NO772745L - PROCEDURES FOR THE PREPARATION OF N-SUBSTITUTED PYRROLIDINES - Google Patents

PROCEDURES FOR THE PREPARATION OF N-SUBSTITUTED PYRROLIDINES

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Publication number
NO772745L
NO772745L NO772745A NO772745A NO772745L NO 772745 L NO772745 L NO 772745L NO 772745 A NO772745 A NO 772745A NO 772745 A NO772745 A NO 772745A NO 772745 L NO772745 L NO 772745L
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Norway
Prior art keywords
carbon atoms
pyrrolidine
radical
alkyl
stated
Prior art date
Application number
NO772745A
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Norwegian (no)
Inventor
Jean-Pierre Kaplan
Henry Najer
Daniel Charles Leon Obitz
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Synthelabo
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Publication date
Priority claimed from FR7623910A external-priority patent/FR2360572A1/en
Priority claimed from FR7635476A external-priority patent/FR2372157A1/en
Priority claimed from FR7719391A external-priority patent/FR2395261A2/en
Application filed by Synthelabo filed Critical Synthelabo
Publication of NO772745L publication Critical patent/NO772745L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

Fremgangsmåte for fremstilling avMethod of manufacture of

N-substituerte pyrrolidiner.N-substituted pyrrolidines.

Foreliggende oppfinnelse vedrører en fremgangsmåte for stereo-spesifikk fremstilling av optisk aktive N-substituerte pyrrolidiner egnet for anvendelse for fremstilling av optisk aktive benzamider som bærer en pyrrol'idinylmetyl-substituent. The present invention relates to a method for the stereo-specific production of optically active N-substituted pyrrolidines suitable for use in the production of optically active benzamides bearing a pyrrol'idinylmethyl substituent.

De N-substituerte pyrrolidiner som fremstilles ved fremgangsmåten i henhold til oppfinnelsen tilsvarer de følgende symmetriske formler I (R) og I (S): The N-substituted pyrrolidines produced by the process according to the invention correspond to the following symmetrical formulas I (R) and I (S):

hvori R står for where R stands for

- enten et alkylradikal CHgR^med 1 til 5 karbonatomer - either an alkyl radical CHgR^ with 1 to 5 carbon atoms

(R^ har 1 til 4 karbonatomer eller står for et hydrogenatom)(R^ has 1 to 4 carbon atoms or stands for a hydrogen atom)

- eller et radikal med formel- or a radical with formula

hvori A er en rettkjedet eller forgrenet alkylenkjede med 1 til 4 karbonatomer og wherein A is a straight or branched alkylene chain of 1 to 4 carbon atoms and

Rg, fijog R^står hver for seg for et hydrogenatom, et halogenatom, spesielt klor eller fluor, et trifluormetyl-radikal, trifluormetoksy, trifluor-metyltio, alkyl med 1 til 4 karbonatomer eller alkoksy med 1 til 4 karbonatomer, Rg, f and R^ each stand for a hydrogen atom, a halogen atom, especially chlorine or fluorine, a trifluoromethyl radical, trifluoromethoxy, trifluoromethylthio, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms,

- eller et radikal med formel- or a radical with formula

hvori ji er en rettkjedet eller forgrenet alkylenkjede med 1 til 4 karbonatomer og m er 2, 3, 4 eller 5. Forbindelsene med formel I er utgangssubstanser for syntese av substituerte optisk aktive benzamider med formel II in which ji is a straight or branched alkylene chain with 1 to 4 carbon atoms and m is 2, 3, 4 or 5. The compounds of formula I are starting substances for the synthesis of substituted optically active benzamides of formula II

hvori in which

R har den ovennevnte betydning og X står for et kloratom, et radikal SOjR^eller S<C>^N Rgff7thvori R^ står for et alkylradikal med 1 til 4 karbonatomer og Rg og R7, som er like eller forskjellige, står for et hydrogenatom eller et alkylradikal med 1 til 4. karbonatomer. R has the above meaning and X represents a chlorine atom, a radical SOjR^or S<C>^N Rgff7thwhere R^ represents an alkyl radical with 1 to 4 carbon atoms and Rg and R7, which are the same or different, represent a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms.

Forbindelsene med formel II oppnås ved kondensering av aminetThe compounds of formula II are obtained by condensation of the amine

I med en o-metoksy-benzosyre eller et av dens derivater. I with an o-methoxy-benzoic acid or one of its derivatives.

Benzamidene II er forbindelser med terapeutisk virkning og er tidligere beskrevet i litteraturen. The benzamides II are compounds with therapeutic action and have previously been described in the literature.

Pyrrolidinene (I (R) og I (S) hvori R er alkyl kan føre til følgende benzamider II» The pyrrolidines (I (R) and I (S) in which R is alkyl can lead to the following benzamides II»

hvori R er alkyl med 1 til .5 karbonatomer, B er et hydrogenatom eller alkyl med 1 til 5 karbonatomer og C, D og E står for.et hydrogenatom, et halogenatom, alkoksy med 1 til 5 karbonatomer, nitro, amlno, alkylamino, dialkylamino eller alkanoylamlno, wherein R is alkyl of 1 to 5 carbon atoms, B is a hydrogen atom or alkyl of 1 to 5 carbon atoms and C, D and E represent a hydrogen atom, a halogen atom, alkoxy of 1 to 5 carbon atoms, nitro, amlno, alkylamino, dialkylamino or alkanoylamino,

acyl med 1 til 5 karbonatomer, cyano, sulfamoyl, alkylsulfamoyl eller dialkylsulfamoyl, alkylsulfonyl, trihalogen-metyl, alkyltio, polyfluor-alkyl eller polyfluor-alkylsulfonyl. acyl with 1 to 5 carbon atoms, cyano, sulfamoyl, alkylsulfamoyl or dialkylsulfamoyl, alkylsulfonyl, trihalomethyl, alkylthio, polyfluoroalkyl or polyfluoroalkylsulfonyl.

Den absolutte konfigurasjon av enantiomerene med formel I (R) og I (S) er påvist ved slektskap med L-prolinol hvor den absolutte konfigurasjon er kjent og den venstre-dreiende enantiomer I The absolute configuration of the enantiomers of formula I (R) and I (S) has been demonstrated by kinship with L-prolinol where the absolute configuration is known and the levorotatory enantiomer I

(S) <-).(S) <-).

L-prolinol har en absolutt konfigurasjon (S) (Sinister mot urviseren) etter reglene til Cahn, Ingold et Prélog, påvist på basis av L-prolin hvor konfigurasjonen (S) er bestemt ved hjelp av en røntgenanalyse (Buckingham et Al. Comm. 1969, 583). L-prolinol has an absolute configuration (S) (Clockwise) according to the rules of Cahn, Ingold et Prélog, demonstrated on the basis of L-proline where the configuration (S) is determined by means of an X-ray analysis (Buckingham et Al. Comm. 1969, 583).

Rekkefølgen av kjemiske reaksjoner, som ikke forstyrrer den absolutte konfigurasjon av det asymmetriske karbon og dets benevnelse (R) eller (S) i regelverket til Cahn, Ingold og Prélog, kan da bare føre til enantiomeren I (S) som selv fører til derivatet ti (S). The sequence of chemical reactions, which does not disturb the absolute configuration of the asymmetric carbon and its designation (R) or (S) in the rules of Cahn, Ingold and Prélog, can then only lead to the enantiomer I (S) which itself leads to the derivative ti (S).

Den foreliggende oppfinnelse vedrører således en stereospesifikk syntese som tillater oppnåelse av enantiomerene (R) eller (S) med formler I og II. The present invention thus relates to a stereospecific synthesis which allows obtaining the enantiomers (R) or (S) with formulas I and II.

Fremgangsmåten i henhold til oppfinnelsen består i å fremstille forbindelsene I ved stereospesifikk syntese ved å gå ut fra prolin eller glutaminsyre (R) eller (S) eller en forbindelse avledet fra disse (pyroglutaminsyre, prolinol) ved å føre utgangsprodukt-pyrrolidinene som bærer et assymetrisk karbonat om i a-stilling til enaminert gruppe, gjennom en rekkefølge av kondensasjoner, forestringer, amideringer, ringslutninger og reduksjoner. The method according to the invention consists in preparing the compounds I by stereospecific synthesis by starting from proline or glutamic acid (R) or (S) or a compound derived from these (pyroglutamic acid, prolinol) by introducing the starting product pyrrolidines which carry an asymmetrical carbonate in the a-position to an enamined group, through a sequence of condensations, esterifications, amidations, ring closures and reductions.

Reaksjonsskjemaene er gjengitt i det følgende. The reaction forms are reproduced below.

