NO121670B

NO121670B -

Info

Publication number: NO121670B
Application number: NO16068A
Authority: NO
Inventors: P Petersen; N Lassen; T Ammitzboell
Original assignee: Kefalas As
Priority date: 1967-01-16
Filing date: 1968-01-15
Publication date: 1971-03-29
Also published as: BE709229A; FR8378M; FR1583194A; DE1668925B1; SE351652B; AT276374B; AT276373B; AT276375B; CH522667A; GB1215132A; FI49978C; CH510041A; DK128813B; NL6800637A; FI49978B

Description

Analogifremgangsmåte for fremstilling av terapeutisk virksomme, basisk substituerte tioftalaner eller syreaddisjonssalter av disse. Analogous process for the production of therapeutically effective, base-substituted thiophthalans or acid addition salts thereof.

Nærværende oppfinnelse vedrorer en fremgangsmåte for fremstilling av hittil ukjente basisk substituerte tioftalaner med den generelle formel: The present invention relates to a process for the production of hitherto unknown base-substituted thiophthalans with the general formula:

hvor og R2er hydrogen eller alkylgrupper med opp til 4 karbonatomer, where and R2 are hydrogen or alkyl groups with up to 4 carbon atoms,

R^og<R>^er hydrogen, alkylgrupper med opp til 4 karbonatomer eller de danner sammen en pentametylen-gruppe, R^and<R>^ are hydrogen, alkyl groups with up to 4 carbon atoms or they together form a pentamethylene group,

"alkylen" er en alkylenkjede, rett eller forgrenet, "alkylene" is an alkylene chain, straight or branched,

med 2-6 karbonatomer, idet minst 2 karbonatomer er i kjeden som direkte forbinder ringkarbonatornet med nitrogenatornet, with 2-6 carbon atoms, with at least 2 carbon atoms in the chain directly connecting the ring carbon atom to the nitrogen atom,

R5er -CO-NHRg, -COOR7, -CO-Rg eller eventuelt halogen- eller trihalogenmetylsubstituert fenyl, R5 is -CO-NHRg, -COOR7, -CO-Rg or optionally halogen- or trihalomethyl-substituted phenyl,

Rg er hydrogen eller fenyl eventuelt substituert med Rg is hydrogen or phenyl optionally substituted with

1 eller 2 alkylgrupper med opp til 4 karbonatomer, 1 or 2 alkyl groups with up to 4 carbon atoms,

R7er hydrogen eller en alkylgruppe med opp til 4 karbonatomer, R7 is hydrogen or an alkyl group with up to 4 carbon atoms,

Rg er en alkylgruppe med opp til 4 karbonatomer, og Rg is an alkyl group with up to 4 carbon atoms, and

X er hydrogen, halogen eller trihalogenmetyl, X is hydrogen, halogen or trihalomethyl,

eller syreaddisjonssalter av disse forbindelser. or acid addition salts of these compounds.

Forbindelsene med formel I og de tilsvarende syreaddisjonssalter er verdifulle terapeutiske stoffer. I eksperimenter på dyr viser de en utpreget potenserende effekt overfor adrenalin og nor-adrenalin, samtidig med at de har sterk anti-reserpinvirk-ning. De viser ytterligere sedative og anti-kolinerge effekter. Denne kombinasjon av effekter sammenholdt med en relativt lav akutt toksisitet gjftr forbindelsene med formel I og de tilsvarende syreaddisjonssalter anvendelige innenfor psykoterapien spesielt for behandling av endogene depresjoner. Forsflk som viser virkningen av et utvalg av forbindelsene, er referert i Acta pharmacol. et toxicol. 1970, 28. Den betydelig stcSrre lipoidopploselighet som forbindelsene med formel I er i besit-telse av, sammenlignet med de tilsvarende ftalaner, som er kjent fra Acta pharmacol. et toxicol, 24, s. 121 - 133 (1966), indikerer bredere anvendelighet innenfor det angjeldende om-rådet av psykiatrien. The compounds of formula I and the corresponding acid addition salts are valuable therapeutic agents. In experiments on animals, they show a distinct potentiating effect against adrenaline and nor-adrenaline, while at the same time having a strong anti-reserpine effect. They show additional sedative and anti-cholinergic effects. This combination of effects combined with a relatively low acute toxicity makes the compounds of formula I and the corresponding acid addition salts applicable in psychotherapy, especially for the treatment of endogenous depressions. Research showing the effect of a selection of the compounds is referred to in Acta pharmacol. a toxicol. 1970, 28. The significantly greater lipoid solubility possessed by the compounds of formula I, compared to the corresponding phthalates, which is known from Acta pharmacol. et toxicol, 24, pp. 121 - 133 (1966), indicates wider applicability within the relevant area of psychiatry.

Syreaddisjonssaltene er fortrinnsvis salter av syrer hvis an-ion er ugiftig i de sedvanlige terapeutiske doser. Som eksempler på slike syreaddisjonssalter kan nevnes hydroklorider, hydrobromider, sulfater, fosfater, nitrater, acetater, laktater, maleater, citrater, tartrater og bitartrater, succinater, oksa-later, metan- og etansulfonater. Andre syreaddisjonssalter kan dog, hvis onsket, fullt ut anvendes. The acid addition salts are preferably salts of acids whose anion is non-toxic in the usual therapeutic doses. Examples of such acid addition salts include hydrochlorides, hydrobromides, sulphates, phosphates, nitrates, acetates, lactates, maleates, citrates, tartrates and bitartrates, succinates, oxalates, methane and ethane sulphonates. However, other acid addition salts can, if desired, be fully used.

Ved fremgangsmåten ifolge oppfinnelsen omsettes In the method according to the invention,

a) en forbindelse med formelen: a) a compound with the formula:

hvor , R2og X har den foran angitte betydning, og where , R2 and X have the previously stated meaning, and

R',- har den for Rj. angitte betydning med unntagelse R',- has it for Rj. stated meaning with exception

av -COOH, of -COOH,

med en forbindelse med formelen: with a compound of the formula:

hvor "hal" er klor, brom eller jod, where "hal" is chlorine, bromine or iodine,

"alkylen", R3og R. har den foran angitte betydning, "alkylene", R 3 and R. have the above meaning,

i nærvær av et kondensasjonsmiddel som et alkalimetallamid eller -hydrid, f .eks. natriumamid eller -hydrid, butyllitium* eller fenyllitium og, i det tilfelle hvor R'^er COOR^forsåpes denne estergruppe, hvis onsket, for å oppnå den frie karboksylsyre, eller ;b} en forbindelse med formelen: ; ; hvor R^, R- 2, "alkylen" og X har den foran angitte betydning» og ;Z er klor, brom eller jod, ;med en forbindelse med formelen: ; ; hvor R3og R^har den foran angitte betydning, eller ;c) er. forbindelse med formelen: ; ; hvor X, 1*2, og R 4 har den foran angitte betydning, R er hydrogen eller en alkylgruppe med opp til 3 karbonatbmer, og in the presence of a condensing agent such as an alkali metal amide or hydride, e.g. sodium amide or -hydride, butyllithium* or phenyllithium and, in the case where R'^ is COOR^, this ester group is saponified, if desired, to obtain the free carboxylic acid, or ;b} a compound of the formula: ; ; where R^, R- 2, "alkylene" and X have the above meaning» and ;Z is chlorine, bromine or iodine, ;with a compound of the formula: ; ; where R 3 and R 3 have the meaning stated above, or ;c) is. connection with the formula: ; ; where X, 1*2, and R 4 have the above meaning, R is hydrogen or an alkyl group with up to 3 carbonate atoms, and

"alkyliden" er en alkylidengruppe med 2-6 karbonatomer, idet minst 2 karbonatomer forbinder det til benzenringene bundne karbonatom med nitrogenatomet, med hydrogensulfid, "alkylidene" is an alkylidene group with 2-6 carbon atoms, with at least 2 carbon atoms connecting the carbon atom bound to the benzene rings with the nitrogen atom, with hydrogen sulphide,

hvoretter en forbindelse med formelen: after which a compound with the formula:

hvor R^, R2, "alkylen" og X har den foran angitte betydning, where R 1 , R 2 , "alkylene" and X have the above meaning,

R<1>2er en alkylgruppe med opp til 4 karbonatomer, R'4er en alkylgruppe med opp til 4 karbonatomer , og R"5har den for R^ angitte betydning med unntagelse R<1>2 is an alkyl group with up to 4 carbon atoms, R'4 is an alkyl group with up to 4 carbon atoms, and R"5 has the meaning given for R^ with an exception

av -COOR7, of -COOR7,

eventuelt omsettes med en klormaursyreester med formelen: possibly reacted with a chloroformate ester with the formula:

hvor Rg er en alkylgruppe med opp til 8 karbonatomer where Rg is an alkyl group with up to 8 carbon atoms

eller en benzylgruppe, or a benzyl group,

hvorpå den dannede forbindelse med formelen: whereupon the formed compound with the formula:

hydrolyseres, eller en oppnådd forbindelse med formelen: hydrolyzed, or an obtained compound with the formula:

hvor R^,R2, R3, R4, "alkylen"og X har den foran angitte betydning, og where R 1 , R 2 , R 3 , R 4 , "alkylene" and X have the above meaning, and

