NO902688L

NO902688L - PROCEDURE AND COMPOUND USED TO DISSOLVE 1-METHYL-3-PHENYL PROPYLAMINE.

Info

Publication number: NO902688L
Application number: NO90902688A
Authority: NO
Inventors: Ernst Vogel
Original assignee: Schering Corp
Priority date: 1987-12-18
Filing date: 1990-06-15
Publication date: 1990-06-15
Also published as: NO902688D0

Description

55636-HS 55636-HS

Oppfinnelsens bakgrunn The background of the invention

Dilevalol, 5-[(R) -l-hydroksy-2-[(R)-(l-metyl-3-fenyl-propyl)amino]etyl]salisylamid, er et nylig utviklet antihyper-tensivt middel. Det er en forbindelse med to asymmetriske sentre, og følgelig er dens kjemiske syntese kompleks. Dilevalol, 5-[(R)-1-hydroxy-2-[(R)-(1-methyl-3-phenyl-propyl)amino]ethyl]salicylamide, is a recently developed antihypertensive agent. It is a compound with two asymmetric centers, and consequently its chemical synthesis is complex.

Forskjellige fremgangsmåter er blitt beskrevet for fremstilling av dilevalol, se f.eks. US patentskrifter nr. 4.658.060 og 4.619.919, og Gold et al., J. Med. Chem. 1982, 25, 1363-1370. Det ville være svært ønskelig dersom dilevalol kunne fremstilles økonomisk og ved høy renhet fra dens enantiomeriske forløpere. Various methods have been described for the production of dilevalol, see e.g. US Patent Nos. 4,658,060 and 4,619,919, and Gold et al., J. Med. Chem. 1982, 25, 1363-1370. It would be highly desirable if dilevalol could be prepared economically and at high purity from its enantiomeric precursors.

En forløper som er foreslått for syntesen av dilevalol, er (R)-l-metyl-3-fenylpropylamin ((R)-MPPA), ettersom denne forbindelse inneholder ett av de to chirale sentrene til di-levalolmolekylet. Forbindelsen må imidlertid være tilgjengelig som en enkelt enantiomer med høy enantiomerisk renhet. Ettersom racemisk l-metyl-3-fenylpropylamin er kommersielt tilgjengelig i stor skala, ville det også være svært ønskelig å ha en enkel oppløsningsprosess som effektivt gir (R)-MPPA i slik renhet fra racematet. A precursor proposed for the synthesis of dilevalol is (R)-1-methyl-3-phenylpropylamine ((R)-MPPA), as this compound contains one of the two chiral centers of the dilevalol molecule. However, the compound must be available as a single enantiomer with high enantiomeric purity. As racemic l-methyl-3-phenylpropylamine is commercially available on a large scale, it would also be highly desirable to have a simple resolution process that effectively yields (R)-MPPA in such purity from the racemate.

En fremgangsmåte brukt til oppløsning av aminer er krystalliseringen av det racemiske amin med en optisk aktiv syre til to diastereomere salter, hvorav ett er forholdsvis uoppløselig. To oppløsningsfremgangsmåter av denne type er beskrevet i litteraturen i forbindelse med l-metyl-3-fenyl-propylamin. Ved den første fremgangsmåte, van Dijk et al. i Reel. Trav. Chim. Pays- Bas, 82, 189 (1963), foreslås det å la racemisk l-metyl-3-fenylpropylamin utkrystallisere som D(-)-mandelsyresaltet under anvendelse av etanol som oppløsnings-middel. Etter flere rekrystalliseringer fås rent (S)-l-metyl-3-fenylpropylamin-D-mandelat-salt, og urent (R)-l-metyl-3-fenylpropylamin-D-mandelat fås i lavt utbytte fra modervæskene. Det er således (S)-MPPA-en som utfelles selektivt og isolerbar i ren form, mens (R)-MPPA-en forblir i modervæsken og er mye vanskeligere å rense. A method used for dissolving amines is the crystallization of the racemic amine with an optically active acid into two diastereomeric salts, one of which is relatively insoluble. Two dissolution methods of this type are described in the literature in connection with 1-methyl-3-phenyl-propylamine. In the first approach, van Dijk et al. in Reel. Trot. Chim. Pays-Bas, 82, 189 (1963), it is proposed to let racemic 1-methyl-3-phenylpropylamine crystallize out as the D(-)-mandelic acid salt using ethanol as solvent. After several recrystallizations, pure (S)-1-methyl-3-phenylpropylamine-D-mandelate salt is obtained, and impure (R)-1-methyl-3-phenylpropylamine-D-mandelate is obtained in low yield from the mother liquors. It is thus the (S)-MPPA that precipitates selectively and can be isolated in pure form, while the (R)-MPPA remains in the mother liquor and is much more difficult to purify.

Ved den andre fremgangsmåten, beskrevet av Cervinka et al. i Coll. Czech. Chem. Commun., 33, 3551 (1968), anvendes L- vinsyre i oppløsningen av l-metyl-3-fenylpropylamin. Etter én utkrystallisering av aminhydrogentartratet fra etanol ble det hevdet å være isolert enantiomerisk urent (R)-MPPA-amin etter frigjøring. Når denne fremgangsmåten ble gjentatt av søkeren, ble imidlertid rent (S)-MPPA-hydrogentartrat (ikke (R)) isolert etter tre rekrystalliseringer. In the second method, described by Cervinka et al. in Coll. Czech. Chem. Commun., 33, 3551 (1968), L-tartaric acid is used in the solution of 1-methyl-3-phenylpropylamine. After one crystallization of the amine hydrogen tartrate from ethanol, enantiomerically impure (R)-MPPA-amine was claimed to be isolated after liberation. However, when this procedure was repeated by the applicant, pure (S)-MPPA hydrogen tartrate (not (R)) was isolated after three recrystallizations.

