DK143229B - METHOD OF ANALOGUE FOR THE PREPARATION OF (+, -) - CIS-ALFA- (3- (2,6-DIMETHYL-1-PIPERIDINYL) PROPYL) -ALFA-PHENYL-2-PYRIDINE METHANOL OR ACID ADDITION SALTS. - Google Patents

Description

(11) FREMLÆGGELSESSKRIFT 143229 DANMARK (51) int.ci.3 c 07 d ao 1 /06 «(21) Ansøgning nr. 752/78 (22) Indleveret den 17· fcb. 1978 (24) Løbedag 17· f©b· 1978 (44) Ansøgningen fremlagt og fremlaeggelsesskriftet offentliggjort den 27 · juli 1 981 DIREKTORATET FOR u , .(11) PUBLICATION 143229 DENMARK (51) int.ci.3 c 07 d ao 1/06 '(21) Application No 752/78 (22) Filed on 17 · fcb. 1978 (24) Race day 17 · f © b · 1978 (44) The application presented and the petition published on 27 · July 1 981 DIRECTORATE FOR u,.

PATENT-OG VAREMÆRKEVÆSENET 0°) Prioritet begæret fradenPATENT AND TRADEMARKET SYSTEM 0 °) Priority requested the claim

25. feb. 1977., 772205, USFeb 25 1977., 772205, US

(41) Aim. tilg. 26. aug. 1978 (7i) PARKE DAVIS & COMPANY, Joseph Campau at the River, Detroit, Michigan 148207, US.(41) Aim. avail. Aug 26 1978 (7i) PARKE DAVIS & COMPANY, Joseph Campau at the River, Detroit, Michigan 148207, US.

(72) Opfinder: Robert Willerton Fleming, 2672 Roseland, Ann Arbor, Michigan 48105, US.(72) Inventor: Robert Willerton Fleming, 2672 Roseland, Ann Arbor, Michigan 48105, US.

(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:

Internationalt Patent-Bureau.International Patent Office.

(54> Analogifremgangsmåde til fremstilling af (+,-)-cis-alfa- (5- (2,6-di« methyl-1 -piperidinyl)propyl)-alfa-phenyl-2-pyridinmethanol eller sy=* readditionssalte heraf.(54> Analogous process for the preparation of (+, -) - cis-alpha- (5- (2,6-dimethyl-1-piperidinyl) propyl) -alpha-phenyl-2-pyridine methanol or its acid addition salts.

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af den hidtil ukendte forbindelse (+,-)-cis-a- [3- (2,6-dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridinmethanol, som har formlenThe present invention relates to an analogous process for the preparation of the novel compound (+, -) - cis-α- [3- (2,6-dimethyl-1-piperidinyl) propyl] -α-phenyl-2-pyridine methanol having formula

CiLf CH3>—xCiLf CH3> -x

^N^6-(CH2)3-N \ IN - 6- (CH 2) 3-N

cfi< \-/ 6 5 CH3^^ eller syreadditionssalte heraf, hvilke forbindelser kan anvendes til behandling af hjertearrhythmi.cfi </ - / 6 5 CH 3 ^^ or acid addition salts thereof, which compounds can be used to treat cardiac arrhythmia.

143229 2143229 2

Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte.The process according to the invention is characterized by the characterizing part of the claim.

Ved fremgangsmåde a) fremstilles de omhandlede forbindelser ved, at man omsætter en forbindelse med formlen .In process a), the compounds of the invention are prepared by reacting a compound of the formula.

^isr Li med en forbindelse med formlen CH,is Li with a compound of formula CH,

0 K0 K

Cz-Hc-C—(CH-) N \ IIIC2-Hc-C— (CH-) N \ III

6 5 2 3 s?6 5 2 3 s?

CH-CH

med cis-konfiguration.with cis configuration.

Denne omsætning udføres almindeligvis i et opløsningsmiddel, såsom en ether (diethylether, tetrahydrofuran eller diethylenglycol-dimethylether), et carbonhydrid (benzen, toluen, hexan eller heptan). eller blandinger heraf i et tidsrum på fra 1 til 12 timer ved fra -80°C til +10°C, fortrinsvis i 1 til 2 timer ved -60°C til -80°C efterfulgt af 1 til 3 timer ved fra -5°C til +5°C. I det foretrukne opløsningsmiddelsystem anvendes der tetrahydrofuran, eventuelt blandet med heptan.This reaction is generally carried out in a solvent such as an ether (diethyl ether, tetrahydrofuran or diethylene glycol dimethyl ether), a hydrocarbon (benzene, toluene, hexane or heptane). or mixtures thereof for a period of from 1 to 12 hours at -80 ° C to + 10 ° C, preferably for 1 to 2 hours at -60 ° C to -80 ° C followed by 1 to 3 hours at from -5 ° C to + 5 ° C. In the preferred solvent system, tetrahydrofuran, optionally mixed with heptane, is used.

