DK150849B - HEXAHYDRO-2H-AZEPIN-2-ONES USED AS INTERMEDIATES IN THE PREPARATION OF HEXAHYDRO-1H-AZEPINE DERIVATIVES OR ANY ACID ADDITION SALT OR QUATERNATE AMMONIUM SALT - Google Patents
HEXAHYDRO-2H-AZEPIN-2-ONES USED AS INTERMEDIATES IN THE PREPARATION OF HEXAHYDRO-1H-AZEPINE DERIVATIVES OR ANY ACID ADDITION SALT OR QUATERNATE AMMONIUM SALT Download PDFInfo
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- C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D223/04—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Description
0 ! 1508490! 150849
Den foreliggende opfindelse angår hidtil ukendte hexa-hydro-2H-azepin-2-oner til anvendelse som mellemprodukter ved fremstilling af hexahydro-lH-azepinderivater eller et syreadditionssalt eller kvaternært ammoniumsalt deraf.The present invention relates to novel hexa-hydro-2H-azepin-2-ones for use as intermediates in the preparation of hexahydro-1H-azepine derivatives or an acid addition salt or quaternary ammonium salt thereof.
5 De her omhandlede hexahydroazepinoner er ejendommelige5 The hexahydroazepinones in question are peculiar
ved, at de har den almene formel Iknow that they have the general formula I
, Y1--^ OR1, Y1 - ^ OR1
ΈΓ - Ν'' I / IΈΓ - Ν '' I / I
hvor R1 betyder et hydrogenatom, en alkylgruppe med højst 6 carbonatomer, en benzylgruppe eller en alkanoylgruppe med højst 6 carbonatomer, R betyder en alkylgruppe med højst 15 6 carbonatomer, R betyder et hydrogenatom, en alkylgruppe med højst 6 carbonatomer, en alkenylgruppe med højst 6 carbonatomer, en alkynylgruppe med højst 6 carbonatomer, en cy-clopropylmethylgruppe, en alkanoylgruppe med højst 6 carbonatomer, en alkoxycarbonylgruppe, hvis alkoxydel højst inde-20 holder 6 carbonatomer, eller en phenalkanoylgruppe med højst 6 carbonatomer i alkanoyldelen, phenethyl- eller β-benzoyl-ethylgruppe, der hver især kan være substitueret i benzenringen med op til 5 halogenatomer og/eller op til 5 alkyl-, alkoxy- eller halogenalkylgrupper med højst 6 carbonatomer, 25 nitrogrupper, aminogrupper eller mono- eller dialkylamino- grupper, hvis alkylgrupper hver især højst indeholder 6 carbonatomer, og en af grupperne Y og Y1 betyder CO, og den anden betyder CH2·wherein R 1 represents a hydrogen atom, an alkyl group of not more than 6 carbon atoms, a benzyl group or an alkanoyl group of not more than 6 carbon atoms, R means an alkyl group of not more than 6 6 carbon atoms, R means a hydrogen atom, an alkyl group of not more than 6 carbon atoms, carbon atoms, an alkynyl group having at most 6 carbon atoms, a cyclopropylmethyl group, an alkanoyl group having at most 6 carbon atoms, an alkoxycarbonyl group having at most 20 carbon atoms, or a phenalkanoyl group having at most 6 carbon atoms in the alkanoyl moiety, phenethyl or β -ethyl group, each of which may be substituted in the benzene ring by up to 5 halogen atoms and / or up to 5 alkyl, alkoxy or haloalkyl groups of not more than 6 carbon atoms, 25 nitro groups, amino groups or mono or dialkylamino groups each of which alkyl groups at most 6 contain carbon atoms and one of the groups Y and Y1 means CO and the other means CH2 ·
En foretrukken række forbindelser er de forbindelser 30 med den almene formel (I) , hvor R-1 betyder et hydrogenatom 2 eller en methylgruppe, R betyder en methyl-, ethyl-, pro- 3 pyl- eller butylgruppe, og R betyder en alkylgruppe, specielt methyl.A preferred variety of compounds are those compounds of general formula (I) wherein R 1 represents a hydrogen atom 2 or a methyl group, R represents a methyl, ethyl, propyl or butyl group, and R represents an alkyl group , especially methyl.
Forbindelser med den almene formel (I), hvor Y1 be-35 tyder CO, og Y betyder CH2, har formlenCompounds of general formula (I) wherein Y 1 represents CO and Y means CH 2 have the formula
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2 1508492 150849
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\. OR1 R3-/] / 5 N--p-\ — / (VIII) i2 og kan fremstilles ved den nedenfor skitserede omsætning, hvor 2 3 R og R har de i forbindelse med formel (I) definerede betyd-10 ninger, R"*" betyder lavere alkyl, Alk betyder en lavere alkyl-gruppe, der fortrinsvis er ethyl, og Hal betyder et halogenatom.\. OR1 R3- /] / 5 N - p- \ - / (VIII) i2 and can be prepared by the reaction outlined below, wherein 2 3 R and R have the meanings defined in formula (I), R "*" means lower alkyl, Alk means a lower alkyl group which is preferably ethyl, and Hal represents a halogen atom.
