the high reaction temperature.

De 4-ketopyrrolidinforbindelser og deres hydrazon- og semicarbazonderivater som anvendes som utgangsmaterialer i den ovenfor beskrevne fremgangsmåte, kan fremstilles ved å omsette de tilsvarende 2,4-pyrrolidin-dioner med ethylenglycol, redusere 2-keto-gruppen i de herved erholdte kondensasjonsprodukter med lithiumaluminiumhydrid og hydrolysere reduksjonsproduktet med mineralsyre. Hydrazonet kan fremstilles fra 4-ketopyrrolidin ved omsetning med hydrazin, og semicarbazonet kan fremstilles ved omsetning av 4-keto-pyr.rolidin med semicarbazid. The 4-ketopyrrolidine compounds and their hydrazone and semicarbazone derivatives, which are used as starting materials in the process described above, can be prepared by reacting the corresponding 2,4-pyrrolidine-diones with ethylene glycol, reducing the 2-keto group in the condensation products obtained thereby with lithium aluminum hydride and hydrolyzing the reduction product with mineral acid. The hydrazone can be prepared from 4-ketopyrrolidine by reaction with hydrazine, and the semicarbazone can be prepared by reaction of 4-ketopyrrolidine with semicarbazide.

I fremgangsmåten ifolge oppfinnelsen kan utgangsmate-rialene anvendes i form av et racemat eller som én av de optisk aktive modifikasjoner. I de tilfelle hvor man onsker å få optisk aktive forbindelser, kan dette oppnåes enten ved å anvende optisk aktive utgangsmaterialer eller ved å anvende optisk inaktive utgangsmaterialer og derpå oppdele de herved erholdte pyrrolidinforbindelser i de optisk aktive komponenter ved fraksjonert krystallisasjon av et salt av forbindelsen med en optisk aktiv syre. Nogen eksempler på de optisk aktive syrer som kan anvendes for dette formål, er d-vinsyre, dibenzoyl-d-vinsyre, d-camfersulfonsyre, d-raandelsyre, di-p-toluoyl-d-vinsyre og dé tilsvarende 1-isomere. Saltdannelsen og den fraksjonerte krystallisasjon av de optisk isomere utfores fortrinnsvis i en lavere alifatisk alkohol som isopropanol, absolutt ethanol eller lignende. Efter adskillelsen av pyrrolidinsaltene med en optisk aktiv syre kan hvert av saltene separat behandles med et alkalisk stoff som et alkalimetallhydroxyd, jordalkalimetallhydroxyd, alkalimetallkarbonat, alkalimetallalkoholat, ammoniakk, alkalimetall- In the method according to the invention, the starting materials can be used in the form of a racemate or as one of the optically active modifications. In cases where it is desired to obtain optically active compounds, this can be achieved either by using optically active starting materials or by using optically inactive starting materials and then dividing the pyrrolidine compounds thus obtained into the optically active components by fractional crystallization of a salt of the compound with an optically active acid. Some examples of the optically active acids that can be used for this purpose are d-tartaric acid, dibenzoyl-d-tartaric acid, d-camphorsulfonic acid, d-raandelic acid, di-p-toluoyl-d-tartaric acid and the corresponding 1-isomers. The salt formation and the fractional crystallization of the optical isomers are preferably carried out in a lower aliphatic alcohol such as isopropanol, absolute ethanol or the like. After the separation of the pyrrolidine salts with an optically active acid, each of the salts can be separately treated with an alkaline substance such as an alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkali metal alcoholate, ammonia, alkali metal

bikarbonat eller et organisk tertiært amin for å få de enkelte op- bicarbonate or an organic tertiary amine to obtain the individual op-

tiske isomere som pyrrolidinforbindelsen i form av fri base. tical isomers such as the pyrrolidine compound in the form of a free base.

I det folgende beskrives som eksempler nogen utforel- In the following, some details are described as examples

sesformer for oppfinnelsen. embodiments of the invention.

