NO175590B

NO175590B - Analogous Process for Preparation of 2-Imino-3-Heterocyclylalkylbenzothiazoline Derivatives and Their Preparation

Info

Publication number: NO175590B
Application number: NO903113A
Authority: NO
Inventors: Patrick Jimonet; Joseph Le Blevec; Conception Nemecek
Original assignee: Rhone Poulenc Sante
Priority date: 1989-07-13
Filing date: 1990-07-12
Publication date: 1994-07-25
Also published as: SK278908B6; FI93109C; FI93109B; EP0409692A3; ES2062445T3; DE69007196T2; CZ281164B6; FI903531A0; NO903113D0; DK0409692T3; PT94701B; AU624972B2; ATE102612T1; AU5884790A; EP0409692B1; PT94701A; CZ342590A3; SK342590A3; JPH0386871A; NO903113L

Abstract

Compounds of formula: <IMAGE> in which R1 denotes a substituted 1-piperazinyl, substituted 1,2,3,6-tetrahydro-1-pyridyl or substituted piperidino radical, R2 denotes a polyfluoroalkoxy radical and n is equal to 2 or 3, salts of these compounds with an acid, processes for their preparation and medications containing them.

Description

Foreliggende oppfinnelsen angår en analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser med formelen: The present invention relates to an analogue method for the production of therapeutically active compounds with the formula:

deres salter, samt deres fremstilling og medikamenter inneholdende forbindelsene. their salts, as well as their preparation and medicaments containing the compounds.

I formel (I) betyr: In formula (I) means:

- Ri - Ride

en 1-piperazinylrest substituert i 4-posisjon med (a) en fenylrest, (b) en fenylrest som er substituert med minst en substituent valgt blant halogenatomer, alkyl- og alkoksyrester, a 1-piperazinyl residue substituted in the 4-position by (a) a phenyl residue, (b) a phenyl residue which is substituted by at least one substituent selected from halogen atoms, alkyl and alkoxy acid residues,

(c) en fenylalkylrest, (c) a phenylalkyl radical,

(d) en pyridylrest eller (d) a pyridyl residue or

(e) en pyrimidinylrest, (e) a pyrimidinyl residue,

en 1,2,3,6-tetrahydro-l-pyridylrest substituert i 4—posisjon med en fenylrest eller en fenylrest substituert med minst en substituent valgt blant halogenatomer, alkyl-og alkoksyrester, a 1,2,3,6-tetrahydro-1-pyridyl residue substituted in the 4-position with a phenyl residue or a phenyl residue substituted with at least one substituent selected from halogen atoms, alkyl and coco acid residues,

en piperidinorest substituert i 4—posisjon med en fenylrest eller en fenylrest substituert med minst en substituent valgt blant halogenatomer, alkyl- og alkoksyrester , a piperidine residue substituted in the 4-position with a phenyl residue or a phenyl residue substituted with at least one substituent selected from halogen atoms, alkyl and olefin residues,

R2 betyr en trifluormetoksyrest, R2 means a trifluoromethoxy acid residue,

n er lik 2 eller 3, n is equal to 2 or 3,

idet i disse definisjoner, alkyl- og alkoksyrester og alkyl-og alkoksydeler inneholder 1 til 4 karbonatomer i rett eller forgrenet kjede. in that in these definitions, alkyl and aldehyde residues and alkyl and aldehyde moieties contain 1 to 4 carbon atoms in a straight or branched chain.

Ealogenatomene er fortrinnsvis fluor-, klor- og bromatomer. The halogen atoms are preferably fluorine, chlorine and bromine atoms.

Oppfinnelsen angår likeledes addisjonssalter av forbindelsene med formel (I) med mineral- eller organiske syrer. The invention likewise relates to addition salts of the compounds of formula (I) with mineral or organic acids.

Forbindelsene med formel (I) kan fremstilles ved hydrolyse av et derivat med formelen: The compounds of formula (I) can be prepared by hydrolysis of a derivative with the formula:

der Ri, R2 og n har den samme betydning som under formel (I). where Ri, R2 and n have the same meaning as under formula (I).

Denne hydrolyse skjer generelt ved hjelp av en base, for eksempel et alkalimetallkarbonat, fortrinnsvis av natrium eller kalium, eller konsentrert ammoniakk, i nærvær av en blanding vann-alkohol, ved en temperatur nær 10°C. This hydrolysis generally takes place with the aid of a base, for example an alkali metal carbonate, preferably of sodium or potassium, or concentrated ammonia, in the presence of a water-alcohol mixture, at a temperature close to 10°C.

Derivatene med formel (II) kan oppnås ved innvirkning av et derivat med formelen: der R2 og n har den samme betydning som under formel (I) og R3 betyr en reaktiv gruppe, for eksempel en metansulfonyl-eller p-toluensulfonylgruppe, på et amin med formelen: The derivatives of formula (II) can be obtained by the action of a derivative of the formula: where R 2 and n have the same meaning as under formula (I) and R 3 means a reactive group, for example a methanesulfonyl or p-toluenesulfonyl group, on an amine with the formula:

der Ri har den samme betydning som under formel (I). where Ri has the same meaning as under formula (I).

Denne reaksjon skjer generelt i nærvær av et inert oppløs-ningsmiddel, for eksempel et aromatisk oppløsningsmiddel som benzen, toluen eller xylen, eller dimetylformamid, ved en temperatur mellom 20°C og oppløsningsmidlets koketemperatur. This reaction generally takes place in the presence of an inert solvent, for example an aromatic solvent such as benzene, toluene or xylene, or dimethylformamide, at a temperature between 20°C and the boiling temperature of the solvent.

Derivatene med formel (III) kan fremstilles ved innvirkning av et derivat med formelen: The derivatives with formula (III) can be prepared by the action of a derivative with the formula:

der R2 og n har den samme betydning som under formel (I), på metansulfonsyreklorid eller p-toluensulfonsyreklorid, enten i nærvær av et inert oppløsningsmiddel, for eksempel et aromatisk oppløsningsmiddel som benzen, toluen eller xylen, eller et klorert oppløsningsmiddel som for eksempel kloroform eller metylenklorid, i nærvær av et tertiært amin som trietylamin, ved en temperatur nær 20"C, eller i nærvær av pyridin ved en temperatur nær 0°C. where R 2 and n have the same meaning as under formula (I), on methanesulfonic acid chloride or p-toluenesulfonic acid chloride, either in the presence of an inert solvent, for example an aromatic solvent such as benzene, toluene or xylene, or a chlorinated solvent such as chloroform or methylene chloride, in the presence of a tertiary amine such as triethylamine, at a temperature near 20°C, or in the presence of pyridine at a temperature near 0°C.

Derivatene med formel (V) kan oppnås ved omsetning av etyltrifluoracetat med et derivat med formelen: The derivatives of formula (V) can be obtained by reacting ethyl trifluoroacetate with a derivative of the formula:

der R2°S n nar den samme betydning som under formel (I). where R2°S n has the same meaning as under formula (I).

Denne reaksjon skjer generelt i en alkohol som metanol eller etanol i nærvær av en tertiær base som trietylamin og ved en temperatur nær 20°C. This reaction generally takes place in an alcohol such as methanol or ethanol in the presence of a tertiary base such as triethylamine and at a temperature close to 20°C.

Derivatene med formel (VI) kan fremstilles ved innvirkning av et halogenert derivat med formelen: The derivatives with formula (VI) can be prepared by the action of a halogenated derivative with the formula:

der n har den samme betydning som under formel (I) og Hal betyr et hydrogenatom, fortrinnsvis brom eller klor, på et 2-amino-6-polyfluoralkoksybenzotiazol. where n has the same meaning as under formula (I) and Hal means a hydrogen atom, preferably bromine or chlorine, on a 2-amino-6-polyfluoroalkoxybenzothiazole.

Denne reaksjon skjer i en alkohol som etanol eller metanol ved oppløsningsmidlets koketemperatur. This reaction takes place in an alcohol such as ethanol or methanol at the solvent's boiling temperature.

2-amino-6-polyfluoralkoksybenzotiazoler kan fremstilles ved anvendelse av eller tilpasning til den metode som er beskrevet av L.M. Yagupol'skii et al. i "Zh. Obshch. Khim.", 33(7), 2301 (1963). 2-amino-6-polyfluoroalkoxybenzothiazoles can be prepared using or adapting the method described by L.M. Yagupol'skii et al. in "Zh. Obshch. Khim.", 33(7), 2301 (1963).

Forbindelsene med formel (I) kan likeledes fremstilles ved innvirkning av brom og et alkalimetalltiocyanat på et derivat med formelen: The compounds of formula (I) can likewise be prepared by the action of bromine and an alkali metal thiocyanate on a derivative of the formula:

der Ri, Rg og n har den samme betydning som i formel (I). where Ri, Rg and n have the same meaning as in formula (I).

Denne reaksjon skjer fortrinnsvis i eddiksyre ved en temperatur nær 20°C. This reaction preferably takes place in acetic acid at a temperature close to 20°C.

Som alkalimetalltiocyanat benyttes fortrinnsvis kaliumtiocyanat. Potassium thiocyanate is preferably used as alkali metal thiocyanate.

Derivatene med formel (VIII) kan oppnås ved innvirkning av et amin med formel (VI) på et derivat med formelen: The derivatives of formula (VIII) can be obtained by the action of an amine of formula (VI) on a derivative of the formula:

der Rg og n har den samme betydning som under formel (I) og R4 og R5 betyr en p-toluensulfonylrest. where Rg and n have the same meaning as under formula (I) and R4 and R5 mean a p-toluenesulfonyl residue.

Denne reaksjon skjer fortrinnsvis i nærvær av natriumhydrogenkarbonat i et inert oppløsningsmiddel som dimetylformamid og ved en temperatur mellom 50"C og 100°C. This reaction preferably takes place in the presence of sodium bicarbonate in an inert solvent such as dimethylformamide and at a temperature between 50°C and 100°C.

Derivatene med formel (IX) kan oppnås ved innvirkning av p—toluensulfonylklorid på et derivat med formelen: The derivatives of formula (IX) can be obtained by the action of p-toluenesulfonyl chloride on a derivative of the formula:

der Rg og n har den samme betydning som under formel (I). where Rg and n have the same meaning as under formula (I).

Denne reaksjon skjer generelt i et inert oppløsningsmiddel, for eksempel et klorert oppløsningsmiddel som kloroform eller metylenklorid, ved en temperatur mellom 0 og 30°C. Derivatene med formel (X) kan oppnås ved omsetning av et 4-polyfluoralkoksyanilin med et derivat med formel (VII). This reaction generally takes place in an inert solvent, for example a chlorinated solvent such as chloroform or methylene chloride, at a temperature between 0 and 30°C. The derivatives of formula (X) can be obtained by reacting a 4-polyfluoroalkoxyaniline with a derivative of formula (VII).

Denne reaksjon skjer generelt ved en temperatur mellom 100°C og 170°C. This reaction generally takes place at a temperature between 100°C and 170°C.

Reaksjonsblandingene som oppnås ved de forskjellige beskrevne prosesser behandles i henhold til klassiske metoder som fordamping, ekstrahering, destillering, krystallisering eller kromatografi, eller kjemiske metoder som saltdannelse og så videre. The reaction mixtures obtained by the various processes described are treated according to classical methods such as evaporation, extraction, distillation, crystallization or chromatography, or chemical methods such as salt formation and so on.

