NO130795B

NO130795B -

Info

Publication number: NO130795B
Application number: NO509669A
Authority: NO
Inventors: T Atsumi; K Kobayashi; Y Takebayashi; H Yamamoto
Original assignee: Sumitomo Chemical Co
Priority date: 1968-12-26
Filing date: 1969-12-23
Publication date: 1974-11-04
Also published as: ES374901A1; GB1276719A; YU321969A; FR2027126A1; DK132755C; BR6915175D0; NL6919358A; DK132755B; YU34123B; CS161100B2; CH525893A; FR2027126B1; NL160252C; DE1962442A1; AT293414B; DE1962442B2; NL160252B; FI51349B; PL80422B1; NO130795C

Description

Analogifremgangsmåter for fremstilling av terapeutisk aktive benzomorfanderivater og salter av disse. Analogy methods for the production of therapeutically active benzomorphan derivatives and salts thereof.

Foreliggende oppfinnelse angår analogifremgangsmåter for fremstilling av nye 6,7-benzomorfanderivater, salter av disse, hvor de nevnte derivater og salter er meget brukbare og verdifulle som ikke-tilvennende, smertestillende og bedøvende midler med beroligende virkning. The present invention relates to analogous methods for the production of new 6,7-benzomorphane derivatives, salts thereof, where the said derivatives and salts are very useful and valuable as non-addictive, pain-relieving and anesthetic agents with a sedative effect.

Mange benzomorfanderivater, f.eks. pentazocin og metyl- Many benzomorphane derivatives, e.g. pentazocine and methyl-

morfin, har vært anvendt som smertestillende midler (se f.eks. morphine, has been used as painkillers (see e.g.

belgisk patent 611.000 eller "Chemistry of the Opium Alkaloids", Belgian patent 611,000 or "Chemistry of the Opium Alkaloids",

U.S. Public Health Reports, Suppl. nr. 103, Washington (1932)), men U.S. Public Health Reports, Suppl. No. 103, Washington (1932)), but

de fleste har i tillegg til den smertestillende aktivitet også vært av tilvennende natur. Man har således i eldre og unge dyr kunnet frembringe en narkose ved en subkutan injeksjon av slike kjente most have, in addition to the pain-relieving activity, also been of an addictive nature. It has thus been possible to induce anesthesia in older and young animals by a subcutaneous injection of such known substances

narkotiske, smertestillende midler, og man har derved kunnet påvise en narkotisk tilstand som opphør av lokomotorisk aktivitet,- sløvhet, etc. narcotic painkillers, and one has thereby been able to demonstrate a narcotic condition such as cessation of locomotor activity, - lethargy, etc.

Foreliggende oppfinnelse omhandler en analogifremgangsmåte for fremstilling av benzomorf ander.i vater med formelen: The present invention relates to an analogous method for the production of benzomorph ander.i vater with the formula:

hvor R er et hydrogenatom, en C<1->C^-alkoksygruppe eller en hydroksylgruppe, R, og R er uavhengig C^-C^-alkylgrupper, R-, er et hydrogenatom, et halogenatom, en C 1-C 3 -alkylgruppe, en C 1-C3-alkoksygruppe, en C<1->C^-alkyltiogruppe, en nitrogruppe, en trifluormetylgruppe eller en hydroksylgruppe, R^ er et hydrogenatom, en C^-C.^-alkylgruppe, 13 ' et halogenatom eller en C -C -alkoksygruppe, mens n er 3 eller 4. Benzomorfanderivatene med formel (I), fremstilles.ifølge oppfinnelsen ved at man hydrolyserer et- etylendioksyderivat med formelen: where R is a hydrogen atom, a C<1->C^-alkyl group or a hydroxyl group, R, and R is independently C^-C^-alkyl groups, R-, is a hydrogen atom, a halogen atom, a C 1-C 3 -alkyl group, a C 1 -C 3 alkoxy group, a C<1->C 3 -alkylthio group, a nitro group, a trifluoromethyl group or a hydroxyl group, R 3 is a hydrogen atom, a C 3 -C 4 -alkyl group, 13 ' a halogen atom or a C -C - alkoxy group, while n is 3 or 4. The benzomorphan derivatives with formula (I) are prepared according to the invention by hydrolyzing an ethylenedioxy derivative with the formula:

hvor R,- R^, R2, R^,. R^ og n .er som angitt ovenfor. where R 1 - R 2 , R 2 , R 2 . R^ and n .are as indicated above.

Benzomorfanderivatene med formel I, fremstilles også ved at man omsetter et 6,7_benzomorfanderivat med formelen: hvor R, R^ og R2 er som definert ovenfor, med et reaktivt halogenid med formelen: The benzomorphane derivatives with formula I are also prepared by reacting a 6,7-benzomorphane derivative with the formula: where R, R^ and R2 are as defined above, with a reactive halide of the formula:

hvor R^, R|| og n er som angitt ovenfor, og X er et halogenatom, i et inert organisk oppløsningsmiddel i nærvær av en base. where R^, R|| and n is as indicated above, and X is a halogen atom, in an inert organic solvent in the presence of a base.

Ovennevnte utgangsforbindelser, nemlig 6,7-benzomorfan-derivater med formel (III) er kjente forbindelser, som kan fremstilles ved å demetylere kjente 2-mety1-6,7~benzomorfanderivater. The above-mentioned starting compounds, namely 6,7-benzomorphane derivatives of formula (III) are known compounds, which can be prepared by demethylating known 2-methyl-6,7-benzomorphane derivatives.

Omsetningen av et 6y7_benzomorfanderivat med formel (III) The conversion of a 6y7_benzomorphane derivative of formula (III)

og et reaktivt halogenid med formel (IV) utføres som nevnt i et organisk, inert oppløsningsmiddel, f.eks. n-héksan, benzen, toluen, xylen, kloroform, dimetylformamid, metanol, etanol, isopropylalkohol og lignende. Videre utføres reaksjonen i nærvær av en base, f.eks. natriumkarbonat, kaliumkarbonat, natriumbikarbonat, kaliumbikarbonat, natriumhydroksyd, kaliumhydroksyd, natriumamid, natriumhydrid, pyridin eller trietylamin. Reaksjonen skjer lett ved temperaturer fra 20 til 200°C, fortrinnsvis fra 60 til 150°C. Reaksjonsprdduktet kan meget lett innvinnes fra reaksjonsblandingen ved filtrering i den,, eksisterende konsentrasjon, og ved å tilsette vann og/eller et eventuelt annet oppløsningsmiddel i hvilket filtratet er uløselig eller bare svakt oppløselig. and a reactive halide of formula (IV) is carried out as mentioned in an organic, inert solvent, e.g. n-hexane, benzene, toluene, xylene, chloroform, dimethylformamide, methanol, ethanol, isopropyl alcohol and the like. Furthermore, the reaction is carried out in the presence of a base, e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, pyridine or triethylamine. The reaction takes place easily at temperatures from 20 to 200°C, preferably from 60 to 150°C. The reaction product can be very easily recovered from the reaction mixture by filtration at the existing concentration, and by adding water and/or any other solvent in which the filtrate is insoluble or only slightly soluble.

Hydrolysen av nevnte .etylendioksyderivat (II) utføres i The hydrolysis of said .ethylenedioxy derivative (II) is carried out in

et egnet oppløsningsmiddel, f.eks. vann, en alkohol med metanol, etanol, n- eller iso-propanol, n-butanol eller lignende, fortrinnsvis ved temperaturer varierende fra romtemperatur til kokepunktet for det anvendte oppløsningsmiddel. Man bør ved reaksjonen eller omsetningen fortrinnsvis anvende en katalytisk mengde av en syre, f.eks. mineralsyrer såsom saltsyre, svovelsyre -eller fosforsyre, eller organiske syrer såsom eddiksyre, etc. Reaksjonen er vanligvis fullstendig etter \ til 2 timer. a suitable solvent, e.g. water, an alcohol with methanol, ethanol, n- or iso-propanol, n-butanol or the like, preferably at temperatures varying from room temperature to the boiling point of the solvent used. A catalytic amount of an acid should preferably be used in the reaction or reaction, e.g. mineral acids such as hydrochloric, sulfuric or phosphoric acid, or organic acids such as acetic acid, etc. The reaction is usually complete after \ to 2 hours.

De fremstilte 6,7-benzomorfanderivater (I) kan,.om ønsket, omdannes til sine syreaddisjonssalter ved vanlige fremgangsmåter, f.eks. behandling med en organisk eller uorganisk syre (f.eks. saltsyre, maleinsyre, sitronsyre, vinsyre) i vann eller i et vanlig inert, organisk oppløsningsmiddel (f. eks. metanol, etanol,. etc). The produced 6,7-benzomorphane derivatives (I) can, if desired, be converted into their acid addition salts by usual methods, e.g. treatment with an organic or inorganic acid (e.g. hydrochloric acid, maleic acid, citric acid, tartaric acid) in water or in a common inert, organic solvent (e.g. methanol, ethanol, etc.).

De fremstilte 6,7-benzomorfanderivater med formel (I), f. eks. 2 ' -hydroksy- 2- /y- (p-fluorbenzoyl)-n-propyl7-5, 9_dimetyl-6,7-benzomorfan, 2-/y-(p-fluorbenzoyl)-n-propyl7-5,9-dimetyl-6,7-benzomorfan, 2'-hydroksy-2-/y-(p-fluorbenzoyl)-n-propyl/-5-metyl-9-etyl-6 ,7-benzomorf an og 2 ' -hydroksy-2-/y- (p--klorbenzoyl)-n-propyl7-5,9-dimetyl-6,7-benzomorfan synes ikke å virke som et narkotikum i mus, rotter og andre dyr. I meget lange prøver har man ikke kunnet påvise at disse forbindelser frembringer en fysisk avhengighet. . Videre har man kunnet påvise at de foreliggende 6,7-benzomorfanderivater (I) har svake eller sterke smertestillende aktiviteter ved en subkutan prøve, og det har vist seg at enkelte av dem har meget sterk smertestillende virkning, dvs. med virkninger som er lik eller overstiger de man finner -hos pentazocin eller metylmorfin (tabell 1). They prepared 6,7-benzomorphane derivatives of formula (I), e.g. 2'-hydroxy-2-(p-fluorobenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan, 2-[y-(p-fluorobenzoyl)-n-propyl7-5,9-dimethyl -6,7-benzomorphan, 2'-hydroxy-2-[y-(p-fluorobenzoyl)-n-propyl]-5-methyl-9-ethyl-6,7-benzomorphan and 2'-hydroxy-2- /y-(p--Chlorobenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan does not appear to act as a narcotic in mice, rats and other animals. In very long trials, it has not been possible to demonstrate that these compounds produce physical dependence. . Furthermore, it has been possible to demonstrate that the present 6,7-benzomorphane derivatives (I) have weak or strong analgesic activities in a subcutaneous test, and it has been shown that some of them have a very strong analgesic effect, i.e. with effects that are equal or exceed those found -with pentazocine or methylmorphine (table 1).