I reaksjonsskjemaene betyr betegnelsene følgende: In the reaction forms, the designations mean the following:

alk » CH3 eller C2H5alk » CH3 or C2H5

X halogen (Coretrukket Cl)X halogen (Co-extracted Cl)

R<*>o enten R^(H eller alkyl med 1 til 4 karbonatomer) R<*>o either R^(H or alkyl of 1 to 4 carbon atoms)

A<*>«= en binding eller alkylen med 1 til 3 karbonatomer. A<*>«= a bond or alkylene with 1 to 3 carbon atoms.

De andre betydninger er som angitt tidligere.The other meanings are as indicated earlier.

I reaksjonsskjemaet I går man ut fra prolin (S) for oppnåelse av aminet (I (S). In reaction scheme I, proline (S) is used to obtain the amine (I (S).

Prolinet (R) fører på samme måte til aminet (I (R).The proline (R) leads in the same way to the amine (I (R).

I reaksjonsskjemaet H går man ut fra glutaminsyre R for oppnåelse av aminet I (R) direkte^In the reaction scheme H, glutamic acid R is used to obtain the amine I (R) directly^

Glutaminsyren (S) kan på samme måte førertil aminet I (S).The glutamic acid (S) can similarly lead to the amine I (S).

I reaksjonsskjemaet 3 går man ut fra glutaminsyren (S) som etter ringslutning, rasemisering og spalting også tillater oppnåelse av aminet I (R). In reaction scheme 3, the starting point is glutamic acid (S), which after cyclization, racemization and cleavage also allows the amine I (R) to be obtained.

I reaksjonsskjemaet 4 går man ut fra prolinol (S) for oppnåelse In reaction scheme 4, prolinol (S) is used as the starting point for obtaining

av aminet I (S).of the amine I (S).

Prolinolet R, oppnådd ved å gå ut fra glutaminsyre (S) ved ringslutning, rasemisering, deretter spalting til pyroglutaminsyre (R) og reduksjon av denne, eller ved ringslutning og reduksjon av glutaminsyre (R), idet dette på samme måte fører til aminet I (R). The prolinole R, obtained by starting from glutamic acid (S) by cyclization, racemization, then cleavage to pyroglutamic acid (R) and reduction thereof, or by cyclization and reduction of glutamic acid (R), as this similarly leads to the amine I (R).

Reaksjonsskjemaene er eksemplifisert i de følgende eksempler.The reaction schemes are exemplified in the following examples.

De endelige reduksjoner gjennomføres foretrukket ved hjelp av dobbel t-hy dr i det av litiom og aluminium... The final reductions are preferably carried out using double t-hy dr in that of lithium and aluminium...

Spaltingen i reaksjonsskjemaet 3 gjennomføres ved hjelp av L-tyrosin-hydrazid. The cleavage in reaction scheme 3 is carried out using L-tyrosine hydrazide.

Eksempel 1 f reaksjonsskjerna 1) v Example 1 f reaction core 1) v

l-cyklopropylmetyl-2-aminometyl-pyrrolidin (S) (-)l-cyclopropylmethyl-2-aminomethyl-pyrrolidine (S) (-)

G G

Trinn 1; 2~etoksykarbonyl~gyrrolldl^ .Step 1; 2~ethoxycarbonyl~gyrrolldl^ .

I en erlenmeyer-kølbe innføres 34.8 g (0.3 mol) L-prolin (S)34.8 g (0.3 mol) L-proline (S) is introduced into an Erlenmeyer flask

og 360 ml etanol. Under avkjøling på et isblandet bad tilføres dråpevis 54.8 g (0.46 mol) tionylklorid. and 360 ml of ethanol. During cooling in an ice bath, 54.8 g (0.46 mol) thionyl chloride are added dropwise.

Det omrøres i 1 time ved omgivelsenes temperatur og blandingen oppvarmes under tilbakeløp i 3 timer. Det inndampes til tørrhet, den resterende olje oppløses i kloroform og mettes med ammoniakk. Ammoniumkloridet frafiltreres og den organiske fase inndampes. Det oppnås en olje. som destilleres. It is stirred for 1 hour at ambient temperature and the mixture is heated under reflux for 3 hours. It is evaporated to dryness, the remaining oil is dissolved in chloroform and saturated with ammonia. The ammonium chloride is filtered off and the organic phase is evaporated. An oil is obtained. which is distilled.

Kokepunkt2Qo 82°CBoiling point2Qo 82°C

T rinn 2. ^-karbamoyl-pYrrolidin .T rinn 2. ^-Carbamoyl-pyrrolidine .

I en erlenmeyér-kolbe innføres 200 ml metanol som mettes med ammoniakk under avkjøling. Det innføres 17.2 g (0.12 mol) av esteren oppnådd i trinn 1 i metanol. Det omrøres i 2 timer og blandingen settes bort over natten. 200 ml of methanol are introduced into an Erlenmeyer flask, which is saturated with ammonia while cooling. 17.2 g (0.12 mol) of the ester obtained in step 1 in methanol are introduced. It is stirred for 2 hours and the mixture is set aside overnight.

Det inndampes til tørrhet og det oppnås et.faststoff som omkrystalliseres i benzen. It is evaporated to dryness and a solid is obtained which is recrystallized in benzene.

faj^ » -78° (c o 1, vann)faj^ » -78° (c o 1, water)

Smp. « 101.5 - 102°C ' Temp. « 101.5 - 102°C '

/V365 - -258.5° (c « 1, vann) /V365 - -258.5° (c « 1, water)

Trinn_3_. l-cyklopropYlka rbonyl-2-karbam^ ( S) (-). Step_3_. 1-CyclopropYlka rbonyl-2-carbam^ ( S) (-).

I en erlenmeyer-kolbé innføres 11.4 g (0.1 mol) av prolinamidet (S), 13.8 g (0.1 mol) kaliumkarbonat og vannfri aceton. 11.4 g (0.1 mol) of the prolinamide (S), 13.8 g (0.1 mol) potassium carbonate and anhydrous acetone are introduced into an Erlenmeyer flask.

Det avkjøles med et isblandet bad og dråpevis.tilsettes 10.45 g (0.1 mol) av kloridet av cyklopropan-karboksylsyre i aceton. It is cooled with an ice bath and 10.45 g (0.1 mol) of the chloride of cyclopropane carboxylic acid in acetone are added dropwise.

Dét omrøres i 1 time ved denne temperatur og blandingen settes bort over natten ved omgivelsenes temperatur. Det inndampes til tørrhet (T^30°C), det ekstraheres med kloroform og vaskes med en minste mengde vann. Den organiske fase tørkes over magnesiumsulfat og inndampes. Det oppnås et faststoff som smelter ved 129 - 130°C. /o/j^g"-130»9° (c » 1, D.M.F.). It is stirred for 1 hour at this temperature and the mixture is set aside overnight at ambient temperature. It is evaporated to dryness (T^30°C), extracted with chloroform and washed with a minimum amount of water. The organic phase is dried over magnesium sulfate and evaporated. A solid is obtained which melts at 129 - 130°C. /o/j^g"-130»9° (c » 1, D.M.F.).

Trinn 4. l- cyklopropYl-2-aminometyl-pyrro^Step 4. 1-Cyclopropyl-2-aminomethyl-pyrrole

I en erlenmeyer-kolbe innføres 13.3 g (0.3§ mol) av dobbelthydridet av litium og aluminium, og 200 ml vannfri eter. Det tilsettes i små mengder 16 g (0.088 mol) av det ovennevnte diamid og det oppvarmes under tilbakeløp i 16 timer. Dét hydrolyseres méd en oppløsning av 10% natrium-kaliumtartrat og faststoffet frafiltreres. Faststoffene vaskes flere ganger med eter og deretter slås eterfasene sammen og inndampes. 13.3 g (0.3§ mol) of the double hydride of lithium and aluminum and 200 ml of anhydrous ether are introduced into an Erlenmeyer flask. 16 g (0.088 mol) of the above-mentioned diamide are added in small amounts and heated under reflux for 16 hours. This is hydrolysed with a solution of 10% sodium-potassium tartrate and the solid is filtered off. The solids are washed several times with ether and then the ether phases are combined and evaporated.

Det oppnås en olje som destilleres.An oil is obtained which is distilled.

Kokepunkt2Q88°C.Boiling point 2Q88°C.

/V365 -201.5° (c » 1, D.M.F.) /V365 -201.5° (c » 1, D.M.F.)

JTol/* 0 - -68.5° (c 1, D.M.F.)JTol/* 0 - -68.5° (c 1, D.M.F.)