Medens der bør anvendes mindst 1 mol pyridyllithium (II) for hvert mol piperidinforbindelse (III), foretrækkes et overskud af li-thiumforbindelsen.While at least 1 mole of pyridyllithium (II) should be used for each mole of piperidine compound (III), an excess of the lithium compound is preferred.

Det som mellemprodukt dannede metalderivat af en forbindelse med formlen I hydrolyseres under sure (fortyndet vandig saltsyre, vandigt ammoniumchlorid eller fortyndet vandig svovlsyre), neutrale eller basiske (fortyndet vandigt natriumhydroxid eller fortyndet vandigt kaliumhydroxid) betingelser, fortrinsvis neutrale betingelser.The intermediate metal derivative of a compound of formula I is hydrolyzed under acidic (dilute aqueous hydrochloric acid, aqueous ammonium chloride or dilute aqueous sulfuric acid), neutral or basic (dilute aqueous sodium hydroxide or dilute aqueous potassium hydroxide) conditions, preferably neutral conditions.

Produktet kan isoleres som den frie base eller som et syreadditionssalt heraf ved passende indstilling af pH-værdien.The product can be isolated as the free base or as an acid addition salt thereof by adjusting the pH value.

Cis-γ- (2,6-dimethylpiperidino) butyrophenonet kan fremstilles ved at omsætte et overskud af cis-2,6-dimethylpiperidin med γ-chlorbuty-rophenon-ethylenketal i nærværelse af natriumiodid under tilbagesvaling i ca. 48 timer, efterfulgt af hydrolyse af den dannede aminoke-tal med vandig saltsyre og derefter basificering med vandigt natriumhydroxid .The cis-γ- (2,6-dimethylpiperidino) butyrophenone can be prepared by reacting an excess of cis-2,6-dimethylpiperidine with γ-chlorobutyrophenone-ethylene ketal in the presence of sodium iodide under reflux for approx. 48 hours, followed by hydrolysis of the resulting amino acid number with aqueous hydrochloric acid and then basification with aqueous sodium hydroxide.

3 143229 γ-Chlorbutyrophenon-ethylenketalet kan fremstilles ved at ansætte γ-chlorbutyrophenon med ethylenglycol under anvendelse af p-toluen-sulfonsyre som katalysator. Omsætningen udføres under anvendelse af benzen som opløsningsmiddel og med en vandfælde indskudt i reaktionssystemet. Reaktionsblandingen tilbagesvalés, indtil den ønskede mængde vand er opsamlet/ hvorefter man neutraliserer syren og fjerner opløsningsmidlet .Γ-Chlorobutyrophenone-ethylene ketal can be prepared by employing γ-chlorobutyrophenone with ethylene glycol using p-toluene sulfonic acid as a catalyst. The reaction is carried out using benzene as the solvent and with a water trap inserted into the reaction system. The reaction mixture is refluxed until the desired amount of water is collected and then the acid is neutralized and the solvent removed.

Ved fremgangsmåde b) fremstilles de omhandlede forbindelser ved, at man omsætter en forbindelse med formlen _In process b), the compounds of the invention are prepared by reacting a compound of the formula:

<N-(CH-),-Li IV<N- (CH -), - Li IV

_/ ch3 med cis-konfiguration med 2-benzoylpyridin i et egnet opløsningsmiddel, såsom en ether (diethylether, tetrahydrofuran eller diethylen-glycoldimethylether) i fra 4 til 24 timer ved 0°C til 60°C. Under de foretrukne reaktionsbetingelser anvendes tetrahydrofuran som opløsningsmiddel og en reaktionstid på fra 12 til 18 timer ved en temperatur i området fra 20°C til 35°C.cis with cis configuration with 2-benzoylpyridine in a suitable solvent such as an ether (diethyl ether, tetrahydrofuran or diethylene glycol dimethyl ether) for from 4 to 24 hours at 0 ° C to 60 ° C. Under the preferred reaction conditions, tetrahydrofuran is used as the solvent and a reaction time of from 12 to 18 hours at a temperature in the range of 20 ° C to 35 ° C.