Fremgangsmåten er basert på den spesifikke antagonisme The procedure is based on the specific antagonism

man finner hos smertestillende midler overfor det typiske syndrom som frembringes av en intraperitonal injeksjon av 0, 6%'s vandig eddiksyre. Syndromet er karakterisert ved indre kontraksjoner i buken, vridninger av kroppen og en forlengelse av bakføttene.. one finds in painkillers against the typical syndrome produced by an intraperitoneal injection of 0.6% aqueous acetic acid. The syndrome is characterized by internal contractions in the abdomen, twisting of the body and an extension of the hind legs.

En gruppe på 5 mus ble brukt på hvert dosenivå. Forbindelsene ble tilført subkutant 20 minutter før injeksjonen av eddiksyren. Antall mus som ikke viste noen smerterespons ble angitt. ED,_Q ble beregnet ifølg.e Litchf ie.ld-Wilcoxon' s metode. A group of 5 mice was used at each dose level. The compounds were administered subcutaneously 20 minutes before the injection of the acetic acid. The number of mice that showed no pain response was indicated. ED,_Q was calculated according to Litchfield-Wilcoxon's method.

Forbindelsene 17 og 18 representerer virkningen til forbindelser med formel IIC og IID, respektivt, fra Journal of Organic Compounds 17 and 18 represent the action of compounds of formula IIC and IID, respectively, from the Journal of Organic

Chemistry 24 (1) 116-117 (1959)- Den benyttede forsøksmetode er angitt ovenfor. Chemistry 24 (1) 116-117 (1959) - The experimental method used is stated above.

2. Akutt toksisitet. 2. Acute toxicity.

Forbindelsene i nedenstående tabell 2 ble administrert ved subkutan injeksjon til mus av ICR-stammen med en vekt på 20-25 g og bestående av 10 dyr pr. gruppe. The compounds in Table 2 below were administered by subcutaneous injection to mice of the ICR strain with a weight of 20-25 g and consisting of 10 animals per group.

3. Abstinens- syndromforsøk. 3. Abstinence syndrome trials.

De i nedenstående tabell 3 angitte forbindelser ble administrert til rotter ved subkutan injeksjon (i tabell, 3 betegnet som S.C.) to ganger daglig i H uker. Dagen etter denne periode ble abstinens-syndromet til rottene undersøkt ved å måle nedgangen i legemsvekt. Dersom en administrert forbindelse bevirker abstinens-syndrom kan en rottes legemsvekt nedsettes betraktelig. Betydningene av symbolene i tabell 3 er følgende: The compounds listed in Table 3 below were administered to rats by subcutaneous injection (in Table 3 designated as S.C.) twice daily for H weeks. The day after this period, the abstinence syndrome of the rats was examined by measuring the decrease in body weight. If an administered compound causes an abstinence syndrome, a rat's body weight can be reduced considerably. The meanings of the symbols in table 3 are as follows:

+++ Sterk nedgang i legemsvekt (omkring 5%' s nedgang) +++ Strong decrease in body weight (around 5%'s decrease)

++ Moderat ++ Moderate

+ Svak + Weak

- Ingen nedgang - No decline

Rotter: Wistar-stamme, <5, 150 g legemsvekt ved begynnelsen av forsøket; hver gruppe besto av 20 dyr., Rats: Wistar strain, <5, 150 g body weight at the beginning of the experiment; each group consisted of 20 animals.,

Forsøksmetoden er også i detalj angitt i Folia Pharma-cologica Japonica 54, 120 (1958) av K. Hosoya et al. The test method is also detailed in Folia Pharmacologica Japonica 54, 120 (1958) by K. Hosoya et al.

Som det klart fremgår fra de i tabellene 1-3 angitte resultater er forbindelsene fremstilt ifølge foreliggende søknad de i den motholdte referanse overlegne ikke bare med hensyn til analgetisk aktivitet, men også når det gjelder lav toksisitet. As is clear from the results given in Tables 1-3, the compounds produced according to the present application are superior to those in the opposed reference not only with regard to analgesic activity, but also when it comes to low toxicity.

Blånt de nevnte forbindelser er det visse som har vist Beyond the aforementioned connections, there are certain ones that have shown

seg å ha meget sterk smertestillende effekt, ikke bare i denne krampeprøve, men også i andre smertestillende, prøver, f. eks. en varmplateprøve, ennvidere i Hoffner-prøven. Videre kan det nevnes at foreliggende forbindelser har en svak beroligende effekt, og i visse tilfeller stimulerer denne effekt også den smertestillende effekt. Videre kan det nevnes at de fremstilte forbindelser ikke har noen ugunstige sideeffekter, f. eks., oppkast eller kvalme, opp-hissende effekter, allergiske reaksjoner, respiratoriske depresjoner, etc, i motsetning til morfin og andre kjente benzomorfan-derivater. to have a very strong pain-relieving effect, not only in this cramp test, but also in other pain-relieving tests, e.g. a hot plate test, further in the Hoffner test. Furthermore, it can be mentioned that the present compounds have a weak sedative effect, and in certain cases this effect also stimulates the pain-relieving effect. Furthermore, it can be mentioned that the compounds produced have no adverse side effects, e.g., vomiting or nausea, excitatory effects, allergic reactions, respiratory depression, etc., in contrast to morphine and other known benzomorphan derivatives.

Forbindelsene kan opparbeides for bruk ved at de'under sterile betingelser i saltform oppløses i vann (eller i en ekvivalent mengde av en ikke-toksisk syre, hvis man anvender den frie-base), eller i et fysiologisk forenlig vandig medium såsom saltvann, og kan lagres i ampuller for videre injeksjon. The compounds can be prepared for use by dissolving them under sterile conditions in salt form in water (or in an equivalent amount of a non-toxic acid, if the free base is used), or in a physiologically compatible aqueous medium such as saline, and can be stored in ampoules for further injection.

Alternativt kan forbindelsene inkorporeres i doserings-enheter (1-15 rag) i form av tabletter eller kapsler for oral administrasjon, enten alene eller sammen med egende fortynnings-midler slik som kalsiumkarbonat, stivelse, laktose, talkum, magne-siumstearat, akaciegummi osv. Alternatively, the compounds can be incorporated into dosage units (1-15 rags) in the form of tablets or capsules for oral administration, either alone or together with appropriate diluents such as calcium carbonate, starch, lactose, talc, magnesium stearate, acacia gum, etc.

De følgende eksempler er representative for fremgangsmåter for fremstilling av nevnte forbindelser. The following examples are representative of methods for preparing said compounds.

Eksempel 1 Example 1

2'- hydroksy- 2-/ y-( p- fluorbenzoyl)- n- propyl/- 5, 9~ dimetyl- 6, 7- benzomorfan (a) 2'- hydroksy- 2-/ 5"-( p- fluorfenyl)- 4", 4"- etylendioksy- n-butyl/- 5, 9~ dimetyl- 6, 7- benzomorfan 2'- hydroxy- 2-/ y-( p- fluorobenzoyl)- n- propyl/- 5, 9~ dimethyl- 6, 7- benzomorphan (a) 2'- hydroxy- 2-/ 5"-( p- fluorophenyl )- 4", 4"- ethylenedioxy-n-butyl/- 5, 9~ dimethyl- 6, 7- benzomorphan

En blanding av 1,08 g 2'-hydroksy-5,9-dimetyl-6,7-benzomorfan, 0,6 g natriumbikarbonat og 15 ml dimetylformamid ble til- A mixture of 1.08 g of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 0.6 g of sodium bicarbonate and 15 ml of dimethylformamide was added

satt 1,43 g 4-(p-fluorfenyl)-4,4-etylendioksy-l-brombutan. Opp-løsningen ble omrørt ved 130-l45°C i 4 timer. Oppløsningsmidlet added 1.43 g of 4-(p-fluorophenyl)-4,4-ethylenedioxy-1-bromobutane. The solution was stirred at 130-145°C for 4 hours. The solvent

ble fjernet under redusert trykk, hvoretter resten ble tilsatt vann. Blandingen ble hensatt i et kjøleskap, og man fikk et bunnfall med was removed under reduced pressure, after which water was added to the residue. The mixture was placed in a refrigerator, and a precipitate was obtained with it

et smp. på 174-179°C. Rekrystallisasjon fra etylacetat gir rene krystaller av 2'-hydroksy-2-/"4"-(p-fluorfenyl)-4",4"-etylendioksy- a m.p. at 174-179°C. Recrystallization from ethyl acetate gives pure crystals of 2'-hydroxy-2-/"4"-(p-fluorophenyl)-4,4"-ethylenedioxy-

n-butyl/-5,9-dimetyl-6,7-benzomorfan , smp. l80-l83°C. n-butyl/-5,9-dimethyl-6,7-benzomorphan, m.p. 180-183°C.

IR pa^afin : l6°5'1582' 1500' 1210' ll47> 1043' 830 IR pa^afin : l6°5'1582' 1500' 1210' ll47> 1043' 830

Analyse, beregnet for C^gH^NO^F: Analysis, calculated for C^gH^NO^F:

C 73,38, H 7,58, N 3,29? C 73.38, H 7.58, N 3.29?

Funnet: C 73,51, H 7,62, N 3,25%. Found: C 73.51, H 7.62, N 3.25%.

(b) 2'- hydroksy- 2-/ y-( p- fluorbenzoyl)- n- propyl7-5, 9~ dimetyl- 6, 7- benzomorfan (b) 2'-hydroxy-2-[y-(p-fluorobenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan

En blanding av 2,4 g 2'-hydroksy-2-/4"-(p-fluorfenyl)-4",4"-etylendioksy-n-butyl7-5,9_diemtyl-6,7-benzomorfan, 20 ml metanol, 10 ml vann og 1,5 ml konsentrert saltsyre ble tilbakeløps-kokt i 1 time. Etter dette ble reaksjonsblandingen konsentrert under redusert trykk, blandingen gjort alkalisk med et overskudd av vandig ammoniakk og deretter ekstrahert med eter. Eterekstrak-tene ble vasket med vann, mettet med natriumklorid, tørket over vannfri natriumsulfat og så filtrert. Filtratet ble konsentrert til tørrhet, hvorved man fikk et råprodukt. Omkrystallisasjon fra etylacetat gir 2'-hydroksy-2-/y-(p-fluorbenzoyl)-n-propyl7-5,9_ dimetyl-6,7-benzomorfan, smp. l66-l69°C. A mixture of 2.4 g of 2'-hydroxy-2-[4"-(p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl 7-5,9_dimethyl-6,7-benzomorphan, 20 ml of methanol, 10 ml of water and 1.5 ml of concentrated hydrochloric acid were refluxed for 1 hour. After this, the reaction mixture was concentrated under reduced pressure, the mixture was made alkaline with an excess of aqueous ammonia and then extracted with ether. The ether extracts were washed with water, saturated with sodium chloride, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness to give a crude product. Recrystallization from ethyl acetate gives 2'-hydroxy-2-[y-(p-fluorobenzoyl)-n-propyl7-5, 9_ dimethyl-6,7-benzomorphan, mp 166-169°C.

IR pa£afin: 2600 (bredt)> 1690, 1598, 1582, 1222, 840, 769 IR pa£afin: 2600 (wide) > 1690, 1598, 1582, 1222, 840, 769

Analyse, beregnet for C2l{<H>2<gN0>2F: Analysis, calculated for C2l{<H>2<gN0>2F:

C 75,56, H 7,40, N 3,67? C 75.56, H 7.40, N 3.67?

