NO115579B

NO115579B -

Info

Publication number: NO115579B
Application number: NO162064A
Authority: NO
Inventors: R Rueegg; G Ryser; U Schwieter
Original assignee: Hoffmann La Roche
Priority date: 1965-03-12
Filing date: 1966-03-11
Publication date: 1968-10-28
Also published as: ES324129A1; DE1543039A1; GB1123942A; GB1123941A; FR1470938A; CH465589A; BE677687A; DE1643412A1; FR5288M; NL6600694A

Description

Fremgangsmåte for fremstilling av nye, terapeutisk aktive acetylenforbindelser. Process for the production of new, therapeutically active acetylene compounds.

Oppfinnelsen vedrører en fremgangsmåte for fremstilling av nye, terapeutisk aktive acetylenforbindelser med den generelle formel hvor Ri betyr en tertiæraminoalkoxyrest med den generelle formel R-(CH2)n-0-, hvor R betyr en dialkylaminogruppe, i særdeleshet di-ethylaminogruppen og n er helt tall fra 1 til 7, i særdeleshet 2 eller 3, R2, R3og R4hydrogen, lavere alkyl eller halogen, R5hydrogen, lavere alkyl, halogen eller nitro og R6hydrogen, lavere alkyl, halogen, nitro eller en tertiæraminoalkoxyrest med den generelle formel R - (CH2)n- O -, hvor R og n har den ovenfor angitte betydning, såvel som salter av disse forbindelser. The invention relates to a process for the production of new, therapeutically active acetylene compounds of the general formula where Ri means a tertiary amino alkoxy radical of the general formula R-(CH2)n-0-, where R means a dialkylamino group, in particular the di-ethylamino group and n is completely numbers from 1 to 7, in particular 2 or 3, R2, R3 and R4hydrogen, lower alkyl or halogen, R5hydrogen, lower alkyl, halogen or nitro and R6hydrogen, lower alkyl, halogen, nitro or a tertiary amino alkoxy radical of the general formula R - (CH2 )n- O -, where R and n have the meaning indicated above, as well as salts of these compounds.

De med R2, R3, R4, R5og R6betegnede lavere alkylgrupper kan inneholde inntil 7 karbonato-mer. Som representanter for denne gruppe kan nevnes: methyl-, ethyl- og isopropyl-gruppen. The lower alkyl groups denoted by R2, R3, R4, R5 and R6 can contain up to 7 carbon atoms. As representatives of this group can be mentioned: the methyl, ethyl and isopropyl group.

De med R2, R3, R4, R5og R6betegnede halo-genatomer er fortrinnsvis fluor, klor og brom. The halogen atoms denoted by R2, R3, R4, R5 and R6 are preferably fluorine, chlorine and bromine.

',■ hvor Ri, R2, R3, R4, R5og Ro har den ovenfor v- angitte betydning, på i for seg kjent måte omsettes med en metallorganisk forbindelse og ace-," tylen og overfører det erholdte produkt eventuelt til et salt. ',■ where Ri, R2, R3, R4, R5 and Ro have the meaning stated above, is reacted in a manner known per se with an organometallic compound and acetylene and optionally transfers the product obtained to a salt.

Som eksempler på forbindelser, som oppnåes etter fremgangsmåten ifølge oppfinnelsen, kan J nevnes: 1,4-bis- [p- (diethylaminoethoxy)-m-tolyl] - 1,4-bis- (m-klorfenyl) -2-butin-l,4-diol As examples of compounds, which are obtained according to the method according to the invention, J can be mentioned: 1,4-bis- [p-(diethylaminoethoxy)-m-tolyl] - 1,4-bis-(m-chlorophenyl)-2-butyn- 1,4-diol

1,4-bis- [p-diethylaminoethoxy)-f enyl]-1,4-bis- (m-klorfenyl)-2-butin-l,4-diol 1,4-bis-(p-diethylaminoethoxy)-phenyl]-1,4-bis-(m-chlorophenyl)-2-butyn-1,4-diol

1,4-bis- [p- (diethylaminoethoxy) -f enyl] - 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-

1,4-bis- (m-fluorf enyl) -2-butin-l,4-diol1,4-bis-(m-fluorophenyl)-2-butyn-1,4-diol

1,4-bis- [p- (diethylaminoethoxy) -f enyl] - 1,4-bis- (p-tolyl) -2-butin-1,4-diol 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(p-tolyl)-2-butyne-1,4-diol

1,4-bis-[p-di-n-propylaminoethoxy)-f enyl]-1,4-bis- (m-klorfenyl)-2-butin-1,4-diol 1,4-bis-[p-di-n-propylaminoethoxy)-phenyl]-1,4-bis-(m-chlorophenyl)-2-butyne-1,4-diol

1,4-bis- [p- (dimethylaminoethoxy) -f enyl] - 1,4-bis-[p-(dimethylaminoethoxy)-phenyl]-

1,4-bis- (m-klorfenyl) -2-butin-l,4-diol ' 1,4-bis-(m-chlorophenyl)-2-butyn-1,4-diol'

1,4-bis- [p- (diethylaminopropoxy) -f enyl] - 1,4-bis-[p-(diethylaminopropoxy)-phenyl]-

1,4-bis- (m-klorfenyl) -2-butin-l,4-diol 1,4-bis-(m-chlorophenyl)-2-butyn-1,4-diol