Forbindelsene med formel (I) i form av fri base kan eventuelt omdannes til addisjonssalter med en mineral- eller organisk syre ved innvirkning av en slik syre i et organisk oppløs-ningsmiddel som en alkohol, et keton, en eter eller et klorert oppløsningsmiddel. The compounds of formula (I) in the form of a free base can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.

Forbindelsene med formel (I) og deres salter oppviser interessante farmakologiske egenskaper. Forbindelsene er aktive overfor konvulsjoner indusert av glutamat og benyttes således ved behandling og prevensjon av konvulsive fenomener, schizofreniske problemer og spesielt mangelformer ved schizofreni, søvnproblemer, fenomener forbundet med cerebral ischemi samt neurologiske tilstander der glutamat kan være implisert slik som ved Alzheimers sykdom, Huntingtons sykdom, amyotrofisk lateral sklerose og olivopontocerebelløs atrofi. The compounds of formula (I) and their salts exhibit interesting pharmacological properties. The compounds are active against convulsions induced by glutamate and are thus used in the treatment and prevention of convulsive phenomena, schizophrenic problems and especially deficiency forms in schizophrenia, sleep problems, phenomena associated with cerebral ischemia as well as neurological conditions where glutamate may be implicated such as in Alzheimer's disease, Huntington's disease , amyotrophic lateral sclerosis and olivopontocerebellar atrophy.

Aktiviteten til forbindelsene med formel (I) overfor konvulsjoner indusert av glutamat bestemmes i henhold til en teknikk som er inspirert av I.P. Lapin i "<J. Neural. Transmission", vol. 54, 229-238, (1982); injeksjonen av glutamat via intracerebroventrikulær vei gjennomføres i henhold til en teknikk inspirert av R. Chermat og P. Simon i "J. Pharmacol." (Paris), vol. 6, 489-492 (1975). ED50-verdien er generelt lik eller under 10 mg/kg. The activity of the compounds of formula (I) against glutamate-induced convulsions is determined according to a technique inspired by I.P. Lapin in "<J. Neural. Transmission", vol. 54, 229-238, (1982); the injection of glutamate via the intracerebroventricular route is carried out according to a technique inspired by R. Chermat and P. Simon in "J. Pharmacol." (Paris), vol. 6, 489-492 (1975). The ED50 value is generally equal to or below 10 mg/kg.

Forbindelsene med formel (I) oppviser en lav toksisitet. LD5Q-verdien ligger over 15 mg/kg intraperitonealt hos mus. The compounds of formula (I) exhibit a low toxicity. The LD5Q value is above 15 mg/kg intraperitoneally in mice.

For medisinsk anvendelse benytter man seg av forbindelsene med formel (I) per se eller i form av farmasøytisk akseptable salter, det vil si salter som ikke er toksiske ved de benyttede doser. For medical use, the compounds of formula (I) are used per se or in the form of pharmaceutically acceptable salts, i.e. salts which are not toxic at the doses used.

Som eksempler på farmasøytisk akseptable salter skal nevnes addisjonssalter med mineralsyrer eller organiske syrer som acetat, propionat, succinat, benzoat, fumarat, maleat, oksalat, metansulfonat, isetionat, teofyllinacetat, sali-cylat, fenolftalinat, metylen-bis-g<->oksynaftoat, klorhydrat, sulfat, nitrat og fosfat. As examples of pharmaceutically acceptable salts, mention should be made of addition salts with mineral acids or organic acids such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isethionate, theophylline acetate, salicylate, phenolphthalinate, methylene-bis-g<->oxynaphthoate , chloral hydrate, sulphate, nitrate and phosphate.

De følgende eksempler skal illustrere oppfinnelsen uten å begrense den. The following examples are intended to illustrate the invention without limiting it.

Eksempel 1 Example 1

1,4 g 3-{2-[4-(2-pyridyl)-l-piperazinyl]-etyl}-2-trifluor-acetylimino-6-trifluormetoksybenzotiazolin i oppløsning i en blanding av 19 cm<5> av en 7 #-ig vandig kaliumkarbonatoppløs-ning og 32 cm<5> metanol oppvarmes ved en temperatur nær 20 "C i 4 timer. Mediet konsentreres ved 2,7 kPa og resten tas opp i 300 cm<5> destillert vann. Den vandige fase ekstraheres med 1.4 g of 3-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline in solution in a mixture of 19 cm<5> of a 7 # -ig aqueous potassium carbonate solution and 32 cm<5> of methanol are heated at a temperature close to 20 "C for 4 hours. The medium is concentrated at 2.7 kPa and the residue is taken up in 300 cm<5> of distilled water. The aqueous phase is extracted with

3 x 200 cm<5> metyleter, tørkes over magnesiumsulfat og konsentreres til tørr tilstand under redusert trykk. Den oppnådde rest renses ved kolonnekromatografi over silikagel med aceton som elueringsmiddel. Efter dannelse av trihydro-kloridet ved tilsetning av 4,2N saltsur eter i aceton, oppnås 0,73 g 2-imino-3-{2-[4-(2-pyridyl)-l-piperazinyl]-etyl>-6-trifluormetoksybenzotiazolin-trihydroklorid med smeltepunkt nær 230°C. 3-{2-[4-(2-pyridyl)-l-piperazinyl] -etyl }-2-trif luor acetyl-imino-6-trifluormetoksybenzotiazolin kan fremstilles i henhold til følgende metode: En blanding av 4,52 g 2-(2-trifluoracetylimino-6-trifluor-metoksy-3-benzotiazolinyl)etyl-metansulfonat i 100 cm<5> toluen og 6,9 g (2-pyridyl)piperazin oppvarmes i 2 timer under tilbakeløp, avkjøles til 4°C og helles derefter av. Det tolueniske filtrat fordampes under redusert trykk og renses ved kolonnekromatografi over silikagel med diklormetan som elueringsmiddel. Man oppnår 1,3 g 3-{2-[4-(2-pyridyl)-l-piperazinyl] - etyl >-2-tr i f luoracetylimino-6-trif luormetoksy-benzotiazolin med smeltepunkt 132°C. 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazo-linyl)etyl-metansulfonat kan fremstilles på følgende måte: 6,9 g trietylamin settes progressivt til en blanding av 120 cm<5> metylenklorid, 7,34 g metansulfonsyreklorid og 12 g 2-(2-tri fluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl )-etanol. Efter en times omrøring ved en temperatur nær 20° C avkjøles reaksjonsmediet til 10°C, helles av, vaskes med 20 cm<5> kold metylenklor id og tørkes derefter ved 40° C under redusert trykk. Man oppnår 10 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat med smeltepunkt 145°C. En andre sats på 2,7 g oppnås ved vasking av filtratet med 100 cm<5> vann, tørking over magnesiumsulfat, konsentrering til et restvolum på 50 cm<5> og avkjøling til 5°C og avhelling. 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzo-tiazolinyl )etanol kan fremstilles på følgende måte: 20,7 g 2-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)etanol-bromhydrat, 9,8 g etyltrifluoracetat og 16,1 cm<5> trietylamin omrøres i 100 cm<5> etanol i 22 timer ved en temperatur nær 20° C. Efter konsentrering til tørr tilstand under redusert trykk blir den oppnådde rest renset ved kolonnekromatografi over silikagel med etylacetat som elueringsmiddel. Man oppnår på denne måte 19,2 g 2-(2-trifluoracetylimino-6-trifluor-metoksy-3-benzotiazolinyl)etanol med smeltepunkt 144°C. 2-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)etanol kan fremstilles på følgende måte: 9,4 g 2-amino-6-trifluormetoksybenzotiazol og 10 g 2-brometanol i 30 cm<3> absolutt etanol oppvarmes i 95 timer til koking. Blandingen avkjøles derefter til en temperatur nær 20°C. Det dannede precipitat filtreres og vaskes med 100 cm<5 >etyleter. Man oppnår 6,4 g 2-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)etanol med smeltepunkt 219°C. 3 x 200 cm<5> methyl ether, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The obtained residue is purified by column chromatography over silica gel with acetone as eluent. After formation of the trihydrochloride by addition of 4.2N hydrochloric acid ether in acetone, 0.73 g of 2-imino-3-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl>-6- trifluoromethoxybenzothiazoline trihydrochloride with a melting point close to 230°C. 3-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl }-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline can be prepared according to the following method: A mixture of 4.52 g of 2- (2-trifluoroacetylimino-6-trifluoro-methoxy-3-benzothiazolinyl)ethyl methanesulfonate in 100 cm<5> toluene and 6.9 g of (2-pyridyl)piperazine are heated for 2 hours under reflux, cooled to 4°C and poured then off. The toluene filtrate is evaporated under reduced pressure and purified by column chromatography over silica gel with dichloromethane as eluent. 1.3 g of 3-{2-[4-(2-pyridyl)-1-piperazinyl]-ethyl>-2-trifluoroacetylimino-6-trifluoromethoxy-benzothiazoline with a melting point of 132°C is obtained. 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulfonate can be prepared as follows: 6.9 g of triethylamine is added progressively to a mixture of 120 cm<5> of methylene chloride, 7.34 g of methanesulfonic acid chloride and 12 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethanol. After stirring for one hour at a temperature close to 20° C, the reaction medium is cooled to 10° C, poured off, washed with 20 cm<5> of cold methylene chloride and then dried at 40° C under reduced pressure. 10 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate with a melting point of 145°C are obtained. A second batch of 2.7 g is obtained by washing the filtrate with 100 cm<5> of water, drying over magnesium sulfate, concentrating to a residual volume of 50 cm<5> and cooling to 5°C and decanting. 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol can be prepared as follows: 20.7 g 2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol bromohydrate, 9.8 g ethyl trifluoroacetate and 16.1 cm<5> triethylamine are stirred in 100 cm<5> ethanol for 22 hours at a temperature close to 20° C. After concentration to a dry state under reduced pressure, the obtained residue is purified by column chromatography over silica gel with ethyl acetate as eluent. 19.2 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol with a melting point of 144°C is obtained in this way. 2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol can be prepared as follows: 9.4 g of 2-amino-6-trifluoromethoxybenzothiazole and 10 g of 2-bromoethanol in 30 cm<3> absolute ethanol are heated to 95 hours for cooking. The mixture is then cooled to a temperature close to 20°C. The precipitate formed is filtered and washed with 100 cm<5 >ethyl ether. 6.4 g of 2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanol with a melting point of 219°C is obtained.

2- amino-6-trifluormetoksy-benzotiazol kan fremstilles i henhold til den metode som er beskrevet av L.M. Yagupol'skii et al. i "Zh. Obshch. Khim.", 33(7), 2301 (1963). 2-amino-6-trifluoromethoxy-benzothiazole can be prepared according to the method described by L.M. Yagupol'skii et al. in "Zh. Obshch. Khim.", 33(7), 2301 (1963).