R^er en alkylgruppe med opp til 4 karbonatomer, eventuelt omsettes med et amin med formelen HjNRg eller med en Grignardforbindelse med formelen: R^ is an alkyl group with up to 4 carbon atoms, optionally reacted with an amine of the formula HjNRg or with a Grignard compound of the formula:

hvor Rg har den foran angitte betydning, og "hal" er klor, brom eller jod, where Rg has the meaning given above, and "hal" is chlorine, bromine or iodine,

hvorpå det i sistnevnte tilfelle oppnådde kompleks hydrolyseres på i og for seg kjent måte, eller en oppnådd forbindelse med formelen: whereupon the complex obtained in the latter case is hydrolyzed in a manner known per se, or a compound obtained with the formula:

hvor R^, R2/ R^; R4./"alkylen" og X har den foran where R 1 , R 2 / R 2 ; R4./"alkylene" and X has it in front

angitte betydning, stated meaning,

eventuelt omsettes med en Grignardforbindelse med formelen: possibly reacted with a Grignard compound with the formula:

hvor Rg har den foran angitte betydning, og where Rg has the meaning stated above, and

"hal" er klor, brom eller jod, "hal" is chlorine, bromine or iodine,

hvorpå det dannede Grignardkompleks hydrolyseres med en fortynnet syre og den dannede forbindelse med formelen I, hvor R^er -CO-Rg, isoleres, hvorpå den dannede forbindelse med formel I isoleres i form av den frie base eller et syreaddisjonssalt av denne. whereupon the formed Grignard complex is hydrolyzed with a dilute acid and the formed compound of formula I, where R^ is -CO-Rg, is isolated, whereupon the formed compound of formula I is isolated in the form of the free base or an acid addition salt thereof.

Utgangsstoffene med formel II, som likeledes er hittil ukjente forbindelser, kan ofte hensiktsmessig fremstilles ifolge folgende reaksjonsskjema: The starting substances with formula II, which are likewise hitherto unknown compounds, can often be suitably prepared according to the following reaction scheme:

idet minst en av og R2skal være hydrogen, og Rcfortrinnsvis er fenyl, eventuelt substituert wherein at least one of and R2 must be hydrogen, and Rc is preferably phenyl, optionally substituted

som tidligere angitt. as previously stated.

Utgangsstoffene med formel II, hvori minst en av R^ og R2 er en lavere alkylgruppe med opp til 4 karbonatomer, og R^fortrinnsvis er fenyl, eventuelt substituert som tidligere angitt, kan hensiktsmessig fremstilles etter folgende reaksjonsskjema: The starting substances with formula II, in which at least one of R^ and R2 is a lower alkyl group with up to 4 carbon atoms, and R^ is preferably phenyl, optionally substituted as previously indicated, can be conveniently prepared according to the following reaction scheme:

Hvis det ved reaksjonen bare anvendes et mol hydrogensulfid, tar reaksjonen fdlgende forlop: If only one mole of hydrogen sulphide is used in the reaction, the reaction proceeds as follows:

Reduksjon kan hensiktsmessig gjennomføres med vannfri maursyre. Reduction can be suitably carried out with anhydrous formic acid.

Utgangsstoffene med formelen II kan likeledes fremstilles ifolge fdlgende reaksjonsskjema: The starting substances with the formula II can also be prepared according to the following reaction scheme:

idet X, R^, R^ og R^har den foran angitte be- where X, R^, R^ and R^ have the previously indicated

tydning, og interpretation, and

X^er halogen. X^ is halogen.

Spesielt når R^er -COOR^eller -CO.Rq, er denne metode å foretrekke. Especially when R^ is -COOR^ or -CO.Rq, this method is preferred.

Utgangsstoffet med formelen III, ifdlge metode b), fremstilles hensiktsmessig ut fra en forbindelse med formelen II, idet denne omsettes med en forbindelse med formelen: The starting material with the formula III, according to method b), is suitably prepared from a compound with the formula II, as this is reacted with a compound with the formula:

hal • alkylen • U hal • alkylene • U

i nærvær av et kondensasjonsmiddel, som natriumamid, natriumhydrid eller lignende. in the presence of a condensing agent, such as sodium amide, sodium hydride or the like.

Utgangsstoffet med formelen IV fremstilles hensiktsmessig etter folgende skjema: The starting material with the formula IV is suitably prepared according to the following scheme:

Kondensasjonene ifolge a) og ved fremstillingen av utgangsstoffene II og III gjennomfdres hensiktsmessig i et inert opplosnings-middel, som dimetylsulfoksyd, benzen, toluen eller xylen. The condensations according to a) and in the preparation of the starting materials II and III are suitably carried out in an inert solvent, such as dimethyl sulphoxide, benzene, toluene or xylene.

Ved den farmakologiske gjennomprdvning av forbindelsene med formelen I eller syreaddisjonssalter derav har spesielt de av forbindelsene hvor X er hydrogen, R^og R2er hydrogen eller metylgrupper, "alkylen" er -CH2-CH2«CH2-, R^ og R^ er hydrogen eller metylgrupper, og R^ er fenyl, vist seg å inneholde de tidligere nevnte farmakodynamiske effekter i en slik grad at det indikerer særlig god anvendelse innenfor psykiatrien. In the pharmacological testing of the compounds of the formula I or acid addition salts thereof, in particular those of the compounds where X is hydrogen, R^ and R^ are hydrogen or methyl groups, the "alkylene" is -CH2-CH2«CH2-, R^ and R^ are hydrogen or methyl groups, and R^ is phenyl, have been shown to contain the previously mentioned pharmacodynamic effects to such an extent that it indicates a particularly good application within psychiatry.

I det folgende skal fremgangsmåten ifolge oppfinnelsen illu-streres ved en rekke eksempler. In the following, the method according to the invention will be illustrated by a number of examples.

EKSEMPEL 1 EXAMPLE 1

Utgangsmaterialet, 1-fenyltioftalan, fremstilles på folgende The starting material, 1-phenylthiophthalan, is prepared as follows

måte: manner:

74 g a-fenyl-ftalylalkohol (fremstilt ved reduksjon av o-benzoyl-benzosyre med litiumaluminiumhydrid) oppltises i 500 ml karbontetraklorid og 70 g friskt destillert fosfortribromid opplost i 200 74 g of a-phenyl-phthalyl alcohol (prepared by reduction of o-benzoyl-benzoic acid with lithium aluminum hydride) are dissolved in 500 ml of carbon tetrachloride and 70 g of freshly distilled phosphorus tribromide dissolved in 200

ml karbontetraklorid tilfoyes under omroring ved en temperatur under 0°C. Derpå heves temperaturen til romtemperatur, og omroringen fortsettes i ca. 18 timer. Reaksjonstemperaturen heves derpå langsomt til 70°C i lopet av 1 time, hvorpå reaksjon sblandingen blir avkjolt, den flytende fase dekanteres fra bunnfallet, vaskes med isvann, torkes over vannfritt magnesiumsulfat, filtreres og inndampes, hvorved a-fenyl-ftalyldibromid oppnås som en gul olje. Denne olje dryppes under omroring til en suspensjon av tort natriumsulfid i etanol. Etter avsluttet tildrypning blir reakjsonsblandingen kokt under tilbakelop i en time på dampbad. Det ved reaksjonen dannede natriumbromid filtreres fra, opplesningen inndampes, og resten opploses i eter. Eterfasen vaskes med vann, torkes over vannfritt magnesiumsulfat, filtreres og destilleres. Derved oppnås 1-fenyl-tioftalan som en gul olje, som koker ved 135-140°C/0,1 mm Hg. Ved omkrystallisasjon fra petroleter blir det oppnådd som et hvitt krystallinsk ml of carbon tetrachloride is added while stirring at a temperature below 0°C. The temperature is then raised to room temperature, and the stirring is continued for approx. 18 hours. The reaction temperature is then raised slowly to 70°C over the course of 1 hour, after which the reaction mixture is cooled, the liquid phase is decanted from the precipitate, washed with ice water, dried over anhydrous magnesium sulfate, filtered and evaporated, whereby α-phenyl-phthalyl dibromide is obtained as a yellow oil. This oil is added dropwise with stirring to a suspension of dry sodium sulphide in ethanol. After completion of the dripping, the reaction mixture is boiled under reflux for one hour in a steam bath. The sodium bromide formed during the reaction is filtered off, the reading is evaporated, and the residue is dissolved in ether. The ether phase is washed with water, dried over anhydrous magnesium sulphate, filtered and distilled. Thereby 1-phenyl-thiophthalan is obtained as a yellow oil, which boils at 135-140°C/0.1 mm Hg. On recrystallization from petroleum ether, it is obtained as a white crystalline

stoff, som smelter ved 60-62°C. Utbytte 42 g. substance, which melts at 60-62°C. Yield 42 g.