Begge litteraturfremgangsmåtene har derfor den betyde-lige ulempe ved å gi den uønskede S-isomer som det krystall-inske salt. Rensing av (R)-MPPA-salt fra modervæsken til mer enn 95 % rent (R)-MPPA er en langvarig fremgangsmåte som gir lavt utbytte, og som ikke er godt egnet for en stor skala-produksjon. Selv om problemet kan løses ved å bruke unaturlig D-vinsyre som en oppløsende syre, er en syre kostbar, spesielt i stor skala, og gjenvinning er vanskelig. Both literature methods therefore have the significant disadvantage of giving the unwanted S-isomer as the crystalline salt. Purification of (R)-MPPA salt from the mother liquor to more than 95% pure (R)-MPPA is a long-term process that gives a low yield and is not well suited for large-scale production. Although the problem can be solved by using unnatural D-tartaric acid as a dissolving acid, an acid is expensive, especially on a large scale, and recovery is difficult.

Oppsummering av oppfinnelsenSummary of the invention

Det er nå uventet blitt funnet at høye utbytter av (R)-l-metyl-3-fenylpropylamin i høy renhet kan fremstilles fra en blanding som inneholder forbindelsen sammen med (S)-l-metyl-3-fenylpropylamin ved å bringe en oppløsning av forbindelsene eller deres oppløselige salter i kontakt med en effektiv mengde av en forbindelse med formel I It has now unexpectedly been found that high yields of (R)-1-methyl-3-phenylpropylamine in high purity can be prepared from a mixture containing the compound together with (S)-1-methyl-3-phenylpropylamine by bringing a solution of the compounds or their soluble salts in contact with an effective amount of a compound of formula I

hvorved det dannes et salt med formel II whereby a salt of formula II is formed

som selektivt utfelles fra oppløsningen; hvor R er -COR"'", which is selectively precipitated from solution; where R is -COR"'",

-CONR2R<3>eller -S02R<4>; R<1>er H, alkyl, substituert alkyl, alkoksy, substituert alkoksy, allyloksy, fenyl, substituert fenyl, fenyloksy, substituert fenyloksy, benzyl, substituert benzyl, benzyloksy, substituert benzyloksy eller 2-furanyl-2 3 metoksy; R og R kan være like eller forskjellige og er hver uavhengig av hverandre valgt blant H, alkyl, substituert alkyl, fenyl, substituert fenyl, benzyl og substituert benzyl; og R<4>er alkyl, substituert alkyl, fenyl, substituert fenyl, benzyl eller substituert benzyl. Denne fremgangsmåte gir en rekke forskjellige fordeler. Det kan anvendes felles polare oppløsningsmidler, slik som lavere alkylalkoholer, f.eks. etanol, lavere alkylketoner, f.eks. aceton, og/eller vann. (S)-MPPA-en, som utskilles i modervæsken, racemiseres lett og kan således resirkuleres for ytterligere fremstilling av (R)-MPPA. Dessuten lar forbindelsen med formel I seg lett avspalte fra saltet med formel II og kan også resirkuleres for ytterligere anvendelse ved fremstillingen av (R)-MPPA. Totalt oppnås en effektiv, økonomisk fremgangsmåte for fremstilling av (R)-MPPA med høy renhet, som så likeledes kan anvendes til å fremstille dilevalol med høy renhet. -CONR2R<3>or -SO2R<4>; R<1> is H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, allyloxy, phenyl, substituted phenyl, phenyloxy, substituted phenyloxy, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy or 2-furanyl-2-3-methoxy; R and R may be the same or different and are each independently selected from H, alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; and R<4> is alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl. This approach offers a number of different advantages. Common polar solvents can be used, such as lower alkyl alcohols, e.g. ethanol, lower alkyl ketones, e.g. acetone, and/or water. The (S)-MPPA, which is secreted in the mother liquor, is easily racemized and can thus be recycled for further production of (R)-MPPA. Moreover, the compound of formula I can be easily separated from the salt of formula II and can also be recycled for further use in the production of (R)-MPPA. Overall, an efficient, economical process for the production of (R)-MPPA with high purity is achieved, which can also be used to produce dilevalol with high purity.

Ved en foretrukket utførelsesform av oppfinnelsen utføres fremgangsmåten med en forbindelse med formel Ia eller Ib: N-formyl-L-fenylalanin er særlig foretrukket. Denne forbindelsen fremstilles lett; den gir et N-formyl-L-fenylalanin/(R)-MPPA-salt med høy enantiomerisk renhet ved to rekrystalliseringer, og et høyt utbytte over 70 % basert på tilgjengelig (R)-MPPA; vann kan anvendes som rekrystalliseringsoppløsnings-midlet, og dette er økonomisk svært fordelaktig; og N-formyl- In a preferred embodiment of the invention, the method is carried out with a compound of formula Ia or Ib: N-formyl-L-phenylalanine is particularly preferred. This compound is easily prepared; it gives an N-formyl-L-phenylalanine/(R)-MPPA salt of high enantiomeric purity by two recrystallizations, and a high yield above 70% based on available (R)-MPPA; water can be used as the recrystallization solvent, and this is economically very advantageous; and N-formyl-

L-fenylalanin utvinnes lett i over 90 % utbytte ved hjelp av alkalisk spalting av saltet, ekstraksjon av (R)-MPPA-en fra den alkaliske fase og surgjøring av den alkaliske fase. N-formyl-L-fenylalanin er kjemisk og optisk stabilt i opp-løsninger ved en pH fra 2 til 12. Oppfinnelsen omfatter også forbindelser med formel II hvor R er som definert ovenfor. De foretrukne forbindelser med formel II er: L-phenylalanine is easily recovered in over 90% yield by alkaline cleavage of the salt, extraction of the (R)-MPPA from the alkaline phase and acidification of the alkaline phase. N-formyl-L-phenylalanine is chemically and optically stable in solutions at a pH from 2 to 12. The invention also includes compounds of formula II where R is as defined above. The preferred compounds of formula II are:

Nærmere beskrivelse av oppfinnelsen Detailed description of the invention

Med mindre annet er angitt har de følgende uttrykk de følgende betydninger: alkyl (inkludert alkyldelene i substituert alkyl, alkoksy, substituert alkoksy, alkanol, alkylketon etc): en rett eller forgrenet karbonkjede som inneholder fra 1 til 6 karbonatomer; Unless otherwise indicated, the following terms have the following meanings: alkyl (including the alkyl moieties of substituted alkyl, alkoxy, substituted alkoxy, alkanol, alkyl ketone etc): a straight or branched carbon chain containing from 1 to 6 carbon atoms;

substituert alkyl (inkludert den substituerte alkyldel i substituert alkoksy): en alkylgruppe hvor minst ett H-atom er erstattet med et fluor-, klor- eller bromatom; og substituert fenyl og substituert benzyl (inkludert de substituerte fenyl- og substituerte benzyldelene i substituert fenyloksy og substituert benzyloksy): en fenyl- eller benzylgruppe hvorpå minst ett H-atom i fenylringen er erstattet med fluor, klor, brom, nitro, alkyl eller alkoksy. substituted alkyl (including the substituted alkyl part of substituted alkoxy): an alkyl group in which at least one H atom is replaced by a fluorine, chlorine or bromine atom; and substituted phenyl and substituted benzyl (including the substituted phenyl and substituted benzyl moieties in substituted phenyloxy and substituted benzyloxy): a phenyl or benzyl group on which at least one H atom in the phenyl ring has been replaced by fluorine, chlorine, bromine, nitro, alkyl or alkoxy .

Egnede COR<1>-grupper omfatter CHO, COCHg, COCH2C<H>3, COCH2CH2CH3, C0CH2C1, C0CHC12, COCClg, COCF3, COPh (Ph = fenyl), CO-(p-N02Ph), (CO)OCH3, (CO)OCH2<C>H3, (CO)OCH2C<H>2C<H>3, (CO)OCH2CH2X,■(CO)OCH2CHX2, (CO)OCH2CX3, (CO)O-allyl, (C0)0-benzyl, (CO)0-t-butyl, (CO)0(p-metoksybenzyl), (CO)0(p-nitro-benzyl), (C0)0(o-, m- eller p-X-benzyl) (hvor X er fluor, klor eller brom), og (CO)0(2-furanylmetyl). Egnede CONR 2 R 3-grupper omfatter CON<H>2, CONHCH3,CON(CH3)2, CON(CH2CH3)2og CONH(t-butyl). Egnede S<0>2R<4->grupper omfatter S02C<H>3, S<0>2C<H>2C<H>3, S02CH2C<H>2C<H>3, S02Ph og S02(p-tolyl). Suitable COR<1> groups include CHO, COCHg, COCH2C<H>3, COCH2CH2CH3, C0CH2C1, C0CHC12, COCClg, COCF3, COPh (Ph = phenyl), CO-(p-NO2Ph), (CO)OCH3, (CO )OCH2<C>H3, (CO)OCH2C<H>2C<H>3, (CO)OCH2CH2X,■(CO)OCH2CHX2, (CO)OCH2CX3, (CO)O-allyl, (C0)O-benzyl, (CO)0-t-butyl, (CO)0(p-methoxybenzyl), (CO)0(p-nitro-benzyl), (C0)0(o-, m- or p-X-benzyl) (where X is fluorine, chlorine or bromine), and (CO)O(2-furanylmethyl). Suitable CONR 2 R 3 groups include CON<H>2, CONHCH3, CON(CH3)2, CON(CH2CH3)2 and CONH(t-butyl). Suitable S<0>2R<4->groups include SO2C<H>3, S<0>2C<H>2C<H>3, SO2CH2C<H>2C<H>3, SO2Ph and SO2(p-tolyl) .

Forbindelsene med formel I er enten kjente stoffer eller kan fremstilles ved hjelp av fremgangsmåter som er godt kjent innen teknikken. For eksempel kan forbindelsene med formel I, hvor R er R"<*>", lages ved hjelp av velkjente acyl-eringsmetoder. The compounds of formula I are either known substances or can be prepared using methods well known in the art. For example, the compounds of formula I, where R is R"<*>", can be made using well-known acylation methods.

Ved fremgangsmåten ifølge oppfinnelsen bringes en oppløsning som inneholder en blanding, vanligvis et racemat, av (R)- og (S)-MPPA i kontakt med en effektiv mengde av en forbindelse med formel I In the method according to the invention, a solution containing a mixture, usually a racemate, of (R)- and (S)-MPPA is brought into contact with an effective amount of a compound of formula I

hvorved det dannes et selektivt uoppløselig salt med formel II hvor R er som definert ovenfor. Det anvendte oppløsningsmiddel kan være hvilket som helst vanlig polart oppløsningsmiddel som oppløser blandingen av (R)- og (S)-aminer, og fortrinnsvis thereby forming a selectively insoluble salt of formula II where R is as defined above. The solvent used can be any common polar solvent which dissolves the mixture of (R)- and (S)-amines, and preferably

også oppløser forbindelsen med formel I. Saltet med formel II er også selektivt uoppløselig i oppløsningsmidlet når det gjelder det tilsvarende (S)-MPPA-salt. Teoretisk kunne forbindelsen med formel I anvendes som en oppslemming eller suspensjon når den bringes i kontakt med oppløsningen, så lenge forbindelsen med formel II er mindre oppløselig enn forbindelsen med formel I, og tilstrekkelig tid kan fås til at likevekt kan oppnås. Egnede oppløsningsmidler omfatter f. eks. lavere (C-^-Cg)-alkanoler, slik som metanol, etanol, propanol, isopropanol etc; lavere alkyl C^-Cg)-ketoner, slik som aceton, metyletyl-keton etc; dioksan; glym (1,2-dimetoksyetan) og lignende stoffer; vann; eller én eller flere blandinger av slike opp-løsningsmidler. Foretrukne oppløsningsmidler omfatter lavere alkoholer, spesielt etanol, aceton, vann eller blandinger derav. Med N-formyl-L-fenylalanin som forbindelsen med formel I er vann det foretrukne oppløsningsmiddel, ettersom det virker svært virkningsfullt og effektivt og er svært økonomisk med færrest kasseringsproblemer. also dissolves the compound of formula I. The salt of formula II is also selectively insoluble in the solvent in the case of the corresponding (S)-MPPA salt. Theoretically, the compound of formula I could be used as a slurry or suspension when brought into contact with the solution, as long as the compound of formula II is less soluble than the compound of formula I, and sufficient time can be allowed for equilibrium to be achieved. Suitable solvents include e.g. lower (C 1 -C 8 )-alkanols, such as methanol, ethanol, propanol, isopropanol etc; lower alkyl C 1 -C 8 ) ketones, such as acetone, methyl ethyl ketone etc; dioxane; glyme (1,2-dimethoxyethane) and similar substances; water; or one or more mixtures of such solvents. Preferred solvents include lower alcohols, especially ethanol, acetone, water or mixtures thereof. With N-formyl-L-phenylalanine as the compound of formula I, water is the solvent of choice, as it works very effectively and efficiently and is very economical with the fewest disposal problems.