Funnet: C 75,48, H 7,43, N 3,8l%. Found: C 75.48, H 7.43, N 3.81%.

Dette 6,7-benzomorfan ble oppløst i kloroform, hvoretter denne oppløsning ble tilført gassformet hydrogenklorid. Oppløsnings-midlet ble fjernet og resten omkrystallisert fra aceton - metanol. Dette hydroklorid hadde smp. på 213-215°C This 6,7-benzomorphan was dissolved in chloroform, after which gaseous hydrogen chloride was added to this solution. The solvent was removed and the residue recrystallized from acetone - methanol. This hydrochloride had m.p. at 213-215°C

-1 -1

IR iLSafMn : 2580' 2550> l690' l620' 15"> 1585' 150U» 1210' IR iLSafMn : 2580' 2550> l690' l620' 15"> 1585' 150U» 1210'

1204, 1148, 831. 1204, 1148, 831.

Analyse, beregnet for C2i)H2gN02CIF: Analysis, calculated for C2i)H2gN02CIF:

C 68,97, H 6,99, N 3,35, Cl 8,48% C 68.97, H 6.99, N 3.35, Cl 8.48%

Funnet: . C 68,98, H 7,19, N 3,63, Cl 8,27% Found: . C 68.98, H 7.19, N 3.63, Cl 8.27%

Eksempel 2 Example 2

2 - ly -( p- fluorbenzoyl)- n- propyl7- 5, 9~ dimetyl- 6, 7~ benzomorfan (a) 2- A"-( p- fluorfenyl)- 4", 4"- etylendioksy- n- butyl7-5 , 9~ dimetyl- 6, 7~ benzomorfan 2 - ly -( p- fluorobenzoyl)- n- propyl7- 5, 9~ dimethyl- 6, 7~ benzomorphan (a) 2- A"-( p- fluorophenyl)- 4", 4"- ethylenedioxy- n- butyl7 -5 , 9~ dimethyl- 6, 7~ benzomorphan

En blanding av 3 g 5,9-dimetyl-6,7-benzomorfan, 1,89 g natriumbikarbonat, 4,29 g 4-(p-fluorfenyl)-4,4-etylendioksyd-l-klorbutan og 30 ml etanol ble oppvarmet under tilbakeløp og om-røring i 6 timer. Blandingen ble konsentrert under redusert trykk inntil mesteparten av etanolen var fjernet, hvoretter vann ble tilsatt. Blandingen ble ekstrahert flere ganger med eter. A mixture of 3 g of 5,9-dimethyl-6,7-benzomorphan, 1.89 g of sodium bicarbonate, 4.29 g of 4-(p-fluorophenyl)-4,4-ethylenedioxide-1-chlorobutane and 30 ml of ethanol was heated under reflux and stirring for 6 hours. The mixture was concentrated under reduced pressure until most of the ethanol was removed, after which water was added. The mixture was extracted several times with ether.

De samlede ekstrakter ble vasket med vann mettet med natriumklorid, tørket over vannfri natriumsulfat og filtrert. Filtratet ble konsentrert, og resten ble destillert under redusert trykk, hvorved man fikk 4,75 g 2- H\"-p-fluorfenyl)-4",4"-etylendioksy-n-. butyl7-5)9-dimetyl-6,7-benzomorfan, kokepunkt 110-119° C7 0,8 mm Hg. The combined extracts were washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was distilled under reduced pressure to give 4.75 g of 2-H\"-p-fluorophenyl)-4",4"-ethylenedioxy-n-.butyl7-5)9-dimethyl-6 ,7-benzomorphan, boiling point 110-119° C7 0.8 mm Hg.

-1 -1

IR Uæg£e : 1605, 1508, 1217, 1150, 1040, 835 IR Uæg£e : 1605, 1508, 1217, 1150, 1040, 835

(b) 2- ly -( p- fluorbenzoyl)- n- propyl7- 5, 9~ dimety1- 6, 7-benzomorfan (b) 2- ly -(p-fluorobenzoyl)-n- propyl7-5,9~ dimethyl-6,7-benzomorphan

En blanding av 4,7 g 2-/4"-(p-fluorfenyl)-4",4"-etylendioksy-n-butyl7-5j9_dimetyl-6,7-benzomorfan, 50 ml metanol og 30 ml vann ble tilsatt 5 ml konsentrert saltsyre. Etter at den resulterende blanding var tilbakeløpskokt i 1 time, ble den konsentrert under redusert trykk til en rest, dette ble gjort alkalisk med vandig ammoniakk og så ekstrahert med eter. Eterekstraktet ble vasket med vann mettet med natriumklorid, tørket over vannfri natriumsulfat og filtrert. Filtratet ble konsentrert til en gul rest, og dette ble under redusert trykk destillert til 1,5 g 2-/y_(p-fluorbenzoyl)-n-propyl7-5,9"dimetyl-6,7-benzomorfan, kokepunkt l4o-150°C/0,5 mm Hg. A mixture of 4.7 g of 2-[4"-(p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl7-5j9_dimethyl-6,7-benzomorphan, 50 ml of methanol and 30 ml of water was added to 5 ml concentrated hydrochloric acid. After the resulting mixture was refluxed for 1 hour, it was concentrated under reduced pressure to a residue, which was made alkaline with aqueous ammonia and then extracted with ether. The ether extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a yellow residue, and this was distilled under reduced pressure to 1.5 g of 2-(γ_(p-fluorobenzoyl)-n-propyl7-5,9"dimethyl-6,7-benzomorphan, b.p. l4o-150°C/0.5 mm Hg.

-1 -1

IR |)æg™e : 1690, 1601, 1510, 1220 , 835, 760, 720 IR |)æg™e : 1690, 1601, 1510, 1220 , 835, 760, 720

En oppløsning av 2-/ y-(p-fluorbenzoyl)-n-propyl/-5,9_ dimetyl-6,7-benzomorfan i eter ble surgjort med gassformet hydrogenklorid. Bunnfallet ble oppsamlet ved filtrering og vasket med eter. A solution of 2-(γ-(p-fluorobenzoyl)-n-propyl)-5,9-dimethyl-6,7-benzomorphan in ether was acidified with hydrogen chloride gas. The precipitate was collected by filtration and washed with ether.

Rekrystallisasjon fra eter - aceton gir 2- ly-(p-fluor-benzoyl )-n-propyl7-5,9-dimetyl-6,7-benzomorfan-hydroklorid, smp. 164-166°C. Recrystallization from ether - acetone gives 2-ly-(p-fluoro-benzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan hydrochloride, m.p. 164-166°C.

-1 -1

IR parafin: 2350 (bredt)3 l68o> l600, 1508, 832, 760, 750, 720. IR paraffin: 2350 (broad)3 l68o> l600, 1508, 832, 760, 750, 720.

Analyse, beregnet- for Cpi|H2gN0CIF: Analysis, calculated- for Cpi|H2gN0CIF:

C 71,72, H 7,27, N 3,48, Cl 8,82% C 71.72, H 7.27, N 3.48, Cl 8.82%

Funnet: C 71,42, H 7,40, N 3,39, Cl 8, 77%. Found: C 71.42, H 7.40, N 3.39, Cl 8, 77%.

Eksempel 3 Example 3

2'- hydroksy- 2-/ y-( p- fluorbenzoyl)- n- propyl7- 5- metyl- 9~ ety1-6, 7- benzomorfan 2'- hydroxy- 2-/ y-( p- fluorobenzoyl)- n- propyl7- 5- methyl- 9~ ethyl1-6, 7- benzomorphan

( a) 2 '-hydroks y- 2-/^ i"-( p- f luorf enyl)- 4" , 4 "- etylendioksy-n- butyl/- 5- metyl-9~ etyl- 6, 7- benzomorfan (a) 2'-Hydrox y- 2-/^ i"-(p- fluorophenyl)- 4" , 4 "- ethylenedioxy-n-butyl/- 5- methyl-9~ ethyl- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel 1 (a) ble 2,31 g 2'-hydroksy-5-metyl-9-ety1-6,7-benzomorfan omsatt med 2,56 g 4-(p-fluorfenyl)-4,4-etylendioksy-l-klorbutan, og dette ga 2'-hydroksy-2-/4"-(p-fluorfenyl)-4",4"-etylendioksy-n-butyl7-5-metyl-9_etyl-6,7-benzomorfan, smp. l6l-l67°C. En rekrystallisasjon fra etylacetat hever smeltepunktet til 170-171°C. According to the method described in example 1 (a), 2.31 g of 2'-hydroxy-5-methyl-9-ethyl-6,7-benzomorphan was reacted with 2.56 g of 4-(p-fluorophenyl)-4 ,4-ethylenedioxy-1-chlorobutane, and this gave 2'-hydroxy-2-[4"-(p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9_ethyl-6,7 -benzomorphan, mp 161-167° C. A recrystallization from ethyl acetate raises the melting point to 170-171° C.

-1 -1

IR pa?afin: l615' l6°5> 1579' 835> 794 IR pa?afin: l615' l6°5> 1579' 835> 794

Analyse, beregnet for C^H^NO^F: Analysis, calculated for C^H^NO^F:

C 73, 77, -:H 7,80, N 3,19% Funnet: C 73,58, H 7,78, N 3,52% (b) 2'- hydroks y- 2-/ y-(p- fluorbenzoyl)- n- propyl7-5- metyl- 9~ ety1- 6, 7- benzomorfan C 73, 77, -:H 7.80, N 3.19% Found: C 73.58, H 7.78, N 3.52% (b) 2'-hydroxy y- 2-/ y-(p - fluorobenzoyl)- n- propyl7-5- methyl- 9~ ethyl1- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel 1 (b), ble 2'-hydroksy-2-/4"-(p-fluorfenyl)-4",4"-etylendioksy-n-butyl7-5-metyl-9-ety1-6,7-benzomorfan omdannet til 2'-hydroksy-2-/y-(p-fluorbenzoyl)-n-propyl7-5-metyl-9-etyi-6,7-benzomorfanhydro-klorid, l60-l65°C. According to the method described in example 1 (b), 2'-hydroxy-2-[4"-(p-fluorophenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9-ethyl -6,7-benzomorphan converted to 2'-hydroxy-2-[y-(p-fluorobenzoyl)-n-propyl7-5-methyl-9-ethyl-6,7-benzomorphan hydrochloride, 160-165°C.