2,7 g natriumhydrid (50% suspensjon i mineralolje) tilfoyes 40 ml dimetylsulfoksyd og oppvarmes til 100°C i fem minutter. Oppløsningen blir avkjølt til 20°C, og 10 g 1-fenyl-tioftalan tilsettes under omroring. Opplosningen blir sterkt rod, og det tiisettes oyeblikkelig 7 g 3-dimetylaminopropylklorid, hvorved en kraftig reaksjon og temperaturstigning til ca. 40° utldses. Opplosningen blir derpå helt i isvann og ekstraheres med eter. Eteropplosningen blir ekstrahert med fortynnet saltsyre, hvorpå det vandige ekstrakt blir gjort alkalisk med fortynnet natrium-hydroksydoppldsning. Den utskilte base blir ristet over i eter, eterfasen tdrkes over vannfritt kaliumkarbonat, filtreres og 2.7 g of sodium hydride (50% suspension in mineral oil) are added to 40 ml of dimethyl sulphoxide and heated to 100°C for five minutes. The solution is cooled to 20°C, and 10 g of 1-phenylthiophthalan is added while stirring. The solution becomes strongly red, and 7 g of 3-dimethylaminopropyl chloride is immediately added, whereby a vigorous reaction and temperature rise to approx. 40° is released. The solution is then poured into ice water and extracted with ether. The ether solution is extracted with dilute hydrochloric acid, after which the aqueous extract is made alkaline with dilute sodium hydroxide solution. The separated base is shaken into ether, the ether phase is dried over anhydrous potassium carbonate, filtered and

inndampes på dampbad. Resten oppldses i 50 ml aceton, og opp-15 sn ingen innstilles på pH 5 med en oppløsning av tcJrt hydrogenklorid i eter. Derved utkrystalliserer 9 g av hydrokloridet av 1-(3-dimetylaminopropyl)-1-fenyl-tioftalan. smp. 200 - 2o2°C. evaporated on a steam bath. The residue is dissolved in 50 ml of acetone, and the mixture is adjusted to pH 5 for 15 minutes with a solution of concentrated hydrogen chloride in ether. Thereby, 9 g of the hydrochloride of 1-(3-dimethylaminopropyl)-1-phenyl-thiophthalan crystallizes out. m.p. 200 - 2o2°C.

EKSEMPEL 2 EXAMPLE 2

Ved å gå frem som beskrevet i eksempel 1, idet det anvendes 7 g 3-metylaminopropylkldrid i stedet for ,3-dimetylaminopropylklorid, oppnås hydrokloridet av 1-(3-raetylaminopropyl)-1-fenyl-tiof talan som hvite krystaller, som smelter ved 155-160°C. Utbytte 7 g. By proceeding as described in Example 1, using 7 g of 3-methylaminopropyl chloride instead of ,3-dimethylaminopropyl chloride, the hydrochloride of 1-(3-ethylaminopropyl)-1-phenyl-thiophthalan is obtained as white crystals, which melt at 155-160°C. Yield 7 g.

EKSEMPEL 3 EXAMPLE 3

Utgangsmaterialet, l-metyl-3-fenyl-tioftalan, fremstilles på fdlgende måte: 1 mol 3-fenylftalid opplflses i 500 ml t8rr tetrahydrofuran, og 1 mol metylmagnesiumjodid i eter tildryppes under tilbakelbp. Etter 3o minutter hydrolyseres reaksjonsblandingen med is og fortynnet saltsyre, og det ekstraheres med eter. Eterfasen tdrkes over vannfritt magnesiumsulfat og inndampes på dampbad. Ved omkrystallisasjon av resten fra eter/petroleter (1:1) oppnås o-acetyl-benzhydrol som et hvitt krystallinsk stoff, som smelter ved 95-97°C. Utbytte 0,75 mol. Ved reduksjon av o-acetyl-benzhydrol med litiumaluminiurrihydrid i tcirr eter oppnås 2-metyl-a'-fenyl-ftalylalkohol som en gulaktig olje. The starting material, 1-methyl-3-phenyl-thiophthalan, is prepared in the following way: 1 mol of 3-phenylphthalide is dissolved in 500 ml of dry tetrahydrofuran, and 1 mol of methylmagnesium iodide in ether is added dropwise under reflux. After 30 minutes, the reaction mixture is hydrolyzed with ice and dilute hydrochloric acid, and it is extracted with ether. The ether phase is dried over anhydrous magnesium sulfate and evaporated on a steam bath. By recrystallization of the residue from ether/petroleum ether (1:1), o-acetyl-benzhydrol is obtained as a white crystalline substance, which melts at 95-97°C. Yield 0.75 mol. By reduction of o-acetyl-benzhydrol with lithium aluminum hydride in ether, 2-methyl-a'-phenyl-phthalyl alcohol is obtained as a yellowish oil.

Av 36 g 2-metyl-a'-fenyl-ftalylalkohol oppnås 12 g l-metyl-3^ fenyl-tioftalan ndyaktig som beskrevet i eksempel 1 for fremstillingen av 1-fenyl-tioftalan. Kp. 138-148°c/0,1 mm Hg. From 36 g of 2-methyl-α'-phenyl-phthalyl alcohol, 12 g of 1-methyl-3-phenyl-thiophthalan are obtained in a manner similar to that described in example 1 for the preparation of 1-phenyl-thiophthalan. Kp. 138-148°c/0.1 mm Hg.

Ved å gjennomfare eksempel 1, idet det anvendes 10 g 1-fenyl- . 3-metyl-tioftalan i stedet for 1-fenyl-tio-ftalan, oppnås hydrokloridet av 1-(3-dimetylaminopropyl)-1-fenyl-3-metyl-tioftalan, som smelter ved 175-178°C. Utbytte 9,5 g. By going through example 1, using 10 g of 1-phenyl-. 3-methyl-thiophthalan instead of 1-phenyl-thio-phthalan, the hydrochloride of 1-(3-dimethylaminopropyl)-1-phenyl-3-methyl-thiophthalan is obtained, which melts at 175-178°C. Yield 9.5 g.

EKSEMPEL 4 EXAMPLE 4

Utgangsmaterialet, 1-fenyl-3,3-dimetyl-tioftalan, fremstilles på fdlgende måte: 55 g (0,25 mol) o-iso-propenyl-benzofenon oppvarmes i en autoklav med 40 g hydrogensulfid ved 250-260°C i en time. Etter avkjaiing og inndamping av overskuddet av hydrogensulfid ekstraheres resten med petroleter, ekstraktet filtreres, behandles med aktivt kull, filtreres og avkjdles. Derved oppnås 30 g 1-fenyl-3,3-dimetyl-tio-ftalan som et gult stoff, som etter omkrystallisasjon fra petroleter smelter ved 70-72°C. The starting material, 1-phenyl-3,3-dimethyl-thiophthalan, is prepared in the following way: 55 g (0.25 mol) of o-iso-propenyl-benzophenone is heated in an autoclave with 40 g of hydrogen sulphide at 250-260°C in a hour. After stripping and evaporation of the excess hydrogen sulphide, the residue is extracted with petroleum ether, the extract is filtered, treated with activated carbon, filtered and cooled. Thereby 30 g of 1-phenyl-3,3-dimethyl-thiophthalan are obtained as a yellow substance, which after recrystallization from petroleum ether melts at 70-72°C.

Ved å gjennomfare eksempel 1, idet det anvendes den ekvivalente mengde 1-fenyl-3,3-dimetyl-tioftalan i stedet for 1-fenyl-tio-ftalan oppnås hydrokloridet av 1-(3-dimetylaminopropyl)-1-fenyl-3,3-dimetyl-tioftalan som fargeiase krystaller, som etter omkrystallisasjon fra etanol smelter ved 224-226°C. Utbytte 10 g. By going through example 1, using the equivalent amount of 1-phenyl-3,3-dimethyl-thiophthalan instead of 1-phenyl-thio-phthalan, the hydrochloride of 1-(3-dimethylaminopropyl)-1-phenyl-3 is obtained, 3-Dimethyl-thiophthalan as colorless crystals, which after recrystallization from ethanol melt at 224-226°C. Yield 10 g.

EKSEMPEL 5 EXAMPLE 5

Utgangsmaterialet, l-dimetylamino-4-(2<1->iso-propenyl-fenyl)-4-fenyl-buten-3 fremstilles av 4-dimetylamino-l-(2'-iso-propenyl-fenyl) -1-fenyl-butanol-l ved behandling med tionylklorid i nærvær av pyridin og karbontetraklorid som oppiasningsmiddel for The starting material, 1-dimethylamino-4-(2<1->iso-propenyl-phenyl)-4-phenyl-butene-3 is prepared from 4-dimethylamino-1-(2'-iso-propenyl-phenyl)-1-phenyl -butanol-1 by treatment with thionyl chloride in the presence of pyridine and carbon tetrachloride as an opiate agent for

reaksjonen. Hydrokloridet smelter ved 170-173°C. the reaction. The hydrochloride melts at 170-173°C.