Når det forholdsvis uoppløselige salt med formel II dannes, kan den behandlede oppløsning varmes opp for å oppnå oppløsning av aminblandingen og forbindelse I om ønsket. Den behandlede oppløsning avkjøles normalt til en temperatur hvor det kan oppnås selektiv separasjon av fast forbindelse med formel II, vanligvis for å maksimalisere utskillelse og utbytte. Fortrinnsvis avkjøles oppløsningen sakte for å øke oppløsningen av aminsaltene. Den valgte sluttemperatur vil avhenge av forbindelsen med formel I og oppløsningsmiddel-system som anvendes. When the relatively insoluble salt of formula II is formed, the treated solution can be heated to achieve dissolution of the amine mixture and compound I if desired. The treated solution is normally cooled to a temperature where selective separation of solid compound of formula II can be achieved, usually to maximize separation and yield. Preferably, the solution is cooled slowly to increase the dissolution of the amine salts. The final temperature chosen will depend on the compound of formula I and the solvent system used.

Forbindelsen med formel I anvendes i en mengde som kan gi den ønskede faste form av forbindelsen med formel II, slik at den selektivt kan utfelles fra dens tilsvarende (S)-MPPA-salt. Fortrinnsvis anvendes det fra ca. 0,3 til ca. 1,5 ekvivalenter, helst fra ca. 0,5 til ca. 1,0 ekvivalenter, av forbindelsen med formel I. Det kan imidlertid anvendes mer eller mindre forbindelse med formel I om ønsket. Andre syrer, inkludert organiske syrer, f.eks. eddiksyre, eller uorganiske syrer, kan også anvendes ved fremgangsmåten ifølge oppfinnelsen for å nøytralisere de gjenværende aminer i blandingen, f.eks. (S)-MPPA, idet slikt nøytralisert amin er oppløselig og således lar seg skille fra den utfelte forbindelse med formel II. The compound of formula I is used in an amount which can give the desired solid form of the compound of formula II, so that it can be selectively precipitated from its corresponding (S)-MPPA salt. Preferably, it is used from approx. 0.3 to approx. 1.5 equivalents, preferably from approx. 0.5 to approx. 1.0 equivalents of the compound of formula I. However, more or less compound of formula I can be used if desired. Other acids, including organic acids, e.g. Acetic acid, or inorganic acids, can also be used in the method according to the invention to neutralize the remaining amines in the mixture, e.g. (S)-MPPA, as such neutralized amine is soluble and thus can be separated from the precipitated compound of formula II.

Separasjonen av forbindelsen med formel II kan utføres ved hjelp av hvilken som helst egnet måte for separering av faste stoffer fra væsker, f.eks. filtrering, dekantering, sentrifugering etc Filtrering er foretrukket. The separation of the compound of formula II can be carried out by any suitable means for separating solids from liquids, e.g. filtration, decantation, centrifugation etc. Filtration is preferred.

Materialet som skilles fra modervæsken, kan rekrystal-liseres på vanlig måte i det samme eller lignende oppløsnings-middelsystem. For eksempel kan, ved en utførelsesform av oppfinnelsen, en blanding av 1 ekvivalent racemisk l-metyl-3-fenylpropylamin med 0,5-1 ekvivalent N-formyl-L-fenylalanin i 1-12 deler vann, fortrinnsvis 3-4 deler vann, oppvarmes til 50-60°C inntil en oppløsning er oppnådd. Dersom bare 0,5 ekvivalent N-formyl-L-fenylalanin anvendes, tilsettes fortrinnsvis 0,5 ekvivalent av en uorganisk eller organisk syre, slik som saltsyre, svovelsyre, maursyre eller eddiksyre. Oppløsningen avkjøles sakte og omrøres ved 20°C i 1-24 timer. Etter filtrering og vasking oppslemmes saltet med formel II i 3-10 deler vann, fortrinnsvis 3-4 deler vann, og oppvarmes til 50-60°C inntil en oppløsning er oppnådd. Oppløsningen avkjøles til 20°C og omrøres i 2-24 timer, hvorved man får en renset forbindelse med formel II i ca. 70 % utbytte. The material separated from the mother liquor can be recrystallized in the usual way in the same or similar solvent system. For example, in one embodiment of the invention, a mixture of 1 equivalent of racemic l-methyl-3-phenylpropylamine with 0.5-1 equivalent of N-formyl-L-phenylalanine in 1-12 parts water, preferably 3-4 parts water , heated to 50-60°C until a solution is obtained. If only 0.5 equivalent of N-formyl-L-phenylalanine is used, preferably 0.5 equivalent of an inorganic or organic acid, such as hydrochloric acid, sulfuric acid, formic acid or acetic acid, is added. The solution is cooled slowly and stirred at 20°C for 1-24 hours. After filtering and washing, the salt of formula II is suspended in 3-10 parts of water, preferably 3-4 parts of water, and heated to 50-60°C until a solution is obtained. The solution is cooled to 20°C and stirred for 2-24 hours, whereby a purified compound of formula II is obtained for approx. 70% yield.