1,4-bis (-p-klorf enyl) -2-butin-1,4-diol 1,4-bis(-p-chlorophenyl)-2-butyne-1,4-diol

1,4-bis-(m,p-diklorf enyl)-2-butin-l,4-diol 1,4-bis-(m,p-dichlorophenyl)-2-butyn-1,4-diol

1,4-bis- [p- (diethylaminoethoxy) -f enyl] - 1,4-bis- (p-methoxyf enyl) -2-butin-l,4-diol 1,4-bis-[p-(diethylaminoethoxy)-f enyl] - 1,4-bis- (p-bromf enyl) -2-butin-il,4-diol 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(p-methoxyphenyl)-2-butyn-1,4-diol 1,4-bis-[p-(diethylaminoethoxy )-phenyl]-1,4-bis-(p-bromophenyl)-2-butyn-yl,4-diol

1,4-bis- [p-diethylaminoethoxy) -m-klorfenyl]-1,4-bis-(m-klorfenyl)-2-butin-l,4-diol 1,4-bis-[p-diethylaminoethoxy)-m-chlorophenyl]-1,4-bis-(m-chlorophenyl)-2-butyn-1,4-diol

1,4-bis- [p- (diethylaminoethoxy) -0,0'-dimethyl-fenyl]-1,4-bis-(o,p-diklorf enyl)-2-butin-1,4-diol 1,4-bis-[p-(diethylaminoethoxy)-0,0'-dimethyl-phenyl]-1,4-bis-(o,p-dichlorophenyl)-2-butyn-1,4-diol

1,1 ;4,4-tetrakis-[p-(diethylaminoethoxy)-fenyl]-2-butin-l,4-diol 1,1;4,4-Tetrakis-[p-(diethylaminoethoxy)-phenyl]-2-butyn-1,4-diol

1,4-bis- [p- (diethylaminoethoxy) -f enyl] - 1,4-bis-(p-nitrofenyl)-2-butin-l,4-diol 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(p-nitrophenyl)-2-butyn-1,4-diol

De fortrinnsvis i p-stilling stående tertiær-aminoalkoxyrester Ri og R6er f. eks. radikaler med formel The preferably in the p-position tertiary amino alkoxy residues Ri and R6 are e.g. radicals with formula

hvor R betyr en dialkylaminogruppe og n er et helt tall fra 1 til 7, i særdeleshet 2 eller 3. where R means a dialkylamino group and n is an integer from 1 to 7, in particular 2 or 3.

Som dialkylaminogruppe er foretrukket i særdeleshet en di-(laverealkyl)aminogruppe, som dimethyl-, diethyl- eller di-n-propylamino-gruppen. As a dialkylamino group, a di-(lower alkyl)amino group, such as the dimethyl, diethyl or di-n-propylamino group, is particularly preferred.

Fremgangsmåten ifølge oppfinnelsen karak-teriseres ved at et benzofenon med den generelle formel The method according to the invention is characterized in that a benzophenone with the general formula

1,4-bis-(o-nitro-p-klorfenyl)-2-butin-1,4-diol. 1,4-bis-(o-nitro-p-chlorophenyl)-2-butyne-1,4-diol.

De som utgangsforbindelser anvendte benzofenoner kan f. eks. oppnås ved å gå ut fra eventuelt substituerte benzoesyrefenylestere ved Fries'ke omleiring. De således erholdte eventuelt substituerte p-hydroxy-benzofenoner lar seg f. eks. forbinde over natriumsaltet på enkel måte i p-stilling med et tertiæraminoalkylhalogenid. The benzophenones used as starting compounds can e.g. is obtained by proceeding from optionally substituted benzoic acid phenyl esters by Fries'ke rearrangement. The optionally substituted p-hydroxy-benzophenones thus obtained can be e.g. connect above the sodium salt in a simple manner in the p-position with a tertiary aminoalkyl halide.

Acetylenforbindelsene med formel I kan f. eks. fremstilles ved omsetning av et benzofenon med formel II med et acetylendimagnesiumhalogenid. The acetylene compounds of formula I can e.g. is prepared by reacting a benzophenone of formula II with an acetylenedimagnesium halide.

Fortrinnsvis innledes herved acetylen i over-skudd i en av et alkyl- .eller arylhalogenid og magnesium fremstilt alkyl- eller arylmagnesium-halogenidoppløsning. Reaksjonen gjennomføres fortrinnsvis i et inert oppløsningsmiddel som f. eks. absolutt ether. Til 1 mol av det dannende acetylendimagnesiumhalogenid anvendes fortrinnsvis minst 2 mol keton. Reaksjonen kan gjennomføres ved en temperatur mellom 0° og kokepunktet for oppløsningsmidlet. Acetylene is preferably introduced in excess in an alkyl or aryl magnesium halide solution prepared from an alkyl or aryl halide and magnesium. The reaction is preferably carried out in an inert solvent such as e.g. absolute ether. At least 2 mol of ketone are preferably used for 1 mol of the forming acetylenedimagnesium halide. The reaction can be carried out at a temperature between 0° and the boiling point of the solvent.