15 g l-dimetylamino-4-(2'-iso-propenylfenyl)-4-fenyl-buten-3 oppvarmes med 15 ml hydrogensulfid i en autoklav ved 225-250°C i 2 1/2 time. Overskuddet av hydrogensulfid avdampes, og resten opplbses i fortynnet eddiksyre og ekstraheres med eter. Den vandige fase gjdres alkalisk med ammoniakkvann og ekstraheres med eter. Eterfasen torkes over vannfritt natriumsulfat, filtreres og inndampes. Derved oppnås 10 g 1-(3-dimetylamino-propyl) -1-f enyl-3, 3-dimetyltiof talan. Hydrokloridet smelter ved 224-226°C. 15 g of 1-dimethylamino-4-(2'-iso-propenylphenyl)-4-phenyl-butene-3 are heated with 15 ml of hydrogen sulphide in an autoclave at 225-250°C for 2 1/2 hours. The excess of hydrogen sulphide is evaporated, and the residue is dissolved in dilute acetic acid and extracted with ether. The aqueous phase is made alkaline with ammonia water and extracted with ether. The ether phase is dried over anhydrous sodium sulphate, filtered and evaporated. Thereby 10 g of 1-(3-dimethylamino-propyl)-1-phenyl-3,3-dimethylthiophthalan are obtained. The hydrochloride melts at 224-226°C.

EKSEMPEL 6 EXAMPLE 6

Utgangsmaterialet, 1-fenyl-3,3-dimetyl-tioftalan, fremstilles på folgende måte: En blanding av lOO g o-iso-propenyl-benzofenon, 0, 5 g Ho^ S^ og 100 g vannfritt hydrogensulfid oppvarmes i en 500 ml autoklav i 3 timer ved 180-185°C. Etter avkjoling avdampes overskuddet av hydrogensulfid, resten opploses i 500 ml petroleter, torkes over vannfritt magnesiumsulfat, behandles med aktivt kull og filtreres. Opplosningen inndampes til 300 ml og avkjdles, hvorved 87 g (80%) 1-fenyl-3,3-dimetyl-tio-ftalan utkrystalliserer som et svakt gulaktig stoff, som smelter ved 67-69°C. Ved omkrystallisasjon fra petroleter oppnås det som hvite krystaller, som smelter ved 71-72°C. The starting material, 1-phenyl-3,3-dimethyl-thiophthalan, is prepared as follows: A mixture of lOO g o-iso-propenyl-benzophenone, 0.5 g Ho^ S^ and 100 g anhydrous hydrogen sulphide is heated in a 500 ml autoclave for 3 hours at 180-185°C. After cooling, the excess hydrogen sulphide is evaporated, the residue is dissolved in 500 ml of petroleum ether, dried over anhydrous magnesium sulphate, treated with activated charcoal and filtered. The solution is evaporated to 300 ml and cooled, whereby 87 g (80%) of 1-phenyl-3,3-dimethyl-thio-phthalan crystallizes as a faint yellowish substance, which melts at 67-69°C. On recrystallization from petroleum ether, it is obtained as white crystals, which melt at 71-72°C.

Ved å gjennomfore eksempel 2, idet det anvendes 1-fenyl-3,3-dimetyl-tioftalan i stedet for 1-fenyl-tio-ftalan, oppnås hydrokloridet av 1-(3-metylaminopropyl)-1-fenyl-3,3-dimetyl-tio-ftalan ved krystallisasjon fra aceton som et hvitt krystallinsk stoff, som smelter ved 173-174°C. By carrying out example 2, using 1-phenyl-3,3-dimethyl-thiophthalan instead of 1-phenyl-thio-phthalan, the hydrochloride of 1-(3-methylaminopropyl)-1-phenyl-3,3- dimethyl-thio-phthalan by crystallization from acetone as a white crystalline substance, melting at 173-174°C.

EKSEMPEL 7 EXAMPLE 7

Ved å gjennomfore eksempel 2, idet det anvendes 1-fenyl-3-metyl-tioftalan i stedet for 1-fenyl-tio-ftalan, oppnås hydrokloridet av l-(3-metyl-aminopropyl)-l^fenyl-3-metyl-tioftalan som hvite By carrying out example 2, using 1-phenyl-3-methyl-thiophthalan instead of 1-phenyl-thio-phthalan, the hydrochloride of 1-(3-methyl-aminopropyl)-1^phenyl-3-methyl- thiophthalan as whites

krystaller, som smelter ved 156-162°C. crystals, melting at 156-162°C.

EKSEMPEL 8 EXAMPLE 8

Utgangsmaterialet, 1-fenyl-3,3-dimetyl-tio-ftalan, fremstilles på folgende måte: En blanding av 100 g o-iso-propenylbenzofenon, 1 g Mo2S3og 50 g hydrogensulfid oppvarmes i en 500 ml autoklav i 16 timer ved 120°C. Etter avkjoling avdampes overskuddet av hydrogensulfid, og resten opparbeides som beskrevet i eksempel 6. 50 g 1-fenyl-3,3-dimetyl-tioftalanol-1 oppnås derved som hvite krystaller, som smelter ved 84-85°C. 38 g av denne tioftalanol oppvarmes i 2 timer på dampbad med 100 ml vannfri maursyre, hvorved den tilsvarende tioftalan gradvis utskilles som en gul olje under samtidig C02-utvikling. Derpå tilfdyes 150 g finknust is, og 1-fenyl-3,3-dimetyltioftalan krystalliserer ut og oppnås etter omkrystallisasjon fra petroleter i et utbytte på 30 g. Smp. 72-73°C. 30 g 1-fenyl-3,3-dimetyl-tioftalan opploses i 200 ml torr eter, og 35 g av en 25%'ig opplosning av butyl-litium i heksan tilfoyes under omroring og avkjoling i nitrogenatmosfære. Opplosningen oppvarmes til 18-20°C i 1 minutt og avkjoles derpå til 0°C. Under avkjoling og omroring tilfoyes 16 g 3-metylaminopropylklorid, hvorpå opplosningen helles i isvann og opparbeides som beskrevet i eksempel 1. 33 g av hydrokloridet av l-(3-metyl-aminopropyl)-1-fenyl-3,3-dimetyl-tioftalan oppnås derved som hvite krystaller, som smelter ved 173-174°c. The starting material, 1-phenyl-3,3-dimethyl-thio-phthalan, is prepared in the following way: A mixture of 100 g of o-iso-propenylbenzophenone, 1 g of Mo2S3 and 50 g of hydrogen sulphide is heated in a 500 ml autoclave for 16 hours at 120° C. After cooling, the excess of hydrogen sulphide is evaporated, and the residue is worked up as described in example 6. 50 g of 1-phenyl-3,3-dimethyl-thiophthalanol-1 is thereby obtained as white crystals, which melt at 84-85°C. 38 g of this thiophthalanol is heated for 2 hours on a steam bath with 100 ml of anhydrous formic acid, whereby the corresponding thiophthalan is gradually separated as a yellow oil with simultaneous CO2 evolution. 150 g of finely crushed ice are then added, and 1-phenyl-3,3-dimethylthiophthalan crystallizes out and is obtained after recrystallization from petroleum ether in a yield of 30 g. M.p. 72-73°C. 30 g of 1-phenyl-3,3-dimethylthiophthalan is dissolved in 200 ml of dry ether, and 35 g of a 25% solution of butyl lithium in hexane is added while stirring and cooling in a nitrogen atmosphere. The solution is heated to 18-20°C for 1 minute and then cooled to 0°C. During cooling and stirring, 16 g of 3-methylaminopropyl chloride are added, after which the solution is poured into ice water and worked up as described in example 1. 33 g of the hydrochloride of 1-(3-methyl-aminopropyl)-1-phenyl-3,3-dimethyl-thiophthalan is thereby obtained as white crystals, which melt at 173-174°c.

EKSEMPEL 9 EXAMPLE 9

Utgangsmaterialet, 1-fenyl-3,3-dimetyl-tioftalan, fremstilles The starting material, 1-phenyl-3,3-dimethyl-thiophthalan, is prepared

på fdlgende måte: in the following way:

En blanding av 170 g 2-(2-klor-fenyl)-propanol-2, 150 g benzyl-merkaptan og 750 ml konsentrert saltsyre omrores i 18 timer på dampbad, hvorpå reaksjonsblandingen helles på finknust is, ekstraheres med eter, eterfasen vaskes med fortynnet natrium- hydroksydoppløsning, torkes over vannfritt magnesiumsulfat, behandles med aktivt kull, filtreres og destilleres. Derved oppnås 2-(2-klor-fenyl)-2-benzyl-merkaptopropan i et utbytte på 171 g, Kp. 149-151°C/0,7 mm Hg. A mixture of 170 g of 2-(2-chloro-phenyl)-propanol-2, 150 g of benzyl mercaptan and 750 ml of concentrated hydrochloric acid is stirred for 18 hours on a steam bath, after which the reaction mixture is poured onto finely crushed ice, extracted with ether, the ether phase is washed with diluted sodium hydroxide solution, dried over anhydrous magnesium sulphate, treated with activated charcoal, filtered and distilled. Thereby 2-(2-chloro-phenyl)-2-benzyl-mercaptopropane is obtained in a yield of 171 g, Kp. 149-151°C/0.7 mm Hg.