Eksempel 1 Example 1

149 g 1,5 dimethyl-3-(m-methoxyfenyl)-3-propyl-4-pyrrolidonhydrokloridet i en liten mengde vann tilsettes til 250 g kaliumhydroxyd, 150 ml 85 % hydrazinhydrat og 1200 ml diethylen- 149 g of the 1,5 dimethyl-3-(m-methoxyphenyl)-3-propyl-4-pyrrolidone hydrochloride in a small amount of water is added to 250 g of potassium hydroxide, 150 ml of 85% hydrazine hydrate and 1200 ml of diethylene

glycol, og den erholdte blanding oppvarmes under tilbakelbpskjbling i 2 timer. Vannet fjernes ved destillasjon, og residuets temperatur heves til 200°C. Den herved erholdte blanding oppvarmes under til-bakelopskjbling i 6 timer, hvorpå den avkjbles, fortynnes-med vann og ekstraheres med ether. Etherekstraktet befries for vann, etheren fordampes og residuet destilleres i vakuum, hvorved man får det bn- glycol, and the resulting mixture is heated under reflux for 2 hours. The water is removed by distillation, and the temperature of the residue is raised to 200°C. The resulting mixture is heated under reflux for 6 hours, after which it is cooled, diluted with water and extracted with ether. The ether extract is freed from water, the ether is evaporated and the residue is distilled in a vacuum, which gives the

skede 1,5-dimethyl-3-(m-methoxyfenyl)-3-propylpyrrolidin; k.p. 114 - sheath 1,5-dimethyl-3-(m-methoxyphenyl)-3-propylpyrrolidine; k.p. 114 -

118°C/0,4 mm Hg; n^° 1,5156.. 118°C/0.4 mmHg; n^° 1.5156..

Det 1,5-dimethyl-3-(m-methoxyfenyl)-3-propyl-4-pyrro- The 1,5-dimethyl-3-(m-methoxyphenyl)-3-propyl-4-pyrro-

lidon som anvendes som utgangsmateriale i dette eksempel, kan frem- lidone, which is used as starting material in this example, can produce

stilles på folgende måte: set as follows:

184,5 g m-methoxyfenyl-acetylklorid og 40 g natrium- 184.5 g of m-methoxyphenyl-acetyl chloride and 40 g of sodium

hydroxyd i 50O ml vann tilsettes samtidig til 500 ml av en vandig N opplbsning av 103 g di-N-methylalanin og 40 g natriumhydroxyd. Reaksjonsblandingen omrbres i 1 time, hvorpå den gjbres sur overfor Kongorbdt og filtreres. Det herved erholdte N-(m-methoxyfenyl)-acetyl-N-methylalanin oppsamles, tbrres og opplbses i 750 ml abso- ' lutt methanol. Oppløsningen tilsettes 1 ml konsentrert saltsyre, hydroxide in 500 ml of water is added simultaneously to 500 ml of an aqueous N solution of 103 g of di-N-methylalanine and 40 g of sodium hydroxide. The reaction mixture is stirred for 1 hour, after which it is acidified with Kongorbdt and filtered. The N-(m-methoxyphenyl)-acetyl-N-methylalanine thus obtained is collected, filtered and dissolved in 750 ml of absolute methanol. 1 ml of concentrated hydrochloric acid is added to the solution,

hvorpå,man lar blandingen stå ved romtemperatur i 72 timer. Den nøytraliseres så med fast natriumkarbonat, inndampes til et volum på ca., 400 ml og tilsettes 400 ml vann. Den herved erholdte methyl- whereupon the mixture is allowed to stand at room temperature for 72 hours. It is then neutralized with solid sodium carbonate, evaporated to a volume of approx. 400 ml and 400 ml of water is added. The thereby obtained methyl-

ester av N-(m-methoxyfenyl)-acetyl-N-methylalanin oppsamles og tbrres. 132,5 g av esteren opplbses i 600 ml toluen. Oppløsningen tilsettes 27 g natriummethylat>■ den omrbres og oppvarmes inntil de- i stillatets temperatur når 75°C. Reaksj onsblandingen avkjbles sa, det faste stoff oppsamles og opplbses i vann. Den vandige opplbs- ester of N-(m-methoxyphenyl)-acetyl-N-methylalanine is collected and filtered. 132.5 g of the ester are dissolved in 600 ml of toluene. 27 g of sodium methylate are added to the solution, it is stirred and heated until the temperature of the scaffold reaches 75°C. The reaction mixture is then cooled, the solid is collected and dissolved in water. The aqueous solution