Eksempel 2 Example 2

Ved å arbeide som i eksempel 1, men ved å gå ut fra 0,9 g 3-{ 2 - [4-( 4-metylfenyl )-l-piperazinyl]-etyl}-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin i 18 cm<5> metanol og 14 cm<5> av en 7 %- ig hydroalkoholisk oppløsning av kaliumkarbonat, oppnås 0,7 g 2-imino-3-(2-[4-(4-metylfenyl)-l-piperazinyl]-etyl>-6-trifluormetoksybenzotiazolin med smeltepunkt 120°C. By working as in example 1, but starting from 0.9 g of 3-{ 2 - [4-( 4-methylphenyl )-1-piperazinyl]-ethyl}-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline in 18 cm<5> of methanol and 14 cm<5> of a 7% hydroalcoholic solution of potassium carbonate, 0.7 g of 2-imino-3-(2-[4-(4-methylphenyl)-1-piperazinyl] is obtained -ethyl>-6-trifluoromethoxybenzothiazoline with melting point 120°C.

3- {2-[4-(4-metylfenyl)-l-piperazinyl]-etyl}-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin kan fremstilles på følgende måte: Man arbeider som i eksempel 1 ut fra 4,52 g 2-(2-trif luor-acetylimino-6-trifluormetoksy-3-benzotiazolinyl)-etyl i 150 cm<5> toluen og 5,29. g 4-(4-metylfenyl)piperazin. Efter rensing ved kolonnekromatografi over silikagel med diklormetan:etylacetat i volumforholdet 98:2 som elueringsmiddel oppnås 0,9 g 3-(2-[4-(4-metylfenyl)-l-piperazinyl]-etyl}-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin. 3- {2-[4-(4-methylphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline can be prepared in the following way: Work as in example 1 from 4.52 g of 2 -(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl in 150 cm<5> toluene and 5.29. g 4-(4-methylphenyl)piperazine. After purification by column chromatography over silica gel with dichloromethane:ethyl acetate in the volume ratio 98:2 as eluent, 0.9 g of 3-(2-[4-(4-methylphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetyl-imino- 6-trifluoromethoxybenzothiazoline.

Eksempel 3 Example 3

Man arbeider som i eksempel 1 fra 5,88 g 2-(2-trifluoracetyl-imino-6-trifluormetoksy-3-benzotiazolinyl)etyl i 200 cm<3 >toluen og 6,87 g 4-(2-metylfenyl)-piperazin og efter 2 timer under tilbakeløp blir toluenfiltratet fordampet under redusert trykk. Til den således oppnådde rest settes 100 cm<3 >metanol og 20 cm<3> 7 #-ig hydroalkoholisk kaliumkarbonat-oppløsning og det hele omrøres i 2 timer ved ca. 20° C. Alkoholen fordampes under redusert trykk og resten renses ved kolonnekromatografi over silikagel med diklormetan:etylacetat i volumforholdet 70:30 som elueringsmiddel og derefter etylacetat:cykloheksan 50:50 som elueringsmiddel. Man oppnår på denne måte 1,8 g 2-imino-3-{2-[4-(2-metylfenyl)-l-piperazinyl]-etyl}-6-trifluormetoksybenzotiazolin med smeltepunkt 135°C. One works as in example 1 from 5.88 g of 2-(2-trifluoroacetyl-imino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl in 200 cm<3 >toluene and 6.87 g of 4-(2-methylphenyl)-piperazine and after 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure. To the thus obtained residue is added 100 cm<3 >methanol and 20 cm<3> 7 #-ig hydroalcoholic potassium carbonate solution and the whole is stirred for 2 hours at approx. 20° C. The alcohol is evaporated under reduced pressure and the residue is purified by column chromatography over silica gel with dichloromethane:ethyl acetate in the volume ratio 70:30 as eluent and then ethyl acetate:cyclohexane 50:50 as eluent. In this way, 1.8 g of 2-imino-3-{2-[4-(2-methylphenyl)-1-piperazinyl]-ethyl}-6-trifluoromethoxybenzothiazoline with a melting point of 135°C is obtained.

Eksempel 4 Example 4

Ved å arbeide som i eksempel 1, men ved å gå ut fra 3,8 g 3-[2-(4-benzyl-1-piperaz iny1)etyl]-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin i 20 cm<3> metanol og 10 cm<3> av en 7 %-ig hydroalkoholisk oppløsning av kaliumkarbonat og efter rensing ved kolonnekromatografi over silikagel med etylacetat : cykloheksan i volumforholdet 50:50 som elueringsmiddel og efter tilsetning av 4,2N saltsur eter oppnås 2,5 g 3-[2-(4-benzyl-l-piperazinyl)etyl]-2-imino-6-trifluormetoksybenzotiazolin-hydroklorid med smeltepunkt nær 230°C. 3 - [ 2 - ( 4 -benzyl-l-piperazinyl)etyl]-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin kan fremstilles på følgende måte: Man arbeider som i eksempel 1, men går ut fra 4,52 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)etyl-metansulfonat i 120 cm<3> toluen og 7 g 4-benzylpiperazin. Efter rensing ved kolonnekromatografi over silikagel med diklormetan:etylacetat i volumforholdet 50.50 som elueringsmiddel oppnås 3,8 g 3-[2-(4-benzyl-l-piperazinyl)etyl]-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin. By working as in example 1, but starting from 3.8 g of 3-[2-(4-benzyl-1-piperazinyl)ethyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline in 20 cm<3> methanol and 10 cm<3> of a 7% hydroalcoholic solution of potassium carbonate and after purification by column chromatography over silica gel with ethyl acetate:cyclohexane in the volume ratio 50:50 as eluent and after the addition of 4.2N hydrochloric acid ether, 2.5 g of 3- [2-(4-benzyl-1-piperazinyl)ethyl]-2-imino-6-trifluoromethoxybenzothiazoline hydrochloride with melting point near 230°C. 3 - [ 2 - ( 4 -benzyl-1-piperazinyl)ethyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline can be prepared in the following way: One works as in example 1, but starts from 4.52 g of 2-(2- trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulfonate in 120 cm<3> toluene and 7 g of 4-benzylpiperazine. After purification by column chromatography over silica gel with dichloromethane:ethyl acetate in the volume ratio 50.50 as eluent, 3.8 g of 3-[2-(4-benzyl-1-piperazinyl)ethyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline are obtained.

Eksempel 5 Example 5

Man arbeider som i eksempel 1, men går ut fra 4,52 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)etyl-metansulfonat i 150 cm<5> toluen og 6,5 g 4-(2-pyrimidinyl )-piperazin og efter 4 timer under tilbakeløp blir det tolueniske filtrat fordampet under redusert trykk. 100 cm<5 >metanol og 20 cm<5> av en 7 #-ig hydroalkoholisk oppløsning av kaliumkarbonat settes derefter til den tolueniske oppløsning. Efter 2 timers omrøring ved ca. 20°C blir metanolen fordampet under redusert trykk og resten renset ved kolonnekromatografi over silikagel med diklormetan:metanol i volumforholdet 90:10 som elueringsmiddel. Efter dannelse av triklorhydrat ved tilsetning av 4,2N saltsur eter oppnås 1,13 g 2-imino-3-{2-[4-(2-pyrimidinyl)-l-piperazinyl]etyl}-6-tr ifluormetoksy-benzotiazolin-trihydroklorid med smeltepunkt nær 270°C. One works as in example 1, but starts from 4.52 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)ethyl methanesulfonate in 150 cm<5> toluene and 6.5 g of 4-(2- pyrimidinyl)-piperazine and after 4 hours under reflux the toluene filtrate is evaporated under reduced pressure. 100 cm<5> of methanol and 20 cm<5> of a 7# hydroalcoholic solution of potassium carbonate are then added to the toluene solution. After 2 hours of stirring at approx. 20°C, the methanol is evaporated under reduced pressure and the residue is purified by column chromatography over silica gel with dichloromethane:methanol in the volume ratio 90:10 as eluent. After formation of trichlorohydrate by addition of 4.2N hydrochloric acid ether, 1.13 g of 2-imino-3-{2-[4-(2-pyrimidinyl)-1-piperazinyl]ethyl}-6-trifluoromethoxy-benzothiazoline-trihydrochloride are obtained with a melting point close to 270°C.

Eksempel 6 Example 6

3,6 g 3-[3-(4-fenyl-l-piperazinyl)propyl]-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin-hydroklorid i oppløsning i en blanding av 45 cm<5> av en 7 %- ig vandig kaliumkarbonat-oppløsning og 150 cm<5> metanol omrøres i 4 timer ved en temperatur nær 20°C. Efter konsentrering til tørr tilstand blir reaksjonsmediet tatt opp i 100 cm<5> destillert vann og den organiske fase ekstrahert med 2 x 100 cm<5> etylacetat, tørket over magnesiumsulfat og konsentrert til tørr tilstand ved 2,7 kPa. Efter dannelse av dihydrokloridet ved tilsetning av 4 cm<5> 4,2N saltsur eter i etylacetat blir precipitatet omkrystallisert fra absolutt etanol:etyleter i volumforholdet 50:50. Man oppnår 1,6 g 2-imino-3-[3-(4-fenyl-1-piperazinyl)-propyl]-6-trifluormetoksybenzotiazolin-dihydroklorid med smeltepunkt 260°C. 3.6 g of 3-[3-(4-phenyl-1-piperazinyl)propyl]-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline hydrochloride in solution in a mixture of 45 cm<5> of a 7% aqueous potassium carbonate solution and 150 cm<5> of methanol are stirred for 4 hours at a temperature close to 20°C. After concentration to dryness, the reaction medium is taken up in 100 cm<5> of distilled water and the organic phase is extracted with 2 x 100 cm<5> of ethyl acetate, dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. After formation of the dihydrochloride by adding 4 cm<5> of 4.2N hydrochloric acid ether in ethyl acetate, the precipitate is recrystallized from absolute ethanol:ethyl ether in the volume ratio 50:50. 1.6 g of 2-imino-3-[3-(4-phenyl-1-piperazinyl)-propyl]-6-trifluoromethoxybenzothiazoline dihydrochloride with melting point 260°C is obtained.