Anvendelse av pyrrolldinet I ( S) : Ved syntese av N-^l-cyklo-propylmetyl-2-pyrrolidinyl)-metyl7-2-metoksy-5-sulfamoyl-benzamid Use of pyrroldinet I (S): In the synthesis of N-[1-cyclopropylmethyl-2-pyrrolidinyl)-methyl7-2-methoxy-5-sulfamoyl-benzamide

(S) (-)(S) (-)

I en erlenmeyer-kolbe innføres 8.8 g (0.057 mol) amin, 14.07 g (0.054 mol) av etylesteren av 2-metoksy-5-sulfamoyl-benzosyre og 18 ral vann. Det oppvarmes ved 120°C i 10 timer. Ved avkjøling oppstår et faststoff. Det tilsettes eter og vann og omrøres. Faststoffet frafiltreres, oppløses i kloroform, tørkes over magnesiumsulfat og inndampes. Det oppnåseet faststoff som omkrystalliseres fra etylacetat. 8.8 g (0.057 mol) of amine, 14.07 g (0.054 mol) of the ethyl ester of 2-methoxy-5-sulfamoyl-benzoic acid and 18 ral of water are introduced into an Erlenmeyer flask. It is heated at 120°C for 10 hours. On cooling, a solid is formed. Ether and water are added and stirred. The solid is filtered off, dissolved in chloroform, dried over magnesium sulphate and evaporated. A solid is obtained which is recrystallized from ethyl acetate.

Smp. « 134 - 134.5°C Temp. « 134 - 134.5°C

/o7p° » -77° (c ol, D.M.F.)./o7p° » -77° (c ol, D.M.F.).

Eksempel 2 (reaksjonsskjerna 2) Example 2 (reaction core 2)

l-cykloheksylmetyl-2-aminometyl-pyrrolidin (R) ( + ) l-cyclohexylmethyl-2-aminomethyl-pyrrolidine (R) ( + )

Tri nn 1. 1-cyk1ohek syImety1- 2-k årbok sy- 5-oks o- pyr rol idi n (R) (-). Tri nn 1. 1-cyc1ohek syImety1- 2-k yearbook sy- 5-ox o- pyr rol idi n (R) (-).

I en erlenmeyerkolbe innføres under nitrogenatrøm og under avkjøling 5,8.8 g (0.4)mol) glutaminsyre (R) og 400 ml NaOH (2N). , Det tilsettes tiråpevis 44.8 g (0.4 mol) cykloheksan-karbaldehyd 5.8.8 g (0.4) mol) of glutamic acid (R) and 400 ml of NaOH (2N) are introduced into an Erlenmeyer flask under a nitrogen atmosphere and while cooling. , 44.8 g (0.4 mol) cyclohexane-carbaldehyde is added dropwise

i metanol. Det omrøres i 1 time, reaksjonsblandingen hydrogeneres i nærvær av Pd/C ved omgivelsenes temperatur og atmosfaoretrykk. Etter at det teoretiske hydrogenvolum er absorbert frafiltreres katalysatoren og metanol avdampes. Den oppnådde vandige fase ekstraheres med eter. Man innstiller pH i den vandige fase til 2.5 med saltsyre IN. Dettoppvarmes ved 100°C i 2 timer.' in methanol. It is stirred for 1 hour, the reaction mixture is hydrogenated in the presence of Pd/C at ambient temperature and atmospheric pressure. After the theoretical volume of hydrogen has been absorbed, the catalyst is filtered off and methanol is evaporated. The aqueous phase obtained is extracted with ether. The pH in the aqueous phase is adjusted to 2.5 with hydrochloric acid IN. This is heated at 100°C for 2 hours.'

Det avkjøles og det hvite faststoff frafiltreres og oppløses i kloroform, det tørkes over magnesiumsulfat og inndampes. pet oppnås et faststoff som renses ved utgnidnlng i cyk1oheksan. ■ It is cooled and the white solid is filtered off and dissolved in chloroform, it is dried over magnesium sulphate and evaporated. a solid is obtained which is purified by trituration in cyclohexane. ■

Smp. 141.5 142°C ^355"-20.5° (c1, D.M.F.) Temp. 141.5 142°C ^355"-20.5° (c1, D.M.F.)

Trinn_21-cyk 1 oh eks ylme tyl- 2~ metoksykarbqnYl-5-okso-pyrrolidin Trinn_21-cyk 1 oh ex ylme tyl- 2~ methoxycarbqnYl-5-oxo-pyrrolidine

cs (R)_(:).cs (R)_(:).

I en 1 liters erlenmeyerkolbe innføres 300 ml metanol og 50 g (0.221 mol) av forbindelsen oppnådd i trinn 1. Det oppvarmes 300 ml of methanol and 50 g (0.221 mol) of the compound obtained in step 1 are introduced into a 1 liter Erlenmeyer flask. It is heated

til 40°C og innføres dråpevis 31.7 g (0.266 mol) tionylklorid. Det.oppvarmes under tilbakeløp i 4 timer, inndampes til tørrhet to 40°C and 31.7 g (0.266 mol) of thionyl chloride are introduced dropwise. It is heated under reflux for 4 hours, evaporated to dryness

og oppnås en olje som destilleres og som krystalliserer ved and an oil is obtained which is distilled and which crystallizes in wood

-avkjøling.- cooling.

Smp. - 87.5 - 88°C Temp. - 87.5 - 88°C

*■ . * ■ ■ *■ . * ■ ■

\ ia/365-6° (cD.M.F.). \ ia/365-6° (cD.M.F.).

Trinn _3. l-c yklohekSYlmetYl-2- k (R)(-). Step _3. l-c yclohexYLmetYl-2-k (R)(-).

I en erlenmeyer-kolbe innfares 400 ml metanol og under avkjoling mettes løsningen med ammoniakk. Det tilsettes 41.2 g (0.172 mol) av esteren oppnådd i trinn 2, omrøres i 2 timer og blandingen settes bort over natten. 400 ml of methanol are introduced into an Erlenmeyer flask and, while cooling, the solution is saturated with ammonia. 41.2 g (0.172 mol) of the ester obtained in step 2 are added, stirred for 2 hours and the mixture is set aside overnight.

Det inndampes til tørrhet,.faststoffene samles og omkrystalliseres fra etylacetat. It is evaporated to dryness, the solids are collected and recrystallized from ethyl acetate.

Smp. =164.5- 165°C... Temp. =164.5- 165°C...

/a?3<g>5- -116° (c 1, D.M.F.)/a?3<g>5- -116° (c 1, D.M.F.)

Trinn 4. l- cykloheksy lmetyl-2-amino metyl-gy rrolidin (R)(♦).Step 4. 1-Cyclohexylmethyl-2-amino methyl-gyrrolidin (R)(♦).

I en erlenmeyerkolbe innføres 13.6 g (0.356 mol) av dobbelthydridet av litium dg aluminium og vannfri eter. Under nitrogen-strøm tilsettes, i små mengder 20 g (0.089 mol) av amidet oppnådd i trinn 3. Det oppvarmes under tilbakeløp i 16 timer . og hydrolyseres med eh oppløsning av nåtrium-kaliumtartrat. Faststoffet frafiltreres og døn organiske fase inndampes. Det oppnås en olje som destilleres. 13.6 g (0.356 mol) of the double hydride of lithium dg aluminum and anhydrous ether are introduced into an Erlenmeyer flask. Under a stream of nitrogen, 20 g (0.089 mol) of the amide obtained in step 3 are added in small amounts. It is heated under reflux for 16 hours. and hydrolyzed with eh solution of sodium-potassium tartrate. The solid is filtered off and the dead organic phase is evaporated. An oil is obtained which is distilled.

Kokepunkt25140°C. Boiling point 25140°C.

</a>^365= +263° (c = 1, D.M.F.) </a>^365= +263° (c = 1, D.M.F.)

. Anvendelse av pyrrolldinet I ( R) for syntese av: N-/(l-cyklo-hek sy Ime tyl-2-pyrr ol idi ny 1 )-are ty V-2-me tok sy-S-sul f amoy 1-benzamid II (R)( + ) „ " . . Application of the pyrrollidine I ( R ) for the synthesis of: N-/(l-cyclo-hex sy Ime tyl-2-pyrr ol idi ny 1 )-are ty V-2-me toc sy-S-sul f amoy 1- benzamide II (R)( + ) „ " .

I en erlenmeyer-kolbé innføres 12 g (0.061 mol) av det ovenfor oppnådde pyrrolidin, 8.44 g (0.061 mol) kaliumkarbonat og aceton.. 12 g (0.061 mol) of the pyrrolidine obtained above, 8.44 g (0.061 mol) potassium carbonate and acetone are introduced into an Erlenmeyer flask.