15 QfUR Hsl- (CHp) 3-GCpAIk' (Qr <VII) I o * O yt 'TV'QfUR Hsl- (CHp) 3-GCpAIk '(Qr <VII) I o * O yt' TV '
R-CH-CN RR-CH-CN R
c.' (III) 20 \c. ' (III) 20
Ειε_^Λ p VΕιε_ ^ Λ p V
pVϋβ1 hh^) *-’ (1^ 25 J r"\ o :i2-G-GII,-KH0 I .GE1 (villa) i„ x‘ ~ s2 30 (VIII)pVϋβ1 hh ^) * - '(1 ^ 25 J r "\ o: i2-G-GII, -KH0 I .GE1 (villa) in" x "~ s2 30 (VIII)
Et substitueret, aliphatisk nitril med formel (III) kan omsættes med natrium i flydende ammoniak efterfulgt af et alkylhalogenbutyrat, fortrinsvis ethyl-4-iodbutyrat, til dannelse af en nitrilester med formel (VII); denne nitril-35 ester kan reduceres, f.eks. fortrinsvis med hydrogen i nærværelse af palladium på trækul ved stuetemperatur i et opløs- 3 150849 0 / ningsmiddel, såsom methylalkohol, indeholdende svovlsyre og 2 under et tryk på ca. 3/5 kg/cm , eller med hydrogen i nærværelse af Raney-nikkel ved temperaturer på 100-150°C i et opløsningsmiddel, såsom cyclohexan, og under tryk på fra 2 5 56 til 84 kg/cm . Lave temperaturer har tendens til at give det åbenkædede produkt med formel (IX), medens højere temperaturer har tendens til at give produktet med formel (Villa). Følgelig kan produktet med formel (IX) opvarmes, f.eks. i et opløsningsmiddel, såsom tilbagesvalende toluen eller decahydro-10 naphthalen, eller med natriumethoxid i absolut alkohol, til dannelse af hexahydro-2H-azepin-2-onen med formel (Villa). "Alkylering" kan derpå gennemføres til indføring af en grup- 3 pe R , der er forskellig fra hydrogen.A substituted aliphatic nitrile of formula (III) may be reacted with sodium in liquid ammonia followed by an alkyl halogen butyrate, preferably ethyl 4-iodobutyrate, to form a nitrile ester of formula (VII); this nitrile ester can be reduced, e.g. preferably with hydrogen in the presence of palladium on charcoal at room temperature in a solvent such as methyl alcohol containing sulfuric acid and 2 under a pressure of approx. 3/5 kg / cm, or with hydrogen in the presence of Raney nickel at temperatures of 100-150 ° C in a solvent such as cyclohexane and under pressure of from 2 to 56 to 84 kg / cm. Low temperatures tend to yield the open-chain product of formula (IX), while higher temperatures tend to yield the product of formula (Villa). Accordingly, the product of formula (IX) may be heated, e.g. in a solvent such as refluxing toluene or decahydro-naphthalene, or with sodium ethoxide in absolute alcohol to give the hexahydro-2H-azepin-2-one of formula (Villa). "Alkylation" can then be carried out to introduce a group R which is different from hydrogen.
Forbindelser med den almene formel (I), hvor Y1 bety-15 der -CH2-, og Y betyder -CO-, har formlen 3 ^ or1 m R -N I / υ og kan fremstilles ved de to nedenfor skitserede reaktioner, hvor R^ betyder en lavere alkylgruppe i den første, medens 1 2 25 R også kan betyde en benzylgruppe i den anden, og R , Alk og Hal har den ovenfor anførte betydning: 30 35Compounds of general formula (I) wherein Y 1 is -CH 2 - and Y is -CO-, have the formula 3 or 1 m R -NI / υ and can be prepared by the two reactions outlined below, wherein R 1 means a lower alkyl group in the first, while 1 2 25 R can also mean a benzyl group in the second, and R, Alk and Hal have the meaning given above:
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4 150849 (A).4 150849 (A).
I Hal- ( CH„ ) z -ON || 5 » kxJJ (XII) R2-CH-CC?Alk R2-C-C0oiilk ^ I d f ηχτ S ^iTVr V^lipyl -7-^1'In Hal- (CH +) z -ON || 5 »kxJJ (XII) R2-CH-CC? Alk R2-C-C0oilk ^ I d f ηχτ S ^ iTVr V ^ lipyl -7- ^ 1 '
10 K10 K
(X) 4- H-K J(X) 4- H-K J
°^xxa‘ <«° ^ xxa '<«
Man kan gå ud fra en substitueret, aliphatisk ester med formel (XI) og omsætte den med f.eks. natrium i flydende ammoniak efterfulgt af 4-iodbutyronitril til dannelse af ni-20 trilesteren med formel (XII); nitrilesteren kan ringsluttes som beskrevet ovenfor ved den foretrukne metode til dannelse af hexahydro-2H-azepin-2-onen med formel (Xa), der kanOne may assume a substituted aliphatic ester of formula (XI) and react with e.g. sodium in liquid ammonia followed by 4-iodobutyronitrile to give the nitrile ester of formula (XII); the nitrile ester can be cyclized as described above by the preferred method of forming the hexahydro-2H-azepin-2-one of formula (Xa) which can be
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"alkyleres" til indføring af en gruppe R , der er forskellig fra hydrogen."alkylated" to introduce a group R other than hydrogen.
0 5 150849 (B). 0 /w®1 2 3 A y^,0 5 150849 (B). 0 / w® 1 2 3 A y ^,
5 I . Hal-(CH0),-N I5 I. Hal- (CH0), - N I
o To T
H^-CH-COgAlk υ , v v (XIII) (XI) \H 2 -CH-COgAlk υ, v v (XIII) (XI) \
10 I10 I
^ V^ V
, , ' \ ) λ E“-C-GC0iilk r- pTT <- . , /fcV^l -1 W to;i2)4-K j,, '\) λ E “-C-GC0iilk r- pTT <-. , / fcV ^ l -1 W to; i2) 4-K j
15 \ C15 ° C
IIII
(Xej c (XIV) 20 En substitueret, aliphatisk ester med formel (XI) om sættes med f.eks. N-(4-iodbutyl)-phthalimid med formel (XIII) til dannelse af en forbindelse med den almene formel (XIV), der kan ringsluttes efter fjernelse af den beskyttende phtha-loylgruppe til dannelse af en forbindelse med formel (Xa), 3 25 der kan "alkyleres" til indføring af en gruppe R , der er forskellig fra hydrogen.(Xej c (XIV)) A substituted aliphatic ester of formula (XI) is reacted with, for example, N- (4-iodobutyl) -phthalimide of formula (XIII) to give a compound of general formula (XIV) which can be cyclized after removal of the protective phthalloyl group to form a compound of formula (Xa), which can be "alkylated" to introduce a group R other than hydrogen.