Acetylenforbindelsene med formel I kan også fremstilles i en 2-trinns fremgangsmåte. Herved omsettes et fra acetylen på i og for seg kjent måte oppnådd alkalimetallacetylid med 1 mol keton til et acetylencarbinol, som etter omdan-nelse til et alkalimetallacetylid reagerer med et andre mol keton under dannelse av den ønskede sluttforbindelse. The acetylene compounds of formula I can also be prepared in a 2-stage process. Hereby, an alkali metal acetylide obtained from acetylene in a known manner is converted with 1 mole of ketone to an acetylene carbinol, which after conversion to an alkali metal acetylide reacts with a second mole of ketone to form the desired final compound.

Reaksjonsproduktet kan hydrolyseres uten rensing. Reaksjonsblandingen kan f. eks. helles på en blanding av is og fortynnet saltsyre og deretter innstilles alkalisk. En foretrukken ar-beidsmåte består i at reaksjonsblandingen inn-røres i en avkjølt, vandig ammoniumklorid opp-løsning. Den dannede acetylenforbindelse kan deretter skilles ved utrystning med egnede med vann ublandbare organiske oppløsningsmidler, f. eks. ved utrystning med kloroform, ether eller methylenklorid, og vasking med vann fra bipro-duktet ved reaksjonen og isoleres. The reaction product can be hydrolysed without purification. The reaction mixture can e.g. poured onto a mixture of ice and dilute hydrochloric acid and then made alkaline. A preferred working method consists in stirring the reaction mixture into a cooled, aqueous ammonium chloride solution. The acetylene compound formed can then be separated by shaking with suitable water-immiscible organic solvents, e.g. by shaking with chloroform, ether or methylene chloride, and washing with water from the by-product of the reaction and isolated.

Oppfinnelsen omfatter også fremstillingen av salter av acetylenforbindelsene med formel I, f. eks. syreaddisjonssalter med uorganiske syrer, som klorhydrogensyre, bromhydrogensyre eller svovelsyre; med organiske syrer, som oxal-syre, eddiksyre, melkesyre, vinsyre eller sitron-syre eller også kvaternære ammoniumsalter, f. eks. med alkylhalogenid, som methylbromid eller ethyljodid eller med dialkylsulfater, som dime-thylsulfat eller også med aralkylhalogenider, som benzylbromid. The invention also encompasses the preparation of salts of the acetylene compounds of formula I, e.g. acid addition salts with inorganic acids, such as hydrochloric acid, hydrobromic acid or sulfuric acid; with organic acids, such as oxalic acid, acetic acid, lactic acid, tartaric acid or citric acid or also quaternary ammonium salts, e.g. with alkyl halide, such as methyl bromide or ethyl iodide or with dialkyl sulfates, such as dimethyl sulfate or also with aralkyl halides, such as benzyl bromide.

Sluttproduktene kan renses ved krystallisasjon eller ved adsorpsjon på aluminiumoxyd, hvorved man oppnår som regel fargeløse krystaller. The end products can be purified by crystallization or by adsorption on aluminum oxide, whereby colorless crystals are usually obtained.

De ifølge oppfinnelsen fremstillbare acetylenforbindelser har anthelminthiske egenskaper og kan derfor anvendes som midler til bekjempelse av orme-angrep hos mennesker og dyr. Fortrinnsvis benytter man de mot tænia, i særdeleshet til bekjempelse av Hymenolopis nana (dvergbendelorm). The acetylene compounds which can be prepared according to the invention have anthelmintic properties and can therefore be used as agents for combating worm infestations in humans and animals. They are preferably used against tapeworms, in particular to combat Hymenolopis nana (dwarf tapeworm).

Fremgangsmåteproduktene kan finne anvendelse som legemidler, f. eks. i form av farma-søytiske preparater, hvilke inneholder de eller deres salter i blanding med et for den enterale administrasjon egnet farmasøytisk, organisk eller uorganisk inert bærematerial, som f. eks. vann, gelatin, melkesukker, stivelse, magnesium-stearat, talkum, vegetabilske oljer, gummi ara-bicum, polyalkylenglykoler, vaselin osv. De far-masøytiske preparatene kan foreligge i fast form, f. eks. som tabletter, drageer, suppositorier, kaps-ler eller i flytende form, f. eks. som oppløsnin-ger, suspensjoner eller emulsjoner. Eventuelt er de sterilisert og/eller inneholder hjelpestoffer, som konserverings-, stabiliserings-, fuktnings-eller emulgermidler, salter til forandring av det osmotiske trykk eller puffer. De kan også inneholde ennå andre therapeutiske verdifulle stof-fer. The process products can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations, which contain them or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and/or contain auxiliary substances, such as preservatives, stabilisers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

Eksempel 1.Example 1.

Fra 9,6 g magnesium i 50 ml absolutt ether og 70 g brombenzol i 120 ml absolutt ether fremstilles på vanlig måte en oppløsning av fenyl-magnesiumbromid og fra denne etter tilsetning av 25 g triethylamin ved innledning av acetylen acetylendimagnesiumbromid. From 9.6 g of magnesium in 50 ml of absolute ether and 70 g of bromobenzene in 120 ml of absolute ether, a solution of phenyl-magnesium bromide is prepared in the usual way and from this after the addition of 25 g of triethylamine by introduction of acetylene acetylenedimagnesium bromide.