3 - [ 3 - ( 4 - f enyl-l-piperazinyl)propyl]-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid kan fremstilles på følgende måte: 4,4 g 3-(2-trifluoracetylimino-6-trifluormetoksy-3-benzo-tiazolinyl)propyl-p-toluensulfonat, 1,44 g N-fenylpiperazin og 0,68 g natriumhydrogenkarbonat i 50 cm<5> dimetylformamid oppvarmes til 80" C i 19 timer. Reaksjonsmediet konsentreres til tørr tilstand ved 0,95 kPa og resten tas opp i 100 cm<3 >destillert vann og den organiske fase ekstraheres med 50 cm<5 >diklormetan. Efter tørking over magnesiumsulfat og konsentrering til tørr tilstand under redusert trykk, blir den oljeaktige rest tatt opp i 15 cm<5> IN vandig saltsyre og hydrokloridet felt ut i 15 cm<5> destillert vann. Man oppnår 4 g 3-[3-(4-fenyl-l-piperazinyl)propyl-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid med smeltepunkt 238° C. 3-(2-trifluoracetylimino-6 -1ri fluormetoksy-3-benzotiazo-linyl)propyl-p-toluensulfonat kan fremstilles i henhold til følgende metode: 11 g 3-(2-trifluoracetylimino-6-trifluormetoksy-3-benzo-tiazolinyl)-propanol settes progressivt til 10,8 g p-toluensulfonylklorid i oppløsning i 200 cm<5> pyridin avkjølt til 0°C. Reaksjonen følges en time ved 5°C og derefter varmes reaksjonsmediet noe opp (6-7°C) i 15 timer. Efter tilsetning til 2 1 destillert vann, ekstrahering med 200 cm<5> etylacetat, vasking med 2 x 50 cm<5> IN saltsyre, tørking over magnesiumsulfat og konsentrering til tørr tilstand under redusert trykk, oppnås 6,7 g 3-(2-trifluoracetylimino-6-trifluor-metoksy-6-benzotiazolinyl)propyl-p-toluensulfonat med smeltepunkt 139<0>C. 3 - ( 2 - tri fluoracetylimino-6-tri fluormetoksy-3-benzotiazo-1inyl)propanol kan fremstilles på følgende måte: 24,8 g 3-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)-propanol, 14,2 g etyltrifluoracetat og 8,6 g trietylamin omrøres i 250 cm<5> absolutt etanol i 24 timer ved en temperatur nær 20°C. Reaksjonsmediet avkjøles derefter til 0-5°C og det dannede precipitat filtreres og tørkes. Man oppnår på 3 - [ 3 - ( 4 - phenyl-1-piperazinyl)propyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows: 4.4 g of 3-(2-trifluoroacetylimino-6-trifluoromethoxy-3- benzo-thiazolinyl)propyl-p-toluenesulfonate, 1.44 g of N-phenylpiperazine and 0.68 g of sodium bicarbonate in 50 cm<5> of dimethylformamide are heated to 80" C for 19 hours. The reaction medium is concentrated to dryness at 0.95 kPa and the residue is taken up in 100 cm<3> of distilled water and the organic phase is extracted with 50 cm<5> of dichloromethane. After drying over magnesium sulfate and concentration to dryness under reduced pressure, the oily residue is taken up in 15 cm<5> IN aqueous hydrochloric acid and the hydrochloride precipitated in 15 cm<5> of distilled water. 4 g of 3-[3-(4-phenyl-1-piperazinyl)propyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride with a melting point of 238° C is obtained. 3-(2-trifluoroacetylimino-6-1trifluoromethoxy-3-benzothiazolinyl)propyl-p-toluenesulfonate can be prepared according to the following method: 11 g of 3-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) -propanol is progressively added to 10.8 g of p-toluenesulfonyl chloride in solution in 200 cm<5> of pyridine cooled to 0°C. The reaction is followed for one hour at 5°C and then the reaction medium is heated somewhat (6-7°C) for 15 hours. After addition to 2 1 of distilled water, extraction with 200 cm<5> ethyl acetate, washing with 2 x 50 cm<5> IN hydrochloric acid, drying over magnesium sulfate and concentration to dryness under reduced pressure, 6.7 g of 3-(2 -trifluoroacetylimino-6-trifluoro-methoxy-6-benzothiazolinyl)propyl-p-toluenesulfonate with melting point 139<0>C. 3 - (2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazo-1inyl)propanol can be prepared in the following way: 24.8 g of 3-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)-propanol, 14, 2 g of ethyl trifluoroacetate and 8.6 g of triethylamine are stirred in 250 cm<5> of absolute ethanol for 24 hours at a temperature close to 20°C. The reaction medium is then cooled to 0-5°C and the precipitate formed is filtered and dried. One achieves on

denne måte 28,2 g 3-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)propanol med smeltepunkt 144°C. in this way 28.2 g of 3-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)propanol with a melting point of 144°C.

3-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)propanol kan fremstilles på følgende måte: 82 g 2-amino-6-trifluormetoksybenzotiazol og 65 cm<5> 3-brompropanol i 25 cm<5> absolutt etanol oppvarmes i 72 timer til koking. Blandingen avkjøles derefter til en temperatur nær 20°C. Den oppnådde olje tas opp ill destillert vann og den organiske fase ekstraheres med 3 x 200 cm<5> diklormetan. Efter tørking over magnesiumsulfat og konsentrering til tørr tilstand under redusert trykk, blir råproduktet renset ved kolonnekromatografi over silikagel med etylacetat som elueringsmiddel. Man oppnår 25 g 3-(2-imino-6-trifluor-metoksy-3-benzotiazolinyl)propanol med smeltepunkt 106°C. 3-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)propanol can be prepared as follows: 82 g of 2-amino-6-trifluoromethoxybenzothiazole and 65 cm<5> of 3-bromopropanol in 25 cm<5> of absolute ethanol are heated in 72 hours for cooking. The mixture is then cooled to a temperature close to 20°C. The oil obtained is taken up in distilled water and the organic phase is extracted with 3 x 200 cm<5> of dichloromethane. After drying over magnesium sulfate and concentration to a dry state under reduced pressure, the crude product is purified by column chromatography over silica gel with ethyl acetate as eluent. 25 g of 3-(2-imino-6-trifluoro-methoxy-3-benzothiazolinyl)propanol with a melting point of 106°C are obtained.

Eksempel 7 Example 7

Ved å arbeide som i eksempel 1 fra 1 g 3-{ 2-[4-(m-tolyl )-l-piperaz inyl]- etyl} - 2- tr if luoracety limino-6 -tr i f luormetoksy-benzotiazolin i 30 cm<5> metanol og 15 cm<3> av 7 #-ig hydro-alkoholoppløsning av kaliumkarbonat og efter rensing ved kolonnekromatografi over silikagel med etylacetat:cykloheksan i volumforholdet 50:50 som elueringsmiddel og derefter følgende tilsetning av 4,2N saltsur eter, oppnås 0,6 g 2-imino-3-< 2-[4-(m-tolyl)-1-piperazinyl]etyl-6-trifluormetoksybenzotiazol in med smeltepunkt nær 250°C. By working as in example 1 from 1 g of 3-{2-[4-(m-tolyl)-l-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxy-benzothiazoline in 30 cm <5> methanol and 15 cm<3> of 7 #-ig hydro-alcohol solution of potassium carbonate and after purification by column chromatography over silica gel with ethyl acetate:cyclohexane in the volume ratio 50:50 as eluent and then the following addition of 4.2N hydrochloric acid ether, is obtained 0.6 g of 2-imino-3-<2-[4-(m-tolyl)-1-piperazinyl]ethyl-6-trifluoromethoxybenzothiazoline with a melting point close to 250°C.

3-{ 2 -[4-(m-tolyl)-1-piperazinyl]-etyl-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin fremstilles på følgende måte: Man arbeider som i eksempel 1 fra 4,52 g 2-(2-trifluoracetyl-imino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat i 150 cm<5> toluen og 5,29 g 4-(3-metylfenyl)piperazin. Efter rensing ved kolonnekromatografi over silikagel med diklormetan : etylacetat i volumforholdet 70:30 som elueringsmiddel, oppnås 1 g 3-{2-[4-(m-tolyl)-l-piperazinyl]-etyl-2-trifluor-acetyl imino-6-trifluormetoksybenzotiazolin. 3-{ 2 -[4-(m-tolyl)-1-piperazinyl]-ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline is prepared in the following way: One works as in example 1 from 4.52 g of 2-(2-trifluoroacetyl -imino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate in 150 cm<5> toluene and 5.29 g of 4-(3-methylphenyl)piperazine. After purification by column chromatography over silica gel with dichloromethane:ethyl acetate in the volume ratio 70:30 as eluent, 1 g of 3-{2-[4-(m-tolyl)-1-piperazinyl]-ethyl-2-trifluoro-acetyl imino-6 is obtained -trifluoromethoxybenzothiazoline.

Eksempel 8 Example 8

Til en blanding av 2,62 g 4-fenyl-l-[2-(4-trifluormetoksy-anilino )-etyl-l,2,3,6-tetrahydropyridin og 2,8 g kaliumtiocyanat i 50 cm? eddiksyre settes dråpevis 1,15 g brom i oppløsning i 15 cm<5> eddiksyre ved en temperatur nær 20° C. Efter vanlig behandling oppnås 0,67 g 2-imino-3-[2-(4-fenyl-1,2,3, 6-tetrahydro-l-pyridyl )-etyl] -6-tr i f luormetoksybenzo-tiazolin med smeltepunkt 256°C. To a mixture of 2.62 g of 4-phenyl-1-[2-(4-trifluoromethoxy-anilino)-ethyl-1,2,3,6-tetrahydropyridine and 2.8 g of potassium thiocyanate in 50 cm? acetic acid, 1.15 g of bromine is added dropwise in solution in 15 cm<5> of acetic acid at a temperature close to 20° C. After the usual treatment, 0.67 g of 2-imino-3-[2-(4-phenyl-1,2 ,3,6-tetrahydro-1-pyridyl)-ethyl]-6-trifluoromethoxybenzothiazoline with melting point 256°C.

4-fenyl-l-[2-(4-trifluormetoksyanilino)-etyl-l,2,3,6-tetrahydropyridin kan fremstilles på følgende måte: En blanding av 5,56 g N-p-toluensulfonyl-2-(4-trifluor-metoksyanilino)-etyl-p-toluensulfonat, 1,84 g 4-fenyl-1,2,3,6-tetrahydropyridin og 0,97 g natriumhydrogenkarbonat i 95 cm<5> dimetylformamid oppvarmes i 18 timer til 80°C. Efter vanlig behandling oppnås 2,62 g 4-fenyl-l-[2-(4-trifluor-metoksyanilino)-etyl-l,2,3,6-tetrahydropyridin i form av en olje som benyttes som sådan i de efterfølgende synteser. 4-phenyl-1-[2-(4-trifluoromethoxyanilino)-ethyl-1,2,3,6-tetrahydropyridine can be prepared as follows: A mixture of 5.56 g of N-p-toluenesulfonyl-2-(4-trifluoro- methoxyanilino)-ethyl-p-toluenesulfonate, 1.84 g of 4-phenyl-1,2,3,6-tetrahydropyridine and 0.97 g of sodium bicarbonate in 95 cm<5> of dimethylformamide are heated for 18 hours at 80°C. After usual treatment, 2.62 g of 4-phenyl-1-[2-(4-trifluoro-methoxyanilino)-ethyl-1,2,3,6-tetrahydropyridine are obtained in the form of an oil which is used as such in the subsequent syntheses.

N-p-toluensulfonyl-2-(4-tri fluormetoksyani 1ino)-etyl-p-toluensulfonat kan fremstilles i henhold til følgende metode: Til 5,0 g 2-(4-trifluormetoksyani1ino)-etanol og 6,35 cm<5 >trietylamin i 50 cm<5> diklormetan ved 0°C settes progressivt 8,6 g p-toluensulfonylklorid. Reaksjonen følges i 2 timer ved en temperatur nær 20°C hvorefter reaksjonsmediet vaskes med 3 x 50 cm<5> destillert vann og den organiske fase tørkes over magnesiumsulfat og konsentreres til tørr tilstand ved 2,7 kPa. Efter tilsetning av 50 cm<5> absolutt etanol blir det dannede precipitat filtrert. Man oppnår 7,3 g N-p-toluen-sulfonyl-2-( 4-trif luormetoksyani 1 ino )-etyl-p-toluensulfonat med smeltepunkt 88°C. N-p-toluenesulfonyl-2-(4-trifluoromethoxycyanino)-ethyl p-toluenesulfonate can be prepared according to the following method: To 5.0 g of 2-(4-trifluoromethoxycyanino)-ethanol and 6.35 cm<5 >triethylamine 8.6 g of p-toluenesulfonyl chloride are progressively added to 50 cm<5> of dichloromethane at 0°C. The reaction is followed for 2 hours at a temperature close to 20°C, after which the reaction medium is washed with 3 x 50 cm<5> of distilled water and the organic phase is dried over magnesium sulfate and concentrated to a dry state at 2.7 kPa. After adding 50 cm<5> of absolute ethanol, the formed precipitate is filtered. 7.3 g of N-p-toluene-sulfonyl-2-(4-trifluoromethoxycyano)-ethyl-p-toluenesulfonate with a melting point of 88°C are obtained.