Hvis en forbindelse med den almene formel (I) frem-1 3 stilles, hvor R og/eller R ikke betyder de ønskede grupper, 1 3 kan én gruppe R og/eller R omdannes til en anden gruppe 1 3 30 R og/eller R inden for de i forbindelse med formel (I) oven- 3 2 for definerede betydninger af R og R . En forbindelse, hvor 3 R er en methylgruppe, kan f.eks. demethyleres ved nitrogen- 3 atomet til dannelse af den tilsvarende forbindelse, hvor R betyder hydrogen. Demethylering kan f.eks. udføres under an-35 vendelse af cyanogenbromid eller ethylchlorformiat. Om ønsket kan dette produkt omdannes til en anden forbindelse med 6 150849 0 samme almene formel ved en vilkårlig af de ovenfor eller nedenfor beskrevne metoder.If a compound of general formula (I) is prepared, wherein R and / or R are not the desired groups, 1 3 one group R and / or R may be converted to another group 1 3 R and / or R within those defined in formula (I) above for defined meanings of R and R. A compound in which 3 R is a methyl group can e.g. is demethylated at the nitrogen atom to form the corresponding compound where R is hydrogen. Demethylation can e.g. is carried out using cyanogen bromide or ethyl chloroformate. If desired, this product can be converted to another compound of the same general formula by any of the methods described above or below.
En forbindelse, hvor R"*" betyder et hydrogenatom, kan fås ud fra de tilsvarende forbindelser med den almene for-5 mel (I), hvor R1 betyder lavere alkyl eller benzyl, ved spaltning af ethergruppen på kendt måde, f.eks. ved behandling af de lavere alkylethere eller benzyletherne med hydrogenbromid eller bortribromid eller ved hydrogenolyse af benzyletherne.A compound wherein R "*" means a hydrogen atom can be obtained from the corresponding compounds of the general formula (I) wherein R 1 is lower alkyl or benzyl, by cleavage of the ether group in a known manner, e.g. by treating the lower alkyl ethers or benzyl ethers with hydrogen bromide or boron tribromide or by hydrogenolysis of the benzyl ethers.
Om ønsket kan det fremkomne produkt derpå acyleres, f.eks.If desired, the resulting product may then be acylated, e.g.
10 med eddikesyreanhydrid, til dannelse af den tilsvarende forbindelse, hvor R^ betyder et lavere alkanoylradikal.10 with acetic anhydride to give the corresponding compound, wherein R 1 represents a lower alkanoyl radical.
En forbindelse, hvor R3 er forskellig fra hydrogen, kan fremstilles ved "alkylering" af en tilsvarende forbindelse, 3 hvor R betyder hydrogen. Anvendt her betyder udtrykket "alky-15 lering" indføring af en gruppe R3, der er forskellig fra hydrogen, på hexahydroazepinringens nitrogenatom. Der kendes mange metoder til alkylering af forbindelser, og den mest egnede metode til dannelse af et ønsket produkt kan anvendes, idet nedenstående metoder almindeligvis foretrækkes.A compound wherein R 3 is different from hydrogen may be prepared by "alkylation" of a corresponding compound 3 wherein R represents hydrogen. As used herein, the term "alkylation" means introducing a group R3 other than hydrogen to the nitrogen atom of the hexahydroazepine ring. Many methods for alkylating compounds are known, and the most suitable method for forming a desired product may be used, the methods below generally being preferred.
20 En forbindelse, hvor R^ er forskellig fra lavere alka- noyl, kan omsættes med et halogenid med den almene formel R3-Hal 25 hvor RJ har den i forbindelse med formel (I) definerede betydning, men er forskellig fra lavere alkanoyl, og Hal betyder et halogenatom, i nærværelse af en syreacceptor, såsom et alkalimetalcarbonat, f.eks. kaliumcarbonat, fortrinsvis i opløsning i et organisk opløsningsmiddel ved f.eks. 25-100°C, 30 fortrinsvis 80-100°C.A compound wherein R 1 is different from lower alkanoyl may be reacted with a halide of the general formula R 3 -Hal 25 wherein R 1 is as defined in formula (I) but is different from lower alkanoyl, and Hal represents a halogen atom, in the presence of an acid acceptor such as an alkali metal carbonate, e.g. potassium carbonate, preferably in solution in an organic solvent, e.g. 25-100 ° C, preferably 80-100 ° C.
33
En methylgruppe R kan indføres i en forbindelse, hvor R betyder hydrogen, ved reduktiv methylering, f.eks. under anvendelse af formaldehyd og hydrogen i nærværelse af en hydrogeneringskatalysator .A methyl group R may be introduced into a compound wherein R is hydrogen by reductive methylation, e.g. using formaldehyde and hydrogen in the presence of a hydrogenation catalyst.
35 7 15084935 7 150849
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Forbindelserne med den almene formel (i) er nyttige som mellemprodukter ved fremstillingen af hexahydro-lH-aze-piner med den almene formel r3'\ ^ /-/°r1 ^-(V/ (xviii) R2 10 12 3 hvor R , R og R har den ovenfor anførte betydning, samt syreadditionssalte og kvaternære ammoniumsalte deraf.The compounds of the general formula (i) are useful as intermediates in the preparation of hexahydro-1H-azepines of the general formula r3 + / - / ° r1 ^ - (V / (xviii) R 2 R and R have the meaning given above, as well as acid addition salts and quaternary ammonium salts thereof.
Forbindelserne med den almene formel (XVIII) kan fremstilles ud fra forbindelserne med den almene formel (I) ved de 15 i dansk patentskrift nr. 141.401 beskrevne metoder.The compounds of the general formula (XVIII) can be prepared from the compounds of the general formula (I) by the methods described in Danish patent specification 141,401.
En forbindelse med den almene formel (I) kan f.eks. re-deceres med et hydrid-overføringsreagens til dannelse af en forbindelse med formel (XVIII).A compound of general formula (I) may e.g. is reacted with a hydride transfer reagent to form a compound of formula (XVIII).
De forbindelser med den almene formel (XVIII), der fås 20 ud fra mellemprodukterne med den almene formel (I), har værdifuld, farmakologisk aktivitet. For eksempel udviser de ved farmakologiske standard-metoder sædvanligvis en evne til at formindske smerte og kan derfor være nyttige som smertestillende midler. Desuden udviser visse af forbindelserne 25 med formel (XVIII) evnen til at modvirke narkotiske smertestillende midler.The compounds of the general formula (XVIII) obtained from the intermediates of the general formula (I) have valuable pharmacological activity. For example, by standard pharmacological methods, they usually exhibit an ability to reduce pain and may therefore be useful as pain relievers. In addition, some of the compounds of formula (XVIII) exhibit the ability to counter narcotic painkillers.