Etter det ønskede antall rekrystalliseringer kan saltet med formel II spaltes ved omsetning med sterk syre eller sterk base, fortrinnsvis sterk base, ved hjelp av teknikker som er godt kjent innen faget. Ikke mer enn 1 ekvivalent base bør fortrinnsvis brukes. Egnede syrer og baser omfatter vandig HC1-, NaOH-, KOH-oppløsninger etc. For eksempel kan et N-formyl-L-fenylalaninsalt med formel II oppslemmes med 4 deler vann og pH reguleres til 12-13 med NaOH (1 ekvivalent) for å spalte saltet og danne det frie (R)-MPPA. After the desired number of recrystallizations, the salt of formula II can be cleaved by reaction with a strong acid or a strong base, preferably a strong base, using techniques well known in the art. No more than 1 equivalent base should preferably be used. Suitable acids and bases include aqueous HC1, NaOH, KOH solutions, etc. For example, an N-formyl-L-phenylalanine salt of formula II can be slurried with 4 parts water and the pH adjusted to 12-13 with NaOH (1 equivalent) for to cleave the salt and form the free (R)-MPPA.

Det frie (R)-MPPA kan behandles på vanlig måte for separasjon. For eksempel kan det frie (R)-MPPA ekstraheres med et egnet oppløsningsmiddel, f.eks. et vannblandbart oppløs-ningsmiddel, slik som metylenklorid, etylacetat, dietyleter, t-butylmetyleter, og særlig toluen. Ekstraktet kan så inn-dampes og (R)-MPPA destilleres, hvorved man får R-MPPA i høy renhet, fortrinnsvis i over 95 % enantiomerisk renhet. The free (R)-MPPA can be processed in the usual way for separation. For example, the free (R)-MPPA can be extracted with a suitable solvent, e.g. a water-miscible solvent, such as methylene chloride, ethyl acetate, diethyl ether, t-butyl methyl ether, and especially toluene. The extract can then be evaporated and (R)-MPPA distilled, thereby obtaining R-MPPA in high purity, preferably in over 95% enantiomeric purity.

Modervæskene fra krystallisasjonene inneholder (S)-MPPA i saltform. Slikt (S)-MPPA kan skilles fra modervæsken og underkastes racemisering, f.eks. ved hjelp av fremgangsmåtene beskrevet i BRD Offenlegungsschrift nr. 2.903.589. En utførel-sesf orm omfatter oppvarming av (S)-MPPA med Raney-nikkel i en ^-atmosfære. Fortrinnsvis er ^-trykket fra ca. 10 til ca. The mother liquors from the crystallizations contain (S)-MPPA in salt form. Such (S)-MPPA can be separated from the mother liquor and subjected to racemization, e.g. using the methods described in BRD Offenlegungsschrift No. 2,903,589. One embodiment comprises heating (S)-MPPA with Raney nickel in a ^-atmosphere. Preferably, the ^ pressure is from approx. 10 to approx.

500 bar, og temperaturen er fra ca. 50 til ca. 300°C. Racemi-seringen utføres fortrinnsvis i hovedsakelig fravær av opp-løsningsmiddel. Det racemiserte materiale kan så anvendes (resirkuleres) som et utgangsmateriale i fremgangsmåten ifølge oppfinnelsen. 500 bar, and the temperature is from approx. 50 to approx. 300°C. The racemization is preferably carried out in the substantial absence of solvent. The racemized material can then be used (recycled) as a starting material in the method according to the invention.

For eksempel kan modervæskene som inneholder (S)-MPPA samles opp og deres pH reguleres til pH 12-13. Det således dannede, frie (S)-MPPA kan ekstraheres med hvilket som helst egnet organisk oppløsningsmiddel, f.eks. metylenklorid, men fortrinnsvis toluen. Etter inndamping av oppløsningsmidlet fås anriket (S)-MPPA. Dette kan varmes opp med 0,02-0,1 del vann og fuktig Raney-nikkel i en autoklav i 10-20 timer ved 100-200°C og ved et trykk på 1034 kg pascal hydrogen (150 psi hydrogen) i et egnet tidsrom, vanligvis ca. 16-20 timer. Forholdsvis rent racemisk l-metyl-3-fenylpropylamin fås etter frafiltrering av katalysatoren og destillering av aminet. For example, the mother liquors containing (S)-MPPA can be collected and their pH adjusted to pH 12-13. The free (S)-MPPA thus formed can be extracted with any suitable organic solvent, e.g. methylene chloride, but preferably toluene. After evaporation of the solvent, enriched (S)-MPPA is obtained. This can be heated with 0.02-0.1 part water and moist Raney nickel in an autoclave for 10-20 hours at 100-200°C and at a pressure of 1034 kg pascal hydrogen (150 psi hydrogen) in a suitable period of time, usually approx. 16-20 hours. Relatively pure racemic 1-methyl-3-phenylpropylamine is obtained after filtering off the catalyst and distilling the amine.

Den oppløsende forbindelse med formel I utvinnes også lett for videre bruk. Ved en utførelsesform, etter at (R)-MPPA og (S)-MPPA er blitt ekstrahert som beskrevet ovenfor, kan de gjenværende væskefaser samles opp og oppkonsentreres på vanlig måte. pH kan reguleres til 2 med sterk syre, slik som HC1, og det kan avkjøles for å utfelle forbindelsen med formel I. Forbindelsen med formel I, f.eks. N-formyl-L-fenylalanin, kan så fraskilles f.eks. ved filtrering for videre bruk ved fremgangsmåten ifølge oppfinnelsen. The dissolving compound of formula I is also easily recovered for further use. In one embodiment, after (R)-MPPA and (S)-MPPA have been extracted as described above, the remaining liquid phases can be collected and concentrated in the usual way. The pH can be adjusted to 2 with a strong acid, such as HCl, and it can be cooled to precipitate the compound of formula I. The compound of formula I, e.g. N-formyl-L-phenylalanine, can then be separated e.g. by filtration for further use in the method according to the invention.

De følgende eksempler er ment å illustrere, men ikke begrense, oppfinnelsen. The following examples are intended to illustrate, but not limit, the invention.