En blanding av 4,8 g natriumhydrid ( i oljesuspensjon 50% w/w), og 250 ml dimetylsulfoksyd oppvarmes på dampbad, deretter av-kjøles til 20°C, og 57 g 2-(2-klor-fenyl)-2-benzylmerkapto-propan tilføyes, idet temperaturen holdes mellom 20 og 30°C. Etter at alt er tilsatt, omrøres reaksjonsblandingen ved romtemperatur i 15 minutter, hvorpå blandingen helles på finknust is og ekstraheres med eter. Eteropplosningen torkes, og eteren avdampes på dampbad. Ved omkrystallisasjon av resten fra eterpetroleter (1:1) oppnås 1-fenyl-3,3-dimetyl-tioftalan i et utbytte på 39 g. Det smelter ved 70-72°C. A mixture of 4.8 g of sodium hydride (in oil suspension 50% w/w) and 250 ml of dimethylsulfoxide is heated on a steam bath, then cooled to 20°C, and 57 g of 2-(2-chloro-phenyl)-2- benzyl mercapto-propane is added, keeping the temperature between 20 and 30°C. After everything has been added, the reaction mixture is stirred at room temperature for 15 minutes, after which the mixture is poured onto finely crushed ice and extracted with ether. The ether solution is dried, and the ether is evaporated on a steam bath. By recrystallization of the residue from ether petroleum ether (1:1), 1-phenyl-3,3-dimethylthiophthalan is obtained in a yield of 39 g. It melts at 70-72°C.

Ved å gjennomføre eksempel 4, idet det anvendes 5,4 g natriumhydrid i stedet for 2,7 g, den ekvivlente mengde av hydrokloridet av 3-aminopropylklorid i stedet for 3-dimetylamino-propylklorid og en oppløsning av benzo-syre i stedet for en oppløsning av hydrogenklorid, oppnås benzoatet av l-(3-amino-propyl)-1-fenyl-3,3-dimetyl-tio-ftalan som et hvitt krystallinsk stoff, som smelter ved 197-200°C. By carrying out Example 4, using 5.4 g of sodium hydride instead of 2.7 g, the equivalent amount of the hydrochloride of 3-aminopropyl chloride instead of 3-dimethylaminopropyl chloride and a solution of benzoic acid instead of a solution of hydrogen chloride, the benzoate of 1-(3-amino-propyl)-1-phenyl-3,3-dimethyl-thio-phthalan is obtained as a white crystalline substance, which melts at 197-200°C.

EKSEMPEL 10 EXAMPLE 10

En blanding av 15 g (0,63 mol) natriumhydrid i oljesuspensjon (50%) og 400 ml dimetylsulfoksyd oppvarmes på dampbad og avkjøles til 20°e, hvorpå 55 g (0,2 mol) 2-(2-klor-f eny])-2-benzylmerkapto-propan tildryppes, mens temperaturen holdes mellom 20 og 30°C. Blandingen omrøres i ytterligere 5 minutter ved ca. 20°C, hvorpå 32 g av hydrokloridet av 3-metylaminopropylklorid tilføyes, og omrøringen fortsettes, inntil den røde fargen er forsvunnet. Reakjsonsblandingen helles derpå på finknust is og ekstraheres med eter. Eterfasen skilles fra og ekstraheres med fortynnet eddiksyre. Den sure oppløsning blir gjort alkalisk med fortynnet ammoniakkvann og ekstraheres med eter. Eterfasen blir tørket over vannfri magnesiumsulfat, behandles med aktivt kull og inndampes. Resten oppløses i aceton og nøytraliseres med en oppløsning av hydrogenklorid i eter. Det krystallinske bunnfall filtreres fra og omkrystalliseres fra aceton. Utbyttet 31 g av hydrokloridet av 1-(3-metylaminopropyl)-l-fenyl-3,3-dimetyl-tioftalan, som smelter ved 173-174°C. A mixture of 15 g (0.63 mol) of sodium hydride in oil suspension (50%) and 400 ml of dimethylsulfoxide is heated on a steam bath and cooled to 20°e, after which 55 g (0.2 mol) of 2-(2-chloro-phenyl) ])-2-benzyl mercapto-propane is added dropwise, while the temperature is kept between 20 and 30°C. The mixture is stirred for a further 5 minutes at approx. 20°C, whereupon 32 g of the hydrochloride of 3-methylaminopropyl chloride are added, and stirring is continued, until the red color has disappeared. The reaction mixture is then poured onto finely crushed ice and extracted with ether. The ether phase is separated and extracted with dilute acetic acid. The acidic solution is made alkaline with dilute ammonia water and extracted with ether. The ether phase is dried over anhydrous magnesium sulphate, treated with activated charcoal and evaporated. The residue is dissolved in acetone and neutralized with a solution of hydrogen chloride in ether. The crystalline precipitate is filtered off and recrystallized from acetone. Yield 31 g of the hydrochloride of 1-(3-methylaminopropyl)-1-phenyl-3,3-dimethyl-thiophthalan, which melts at 173-174°C.

EKSEMPEL 11 EXAMPLE 11

Utgangsmaterialet, 1-karbamyl-3,3-dimetyl-tioftalan, fremstilles på folgende måte: En blanding av 341 g 2-(2-klorfenyl)-propanol-2, 340 g tio-glykolsyre og .1250 ml konsentrert saltsyre oppvarmes under omrøring på dampbad i fire timer, helles derpå på finknust is og ekstraheres med eter. Eterfasen ekstraheres med fortynnet ammoniakkvann og det vandige ekstrakt gjøres surt med fortynnet saltsyre og ekstraheres med eter. Eterfasen torkes over vannfritt magnesiumsulfat, eteren avdampes og overskudd av tiogly-kolsyre avdestilleres i vakuum. Resten blir omkrystallisert fra eter/petroleter (1:1) og (1-metyl-l-(2-klorfenyl)-etyl-merkapto)-eddiksyre oppnås som fargeløse krystaller, som smelter ved 53-54°C. Utbytte 367 g. The starting material, 1-carbamyl-3,3-dimethyl-thiophthalan, is prepared in the following way: A mixture of 341 g of 2-(2-chlorophenyl)-propanol-2, 340 g of thio-glycolic acid and .1250 ml of concentrated hydrochloric acid is heated while stirring on a steam bath for four hours, then poured onto finely crushed ice and extracted with ether. The ether phase is extracted with dilute ammonia water and the aqueous extract is acidified with dilute hydrochloric acid and extracted with ether. The ether phase is dried over anhydrous magnesium sulphate, the ether is evaporated and excess thioglycolic acid is distilled off in a vacuum. The residue is recrystallized from ether/petroleum ether (1:1) and (1-methyl-1-(2-chlorophenyl)-ethyl-mercapto)-acetic acid is obtained as colorless crystals, which melt at 53-54°C. Yield 367 g.

En blanding av 53 g natriumhydrid i oljesuspensjon (50%) og 1300 ml dimetylsulfoksyd oppvarmes på dampbad. Etter avsluttet reaksjon avkjøles blandingen, og 245 g (1-metyl-l-(2-klorfenyl)-etylmerkapto)-eddiksyre oppløst i dimetylsulfoksyd tildryppes ved 20-30°C. Etter omrøring ved 20°C i fem minutter blir reakjsonsblandingen helt på finknust is og den resulterende blanding ekstraheres med eter. Den vandige fase blir gjort sur med konsentrert saltsyre og ekstraheres med eter. Eterfasen blir tørket over vannfritt magnesiumsulfat og inndampes. Resten omkrystalliseres fra eter/petroleter (1:1), hvorved 187 g 3,3-dimetyl-tioftalan-karboksylsyre-1 oppnås som et hvitt krystallinsk stoff, som smelter ved 86-87°C. A mixture of 53 g of sodium hydride in oil suspension (50%) and 1300 ml of dimethyl sulphoxide is heated on a steam bath. After completion of the reaction, the mixture is cooled, and 245 g of (1-methyl-1-(2-chlorophenyl)-ethylmercapto)-acetic acid dissolved in dimethylsulfoxide is added dropwise at 20-30°C. After stirring at 20°C for five minutes, the reaction mixture is poured onto crushed ice and the resulting mixture is extracted with ether. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The ether phase is dried over anhydrous magnesium sulfate and evaporated. The residue is recrystallized from ether/petroleum ether (1:1), whereby 187 g of 3,3-dimethyl-thiophthalan-carboxylic acid-1 is obtained as a white crystalline substance, which melts at 86-87°C.

En blanding av 100 g 3,3-dimetyl-tioftalan-karboksylsyre-1 og 230 g tionylklorid oppvarmes under tilbakeløp i 15 minutter. Overskudd av tionylklorid avdestilleres, og resten, som hoved- sakelig består av 3,3-dimetyl-tioftalan-karboksylsyreklorid-1, oppløses i kloroform og dryppes til overskudd av flytende ammoniakk. Blandingen omrores i 30 minutter, oppvarmes til til-bakeløp, vann tilfoyes, og det ekstraheres med kloroform. Kloroform-fasen torkes, behandles med aktivt kull, filtreres og inndampes. Resten omkrystalliseres fra eter, hvorved 87 g 1-karbamyl-3,3-dimetyl-tioftalan oppnås som et hvitt krystallinsk stoff, som smelter ved 124-125°C. A mixture of 100 g of 3,3-dimethyl-thiophthalan-carboxylic acid-1 and 230 g of thionyl chloride is heated under reflux for 15 minutes. Excess thionyl chloride is distilled off, and the residue, which mainly consists of 3,3-dimethyl-thiophthalan-carboxylic acid chloride-1, is dissolved in chloroform and dripped to an excess of liquid ammonia. The mixture is stirred for 30 minutes, heated to reflux, water is added and it is extracted with chloroform. The chloroform phase is dried, treated with activated charcoal, filtered and evaporated. The residue is recrystallized from ether, whereby 87 g of 1-carbamyl-3,3-dimethyl-thiophthalan is obtained as a white crystalline substance, which melts at 124-125°C.