Ved en temperatur 10°C og under nitrogenstrøm tilsettes dråpevis 15.2 g (0.061 mol) av kloridet av 2-metoksy-5-sulfamoyl-benzosyre i aceton. At a temperature of 10°C and under a stream of nitrogen, 15.2 g (0.061 mol) of the chloride of 2-methoxy-5-sulfamoyl-benzoic acid in acetone are added dropwise.

Det omrøres i 2 timer, inndampes til tørrhet og resten underkastes en utgnidning i en blanding av vann pluss eter. Faststoffet frafiltreres og oppløses i kloroform, tørkes over magnesiumsulfat og inndampes. Det oppnås et faststoff som omkrysta!liseres fra en blanding eter/etylacetat. It is stirred for 2 hours, evaporated to dryness and the residue subjected to trituration in a mixture of water plus ether. The solid is filtered off and dissolved in chloroform, dried over magnesium sulphate and evaporated. A solid is obtained which is recrystallized from an ether/ethyl acetate mixture.

Smp. « 141.5 - 142°C. Temp. « 141.5 - 142°C.

7"a7p°+96° (C i» dl,D.M.F.) 7"a7p°+96° (C i» dl,D.M.F.)

Metansulfonatétay dette benzamid har en konfigurasjon (R)(-).Methanesulfonatétay this benzamide has a configuration (R)(-).

Det smelter ved 164 - 165°C.It melts at 164 - 165°C.

/o7§° » -4.2° (c « 1, D.M.F.)./o7§° » -4.2° (c « 1, D.M.F.).

Eksempel 3 (reaksjonsskjerna 3 V Example 3 (reaction core 3 V

1-p-fluorbénzyl-2-aminometyl-pyrrolidin (R)'( + )1-p-fluorobenzyl-2-aminomethyl-pyrrolidine (R)'( + )

Trinn It Racemisk^pyroglutaminsyre.Step It Racemic^pyroglutamic acid.

I en 1 liters autoklav innføres 200 g (1.359 mol) glutaminsyre Sog 700 ml vann. Blandingen bringes til 200°C i 6 timer ved omrøring. Ved avkjøling til omgivelsenes/temperatur utkrystalliseres fra den resulterende oppløsning et hvitt faststoff. Into a 1 liter autoclave, introduce 200 g (1,359 mol) glutamic acid and suck up 700 ml of water. The mixture is brought to 200°C for 6 hours with stirring. On cooling to ambient/temperature, a white solid crystallizes from the resulting solution.

Smp.T183 - 185°C. M.p. T183 - 185°C.

Trinn 2i _ Race roisk ety 1-pyrog lutamat.Step 2i _ Race roisk ety 1-pyrog lutamate.

i en 2 liters kolbe med tilbakeløp-avkjøling og magnetisk omrøring anbringes 200 g (1.549 mol) racemisk pyroglutaminsyre i suspensjon 1.5 liter etanol :.og det tilsettes omtrent 50 ml harpiks "Aroberl i te" IR 120 (H) på forhånd vasket med alkohol f or': å-fjerne vvann. Blandingen bringes til tilbakeløp og det uoppløselige faststoff løses hurtig og fullstendig. Det kokes under tilbakeløp i omtrent'12 timer og deretter avsuges harpiksen på filter og filtratet inndampes. Det oppnås en in a 2 liter flask with reflux cooling and magnetic stirring, 200 g (1.549 mol) of racemic pyroglutamic acid are placed in suspension in 1.5 liters of ethanol:.and approximately 50 ml of resin "Aroberl in tea" IR 120 (H), previously washed with alcohol, is added f or': to-remove water. The mixture is brought to reflux and the insoluble solid dissolves quickly and completely. It is boiled under reflux for about 12 hours and then the resin is sucked off on a filter and the filtrate is evaporated. A is achieved

■ fargeløs o£je.■ colorless o£je.

Denne olje destilleres under redusert trykk. Etter en liten forløpsfraksjon destillerer produktet til en fargeløs olje som krystalliserer spontant og gir et hvitt faststoff. Det blir tilbake en ikke-destillerbar brun rest. This oil is distilled under reduced pressure. After a small run-off fraction, the product distills to a colorless oil which crystallizes spontaneously and gives a white solid. A non-distillable brown residue remains.

Etter knusing av den destillerte krystalliserte forbindelse oppnås ét hvitt pulver:Kokepunkt0<005^ 135 - 140°C. Smp.T = 61 - 62.5°C . After crushing the distilled crystallized compound, a white powder is obtained: Boiling point 0<005^ 135 - 140°C. Smp.T = 61 - 62.5°C.

Trinn 3^ Racemi sk ety1- 1- p- f 1ubrobe nzy1-2-okso-pyrro1 idin-5- kårboksylat. Step 3^ Racemi sk ety1- 1- p- f 1ubrobe nzy1-2-oxo-pyrro1 idine-5- kørcarboxylate.

I en erlenmeyer-kolbe med slipt hals} under nitrogenatmosfærej anbringes 4.8 g (0.1 mol) natriumhydrid 50% i olje og det vaskes ved dekantering tre ganger med tørr petroleter, hvoretter blandingen overhelles. med 100 ml rent DMF. Denne suspensjon avkjøles svakt for å holde temperaturen konstant ved 20°C under alle disse operasjoner. Det innføres deretter dråpevis en oppløsning av 15.72 g (0.1 mol) av den ovennevnte ester i 50 ml DMF. Man bemerker ved begynnelsen av denne tilsetning en rikélig og jevn'gassutvikling som viser at natrium innføres.. Man lar , blandingen stå by^r natten ved omgivelsenes temperatur for å fullføre -denne reaksjon. Man avkjøler så på, isbad og tilsetter dråpevis en oppløsning av 14.48 g (0.1 mol) av p-fluorobenzyl-klorid i 30 ml DMF,, hvoretter man lar temperaturen gradvis stige til 20°C3: Etter 3 timer under omrøring avdampes DMF til tørrhet ved 35°C under vakuum. Resten ekstraheres med eter tre ganger, 4.8 g (0.1 mol) of sodium hydride 50% in oil are placed in an Erlenmeyer flask with a ground neck} under a nitrogen atmosphere and washed by decantation three times with dry petroleum ether, after which the mixture is poured over. with 100 ml of pure DMF. This suspension is cooled slightly to keep the temperature constant at 20°C during all these operations. A solution of 15.72 g (0.1 mol) of the above-mentioned ester in 50 ml of DMF is then introduced dropwise. One notes at the beginning of this addition a copious and steady evolution of gas which shows that sodium is being introduced. The mixture is allowed to stand overnight at ambient temperature to complete this reaction. It is then cooled in an ice bath and a solution of 14.48 g (0.1 mol) of p-fluorobenzyl chloride in 30 ml DMF is added dropwise, after which the temperature is allowed to rise gradually to 20°C3: After 3 hours with stirring, the DMF is evaporated to dryness at 35°C under vacuum. The residue is extracted with ether three times,

i nærvær av meget svakt surgjort vann. Eterekstrakten vaskes med vann og tørkes deretter over magnesiumsulfat i nærvær av dyrekull. Etter filtrering og avdamping av løsningsmidlet blir det tilbake en gul olje. in the presence of very weakly acidified water. The ether extract is washed with water and then dried over magnesium sulfate in the presence of animal charcoal. After filtering and evaporating the solvent, a yellow oil remains.

Ved destillasjon for analyse av 0.9 gi en kule-kolonne oppnås en fargeløs olje: By distillation for analysis of 0.9 g a ball column, a colorless oil is obtained:

K6kepunkt0#005 mm » 150°C...K6kepunkt0#005 mm » 150°C...

Trinn 4: R acemlsk,1-P-fluoro ben2 yl-2- okso~pyrrolidin~5-» Step 4: Racemic,1-P-fluoro benzyl-2-oxo~pyrrolidine~5-»

k årbok sylsyre. k yearbook sylic acid.

Til en oppløsning av.-18.5 g (0.0697 mol) av den rå ester fra trinn 3 i 100 ml etanol tilsettes som oppløsning av 2,8 g (0.0697 mol) natriumhydroksyd i 10 ml vann og blandingen omrøres i 2 timer. Løsningsmidlet avdampes deretter under vakuum og resten utrastes mellom vann og eter. Etter 2 ekstraksjoner med eter avkjøles den alkaliske vandige fase i is og surgjøres med konsentrert saltsyre tii omtrent pH 1. Det gulhvite faststoff som krystalliserer avsuges på filteret, vaskes.med vann og deretter med pentan og tørkes under redusert trykk i nærvær av fosforsyreanhydrid. To a solution of 18.5 g (0.0697 mol) of the crude ester from step 3 in 100 ml of ethanol is added as a solution of 2.8 g (0.0697 mol) of sodium hydroxide in 10 ml of water and the mixture is stirred for 2 hours. The solvent is then evaporated under vacuum and the residue is triturated between water and ether. After 2 extractions with ether, the alkaline aqueous phase is cooled in ice and acidified with concentrated hydrochloric acid to approximately pH 1. The yellowish-white solid which crystallizes is filtered off with suction, washed with water and then with pentane and dried under reduced pressure in the presence of phosphoric anhydride.