Acetylidet avkjøles etter tilsetning av 200 ml methylenklorid i isbad og tilsettes dråpevis en oppløsning av 61 g 4-^-diethylaminoethoxy-4'-methylbenzofenon i 200 ml methylenklorid. Deretter oppvarmes reaksjonsblandingen 2 timer under tilbakeløpsbetingelser til koking, avkjøles deretter, helles i en iskald mettet ammonium-kloridoppløsning og ekstraheres med methylenklorid. Ekstraktet vaskes flere ganger med vann, tørkes så over natriumsulfat, filtreres og inn-dampes under forminsket trykk. Det tilbakebli-vende rå 1,4-bis-[p-(diethylaminoethoxy)-f e-nyl ] -1,4-bis- (p-tolyl) -2-butin-1,4-diol smelter etter omkrystallisering fra eddiksyreethylester/ petrolether (kokeområdé 40—45° C) i form av fargeløse krystaller ved 104—106° C. The acetylide is cooled after adding 200 ml of methylene chloride in an ice bath and a solution of 61 g of 4-^-diethylaminoethoxy-4'-methylbenzophenone in 200 ml of methylene chloride is added dropwise. The reaction mixture is then heated for 2 hours under reflux conditions to boiling, then cooled, poured into an ice-cold saturated ammonium chloride solution and extracted with methylene chloride. The extract is washed several times with water, then dried over sodium sulphate, filtered and evaporated under reduced pressure. The remaining crude 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(p-tolyl)-2-butyn-1,4-diol melts after recrystallization from acetic acid ethyl ester / petroleum ether (boiling range 40-45° C) in the form of colorless crystals at 104-106° C.

Det som utgangsstoff anvendte 4-^-diethylaminoethoxy-4'-methyl-benzofenon kan fremstilles på følgende måte: 255 g 4-toluylsyrefenylester oppløses i 680 ml nitrobenzol og oppvarmes etter tilsetning av 204 g pulverisert alumihiumklorid 24 timer til 60° C. Den avkjølte oppløsning helles så på iskald 3-n saltsyre og ekstraheres med ether. Etherekstraktet vaskes ennå to ganger med 2-n saltsyre og ekstraheres herpå med 7,5 %'ig natronlut, inntil den alkalisk-vandige oppløsning ikke mer er farget. Det alkalisk-vandige uttrekk The starting material 4-^-diethylaminoethoxy-4'-methyl-benzophenone can be prepared in the following way: 255 g of 4-toluyl acid phenyl ester is dissolved in 680 ml of nitrobenzene and, after the addition of 204 g of powdered aluminum chloride, is heated for 24 hours to 60° C. The cooled solution is then poured onto ice-cold 3-n hydrochloric acid and extracted with ether. The ether extract is further washed twice with 2-N hydrochloric acid and then extracted with 7.5% caustic soda until the alkaline-aqueous solution is no longer colored. The alkaline-aqueous extract

ansyres med konsentrert saltsyre, ekstraheres med ether og etherfasen vaskes fire ganger med acidified with concentrated hydrochloric acid, extracted with ether and the ether phase washed four times with

vann, tørkes over natriumsulfat, filtreres og inn-dampes i vakuum. Man oppnår rå 4-hydroxy-4'-methyl-benzofenon, som smelter etter omkrystallisering fra en aceton/benzol-blanding (forhold 1 : 10) ved 164—165° C. water, dried over sodium sulphate, filtered and evaporated in vacuo. Crude 4-hydroxy-4'-methyl-benzophenone is obtained, which melts after recrystallization from an acetone/benzene mixture (ratio 1:10) at 164-165°C.

142,4 g 4-hydroxy-4'-methyl-benzofenon oppløses i en blanding av 2,8 liter klorbenzol og 142.4 g of 4-hydroxy-4'-methyl-benzophenone is dissolved in a mixture of 2.8 liters of chlorobenzene and

150 ml ethanol i varme. Etter tilsetning av 37 150 ml ethanol in heat. After adding 37

g natriummethylat destillerer man ved normaltrykk ca. 1/3 av oppløsningsmiddelblandingen fra g of sodium methylate is distilled at normal pressure approx. 1/3 of the solvent mixture from

(inntil oppnåelse av koketemperaturen for klorbenzol) og lar reaksjonsblandingen avkjøle. Nå tildrypper man 110 g N-diethylaminoethylklorid og oppvarmer etter avsluttet tilsetning 20 timer til koking. Man lar den erholdte suspensjon av-kjøle, ekstraherer med methylenklorid og vasker det erholdte methylenkloridekstrakt i rekkefølge med 2 %'ig natronlut og fire ganger med vann. (until the boiling temperature of chlorobenzene is reached) and allow the reaction mixture to cool. Now 110 g of N-diethylaminoethyl chloride are added drop by drop and, after the addition has been completed, heat to boiling for 20 hours. The suspension obtained is allowed to cool, extracted with methylene chloride and the methylene chloride extract obtained is washed successively with 2% caustic soda and four times with water.

Etter tørking over natriumsulfat inndamper man det filtrerte methylenkloridekstrakt i vakuum. Det erholdte 4-/S-diethylaminoethoxy-4'-methylbenzofenon kan renses ved destillasjon i høyvakuum; kokepunkt ved 10870,02 mm. After drying over sodium sulphate, the filtered methylene chloride extract is evaporated in vacuo. The 4-/S-diethylaminoethoxy-4'-methylbenzophenone obtained can be purified by distillation in high vacuum; boiling point at 10870.02 mm.