Det foretrækkes at anvende omtrent ækvivalente mængder af li-thiumderivatet med formlen IV og 2-benzoylpyridin.It is preferred to use approximately equivalent amounts of the lithium derivative of formula IV and 2-benzoylpyridine.

Det som mellemprodukt dannede metalderivat af en forbindelse med formlen I hydrolyseres under sure (fortyndet vandig saltsyre, vandigt ammoniumchlorid eller fortyndet vandig svovlsyre), neutrale eller basiske (fortyndet vandigt natriumhydroxid eller fortyndet vandigt kaliumhydroxid) betingelser, fortrinsvis neutrale betingelser.The intermediate metal derivative of a compound of formula I is hydrolyzed under acidic (dilute aqueous hydrochloric acid, aqueous ammonium chloride or dilute aqueous sulfuric acid), neutral or basic (dilute aqueous sodium hydroxide or dilute aqueous potassium hydroxide) conditions, preferably neutral conditions.

Produktet kan isoleres som den frie base eller som et syreadditionssalt heraf ved passende indstilling af pH-værdien.The product can be isolated as the free base or as an acid addition salt thereof by adjusting the pH value.

Cis-1-(3-lithiopropyl)-2,6-dimethylpiperidinet fremstilles ved af omsætte 1 ækvivalent cis-1-(3-chlorpropyl)-2,6-dimethylpiperi-din med 2 ækvivalenter lithium over et tidsrum på 6 timer i tetrahydrofuran. Efter filtrering omsættes den opnåede opløsning direkte med benzophenon.The cis-1- (3-lithiopropyl) -2,6-dimethylpiperidine is prepared by reacting 1 equivalent of cis-1- (3-chloropropyl) -2,6-dimethylpiperidine with 2 equivalent of lithium over a period of 6 hours in tetrahydrofuran . After filtration, the solution obtained is reacted directly with benzophenone.

Cis-1-(3-chlorpropyl)-2,6-dimethy]piperidinet kan fremstilles ved at omsætte thionylchlorid med cis-2,6-dimethyl-l-piperidinpropanol i benzen ved en temperatur på fra 0°C til 5°C i 30 minutter efterfulgt af 2 timers tilbagesvaling. Det chlorerede produkt isoleres som hy-drochloridet ved filtrering.The cis-1- (3-chloropropyl) -2,6-dimethyl] piperidine can be prepared by reacting thionyl chloride with cis-2,6-dimethyl-1-piperidine propanol in benzene at a temperature of from 0 ° C to 5 ° C. 30 minutes followed by 2 hours of reflux. The chlorinated product is isolated as the hydrochloride by filtration.

143229 4143229 4

Cis-2,6-dimethyl-1-piperidinpropanolet kan fremstilles ved at ansætte 3-brompropanol med et overskud af cis-2,6-dimethylpiperidin i tilbagesvalende xylen i et tidsrum på ca. 2 timer. Cis-2,6-dimethyl-1-piperidinpropanolet fraskilles ved destillation.The cis-2,6-dimethyl-1-piperidine propanol can be prepared by employing 3-bromopropanol with an excess of cis-2,6-dimethylpiperidine in refluxing xylene for a period of approx. 2 hours. The cis-2,6-dimethyl-1-piperidine propanol is separated by distillation.

Den frie base med formlen I danner syreadditionssalte , som også falder ind under de omhandlede forbindelser, med en vilkårlig af mange forskellige uorganiske og organiske syrer. Typiske syread-ditionssalte dannes med sådanne syrer som saltsyre, hydrogenbromid-syre, svovlsyre, sulfaminsyre, salpetersyre, phosphorsyre, eddikesyre, citronsyre, vinsyre, ravsyre, oxalsyre, benzoesyre, maleinsyre, æblesyre, mælkesyre, gluconsyre, naphthalen-l,5-disulfonsyre, methan-sulfonsyre, p-toluensulfonsyre og pamoesyre. De frie baser og deres saltformer kan gensidigt omdannes til hinanden ved indstilling af pH-værdien. De adskiller sig med hensyn til opløselighedsegenskaber, men er i øvrigt ækvivalente med hensyn til opfindelsens formål.The free base of formula I forms acid addition salts, which also fall under the compounds of this invention, with any of a variety of inorganic and organic acids. Typical acid addition salts are formed with such acids as hydrochloric, hydrobromic, sulfuric, sulfamic, nitric, phosphoric, acetic, citric, tartaric, succinic, oxalic, benzoic, maleic, malic, lactic, gluconic, naphthalic, naphthalic, , methanesulfonic acid, p-toluenesulfonic acid and pamoic acid. The free bases and their salt forms can be mutually converted by adjusting the pH. They differ in solubility properties, but are otherwise equivalent to the purposes of the invention.