Ved den farmakologiske vurdering af disse forbindelsers egenskaber prøves forbindelsernes in vivo-virkninger på mus ved Haffner1 s "tail clip"-metode (jvf. F. Haffner, Deutsch.In the pharmacological assessment of the properties of these compounds, the in vivo effects of the compounds on mice are tested by Haffner1's tail clip method (cf. F. Haffner, Deutsch.
30 Med. Wschr. 5^5, 731 (1929)) eller ved en "strålevarme på halen"-metode ifølge D'Amour og Smith (J. Pharmacol, 72./ 74 35 8 15084930 Med. Wschr. 5 ^ 5, 731 (1929)) or by a "radiant heat on the tail" method according to D'Amour and Smith (J. Pharmacol, 72/7435,8150849
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(1941)). Den smertestillende antagonisme kan prøves ved en metode ifølge Casy et al. beskrevet i J. Pharm. Pharmacol, 20, 768 (1968).(1941)). The analgesic antagonism can be tested by a method of Casy et al. described in J. Pharm. Pharmacol, 20, 768 (1968).
Forbindelserne med formel (XVIII) udviste sædvanligvis 5 smertestillende virkninger ved de ovennævnte forsøgsfremgangsmåder, når de blev indgivet oralt og/eller intraperitonealt i en dosering på ca. 10 til ca. 200 mg/kg.The compounds of formula (XVIII) usually exhibited 5 analgesic effects in the aforementioned test methods when administered orally and / or intraperitoneally at a dosage of ca. 10 to approx. 200 mg / kg.
Nedenstående eksempler tjener til illustrering af opfindelsen.The following examples serve to illustrate the invention.
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Eksempel 1 6-(m-Methoxyphenyl)-6-propylhexahydro-2H-azepin-2-on (a) 75,6 g (0,4 mol) 2-(m-methoxyphenyl)-pentannitril i 15 200 ml tør ether sættes til en omrørt suspension af natrium amid (ud fra 9,4 g natrium) i 400 ml flydende ammoniak. Blandingen omrøres i 30 minutter, dernæst tilsættes dråbevis 99,25 g (0,4 mol) ethyl-4-iodbutyrat i 200 ml tør ether. Blandingen omrøres ved flydende ammoniaks tilbagesvalingstempera- 20 tur i 5 timer. 10 g ammoniumchlorid tilsættes, og blandingen får lov at opvarmes til stuetemperatur. 300 ml vand tilsættes, det organiske lag skilles fra, vaskes med vand, 2 N svovlsyre og vand. Efter tørring over magnesiumsulfat og fjernelse af etheren destilleres produktet, hvorved der fås 77,6 g ethyl-25 -5-cyano-5-(m-methoxyphenyl)-octanoat med kp. 156-175°C ved 0,02 mm Hg, n^ = 1,5020.Example 1 6- (m-Methoxyphenyl) -6-propylhexahydro-2H-azepin-2-one (a) 75.6 g (0.4 mole) of 2- (m-methoxyphenyl) pentanitrile in 200 ml of dry ether are added. to a stirred suspension of sodium amide (from 9.4 g of sodium) in 400 ml of liquid ammonia. The mixture is stirred for 30 minutes, then 99.25 g (0.4 mole) of ethyl 4-iodobutyrate is added dropwise in 200 ml of dry ether. The mixture is stirred at refluxing liquid ammonia for 5 hours. 10 g of ammonium chloride are added and the mixture is allowed to warm to room temperature. 300 ml of water are added, the organic layer is separated, washed with water, 2N sulfuric acid and water. After drying over magnesium sulfate and removing the ether, the product is distilled off to give 77.6 g of ethyl 25 -5-cyano-5- (m-methoxyphenyl) octanoate with b.p. 156-175 ° C at 0.02 mm Hg, n + = 1.5020.
Ethyl-5-cyano-5-(m-methoxyphenyl)-octanoat kan også fremstilles ved hydrolyse i 30 timer af 5-cyano-5-(m-methoxyphenyl) -octannitr il med en blanding af svovlsyre og ethylalko-30 hol i rumfangsforholdet 1:10.Ethyl 5-cyano-5- (m-methoxyphenyl) octanoate can also be prepared by hydrolysis for 30 hours of 5-cyano-5- (m-methoxyphenyl) octanitrile with a mixture of sulfuric acid and ethyl alcohol in volume. 1:10.
(b) 32,0 g ethyl-5-cyano-5-(m-methoxyphenyl)-octanoat hy- 2 drogeneres ved et begyndelsestryk på 84 kg/cm og en sluttemperatur på 140°C i 400 ml cyclohexan med ca. 8 g nikkelkatalysator i 18 timer. Fjernelse af katalysatoren og afdampning af 35 cyclohexanet giver en farveløs, viskos olie, som krystalliseres fra ethylacetat, hvorved der fås 18,3 g farveløse nåle(b) 32.0 g of ethyl 5-cyano-5- (m-methoxyphenyl) octanoate is hydrogenated at an initial pressure of 84 kg / cm and a final temperature of 140 ° C in 400 ml of cyclohexane with approx. 8 g nickel catalyst for 18 hours. Removal of the catalyst and evaporation of the cyclohexane give a colorless, viscous oil which is crystallized from ethyl acetate to give 18.3 g of colorless needles
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9 150849 af 6-(m-methoxyphenyl)-6-propylhexahydro-2H-azepin-2-on med smp. 109-110°C.No. 9,150,849 of 6- (m-methoxyphenyl) -6-propylhexahydro-2H-azepin-2-one, m.p. 109-110 ° C.
Når reduktionen udføres ved en lavere temperatur, består produktet hovedsageligt af ethyl-5-aminomethyl-5-5 -(m-methoxyphenyl)-octanoat. Ringslutning af denne forbindel se kan opnås ved opvarmning under tilbagesvaling i 18 timer i decalin eller ved opvarmning under tilbagesvaling med en opløsning af natriumethoxid i absolut ethanol.When the reduction is carried out at a lower temperature, the product mainly consists of ethyl 5-aminomethyl-5-5 - (m-methoxyphenyl) octanoate. Closure of this compound can be obtained by refluxing for 18 hours in decalin or by refluxing with a solution of sodium ethoxide in absolute ethanol.