ning tilsettes 6 N saltsyre, og det erholdte 1,5-dimethyl-3-(m-methoxyfenyl)-2,4-pyrrolidin-dion oppsamles og omkrystalliseres fra methanol. 58,2 g av dionet opplbses i 50 ral dimethylforraamid, og opplbsningen tilsettes langsomt og under omrøring til 6,4 g natrium-hydrid i 150 ml dimethylformamid. 40 g av propylbromid tilsettes 6 N hydrochloric acid is added, and the 1,5-dimethyl-3-(m-methoxyphenyl)-2,4-pyrrolidinedione obtained is collected and recrystallized from methanol. 58.2 g of the dione is dissolved in 50 ral of dimethylformamide, and the solution is added slowly and with stirring to 6.4 g of sodium hydride in 150 ml of dimethylformamide. 40 g of propyl bromide are added

derpå porsjonsvis til blandingen under omroring, og den oppvarmes til 80°C i 4 timer. Reaksjonsblandingen filtreres derpå, filtratet avkjbles og fortynnes med sitt eget volum vann. Det herved erholdte 1,5-dimethyl-3-(m-methoxyfenyl)-3-propyl-2,4-pyrrolidin-dion oppsamles, vaskes med vann. 276 g 1,5-dimethyl-3-(m-methoxyfenyl)-3-propyl-2,4-pyrrolidin-dion og 70 g ethylenglycol opplbses i 600 ml benzen. 3 g p-toluensulfonsyre tilsettes til blandingen, og den then portionwise to the mixture while stirring, and it is heated to 80°C for 4 hours. The reaction mixture is then filtered, the filtrate is cooled and diluted with its own volume of water. The 1,5-dimethyl-3-(m-methoxyphenyl)-3-propyl-2,4-pyrrolidinedione thus obtained is collected and washed with water. 276 g of 1,5-dimethyl-3-(m-methoxyphenyl)-3-propyl-2,4-pyrrolidine-dione and 70 g of ethylene glycol are dissolved in 600 ml of benzene. 3 g of p-toluenesulfonic acid is added to the mixture, and it

oppvarmes under tilbakelbpskjbling under anvendelse av en vannutskil-ler inntil ytterligere mengder vann ikke skiller sig ut. Blandingen vaskes så med fortynnet natriurabikarbonatopplbsning, og det organiske skikt som inneholder ketalet i form av råprodukt, befries for vann. Denne opplbsning inneholdende ketalet tilsettes derpå dråpe-vis og under omroring til 38 g lithiumaluminiumhydrid i 2 liter torr ether, og den erholdte blanding oppvarmes under tilbakelbpskjbling i 6 timer. Den tilsettes derpå 40 ml vann, derefter 30 ml 20 %' s natriumhydroxydopplbsning og sluttelig 140 ml vann. Derpå filtreres reaksjonsblandingen, og filtratet inndampes til tbrrhet i vakuum. is heated under reflux using a water separator until further amounts of water do not separate. The mixture is then washed with dilute sodium bicarbonate solution, and the organic layer containing the ketal in the form of crude product is freed from water. This solution containing the ketal is then added dropwise and with stirring to 38 g of lithium aluminum hydride in 2 liters of dry ether, and the resulting mixture is heated under reflux for 6 hours. It is then added to 40 ml of water, then 30 ml of 20% sodium hydroxide solution and finally 140 ml of water. The reaction mixture is then filtered, and the filtrate is evaporated to dryness in vacuo.

Residuet taes opp i 600 ml vann som inneholder lOO ml konsentrert saltsyre, og den erholdte opplbsning oppvarmes under tilbakelbpskjbling i 6 timer. Den inndampes derpå til tbrrhet i vakuum, hvorved man får det bnskede 1,5-dimethyl-3-(m-methoxyfenyl)-3-propyl-4-pyrrolidonhydroklorid. The residue is taken up in 600 ml of water containing 100 ml of concentrated hydrochloric acid, and the solution obtained is heated under reflux for 6 hours. It is then evaporated to dryness in vacuo, whereby the desired 1,5-dimethyl-3-(m-methoxyphenyl)-3-propyl-4-pyrrolidone hydrochloride is obtained.