De omhandlede forbindelser kan foreligge såvel i vandfri form som i solvatiserede og herunder hydratiserede former. Almindeligvis er de hydratiserede former og de solvatiserede former med farmaceutisk acceptable opløsningsmidler ækvivalente med de vandfri eller usolvatiserede former med hensyn til opfindelsens formål. De omhandlede forbindelser kan også opnås som R- og S-isomere ved sædvanlige opspaltningsmetoder.The compounds of the invention can be present in both anhydrous and solvated and including hydrated forms. Generally, the hydrated forms and the solvated forms with pharmaceutically acceptable solvents are equivalent to the anhydrous or unsolvated forms for the purposes of the invention. The compounds of the invention can also be obtained as R and S isomers by conventional cleavage methods.

De omhandlede, hidtil ukendte forbindelser har værdifulde farmakologiske virkninger. Nærmere angivet har disse forbindelser antiarrhytmisk virkning.The novel compounds of the invention have valuable pharmacological effects. More specifically, these compounds have antiarrhythmic effects.

Fra britisk patentskrift nr. 682.160 kendes der med de omhandlede forbindelser nært beslægtede forbindelser med formlen R]\ Z*3 /f " (CH2>n V R^ OH ^R4 hvori R1 og R2 hver især kan være en phenyl- eller pyridylgruppe, og NRgRj kan være en eventuelt med én eller flere alkylgrupper substitueret piperidinogruppe, medens n er et helt tal fra 4 til 10. Om disse forbindelser angives det imidlertid kun kort, at de er nyttige som terapeutiske midler uden nærmere præcisering.British Patent No. 682,160 discloses closely related compounds of the formula R] \ Z * 3 / f "(CH 2> n VR NRgRj may be an optionally substituted piperidino group with one or more alkyl groups, while n is an integer from 4 to 10. However, these compounds are briefly stated to be useful as therapeutic agents without further clarification.

Fra US-patentskrift nr. 2.712.022 kendes der med de omhandlede forbindelser nært beslægtede forbindelser med formlen 5 143229U.S. Pat. No. 2,712,022 discloses closely related compounds of formula 5

R1 .ORR1 .OR

\ / 2\ / 2

- CH2 CH2 N = R- CH2 CH2 N = R

Gå 1 2 hvori R kan være en phenyl gruppe, og N=R kan være en piperidmo- gruppe. Om disse forbindelsers terapeutiske egenskaber angives det til nærmere præcisering kun, at de har værdifulde antihistaminegenskaber.Go 1 2 wherein R may be a phenyl group and N = R may be a piperidine group. As to the therapeutic properties of these compounds, it is stated, more precisely, that they have valuable antihistamine properties.

På denne baggrund er de her omhandlede forbindelsers anti-arrhytmiske virkning overraskende.Against this background, the anti-arrhythmic effect of the compounds of this invention is surprising.

Virkningen af de omhandlede forbindelser eftervistes ved følgende antiarrhytmiske screen-prøve.The effect of the subject compounds was demonstrated by the following antiarrhythmic screen test.

Hunde opereredes efter åbn procedure, der er rapporteret i Circulation 1, 1318 (1950). ( + ,-)-cis-a-[,3-(2,6-Dimethyl-l-piperidi-nyl)propyl]-a-phenyl-2-pyridinmethanol, lidocain og quinidin afprøvedes intravenøst 19 til 24 timer efter coronararterieunderbinding. Graden af forbindelsens effektivitet bestemtes ved graden af omdannelse af ventrikulære ekstrasystoler til sinus-slag. I nedenstående tabel er der angivet resultaterne af screen-prøven foretaget på (+,-)-cis-α- [3-(2,6-dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridinmetha-nol og de kendte antiarrhytmiske midler lidocain og quinidin.Dogs were operated according to open procedure reported in Circulation 1, 1318 (1950). (+, -) - cis-α - [, 3- (2,6-Dimethyl-1-piperidinyl) propyl] -α-phenyl-2-pyridine methanol, lidocaine and quinidine were tested intravenously 19 to 24 hours after coronary artery ligation. The degree of compound efficiency was determined by the degree of conversion of ventricular extrasystoles into sinus strokes. The following table shows the results of the screen test performed on (+, -) - cis-α- [3- (2,6-dimethyl-1-piperidinyl) propyl] -α-phenyl-2-pyridine methanol and the known antiarrhythmic agents lidocaine and quinidine.