Til 20 g natriumamid i flytende ammoniakk tilsettes 52 g 1-karbamyl-3,3-dimetyl-tioftalan under omroring, og denne fortsettes i 30 minutter, hvorpå 27 g 3-dimetylamino-propylklorid blir tilføyet, og omrøringen fortsettes i 15 minutter. Derpå tilsettes 30 g ammoniumklorid, og blandingen helles på is og ekstraheres med eter. Eterfasen ekstraheres med fortynnet eddiksyre. Den vandige fase vaskes med eter, gjøres basisk med ammoniakkvann og ekstraheres med eter. Eterfasen torkes over vannfritt magnesiumsulfat, behandles med aktivt kull og inndampes. Resten opploses i aceton og hydrokloridet av l-(3-dimetylaminopropyl)-l-karbamyl-3,3-dimetyl-tioftalan felles ved noytralisasjon med en oppløsning av hydrogenklorid i eter. Etter omkrystallisasjon fra aceton smelter det ved 208-210°C. Utbytte 27 g. To 20 g of sodium amide in liquid ammonia, 52 g of 1-carbamyl-3,3-dimethylthiophthalan is added while stirring, and this is continued for 30 minutes, after which 27 g of 3-dimethylaminopropyl chloride is added, and stirring is continued for 15 minutes. 30 g of ammonium chloride are then added, and the mixture is poured onto ice and extracted with ether. The ether phase is extracted with dilute acetic acid. The aqueous phase is washed with ether, made basic with ammonia water and extracted with ether. The ether phase is dried over anhydrous magnesium sulphate, treated with activated charcoal and evaporated. The residue is dissolved in acetone and the hydrochloride of 1-(3-dimethylaminopropyl)-1-carbamyl-3,3-dimethyl-thiophthalan is combined by neutralization with a solution of hydrogen chloride in ether. After recrystallization from acetone, it melts at 208-210°C. Yield 27 g.

EKSEMPEL 12 EXAMPLE 12

Utgangsmaterialet, l-karbetoksy-3,3-dimetyl-tioftalan, fremstilles på folgende måte: 100 g 3,3-dimetyl-tioftalan-karboksylsyre-1, 300 ml absolutt etanol og lo ml konsentrert svovelsyre kokes under tilbakelop i 18 timer, avkjøles, helles på finknust is, gjøres alkalisk med natriumbikarbonat og ekstraheres med eter. Eterfasen tørkes over vannfritt magnesiumsulfat, behandles med aktivt kull og distilleres. Utbytte 95 g l-karbetoksy-3,3-dimetyl-tioftalan, som koker ved 108-lll°C/0,2 mm Hg. The starting material, 1-carbethoxy-3,3-dimethyl-thiophthalan, is prepared as follows: 100 g of 3,3-dimethyl-thiophthalan-carboxylic acid-1, 300 ml of absolute ethanol and 10 ml of concentrated sulfuric acid are boiled under reflux for 18 hours, cooled , poured onto finely crushed ice, made alkaline with sodium bicarbonate and extracted with ether. The ether phase is dried over anhydrous magnesium sulphate, treated with activated charcoal and distilled. Yield 95 g of 1-carbethoxy-3,3-dimethyl-thiophthalane, which boils at 108-11°C/0.2 mm Hg.

En blanding av 6 g natriumhydrid i oljesuspensjon (50%) og 2 50 ml dimetylsulfoksyd oppvarmes på dampbad, til reaksjonen er avsluttet. A mixture of 6 g of sodium hydride in oil suspension (50%) and 2 50 ml of dimethyl sulphoxide is heated on a steam bath until the reaction is complete.

Ved en temperatur på 20-30°C tilfoyes 53 g l-karbetoksy-3, 3-dimetyl-tioftalan og derpå 22 g 3-dimetylamino-propylklorid. Omrøringen fortsettes i 5 minutter, hvorpå blandingen helles på is og opparbeides som beskrevet i eksempel 11. Hydrokloridet av 1-(3-dimetylaminopropyl)-l-karbetoksy-3,3-dimetyl-tioftalan oppnås derved som hvite krystaller, som smelter ved 146-148°C. Utbytte 45 g. Den frie base koker ved 150-152°C/0,2 mm Hg. At a temperature of 20-30°C, 53 g of 1-carbethoxy-3,3-dimethylthiophthalan and then 22 g of 3-dimethylaminopropyl chloride are added. Stirring is continued for 5 minutes, after which the mixture is poured onto ice and worked up as described in example 11. The hydrochloride of 1-(3-dimethylaminopropyl)-1-carbethoxy-3,3-dimethyl-thiophthalan is thereby obtained as white crystals, which melt at 146 -148°C. Yield 45 g. The free base boils at 150-152°C/0.2 mm Hg.

Det tilsvarende oksalat smelter ved 132-140°C. The corresponding oxalate melts at 132-140°C.

EKSEMPEL 13 EXAMPLE 13

En blanding av 31 g 1-(3-dimetylaminopropyl)-l-karbetoksy-3,3-dimetyl-tioftalan, 8,5 g kaliumhydroksyd og 250 ml etanol kokes under tilbakeløp i 4 timer, hvorpå blandingen nøytraliseres til pH 5-6 med en oppløsning av hydrogenklorid i eter og avkjøles. Det utfelte kaliumklorid filtreres fra. Filtratet inndampes, A mixture of 31 g of 1-(3-dimethylaminopropyl)-1-carbethoxy-3,3-dimethyl-thiophthalan, 8.5 g of potassium hydroxide and 250 ml of ethanol is refluxed for 4 hours, after which the mixture is neutralized to pH 5-6 with a solution of hydrogen chloride in ether and cooled. The precipitated potassium chloride is filtered off. The filtrate is evaporated,

og tørr eter tilfoyes. Det utskilte bunnfall består av l-(3-dimetylaminopropyl)-3,3-dimetyl-tioftalan-karboksylsyre-1, som etter omkrystallisasjon fra aceton/kloroform (1:1) smelter ved 184-185°C. Utbytte 17 g. Det tilsvarende hydroklorid smelter ved 209-211°C etter omkrystallisasjon fra aceton. and dry ether is added. The separated precipitate consists of 1-(3-dimethylaminopropyl)-3,3-dimethyl-thiophthalan-carboxylic acid-1, which after recrystallization from acetone/chloroform (1:1) melts at 184-185°C. Yield 17 g. The corresponding hydrochloride melts at 209-211°C after recrystallization from acetone.

EKSEMPEL 14 EXAMPLE 14

Ved å gjennomføre eksempel 12, idet det anvendes metanol i stedet for etanol, isolering av mellomproduktet 1-karbometoksy-3, 3-dimetyl-tioftalan, som koker ved 122-124°c/0,5 mm Hg, og forøvrig gås frem som beskrevet i eksempel 12, oppnås hydrokloridet av 1-(3-dimetylaminopropyl)-l-karbometoksy-3,3-dimetyl-tioftalan som et hvitt krystallinsk stoff, som smelter ved 153-154°C. By carrying out example 12, using methanol instead of ethanol, isolation of the intermediate 1-carbomethoxy-3, 3-dimethyl-thiophthalan, which boils at 122-124°c/0.5 mm Hg, and otherwise proceed as described in Example 12, the hydrochloride of 1-(3-dimethylaminopropyl)-1-carbomethoxy-3,3-dimethyl-thiophthalan is obtained as a white crystalline substance, which melts at 153-154°C.

EKSEMPEL 15 EXAMPLE 15

En oppløsning av metylmagnesiumjodid i tørr eter fremstilles på kjent måte fra 0,175 mol metyljodid og 0,33 mol magnesium. Til denne oppløsning tilføyes 25 g tørr anilin og etter tilbakeløps- behandling i 10 minutter 21 g 1-(3-dimetylaminopropyl)-1-karbetoksy-3,3-dimetyl-tioftalan. Blandingen kokes under til-bakeløp i 2 timer, derpå hydrolyseres den med fortynnet saltsyre og vaskes med eter. Den vandige fase gjøres alkalisk og ekstraheres med eter. Eterfasen inndampes og overskudd av anilin fjernes ved destillasjon. Resten opploses i fortynnet saltsyre, vaskes med eter, gjøres alkalisk og ekstraheres med eter. Eterfasen torkes og inndampes, resten opploses i aceton og hydrokloridet av 1-(3-dimetylaminopropyl)-1-fenylkarbamyl-3,3-dimetyl-tioftalan felles ved nøytralisasjon med en oppløsning av hydrogenklorid i eter som hvite krystaller, som etter omkrystallisasjon fra kloroform smelter ved 209-210°C. Utbytte 16 g. A solution of methylmagnesium iodide in dry ether is prepared in a known manner from 0.175 mol of methyl iodide and 0.33 mol of magnesium. To this solution are added 25 g of dry aniline and, after refluxing for 10 minutes, 21 g of 1-(3-dimethylaminopropyl)-1-carbethoxy-3,3-dimethyl-thiophthalan. The mixture is refluxed for 2 hours, then hydrolysed with dilute hydrochloric acid and washed with ether. The aqueous phase is made alkaline and extracted with ether. The ether phase is evaporated and excess aniline is removed by distillation. The residue is dissolved in dilute hydrochloric acid, washed with ether, made alkaline and extracted with ether. The ether phase is dried and evaporated, the residue is dissolved in acetone and the hydrochloride of 1-(3-dimethylaminopropyl)-1-phenylcarbamyl-3,3-dimethyl-thiophthalan is collected by neutralization with a solution of hydrogen chloride in ether as white crystals, which after recrystallization from chloroform melts at 209-210°C. Yield 16 g.