Eksempel 2.Example 2.

Ved anvendelse av 62 g 4-^-diethylaminoethoxy-3'-fluor-benzofenon oppnås etter de i eksempel 1 angitte arbeidsbetingelser 1,4-bis-[p-(diethylaminoethoxy)-f enyl]-1,4-bis-(m-fluor-fenyl)-2-butin-1,4-diol, som smelter etter omkrystallisering fra eddiksyreethylester/petroleter (kokeområdé 40—45° C) i form av fargeløse krystaller ved 129—131° C. By using 62 g of 4-β-diethylaminoethoxy-3'-fluoro-benzophenone, 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(m -fluoro-phenyl)-2-butyn-1,4-diol, which melts after recrystallization from acetic acid ethyl ester/petroleum ether (boiling range 40-45° C) in the form of colorless crystals at 129-131° C.

Det som utgangsstoff anvendte 4-^-diethylaminoethoxy-3'-fluor-benzofenon (kp. 155— 158° C/0,01 mm Hg; = 1,5632) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 3-fluor-benzoesyrefenyl-ester over 3-fluor-4'-hydroxy-benzofenonet (frysepunkt 132—134° C). The 4-^-diethylaminoethoxy-3'-fluoro-benzophenone used as starting material (bp. 155—158° C/0.01 mm Hg; = 1.5632) can be prepared according to the work regulations stated in example 1 by proceeding from 3-Fluoro-benzoic acid phenyl ester over the 3-fluoro-4'-hydroxy-benzophenone (freezing point 132-134° C).

Eksempel 3.Example 3.

Fra 9,6 g magnesium i 50 ml absolutt ether og 45 g ethylbromid i 200 ml absolutt ether fremstilles på vanlig måte en oppløsning av ethylmagnesiumbromid, og fra denne ved innledning av acetylen acetylendimagnesiumbromid. From 9.6 g of magnesium in 50 ml of absolute ether and 45 g of ethyl bromide in 200 ml of absolute ether, a solution of ethylmagnesium bromide is prepared in the usual way, and from this by introducing acetylene acetylenedimagnesium bromide.

Acetylidet avkjøles etter tilsetning av 200 ml methylenklorid i isbad og tilsettes dråpevis en oppløsning av 80 g 4-^-diethylaminoethoxy-3'-klorbenzofenon og opparbeides etter de i eksempel i angitte arbeidsbetingelser. Det rå 1,4-bis- [p- (diethylaminoethoxy) -fenyl] - 1,4-bis- (m-klorfenyl)-2-butin-l,4-diol smelter etter omkrystallisering fra eddiksyreethylester/petrolether (kokeområdé 60—90° C) eller fra ethylalkohol i form av fargeløse krystaller ved 138— 140° C. The acetylide is cooled after adding 200 ml of methylene chloride in an ice bath and a solution of 80 g of 4-^-diethylaminoethoxy-3'-chlorobenzophenone is added dropwise and worked up according to those in the example under the specified working conditions. The crude 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(m-chlorophenyl)-2-butyne-1,4-diol melts after recrystallization from ethyl acetate/petroleum ether (boiling range 60— 90° C) or from ethyl alcohol in the form of colorless crystals at 138-140° C.

Det som utgangsstoff anvendte 4-/?-diethylaminoethoxy-3'-klorbenzofenon (kp. 128—132°C;2DB =1,5800) kan fremstilles etter den i eksempel I angitte arbeidsforskrift ved å gå ut fra 3-klorbenzoesyrefenylester over 3-klor-4'-hydroxy-benzofenonet (frysepunkt 168—169° C). The starting material 4-/?-diethylaminoethoxy-3'-chlorobenzophenone (b.p. 128-132°C; 2DB = 1.5800) can be prepared according to the work instructions given in example I by starting from 3-chlorobenzoic acid phenyl ester over 3- the chloro-4'-hydroxy-benzophenone (freezing point 168-169° C).

Eksempel 4.Example 4.

Ved anvendelse av 72 g 4-/J-di-n-propylami-noethoxy-3'-klor-benzofenon oppnås etter de i eksempel 1 angitte arbeidsbetingelser 1,4-bis-[p-(di-n-propylaminoethoxy)-fenyl]-l,4-bis-(m-klorfenyl)-2-butin-l,4-diol, som smelter etter omkrystallisering fra ethylalkohol i form av far-geløse krystaller ved 113—117° C. By using 72 g of 4-/J-di-n-propylamino-ethoxy-3'-chloro-benzophenone, 1,4-bis-[p-(di-n-propylaminoethoxy)-phenyl is obtained under the working conditions stated in example 1 ]-1,4-bis-(m-chlorophenyl)-2-butyn-1,4-diol, which melts after recrystallization from ethyl alcohol in the form of colorless crystals at 113-117°C.

Det som utgangsstoff anvendte 4-/?-di-n-propylaminoethoxy-3'-klorbenzofenon (kp. 193— 198° C/0,015 mm Hg; n 2D5 = 1,5670) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 3-klorbenzoesyrefenylester over 3-klor-4'-hydroxy-benzofenon (frysepunkt 168— 169° C). The 4-/?-di-n-propylaminoethoxy-3'-chlorobenzophenone used as starting material (bp. 193—198° C/0.015 mm Hg; n 2D5 = 1.5670) can be prepared according to the work regulations stated in example 1 by start from 3-chlorobenzoic acid phenyl ester over 3-chloro-4'-hydroxy-benzophenone (freezing point 168-169° C).