TabelTable

Forbindelse Dosis_Tid efter dosis_% OmdannelseConnection Dose_Time after dose_% Conversion

Lidocain 10 mg/kg i.v. 5 min. 92 20 min. 0 55 min. 0Lidocaine 10 mg / kg i.v. 5 min. 92 20 min. 0 55 min. 0

Quinidin 20 mg/kg i.v. 5 min. 66 20 min. 35 55 min. 41 (+,-)-cis-a- 5 mg/kg i.v. 2 min. 91 [3-(2,6-di- ./1. 20 mm. 76 methyl-1- piperidinyl)- 55 min. 66 propyl]-a- phenyl-2-pyri- dinmethanol £Quinidine 20 mg / kg i.v. 5 min. 66 20 min. 35 55 min. 41 (+, -) - cis-α- 5 mg / kg i.v. 2 min. 91 [3- (2,6-di- / 1. 20 mm. 76 methyl-1-piperidinyl) - 55 min. 66 propyl] -a-phenyl-2-pyridinemethanol

Dosis beregnet som fri base, afprøvet som salte.Dose calculated as free base, tested as salts.

143229 6143229 6

Baseret på opfindelsen kan der tilvejebringes farmaceutiske præparater og metoder, hvori der anvendes (+,-)-cis-a-[3-(2,6-di-methyl-l-piperidinyl)propyl-a-phenyl-2-pyridinmethanol og farmaceutisk acceptable syreadditionssalte heraf. Som typiske eksempler på farmaceutisk acceptable syreadditionssaltformer kan der nævnes hy-drochloridet, sulfatet, phosphatet, citratet, pamoatet, acetatet og maleatet.Based on the invention, pharmaceutical compositions and methods may be provided employing (+, -) - cis-α- [3- (2,6-dimethyl-1-piperidinyl) propyl-α-phenyl-2-pyridine methanol and pharmaceutically acceptable acid addition salts thereof. Typical examples of pharmaceutically acceptable acid addition salt forms include the hydrochloride, sulfate, phosphate, citrate, pamoate, acetate and maleate.

Nærmere angivet er (+,-)-cis-[3-(2,6-dimethyl-l-piperidinyl)-propylJ-a-phenyl-2-pyridinmethanol og farmaceutisk acceptable syreadditionssalte heraf i høj grad nyttige til behandling af hjerte-arrhytmi hos pattedyr, såsom katte, hunde, heste eller mennesker, når de administreres i mængder i området fra ca. 0,1 mg til ca. 10 mg pr. kg legemsvægt pr. dag, og der benyttes sådanne doseringsenheder, at der i alt administreres fra ca. 7 mg til ca. 700 mg aktiv bestanddel til et individ af en legemsvægt på ca. 70 kg i en 24 timers periode, fortrinsvis i delte doser. Ifølge en foretrukken doseringsplan anvendes der fra 1 til 5 mg aktiv bestanddel pr. kg legemsvægt pr. dag, idet den totale daglige dosis deles i fire enheder, som hver tages efter et passende tidsinterval.More specifically, (+, -) - cis- [3- (2,6-dimethyl-1-piperidinyl) -propyl] -α-phenyl-2-pyridine methanol and pharmaceutically acceptable acid addition salts thereof are highly useful in the treatment of cardiac arrhythmia in mammals such as cats, dogs, horses or humans when administered in amounts ranging from about 0.1 mg to approx. 10 mg per kg body weight per per day, and such dosage units are used that a total of about 7 mg to approx. 700 mg of active ingredient for a subject of a body weight of approx. 70 kg in a 24 hour period, preferably in divided doses. According to a preferred dosing schedule, from 1 to 5 mg of active ingredient per day is used. kg body weight per day, dividing the total daily dose into four units, each taken after a suitable time interval.