10 Eksempel 2 6-(m-Methoxypheny1)-6-methylhexahydro-2H-azepin-2-on (a) 25,2 g 2-(m-methoxyphenyl)-propionitril omsættes med natriumamid (ud fra 3,6 g natrium) i 300 ml flydende ammoniak 15 og 38,5 g ethyl-4-iodbutyrat ifølge den i eksempel 1(a) beskrevne metode. Efter lignende oparbejdning destilleres produktet, hvorved der fås 22,5 g ethyl-5-cyano-5-(m-methoxyphenyl) -hexanoat med kp. 132-142°C/0,03 mm Hg.Example 2 6- (m-Methoxyphenyl) -6-methylhexahydro-2H-azepin-2-one (a) 25.2 g of 2- (m-methoxyphenyl) propionitrile are reacted with sodium amide (starting from 3.6 g of sodium) in 300 ml of liquid ammonia 15 and 38.5 g of ethyl 4-iodobutyrate according to the method described in Example 1 (a). After similar work-up, the product is distilled to give 22.5 g of ethyl 5-cyano-5- (m-methoxyphenyl) hexanoate with b.p. 132-142 ° C / 0.03 mm Hg.
(b) 15,2 g af denne forbindelse hydrogeneres ved et begyn-20 delsestryk på 70 kg/cm2 og en sluttemperatur på 140°C i nærværelse af ca. 6 g nikkelkatalysator i 250 ml cyclohexan i 20 timer. Katalysatoren fjernes ved filtrering, cyclohexanet fjernes, hvorved der fås 14,1 g af en viskos olie, der opvarmes under tilbagesvaling i decalin i en nitrogenatmosfære 25 i 20 timer. Decalinet fjernes under formindsket tryk, og remanensen krystalliseres fra ethylacetat til dannelse af 5,3 g farveløse nåle af 6-(m-methoxyphenyl)-6-methyl-hexahy-dro-2H-azepin-2-on med smp. 114-115°C.(b) 15.2 g of this compound is hydrogenated at an initial pressure of 70 kg / cm 2 and a final temperature of 140 ° C in the presence of approx. 6 g nickel catalyst in 250 ml cyclohexane for 20 hours. The catalyst is removed by filtration, the cyclohexane is removed to give 14.1 g of a viscous oil which is refluxed in decalin in a nitrogen atmosphere 25 for 20 hours. The decalin is removed under reduced pressure and the residue is crystallized from ethyl acetate to give 5.3 g of colorless needles of 6- (m-methoxyphenyl) -6-methyl-hexahydro-2H-azepin-2-one with m.p. 114-115 ° C.
Yderligere 2,7 g krystallinsk materiale kan fås ved 30 destillering af modervæskerne efterfulgt af omkrystallisation fra ethylacetat.An additional 2.7 g of crystalline material can be obtained by distilling the mother liquors followed by recrystallization from ethyl acetate.
Eksempel 3 10 150849EXAMPLE 3
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6-Butyl-e-(m-methoxyphenyl)-hexahydro-2H-azepin-2-on (a) Ethyl-5-cyano-5-(m-methoxyphenyl)-nonanoat fremstilles 5 ved den i eksempel 1(a) beskrevne metode under anvendelse af natriumamid (ud fra 5,36 g natrium) i 400 ml flydende ammoniak og 45 g 2-(m-methoxyphenyl)-hexanitril. Produktet fås som en farveløs olie (48,7 g) med kp. 150-166°C/0,01 mm Hg.6-Butyl-e- (m-methoxyphenyl) hexahydro-2H-azepin-2-one (a) Ethyl 5-cyano-5- (m-methoxyphenyl) nonanoate is prepared by the example described in Example 1 (a) method using sodium amide (from 5.36 g of sodium) in 400 ml of liquid ammonia and 45 g of 2- (m-methoxyphenyl) hexanitrile. The product is available as a colorless oil (48.7 g) with b.p. 150-166 ° C / 0.01 mm Hg.
(b) 30,0 g af produktet fra eksempel 3(a) hydrogeneres i 10 nærværelse af ca. 6 g Raney-nikkel og 400 ml cyclohexan på den i eksempel 1(b) angivne måde. Produktet omkrystalliseres fra ethylacetat, hvorved der fås 15,12 g 6-butyl-6-(m-methoxyphenyl) -hexahydro-2H-azepin- 2 -on med smp. 108-109°C.(b) 30.0 g of the product of Example 3 (a) is hydrogenated in the presence of ca. 6 g Raney nickel and 400 ml cyclohexane in the manner set forth in Example 1 (b). The product is recrystallized from ethyl acetate to give 15.12 g of 6-butyl-6- (m-methoxyphenyl) hexahydro-2H-azepin-2-one, m.p. 108-109 ° C.
15 Eksempel 4 6-Ethyl-6-(m-methoxyphenyl)-hexahydro-2H-azepin-2-on (a) Ethyl-5-cyano-5-(m-methoxyphenyl)-heptanoat fremstilles på den i eksempel 1(a) beskrevne måde under anvendelse af natriumamid (ud fra 3,74 g natrium) i 150 ml flydende 20 ammoniak og 26,3 g 2-(m-methoxyphenyl)-butyronitril. Produktet destilleres, kogepunkt 148-155°C/0,01 mm Hg, hvorved der fås 27,1 g af en farveløs væske.Example 4 6-Ethyl-6- (m-methoxyphenyl) hexahydro-2H-azepin-2-one (a) Ethyl 5-cyano-5- (m-methoxyphenyl) heptanoate is prepared on the one of Example 1 (a) ) described using sodium amide (from 3.74 g of sodium) in 150 ml of liquid ammonia and 26.3 g of 2- (m-methoxyphenyl) -butyronitrile. The product is distilled, boiling point 148-155 ° C / 0.01 mm Hg to give 27.1 g of a colorless liquid.