Eksempel 5.Example 5.

Ved anvendelse av 69 g 4-/?-diethylaminoethoxy-3-methyl-3'-klorbenzofenon oppnås etter de i eksempel 1 angitte arbeidsbetingelser 1,4-bis- [p- (diethylaminoethoxy) -m-tolyl] -1,4-bis-(m-klorfenyl)-2-butin-l,4-diol, som smelter etter omkrystallisering fra ethylalkohol i form av far-geløse krystaller ved 133—137° C. By using 69 g of 4-/?-diethylaminoethoxy-3-methyl-3'-chlorobenzophenone, 1,4-bis-[p-(diethylaminoethoxy)-m-tolyl]-1,4- bis-(m-chlorophenyl)-2-butyn-1,4-diol, which melts after recrystallization from ethyl alcohol in the form of colorless crystals at 133-137°C.

Det som utgangsstoff anvendte 4-^-diethylaminoethoxy-3-methyl-3'-klor-benzofenon (kp. 180—184° C/0,02 mm Hg; 1,5780) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 3-klorbenzoesyre-2-tolyl-ester over 3-klor-3'-methyl-4'-hydroxy-benzofenonet (n2D4=1,5672). The 4-^-diethylaminoethoxy-3-methyl-3'-chloro-benzophenone used as starting material (bp. 180-184° C/0.02 mm Hg; 1.5780) can be prepared according to the work regulations stated in example 1 by start from 3-chlorobenzoic acid-2-tolyl ester over the 3-chloro-3'-methyl-4'-hydroxy-benzophenone (n2D4=1.5672).

Eksempel 6.Example 6.

Ved anvendelse av 90 g 4-/?-diethylaminoethoxy-4'-brombenzofenon oppnås etter de i eksempel 3 angitte arbeidsbetingelser 1,4-bis-[p-(diethylaminoethoxy) -f enyl] -1,4-bis- (p-brom-fenyl)-2-butin-l,4-diol i form av fargeløse krystaller, som smelter etter omkrystallisering fra eddiksyreethylester/petrolether (kokeområdé 40 By using 90 g of 4-/?-diethylaminoethoxy-4'-bromobenzophenone, 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4-bis-(p- bromo-phenyl)-2-butyn-1,4-diol in the form of colorless crystals, which melt after recrystallization from acetic acid ethyl ester/petroleum ether (boiling range 40

—45° C) ved 138—140° C. 4-/?-diethylaminoethoxy-4'-brom-benzofenon kan fremstilles på følgende måte: 126 g 4-brombenzoesyrefenylester oppløses i 400 ml. nitrobenzol og oppvarmes etter tilsetning av 90 g pulverisert aluminiumklorid 40 timer ved 60°. Den avkjølte oppløsning helles deretter på iskald 3-n saltsyre og ekstraheres med ether. Etherekstraktet vaskes to ganger med 2-n salt- -45° C) at 138-140° C. 4-/?-diethylaminoethoxy-4'-bromobenzophenone can be prepared as follows: 126 g of 4-bromobenzoic acid phenyl ester are dissolved in 400 ml. nitrobenzene and heated after adding 90 g of powdered aluminum chloride for 40 hours at 60°. The cooled solution is then poured onto ice-cold 3-n hydrochloric acid and extracted with ether. The ether extract is washed twice with 2-N saline

syre og ekstraheres deretter med 7,5 %'ig natronlut, inntil den alkalisk-vandige oppløsning ikke mer er farget. Det alkalisk-vandige uttrekk ansyres med konsentrert saltsyre, ekstraheres med ether, og etherfasen vaskes fire ganger med vann, tørkes over natriumsulfat, filtreres og inn-dampes i vakuum. Man oppnår rå 4-hydroxy-4'-brom-benzofenon, som etter omkrystallisasjon fra en aceton/benzol-blanding (forhold 1 : 10) smelter ved 192—193° C. acid and then extracted with 7.5% caustic soda, until the alkaline-aqueous solution is no longer colored. The alkaline-aqueous extract is acidified with concentrated hydrochloric acid, extracted with ether, and the ether phase is washed four times with water, dried over sodium sulfate, filtered and evaporated in vacuo. Crude 4-hydroxy-4'-bromo-benzophenone is obtained, which after recrystallization from an acetone/benzene mixture (ratio 1:10) melts at 192-193°C.

85,0 g 4-hydroxy-4'-brom-benzofenon opp-løses i en blanding av 1 liter klorbenzol og 70 ml ethanol i varme. Etter tilsetning av 22 g na-triumethylat destillerer man ved normaltrykk ca. 1/3 av oppløsningsmiddelblandingen av (inntil oppnåelse av koketemperaturen for klorben-zolen) og lar reaksjonsblandingen avkjøle. Nå tildrypper man 55 g N-diethyl-aminoethylklorid og oppvarmer etter avsluttet tilsetning 10 timer til kokning. Man lar den erholdte suspensjon avkjøle, ekstraherer med ether og vasker den erholdte ether i rekkefølge med 2 %'ig natronlut og fire ganger med vann. 85.0 g of 4-hydroxy-4'-bromo-benzophenone are dissolved in a mixture of 1 liter of chlorobenzene and 70 ml of ethanol in heat. After adding 22 g of sodium ethylate, approx. 1/3 of the solvent mixture off (until the boiling temperature of the chlorobenzene is reached) and allow the reaction mixture to cool. Now 55 g of N-diethyl-aminoethyl chloride is added drop by drop and, after the addition is finished, heat for 10 hours until boiling. The suspension obtained is allowed to cool, extracted with ether and the ether obtained is washed successively with 2% caustic soda and four times with water.