De omhandlede forbindelser kan administreres ad vilkårlig bekvem vej, såsom oralt, intraperitonealt, subkutant, intramuskulært eller intravenøst.The present compounds may be administered by any convenient route, such as orally, intraperitoneally, subcutaneously, intramuscularly or intravenously.

Fremgangsmåden ifølge opfindelsen belyses nærmere ved hjælp af de efterfølgende eksempler.The process according to the invention is further elucidated by the following examples.

Eksempel 1Example 1

Ved -78°C sættes 180 ml af en 1,6 M opløsning af butyllithium i heptan til 200 ml tetrahydrofuran under omrøring. Blandingen omrøres under nitrogen, medens der langsomt tilsættes en opløsning af 43 g 2-brompyridin i 50 ml tetrahydrofuran, idet temperaturen holdes under -65°C. Efter omrøring i 1 time behandles blandingen med en opløsning af 65 g cis-γ-(2,6-dimethylpiperidino)butyrophenon i 70 ml tetrahydrofuran over et tidsrum på 10 minutter og omrøres ved -65 til -75°C i endnu 1 time. Blandingen omrøres, og man lader den opvarme til 0°C over et tidsrum på 2 timer, hvorefter man behandler den med 30 ml vand. Det overliggende organiske lag dekanteres fra det udfældede faste stof og inddampes under formindsket tryk til ca. 1/3 af dets oprindelige volumen. Remanensen hældes ud i 2,5 liter kold , fortyndet vandig: natriumhydroxidopløsning. Det opnåede bundfald af 143229 7 (+,-)-cis-α-[3-(2,6-dimethyl-1-piperidinyl)propyl]-a-phenyl-2-pyri-dinmethanol udvindes ved filtrering, vaskes med vand og tørres, smp. 70-71°C efter omkrystallisation af petroleumsether.At -78 ° C, 180 ml of a 1.6 M solution of butyllithium in heptane is added to 200 ml of tetrahydrofuran with stirring. The mixture is stirred under nitrogen while slowly adding a solution of 43 g of 2-bromopyridine in 50 ml of tetrahydrofuran, keeping the temperature below -65 ° C. After stirring for 1 hour, treat the mixture with a solution of 65 g of cis-γ- (2,6-dimethylpiperidino) butyrophenone in 70 ml of tetrahydrofuran over a period of 10 minutes and stir at -65 to -75 ° C for a further 1 hour. The mixture is stirred and allowed to warm to 0 ° C over a period of 2 hours, after which it is treated with 30 ml of water. The overlying organic layer is decanted from the precipitated solid and evaporated under reduced pressure to ca. 1/3 of its original volume. The residue is poured into 2.5 liters of cold, dilute aqueous sodium hydroxide solution. The resulting precipitate of (+, -) - cis-α- [3- (2,6-dimethyl-1-piperidinyl) propyl] -α-phenyl-2-pyridinemethanol is recovered by filtration, washed with water and dried, m.p. 70-71 ° C after recrystallization from petroleum ether.

Hvis produktet omkrystalliseres af vandigt methanol, dannes der et monohydrat, smp. 101-102°C.If the product is recrystallized from aqueous methanol, a monohydrate is formed, m.p. 101-102 ° C.

Monohydrochloridsaltet fremstilles ved at opløse den vandfri frie base i 2-propanol og tilsætte en ækvivalent mængde af en 10%’s opløsning af tørt hydrogenchlorid i 2-propanol, efterfulgt af fortynding med ether og frafiltrering af det udfældede salt, smp. 171-172°C.The monohydrochloride salt is prepared by dissolving the anhydrous free base in 2-propanol and adding an equivalent amount of a 10% dry hydrogen chloride solution in 2-propanol, followed by dilution with ether and filtration of the precipitated salt, m.p. 171-172 ° C.

Mellemprodukter a) cis-γ- (2,6-Dimethylpiperidino)butyrophenon.Intermediates a) cis-γ- (2,6-Dimethylpiperidino) butyrophenone.