2-(4-trifluormetoksyanilino)-etanol kan fremstilles som følger: 88,5 g 4-trifluormetoksyani1 in og 31,2 g 2-brometanol oppvarmes til 160° C i IV2 time. Efter avkjøling til en temperatur nær 20°C, blir reaksjonsmediet tatt opp i 200 cm<5>2-(4-trifluoromethoxyaniline)-ethanol can be prepared as follows: 88.5 g of 4-trifluoromethoxyaniline and 31.2 g of 2-bromoethanol are heated to 160° C. for 42 hours. After cooling to a temperature close to 20°C, the reaction medium is taken up in 200 cm<5>

diklormetan, det uoppløselige filtrert fra og filtratet konsentrert til tørr tilstand under redusert trykk. Efter rensing ved kolonnekromatografi over silikagel med etylacetat : cykloheksan i volumforholdet 40:60 oppnås 26,8 g 2-(4-trifluormetoksyanilino)etanol i form av en oransjefarvet olje. dichloromethane, the insoluble filtered off and the filtrate concentrated to dryness under reduced pressure. After purification by column chromatography over silica gel with ethyl acetate:cyclohexane in the volume ratio 40:60, 26.8 g of 2-(4-trifluoromethoxyanilino)ethanol are obtained in the form of an orange colored oil.

Eksempel 9 Example 9

1,1 g 3-[2-(4-fenylpiperazinyl)-etyl]-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid i oppløsning i en blanding av 5 cm<3> av en 7 #-ig vandig natriumkarbonatoppløs-ning og 100 cm<5> metanol omrøres ved en temperatur nær 20°C i 5 timer. Reaksjonsmediet settes til 200 cm<5> destillert vann og den organiske fase ekstraheres med 3 x 150 cm<5> etylacetat, tørkes over magnesiumsulfat og konsentreres til tørr tilstand ved 2,7 kPa. Efter dannelse av hydrokloridet ved tilsetning av 0,45 cm<5> 4,2N saltsur eter i 30 cm<5> etylacetat oppnås 0,8 g 2-imino-3-[3-(4-fenylpiperazinyl)etyl]-6-trifluormetoksybenzotiazol in med smeltepunkt 230°C. 1.1 g of 3-[2-(4-phenylpiperazinyl)-ethyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in solution in a mixture of 5 cm<3> of a 7#-ig aqueous sodium carbonate solution and 100 cm<5> methanol is stirred at a temperature close to 20°C for 5 hours. The reaction medium is added to 200 cm<5> of distilled water and the organic phase is extracted with 3 x 150 cm<5> of ethyl acetate, dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. After formation of the hydrochloride by addition of 0.45 cm<5> 4.2N hydrochloric acid ether in 30 cm<5> ethyl acetate, 0.8 g of 2-imino-3-[3-(4-phenylpiperazinyl)ethyl]-6- trifluoromethoxybenzothiazole with a melting point of 230°C.

3 -[2 -(4-f enylpiperazinyl)-etyl]-2-tr ifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid kan fremstilles som følger: 6,5 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzo-tiazolinyl)-etyl-p-toluensulfonat, 2,2 g N-fenylpiperazin og 1,0 g natriumbikarbonat i 80 cm<5> dimetylformamid oppvarmes til 60°C i 16 timer. Reaksjonsmediet settes til 300 cm<5 >destillert vann og den organiske fase ekstraheres med 3 x 50 cm<5> diklormetan. Efter tørking over magnesiumsulfat og konsentrasjon til tørr tilstand under redusert trykk blir den oljeaktige rest tatt opp i 20 cm<3> IN saltsyre og det dannede hydrokloridet precipitert i 20 cm<5> etanol. Man oppnår 1,1 g 3-[2-(4-fenylpiperazinyl)-etyl]-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid med smeltepunkt 204°C. 2 - ( 2-trifluoracetylimino-6-1ri fluormetoksy-3-benzot iazo-linyl)-etyl-p-toluensulfonat kan fremstilles som følger: 19,3 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzo-tiazolinyl)-etanol settes progressivt til 19,7 g p-toluensulfonylklorid i oppløsning i 120 cm<5> pyridin avkjølt til 0°C. Reaksjonen følges i en time ved 10-15°C. Reaksjonsmediet settes til 500 cm<5> destillert vann og den organiske fase ekstraheres med 3 x 100 cm<5> diklormetan. Efter vasking med 2 x 50 cm<5> IN saltsyre og derefter 2 x 50 cm<5> destillert vann, tørking over magnesiumsulfat og konsentrering til tørr tilstand ved 2,7 kPa, oppnås 14,1 g 2-(2-trifluoracetylimino-6 -t r i f luormet ok sy-3-benzo t i azol inyl ) -etyl-p-toluensulf onat med smeltepunkt 143°C. 2-(2-trifluoracetylimino-6-tri fluormetoksy-3-benzoti azo-linyl)-etanol kan fremstilles som følger: 20,7 g 2-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)-etanol-hydrobromid, 9,8 g etyltrifluoracetat og 16,1 cm<5 >trietylamin oppvarmes i 100 cm<5> etanol i 22 timer ved en temperatur nær 20°C. Efter konsentrasjon til tørr tilstand under redusert trykk blir den oppnådde rest renset ved kolonnekromatografi over silikagel med etylacetat som elueringsmiddel. Man oppnår 19,2 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)-etanol med smeltepunkt 144°C . 2-( 2-imino-6-tri fluormetoksy-3-benzot iazolinyl^etanol-hydrobromid kan fremstilles som følger: 9,4 g 2-amino-6-trifluormetoksybenzotiazol og 10 g 2-brometanol i 30 cm<5> absolutt etanol oppvarmes i 95 timer til koking. Blandingen avkjøles derefter til en temperatur nær 20°C. Det dannede precipitat filtreres og vaskes med 100 cm<5 >etyleter. Man oppnår 6,4 g 2-(2-imino-6-trifluormetoksy-3-benzotiazolinyl)-etanol-hydrobromid med smeltepunkt 219°C. 3-[2-(4-phenylpiperazinyl)-ethyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows: 6.5 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzo-thiazolinyl) )-ethyl-p-toluenesulfonate, 2.2 g of N-phenylpiperazine and 1.0 g of sodium bicarbonate in 80 cm<5> of dimethylformamide are heated to 60°C for 16 hours. The reaction medium is added to 300 cm<5> of distilled water and the organic phase is extracted with 3 x 50 cm<5> of dichloromethane. After drying over magnesium sulfate and concentration to a dry state under reduced pressure, the oily residue is taken up in 20 cm<3> IN hydrochloric acid and the hydrochloride formed is precipitated in 20 cm<5> ethanol. 1.1 g of 3-[2-(4-phenylpiperazinyl)-ethyl]-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride with a melting point of 204°C is obtained. 2-(2-trifluoroacetylimino-6-1trifluoromethoxy-3-benzothiazolinyl)-ethyl-p-toluenesulfonate can be prepared as follows: 19.3 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl) )-ethanol is added progressively to 19.7 g of p-toluenesulfonyl chloride in solution in 120 cm<5> of pyridine cooled to 0°C. The reaction is followed for one hour at 10-15°C. The reaction medium is added to 500 cm<5> of distilled water and the organic phase is extracted with 3 x 100 cm<5> of dichloromethane. After washing with 2 x 50 cm<5> IN hydrochloric acid and then 2 x 50 cm<5> distilled water, drying over magnesium sulfate and concentration to a dry state at 2.7 kPa, 14.1 g of 2-(2-trifluoroacetylimino- 6-trifluorooxy-3-benzotriazolinyl)-ethyl-p-toluenesulfonate with melting point 143°C. 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethanol can be prepared as follows: 20.7 g of 2-(2-imino-6-trifluoromethoxy-3-benzothiazolinyl)-ethanol hydrobromide, 9.8 g of ethyl trifluoroacetate and 16.1 cm<5>triethylamine are heated in 100 cm<5> ethanol for 22 hours at a temperature close to 20°C. After concentration to a dry state under reduced pressure, the obtained residue is purified by column chromatography over silica gel with ethyl acetate as eluent. 19.2 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethanol with a melting point of 144°C is obtained. 2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl^ethanol hydrobromide can be prepared as follows: 9.4 g of 2-amino-6-trifluoromethoxybenzothiazole and 10 g of 2-bromoethanol in 30 cm<5> absolute ethanol heated for 95 hours to boiling. The mixture is then cooled to a temperature near 20° C. The precipitate formed is filtered and washed with 100 cm<5 >ethyl ether. 6.4 g of 2-(2-imino-6-trifluoromethoxy-3 -benzothiazolinyl)-ethanol hydrobromide with a melting point of 219°C.

2-amino-6-trifluormetoksybenzotiazol kan fremstilles i 2-amino-6-trifluoromethoxybenzothiazole can be prepared in

henhold til den metode som er beskrevet av L.M. Yagupol'ski i et al. i "Zh. Obshch. Khim.", 33(7), 2301 (1963). according to the method described by L.M. Yagupol'ski in et al. in "Zh. Obshch. Khim.", 33(7), 2301 (1963).

Eksempel 10 Example 10

1,53 g 3-(2-[4-(4-metoksyfenyl)-l-piperazinyl]-etyl-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin, 33 cm<5 >metanol og 21 cm<5> av en 7 %- ig kaliumkarbonatoppløsning i en blanding av 2 volumer metanol og 5 volumer vann, omrøres i 4 timer ved en temperatur nær 20°C. Reaksjonsblandingen konsentreres til tørr tilstand og ekstraheres derefter med svovelsur eter. Den organiske fase tørkes over magnesiumsulfat og derefter tilsettes det et overskudd av en alkoho-lisk saltsyreoppløsning. Precipitatet helles av, vaskes med svovelsur eter, tørkes ved 50°C og 20 mm Hg. Man oppnår 1,05 g 2-imino-3-{2-[4-(4-metoksyfenyl)-l-piperazinyl]-etyl-6-trifluormetoksybenzotiazolin-trihydroklorid med smeltepunkt 240°C. 1.53 g of 3-(2-[4-(4-methoxyphenyl)-1-piperazinyl]-ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline, 33 cm<5 >methanol and 21 cm<5> of a 7%- ig of potassium carbonate solution in a mixture of 2 volumes of methanol and 5 volumes of water, is stirred for 4 hours at a temperature close to 20° C. The reaction mixture is concentrated to dryness and then extracted with sulfuric ether. The organic phase is dried over magnesium sulfate and then an excess is added of an alcoholic hydrochloric acid solution. The precipitate is poured off, washed with sulfuric ether, dried at 50°C and 20 mm Hg. 1.05 g of 2-imino-3-{2-[4-(4-methoxyphenyl)- 1-piperazinyl]-ethyl-6-trifluoromethoxybenzothiazoline trihydrochloride with melting point 240°C.