(b) 20,5 g af produktet fra eksempel 4(a) i 200 ml cyclohexan hydrogeneres i nærværelse af ca. 6 g Raney-nikkel på 25 den i eksempel 2(b) beskrevne måde. Det produkt, der fremkommer efter destillation, omkrystalliseres fra ethylacetat, hvorved der fås 10,0 g 6-ethyl-6-(m-methoxyphenyl)-hexahy-dro-2H-azepin-2-on med smp. 87-88°C.(b) 20.5 g of the product of Example 4 (a) in 200 ml of cyclohexane is hydrogenated in the presence of ca. 6 grams of Raney nickel in the manner described in Example 2 (b). The product obtained after distillation is recrystallized from ethyl acetate to give 10.0 g of 6-ethyl-6- (m-methoxyphenyl) hexahydro-2H-azepin-2-one, m.p. 87-88 ° C.
30 Eksempel 5 6-(m-Methoxyphenyl)-6-iso-propylhexahydro-2H-azepin-2-on (a) 37,8 g 2-(m-methoxyphenyl) - 3-methylbutyronitril sættes dråbevis til en suspension af natriumamid (ud fra 4,6 g 35 natrium) i 200 ml flydende ammoniak. Efter endt tilsætning om-/røres reaktionsblandingen ved -30°C i 1/2 time, derpå tilsættes dråbevis 50,8 g ethyl-4-iodbutyrat i 150 ml ether. Reak- Ο η 150849 / tionsblandingen omrøres i 3 timer og får lov at henstå natten over. Reaktionsblandingen oparbejdes som beskrevet i eksempel 1(a). Produktet destilleres, hvorved der fås 28,6 g ethyl-5-cyano-5-m-methoxyphenyl-6-methylheptanoat med 5 kp. 146-148°C/0,01 mm Hg.Example 5 6- (m-Methoxyphenyl) -6-iso-propylhexahydro-2H-azepin-2-one (a) 37.8 g of 2- (m-methoxyphenyl) -3-methylbutyronitrile are added dropwise to a suspension of sodium amide ( (4.6 g of sodium) in 200 ml of liquid ammonia. After the addition is complete, the reaction mixture is stirred at -30 ° C for 1/2 hour, then 50.8 g of ethyl 4-iodo-butyrate is added dropwise in 150 ml of ether. The reaction mixture is stirred for 3 hours and allowed to stand overnight. The reaction mixture is worked up as described in Example 1 (a). The product is distilled to give 28.6 g of ethyl 5-cyano-5-m-methoxyphenyl-6-methylheptanoate with 5 kp. 146-148 ° C / 0.01 mm Hg.
(b) 24,8 g af ovennævnte ester hydrogeneres i 250 ml cyclohexan i nærværelse af ca. 6,0 g nikkelkatalysator som beskrevet i eksempel 2(b). Fjernelse af opløsningsmidlet giver 4,69 g hvide krystaller med smp. 146-148°C. Omkrystalli-10 sation fra ethylacetat giver farveløse nåle af 6-(m-methoxy- phenyl)-6-iso-propylhexahydro-2H-azepin-2-on med smp. 148-150°C.(b) 24.8 g of the above ester are hydrogenated in 250 ml of cyclohexane in the presence of ca. 6.0 g nickel catalyst as described in Example 2 (b). Removal of the solvent gives 4.69 g of white crystals with m.p. 146-148 ° C. Recrystallization from ethyl acetate affords colorless needles of 6- (m-methoxyphenyl) -6-iso-propylhexahydro-2H-azepin-2-one with m.p. 148-150 ° C.
Fundet: C = 73,7%, H = 9,0%, N = 5,2%.Found: C = 73.7%, H = 9.0%, N = 5.2%.
C16H23N02 kræver: c = 73,35%, H = 8,9%, N = 5,4%.C 16 H 23 NO 2 requires: c = 73.35%, H = 8.9%, N = 5.4%.
15 Eksempel 6 6-Ethyl-6-(m-methoxyphenyl)-hexahydro-2H-azepin-2-on (a) En blanding af 16,0 g ethyl-5-cyano-5-(m-methoxyphe- nyl)-heptanoat, 11,9 ml koncentreret svovlsyre og 2,0 g 20 palladium-på-trækul-katalysator i 125 ml methanol hydrogene- 2 res ved stuetemperatur og et tryk på 3,5 kg/cm i en Parr--hydrogenator. Katalysatoren filtreres fra, vaskes med methanol, og filtratet og vaskevæskerne forenes og inddampes i vakuum. Remanensen gøres basisk med 0,880 ammoniakopløsning, 25 ekstraheres med ether, tørres over magnesiumsulfat og inddampes, hvorved der fås 15,2 g 5-aminomethyl-5-(m-methoxyphenyl )-heptanoat.Example 6 6-Ethyl-6- (m-methoxyphenyl) hexahydro-2H-azepin-2-one (a) A mixture of 16.0 g of ethyl 5-cyano-5- (m-methoxyphenyl) - heptanoate, 11.9 ml of concentrated sulfuric acid and 2.0 g of palladium-on-charcoal catalyst in 125 ml of methanol are hydrogenated at room temperature and a pressure of 3.5 kg / cm in a Parr hydrogenator. The catalyst is filtered off, washed with methanol, and the filtrate and washings are combined and evaporated in vacuo. The residue is basified with 0.880 ammonia solution, extracted with ether, dried over magnesium sulfate and evaporated to give 15.2 g of 5-aminomethyl-5- (m-methoxyphenyl) heptanoate.
(b) Den ovennævnte amino-ester opvarmes under tilbagesvaling i 200 ml toluen i 24 timer, den frigjorte ethanol/tolu- 30 en-azeotrop fjernes ved destillation i en egnet kolonne. Overskuddet af toluen afdampes i vakuum, og remanensen krystalliseres fra en blanding af ethylacetat og petroleumsether, kogepunkt 60-80°C, hvorved der fås 8,05 g 6-ethyl-6-(m-methoxyphenyl) -hexahydro-2H-azepin- 2 -on med smp. 87-89°C.(b) The above amino ester is heated under reflux in 200 ml of toluene for 24 hours, the ethanol / toluene azeotrope released is removed by distillation in a suitable column. The excess toluene is evaporated in vacuo and the residue is crystallized from a mixture of ethyl acetate and petroleum ether, boiling at 60-80 ° C to give 8.05 g of 6-ethyl-6- (m-methoxyphenyl) hexahydro-2H-azepine. 2 -one with m.p. 87-89 ° C.