Etter tørking over natriumsulfat inndamper man det filtrerte etherekstrakt i vakuum. Det erholdte 4-J#-diethyl-aminoethoxy-4'-brom-benzofenon kan renses ved krystallisasjon fra petrolether (kokeområdé 60^—90°); smeltepunkt 75—76° C. 2 g 4-jtf-diethylaminoethoxy-4'-brom-benzofenon oppløses i 20 ml ether, tilsettes 10 ml 3-n saltsyre og rystes i 10 minutter. Det utskilte salt filtreres fra, vaskes med ether og lite vann og omkrystalliseres fra 10 ml alkohol. Man oppnår hydrokloridet med et smeltepunkt på 180— 182° C. After drying over sodium sulphate, the filtered ether extract is evaporated in vacuo. The 4-N-diethyl-aminoethoxy-4'-bromo-benzophenone obtained can be purified by crystallization from petroleum ether (boiling range 60°—90°); melting point 75-76° C. Dissolve 2 g of 4-jtf-diethylaminoethoxy-4'-bromo-benzophenone in 20 ml of ether, add 10 ml of 3-n hydrochloric acid and shake for 10 minutes. The separated salt is filtered off, washed with ether and a little water and recrystallized from 10 ml of alcohol. The hydrochloride is obtained with a melting point of 180-182°C.

Eksempel 7.Example 7.

Ved anvendelse av 88 g 4-/?-diethylaminoethoxy-3-klor-3'-klor-benzofenon oppnås etter de i eksempel 3 angitte arbeidsbetingelser 1,4-bis- [p- (diethylaminoethoxy) -m-klorfenyl] -1,4-bis-(m-klorfenyl)-2-butin-l,4-diol i form av far-geløse krystaller, som smelter etter omkrystallisering fra benzol ved 163—164° C. By using 88 g of 4-/?-diethylaminoethoxy-3-chloro-3'-chloro-benzophenone, 1,4-bis-[p-(diethylaminoethoxy)-m-chlorophenyl]-1 is obtained under the working conditions stated in example 3, 4-bis-(m-chlorophenyl)-2-butyn-1,4-diol in the form of colorless crystals, which melt after recrystallization from benzene at 163-164° C.

Det som utgangsstoff anvendte 4-/?-diethylaminoethoxy-3-klor-3'-klor-benzofenon (n 2D7 = 1,5773) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 3-klor-benzoesyre-2-klorfenyl-ester over 3-klor-3'-klor-4'-hydroxy-benzofenon (frysepunkt 134—135°C). The 4-/?-diethylaminoethoxy-3-chloro-3'-chloro-benzophenone used as starting material (n 2D7 = 1.5773) can be prepared according to the work regulations stated in example 1 by starting from 3-chloro-benzoic acid-2 -chlorophenyl ester over 3-chloro-3'-chloro-4'-hydroxy-benzophenone (freezing point 134-135°C).

Eksempel 8.Example 8.

Ved anvendelse av 94 g 4-/?-diethylaminoethoxy-2,6-dimethyl-2', 4'-diklor-benzofenon oppnås etter de i eksempel 3 angitte arbeidsbetingelser 1,4-bis- [p- (diethylaminoethoxy) - o,o'-dimethylfenyl]-1,4-bis-(o,p-diklorf enyl)-2-butin-1,4-diol i form av fargeløse krystaller, som smelter etter omkrystallisering fra eddiksyreethylester/petrolether (kokeområdé 40—45° C) ved 200—201° C. By using 94 g of 4-/?-diethylaminoethoxy-2,6-dimethyl-2', 4'-dichloro-benzophenone, 1,4-bis-[p-(diethylaminoethoxy)-o, o'-dimethylphenyl]-1,4-bis-(o,p-dichlorophenyl)-2-butyn-1,4-diol in the form of colorless crystals, which melt after recrystallization from acetic acid ethyl ester/petroleum ether (boiling range 40-45° C) at 200-201°C.

Det som utgangsstoff anvendte 4-/?-diethylaminoethoxy-2,6-dimethyl-2', 4'-diklor-benzofe non (ny= 1,5801) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 2,4-diklorbenzoesyre-3,5-dimethyl-fenylester over 2,4-diklor-2,6'-dimethyl-4'-hydroxybenzo-fenon (frysepunkt 184—185° C). The starting material 4-/?-diethylaminoethoxy-2,6-dimethyl-2', 4'-dichloro-benzophenone (ny= 1.5801) can be prepared according to the work regulations stated in example 1 by starting from 2, 4-dichlorobenzoic acid-3,5-dimethyl-phenyl ester over 2,4-dichloro-2,6'-dimethyl-4'-hydroxybenzo-phenone (freezing point 184-185° C).

Eksempel 9.Example 9.