3-(2-[4-(4-metoksyf enyl )-1-piperaz inyl]-etyl-2-tri fluor-acetylimino-6-trifluormetoksybenzotiazolin-hydroklorid kan fremstilles på følgende måte: 3-(2-[4-(4-Methoxyphenyl)-1-piperazinyl]-ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows:

En blanding av 4,25 g 2-(2-trifluoracetylimino-6-trifluor-metoksy-3-benzotiazolinyl)-etyl-metansulfonat, 120 cm<5> toluen og basen som settes fri fra 10,56 g 4-p-metoksyfenyl-piperazin-dihydroklorid oppvarmes i en time under tilbakeløp, avkjøles til +5°C og helles derefter av. Det tolueniske filtrat fordampes under redusert trykk og derefter tilsettes det 45 cm<5> av en vandig 1,2N saltsyre. Hydroklor idet separeres i amorf form og krystalliseres så ved triturering med 50 cm<5> etanol. Efter tørking, vasking med 15 cm<5> etanol og tørking ved 50° C under 20 mm Hg oppnås 1,7 g 3-{2-[4-(4-me tok sy f enyl )-l -piper az inyl] - etyl - 2-trif luoracetyl imino-6 - trifluormetoksybenzotiazolin-hydroklorid. 2 - ( 2 -1r i fluoracetylimino-6-tri fluormetoksy-3-benzotiazo-linyl)-etyl-metansulfonat kan fremstilles som følger: 6,9 g trietylamin settes progressivt til en blanding av 120 cm<5> metylenklorid, 7,34 g metansulfonsyreklorid og 12 g 2-(2-tr i fluoracetylimino-6-tri fluormetoksy-3-benzotiazolinyl )-etanol. Efter en times omrøring ved en temperatur nær 20° C blir reaksjonsmediet avkjølt til 10°C, helt av, vasket med 20 cm<5> kold metylenklorid og derefter tørket ved 40° C under redusert trykk. Man oppnår 10 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat med smeltepunkt 145°C. Et andre utbytte på 2,7 g oppnås ved vasking av filtratet med 100 cm<3> vann, tørking over magnesiumsulfat, konsentrering til et restvolum på ca. 50 cm<5> og avkjøling til 5°C med avhelling. A mixture of 4.25 g of 2-(2-trifluoroacetylimino-6-trifluoro-methoxy-3-benzothiazolinyl)-ethyl methanesulfonate, 120 cm<5> toluene and the base liberated from 10.56 g of 4-p-methoxyphenyl -piperazine dihydrochloride is heated for one hour under reflux, cooled to +5°C and then poured off. The toluene filtrate is evaporated under reduced pressure and then 45 cm<5> of an aqueous 1.2N hydrochloric acid is added. The hydrochloride is then separated in amorphous form and then crystallized by trituration with 50 cm<5> of ethanol. After drying, washing with 15 cm<5> ethanol and drying at 50° C under 20 mm Hg, 1.7 g of 3-{2-[4-(4-metocyphenyl)-l-piperazinyl] is obtained - ethyl - 2-trifluoroacetyl imino-6 - trifluoromethoxybenzothiazoline hydrochloride. 2 - ( 2 -1r in fluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate can be prepared as follows: 6.9 g of triethylamine is added progressively to a mixture of 120 cm<5> methylene chloride, 7.34 g of methanesulfonic acid chloride and 12 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethanol. After one hour of stirring at a temperature close to 20° C, the reaction medium is cooled to 10° C, drained, washed with 20 cm<5> of cold methylene chloride and then dried at 40° C under reduced pressure. 10 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate with a melting point of 145°C are obtained. A second yield of 2.7 g is obtained by washing the filtrate with 100 cm<3> of water, drying over magnesium sulfate, concentration to a residual volume of approx. 50 cm<5> and cooling to 5°C with decanting.

Eksempel 11 Example 11

Ved å arbeide som i eksempel 9, men fra 1,4 g 3-{2-[4-(3,4-dimetoksyfenyl)-l-piperazinyl]-etyl}-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid i 30 cm<3> metanol og 19 cm<3> av en 7 #-ig hydroalkoholisk kaliumkarbonatoppløsning oppnås 0,97 g 2-imino-3-{2-[4-(3,4-dimetoksyfenyl )-1-piperazinyl] -etyl - 6-t r i f luormet oksybenzotiazol in-tr ihydro-klorid med smeltepunkt 250°C. By working as in Example 9, but from 1.4 g of 3-{2-[4-(3,4-dimethoxyphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in 30 cm <3> methanol and 19 cm<3> of a 7# hydroalcoholic potassium carbonate solution yield 0.97 g of 2-imino-3-{2-[4-(3,4-dimethoxyphenyl)-1-piperazinyl]-ethyl - 6-trifluorinated oxybenzothiazole in trihydrochloride with a melting point of 250°C.

3-{2-[4-(3,4-dimetoksyfenyl)-l-piperazinyl]-etyl}-2-trifluor-acetylimino-6-trifluormetoksybenzotiazolin-hydroklorid kan fremstilles som følger: Man arbeider som i eksempel 9 fra 4,3 g 2-(2-trifluoracetyl-imino-6-trifluormetoksy-3-benzotiazolinyl )-etyl-metansulfonat, 70 cm<3> toluen og den frigitte base fra 14 g 4-(3,4-dimetoksyfenyl)-piperazin-dihydroklorid. Man oppnår 1,45 g av det tilsiktede hydroklorid med smeltepunkt 260°C. 3-{2-[4-(3,4-dimethoxyphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows: One works as in example 9 from 4,3 g of 2-(2-trifluoroacetyl-imino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate, 70 cm<3> toluene and the liberated base from 14 g of 4-(3,4-dimethoxyphenyl)-piperazine dihydrochloride. 1.45 g of the intended hydrochloride with a melting point of 260°C is obtained.

Eksempel 12 Example 12

Man arbeider som i eksempel 9, men går ut fra 1,7 g 3-{2-[4-( 4-fluo rf enyl)-l-piperazinyl]-etyl}-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid, 36 cm<3> metanol og 21 cm<3> av en 7 $-ig hydrometanolisk kaliumkarbonatoppløsning. Man oppnår 3-{2-[4-(4-fluorfenyl )-l-piperazinyl]-etyl}-2-imino-6-trifluormetoksybenzotiazolin-dihydroklorid med smeltepunkt 260°C. One works as in example 9, but starting from 1.7 g of 3-{2-[4-(4-fluorophenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride, 36 cm<3> of methanol and 21 cm<3> of a 7% hydromethanolic potassium carbonate solution. 3-{2-[4-(4-fluorophenyl)-1-piperazinyl]-ethyl}-2-imino-6-trifluoromethoxybenzothiazoline dihydrochloride with a melting point of 260°C is obtained.

3-{2-[4-(4-fluorfenyl)-l-piperazinyl]-etyl>-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin-hydroklorid kan fremstilles på følgende måte: Man arbeider som i eksempel 9 fra 9 g 4-(4-fluorfenyl)-piperazin, 70 cm<5> toluen og 4,52 g 2-(2-trifluoracetylimino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat. Man oppnår 1,7 g av det tilsiktede produkt med smeltepunkt 240°C. 3-{2-[4-(4-fluorophenyl)-1-piperazinyl]-ethyl>-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared in the following way: One works as in example 9 from 9 g of 4- (4-fluorophenyl)-piperazine, 70 cm<5> toluene and 4.52 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate. 1.7 g of the intended product with a melting point of 240°C is obtained.

Eksempel 13 Example 13

Man arbeider som i eksempel 9, men går ut fra 1,40 g 3-{2-[4-(4-klorfenyl )-l-piperazinyl] -etyl}-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin, 30 cm<5> metanol og 19 cm<5> av en 7 %- ig hydrometanolisk kaliumkarbonatoppløsning, oppnås 0,9 g 3-{2-[4-(4-klorfenyl)-l-piperazinyl]-etyl}-2-imino-6-trifluormetoksybenzotiazolin-dihydroklorid med smeltepunkt 270°C. One works as in example 9, but starts from 1.40 g of 3-{2-[4-(4-chlorophenyl)-l-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline, 30 cm<5> methanol and 19 cm<5> of a 7% hydromethanolic potassium carbonate solution, 0.9 g of 3-{2-[4-(4-chlorophenyl)-1-piperazinyl]-ethyl}-2-imino-6-trifluoromethoxybenzothiazoline is obtained -dihydrochloride with a melting point of 270°C.

3-{2-[4-( 4-klorfenyl)-l-piperazinyl]-etyl>-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin kan fremstilles som følger: Man oppvarmer i 1 time og 15 minutter og under tilbakeløp en blanding av 4,52 g 2-(2-trifluoracetylimino-6-trifluor-metoksy-3-benzotiazolinyl)-etyl-metansulfonat, 70 cm<3> toluen og basen som settes fri fra 13,45 g 4-(4-klorfenyl)piperazin-dihydroklorid. Efter avkjøling til 10°C og avhelling av precipitatet blir det tolueniske filtrat konsentrert og så renset ved kolonnekromatografi over silikagel med cyklo-heksan : etylacetat i volumforholdet 50:50 som elueringsmiddel. Efter omkrystallisering fra 50 cm<5> etanol oppnås 1,4 g tilsiktet produktet med smeltepunkt 165°C. 3-{2-[4-(4-chlorophenyl)-1-piperazinyl]-ethyl>-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline can be prepared as follows: One heats for 1 hour and 15 minutes and under reflux a mixture of 4.52 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate, 70 cm<3> toluene and the base liberated from 13.45 g of 4-(4-chlorophenyl)piperazine -dihydrochloride. After cooling to 10°C and decanting the precipitate, the toluene filtrate is concentrated and then purified by column chromatography over silica gel with cyclohexane:ethyl acetate in the volume ratio 50:50 as eluent. After recrystallization from 50 cm<5> ethanol, 1.4 g of the intended product with a melting point of 165°C is obtained.

Eksempel 14 Example 14

3,0 g 4-fenyl-l-[2-(4-trifluormetoksyani1ino)-etyl]-piperidin og 3,2 g kaliumtiocyanat i 25 cm<5> eddiksyre behandles 3.0 g of 4-phenyl-1-[2-(4-trifluoromethoxycyanino)-ethyl]-piperidine and 3.2 g of potassium thiocyanate in 25 cm<5> acetic acid are treated

dråpevis med 1,3 g brom i oppløsning i 15 cm<5> eddiksyre ved en temperatur nær 20°C. Reaksjonen følges i 18 timer ved denne temperatur. Efter tilsetning av 100 cm<5> destillert vann blir reaksjonsmediet nøytralisert med 30 %- ig NaOH og den organiske fase ekstrahert med 3 x 50 cm<5> etylacetat, tørket over magnesiumsulfat og konsentrert til tørr tilstand ved 2,7 kPa. Den oppnådde rest renses ved kolonnekromatografi over silikagel med etylacetat som elueringsmiddel. Efter dannelse av dihydrokloridet ved tilsetning av 4 cm<5> 4,2N saltsur eter i 30 cm<5> etylacetat, oppnås 2,4 g 2-imino-3-[2-(4-fenyl-piperidino)-etyl]-6-trifluormetoksybenzotiazolin-dihydroklorid som sublimerer nær 220°C. dropwise with 1.3 g of bromine in solution in 15 cm<5> of acetic acid at a temperature close to 20°C. The reaction is followed for 18 hours at this temperature. After adding 100 cm<5> of distilled water, the reaction medium is neutralized with 30% NaOH and the organic phase is extracted with 3 x 50 cm<5> of ethyl acetate, dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. The obtained residue is purified by column chromatography over silica gel with ethyl acetate as eluent. After formation of the dihydrochloride by addition of 4 cm<5> 4.2N hydrochloric acid ether in 30 cm<5> ethyl acetate, 2.4 g of 2-imino-3-[2-(4-phenyl-piperidino)-ethyl]- 6-trifluoromethoxybenzothiazoline dihydrochloride which sublimes near 220°C.