Eksempel 1Example 1

a) Saltdannelsea) Salt formation

Til en suspensjon av 1,932 kg (10 mol) N-formyl-L-fenylalanin i 12,66 1 vann ble 1,492 kg (10 mol) (R,S)-1-metyl-3-fenylpropylamin tilsatt med en gang. Reaksjonsblandingen ble varmet opp til 60°C og den klare oppløsning avkjølt sakte inntil krystallisering startet. Suspensjonen ble avkjølt videre til 20°C og omrørt i 24 timer ved 17-22°C. Produktet ble frafiltrert og vasket med 950 ml kaldt vann. Utbytte: 2,485 kg R-MPPA/N-formyl-L-fenylalanin-salt (III), vannfuktet. To a suspension of 1.932 kg (10 mol) of N-formyl-L-phenylalanine in 12.66 L of water, 1.492 kg (10 mol) of (R,S)-1-methyl-3-phenylpropylamine was added at once. The reaction mixture was heated to 60°C and the clear solution cooled slowly until crystallization started. The suspension was further cooled to 20°C and stirred for 24 hours at 17-22°C. The product was filtered off and washed with 950 ml of cold water. Yield: 2.485 kg R-MPPA/N-formyl-L-phenylalanine salt (III), water-moistened.

Modervæsken ble oppkonsentrert til ca. 9 1 volum, og ved hjelp av saltspaltingsfremgangsmåten beskrevet nedenunder ble 741,7 g (49,7 %) anriket (S)-MPPA og 853 g (44,1 %) N-formyl-L-fenylalanin utvunnet. The mother liquor was concentrated to approx. 9 1 volume, and by means of the salt cleavage method described below, 741.7 g (49.7%) of enriched (S)-MPPA and 853 g (44.1%) of N-formyl-L-phenylalanine were recovered.

b) Rekrystalliseringb) Recrystallization

Det vannfuktede salt III (2,485 kg) fra trinn a) ble rekrystallisert fra 5,1 1 vann ved å varme opp til 60°C og avkjøle sakte til 20°C. Etter omrøring i 20 timer ved 20°C ble produktet frafiltrert, vasket med 750 ml kaldt vann og tørket i en vakuumovn ved 60°C. Utbytte: 1,34 kg (39 % basert på (R,S)-amin) hvitt R-MPPA/N-formyl-L-fenylalanin-salt (III), sm.p. 138-139°C. The water-wet salt III (2.485 kg) from step a) was recrystallized from 5.1 L of water by heating to 60°C and cooling slowly to 20°C. After stirring for 20 hours at 20°C, the product was filtered off, washed with 750 ml of cold water and dried in a vacuum oven at 60°C. Yield: 1.34 kg (39% based on (R,S)-amine) white R-MPPA/N-formyl-L-phenylalanine salt (III), m.p. 138-139°C.

Modervæsken ble oppkonsentrert til ca. 1,5 1 volum, og 147,3 g (10 %) anriket (S)-MPPA og 200,5 g (10,3 %) N-formyl-L-f enylalanin ble utvunnet. The mother liquor was concentrated to approx. 1.5 1 volume, and 147.3 g (10%) of enriched (S)-MPPA and 200.5 g (10.3%) of N-formyl-L-phenylalanine were recovered.

c) Saltspaltingc) Salt splitting

1,33 kg av saltet III ble oppslemmet i 5,16 1 vann, det ble avkjølt til 5-10°C, og pH ble regulert til 12,5-13,0 med 30 % natriumhydroksidoppløsning. Den resulterende oppløsning ble ekstrahert fire ganger med i alt 6 1 metylenklorid. Etter vasking av de sammenslåtte organiske faser med 3 1 vann ble oppløsningsmidlet avdampet under vakuum, og oljeresten ble destillert ved 50°C/0,7 mbar. 1.33 kg of the salt III was slurried in 5.16 L of water, it was cooled to 5-10°C, and the pH was adjusted to 12.5-13.0 with 30% sodium hydroxide solution. The resulting solution was extracted four times with a total of 6 L of methylene chloride. After washing the combined organic phases with 3 1 of water, the solvent was evaporated under vacuum, and the oil residue was distilled at 50°C/0.7 mbar.

Utbytte: 550 g (R)-MPPA (95 % i saltspalting; 36,8 % totalt) Yield: 550 g (R)-MPPA (95% in salt cleavage; 36.8% in total)

[a]20:-18,0° (c=5 i cykloheksan) [a]20:-18.0° (c=5 in cyclohexane)

enantiomerisk renhet: 97,3 % (R)-MPPA. enantiomeric purity: 97.3% (R)-MPPA.

d) Saltspaltingd) Salt splitting

1,00 kg av saltet III ble oppslemmet i 1,15 1 vann, det ble avkjølt til 10-15°C, og pH ble regulert til 12,5-13,0 med 30 % natriumhydroksidoppløsning (1 ekvivalent). Den resulterende oppløsning ble ekstrahert fire ganger med i alt 2,4 1 toluen ved 25-30°C. De sammenslåtte organiske faser ble vasket med 1 1 vann, oppløsningsmidlet ble inndampet under vakuum, og den oljeaktige rest ble destillert ved 50°C/0,7 mbar. 1.00 kg of the salt III was slurried in 1.15 L of water, it was cooled to 10-15°C, and the pH was adjusted to 12.5-13.0 with 30% sodium hydroxide solution (1 equivalent). The resulting solution was extracted four times with a total of 2.4 L of toluene at 25-30°C. The combined organic phases were washed with 1 1 of water, the solvent was evaporated under vacuum, and the oily residue was distilled at 50°C/0.7 mbar.