Eksempel 2 Example 2

En opplbsning av 5,0 g l-methyl-3-(m-methoxyfenyl)-3-propylpyrrolidin (ikke oppdelt i de optisk isomere) i 70 ml varm isopropanol blandes med en opplbsning av 9,0 g (-)-di-p-toluoyl-L-(+)-vinsyre i 70 ml varm isopropanol. Ved avkjbling av blandingen får man (-)-di-p-toluoyl-L-(+)-tartratet av (-)-l-methyl-3-(m-methoxyfenyl)-3-propyipyrrolidin, sm.p. 134°C efter to omkrystalli-sasjoner fra isopropanol. [a]D » -90°. En opplbsning av 5,35 g av dette optisk aktive tartrat gjbres alkalisk med vandig natrinm-hydroxyd, og oppIbsningen ekstraheres derpå med fire 25 ml porsjo-ner ether. Etherekstraktene blandes og befries for vann, etheren avdestilleres, og residuet destilleres under forminsket trykk, hvor-• ved man får det bnskede (-)-l-aethyl-3-(m-methoxyfenyl)-3-propyl-pyrrolidin, k.p. 120°C/l mm Hg, [ajp<1>'<5>-19,8°. A solution of 5.0 g of 1-methyl-3-(m-methoxyphenyl)-3-propylpyrrolidine (not separated into the optical isomers) in 70 ml of hot isopropanol is mixed with a solution of 9.0 g of (-)-di- p-toluoyl-L-(+)-tartaric acid in 70 ml of hot isopropanol. When the mixture is cooled, the (-)-di-p-toluoyl-L-(+)-tartrate of (-)-l-methyl-3-(m-methoxyphenyl)-3-propypyrrolidine is obtained, m.p. 134°C after two recrystallizations from isopropanol. [a]D » -90°. A solution of 5.35 g of this optically active tartrate is made alkaline with aqueous sodium hydroxide, and the solution is then extracted with four 25 ml portions of ether. The ether extracts are mixed and freed from water, the ether is distilled off, and the residue is distilled under reduced pressure, whereby the desired (-)-1-ethyl-3-(m-methoxyphenyl)-3-propyl-pyrrolidine is obtained, b.p. 120°C/l mm Hg, [ajp<1>'<5>-19.8°.

De isopropanol-moderluter fra hvilke tartratet av den venstredreiende isomer er utskilt, inndampes til tørrhet, residuet taes opp i vann og den erholdte opplbsning gjbres alkalisk med vandig natriumhydroxydopplbsning. Opplbsningen ekstraheres derpå med ether, etheren fordampes, og det oljeaktige stoff man får som residuum, opplbses i isopropanol. Opplbsningen tilsettes (+)-di-p-toluoyl-D-(-)-vinsyre i isopropanol, og det herved erholdte (+)-di-p-toluoyl-D-(-)-tartrat av (+)-l-methyl-3-(m-methoxyfenyl)-3-propylpyrrolidin oppsamles og renses ved omkrystallisasjon fra isopropanol. Forbindelsens smeltepunkt er 134°e, [alD +89,7°. Ved overforing til den frie base, således som beskrevet ovenfor i forbindelse med den venstredreiende isomer, får man (+)-l-methyl-3-(m-methoxyfenyl)-3-propylpyrrolidin, k.p. 120°C/0,9^ mm Hg, The isopropanol mother liquors from which the tartrate of the levorotatory isomer is separated are evaporated to dryness, the residue is taken up in water and the solution obtained is rendered alkaline with aqueous sodium hydroxide solution. The solution is then extracted with ether, the ether is evaporated, and the oily substance obtained as a residue is dissolved in isopropanol. (+)-di-p-toluoyl-D-(-)-tartaric acid in isopropanol is added to the solution, and the thereby obtained (+)-di-p-toluoyl-D-(-)-tartrate of (+)-l- methyl-3-(m-methoxyphenyl)-3-propylpyrrolidine is collected and purified by recrystallization from isopropanol. The compound's melting point is 134°e, [alD +89.7°. On transfer to the free base, as described above in connection with the levorotatory isomer, one obtains (+)-1-methyl-3-(m-methoxyphenyl)-3-propylpyrrolidine, b.p. 120°C/0.9^ mm Hg,

[ all6 +16>5°'[ all6 +16>5°'

Claims

Process for the preparation of new, therapeutically active, optically active or racemic pyrrolidine compounds of the general formula:

in which R denotes a lower alkyl radical, R.^ denotes an alkyl radical with from 2 to 4 carbon atoms and R^ denotes hydrogen or an alkyl radical with 1 or 2 carbon atoms, or of acid addition salts of such compounds, characterized in that an optically active or racemic 4- pyrrolidone defivate with the general formula:

in which Z denotes hydrogen or the group CONH2, while R, R^ and have the meanings given above, is heated with an alkaline catalyst to a temperature between 150 and 210°C, whereupon, if necessary, the obtained pyrrolidine compound is transferred to an acid addition salt by reaction with an acid, whereby, if desired, a formed racemic compound is resolved into its optically active isomers over an acid addition salt with an optically active organic acid.