4-fenyl-1-[2-(4-trifluormetoksyani1ino)-etyl]-piperidin kan fremstilles på følgende måte: En blanding av 7,2 g N-p-toluensulfonyl-2-(4-trifluormetoksy-anilino)-etyl-p-toluensulfonat, 4,9 g 4-fenylpiperidin og 2,4 g natriumhydrogenkarbonat i 50 cm<5> dimetylformamid oppvarmes i 18 timer til 80°C. Efter avkjøling ved en temperatur nær 20°C blir reaksjonsmediet konsentrert til tørr tilstand ved 0,95 kPa. Resten vaskes to ganger med 30 cm<5> vann og tas derefter opp i 50 cm<5> etanol og konsentreres til tørr tilstand under redusert trykk. Råproduktet behandles med 30 cm<5> 37 %- ig saltsyre i en blanding av 30 cm<5> eddiksyre og 20 cm<5> destillert vann. Blandingen oppvarmes i 3 timer til koking. Efter avkjøling til en temperatur nær 20" C og tilsetning av 100 cm<3> destillert vann blir den vandige oppløsning nøytralisert med 30 %- ig natriumhydroksyd og den organiske fase ekstrahert med etylacetat. Man oppnår 4,0 g 4-fenyl-l-[2-(4-trifluormetoksyanilino)-etyl]-piperidin i form av en brun olje som benyttes som sådan ved den følgende reaksj on. 4-phenyl-1-[2-(4-trifluoromethoxyanilino)-ethyl]-piperidine can be prepared as follows: A mixture of 7.2 g of N-p-toluenesulfonyl-2-(4-trifluoromethoxy-anilino)-ethyl-p- toluenesulfonate, 4.9 g of 4-phenylpiperidine and 2.4 g of sodium bicarbonate in 50 cm<5> of dimethylformamide are heated for 18 hours at 80°C. After cooling at a temperature close to 20°C, the reaction medium is concentrated to a dry state at 0.95 kPa. The residue is washed twice with 30 cm<5> of water and then taken up in 50 cm<5> of ethanol and concentrated to dryness under reduced pressure. The raw product is treated with 30 cm<5> 37% hydrochloric acid in a mixture of 30 cm<5> acetic acid and 20 cm<5> distilled water. The mixture is heated for 3 hours until boiling. After cooling to a temperature close to 20" C and adding 100 cm<3> of distilled water, the aqueous solution is neutralized with 30% sodium hydroxide and the organic phase is extracted with ethyl acetate. 4.0 g of 4-phenyl-1- [2-(4-trifluoromethoxyanilino)-ethyl]-piperidine in the form of a brown oil which is used as such in the following reaction.

N-p-toluensulfonyl-2-(4-tri fluormetoksyani 1ino)-etyl-p-toluensulfonat kan fremstilles som følger: Til 5,0 g 2-(4-trifluormetoksyanilino)-etanol og 6,35 cm<5 >trietylamin i 50 cm<5> diklormetan ved 0"C settes progressivt 8.6 g p-toluensulfonylklorid. Reaksjonen følges i 2 timer ved en temperatur nær 20°C og derefter vaskes reaksjonsmediet med 3 x 50 cm<5> destillert vann og den organiske fase tørkes over magnesiumsulfat og konsentreres til tørr tilstand ved 2.7 kPa. Efter tilsetning av 50 cm<5> absolutt etanol blir det dannede precipitat filtrert. Man oppnår 7,3 g N-p-toluen-sulfonyl-2-(4-tri f luormetoksyani 1 ino)-etyl-p-toluensulf onat med smeltepunkt 88°C. N-p-Toluenesulfonyl-2-(4-trifluoromethoxyaniline)-ethyl-p-toluenesulfonate can be prepared as follows: To 5.0 g of 2-(4-trifluoromethoxyaniline)-ethanol and 6.35 cm<5 >triethylamine in 50 cm <5> dichloromethane at 0"C is progressively added 8.6 g of p-toluenesulfonyl chloride. The reaction is followed for 2 hours at a temperature close to 20°C and then the reaction medium is washed with 3 x 50 cm<5> of distilled water and the organic phase is dried over magnesium sulfate and concentrated to dryness at 2.7 kPa. After addition of 50 cm<5> absolute ethanol, the precipitate formed is filtered. 7.3 g of N-p-toluene-sulfonyl-2-(4-trifluoromethoxycyano)-ethyl- p-toluenesulfonate with a melting point of 88°C.

2- (4-trifluormetoksyani1ino)-etanol kan fremstilles på følgende måte: 88,5 g 4-trifluormetoksyanilin og 31,2 g 2-brometanol oppvarmes til 160° C i VA - time. Efter avkjøling til en temperatur nær 20° C blir reaksjonsmediet tatt opp i 200 cm<5 >diklormetan, uoppløselige stoffer filtrert av og filtratet konsentrert til tørr tilstand under redusert trykk. Efter rensing ved kolonnekromatografi over silikagel med etylacetat : cykloheksan i volumforholdet 40:60 som elueringsmiddel oppnås 26,8 g 2-(4-trifluormetoksyanilino)-etanol i form av en oransje olje. 2-(4-trifluoromethoxyaniline)-ethanol can be prepared in the following way: 88.5 g of 4-trifluoromethoxyaniline and 31.2 g of 2-bromoethanol are heated to 160° C. for VA - hour. After cooling to a temperature close to 20° C, the reaction medium is taken up in 200 cm<5 >dichloromethane, insoluble substances are filtered off and the filtrate is concentrated to dryness under reduced pressure. After purification by column chromatography over silica gel with ethyl acetate:cyclohexane in the volume ratio 40:60 as eluent, 26.8 g of 2-(4-trifluoromethoxyanilino)-ethanol are obtained in the form of an orange oil.

Eksempel 15 Example 15

Man arbeider som i eksempel 1, men går ut fra 0,6 g 3-{2-[4-(2-f luorfenyl )-l-piperazinyl]-etyl}-2-trifluoracetylimino-6-trifluormetoksybenzotiazol in, 20 cm<5> metanol og 10 cm<5> av en 7 $-ig hydroalkoholisk kaliumkarbonatoppløsning. Efter tilsetning av 4,2N saltsur eter oppnås 0,335 g 2-imino-3-{2-[4-(2-fluorfenyl)-l-piperazinyl]-etyl}-6-tr ifluormetoksy-benzotiazolin-dihydroklorid med smeltepunkt nær 260°C. One works as in example 1, but starting from 0.6 g of 3-{2-[4-(2-fluorophenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazolin, 20 cm< 5> methanol and 10 cm<5> of a 7% hydroalcoholic potassium carbonate solution. After the addition of 4.2N hydrochloric acid ether, 0.335 g of 2-imino-3-{2-[4-(2-fluorophenyl)-1-piperazinyl]-ethyl}-6-trifluoromethoxy-benzothiazoline dihydrochloride with a melting point close to 260° is obtained C.

3- {2-[4-(2-fluorfenyl)-1-piperazinyl]-etyl}-2-trifluoracetyl-imino-6-trifluormetoksybenzotiazolin kan fremstilles som følger: Ved å arbeide som i eksempel 1 for fremstilling av 3-{2-[4-(2-pyridyl)-l-piperazinyl]-etyl-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin, fra 4,52 g 2-(2-trifluoracetyl-imino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat 3- {2-[4-(2-fluorophenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetyl-imino-6-trifluoromethoxybenzothiazoline can be prepared as follows: By working as in Example 1 for the preparation of 3-{2 -[4-(2-pyridyl)-1-piperazinyl]-ethyl-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline, from 4.52 g of 2-(2-trifluoroacetyl-imino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl- methanesulfonate

i 70 cm<5> toluen og 9 g 4-(2-fluorfenyl)-piperazin. Man oppnår efter rensing ved kolonnekromatografi over silikagel med etylacetat som elueringsmiddel 0,6 g 3-{2-[4-(2-fluorfenyl)-1- piperazinyl]-etyl}-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin. in 70 cm<5> toluene and 9 g of 4-(2-fluorophenyl)-piperazine. After purification by column chromatography over silica gel with ethyl acetate as eluent, 0.6 g of 3-{2-[4-(2-fluorophenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline is obtained.

Eksempel 16 Example 16

Man arbeider som i eksempel 1 fra 4,52 g 2-(2-trifluoracetyl-imino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat i 120 cm<5> toluen og 7,8 g 4-(3-klorfenyl)piperazin. Efter 2 timer under tilbakeløp blir toluenfiltratet fordampet under redusert trykk og 100 cm<5> metanol og 10 cm<5> av en 7 #-ig hydroalkoholisk kaliumkarbonatoppløsning satt til toluenresten. Blandingen omrøres ved ca. 20°C. Metanolen fordampes under redusert trykk og resten renses ved kolonnekromatografi over silikagel med diklormetan:metanol i volumforholdet 95:5 som elueringsmiddel og derefter med etylacetat som elueringsmiddel. Efter tilsetning av 4,2N saltsur eter oppnås 0,9 g 2-imino-3-{2-[4-(3-klorfenyl)-1-piperazinyl]-etyl}-6-trifluormetoksybenzotiazolin-trihydroklorid som smelter nær 260°C. One works as in example 1 from 4.52 g of 2-(2-trifluoroacetyl-imino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate in 120 cm<5> toluene and 7.8 g of 4-(3-chlorophenyl ) piperazine. After 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure and 100 cm<5> of methanol and 10 cm<5> of a 7# hydroalcoholic potassium carbonate solution are added to the toluene residue. The mixture is stirred at approx. 20°C. The methanol is evaporated under reduced pressure and the residue is purified by column chromatography over silica gel with dichloromethane:methanol in the volume ratio 95:5 as eluent and then with ethyl acetate as eluent. After addition of 4.2N hydrochloric acid ether, 0.9 g of 2-imino-3-{2-[4-(3-chlorophenyl)-1-piperazinyl]-ethyl}-6-trifluoromethoxybenzothiazoline trihydrochloride is obtained which melts near 260°C .