EKSEMPEL 16 EXAMPLE 16

Ved å gjennomfore eksempel 15, idet det anvendes den ekvivalente mengde 2,2-dimetylanilin i stedet for anilin, oppnås hydrokloridet av 1-(3-dimetylaminopropyl)-1-(2,6-dimetylfehylkarbamyl)-3,3-dimetyl-tioftalan som hvite krystaller, som smelter ved 193-194°C. Det frie amin krystalliserer fra petroleter og smelter ved 108-110°C. By carrying out Example 15, using the equivalent amount of 2,2-dimethylaniline instead of aniline, the hydrochloride of 1-(3-dimethylaminopropyl)-1-(2,6-dimethylphenylcarbamyl)-3,3-dimethylthiophthalan is obtained as white crystals, melting at 193-194°C. The free amine crystallizes from petroleum ether and melts at 108-110°C.

EKSEMPEL 17 EXAMPLE 17

Til en oppløsning av metylmagnesiumjodid i tørr eter, fremstilt på kjent måte av 0,4 mol metyljodid, tilføyes 27 g 1-(3-dimetyl-aminopropyl) -1-karbamyl- 3, 3-dimetyl-tiof talan oppløst i 150 ml tørr benzen. Reaksjonsblandingen kokes under tilbakeløp i 18 timer, oppløsningsmidlene avdampes og resten oppvarmes på dampbad i 4 timer, hvorpå den blir oppløst i fortynnet saltsyre og ekstraheres med eter. Den vandige fase gjores alkalisk med ammoniakkvann og ekstraheres med eter. Eterfasen tørkes over vannfritt magnesiumsulfat, behandles med aktivt kull og inndampes. Resten oppløses i aceton og nøytraliseres med en oppløsning av hydrogenklorid i eter. Bunnfallet, som filtreres fra og tørkes, består av hydrokloridet av 1-(3-dimetylaminopropyl)-1-acetyl-3,3-dimetyl-tioftlan, som - etter omkrystallisasjon fra kloro form/aceton (1:1) - smelter ved 144-147°C. Utbytte 4 g. To a solution of methyl magnesium iodide in dry ether, prepared in a known manner from 0.4 mol of methyl iodide, is added 27 g of 1-(3-dimethyl-aminopropyl)-1-carbamyl-3,3-dimethyl-thiophthalan dissolved in 150 ml of dry benzene. The reaction mixture is refluxed for 18 hours, the solvents are evaporated and the residue is heated on a steam bath for 4 hours, after which it is dissolved in dilute hydrochloric acid and extracted with ether. The aqueous phase is made alkaline with ammonia water and extracted with ether. The ether phase is dried over anhydrous magnesium sulphate, treated with activated charcoal and evaporated. The residue is dissolved in acetone and neutralized with a solution of hydrogen chloride in ether. The precipitate, which is filtered off and dried, consists of the hydrochloride of 1-(3-dimethylaminopropyl)-1-acetyl-3,3-dimethyl-thiophtlane, which - after recrystallization from chloroform/acetone (1:1) - melts at 144 -147°C. Yield 4 g.

EKSEMPEL 18 EXAMPLE 18

Ved å gjennomfare eksempel 4, idet det anvendes de ekvivalente mengder av henholdsvis 3-dietylaminopropylklorid og 3-N-piperi-dinylpropylklorid i stedet for 3-dimetylaminopropylklorid, oppnås henholdsvis hydrokloridet av 1-(3-dietylaminopropyl)-1-fenyl-3,3-dimetyl-tioftalan (smp. 130-132°C) og hydrokloridet av 1-(3-N-piperidinylpropyl)-1-fenyl-3,3-dimetyl-tioftalan (smp. 190-192°C). By going through example 4, using the equivalent amounts of 3-diethylaminopropyl chloride and 3-N-piperidinylpropyl chloride instead of 3-dimethylaminopropyl chloride, respectively, the hydrochloride of 1-(3-diethylaminopropyl)-1-phenyl-3, 3-dimethylthiophthalan (m.p. 130-132°C) and the hydrochloride of 1-(3-N-piperidinylpropyl)-1-phenyl-3,3-dimethyl-thiophthalan (m.p. 190-192°C).

EKSEMPEL 19 EXAMPLE 19

Ved å gjennomfore eksempel 4, idet det anvendes den ekvivalente mengde 2-dimetylaminoetylklorid i stedet for 3-dimetylamino-propylklorid, oppnås hydrokloridet av 1-(2-dimetylaminoetyl)-1-fenyl-3,3-dimetyl-tioftalan som et hvitt krystallinsk stoff. By carrying out Example 4, using the equivalent amount of 2-dimethylaminoethyl chloride instead of 3-dimethylaminopropyl chloride, the hydrochloride of 1-(2-dimethylaminoethyl)-1-phenyl-3,3-dimethyl-thiophthalan is obtained as a white crystalline fabric.

EKSEMPEL 20 EXAMPLE 20

Til en opplesning av 33 g (0,1 mol) l-(3-dimetylaminopropyl)-1-fenyl-3,3-dimetyl-tioftalan i 250 ml tørr benzen dryppes 33 g (0,3 mol) klormaursyreetylester under omroring. Temperaturen stiger til omkring 35°C. Etterat tildrypningen er avsluttet, blir reaksjonsblandingen oppvarmet i 1 1/2 time ved 40°C under omrøring. Etter avkjøling blir reaksjonsblandingen vasket med fortynnet saltsyre og inndampet på dampbad, til slutt ved redusert trykk. l-[3-(N-karbetoksy-metylamino)propyl]-l-fenyl-3, 3-dimetyl-tioftalan oppnås derved som en gul olje. To a reading of 33 g (0.1 mol) of 1-(3-dimethylaminopropyl)-1-phenyl-3,3-dimethyl-thiophthalan in 250 ml of dry benzene, 33 g (0.3 mol) of chloroformic acid ethyl ester are added dropwise while stirring. The temperature rises to around 35°C. After the dropwise addition is finished, the reaction mixture is heated for 1 1/2 hours at 40° C. with stirring. After cooling, the reaction mixture is washed with dilute hydrochloric acid and evaporated on a steam bath, finally at reduced pressure. 1-[3-(N-carbethoxy-methylamino)propyl]-1-phenyl-3,3-dimethyl-thiophthalan is thereby obtained as a yellow oil.

Den nevnte gule olje kokes i 20 timer under tilbakeløp med en blanding av 18 ml vann, 18 g kaliumhydroksyd og 125 ml dietylen-glykol-monometyleter. Etter avkjøling blir reaksjonsblandingen helt i 600 ml vann og ekstraheres med eter. Eterfasen ekstraheres derpå to ganger med fortynnet eddiksyre, og det sure ekstrakt gjøres alkalisk med ammoniakkvann, hvorpå oljen, som utskilles, blir ekstrahert med eter. Eterfasen tørkes over vannfritt kaliumkarbonat, filtreres og inndampes på dampbad. Resten opploses i 100 ml aceton og nøytraliseres til pH 5 med en opp-løsning av torr hydrogenklorid i eter. De hvite krystaller, The aforementioned yellow oil is refluxed for 20 hours with a mixture of 18 ml of water, 18 g of potassium hydroxide and 125 ml of diethylene glycol monomethyl ether. After cooling, the reaction mixture is poured into 600 ml of water and extracted with ether. The ether phase is then extracted twice with dilute acetic acid, and the acidic extract is made alkaline with ammonia water, after which the oil, which separates, is extracted with ether. The ether phase is dried over anhydrous potassium carbonate, filtered and evaporated on a steam bath. The residue is dissolved in 100 ml of acetone and neutralized to pH 5 with a solution of dry hydrogen chloride in ether. The white crystals,

som skilles ut, består av hydrokloridet av 1-(3-metylaminopropyl)-l-fenyl-3,3-demetyl-tioftalan og smelter ved 173-174°C. Utbytte 15 g. which is separated, consists of the hydrochloride of 1-(3-methylaminopropyl)-1-phenyl-3,3-dimethyl-thiophthalan and melts at 173-174°C. Yield 15 g.