Smp.T» 131 - 132°C. Mp.T» 131 - 132°C.

Trinn_5_: i~P~f i u °rqbenz y 1 - 2- ok so- pyrr ol idln-5- k årbok syl syre Step_5_: i~P~f i u °rqbenz y 1 - 2- ok so- pyrr ol idln-5- k yearbook syl syre

(S)(=) (S)(=)

1°) Fremstilling av saltet av L- tyrosin- hydrazld ( S) 1°) Preparation of the salt of L-tyrosine hydrazld (S)

I én 1 liters erlenmeyerkolbe anbringes 42.7 g (0.18 mol) avIn one 1 liter Erlenmeyer flask, place 42.7 g (0.18 mol) of

den foregående, racemiske syre (trinn 4) og 35.14 g (0.18 mol) L-tyrosin-hydrazid og det tilsettes 550 ml etylalkohol hvoretter blandingen kokes under tilbakeløp. Det avsuges på filter en liten mengde uoppløselig substans og oppløsningen podes i varm tilstand the preceding, racemic acid (step 4) and 35.14 g (0.18 mol) L-tyrosine hydrazide and 550 ml of ethyl alcohol are added, after which the mixture is boiled under reflux. A small amount of insoluble substance is sucked off the filter and the solution is inoculated while warm

med allerede spaltet salt. Litt etter litt kommer det et fint hvitt faststoff tilsyne.! Blandingen settes bort over natten, with already split salt. Little by little, a nice white solid appears.! The mixture is set aside overnight,

den krystallinske masse knuses og suspensjonen omrøres.i ytterligere 10 timer. Det hvite faststoff avsuges pa filter, vaskes med litt kold alkohol og deretter med eter og tørkes i tørkeskap. the crystalline mass is crushed and the suspension is stirred for a further 10 hours. The white solid is sucked off on a filter, washed with a little cold alcohol and then with ether and dried in a drying cabinet.

Smp.T125 - 130°C*Temp.T125 - 130°C*

Etter omkrystallisering fra 200 ml isopropanol og 150 ml etanol oppnås et pulver. After recrystallization from 200 ml of isopropanol and 150 ml of ethanol, a powder is obtained.

Smp.T135 - 137°C. M.p. T135 - 137°C.

^365"-66.6° (c 0.5 D.M.F.) ^365"-66.6° (c 0.5 D.M.F.)

2°) Fremstilling av syren ( R)(-)2°) Production of the acid ( R)(-)

16.65 g (0.0385 mol) av sal tet.: f ra forrige trinn oppløses i litt vann, det tilsettes omtrent 200 ml eter og surgjøres med konsentrert HC1 i overskudd. Den vandige fase ekstraheres tre ganger med eter, ekstraktene vaskes med vann og tørkes- deretter over magriésiumsulfat. Etter avdamping av løsningsmidlet er det tilbake en hvit krystallinsk forbindelse som behandles under pentan, avsuges på filter og vaskes og tørkes deretter under redusert trykk ved 60°C. Dissolve 16.65 g (0.0385 mol) of the salt from the previous step in a little water, add approximately 200 ml of ether and acidify with concentrated HCl in excess. The aqueous phase is extracted three times with ether, the extracts are washed with water and then dried over magnesium sulphate. After evaporation of the solvent, a white crystalline compound remains which is treated under pentane, filtered off with suction and washed and then dried under reduced pressure at 60°C.

Smp.T» 107 - 108°C. Mp.T» 107 - 108°C.

^365-120*87° (c - 2»D-M.P.) ^365-120*87° (c - 2»D-M.P.)

Trinn 6; Metyl-l~p-flUorobenz yl- 2- okso» pyrrolidin~ 5-k arboksylat (R)(~). Step 6; Methyl-l~p-fluorobenz yl- 2- oxo» pyrrolidine~ 5-carboxylate (R)(~).

I en erlenmeyer-kolbe innføres 40 g (0.168 mol.})av 1-p-fluoro-benzyl-2-okso-pyrrolidin-5-karboksylsyre (R)(-) og 100 ml metanol. Det oppvarmes ved 40°C og tilGettes dråpevis 24-g (012 mol) tionylklerid. Dét oppvarmes under tilbakeløp i 8 timer og den alkoholiske oppløsning inndampes til tørrhet og dét gjenvinnes en oljeaktig rest som destilleres. 40 g (0.168 mol) of 1-p-fluoro-benzyl-2-oxo-pyrrolidine-5-carboxylic acid (R)(-) and 100 ml of methanol are introduced into an Erlenmeyer flask. It is heated at 40°C and 24 g (0.12 mol) of thionyl chloride are added dropwise. It is heated under reflux for 8 hours and the alcoholic solution is evaporated to dryness and an oily residue is recovered which is distilled.

Kokepunkt,- nc mm 144°C Boiling point, - nc mm 144°C

0.05 mm 0.05 mm

^7365 -56-86°<c 2»D.M.F ) ^7365 -56-86°<c 2»D.M.F )

Tr inn 7? . 1-p-f luqrolæ (R)(-) Enter 7? . 1-p-f luqrolæ (R)(-)

I en 1 liters erlenmeyer-kolbe innføres 400 ml metanol og oppløsningen mettes med ammoniakk under avkjøling på is. Det innføres deretter dråpevis 22 g (0.087 mol) metyl-l-p-fluorobenzyl-2-okso-pyrrolidin-karbdksylat (R)(-) og det omrøres i 8 timer ved omgivelsenes temperatur. Det inndampes til tørrhet og det oppnås et faststoff som tørkes under redusert trykk over fosforsyreanhydrid. Man omkrystalliserer fra den minst mulige mengde kloroform. Forbindelsen er et hvitt pulver. 400 ml of methanol are introduced into a 1 liter Erlenmeyer flask and the solution is saturated with ammonia while cooling on ice. 22 g (0.087 mol) of methyl-1-p-fluorobenzyl-2-oxo-pyrrolidine-carbdxylate (R)(-) are then introduced dropwise and the mixture is stirred for 8 hours at ambient temperature. It is evaporated to dryness and a solid is obtained which is dried under reduced pressure over phosphoric anhydride. One recrystallizes from the smallest possible amount of chloroform. The compound is a white powder.

Smp.T179.5 - 180°C M.p. T179.5 - 180°C

Za?3g5 = -305.6° (c = 0.7, D.M.F.) Za?3g5 = -305.6° (c = 0.7, D.M.F.)

<Trinn>_<8:>l-p—fluorobenzyl-2-ami nometyl-pyr rolidiri ( R) (+ )<Step>_<8:>1-p-fluorobenzyl-2-aminomethyl-pyrrolidiri ( R) (+ )

I en erlenmeyer-kolbe innføres 300 ml vannfri eter og under en strøm av tørt nitrogen tilsettes 13 g (0.342 mol) av dobbelthydridet av litium og aluminium. Det oppvarmes deretter til tilbakeløp av eteren og det innføres i små porsjoner 20.2 g (0.085 mol) av det foregående amid og blandingen holdes under tilbakeløp i 16 timer.. Det hydrolyseres med en oppløsning av dobbelt"tartratet av natrium og kalium.1 Faststoffene filtreres og det vaskes flere ganger med eter. Eterfasene forenes og konsentreres under redusert trykk. Det oppnås en olje som destilleres. 300 ml of anhydrous ether are introduced into an Erlenmeyer flask and 13 g (0.342 mol) of the double hydride of lithium and aluminum are added under a stream of dry nitrogen. It is then heated to reflux of the ether and 20.2 g (0.085 mol) of the preceding amide is introduced in small portions and the mixture is kept under reflux for 16 hours. It is hydrolyzed with a solution of the double tartrate of sodium and potassium. 1 The solids are filtered and it is washed several times with ether. The ether phases are combined and concentrated under reduced pressure. An oil is obtained which is distilled.

Denne er en ufarget væske. This is a colorless liquid.

Kokepunkt0<05 mm 92°CBoiling point0<05 mm 92°C

/a7p5 +81.8° (c 0.5, D.M.F.). /a7p5 +81.8° (c 0.5, D.M.F.).