Eksempel 17 Example 17

Man arbeider som i eksempel 1 fra 4,52 g 2-(2-trifluoracetyl-imino-6-trifluormetoksy-3-benzotiazolinyl)-etyl-metansulfonat i 120 cm<5> toluen og 6,7 g 4-(3-fluorfenyl)piperazin. Efter 2 timer under tilbakeløp blir toluenfiltratet fordampet under redusert trykk og 100 cm<5> metanol og 20 cm<5> av en 7 #-ig hydroalkoholisk kaliumkarbonatoppløsning tilsatt til toluenresten. Efter 2 timers omrøring ved ca. 20°C blir metanolen fordampet under redusert trykk og resten renses ved kolonnekromatografi over silikagel med diklormetan:metanol i volumforholdet 98:2 som elueringsmiddel og derefter med etylacetat. Efter tilsetning av 4,2N saltsur eter oppnås 1 g 2- imino-3-{ 2 -[4 -(3-fluorf enyl)-1-piperazinyl]- etyl }-6-trifluormetoksybenzotiazolin-dihydroklorid med smeltepunkt nær 270°C. One works as in example 1 from 4.52 g of 2-(2-trifluoroacetyl-imino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate in 120 cm<5> toluene and 6.7 g of 4-(3-fluorophenyl ) piperazine. After 2 hours under reflux, the toluene filtrate is evaporated under reduced pressure and 100 cm<5> of methanol and 20 cm<5> of a 7# hydroalcoholic potassium carbonate solution are added to the toluene residue. After 2 hours of stirring at approx. 20°C, the methanol is evaporated under reduced pressure and the residue is purified by column chromatography over silica gel with dichloromethane:methanol in the volume ratio 98:2 as eluent and then with ethyl acetate. After addition of 4.2N hydrochloric acid ether, 1 g of 2-imino-3-{2-[4-(3-fluorophenyl)-1-piperazinyl]-ethyl}-6-trifluoromethoxybenzothiazoline dihydrochloride with a melting point close to 270°C is obtained.

Eksempel 18 Example 18

Man arbeider som i eksempel 1, men går ut fra 1,8 g 3-{2-[4-(2-me tok sy f enyl)-1-piperazinyl]-etyl}-2-trifluoracetylimino-6-trifluormetoksybenzotiazolin-hydroklorid i 39 cm<5> metanol og 23 cm<5> av en 7 #-ig hydroalkoholisk kaliumkarbonatoppløs-ning. Efter rensing ved kolonnekromatografi over silikagel og med aceton som elueringsmiddel og så med tilsetning av 4,2N saltsur eter, oppnås 1,2 g 2-imino-3-{2-[4-(2-metoksyfenyl )-1-piperazinyl]-etyl}-6-trifluormetoksybenzotiazolin-trihydroklorid med smeltepunkt nær 210°C. One works as in example 1, but starting from 1.8 g of 3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride in 39 cm<5> of methanol and 23 cm<5> of a 7# hydroalcoholic potassium carbonate solution. After purification by column chromatography over silica gel and with acetone as eluent and then with the addition of 4.2N hydrochloric acid ether, 1.2 g of 2-imino-3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]- ethyl}-6-trifluoromethoxybenzothiazoline trihydrochloride with a melting point close to 210°C.

3-{2-[4-(2-metoksyfenyl)-l-piperazinyl]-etyl}-2-trifluor-acetylimino-6-trifluormetoksybenzotiazolin-hydroklorid kan fremstilles som følger: Man arbeider som i eksempel 1 og går ut fra 4,52 g 2-(2-tri fluoracetylimino-6-tr i fluormetoksy-3-benzoti azol inyl )-etyl-metansulf onat i 120 cm<5> toluen og 7,7 g 4-(2-metoksy-fenyl)-piperazin. Efter tilsetning av 4,2N saltsur eter oppnås 1,8 g 3-{2-[4-(2-metoksyfenyl)-l-piperazinyl]-etyl}-2-trifluoracetylimino-6-tri fluormetoksybenzot iazolin-hydroklorid som smelter ved 230°C. 3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride can be prepared as follows: Work as in example 1 and start from 4, 52 g of 2-(2-trifluoroacetylimino-6-trifluoromethoxy-3-benzothiazolinyl)-ethyl methanesulfonate in 120 cm<5> toluene and 7.7 g of 4-(2-methoxy-phenyl)-piperazine . After addition of 4.2N hydrochloric acid ether, 1.8 g of 3-{2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl}-2-trifluoroacetylimino-6-trifluoromethoxybenzothiazoline hydrochloride is obtained which melts at 230 °C.

Som faste preparater for oral administrering kan man benyttes Solid preparations for oral administration can be used

tabletter, piller, pulvere (gelatinkapsler, poser) eller granulat. I preparatene er den aktive bestanddel ifølge oppfinnelsen blandet med en eller flere inerte fortynningsmidler som stivelse, cellulose, sakkarose, laktose eller silisiumdioksyd. tablets, pills, powders (gelatin capsules, sachets) or granules. In the preparations, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silicon dioxide.

Preparatene kan likeledes omfatte andre stoffer enn fortynningsmidler, for eksempel ett eller flere smøremidler som magnesiumstearat eller talkum, et farvestoff, en omhylling eller en ferniss. The preparations may also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating or a varnish.

Som flytende preparater for oral administrering kan man benytte oppløsninger, suspensjoner, emulsjoner, siruper og farmasøytisk akseptable eliksirer inneholdende inerte fortynningsmidler som vann, etanol, glycerol, vegetabilske oljer eller parafinolje. Preparatene kan omfatte andre stoffer enn fortynningsmidlene, for eksempel fuktemidler, drøyemidler, fortykningsmidler, aromastoffer eller stabili-ser ingsmidler . As liquid preparations for oral administration, solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil can be used. The preparations may include substances other than the diluents, for example wetting agents, emollients, thickeners, flavoring agents or stabilizers.

Sterile preparater for parenteral administrering er fortrinnsvis eventuelt vandige oppløsninger, suspensjoner eller emulsjoner. Som oppløsningsmiddel eller bærer kan man benytte vann, propylenglykol, en polyetylenglykol, vegetabilske oljer og spesielt olivenolje, organiske injiserbare estere som etyloleat eller andre organiske hensiktsmessige oppløsningsmidler. Preparatene kan likeledes inneholde tilsetningsstoffer og spesielt fuktemidler, isotoniserende midler, emulgerings-, dispergerings- og stabiliseringsmidler. Steriliseringen kan skje på flere måter, for eksempel ved aseptisk filtrering, ved i preparatet å innarbeide steri-liserende midler, ved bestråling eller ved oppvarming. De kan likeledes fremstilles i form av faste sterile preparater som kan oppløses på bruksøyeblikket i sterilt vann eller et hvilket som helst annet sterilt injiserbart medium. Sterile preparations for parenteral administration are preferably possibly aqueous solutions, suspensions or emulsions. Water, propylene glycol, a polyethylene glycol, vegetable oils and especially olive oil, organic injectable esters such as ethyl oleate or other suitable organic solvents can be used as solvent or carrier. The preparations may also contain additives and especially wetting agents, isotonizing agents, emulsifying, dispersing and stabilizing agents. Sterilization can take place in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the preparation, by irradiation or by heating. They can likewise be produced in the form of solid sterile preparations which can be dissolved at the moment of use in sterile water or any other sterile injectable medium.

Preparater for rektal administrering er suppositorier eller rektale kapsler som i tillegg til den aktive bestanddel inneholder drøyemidler som kakaosmør, semisyntetiske glycerider eller polyetylenglykoler. Preparations for rectal administration are suppositories or rectal capsules which, in addition to the active ingredient, contain laxatives such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Preparater for topisk administrering kan for eksempel være kremer, pomader, lotioner, kollyrer, kollutorier, nesedråper eller aerosoler. Preparations for topical administration can be, for example, creams, pomades, lotions, eye drops, colloquials, nasal drops or aerosols.

På det humanterapeutiske området blir forbindelsene spesielt benyttet ved behandling og prevensjon av konvulsive fenomener, schizofreni vanskeligheter og spesielt mangelformer ved schizofreni, søvnproblemer, fenomener forbundet med cerebral ischemi samt neurologiske affektasjoner der glutamat kan være implisert, for eksempel Alzheimers sykdom, Huntingtons sykdom, amyotrofisk lateral sklerose og olivo-pontocerebelløs atrofi. In the human therapeutic area, the compounds are particularly used in the treatment and prevention of convulsive phenomena, schizophrenia difficulties and especially deficiency forms in schizophrenia, sleep problems, phenomena associated with cerebral ischemia as well as neurological affections where glutamate may be implicated, for example Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivo-pontocerebellar atrophy.

Dosene avhenger av den tilsiktede virkning, behandlingsvarig-heten og den administreringsmåte som benyttes, den ligger generelt mellom 30 og 300 mg pr. dag via oral administrering til en voksen med enhetsdoser som går fra 10 til 100 mg aktiv bestanddel. The doses depend on the intended effect, the duration of treatment and the method of administration used, it is generally between 30 and 300 mg per day via oral administration to an adult with unit doses ranging from 10 to 100 mg of active ingredient.

Rent generelt bestemmer legen posologien som funksjon av alder, vekt og alle andre faktorer i forbindelse med personen som skal behandles. In general, the doctor determines the dosage as a function of age, weight and all other factors in connection with the person to be treated.

De følgende eksempler illustrerer mulige preparater. The following examples illustrate possible preparations.

Eksempel A Example A

Man fremstiller på vanlig måte doserte gelpiller på 50 mg aktiv bestanddel med følgende sammensetning: Dosed gel pills of 50 mg active ingredient with the following composition are produced in the usual way:

Eksempel B Example B

Man fremstiller på vanlig måte piller dosert til 50 mg aktiv bestanddel og med følgende generelle sammensetning: Pills dosed to 50 mg of active ingredient and with the following general composition are usually produced:

Eksempel C Example C

Man fremstiller en injiserbar oppløsning inneholdende 10 mg aktiv bestanddel og med følgende sammensetning: An injectable solution is prepared containing 10 mg of active ingredient and with the following composition:

Claims

Analogous procedure for the preparation of therapeutically active compounds with the formula:

there

Ri means

a 1-piperazinyl radical substituted in the 4-position by (a) a phenyl radical, (b) a phenyl radical which is substituted by at least one substituent selected from halogen atoms, alkyl and alkoxy acid radicals, (c) a phenylalkyl radical, (d) a pyridyl radical or ( e) a pyrimidinyl residue,

a 1,2,3,6-tetrahydro-1-pyridyl residue substituted in the 4-position with a phenyl residue or a phenyl residue substituted with at least one substituent selected from halogen atoms, alkyl and alkoxy acid residues,

a piperidine residue substituted in the 4-position with a phenyl residue or a phenyl residue substituted with at least one substituent selected from halogen atoms, alkyl and coco acid residues,

R2 means a trifluoromethoxy acid residue, - n is equal to 2 or 3,

provided that alkyl and alkoxy acid residues and alkyl and alkoxy moieties contain 1 to 4 carbon atoms in a straight or branched chain, as well as

their salts with mineral and organic acids,

characterized by the fact that one

A for the preparation of compounds of formula (I), hydroly-

sers a derivative with the formula:

where Ri, Rg °S n has the same meaning as above, isolates the product and optionally transfers it to an acid addition salt with a mineral or organic acid, or

B for the preparation of compounds of formula (I), reactant

bromine and an alkali metal thiocyanate with a compound of the formula:

where R]_, R 2 and n have the same meaning as above, isolate the product and transfer it to an acid addition salt with a mineral or organic acid.