EKSEMPEL 21 EXAMPLE 21

Ved å gjennomføre eksempel 1, idet det anvendes den ekvivalente mengde av l-fenyl-3,3-dimetyl-5-trifluormetyltioftalan i stedet for 1-fenyltioftalan, oppnås oksalatet av 1-(3-dimetylamino-propyl) -1-fenyl-3,3-dimetyl-5-trifluormetyltioftalan som et hvitt krystallinsk stoff, som smelter ved 148-150°C. By carrying out Example 1, using the equivalent amount of 1-phenyl-3,3-dimethyl-5-trifluoromethylthiophthalan instead of 1-phenylthiophthalan, the oxalate of 1-(3-dimethylamino-propyl)-1-phenyl- 3,3-dimethyl-5-trifluoromethylthiophthalan as a white crystalline substance, melting at 148-150°C.

EKSEMPEL 22 EXAMPLE 22

Utgangsforbindelsen 1-(2-brometyl)-l-fenyl-3,3-dimatyl-tioftalan fremstilles på følgende måte: The starting compound 1-(2-bromomethyl)-1-phenyl-3,3-dimethyl-thiophthalan is prepared as follows:

Til en oppløsning av 13 g (0,2 mol) butyllitium i 200 ml tørr To a solution of 13 g (0.2 mol) butyllithium in 200 ml dry

eter tilsettes i nitrogenatmosfære under omrøring ved 0-10°C ether is added in a nitrogen atmosphere with stirring at 0-10°C

en oppløsning av 40 g (0,17 mol) 1,1-dimetyl-3-fenyltioftalan i 100 ml tørr eter. Oppløsningen varmes opp til 15-18°C i 5 min. a solution of 40 g (0.17 mol) of 1,1-dimethyl-3-phenylthiophthalan in 100 ml of dry ether. The solution is heated to 15-18°C for 5 min.

og kjøles deretter til 0°C. Under omrøring og kjøling til- and then cooled to 0°C. While stirring and cooling until

dryppes en oppløsning av 10 ml etylenoksyd i 50 ml tørr eter. Etter avsluttet reaksjon vaskes eteroppløsningen med vann, a solution of 10 ml of ethylene oxide in 50 ml of dry ether is dripped. After completion of the reaction, the ether solution is washed with water,

tørkes mad vannfritt kaliumkarbonat og dampes inn. Herved fås 50 g urent 1-(2-hydroksyetyl)-l-fenyl-3,3-dimetyltioftalan som en lysegul olje. dried with anhydrous potassium carbonate and evaporated. This gives 50 g of impure 1-(2-hydroxyethyl)-1-phenyl-3,3-dimethylthiophthalan as a pale yellow oil.

Denne oppløses i 125 ml karbontetraklorid, og under kjøling og omroring tildryppes ved -10 til -5°C en oppløsning av 20 g fosfortribromid i 50 ml karbontetraklorid. Oppløsningen røres om ved 0° i 4 timer og ved romtemperatur i 20 timer, hvoretter man i løpet av 4 timer lar temperaturen stige til 75°C. Der- This is dissolved in 125 ml of carbon tetrachloride, and while cooling and stirring, a solution of 20 g of phosphorus tribromide in 50 ml of carbon tetrachloride is added dropwise at -10 to -5°C. The solution is stirred at 0° for 4 hours and at room temperature for 20 hours, after which the temperature is allowed to rise to 75°C over the course of 4 hours. There-

etter helles oppløsningen i isvann, tørkes over tørt kaliumkarbonat og destilleres i vakuum. Herved fås 40 g 1-(2-brom-etyl) -l-fenyl-3, 3-dimetyltiof talan som en fargeløs olje med kp. 177-183°C/0,5 mm Hg. Ved oppløsning i petroleumseter og henstand then the solution is poured into ice water, dried over dry potassium carbonate and distilled in a vacuum. This gives 40 g of 1-(2-bromo-ethyl)-1-phenyl-3, 3-dimethylthiophthalan as a colorless oil with b.p. 177-183°C/0.5 mm Hg. By dissolving in petroleum ether and standing

krystalliserer stoffet. Det fås 35 g av et hvitt krystallinsk stoff med smp. 65-66°C. crystallizes the substance. 35 g of a white crystalline substance with m.p. 65-66°C.

10 g 1-(2-brometyl)-1-fenyl-3,3-dimetyltioftalan varmes i en autoklav med 10 ml vannfri dimetylamin til 120°C i 2 timer. Overskudd av dimetylamin dampes av og inndampningsresten opp- 10 g of 1-(2-bromomethyl)-1-phenyl-3,3-dimethylthiophthalan are heated in an autoclave with 10 ml of anhydrous dimethylamine to 120°C for 2 hours. Excess dimethylamine is evaporated off and the evaporation residue

loses i fortynnet eddiksyre og vaskes med eter. Vannfasen gjores basisk med fortynnet natriumhydroksyd og ekstraheres med eter. Eterfasen tørkes med vannfritt kaliumkarbonat og dampes inn. Inndampningsresten opploses i 50 ml aceton og nøytrali- dissolve in dilute acetic acid and wash with ether. The water phase is made basic with dilute sodium hydroxide and extracted with ether. The ether phase is dried with anhydrous potassium carbonate and evaporated. The evaporation residue is dissolved in 50 ml of acetone and neutralized

seres til pH 5 med en oppløsning av tørt hydrogenklorid i eter. adjusted to pH 5 with a solution of dry hydrogen chloride in ether.

Etter henstand krystalliserer 7 g hydroklorid av 1-(2-dimetyl-aminoetyl)-l-fenyl-3,3-dimetyltioftalan som et hvitt krystallinsk stoff, som smelter ved 183-184°C. After standing, 7 g of hydrochloride of 1-(2-dimethylaminoethyl)-1-phenyl-3,3-dimethylthiophthalan crystallizes as a white crystalline substance, which melts at 183-184°C.

Claims

1. Analogy method for the preparation of therapeutically active compounds of the general formula:

where and R2 are hydrogen or alkyl groups with up to 4 carbon atoms, R^ and R^ are hydrogen, alkyl groups with up to 4 carbon atoms or they together form a pentamethylene group, "alkylene" is an alkylene chain, straight or branched, with 2-6 carbon atoms, at least 2 carbon atoms being in the chain directly connecting the ring carbon atom to the nitrogen atom, R5 is -CO-NHR6, -COOR7, -CO-Rg or optionally halogen- or trihalomethyl-substituted phenyl, Rg is hydrogen or phenyl optionally substituted with 1 or 2 alkyl groups with up to 4 carbon atoms, Ry is hydrogen or an alkyl group with up to 4 carbon atoms , Rg is an alkyl group with up to 4 carbon atoms, and X is hydrogen, halogen or trihalomethyl, or acid addition salts of these compounds. characterized by reacting: a) a compound with the formula:

where R^, R2 and X have the meaning stated above, and R', has the meaning stated for R^ with the exception of -COOH, with a compound of the formula:

where "Hal" is chlorine, bromine or iodine, "alkylene", R₁ and R₄ have the meanings given above, in the presence of a condensing agent such as an alkali metal amide or hydride, e.g. sodium amide or hydride, butyllithium or phenyllithium and, in the case where R'^ is COOR^, this ester group is saponified, if desired, to obtain the free carboxylic acid, or b) a compound of the formula:

where R^, R^, R^, "alkylene" and X have the above meaning, and Z is chlorine, bromine or iodine, with a compound of the formula:

where R^ and R^ have the meaning stated above, or c) a compound with the formula:

where X, , R-j and R 4 have the above meaning, R is hydrogen or an alkyl group with up to 3 carbon atoms, and "alkylidene" is an alkylidene group with from 2-6 carbon atoms, with at least 2 carbon atoms connecting the carbon atom bound to the benzene rings with the nitrogen atom, with hydrogen sulphide, after which a compound with the formula:

where R^, R2, "alkylene" and X have the above meaning, R'2 is an alkyl group with up to 4 carbon atoms, R<1>4 is an alkyl group with up to 4 carbon atoms, and R"j. has the meaning given for R,- with the exception of -COOR7, possibly reacted with a chloroformate ester with the formula:

where Rg is an alkyl group with up to 8 carbon atoms or a benzyl group, whereupon the formed compound with the formula:

hydrolyzed, or an obtained compound with the formula:

where R^, R2, R3, R4#"alkylene" and X have the above meaning, and R^ is an alkyl group with up to 4 carbon atoms, possibly reacted with an amine of the formula I^NRg or with a Grignard compound of the formula:

where Rg has the meaning stated above, and "hal" is chlorine, bromine or iodine, whereupon the complex obtained in the latter case is hydrolyzed in a manner known per se, or a compound obtained with the formula:

where R 1 , R 2 , R 3 , R 4 , "alkylene" and X have the above meaning, possibly reacted with a Grignard compound with the formula:

where Rg has the meaning stated above, and "hal" is chlorine, bromine or iodine, whereupon the Grignard complex formed is hydrolyzed with a dilute acid and the compound of formula I formed, where R^ is -CO-Rg, is isolated, whereupon the compound of formula I formed is isolated in the form of the free base or an acid addition salt thereof.

2. Method according to claim 1, characterized in that starting substances are used where R is hydrogen, and R 1 , R 2 , R 3 and R 3 are each hydrogen or a methyl group, the "alkylene" is -CH 2 -CH 2 -CH 2 -, R 5 is phenyl, and X is hydrogen. Publications cited: Acta pharmacol. et toxicol., Vol 24, p. 121-133 (1966)