En blanding af 619 g γ-chlorbutyrophenon-ethylenketal, 700 g cis-2,6-dimethylpiperidin og 16 g natriumiodid omrøres og opvarmes under tilbagesvaling i 48 timer. Blandingen afkøles, fortyndes med 1 liter vandfri ether og filtreres til fjernelse af cis-2,6-dimethyl-piperidin-hydrochlorid. Filterkagen vaskes med 1 liter ether, og filtratet og vaskevæskerne hældes sammen. Den opnåede etheropløsning vaskes 5 gange med 500 ml-portioner af vand og ekstraheres derpå med en opløsning af 300 ml koncentreret saltsyre i 3 liter vand. Den sure ekstrakt vaskes med 500 ml ether og opvarmes derpå til 70-80°C, hvorefter man lader den afkøle til stuetemperatur over et tidsrum på 16 timer. Den opnåede opløsning gøres basisk med 50%'s vandig natriumhydroxidopløsning, og det organiske lag fraskilles. Det vandige lag ekstraheres med 500 ml ether, og ekstrakten hældes sammen med det organiske lag. Den samlede ekstrakt vaskes flere gange med vand, tørres og inddampes. Den olieagtige remanens destilleres under formindsket tryk til opnåelse af cis-γ-(2,6-dimethylpiperidino)butyrophenon, kp. 138-141°C/0,1 mm Hg.A mixture of 619 g of γ-chlorobutyrophenone-ethylene ketal, 700 g of cis-2,6-dimethylpiperidine and 16 g of sodium iodide is stirred and heated under reflux for 48 hours. The mixture is cooled, diluted with 1 liter of anhydrous ether and filtered to remove cis-2,6-dimethyl-piperidine hydrochloride. The filter cake is washed with 1 liter of ether and the filtrate and washings are combined. The ether solution obtained is washed 5 times with 500 ml portions of water and then extracted with a solution of 300 ml of concentrated hydrochloric acid in 3 liters of water. The acidic extract is washed with 500 ml of ether and then heated to 70-80 ° C, then allowed to cool to room temperature over a period of 16 hours. The solution obtained is made basic with 50% aqueous sodium hydroxide solution and the organic layer is separated. The aqueous layer is extracted with 500 ml of ether and the extract is combined with the organic layer. The combined extract is washed several times with water, dried and evaporated. The oily residue is distilled under reduced pressure to give cis-γ- (2,6-dimethylpiperidino) butyrophenone, b.p. 138-141 ° C / 0.1 mm Hg.

b) γ-Chlorbutyrophenon-ethylenketal.b) γ-Chlorobutyrophenone-ethylene ketal.

En blanding af 500 g γ-butyrophenon, 225 g ethylenglycol, 10 g p-toluensulfonsyre og 1,5 liter benzen opvarmes under tilbagesvaling under en vandseparator, indtil vandopsamlingen ophører. Den opnåede opløsning afkøles, neutraliseres med 10 ml triethylamin og inddampes under formindsket tryk til opnåelse af γ-chlorbutyrophenon-ethylenketal, der er egnet til anvendelse uden yderligere rensning. (Det rene stof koger ved 100-118°C/0,l-0,8 mm Hg og smelter ved 57-59°C).A mixture of 500 g of γ-butyrophenone, 225 g of ethylene glycol, 10 g of p-toluenesulfonic acid and 1.5 liters of benzene is heated under reflux under a water separator until the water collection ceases. The solution obtained is cooled, neutralized with 10 ml of triethylamine and evaporated under reduced pressure to give γ-chlorobutyrophenone-ethylene ketal suitable for use without further purification. (The pure substance boils at 100-118 ° C / 0.1-1.8 mm Hg and melts at 57-59 ° C).