Utbytte: 406 g (R)-MPPA (93 % i saltspalting; 36,3 % totalt) Yield: 406 g (R)-MPPA (93% in salt cleavage; 36.3% overall)

[a]<20>:-18,0° (c = 5 i cykloheksan) [a]<20>:-18.0° (c = 5 in cyclohexane)

enantiomerisk renhet: 97,3 % (R)-MPPA. enantiomeric purity: 97.3% (R)-MPPA.

e) N- formyl- L- fenylalanin- utvinninge) N-formyl-L-phenylalanine extraction

Vannsjiktet fra trinn c) (eller d)) ovenfor ble etter aminekstråksjon regulert til pH 2,0 med konsentrert saltsyre. Suspensjonen ble omrørt ved 10°C i 2 timer og produktet frafiltrert, vasket med 7 1 kaldt vann og tørket under vakuum ved 60°C. The aqueous layer from step c) (or d)) above was adjusted to pH 2.0 with concentrated hydrochloric acid after amine extraction. The suspension was stirred at 10°C for 2 hours and the product filtered off, washed with 7 l of cold water and dried under vacuum at 60°C.

Utbytte: 685 g (35,5 %) N-formyl-L-fenylalanin Yield: 685 g (35.5%) of N-formyl-L-phenylalanine

sm.p.: 167°C m.p.: 167°C

enantiomerisk renhet: 99,9 % 1 enantiomeric purity: 99.9% 1

total utvinning av N-formyl-L-fenylalanin: total recovery of N-formyl-L-phenylalanine:

1738,5 g (90 %). 1738.5 g (90%).

Eksempel 2Example 2

a) Saltdannelsea) Salt formation

Til en suspensjon av 97,8 g (0,4 mol) N-metansulfonyl-L-fenylalanin i 1,1 1 aceton ble 60 g (0,4 mol) (R,S)-1-metyl-3-fenylpropylamin tilsatt. Reaksjonsblandingen ble varmet opp til koking under tilbakeløpskjøling inntil en klar oppløsning var oppnådd og så avkjølt til 20°C. Etter omrøring i 24 timer ble produktet frafiltrert, vasket og tørket under vakuum. To a suspension of 97.8 g (0.4 mol) of N-methanesulfonyl-L-phenylalanine in 1.1 1 of acetone was added 60 g (0.4 mol) of (R,S)-1-methyl-3-phenylpropylamine . The reaction mixture was heated to boiling under reflux until a clear solution was obtained and then cooled to 20°C. After stirring for 24 hours, the product was filtered off, washed and dried under vacuum.

Utbytte: 75 g (48,5 %) (R)-MPPA/N-metansulfonyl-L-fenylalanin-salt (IV). Yield: 75 g (48.5%) (R)-MPPA/N-methanesulfonyl-L-phenylalanine salt (IV).

b) Rekrystalliseringb) Recrystallization

74 g av det anrikede salt IV ble rekrystallisert fra 770 ml varm aceton. Etter avkjøling til 20°C og omrøring i 24 timer ble produktet frafiltrert, vasket og tørket under vakuum. 74 g of the enriched salt IV was recrystallized from 770 ml of hot acetone. After cooling to 20°C and stirring for 24 hours, the product was filtered off, washed and dried under vacuum.

Utbytte: 50,1 g (67,7 % ved rekrystallisering) av salt Yield: 50.1 g (67.7% on recrystallization) of salt

IV. IV.

Sm.p.: 171,5-172°C Melting point: 171.5-172°C

optisk rotasjon: [a]^w=2,9° (c = 5 i CHgOH) enantiomerisk renhet (amin): 95 % R. optical rotation: [a]^w=2.9° (c = 5 in CHgOH) enantiomeric purity (amine): 95% R.

Det frie (R)-MPPA kan fås fra saltet IV ved hjelp av den samme fremgangsmåte som beskrevet i eksempel 1 ovenfor. The free (R)-MPPA can be obtained from the salt IV using the same method as described in example 1 above.

Eksempel 3Example 3

a) Saltdannelsea) Salt formation

Til en suspensjon av 96,6 g (0,5 mol) N-formyl-L-fenylalanin i 606 ml vann ble 30,1 g (0,5 mol) eddiksyre og 149,2 g (1 mol) (R,S)-l-metyl-3-fenylpropylamin tilsatt. Reaksjonsblandingen ble varmet opp til 60°C, og den resulterende klare oppløsning ble sakte avkjølt inntil krystallisering startet. Suspensjonen ble avkjølt videre til 3°C og omrørt i 24 timer ved 0-5°C. Produktet ble filtrert fra og vasket to ganger med 45 ml kaldt vann, hvorved man fikk etter tørking ved 60°C: 150,0 g R-MPPA/N-formyl-L-fenylalanin-salt (V). To a suspension of 96.6 g (0.5 mol) N-formyl-L-phenylalanine in 606 ml water were added 30.1 g (0.5 mol) acetic acid and 149.2 g (1 mol) (R,S )-1-methyl-3-phenylpropylamine added. The reaction mixture was heated to 60°C and the resulting clear solution was slowly cooled until crystallization started. The suspension was further cooled to 3°C and stirred for 24 hours at 0-5°C. The product was filtered off and washed twice with 45 ml of cold water, whereby after drying at 60°C: 150.0 g of R-MPPA/N-formyl-L-phenylalanine salt (V) was obtained.

b) Rekrystalliseringb) Recrystallization

Saltet V (146,3 g) fra trinn a) ovenfor ble rekrystallisert fra 438 ml vann ved å varme opp til 60°C og avkjøle sakte til 3°C. Etter omrøring i 24 timer ved 0-5°C ble produktet frafiltrert, vasket to ganger med 65 ml kaldt vann og tørket i en vakuumovn ved 60°C, hvorved man fikk: 137,2 g (41 % basert på (R,S)-MPPA) hvitt R-MPPA/N-formyl-L-fenylalanin-salt (V), sm.p. 136-137°C; enantiomerisk renhet (MPPA): 96,8 % R. The salt V (146.3 g) from step a) above was recrystallized from 438 ml of water by heating to 60°C and cooling slowly to 3°C. After stirring for 24 hours at 0-5°C, the product was filtered off, washed twice with 65 ml of cold water and dried in a vacuum oven at 60°C, thereby obtaining: 137.2 g (41% based on (R,S )-MPPA) white R-MPPA/N-formyl-L-phenylalanine salt (V), m.p. 136-137°C; enantiomeric purity (MPPA): 96.8% R.