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,, 150849 12,, 150849 12
Denne forbindelse er også blevet fremstillet ved reduktion i ét trin og ringslutning ved høj temperatur uden isolering af den som mellemprodukt fremkomne aminomethylester fra afsnit (a) i dette eksempel. Ettrinsfremgangsmåden er be-5 skrevet nærmere i eksempel 4(b).This compound has also been prepared by one-step reduction and high-temperature cyclization without isolating the intermediate amino methyl ester of section (a) of this example. The one-step method is described in more detail in Example 4 (b).
Eksempel 7 3-(m-Methoxyphenyl)-3-propylhexahydro-lH-azepin 10 (a) 12 g (6-(m-methoxyphenyl)-6-propylhexahydro-2H-azepin- -2-on fra eksempel 1 i 200 ml tørt tetrahydrofuran sættes dråbevis til en omrørt suspension af 12 g lithiumaluminiumhy-drid i 200 ml ether, og blandingen omrøres derpå og opvarmes under tilbagesvaling i 7 timer. Reaktionsblandingen søn-15 derdeles ved tilsætning af 12 ml vand, 24 ml 2 N natriumhydroxid efterfulgt af 12 ml vand. Det organiske materiale, som udfælder, frafiltreres, opløsningsmidlerne fjernes, og den tilbageblivende, farveløse olie destilleres, hvorved der fås 9,8 g 3-(m-methoxyphenyl)-3-propylhexahydro-lH-aze-20 pin med kp. 123-124°C/0,15 mm Hg.Example 7 3- (m-Methoxyphenyl) -3-propylhexahydro-1H-azepine 10 (a) 12 g (6- (m-methoxyphenyl) -6-propylhexahydro-2H-azepin-2-one from Example 1 in 200 ml Dry tetrahydrofuran is added dropwise to a stirred suspension of 12 g of lithium aluminum hydride in 200 ml of ether and the mixture is then stirred and refluxed for 7 hours. The reaction mixture is then decomposed by the addition of 12 ml of water, 24 ml of 2 N sodium hydroxide, followed by The organic material which precipitates is filtered off, the solvents are removed and the residual colorless oil is distilled to give 9.8 g of 3- (m-methoxyphenyl) -3-propylhexahydro-1H-aze-20 pin. bp 123-124 ° C / 0.15 mm Hg.
(b) Denne forbindelse kan methyleres til opnåelse af 3-(m-methoxyphenyl)-l-methyl-3-propylhexahydro-lH-azepin, eller den kan omsættes med allylbromid til opnåelse af l-allyl-3-(m-methoxyphenyl)-3-propyl-hexahydro-lH-azepin.(b) This compound can be methylated to give 3- (m-methoxyphenyl) -1-methyl-3-propylhexahydro-1H-azepine, or it can be reacted with allyl bromide to give 1-allyl-3- (m-methoxyphenyl) -3-propyl-hexahydro-lH-azepine.
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Eksempel 8 3-(m-Methoxyphenyl)-1,3-dimethylhexahydro-lH-azepin (a) 11,7 g af hexahydro-2H-azepin-2-onen fra eksempel 2 i 30 tørt tetrahydrofuran sættes til en suspension af 12 g lithium-aluminiumhydrid i 200 ml ether. Den i eksempel 7 beskrevne fremgangsmåde følges, og det opnåede produkt destilleres, hvorved der fås 8,9 g 3-(m-methoxyphenyl)-3-methylhexahydro-azepin med kp. 118-125°C/0,5 mm Hg.Example 8 3- (m-Methoxyphenyl) -1,3-dimethylhexahydro-1H-azepine (a) 11.7 g of hexahydro-2H-azepin-2-one from Example 2 in dry tetrahydrofuran are added to a suspension of 12 g. lithium aluminum hydride in 200 ml of ether. The procedure described in Example 7 is followed and the product obtained is distilled to give 8.9 g of 3- (m-methoxyphenyl) -3-methylhexahydrozepine with b.p. 118-125 ° C / 0.5 mm Hg.
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13 150849 (b) 8/75 g 3-(m-methoxyphenyl)-3-methylhexahydro-lH-aze- pin omsættes med 4 ml 40%'s vandigt formaldehyd i nærværelse af 1,5 g 10%'s palladium på trækul i 100 ml ethanol i nærværelse af hydrogen ved 40 atmosfærers tryk, hvorved 5 der fås 7,7 g 3-(m-methoxyphenyl)-1,3-dimethylhexahydro-lH--azepin som en farveløs olie, kogepunkt 106-107°C/0,4 mm Hg, n33 = 1,5339.(B) 8/75 g of 3- (m-methoxyphenyl) -3-methylhexahydro-1H-azepine is reacted with 4 ml of 40% aqueous formaldehyde in the presence of 1.5 g of 10% palladium on charcoal in 100 ml of ethanol in the presence of hydrogen at 40 atmospheres to give 7.7 g of 3- (m-methoxyphenyl) -1,3-dimethylhexahydro-1H-azepine as a colorless oil, bp 106-107 ° C / 0.4 mm Hg, n33 = 1.5339.
Fundet: C = 76,8%, H = 9,8%, N * 5,9%.Found: C = 76.8%, H = 9.8%, N * 5.9%.
C15H23NO kræver: C = 77,2%, H = 9,9%, N = 6,0%.C 15 H 23 NO requires: C = 77.2%, H = 9.9%, N = 6.0%.
10 Hydrochloridet med smp. 154-155°C kan fremstilles ved behandling med propan-2-ol og en opløsning af hydrogenchlorid i ether.The hydrochloride with m.p. 154-155 ° C can be prepared by treatment with propan-2-ol and a solution of hydrogen chloride in ether.
Fundet: C = 66,7%, H = 8,9%, N = 5,0%.Found: C = 66.7%, H = 8.9%, N = 5.0%.