-1 -1

IR paJafin: l692> l620' 1597> 1582' 1500' 838 IR paJafin: l692> l620' 1597> 1582' 1500' 838

Analyse, beregnet for C0£-H-,, NO ^CIF: Analysis, calculated for C0£-H-,, NO ^CIF:

C 69,82, H 7,23, N 3,24% C 69.82, H 7.23, N 3.24%

Funnet: C 69,78, H 7,29, N 3,29$ ' Eksempel 4 Found: C 69.78, H 7.29, N 3.29$ ' Example 4

2 ' - hydroksy- 2- / y- ( p- klorbenzoyl) - n- propy 1 / - 2 ' - hydroxy- 2- / y - (p- chlorobenzoyl) - n- propy 1 / -

5, 9- dimetyl- 6, 7~ benz6morfan 5, 9- dimethyl- 6, 7~ benz6morphan

(a) ' 2 1 -hyd roksy- 2- / 4 "- ( p- klorf eny 1) - 4 4 "-etylendioksy-n- buty1/- 5 3 9- dimetyl- 6, 7~ benzomorfan (a) ' 2 1 -hydroxy- 2- / 4 "- ( p- chloropheny 1)- 4 4 "-ethylenedioxy-n- buty1/- 5 3 9- dimethyl- 6, 7~ benzomorphan

En blanding av 2,17 g 2'-hydroksy-5>9-dimetyl-5,7~ benzomorfan, 1,26 g na triumbikarbonat, 30 ml dimetylformamid og 3,29 g 4-(p-klorfenyl)-4,4-etylendioksy-1-kiorbutan omrørt ved 130-140°C i 3 timer. Oppløsningsmidiet ble fjernet under redusert trykk til en rest som ble tilsatt vann. Det frembragte funnfall ble oppsamlet ved filtrering og omkrystallisert fra eter - metanol til 2'-hydroksy-2-/4"-(p-klorfenyl)-4",4"-etylendioksy-n-butyl7-5,9-dimetyl-6,7-benzomorfan, smp. l69-170°C. A mixture of 2.17 g of 2'-hydroxy-5>9-dimethyl-5,7~ benzomorphan, 1.26 g of sodium bicarbonate, 30 ml of dimethylformamide and 3.29 g of 4-(p-chlorophenyl)-4,4 -ethylenedioxy-1-chlorobutane stirred at 130-140°C for 3 hours. The dissolution medium was removed under reduced pressure to a residue to which water was added. The precipitate produced was collected by filtration and recrystallized from ether - methanol to 2'-hydroxy-2-[4"-(p-chlorophenyl)-4",4"-ethylenedioxy-n-butyl7-5,9-dimethyl-6 ,7-benzomorphan, mp 169-170°C.

-1 -1

IR : 2650 (bredt), 1620, 1603, 1585, 1495, 1225, 1047, 830 Uul di -LII Analyse, beregnet for CpgH-j^NOCl: C 70,65, H 7,30, N 3,17, Cl 8,02% ' Funnet: C 70,65, H 7,27, N 3,14, Cl 8,23% (b) 2'- hydroksy-2-/ y-( p- klorbenzoyl)- n- propyl7-5, 9- dimetyl- 6, 7- benzomorfan IR : 2650 (broad), 1620, 1603, 1585, 1495, 1225, 1047, 830 Uul di -LII Analysis, calculated for CpgH-j^NOCl: C 70.65, H 7.30, N 3.17, Cl 8.02% ' Found: C 70.65, H 7.27, N 3.14, Cl 8.23% (b) 2'-hydroxy-2-/y-(p-chlorobenzoyl)-n-propyl7-5,9- dimethyl- 6, 7- benzomorphan

En blanding av 3,65 g 2'-hydroksy-2-/4"-(p-klorfenyl)-4",4"-etylendioksy-n-butyl7-5,9-dimetyl-6,7-benzomorfan, 50 ml metanol og 30 ml vann ble tilsatt 5 ml konsentrert saltsyre. Etter at den resulterende blanding var tilbakeløpskokt i 1 time, ble den under redusert trykk konsentrert til et residuum, dette ble gjert alkalisk med et overskudd av vandig ammoniakk og ekstrahert med eter. Den organiske oppløsning ble vasket med vann, tørket ever vannfri natriumsulfat og filtrert. Filtratet ble konsentrert til et fast stoff. Omkrystallisasjon fra eter - aceton gir 2'-hydroksy-2-/y-(p-klorbenzoyl)-n-propyl7-5,9~dimety1-6,7-benzomorfan, smp. 179-l8l°C. A mixture of 3.65 g of 2'-hydroxy-2-[4"-(p-chlorophenyl)-4",4"-ethylenedioxy-n-butyl7-5,9-dimethyl-6,7-benzomorphan, 50 ml methanol and 30 ml of water was added to 5 ml of concentrated hydrochloric acid. After the resulting mixture was refluxed for 1 hour, it was concentrated under reduced pressure to a residue, which was made alkaline with an excess of aqueous ammonia and extracted with ether. The organic solution was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to a solid. Recrystallization from ether - acetone gives 2'-hydroxy-2-[y-(p-chlorobenzoyl)-n-propyl7-5,9 ~dimethyl1-6,7-benzomorphan, mp 179-181°C.

IR U CnV : 2600 (bred), 1690, 1625, 1590, 1.495., 1235, 1216, parafin ' ' IR U CnV : 2600 (wide), 1690, 1625, 1590, 1.495., 1235, 1216, paraffin ' '

1083-, 766 1083-, 766

Analyse, beregnet for C2^H?<gN0?Cl>Analysis, calculated for C2^H?<gN0?Cl>

C 72 , 44 , K 7,09, N 3,52, Cl -8,91% C 72 , 44 , K 7.09, N 3.52, Cl -8.91%

Funnet: C. 72,17, H 7,25, N 3,89, Cl 8,86% Found: C. 72.17, H 7.25, N 3.89, Cl 8.86%

Den frie base ble omdannet til bydrokloridet ved en kontakt med tørr, gassformet hydrogenklorid. Bunnfallet ble oppsamlet ved filtrering og vasket med eter. Omkrystallisasjon fra metanol - aceton går 2'-hydroksy-2-/y-(p-klorbenzoyl)-n-propyl~-5 , 9-dimetyl-6,7-benzomorfan-hydroklorid, 191-192°C. The free base was converted to the byhydrochloride by contact with dry, gaseous hydrogen chloride. The precipitate was collected by filtration and washed with ether. Recrystallization from methanol - acetone gives 2'-hydroxy-2-[y-(p-chlorobenzoyl)-n-propyl~-5,9-dimethyl-6,7-benzomorphan hydrochloride, 191-192°C.

IR pa£afin: 255°' 1685' 16165 1590j 157°' 15°5' 1230' 108l> 8l0' 757 IR pa£afin: 255°' 1685' 16165 1590j 157°' 15°5' 1230' 108l> 8l0' 757

Analyse, beregnet for C^H^NC^Cl: Analysis, calculated for C^H^NC^Cl:

C 66,36, H 6,73, N 3,22, Cl 16,32% C 66.36, H 6.73, N 3.22, Cl 16.32%

Funnet: C 65,86, H 6,96, N 3,52, Cl 16,73% Found: C 65.86, H 6.96, N 3.52, Cl 16.73%

E ksempel 5 Example 5

2'- hydroksy- 2-/ y-( p- metoksybenzoyl)- n- propy1/- 5, 9~ dimetyl-6 , 7~ benzomorfan 2'- hydroxy- 2-/ y-( p- methoxybenzoyl)- n- propy1/- 5, 9~ dimethyl-6 , 7~ benzomorphan

(a) 2'- hydroksy- 2-/ 4"-( p- metoksyfenyl)- 4", 4"- etylendioksy-n- butyl7- 5, 9~ dimetyl- 6, 7- benzomorfan (a) 2'- hydroxy- 2-/ 4"-( p- methoxyphenyl)- 4", 4"- ethylenedioxy-n-butyl7- 5, 9~ dimethyl- 6, 7- benzomorphan

En oppløsning av 2,17 g 2'-hydroksy-5,9_dimetyl-6,7-benzomorfan i 30 ml dimetylformamid ble tilsatt 1,2 g natriumbikarbonat og 2,7 g 4-(p-metoksyfenyl)-4,4-etylendioksy-1-klorbutan. Blandingen ble rørt ved 120-l40°C i 2 timer. Oppløsningsmidlet ble fordampet under redusert trykk, hvoretter vann ble tilsatt. Etter at blandingen var hensatt i et kjøleskap, ble bunnfallet oppsamlet ved filtrering og rekrystallisert fra etylacetat, hvorved man fikk 2'-hydroksy-2-/3"-(p-metoksyfenyl)-4",4"-etylendioksy-n-buty1/-5,9~ dimetyl-6 , 7-benzomorf an ,. smp. 156-158,5°C To a solution of 2.17 g of 2'-hydroxy-5,9_dimethyl-6,7-benzomorphan in 30 ml of dimethylformamide was added 1.2 g of sodium bicarbonate and 2.7 g of 4-(p-methoxyphenyl)-4,4-ethylenedioxy -1-chlorobutane. The mixture was stirred at 120-140°C for 2 hours. The solvent was evaporated under reduced pressure, after which water was added. After the mixture was placed in a refrigerator, the precipitate was collected by filtration and recrystallized from ethyl acetate to give 2'-hydroxy-2-[3"-(p-methoxyphenyl)-4",4"-ethylenedioxy-n-buty1 /-5,9~ dimethyl-6,7-benzomorph an,.mp 156-158.5°C

-1 -1

IR u cmf>. : 2650 (bred),. 1615, 1580, 1515, 1500,' 1245 , 1050 , 830 IR u cmf>. : 2650 (wide),. 1615, 1580, 1515, 1500,' 1245 , 1050 , 830

p cLPS lin on cLPS linen

Analyse, beregnet for C^H^NO^: Analysis, calculated for C^H^NO^:

C 74,11, H 8,06, N 3,20% Funnet: C 73,74, H 8,20, N 3,60% (b) 2'- hydroksy- 2-/ y-( p- metoksybenzoyl)- n- propy 17-5, 9- dimetyl- 6, 7- benzomorfan C 74.11, H 8.06, N 3.20% Found: C 73.74, H 8.20, N 3.60% (b) 2'-hydroxy-2-/y-(p-methoxybenzoyl) - n- propy 17-5, 9- dimethyl- 6, 7- benzomorphan

En blanding av 2,0 g 2'-hydroksy-2-/4"-(p-metoksyfenyl)-4",4"-etylendioksy-n-butyl7-5,9-dimetyl-6,7-benzomorfan, 20 ml metanol og 10 ml vann ble tilsatt 1,5 ml konsentrert saltsyre. , Blandingen ble oppvarmet under røring i 1 time. Den ble så konsentrert under redusert trykk for å fjerne .metanolen.og deretter gjort alkalisk-médi-vandig^ ammoniakk. Den ble så ekstrahert med kloroform. Ekstraktet ble vasket med vann mettet med natriumklorid, tørket over vannfri natriumsulfat og filtrert. Oppløsningsmidlet ble fjernet, hvorved man fikk et råprodukt. Rekrystallisasjon fra etylacetat gir 2'-hydroksy-2-/y-(p-metoksybenzoyl)-n-propy1/-5,9-dimet,v 1-6,7-benzomorfan, smp. 148-152,8°C. A mixture of 2.0 g of 2'-hydroxy-2-[4"-(p-methoxyphenyl)-4",4"-ethylenedioxy-n-butyl7-5,9-dimethyl-6,7-benzomorphan, 20 ml methanol and 10 ml of water was added to 1.5 ml of concentrated hydrochloric acid. , The mixture was heated with stirring for 1 hour. It was then concentrated under reduced pressure to remove the methanol and then made alkaline-medi-aqueous ammonia. It was then extracted with chloroform. The extract was washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate and filtered. The solvent was removed to give a crude product. Recrystallization from ethyl acetate gives 2'-hydroxy-2-[y-(p-methoxybenzoyl) -n-propyl/-5,9-dimeth,v 1-6,7-benzomorphan, mp 148-152.8°C.