(S)-MPPA-utvinningen, saltspaltingen og N-formyl-L-fenylalanin-utvinningen kan utføres som i eksempel 1 ovenfor. The (S)-MPPA extraction, the salt cleavage and the N-formyl-L-phenylalanine extraction can be carried out as in Example 1 above.

Ved hjelp av hovedsakelig de samme utkrystalliserings-fremgangsmåter som beskrevet ovenfor, under anvendelse av de mengdene av racemisk amin (R,S-MPPA), de oppløsende syrer og oppløsningsmidlene som er angitt i de første tre spaltene i tabell 1 nedenunder, ble resultatene (utbytte og enantiomerisk renhet som % (R)-MPPA) som er angitt i de fire spaltene til høyre i tabell 1, oppnådd: Using essentially the same crystallization procedures as described above, using the amounts of racemic amine (R,S-MPPA), the dissolving acids, and the solvents indicated in the first three columns of Table 1 below, the results were ( yield and enantiomeric purity as % (R)-MPPA) which are indicated in the four columns to the right of Table 1, obtained:

Mens foreliggende oppfinnelse er blitt beskrevet i forbindelse med de bestemte utførelsesformene som er angitt ovenfor, vil mange alternativer, modifikasjoner og variasjoner derav være åpenbare for personer med gjennomsnittlig fagkunn-skap innen teknikken. Alle slike alternativer, modifikasjoner og variasjoner er ment å falle innenfor ånden og omfanget av foreliggende oppfinnelse. While the present invention has been described in connection with the particular embodiments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. Process for dissolving a mixture of (R)-1-methyl-3-phenylpropylamine and (S)-1-methyl-3-phenylpropylamine, characterized in that:A. A solution containing the compound or soluble salts thereof is contacted with an effective amount of a compound of formula I

whereby a salt of formula II is formed

which selectively precipitates from the solution; where R is -COR"<*>" , -CONR 2R<3> or -SO 2 R<4>; R<1> is H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, allyloxy, phenyl, substituted phenyl, phenyloxy, substituted phenyloxy, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy or 2-furanyl-2-3-methoxy; R and R may be the same or different and are each independently selected from H, alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; and R 4 is alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl; and B. The precipitated salt of formula II is separated from the solution; where the following definitions are used: alkyl: a straight or branched carbon chain containing from 1 to 6 carbon atoms; substituted alkyl: an alkyl group in which at least one H atom is replaced by a fluorine, chlorine or bromine atom; and substituted phenyl and substituted benzyl: a phenyl or benzyl group on which at least one H atom in the phenyl ring has been replaced by fluorine, chlorine, bromine, nitro, alkyl or alkoxy.

2. Method according to claim 1, characterized in that the solution comprises water, lower alkanols, lower alkyl ketones or mixtures thereof as solvent.

3. Method according to claim 2, characterized in that the solution comprises water, ethanol, acetone or mixtures thereof as solvent.

4. Method according to claim 1, characterized in that the amount of the compound, with formula I added to the solution is from approx. 0.3 to approx. 1.5 equivalents relative to (R)-1-methyl-3-phenylpropyl-amine.

5. Method according to claim 1, characterized in that the amount of the compound of formula I added to the solution is from approx. 0.5 to approx. 1.0 equivalents relative to (R)-1-methyl-3-phenylpropylamine.

6. Method according to claims 2, 3 or 4, characterized in that the compound of formula I is

or

7. Method according to claim 6, characterized in that the solution is an aqueous solution and the compound of formula I is

8. Method according to claim 1, characterized in that the solution brought into contact is cooled to precipitate the salt with formula II.

10. Process according to claim 1, characterized in that it further comprises treating the separated salt of formula II with acid or base to cleave the salt and give a mixture containing free (R)-1-methyl-3-phenylpropylamine or its acid addition salt and . a compound of formula I.

11. Method according to claim 10, characterized in that up to 1 equivalent base is used to cleave the salt.

12. Method according to claim 10 or claim 11, characterized in that it further comprises bringing the mixture containing free (R)-1-methyl-3-phenyl-propylamine into contact with a water-immiscible solvent which extracts free (R)-1- methyl-3-phenylpropylamine, thereby obtaining (1) an extract solution containing extracted (R)-1-methyl-3-phenylpropylamine and (2) a residual solution.

13. Method according to claim 12, characterized in that it further comprises acidifying and cooling the residual solution in order to precipitate the compound of formula I, the precipitation being separated from the residual solution.

14. Method according to claim 1, characterized in that the compound of formula I is N-formyl-L-phenylalanine.

15. Method according to claim 1, characterized in that it further comprises racemization of the (S)-1-methyl-3-phenylpropylamine in the remaining solution.

16. Method according to claim 15, characterized in that it further comprises recycling the racemized material for use in the contact with the compound of formula I.

17. Connection, characterized in that it has formula II

where R is -COR<1> , -CONR 2R<3> or -SO 2 R<4> ; R<1> is H, alkyl, substituted alkyl, alkoxy, substituted alkoxy, allyloxy, phenyl, substituted phenyl, phenyloxy, substituted phenyloxy, benzyl, substituted benzyl, benzyloxy, substituted benzyloxy or 2-furanylmethoxy; R 2 and R 3 may be the same or different and are each independently selected from H, alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; and R<4> is alkyl, substituted alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl; and where the following definitions are also used: alkyl: a straight or branched carbon chain containing from 1 to 6 carbon atoms; substituted alkyl: an alkyl group in which at least one H atom is replaced by a fluorine, chlorine or bromine atom; and substituted phenyl and substituted benzyl: a phenyl or benzyl group on which at least one H atom in the phenyl ring has been replaced by fluorine, chlorine, bromine, nitro, alkyl or alkoxy.

18. Compound according to claim 17, characterized in that R is CHO, COO-benzyl or SO2 C<H>3.

19. Compound according to claim 17, characterized in that it is

20. Compound according to claim 17, characterized in that it is