Ved anvendelse av 82 g 4,4'-bis-(4-ji§-diethylaminoethoxy)-benzofenon oppnås etter de i eksempel 3 angitte arbeidsbetingelser 1,1; 4,4- te-trakis- [p- (diethylaminoethoxy) -f enyl] -2-butin-1,4-diol, en seig, lysebrun olje, som kan renses ved adsorpsjon på aluminiumoxyd (aktivitets-trinn III). When using 82 g of 4,4'-bis-(4-jig-diethylaminoethoxy)-benzophenone, 1.1 is obtained under the working conditions stated in example 3; 4,4-te-trachys-[p-(diethylaminoethoxy)-phenyl]-2-butyn-1,4-diol, a tough, light brown oil, which can be purified by adsorption on aluminum oxide (activity stage III).

Det som utgangsstoff anvendte 4,4'-bis-(4-/g-diethylaminoethoxy)-benzofenon (n2D6 = 1,5488) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 4-hydroxy-ben-zoesyrefenylester over 4,4'-dihydroxy-benzofeno-net (frysepunkt 206° C). The 4,4'-bis-(4-/g-diethylaminoethoxy)-benzophenone (n2D6 = 1.5488) used as a starting material can be prepared according to the work instructions given in example 1 by starting from 4-hydroxy-benzoic acid phenyl ester above 4,4'-dihydroxy-benzophenone (freezing point 206° C).

Eksempel 10.Example 10.

Ved anvendelse av 80 g 4-^-diethylaminoethoxy-4'-nitro-benzofenon oppnås etter de i eksempel 3 angitte arbeidsbetingelser 1,4-bis-[-p- (diethylaminoethoxy) -f enyl] - 1,4-bis- (p-nitrofenyl)-2-butin-l,4-diol i form av svakt gulfargede krystaller, som smelter etter omkrystallisering fra eddiksyreethylester ved 94—98° C. By using 80 g of 4-^-diethylaminoethoxy-4'-nitro-benzophenone, 1,4-bis-[-p-(diethylaminoethoxy)-phenyl]-1,4-bis- ( p-nitrophenyl)-2-butyn-1,4-diol in the form of slightly yellow crystals, which melt after recrystallization from acetic acid ethyl ester at 94-98° C.

Det som utgangsstoff anvendte 4-y?-diethylaminoethoxy-4'-nitrobenzofenon (frysepunkt 89 —90° C) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 4-nitro-benzoesyre-fenylester over 4-nitro-4'-hydroxy-benzofenonet (frysepunkt 191—193° C). The 4-y?-diethylaminoethoxy-4'-nitrobenzophenone used as starting material (freezing point 89-90° C) can be prepared according to the work instructions given in example 1 by starting from 4-nitro-benzoic acid phenyl ester over 4-nitro-4 the '-hydroxy-benzophenone (freezing point 191-193° C).

Eksempel 11.Example 11.

Ved anvendelse av 30 g 4-^-diethylaminoethoxy-2'-nitro-4'-klor-benzofenon oppnås etter de i eksempel 3 angitte arbeidsbetingelser 1,4-bis- [p- (diethylaminoethoxy) -f enyl] -1,4-bis- (o-nitro-p-klorfenyl)-2-butin-l,4-diol i form av svakt gulfargede krystaller, som smelter etter omkrystallisering fra eddiksyreethylester/petrolether (kokeområdé 40—45° C) ved 121—123° C. By using 30 g of 4-^-diethylaminoethoxy-2'-nitro-4'-chloro-benzophenone, 1,4-bis-[p-(diethylaminoethoxy)-phenyl]-1,4 -bis-(o-nitro-p-chlorophenyl)-2-butyn-1,4-diol in the form of slightly yellow crystals, which melt after recrystallization from acetic acid ethyl ester/petroleum ether (boiling range 40—45° C) at 121—123° C.

Det som utgangsstoff anvendte 4-^-diethylaminoethoxy-2'-nitro-4'-klor-benzofenon (n y= 1,5948) kan fremstilles etter den i eksempel 1 angitte arbeidsforskrift ved å gå ut fra 2-nitro-4-klor-4'-hydroxy-benzofenonet (frysepunkt 190 —192° C). The 4-^-diethylaminoethoxy-2'-nitro-4'-chloro-benzophenone used as starting material (n y= 1.5948) can be prepared according to the work regulations stated in example 1 by starting from 2-nitro-4-chloro- The 4'-hydroxy-benzophenone (freezing point 190 —192° C).

Claims

Process for the preparation of new, therapeutically active acetylene compounds of the general formula

where R 1 means a tertiary amino alkoxy radical with the general formula R-(CH 2 )n -0-, where R means a dialkylamino group, in particular the diethyl amino group and n an integer from 1 to 7, in particular 2 or 3, R 2 , R 3 and R4 hydrogen, lower alkyl or halogen, R5 hydrogen, lower alkyl, halogen or nitro and R6 hydrogen, lower alkyl, halogen, nitro or a tertiary amino alkoxy radical with the general formula R-(CH2 )n -0-, where R and n have the above meaning, as well as salts of these compounds, characterized in that a benzophenone with the general formula

where R 1 , R 2 , R 3 , R 4 , R 5 and R 8 have the meaning indicated above, is reacted in a manner known per se with an organometallic compound and acetylene, and optionally transfers the product obtained to a salt.