-1 -1

IR parafin'' 2650 (bred)> l68o> l6o°» !580, 1500, 1255, Il60, IR paraffin'' 2650 (broad)> l68o> l6o°» !580, 1500, 1255, Il60,

1020, 820, 760 1020, 820, 760

Analyse, beregnet for C^n^NO-^: Analysis, calculated for C^n^NO-^:

C 76,30, H 7,94, N 3,56% C 76.30, H 7.94, N 3.56%

Funnet: C 76,16, H 7,88, N 3,42% Found: C 76.16, H 7.88, N 3.42%

E ksempel 6 Example 6

2'- hydroksy- 2-/ y-( p- metyIbenzoyl)- n- propy17-5, 9~ dimetyl- 6, 7~ benzomorfan 2'-hydroxy-2-/y-(p-methylbenzoyl)-n-propyl 17-5, 9~ dimethyl- 6, 7~ benzomorphan

( a) 2'- hydroksy- 2-/ 4"-( p- metylfenyl)- 4", 4"- etyle ndioksy-n- butyl7-5,9- dimetyl- 6, 7- benzomorfan (a) 2'- hydroxy- 2-/ 4"-( p- methylphenyl)- 4", 4"- ethylenedioxy-n-butyl7-5,9- dimethyl- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i' eksempel 1 According to the method described in example 1

(a) og ved å bruke 2,17 g 2'-hydroksy-5,9-dimetyl-6,7-benzomorfan, 1,2 g natriumbikarbonat,' 30 ml dimetylformamid og 2,06 g 4-(p-metyl-fenyl)-4,4-etylendioksy-1-klorbutan, fikk man fremstilt et" råprodukt av '2 ' - hydroksy- 2-/4"- (p-metylf enyl)-4"', 4"-etylendioksy-n-butyl7-5,9_dimetyl-6,7-benzomorfan. - Rekrystallisasjori av dette råprodukt fra etylacetat gir rene krystaller av 2'-hydroksy-2-/<4>"-(p-metylfenyl)-4",4"-etylendioksy-n-butyl7-5,9"dimety1-6,7-benzomorfan med et smp. fra 173 til 176°C. (a) and using 2.17 g of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan, 1.2 g of sodium bicarbonate,' 30 ml of dimethylformamide and 2.06 g of 4-(p-methyl- phenyl)-4,4-ethylenedioxy-1-chlorobutane, a "crude product of '2'-hydroxy-2-/4"-(p-methylphenyl)-4"', 4"-ethylenedioxy-n- butyl7-5,9_dimethyl-6,7-benzomorphan. - Recrystallization of this crude product from ethyl acetate gives pure crystals of 2'-hydroxy-2-/<4>"-(p-methylphenyl)-4",4"-ethylenedioxy-n-butyl7-5,9"dimethyl1-6, 7-benzomorphan with a m.p. from 173 to 176°C.

-1 -1

IR paJafirr .265° ^ hred\ > l6l'5> 1.580 , 1505, 1240 , 1050 , 820 IR paJafirr .265° ^ hred\ > l6l'5> 1.580 , 1505, 1240 , 1050 , 820

Analyse, beregnet for C2<yH>^^<N>0,^:Analysis, calculated for C2<yH>^^<N>0,^:

C 7 6,92, H 8,37, N 3,32? C 7 6.92, H 8.37, N 3.32?

Funnet: C 7 6,84, H 8', 55, N 3,82%. Found: C 7 6.84, H 8', 55, N 3.82%.

( b) 2'- hydroksy- 2-/ y-( p- metyIbenzoyl)- n- propyl7- 5, 9~ (b) 2'-hydroxy-2-[y-(p-methylbenzoyl)-n-propyl7-5,9~

dImetyl- 6, 7- benzomorfan Dimethyl-6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel l(b), men ved å bruke 2,5 g 2'-hydroksy-2-/4"-(p-metylfenyl)-4",4"-etylendioksy-n-butyl7-5,9-dimetyl-6,7-benzomorfan fikk man fremstilt et råprodukt som ble rekrystallisert fra etylacetat, hvorved man fikk rene krystaller av 2'-hydroksy-2-/y-(p-metyIbenzoyl)-n-propyl/- 5-, 9- d.Trrio.ty '!■- b-orvz-omo r Pan , snrp-. F 5 7, 5~'-&}-, 5<:>>C. According to the method described in example 1(b), but using 2.5 g of 2'-hydroxy-2-[4"-(p-methylphenyl)-4",4"-ethylenedioxy-n-butyl7- 5,9-dimethyl-6,7-benzomorphan, a crude product was produced which was recrystallized from ethyl acetate, thereby obtaining pure crystals of 2'-hydroxy-2-[y-(p-methylbenzoyl)-n-propyl]- 5 -, 9- d.Trrio.ty '!■- b-orvz-omo r Pan , snrp-. F 5 7, 5~'-&}-, 5<:>>C.

-1 -1

^a^afin: 2600 ttreå), I063, 1610 ,.1580, 1498, 1233, 800, 765. ^a^afin: 2600 ttreå), I063, 1610 ,.1580, 1498, 1233, 800, 765.

Analyse, beregnet for C„-H^ -, N0o : Analysis, calculated for C„-H^ -, N0o :

C'79,53, K 8,28, N 3,71% C'79.53, K 8.28, N 3.71%

Funnet: C 79,45, K 8,25, N 3,30% Found: C 79.45, K 8.25, N 3.30%

Eksempel 7 Example 7

2'- hydroksy- 2-/ y-( p- trifluormetyIbenzoyl)- n- propyI/- 5 , 9- dimetyl - 6 , 7- benzqraorfan 2'-hydroxy-2-[y-(p-trifluoromethylbenzoyl)-n-propyl]-5,9-dimethyl-6,7-benzqraorphan

En blanding av 1,19 g 2'-hydroksy-5,9_dimetyl-6,7-benzomorf an, 0,6 g natriumbikarbonat, 1,77 g 4-(p-trlfluormetylfenyl)-4,4-etylendioksy-1-klorbutan og 15 ml dimetylformamid ble rørt ved 130-1M5°C i 3 timer. Reaks.j onsblandingen ble så konsentrert under redusert trykk inntil mesteparten av dimetylformamidet var fjernet, hvoretter vann ble tilsatt og det. hele ekstrahert med eter. Eterekstraktet ble vasket med vann, tørket over vannfri natriumsulfat og filtrert. Filtratet ble så behandlet med avfargende trekull og konsentrert under redusert trykk. Den gjenværende olje ble oppløst i varm, vandig metanol og så behandlet med konsentrert saltsyre til pH 1. Oppløsningen ble så refluksert i 1 time, og deretter behandlet med trekull og igjen filtrert. Filtratet ble konsentrert under redusert trykk, gjort alkalisk med vandig ammoniakk, og ekstrahert med kloroform. Ekstraktet ble vasket med vann, tørket over vannfri natriumsulfat, filtrert og konsentrert til et amorft residuum. Dette residuum ble kromatografert på en silisiumdioksydgel-kolonne med etylacetat til et råprodukt. Dette råprodukt ble rekrystallisert fra etylacetat til 2'-hydroksy-2-/y-(p-trifluormetyIbenzoyl)-n-propyl/-5,9-dimetyl-6,7-benzomorfan, smp. 116,5-120°C. A mixture of 1.19 g of 2'-hydroxy-5,9-dimethyl-6,7-benzomorph ane, 0.6 g of sodium bicarbonate, 1.77 g of 4-(p-trifluoromethylphenyl)-4,4-ethylenedioxy-1-chlorobutane and 15 ml of dimethylformamide was stirred at 130-1M5°C for 3 hours. The reaction mixture was then concentrated under reduced pressure until most of the dimethylformamide was removed, after which water was added and the whole extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was then treated with decolorizing charcoal and concentrated under reduced pressure. The remaining oil was dissolved in hot aqueous methanol and then treated with concentrated hydrochloric acid to pH 1. The solution was then refluxed for 1 hour, and then treated with charcoal and again filtered. The filtrate was concentrated under reduced pressure, made alkaline with aqueous ammonia, and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to an amorphous residue. This residue was chromatographed on a silica gel column with ethyl acetate to a crude product. This crude product was recrystallized from ethyl acetate to give 2'-hydroxy-2-[y-(p-trifluoromethylbenzoyl)-n-propyl]-5,9-dimethyl-6,7-benzomorphan, m.p. 116.5-120°C.

- ]_ - ]_

IR v c?%. : 1690, 1512 , 1578, 1128, 1065, 1015, 830 IR v c?%. : 1690, 1512 , 1578, 1128, 1065, 1015, 830

parafin ' ' ' ' 5 ' kerosene ' ' ' ' 5 '

Analyse, beregnet for C25<H>28<M>°2<F>3<:>Analysis, calculated for C25<H>28<M>°2<F>3<:>

C 69,59 , H 6,54, 3,25%- C 69.59 , H 6.54, 3.25%-

Funnet: C 69,81, H 6,73, 3,40% Found: C 69.81, H 6.73, 3.40%

Eksempel 8 Example 8

2'- hydroksy- 2-/ y-( p- metoksybenzoyl)- n- propyl7- 5~ metyl-9~ etyl- 6, 7- benzomorfan 2'- hydroxy- 2-/ y-( p- methoxybenzoyl)- n- propyl7- 5~ methyl-9~ ethyl- 6, 7- benzomorphan

(a) 2 '- hydroksy- 2- / 4"-( p- metoksyf enyl)- 4", 4 "- etyler. di oksy-n- butyl/- 5- metyl- 9- etyl- 6, 7- benzomorfan (a) 2 '- hydroxy- 2- / 4"-( p- methoxy phenyl)- 4", 4 "- ethyl. dioxy-n- butyl /- 5- methyl- 9- ethyl- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel '5(a), gir en omsetning av 2'-hydroksy-5-metyl-9-etyl-6,7-benzomorfan (2,3 g) med 2,7 g 4t(p-metoksyfenyl)-4,4-etylendioksy-l-klorbutan,-2'-hydroksy-2-/^i"-( p-metoksyf enyl )-4", 4 "-etylendioksy-n-"outyl7-5-metyl-9-etyl-6,7-benzomorf an, smp. l4o-l42°C. According to the method described in example '5(a), a reaction of 2'-hydroxy-5-methyl-9-ethyl-6,7-benzomorphan (2.3 g) with 2.7 g of 4t(p -methoxyphenyl)-4,4-ethylenedioxy-1-chlorobutane,-2'-hydroxy-2-[i"-(p-methoxyphenyl)-4",4"-ethylenedioxy-n-"outyl7-5-methyl -9-ethyl-6,7-benzomorph an, m.p. 140-142°C.

IR paSfin: 2650> 2550> l6l3> 158o> 1510' V497> 125?> 1053>IR paSfin: 2650> 2550> l6l3> 158o> 1510' V497> 125?> 1053>

1038, 836. 1038, 836.

Analyse, beregnet for CggH^NC^: Analysis, calculated for CggH^NC^:

C 74,47, H 8,26, N 3,105! C 74.47, H 8.26, N 3.105!