. Anvendelse av aminet I ( R) for fremstilling av N-/"-(l-p~f luorobenzyl- 2~ pyrrolidinyl)- metyl7~ 2~ metoksy- 5-- sulf amoyl~ benzamid ( R)(+) . Use of the amine I (R) for the preparation of N-/"-(l-p~fluorobenzyl-2~ pyrrolidinyl)-methyl7~ 2~ methoxy-5--sulfamoyl~ benzamide ( R)(+)

I en erlenmeyer-kolbe innføres 4 g (0.019 mol) 2-araino-metyl-1-p-fluorobenzyl—pyrrolldin (R)(+) og videre 2.7 g (0.0196 mol) kaliumkarbonat i suspensjon i aceton. I kulden (T ^10°C) tilsettes dråpevis en oppløsning av 4.8 g (0.019 mol) av kloridet, av 2-metoksy-5-sulfamoyl-benzosyre i aceton. Det omrøres ved omgivelsenes temperatur i 2 timer. 4 g (0.019 mol) of 2-araino-methyl-1-p-fluorobenzyl-pyrroldine (R)(+) and further 2.7 g (0.0196 mol) of potassium carbonate in suspension in acetone are introduced into an Erlenmeyer flask. In the cold (T ^10°C) a solution of 4.8 g (0.019 mol) of the chloride of 2-methoxy-5-sulfamoyl-benzoic acid in acetone is added dropwise. It is stirred at ambient temperature for 2 hours.

Reaksjonsblandingen inndampes til tørrhet under redusert trykk ved temperatur lavere enn 30°C.' Resten vaskes med en blanding av kloroform-vann.- Den organiske fase fraskilles og tørkes over magnesiumsulfat, dét inndampes og det oppnås et fast stoff. The reaction mixture is evaporated to dryness under reduced pressure at a temperature lower than 30°C. The residue is washed with a mixture of chloroform and water. - The organic phase is separated and dried over magnesium sulphate, which is evaporated and a solid substance is obtained.

Faststoffet orakkystalliseres fra en blanding isopropyleter-etylalkohol og er et hvitt fast s,toff. The solid is crystallized from an isopropyl ether-ethyl alcohol mixture and is a white solid.

SMP.T148 - 148.5°C. SMP.T148 - 148.5°C.

Zo7^<5>+92° (c » 0.6 D.M.F.).Zo7^<5>+92° (c » 0.6 D.M.F.).

Eksempel 4 (Reaksjonsskjerna 4) l-etyl-2-aminometyl-pyrrolidin I (S) og dets oksalat. Example 4 (Reaction core 4) 1-ethyl-2-aminomethyl-pyrrolidine I (S) and its oxalate.

Trinn_l£l- aætY l~ 2- acetoksymetyl-py rro lldin ( S) (.-).Step_l£l- aætY l~ 2- acetoxymethyl-pyrro lldin ( S) (.-).

I en 1 liters erlenmeyer-kolbe innføres 44 g (0.435 mol)Into a 1 liter Erlenmeyer flask, introduce 44 g (0.435 mol)

prolinol (S) og 60 g (0.435 mol) kallumkarbonat i suspensjon i 600 ml aceton. Det tilsettes dråpevis i kulden under omrøring 78.5 g Cl moi) acetylklorid, deretter oppvarmes ved tilbakeløps-températur i 8 timer. Suspensjonen filtreres deretter og det uorganiske faststoff vaskes med det samme løsningsmiddel. De forenede filtrater inndampes og resten opptas i eter og omrøres prolinol (S) and 60 g (0.435 mol) of callum carbonate in suspension in 600 ml of acetone. 78.5 g Cl moi) acetyl chloride is added dropwise in the cold with stirring, then heated at reflux temperature for 8 hours. The suspension is then filtered and the inorganic solid is washed with the same solvent. The combined filtrates are evaporated and the residue taken up in ether and stirred

i nærvær av dyrekull. Etter filtrering inndampes løsningen og resten destilleres. Den oppnådde olje krystalliserer deretter spontant. Den utgjøres, av diacetylderivatet.(amidoesteren). in the presence of animal litter. After filtration, the solution is evaporated and the residue is distilled. The obtained oil then crystallizes spontaneously. It is made up of the diacetyl derivative (the amido ester).

KokepunktQ x = 113 -115°C.Boiling pointQ x = 113 -115°C.

Smp.To 44 - 46°C. Smp.To 44 - 46°C.

Dette produkt er tilstrekkelig rent for fortsatt syntese.This product is sufficiently pure for further synthesis.

A7p<&>-53.2° (c » 4.65, D.M.F.). Δ7p<&>-53.2° (c » 4.65, D.M.F.).

Trinrv2: l- acetYl- 2-hydroksymetYl-pyr rolidin S(S)(+)»Step 2: 1-acetyl-2-hydroxymethyl-pyrrolidine S(S)(+)»

Til en avkjølt løsning av 50 g (0.27 mol) av den ovennevnte amidoester i 50 ml etanol tilsettes dråpevis 270 ml alkoholisk KOH IN (0.27 mol). Blandingen får reagere i 24 timer ved vanlig temperatur og inndampes deretter til tørrhet og resten ekstraheres flere ganger med eter under omrøring. Eterfasen konsentreres og den resulterende olje underkastes en destillasjon uc'sk- To a cooled solution of 50 g (0.27 mol) of the above-mentioned amido ester in 50 ml of ethanol, 270 ml of alcoholic KOH IN (0.27 mol) are added dropwise. The mixture is allowed to react for 24 hours at ordinary temperature and is then evaporated to dryness and the residue is extracted several times with ether while stirring. The ether phase is concentrated and the resulting oil is subjected to a distillation uc'sk-

under redusert trykk. Oet oppnås den tilsiktede amino—alkohol. under reduced pressure. The intended amino alcohol is thus obtained.

KokepunktQ Q1 «» 95 - 96°G. Boiling pointQ Q1 «» 95 - 96°G.

faj^ +51° (c = i, D.M.F.).faj^ +51° (c = i, D.M.F.).

Tr inn_3_i 1^ acetyl^g-klo.^ (S)(-).Tr inn_3_i 1^ acetyl^g-klo.^ (S)(-).

1) Fremstilling av hydrokloridet. 1) Preparation of the hydrochloride.

Til en oppløsning avkjølt til minst 10°C av 23.8 g (0.20r.mol) )av den ovennevnte amidoalkohol i 200 ml. kloroform inneholdende noen dråper pyrridin, tilsettes dråpevis en løsning av 21.7 ml (0.3 mol) tionylklorid i 50 ml kloroform. Reaksjonsblandingeh .' omrøres i 4 timer ved en temperatur lavere enn 10°C og konsentreres deretter under redusert trykk uten oppvarming. Resten opptas i kloroform, hvoretter det tilsettes trietylamin til nøytral reaksjon. Det konsentreres på nytt til tørrhet, resten opptas i eter i nærvær av dyrekull, omrøres, filtreres To a solution cooled to at least 10°C of 23.8 g (0.20 r.mol) of the above-mentioned amido alcohol in 200 ml. chloroform containing a few drops of pyridine, a solution of 21.7 ml (0.3 mol) thionyl chloride in 50 ml chloroform is added dropwise. Reaction mixtureh .' stirred for 4 hours at a temperature lower than 10°C and then concentrated under reduced pressure without heating. The residue is taken up in chloroform, after which triethylamine is added to a neutral reaction. It is concentrated again to dryness, the residue is taken up in ether in the presence of animal charcoal, stirred, filtered

og filtratet konsentreres. Den oljeaktige rest destilleres under redusert trykk. and the filtrate is concentrated. The oily residue is distilled under reduced pressure.

Kokepunkt^ « 90 - 94°C.Boiling point^ « 90 - 94°C.

Denne olje oppløses i vannfri eter og behandles med et overskudd • av vannfri hydrogenkloridgass pg fører til ét hvitt hydroskopisk faststoff som er godt krystallisert, nemlig hydrokloridet av ib^acetyl-2-klorometyl-pyrrolidin. This oil is dissolved in anhydrous ether and treated with an excess • of anhydrous hydrogen chloride gas pg leads to a white hydroscopic solid which is well crystallized, namely the hydrochloride of ib^acetyl-2-chloromethyl-pyrrolidine.

Smp.T=125- 126°C. M.p.T=125-126°C.