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Eksempel 2Example 2

En opløsning af 18,9 g cis-1-(3-chlorpropyl)-2,6-dimethylpipe-ridin i 50 ml tetrahydrofuran sættes dråbevis under en nitrogenat-mosfære til en omrørt blanding af 1,4 g lithiumtråd og 50 ml tetrahydrofuran over et tidsrum på 2 timer. Efter endt tilsætning omrøres blandingen i endnu 4 timer under nitrogen, overskuddet af lithiumme-tal fjernes manuelt, og en opløsning af 18,3 g 2-benzoylpyridin i 100 ml tetrahydrofuran tilsættes dråbevis under omrøring over et tidsrum på 2 timer. Blandingen omrøres i 16 timer og behandles derefter med 5 ml vand. Den organiske fase dekanteres fra det udfældede faste stof og inddampes under formindsket tryk til ca. 1/4 af dets oprindelige volumen. Denne opløsning hældes ud i 400 ml vand, og opløsningen syr-nes med eddikesyre og vaskes med ether. Den vandige sure opløsning gøres basisk med vandig natriumhydroxidopløsning og ekstraheres med ether. Etherekstrakten vaskes med vand, tørres og inddampes til opnåelse af (+,-)-cis-a-[3-(2,6-dimethyl-l-piperidinyl)propyl]-a-phenyl-2-pyridinmethanol, smp. (monohydrat) 100-102°C efter omkrystallisation af vandigt methanol.A solution of 18.9 g of cis-1- (3-chloropropyl) -2,6-dimethylpiperidine in 50 ml of tetrahydrofuran is added dropwise under a nitrogen atmosphere to a stirred mixture of 1.4 g of lithium wire and 50 ml of tetrahydrofuran. a period of 2 hours. After the addition is complete, the mixture is stirred for another 4 hours under nitrogen, the excess lithium metal is manually removed and a solution of 18.3 g of 2-benzoylpyridine in 100 ml of tetrahydrofuran is added dropwise with stirring over a period of 2 hours. The mixture is stirred for 16 hours and then treated with 5 ml of water. The organic phase is decanted from the precipitated solid and evaporated under reduced pressure to ca. 1/4 of its original volume. This solution is poured into 400 ml of water and the solution is acidified with acetic acid and washed with ether. The aqueous acidic solution is made basic with aqueous sodium hydroxide solution and extracted with ether. The ether extract is washed with water, dried and evaporated to give (+, -) - cis-α- [3- (2,6-dimethyl-1-piperidinyl) propyl] -α-phenyl-2-pyridine methanol, m.p. (monohydrate) 100-102 ° C after recrystallization from aqueous methanol.

Mellemprodukter a) cis-1-(3-Chlorpropyl)-2,6-dimethylpiperidin.Intermediates a) cis-1- (3-Chloropropyl) -2,6-dimethylpiperidine.

En omrørt opløsning af 171 g cis-2,6-dimethyl-l-piperidinpro-pariol i 400 ml benzen afkøles til 0-5°C, og 143 g thionylchlorid tilsættes dråbevis over et tidsrum på 30 minutter. Blandingen opvarmes derpå under tilbagesvaling i 2 timer, afkøles og fortyndes med 1 liter ether. Den dannede bundfald af cis-l~(3-chlorpropyl)-2,6-dime-thylpiperidin-hydrochlorid opsamles ved filtrering, smp. 173-174°C efter omkrystallisation af 2-propanol-ether. Den frie base fremstilles om ønsket ved opløsning af hydrochloridet i en minimal mængde vand, afkøling og tilsætning af et ringe overskud af 50%1 s vandig natriumhydroxidopløsning. Den frigjorte base ekstraheres straks med flere portioner benzen. Ekstrakterne hældes sammen, tørres og inddampes til opnåelse af den frie base, cis-1-(3-chlorpropyl)-2,6-dimethylpiperidin .A stirred solution of 171 g of cis-2,6-dimethyl-1-piperidine propiol in 400 ml of benzene is cooled to 0-5 ° C and 143 g of thionyl chloride is added dropwise over a period of 30 minutes. The mixture is then refluxed for 2 hours, cooled and diluted with 1 liter of ether. The resulting precipitate of cis-1- (3-chloropropyl) -2,6-dimethylpiperidine hydrochloride is collected by filtration, m.p. 173-174 ° C after recrystallization from 2-propanol ether. The free base is prepared, if desired, by dissolving the hydrochloride in a minimal amount of water, cooling and adding a slight excess of 50% 1 s aqueous sodium hydroxide solution. The released base is immediately extracted with several portions of benzene. The extracts are combined, dried and evaporated to give the free base, cis-1- (3-chloropropyl) -2,6-dimethylpiperidine.

b) cis-2,6-Dimethyl-l-piperidinpropanol.b) cis-2,6-Dimethyl-1-piperidine propanol.

En omrørt opløsning af 460 g cis-2,6-dimethylpiperidin i 300 ml xylen behandles med 278 g 3-brompropanol over et tidsrum på 15 minutter. Blandingen omrøres og opvarmes under tilbagesvaling i 2 ti-A stirred solution of 460 g of cis-2,6-dimethylpiperidine in 300 ml of xylene is treated with 278 g of 3-bromopropanol over a period of 15 minutes. The mixture is stirred and heated under reflux for 2 hours.