Funnet: C 74,69, H 8,24, N 3,4355 Found: C 74.69, H 8.24, N 3.4355

(b) 2'- hydroksy- 2-/ y-( p- metoksybenzoyl)- n- propyl7-5- metyl- 9- etyl- 6, 7- benzomorfan (b) 2'-hydroxy-2-[y-(p-methoxybenzoyl)-n-propyl7-5-methyl-9-ethyl-6,7-benzomorphan

Ved å underkaste 2'-hydroksy-2-/4"-(p-metok3yfenyl)-4",4"-etylendioksy-n-butyl7-5-metyl-9-etyl-6,7-benzomorfan den fremgangsmåte som er beskrevet i eksempel 5 (b), fikk man fremstilt et råprodukt, og dette ble omkrystallisert fra metanol - aceton, hvorved man fikk rene krystaller av 2'-hydroksy-2-/y-(p-metoksy-benzoyl )-n-propyl7-5~metyl-9-etyl-6,7-benzomorfan-hydroklorid, By subjecting 2'-hydroxy-2-(4"-(p-methoxyphenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9-ethyl-6,7-benzomorphan to the procedure described in example 5 (b), a crude product was prepared, and this was recrystallized from methanol - acetone, whereby pure crystals of 2'-hydroxy-2-[y-(p-methoxy-benzoyl)-n-propyl7- 5-methyl-9-ethyl-6,7-benzomorphan hydrochloride,

smp. 148,5-150°C. m.p. 148.5-150°C.

TR pa°afin: l675s l6l2j 1598' 1570' 1510j l5°K TR pa°afin: l675s l6l2j 1598' 1570' 1510j l5°K

Analyse, beregnet for C^gH^NO^Cl: Analysis, calculated for C^gH^NO^Cl:

C 70,33, H 7,72, N 3,15* ;Funnet: C 70,14, H 7,77, N 3,14* C 70.33, H 7.72, N 3.15* ;Found: C 70.14, H 7.77, N 3.14*

På lignende måte som angitt ovenfor oppnås 2'-hydroksy-2/y-(2,4-difluorbenzoyl)-n-propyl7-5,9-dimetyl-6,7-benzomorfan, In a similar manner as stated above, 2'-hydroxy-2H-(2,4-difluorobenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan is obtained,

smp. 190-193°C m.p. 190-193°C

Eksempel 9 Example 9

2'- hydroksy- 2-/ 5-( p- fluorbenzoyl)- n- butyl7- 5, 9- dimetyl-6, 7- benzomor<f>an 2'- hydroxy- 2-/ 5-( p- fluorobenzoyl)- n- butyl7- 5, 9- dimethyl-6, 7- benzomor<f>an

En blanding av 2,17 g 2l<->hydroksy-5,9-aimetyl-6,7-benzc-morfan, 1,26 g natriumbikarbonat, 3,88 g 5-(p-fluorfenyl;-5,5-etylendioksy-l-klorpentan og 30 ml dimetylformamid ble omrørt ved 125-130°C i 4 timer. Blandingen ble konsentrert under redusert trykk inntil dimetylformamidet var fjernet, vann ble tilsatt og det hele ble ekstrahert med eter. Ekstraktet ble vasket med vann, tørket over vannfri natriumsulfat og filtrert. Filtratet ble konsentrert under redusert trykk til tørrhet. Den oppnådde rest ble brukt uten rensing. En blanding av 4,0 g 2'-hydroksy-2-/5"-(p-fluorfenyl)-5" ,5"-etylendioksy-n-pentyl7-5,9-dimetyl-6,7-benzomorfan, 50 ml metanol og 30 ml vann ble tilsatt 5 ml konsentrert saltsyre. Blandingen ble kokt i 1 time, behandlet med avfargede trekull og filtrert varmt. Filtratet ble fordampet til tørrhet under redusert trykk. En behandling av residuet med eter gir råprodukt av 2'-hydroksy-2-/6-(p-fluorbenzoyl)-n-butyl7-5,9-dimetyl-6,7-benzomorfan-hydroklorid. Rekrystallisasjon fra metanol - aceton gir rene krystaller av 2'-hydroksy-2-/6-(p-fluorbenzoyl)-n-butyl7-5,9-dimetyl-6,7-benzomorfan-hydroklorid, smp. 229-231°C. A mixture of 2.17 g of 2l<->hydroxy-5,9-aimethyl-6,7-benzc-morphane, 1.26 g of sodium bicarbonate, 3.88 g of 5-(p-fluorophenyl;-5,5-ethylenedioxy -1-chloropentane and 30 ml of dimethylformamide were stirred at 125-130°C for 4 hours. The mixture was concentrated under reduced pressure until the dimethylformamide was removed, water was added and the whole was extracted with ether. The extract was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to dryness. The residue obtained was used without purification. A mixture of 4.0 g of 2'-hydroxy-2-(5"-(p-fluorophenyl)-5" ,5 "-ethylenedioxy-n-pentyl7-5,9-dimethyl-6,7-benzomorphane, 50 ml of methanol and 30 ml of water were added to 5 ml of concentrated hydrochloric acid. The mixture was boiled for 1 hour, treated with decolorized charcoal and filtered hot. The filtrate was evaporated to dryness under reduced pressure.Treatment of the residue with ether gives crude product of 2'-hydroxy-2-(p-fluorobenzoyl)-n-butyl 7-5,9-dimethyl-6,7-benzomorphan hydrochloride .Recrystallization from methanol - acetone gives pure crystals of 2'-hydroxy-2-/6-(p-fluorobenzoyl)-n-butyl7-5,9-dimethyl-6,7-benzomorphan hydrochloride, m.p. 229-231°C.

IR parafin: 2675> l68o> l6o8> 1590> l498> 1215> 1200> ll6o> 993> 8M5 IR paraffin: 2675> l68o> l6o8> 1590> l498> 1215> 1200> ll6o> 993> 8M5

Analyse, beregnet for C^H-^NC^CIF: Analysis, calculated for C^H-^NC^CIF:

C 69,51, H 7,25, N 3,24, Cl 8,21% C 69.51, H 7.25, N 3.24, Cl 8.21%

Funnet: C 69,66, H 7,38, N 3,27, Cl 8,13% Found: C 69.66, H 7.38, N 3.27, Cl 8.13%

På lignende måte som angitt ovenfor oppnås 2'-hydroksy-2 ly-(p-hydroksybenzoyl)-n-propyl7-5,9-dimetyl-6,7-benzomorfan, In a similar manner as stated above, 2'-hydroxy-2-ly-(p-hydroxybenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan is obtained,

smp. 236°C (dekomp.). m.p. 236°C (decomp.).

E ksempel 10 Example 10

2'- hydroksy- 2-/ 6-( p- metoksybenzoyl)- n- butyl7- 5, 9~ 2'- hydroxy- 2-/ 6-( p- methoxybenzoyl)- n- butyl7- 5, 9~

dimetyl- 6, 7~ benzomorfan dimethyl- 6, 7~ benzomorphan

(a) 2'- hydroksy- 2-/ 5"-( p- metoksyfenyl)- 5", 5"- etylendioksy-n- pentyl7~ 5, 9- dimetyl- 6, 7~ benzomorfan (a) 2'- hydroxy- 2-/ 5"-( p- methoxyphenyl)- 5", 5"- ethylenedioxy-n-pentyl7~ 5, 9- dimethyl- 6, 7~ benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel 9, men ved å anvende 5-(p-metoksyfenyl)-5,5-etylendioksy-l-klorpentan, fikk man fremstilt 2'-hydroksy-2-/5"_(p-metoksyfenyl)~5",5"_etylen-dioksy-n-pentyl7-5,9-dimetyl-6,7-benzomorfan, smp. 175-177°C. According to the method described in example 9, but by using 5-(p-methoxyphenyl)-5,5-ethylenedioxy-1-chloropentane, 2'-hydroxy-2-[5"_(p-methoxyphenyl )~5",5"_ethylene-dioxy-n-pentyl7-5,9-dimethyl-6,7-benzomorphan, m.p. 175-177°C.

IR parafin: 2600' 1620' 1597> 15lH' lH97> 1179' 1038' 9?8' 850' 808 IR kerosene: 2600' 1620' 1597> 15lH' lH97> 1179' 1038' 9?8' 850' 808

Analyse, beregnet for C^<H->^NO^: Analysis, calculated for C^<H->^NO^:

C 74,47, H 8,26, N 3,10% C 74.47, H 8.26, N 3.10%

Funnet: C 74,63, H 8,10, N 2,17% (b) 2'- hydroksy-2-/ 6-( p- metoksybenzoy1)- n- butyl7-5, 9- dimetyl- 6, 7- benzomorfan Found: C 74.63, H 8.10, N 2.17% (b) 2'- hydroxy-2-/ 6-( p- methoxybenzoy1)- n- butyl7-5, 9- dimethyl- 6, 7- benzomorphan

Ved å anvende den fremgangsmåte som er beskrevet i eksempel 9, men ved å bruke 2'-hydroksy-2-/5"-(p-metoksyfenyl)-5",5"-etylendioksy-n-pentyl7-5,9"-dimetyl-6,7-benzomorfan, fikk man fremstilt et råprodukt som ble rekrystallisert fra n-butanol, hvorved man fikk rent 2<1->hydroksy-2-/6-(p-metoksybenzoyl)-n-butyl7-5,9~ dimetyl-6,7-benzomorfan, smp. l8l-l82°C. Using the method described in Example 9, but using 2'-hydroxy-2-[5"-(p-methoxyphenyl)-5",5"-ethylenedioxy-n-pentyl7-5,9"- dimethyl-6,7-benzomorphan, a crude product was produced which was recrystallized from n-butanol, whereby pure 2<1->hydroxy-2-/6-(p-methoxybenzoyl)-n-butyl7-5,9 ~ dimethyl-6,7-benzomorphan, m.p. 181-182°C.

-1 -1

IR parafin1 26°0' l668> 1592' 1569' l<i>t95' 1169' 1032> 971>IR paraffin1 26°0' l668> 1592' 1569' l<i>t95' 1169' 1032> 971>

844, 800 844, 800

Analyse, beregnet for C2gH-^NO ^: Analysis, calculated for C2gH-^NO^:

C 76,62, H 8,61, N 3,44% C 76.62, H 8.61, N 3.44%

Funnet: C 76,19, H 8,48, N 3,60% Found: C 76.19, H 8.48, N 3.60%

Eksempel 11 Example 11

2 '- hydroksy- 2-/ y-( 3, 4- dimetoksybenzoyl)- n- propyl7-5 , 9- dimetyl- 6, 7- benzomorfan 2'-hydroxy-2-[y-(3,4-dimethoxybenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan

( a) 2'- hydroksy- 2-/ 4"-( 3, 4- dimetoksyfenyl)- 4", 4"-etylendioksy- n- butyl7- 5, 9- dimetyl- 6, 7- benzomorfan (a) 2'- hydroxy- 2-/ 4"-( 3, 4- dimethoxyphenyl)- 4", 4"- ethylenedioxy- n- butyl7- 5, 9- dimethyl- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel l(a), gir reaksjonen mellom 1,52 g 2'-hydroksy-5,9-dimetyl-6,7-benzomorfan og 2,2 g 4-(3',4'-dimetoksyfenyl)-4,4-etylendioksy-l-klor-butan, 2'-hydroksy-2-/4"-(3,4-dimetoksyfenyl)-4",4"-etylendioksy-n-butyl7-5,9-dimetyl-6,7-benzomorfan, smp. 162-163°C. According to the method described in example 1(a), the reaction between 1.52 g of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan and 2.2 g of 4-(3',4'- dimethoxyphenyl)-4,4-ethylenedioxy-1-chloro-butane, 2'-hydroxy-2-/4"-(3,4-dimethoxyphenyl)-4",4"-ethylenedioxy-n-butyl7-5,9- dimethyl-6,7-benzomorphan, mp 162-163°C.