2) Fremstilling av l- acetyl- 2- klorooretYl- pyrrolidin ( SH- K2) Production of l-acetyl-2-chloroethyl-pyrrolidine (SH-K

Dét ovennevnte hydroklorid behandles med en oppløsning av trietylamin i eter i overskudd. Hydrokloridet av trietylamin avsuges på filter og filtratet inndampes og destilleres forsiktig. Det oppnås 1-acetyl— 2—klormetyl-pyrrolidin i væskeform. The above-mentioned hydrochloride is treated with a solution of triethylamine in ether in excess. The triethylamine hydrochloride is suctioned off on a filter and the filtrate is evaporated and carefully distilled. 1-acetyl-2-chloromethyl-pyrrolidine is obtained in liquid form.

Kokepunktj= 90 91°C. v £&* 5 » -61*8° (c 0.5, D.M.F.) Boiling pointj= 90 91°C. v £&* 5 » -61*8° (c 0.5, D.M.F.)

Trinn 4: ■l-ace tyl- 2^ azldomet yl- pyrrol idin ( S) Step 4: ■1-acetyl-2^azldometyl-pyrrolidine (S)

I 8 timer<y>ed 110°C oppvarmes en suspensjon av 14.3 g (0.0835 mol) av forbindelsen oppnådd i trinn 1, 11.5 g (0.177 mol) Yiatrium-azid og 1.5 g (0.009 mol) kaliumjodid i 200 ml dimetyl-formamid. A suspension of 14.3 g (0.0835 mol) of the compound obtained in step 1, 11.5 g (0.177 mol) of sodium azide and 1.5 g (0.009 mol) of potassium iodide in 200 ml of dimethylformamide is heated for 8 hours at 110°C. .

Man avdamper; deretter/under redusert trykk mest mulig av DMF, resten opptas i kloroform, uoppløselig substans frafiltreres og filtratet konsentreres til tørrhet. Det blir tilbake en olje , . som ikke er renset og som utgjøres av det ønskede azidodérivat. One evaporates; then/under reduced pressure as much DMF as possible, the residue is taken up in chloroform, insoluble substance is filtered off and the filtrate is concentrated to dryness. An oil remains, . which is not purified and which consists of the desired azido derivative.

Trin n Si 1—ety l- 2- amlnom etYl- pyrrolidin og d ets oksalat I ( S)(-). Step n Si 1—ety l- 2- amlnom etYl- pyrrolidine and d ets oxalate I ( S)(-).

1) Diamin.1) Diamine.

I en trehalskolbe utstyrt med røreverk, dråpetrakt og tilbakeløps-kjøler anbringes under nitrogenstrøm 20.2 g (0.532 mol) av dobbelthydridet av litium og aluminium i 500 ml>tørr,eter. Det avkjøles og under god omrøring tilsettes dråpevis 14.9 g (0.0886 mol) av det ovennevnte azid. Det oppvarmes deretter i 8 timer ved tilbakeløpstemperaturen og deretter hydrolyseres i kulden ved forsiktig tilsetning av 38.2 ml av en vandig løsning av 1096 dobbel t-t ar tr a tet av natrium og kalium. Etter 1 times ytterligere omrøring for å gjennomføre hydrolysen filtreres suspensjonen og odet uorganiske faststoff. vaskes tre ganger, med 200 ml eter hver gang. Eterfåsene slås sammen og konsentreres og fører til en rest som destilleres under redusert trykk. l-etyl-2-aminometyl-pyrrolidin som oppnås er en ufarget væske. In a three-necked flask equipped with a stirrer, dropping funnel and reflux condenser, 20.2 g (0.532 mol) of the double hydride of lithium and aluminum are placed in 500 ml of dry ether under a stream of nitrogen. It is cooled and, with good stirring, 14.9 g (0.0886 mol) of the above-mentioned azide are added dropwise. It is then heated for 8 hours at the reflux temperature and then hydrolyzed in the cold by the careful addition of 38.2 ml of an aqueous solution of 1096 double t-t ar tr a tet of sodium and potassium. After 1 hour of further stirring to complete the hydrolysis, the suspension is filtered and inorganic solids removed. washed three times, with 200 ml of ether each time. The ether fractions are combined and concentrated, leading to a residue which is distilled under reduced pressure. The 1-ethyl-2-aminomethyl-pyrrolidine obtained is a colorless liquid.

Kokepunkt25» 78 - 80°CBoiling point 25» 78 - 80°C

/V2,5 -86.1° (c * 0.6,D.M.F.). /V2.5 -86.1° (c * 0.6, D.M.F.).

2) Oksalatét.2) Oxalate.

Oksalatét fremstilles vesldinnvlrkning av 0.256 g av detteThe oxalate is prepared by dissolving 0.256 g of this

diamin på 0.18 g oksalsyre i metanol. Saltet krystalliserer .hurtig,.avsuges på filter og vaskes med kokende metanol, avsuges på filter og tørkes. diamine of 0.18 g of oxalic acid in methanol. The salt crystallizes rapidly, is filtered off and washed with boiling methanol, filtered off and dried.

Smp.T =174 - 175°C. Melting point T = 174 - 175°C.

Z"ft7p5 = -36.3° (c 0.6, H20) Z"ft7p5 = -36.3° (c 0.6, H20)

Anvendelse av pyrrolidinet I ( S)(-) l-etyl-2-aminometyl-pyrrolidinet i (S)(-), fører ved kondensering med kloridet av 2-metoksy«r5-sul f amoyl-benzosyren, foretrukket Use of the pyrrolidine I (S)(-) 1-ethyl-2-aminomethyl-pyrrolidine in (S)(-), leads by condensation with the chloride of the 2-methoxy«r5-sulfamoyl-benzoic acid, preferred

i aeetonmlljø som er gjort alkalisk med et basisk karbonat,in acetone-mll water which has been made alkaline with a basic carbonate,

til 2-metoksy-5-sulfamoyl-benzamid II med struktur (S)X-). ? to 2-methoxy-5-sulfamoyl-benzamide II of structure (S)X-). ?

N-/I-etyl-2-pyrrolidinyi7-metyl-2-metoksy-5-sulfamoyl-benzamidet N-/I-ethyl-2-pyrrolidinyi7-methyl-2-methoxy-5-sulfamoyl-benzamide

(S)(-;) som oppnås smelter ved 185 - 186°C (S)(-;) which is obtained melts at 185 - 186°C

Za/jp «-66.8° (c 0.5, D.M.F.)Za/jp «-66.8° (c 0.5, D.M.F.)

I den etterfølgende tabell ér angitt forbindelser I oppnådd ved fremgangsmåten i-henhold til oppfinnelsen. The following table shows compounds I obtained by the method according to the invention.

Analyser, og IR og RMN har i hvert tilfelle bekreftet strukturen av de oppnådde forbindelser. Analyses, and IR and NMR have in each case confirmed the structure of the obtained compounds.

Smeltepunktene er bestemt ved hjelp av et Tottoli-apparat. The melting points are determined using a Tottoli apparatus.

Claims (11)