-1 -1

IR parafin1 2650' l618' 158°' 1510> 102^ > 800 > 766 IR paraffin1 2650' l618' 158°' 1510> 102^ > 800 > 766

Analyse, beregnet for C^gH-^NO^: Analysis, calculated for C^gH-^NO^:

C 71,92, H 7,98, N 3,00% Funnet: C 71,96, H 7,82, N 2,93% (b) 2'- hydroksy- 2-/ y~( 3, 4- dimetoksybenzoy1)- n- propyl7-5, 9- dimetyl- 6, 7- benzomorfan C 71.92, H 7.98, N 3.00% Found: C 71.96, H 7.82, N 2.93% (b) 2'- hydroxy- 2-/ y~( 3, 4- dimethoxybenzoy1)- n- propyl7-5, 9- dimethyl- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel l(b), ble 2 ' -hydroksy-2-/ 4"- (3, 4-dimetoksyf enyl) -4"!, 4"-ety lend ioksy-n-butyl7-5,9-dimetyl-6,7-benzomorfan omdannet til 2'-hydroksy-2-/ Y_ ( 3, 4-dimetoksybenzoyl) - n-propy l7- 5-, 9_dimetyl - 6 ,7-benzomorf an , smp. 156-158°C. According to the method described in example 1(b), 2'-hydroxy-2-[4"-(3,4-dimethoxyphenyl)-4"!,4"-ethylend ioxy-n-butyl7-5 ,9-Dimethyl-6,7-benzomorphan converted to 2'-hydroxy-2-/Y_ (3,4-dimethoxybenzoyl)-n-propyl 17-5-,9_dimethyl-6,7-benzomorph an , m.p. 156- 158°C.

-1 -1

IR v °™ ■ 2650, 1660, 1615, 1580, 1510, 1030, 799, 767, IR v °™ ■ 2650, 1660, 1615, 1580, 1510, 1030, 799, 767,

pdl dl 1 11 pdl dl 1 11

Analyse, beregnet for C^gH^NO^: Analysis, calculated for C^gH^NO^:

C 73,73, H 7,85, N 3,31% C 73.73, H 7.85, N 3.31%

Funnet: C 74,03, H 8,13, N 3,57% Found: C 74.03, H 8.13, N 3.57%

Eksempel 12 Example 12

2'- hydroksy- 2-/ y-( 3~ fluor- 4- metyIbenzoyl)- n- propyl7-5, 9- dimetyl- 6, 7- benzomorfan 2'- hydroxy- 2- / y-( 3~ fluoro- 4- methylbenzoyl)- n- propyl7-5, 9- dimethyl- 6, 7- benzomorphan

Ifølge fremgangsmåten fra eksempel 9, men ved å anvende 4-(3-fluor-4-metylfenyl)-4,4-etylendioksy-l-klorbutan, fikk man fremstilt 2'-hydroksy-2-/y-(3~fluor-4-metyIbenzoyl)-n-propyl7-5,9-dimetyl-6,7-benzomorfan, smp. 131-134°C. According to the procedure from example 9, but by using 4-(3-fluoro-4-methylphenyl)-4,4-ethylenedioxy-1-chlorobutane, 2'-hydroxy-2-[y-(3-fluoro- 4-methylbenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan, m.p. 131-134°C.

-1 -1

IR parafin' 2600 > 1685» l609> 15?6' l493> 124o> 758 IR paraffin' 2600 > 1685» l609> 15?6' l493> 124o> 758

Analyse, beregnet for C^H^qNC^F: Analysis, calculated for C^H^qNC^F:

C 75,92, H 7,65, N 3,54% C 75.92, H 7.65, N 3.54%

Funnet: C 75,93, H 7,48, N 3,51% Found: C 75.93, H 7.48, N 3.51%

Eksempel 13 2'- hydroksy- 2-/ y-( p- metyltiobenzoyl)- n- propyl7-5, 9- dimetyl- 6, 7- benzomorfan Example 13 2'-hydroxy-2-[y-(p-methylthiobenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan

Ved å anvende fremgangsmåten fra eksempel 7, men ved å anvende 4-(p-metyltiofenyl)-4,4-etylendioksy-l-klorbutan, fikk man fremstilt et råprodukt, som ble rekrystallisert fra etylacetat, hvorved man fikk et rent 2'-hydroksy-2-/y-(p-metyltiobenzoyl)-n-propyl7-5,9-dimetyl-6,7-benzomorfan, smp. 154-156°C. By applying the method from example 7, but by using 4-(p-methylthiophenyl)-4,4-ethylenedioxy-1-chlorobutane, a crude product was produced, which was recrystallized from ethyl acetate, whereby a pure 2'- hydroxy-2-[y-(p-methylthiobenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan, m.p. 154-156°C.

-1 -1

IR parafin: 2600> l6?8' 1615' 1586' 1236' 1090' 802 IR Kerosene: 2600> l6?8' 1615' 1586' 1236' 1090' 802

Analyse, beregnet for C^H^NO^S: Analysis, calculated for C^H^NO^S:

C 73,31, H 7,63, N 7,42, S 7,83% C 73.31, H 7.63, N 7.42, S 7.83%

Funnet: C 73,68, H 7,65, N 3,43, S 7,88% Found: C 73.68, H 7.65, N 3.43, S 7.88%

Eksempel 14 Example 14

2'- hydroksy- 2-/ y-( o- metoksybenzoy1)- n- propyl7-5, 9- dimetyl- 6, 7- benzomorfan 2'- hydroxy- 2-/ y-( o- methoxybenzoyl)- n- propyl7-5, 9- dimethyl- 6, 7- benzomorphan

Alternativt kan 2'-hydroksy-2-/y-(o-metoksybenzoyl)-n-propyl7-5,9-dimetyl-6,7_benzomorfan fremstilles ved fremgangsmåten fra eksempel 5- Smp. 132-137°C. Alternatively, 2'-hydroxy-2-[y-(o-methoxybenzoyl)-n-propyl7-5,9-dimethyl-6,7-benzomorphan can be prepared by the method from example 5- M.p. 132-137°C.

IR parafin' l6?5' l620' 1602> 1583' 765 IR paraffin' l6?5' l620' 1602> 1583' 765

Analyse, beregnet for C^H^NO^: Analysis, calculated for C^H^NO^:

C 76,30, H 7,94, N 3,56$ C 76.30, H 7.94, N 3.56$

Funnet: C 76,37, H 7,82, N 3,^8% Found: C 76.37, H 7.82, N 3.^8%

Eksempel 15 Example 15

2'- hydroksy- 2-/ y -( o- metoksybenzoyl)- n- propyl7~ 2'- hydroxy- 2-/ y -( o- methoxybenzoyl)- n- propyl7~

5- metyl- 9~ etyl- 6, 7~ benzomorfan 5- methyl- 9~ ethyl- 6, 7~ benzomorphan

(a) 2'- hydroksy- 2-/ 4"-( o- metoksyfenyl)- 4", 4"- etylendioksy-n- butyl7- 5- metyl- 9~ etyl- 6, 7- benzomorfan - (a) 2'- hydroxy- 2-/ 4"-( o- methoxyphenyl)- 4", 4"- ethylenedioxy-n- butyl7- 5- methyl- 9~ ethyl- 6, 7- benzomorphan -

En blanding av 1,73 g 2'-hydroksy-5-metyl-9-etyl-6,7~ benzomorfan, 0,9 g natriumbikarbonat og 20 ml dimetylformamid ble tilsatt 2,0 g 4-(o-metoksyfeny1)-4,4-etylendioksy-l-klorbutan. Blandingen ble i 4 timer rørt ved l40-l45°C. Oppløsningsmidlet ble så fjernet under redusert trykk, hvoretter residuet ble tilsatt vann. Blandingen ble så ekstrahert med eter. Eterekstraktet ble konsentrert til tørrhet, hvorved man fikk et råprodukt. Rekrystallisasjon fra etylacetat gir 2'-hydroksy-2-/4"-(o-metoksyfeny1)-4",4"-etylendioksy-n-butyl7-5-metyl-9-etyl-6,7-benzomorfan, smp. 157,5-159°C. A mixture of 1.73 g of 2'-hydroxy-5-methyl-9-ethyl-6,7~ benzomorphan, 0.9 g of sodium bicarbonate and 20 ml of dimethylformamide was added to 2.0 g of 4-(o-methoxyphenyl)-4 ,4-ethylenedioxy-1-chlorobutane. The mixture was stirred for 4 hours at 140-145°C. The solvent was then removed under reduced pressure, after which water was added to the residue. The mixture was then extracted with ether. The ether extract was concentrated to dryness to give a crude product. Recrystallization from ethyl acetate gives 2'-hydroxy-2-[4"-(o-methoxyphenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9-ethyl-6,7-benzomorphan, m.p. 157 .5-159°C.

IR parafin' l6l°' l600' 1582> 15°0' 752 IR paraffin' l6l°' l600' 1582> 15°0' 752

Analyse, beregnet for C2 gH^NO^: Analysis, calculated for C2 gH^NO^:

C 74,47, H 8,26, N 3,10% Funnet: C 74,37, H 8,18, N 3,18% (b) 2'- hydroksy- 2- ly -( o- metoksybenzoyl)- n- propyl7-5- metyl- 9~ etyI- 6, 7~ benzomorfan C 74.47, H 8.26, N 3.10% Found: C 74.37, H 8.18, N 3.18% (b) 2'-hydroxy-2-ly-(o-methoxybenzoyl)- n- propyl7-5- methyl- 9~ ethyl- 6, 7~ benzomorphan

En blanding av 2,5 g 2'-hydroksy-2-/4"-(o-metoksyfenyl)-4",4"-etylendioksy-n-butyl7-5-metyl-9_etyl-6,7-benzomorfan, 20 ml metanol, 10 ml vann og 1,5 ml konsentrert saltsyre ble refluksert i 1 time. Etter at reaksjonsblandinge var konsentrert under redusert trykk, ble blandingen gjort alkalisk med vandig ammoniakk og så ekstrahert med eter. Eterekstraktet ble vasket med vann, tørket over vannfri natriumsulfat og deretter filtrert. Filtratet ble konsentrert til tørrhet, hvorved man fikk et råprodukt. En rekrystallisasjon fra aceton gir 2'-hydroksy-2-/y-(o-metoksybenzoyl)-n-propyl/- 5-metyl-9-etyl-6,7-benzomorfan, smp. l48-152°C. A mixture of 2.5 g of 2'-hydroxy-2-[4"-(o-methoxyphenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9-ethyl-6,7-benzomorphan, 20 ml methanol, 10 ml of water and 1.5 ml of concentrated hydrochloric acid were refluxed for 1 hour. After the reaction mixtures were concentrated under reduced pressure, the mixture was made alkaline with aqueous ammonia and then extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to dryness to give a crude product. A recrystallization from acetone gives 2'-hydroxy-2-[y-(o-methoxybenzoyl)-n-propyl]-5-methyl-9-ethyl- 6,7-benzomorphan, mp 148-152°C.