1. Fremgangsmåte for stereospesif ikle syntese av optisk aktive pyrrolidiner tilsvarende de symmetriske formler I (R) og1. Procedure for the stereospecific synthesis of optically active pyrrolidines corresponding to the symmetrical formulas I (R) and 1 (S) 1 (S) hvori R representerer enten et alkylradikal C^Rj med 1 til 5 karbonatomer idet Rj^ har 1 til . 4 karbonatomer eller står for et hydrogenatom.- eller et radikal med formel in which R represents either an alkyl radical C^Rj with 1 to 5 carbon atoms, Rj^ having 1 to . 4 carbon atoms or stands for a hydrogen atom.- or a radical with formula hvori A er rettkjedet eller forgrenet alkyl med 1 til 4 karbonatomer og R2 , R3 og R4 står hver for seg for hydrogen, halogen, spesielt klor eller fluor, trifluormetyl, trifluormetoksy, trifluormetyltio, alkyl méd 1 til 4 karbonatomer eller alkoksy med 1 til 4 karbonatomer,- eller et radikal med formel wherein A is straight or branched chain alkyl of 1 to 4 carbon atoms and R 2 , R 3 and R 4 each stand for hydrogen, halogen, especially chlorine or fluorine, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms, - or a radical of the formula hvori A er rett eller forgrenet alkyl med 1 til -4 karbonatomer og m er 2, 3, 4 eller 5, karakterisert ved at en aminosyre, glutaminsyre eller prolin (R) eller (S) eller en forbindelse avledet fra de sistnevnte forbindelser (pyrcglutaminsyre, prolinol) ved en rekke kondensasjoner, forestringer, forsepninger, amideringer, ringslutninger og reduksjoner via mellomprodukt© pyrrolidiner omfattende et asymmetrisk karbonatom i a-stilling til en aminert gruppe.wherein A is straight or branched alkyl of 1 to -4 carbon atoms and m is 2, 3, 4 or 5, characterized in that an amino acid, glutamic acid or proline (R) or (S) or a compound derived from the latter compounds (pyrcglutamic acid, prolinol) by a series of condensations, esterifications, saponifications, amidations, ring closures and reductions via intermediate © pyrrolidines comprising an asymmetric carbon atom in the a-position to an aminated group. 2. Fremgangsmåte som angitt i krav 1, karakterisert ved at man går ut fra prolinet (S) eller (R) og forestrer, esteren omdannes til amidet, man acylerer på nitrogenatornet av 2-karbamoyl-pyrrolidin oppnådd ved hjelp av en forbindelse R <*> COOH eller et av dens derivater (kloridet eller anhydridet) til lrr acyl-2-karbamoyl-pyrrolidin som reduseres til 2-aminometyl-pyrrolidin KS) eller (R) som på nitrogenatornet barer radikalet R, idet R har den ovennevnte betydning og R• er- enten (H eller alkyl med 1 til 4 karbonatomer) ;A* » en binding eller alkylen med 1 til 3 karbonatomer.2. Procedure as stated in claim 1, characterized in that one starts from the proline (S) or (R) and esterifies, the ester is converted to the amide, one acylates on the nitrogen atom of 2-carbamoyl-pyrrolidine obtained by means of a compound R <*> COOH or one of its derivatives ( the chloride or the anhydride) to lrr acyl-2-carbamoyl-pyrrolidine which is reduced to 2-aminomethyl-pyrrolidine KS) or (R) which bears the radical R on the nitrogen atom, R having the above meaning and R• being either (H or alkyl with 1 to 4 carbon atoms) ;A* » a bond or alkylene with 1 to 3 carbon atoms. 3. Fremgangsmåte som angitt 1 krav 1, karakterisert ved at man går ut fra glutaminsyre (R) eller (S) som ringsluttes.til syren R-l 2-okso-pyrrolidin-5-karboksylsyre ved behandling i rekkefølge med et aldehyd R <»> CHO, reduksjon og sur ringslutning^ den oppnådde syre forestres og den oppnådde ester omdannes til amidet og dette reduseres til R-l 2-aminometyl-pyrrolidin i (R) eller (S), idet R har den ovennevnte betydning.3. Method as set forth in claim 1, characterized in that one starts from glutamic acid (R) or (S) which is ring-closed to the acid R-1 2-oxo-pyrrolidine-5-carboxylic acid by treatment in sequence with an aldehyde R <»> CHO, reduction and acidic cyclization^ the obtained acid is esterified and the ester obtained is converted to the amide and this is reduced to R-1 2-aminomethyl-pyrrolidine in (R) or (S), R having the above meaning. 4. Fremgangsmåte som angitt i krav 1, karakterisert ved at man går ut fra naturlig glutaminsyre (S) som ringsluttes og racemiseres til pyrD glutaminsyre som omdannes til racemisk alkylester og denne omsettes med en forbindelse RX (R har den betydning som er angitt i krav 1 og X er et halogen), R-l 2-okso-5-alkoksykarbonyl-pyrrolidin forsepes, R-l 2-okso-5-karboksy-pyrrolidinet spaltes til den ønskede optiske isomere som forestres og esteren amideres og til- slutt reduséres R-l 2-okso-5-karbamoyl-pyrrolidinet til R-l 2-aminometyl-pyrrolidinet I (R) eller (S).4. Procedure as stated in claim 1, characterized by starting from natural glutamic acid (S) which is cyclized and racemized to pyrD glutamic acid which is converted into racemic alkyl ester and this is reacted with a compound RX (R has the meaning stated in claim 1 and X is a halogen), R-l 2-oxo-5-alkoxycarbonyl-pyrrolidine is saponified, the R-l 2-oxo-5-carboxy-pyrrolidine is cleaved to the desired optical isomer which is esterified and the ester is amidated and finally the R-l 2-oxo-5-carbamoyl-pyrrolidine is reduced to R-l 2 -aminomethyl-pyrrolidine I (R) or (S). 5.F remgangsmåte som angitt i krav 1, karakterisert ved' at man går' ut fra prolinol (R) eller (S) som behandles med et klorid av syren R^OCl (R' har den betydning som er gitt i krav 2), hvoretter esterfunksjonen i den oppnådde amidoester forsepes, det oppnådde l-acyl-2-hydroksymetyl-pyrrolidin omdannes til halogenert derivat som behandles med natriumazid og dét oppnådde åzid reduseres til R-l 2-aminometyl-pyrrolidin I (R) eller (S) hvonrR har den betydning som er gitt i krav 1.5. Process as stated in claim 1, characterized in that one starts from prolinol (R) or (S) which is treated with a chloride of the acid R^OCl (R' has the meaning given in claim 2) , after which the ester function in the obtained amido ester is saponified, the obtained 1-acyl-2-hydroxymethyl-pyrrolidine is converted into a halogenated derivative which is treated with sodium azide and the obtained azide is reduced to R-1 2-aminomethyl-pyrrolidine I (R) or (S) where R has the meaning given in claim 1. 6. Fremgangsmåte som angitt i krav 1—5, karakterisert ved at de endelige reduksjoner •' foretas ved hjelp av dobbelthydridet av litium og aluminium.6. Method as stated in claims 1-5, characterized in that the final reductions are carried out using the double hydride of lithium and aluminium. 7. Fremgangsmåte som angitt i krav 4, karakterisert ved at spaltingen gjennomføres ved hjelp av L-tyrosin-hydrazid.7. Procedure as stated in claim 4, characterized in that the cleavage is carried out using L-tyrosine hydrazide. 8. Optisk aktive pyrrolidiner med generelle formler 8. Optically active pyrrolidines with general formulas hvori R representerer enten et alkylradikal Cfr^R^ med 1 til 5 karbonatomer hvor Ry har 1 til 4 karbonatomer eller står for et hydrogenatom- eller et radikal med formel where R represents either an alkyl radical Cfr^R^ with 1 to 5 carbon atoms where Ry has 1 to 4 carbon atoms or stands for a hydrogen atom or a radical with the formula hvori A er rettkjedet eller forgrenet alkyl med 1 til 4 karbonatomer og R2, Rj og R^ står Hver for seg for hydrogen, halogen, spesielt klor eller fluor, trifluormetyl, trifluormetoksy, trifluormetyltio, alkyl med 1 til 4 karbonatomer eller alkoksy med .1 til 4 karbonatomer,- eller et radikal med formel wherein A is straight or branched chain alkyl of 1 to 4 carbon atoms and R2, Rj and R^ each stand for hydrogen, halogen, in particular chlorine or fluorine, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, alkyl with 1 to 4 carbon atoms or alkoxy with .1 to 4 carbon atoms, - or a radical of the formula hvori Å er rettkjedet eller forgrenet alkyl med 1 til 4 karbonatomer og m er 2, 3, 4 eller 5.wherein Å is straight or branched chain alkyl of 1 to 4 carbon atoms and m is 2, 3, 4 or 5. 9. Pyrrolidiner som angitt i krav 8, karakterisert ved at R er et radikal 9. Pyrrolidines as stated in claim 8, characterized in that R is a radical 10. Pyrrolidiner som angitt i krav 8, karakterisert ved at R er et. radikal 10. Pyrrolidines as stated in claim 8, characterized in that R is et. radical 11. Anvendelse av pyrrolidineit I (R) eller I (S) for syntese av benzamider svarende til formel II 11. Use of pyrrolidineite I (R) or I (S) for the synthesis of benzamides corresponding to formula II hvori R har den ovennevnte betydning og X ,står for ét kloratom, et radikal S02 R^ .eller S02 N RgR 7 hvori Rj. betyr radikal med 1 til 4. karbonatomer og R^: og Ry, som er. like eitler forskjellige, står for et hydrogenatom eller et alkylradikal med 1 til 4 karbonatomer.in which R has the above meaning and X stands for one chlorine atom, a radical S02 R^ .or S02 N RgR 7 in which Rj. means radical with 1 to 4 carbon atoms and R^: and Ry, which are. like or different, stand for a hydrogen atom or an alkyl radical with 1 to 4 carbon atoms.
NO772745A 1976-08-05 1977-08-04 PROCEDURES FOR THE PREPARATION OF N-SUBSTITUTED PYRROLIDINES NO772745L (en)

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FR7623910A FR2360572A1 (en) 1976-08-05 1976-08-05 Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals
FR7635476A FR2372157A1 (en) 1976-11-25 1976-11-25 Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals
FR7719391A FR2395261A2 (en) 1977-06-24 1977-06-24 Optically active (2)-amino-methyl-(1)-substd. pyrrolidine derivs. - intermediates for benzoylamino-methyl-pyrrolidine pharmaceuticals

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