-1 -1

TR parafin' l670' l6l2> 1595' 15?8' 759' TR kerosene' l670' l6l2> 1595' 15?8' 759'

Analyse, beregnet for C^<gH->^NOy Analysis, calculated for C^<gH->^NOy

C 76,62, H 8,16, N 3,44% C 76.62, H 8.16, N 3.44%

Funnet: C 76,81, H 8,27, N' 3,43% Found: C 76.81, H 8.27, N' 3.43%

Eksempel 16 Example 16

2'- hydroksy- 2-/ y-( 2, 5- dimetyIbenzoyl)- n- propyl7-5- metyl- 9~ etyl- 6, 7~ benzomorfan 2'-hydroxy-2-[y-(2,5-dimethylbenzoyl)-n-propyl7-5-methyl-9~ ethyl-6,7~ benzomorphan

(a) 2'- hydroksy- 2-/ 4"-( 2, 5- dimetylfenyl)- 4", 4"-etylendioksy- n- butyl7- 5- metyl- 9- etyI- 6, 7- benzomorfan (a) 2'- hydroxy- 2-/ 4"-( 2, 5- dimethylphenyl)- 4", 4"- ethylenedioxy- n- butyl7- 5- methyl- 9- ethyl- 6, 7- benzomorphan

Ifølge fremgangsmåten fra eksempel 1 (a), men ved å anvende 4-(2',5'-dimetylfenyl)-4,4-etylendioksy-l-klorbutan, fikk man fremstilt 2'-hydroksy-2-/4"-(2,5-dimetylfenyl)-4",4"-etylendioksy-n-butyl7-5-metyl-9~ety1-6,7-benzomorfan, smp. 162-164°C. According to the procedure from example 1 (a), but by using 4-(2',5'-dimethylphenyl)-4,4-ethylenedioxy-1-chlorobutane, 2'-hydroxy-2-[4"-( 2,5-dimethylphenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9-ethyl-6,7-benzomorphan, mp 162-164°C.

IR pa?afin: 1615 > 1580' l498> 1085> 1060 IR pa?afin: 1615 > 1580' l498> 1085> 1060

Analyse, beregnet for O^H^NC^: Analysis, calculated for O^H^NC^:

C 77,46, H 8,74, N 3,12% Funnet: C 77,43, H 8,75, N 3,10% (b) 2'- hydroksy- 2- ly -( 2, 5- dimetoksybenzoyl)- n- propyl7-5- metyl- 9~ etyl- 6, 7- benzomorfan C 77.46, H 8.74, N 3.12% Found: C 77.43, H 8.75, N 3.10% (b) 2'-hydroxy-2-ly-(2,5-dimethoxybenzoyl )- n- propyl7-5- methyl- 9~ ethyl- 6, 7- benzomorphan

Ved å anvende fremgangsmåte fra eksempel 1 (b), men ved By using the method from example 1 (b), but by

å bruke 2'-hydroksy-2-/3"-(2,5-dimetylfeny1)-4",4"-etylendioksy-n-butyl7-5-metyl-9-etyl-6,7-benzomorfan, fikk man fremstilt et råprodukt som ble rekrystallisert fra aceton, hvorved man fikk rent 2'-hydroksy-2-/y-(2,5-dimetyIbenzoyl)-n-propyl7-5-metyl-9-etyl-6,7-benzomorfan, smp. 152-155°C. using 2'-hydroxy-2-[3"-(2,5-dimethylphenyl)-4",4"-ethylenedioxy-n-butyl7-5-methyl-9-ethyl-6,7-benzomorphan, one was able to prepare a crude product which was recrystallized from acetone to give pure 2'-hydroxy-2-[y-(2,5-dimethylbenzoyl)-n-propyl7-5-methyl-9-ethyl-6,7-benzomorphan, m.p. 152-155°C.

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IR parafin<1> l69°' 1615 > 1585' l495> 1238' 8l9' 790 IR paraffin<1> l69°' 1615 > 1585' l495> 1238' 8l9' 790

Analyse, beregnet for C^yH^^NO^: Analysis, calculated for C^yH^^NO^:

C 79,96, H 8,70, N 3,45% C 79.96, H 8.70, N 3.45%

Funnet: C 80,11, H 8,72, N 3,42% Found: C 80.11, H 8.72, N 3.42%

Eksempel 17 Example 17

2'- hydroksy- 2-/ y-( m- nitrobenzoyl)- n- propyl7- 5, 9~ dimetyl- 6, 7- benzomorfan 2'- hydroxy- 2-/ y-( m- nitrobenzoyl)- n- propyl7- 5, 9~ dimethyl- 6, 7- benzomorphan

Ved å underkaste 4-(m-nitrofenyl)-4,4-etylendioksy-l-klorbutan den fremgangsmåte som er beskrevet i eksempel 7, fikk man fremstilt 2<1->hydroksy-2-/y-(m-nitrobenzoyl)~ri-propyl7-5,9~ dimetyl-6,7-benzomorfan, smp. 168,5-173°C.. By subjecting 4-(m-nitrophenyl)-4,4-ethylenedioxy-1-chlorobutane to the procedure described in example 7, 2<1->hydroxy-2-[y-(m-nitrobenzoyl)~ was produced ri-propyl7-5,9~ dimethyl-6,7-benzomorphan, m.p. 168.5-173°C..

IR £arafin: 1695' l6l0> 1582' 1528> 1345 IR £arafin: 1695' l6l0> 1582' 1528> 1345

Analyse, beregnet for C2<i>)<H>2<gN>20^: Analysis, calculated for C2<i>)<H>2<gN>20^:

C 70,56, H 6,91, N 6,86% C 70.56, H 6.91, N 6.86%

Funnet: C 69,56, H 6,75, N 6,33%. Found: C 69.56, H 6.75, N 6.33%.

Eksempel 18 Example 18

2'- hydroksy- 2-( y- benzoyl- n- propyl)- 5~ metyl- 9~ etyl- 6, 7" benzomorfan 2'- hydroxy- 2-( y- benzoyl- n- propyl)- 5~ methyl- 9~ ethyl- 6, 7" benzomorphan

En blanding av 1,15 g 2'-hydroksy-5_metyl-9-etyl-6,7-benzomorfan, 0,63 g natriumbikarbonat og 20 ml dimetylformamid ble tilsatt 1,4 g y-klorbutyrofenon. Den resulterende blanding ble i 2 timer rørt ved 125-133°C. Det uorganiske fremstilte, faste stoff ble fjernet ved filtrering, hvoretter filtratet ble konsentrert til tørrhet. Residuet ble vasket med aceton og filtrert. Moderluten ble hensatt i et kjøleskap, hvorved man fikk et bunnfall. Re-krystallisasj on fra etylacetat gir 2'-hydroksy-2-(y-benzoyl-n-propyl)-5-metyl-9_etyl-6,7-benzomorfan, smp. 168-170°C. A mixture of 1.15 g of 2'-hydroxy-5-methyl-9-ethyl-6,7-benzomorphan, 0.63 g of sodium bicarbonate and 20 ml of dimethylformamide was added to 1.4 g of γ-chlorobutyrophenone. The resulting mixture was stirred for 2 hours at 125-133°C. The inorganic solid produced was removed by filtration, after which the filtrate was concentrated to dryness. The residue was washed with acetone and filtered. The mother liquor was placed in a refrigerator, whereby a precipitate was obtained. Recrystallization from ethyl acetate gives 2'-hydroxy-2-(γ-benzoyl-n-propyl)-5-methyl-9-ethyl-6,7-benzomorphan, m.p. 168-170°C.

IR parafin: 2650 > l683' 1615' 1592' 1575' 921' 8565 792' 688 IR kerosene: 2650 > l683' 1615' 1592' 1575' 921' 8565 792' 688

Analyse, beregnet for C^H^NO,,: Analysis, calculated for C^H^NO,,:

C 79,53, H 8,28, N 3,71% C 79.53, H 8.28, N 3.71%

Funnet: C 79,11, H 8,63, N 4,14% Found: C 79.11, H 8.63, N 4.14%

Eksempel 19 Example 19

2'- hydroksy- 2-( y- benzoy1-n- propyl)- 5, 9- dimetyl- 6, 7- benzomorfan 2'- hydroxy- 2-( y- benzoyl-n- propyl)- 5, 9- dimethyl- 6, 7- benzomorphan

Ifølge den fremgangsmåte som er beskrevet i eksempel 18, According to the method described in example 18,

fikk man ved hjelp av 2'-hydroksy-5,9_dimetyl-6,7-benzomorfan og y-klorbutyrofenon, fremstilt 2'-hydroksy-2-(y-benzoyl-n-propyl)-5,9~dimetyl-6,7-benzomorfan. with the help of 2'-hydroxy-5,9-dimethyl-6,7-benzomorphan and y-chlorobutyrophenone, 2'-hydroxy-2-(y-benzoyl-n-propyl)-5,9-dimethyl-6, 7-benzomorphan.

Denne forbindelse ble også fremstilt ifølge fremgangsmåten This compound was also prepared according to the method

fra eksempel 1. Smp. 172-174°C. from example 1. Smp. 172-174°C.

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IR parafin' 2600' 1685' 1615' 159^' 15?8' l495' 865' ?42' 691 IR paraffin' 2600' 1685' 1615' 159^' 15?8' l495' 865' ?42' 691

Analyse, beregnet for C2^H2gNQ2: Analysis, calculated for C2^H2gNQ2:

C 79,30, H 8,04, N 3,85% C 79.30, H 8.04, N 3.85%

Funnet: C 79,23, H 7,85, N 3,91% Found: C 79.23, H 7.85, N 3.91%

Claims

Analogous process for the preparation of therapeutically active benzomorphan derivatives with the general formula:

where R is a hydrogen atom, a C₁-C₁ alkoxy group or a hydroxyl group, R, and R? is independently C<1->C<3->alkyl groups, R., is a hydrogen atom, a halogen atom, a C 1-C 3 alkyl group, a C 1-C 3 alkoxy group, a C^-C^ alkylthio group, a nitro group, a trifluoromethyl group, or a hydroxyl group, Rn is a hydrogen atom, a C₁-C₁-alkyloxy-13 group, a C₁-C₁-alkyl group or a halogen atom, while n is 3 or 4, as well as salts of these derivatives , characterized in that one a) in the presence of a catalytic amount of mineral acid hydrolyzes an ethylenedioxy derivative with the formula: where R, R-p R^, R^, R^ and n have the above meaning, or b) reacts a 6,7_benzomorphane derivative with the formula : where R, R^ and R^ have the meaning given above, with a reactive halide of the formula: where R^, R^ and n have the meaning given above and X is a halogen atom, in an organic inert solvent in the presence of a base, after which, if desired, converts a compound obtained into a pharmaceutically acceptable salt thereof.