C15H23NO,HCl kræver: c = 66,7%, H = 8,9%, N = 5,2%.C 15 H 23 NO, HCl requires: c = 66.7%, H = 8.9%, N = 5.2%.
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Eksempel 9 3-(m-Hydroxyphenyl)-1,3-dimethylhexahydro-lH-azepin 5,1 g af produktet ifølge eksempel 8 opvarmes under til-20 bagesvaling med 50 ml 48-50%'s hydrogenbromidsyre i 3 timer. Hydrogenbromidet fjernes under formindsket tryk, og den tilbageblevne olie tørres ved gentagen inddampning fra propan-2--ol. 3-(m-Hydroxyphenyl)-1,3-dimethylhexahydro-lH-azepin krystalliserer som hydrobromidet i 6,0 g farveløse nåle ud 25 fra en blanding af propan-2-ol og ether, smeltepunkt 174-175°C. Fundet: C = 55,8%, H = 7,2%, N = 4,4%.Example 9 3- (m-Hydroxyphenyl) -1,3-dimethylhexahydro-1H-azepine 5.1 g of the product of Example 8 is heated under reflux with 50 ml of 48-50% hydrogen bromic acid for 3 hours. The hydrogen bromide is removed under reduced pressure and the residual oil is dried by repeated evaporation from propan-2-ol. 3- (m-Hydroxyphenyl) -1,3-dimethylhexahydro-1H-azepine crystallizes as the hydrobromide in 6.0 g of colorless needles from a mixture of propan-2-ol and ether, mp 174-175 ° C. Found: C = 55.8%, H = 7.2%, N = 4.4%.
Ci4H2iNO,HBr kræver: C = 56,0%, H = 7,4%, N = 4,6%.C44H₂iNO, HBr requires: C = 56.0%, H = 7.4%, N = 4.6%.
Eksempel 10 30 3-(m-Acetoxyphenyl)-1,3-dimethylhexahydro-lH-azepin 2,0 g af produktet ifølge eksempel 9 opvarmes under tilbagesvaling med 6 ml eddikesyreanhydrid og 3 ml pyridin i 3 timer. Reaktionsblandingen inddampes til en brun olie, 35 der opløses i vand og gøres basisk med natriumbicarbonatopløsning. Det basiske materiale ekstraheres med ether, tørres over 14 150849Example 10 3- (m-Acetoxyphenyl) -1,3-dimethylhexahydro-1H-azepine 2.0 g of the product of Example 9 is heated under reflux with 6 ml of acetic anhydride and 3 ml of pyridine for 3 hours. The reaction mixture is evaporated to a brown oil which is dissolved in water and made basic with sodium bicarbonate solution. The basic material is extracted with ether, dried over 1450849
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magnesiumsulfat og inddampes til en farveløs olie. Olien opløses i propan-2-ol og behandles med en opløsning af hydro-genchlorid i tør ether, hvorved der fås hydrochloridet af 3-(m-acetoxyphenyl)-1,3-dimethylhexahydro-lH-azepin. Udbytte 5 1/7 g med smp. 164-165°C.magnesium sulfate and evaporated to a colorless oil. The oil is dissolved in propan-2-ol and treated with a solution of hydrogen chloride in dry ether to give the hydrochloride of 3- (m-acetoxyphenyl) -1,3-dimethylhexahydro-1H-azepine. Yield 5 1/7 g with m.p. 164-165 ° C.
Fundet: C = 64,3%, H = 8,2%, N = 4,6%.Found: C = 64.3%, H = 8.2%, N = 4.6%.
C16H24N02C1 kræver: c = 64,55%, H = 8,1%, N = 4,7%.C 16 H 24 NO 2 Cl requires: c = 64.55%, H = 8.1%, N = 4.7%.
Eksempel 11 10 3-(m-Acetoxyphenyl)-l-methyl-3-propylhexahydro-lH-azepin Fremgangsmåden ifølge eksempel 10 følges, men under anvendelse af 1,5 g 3-(m-hydroxyphenyl)-l-methyl-3-propylhexa-hydro-lH-azepin som udgangsmateriale til dannelse af 1,36 g 15 3-(m-acetoxyphenyl)-l-methyl-3-propylhexahydro-lH-azepin efter basificering med natriumcarbonat, kogepunkt 176-178°C/0,01 mm Hg.Example 11 3- (m-Acetoxyphenyl) -1-methyl-3-propylhexahydro-1H-azepine The procedure of Example 10 is followed but using 1.5 g of 3- (m-hydroxyphenyl) -1-methyl-3- propylhexa-hydro-1H-azepine as starting material to give 1.36 g of 3- (m-acetoxyphenyl) -1-methyl-3-propylhexahydro-1H-azepine after basification with sodium carbonate, bp 176-178 ° C / 0, 01 mm Hg.
Fundet: C = 74,8%, H = 9,5%, N = 4,8%.Found: C = 74.8%, H = 9.5%, N = 4.8%.
C18H27N02 kræver: c = 74,7%, H = 9,4%, N = 4,8%.C18 H27 NO2 requires: c = 74.7%, H = 9.4%, N = 4.8%.
2020
Eksempel 12 3-Butyl-3-(m-methoxyphenyl)-1-methylhexahydro-lH-azepin (a) 12,2 g af produktet fra eksempel 3 i 200 ml tørt tetra- 25 hydrofuran reduceres med 12 g aluminiumlithiumhydrid i 200 ml tør ether på den i eksempel 7 beskrevne måde. Produktet destilleres, kogepunkt 130-140°C/0,25 mm Hg, hvorved der fås 7,14 g 3-butyl-3-(m-methoxyphenyl)-hexahydro-lH-azepin som en farveløs, mobil olie.Example 12 3-Butyl-3- (m-methoxyphenyl) -1-methylhexahydro-1H-azepine (a) 12.2 g of the product of Example 3 in 200 ml of dry tetrahydrofuran are reduced with 12 g of aluminum lithium hydride in 200 ml of dry ether in the manner described in Example 7. The product is distilled, boiling at 130-140 ° C / 0.25 mm Hg to give 7.14 g of 3-butyl-3- (m-methoxyphenyl) hexahydro-1H-azepine as a colorless mobile oil.
30 (b) 7,14 g af den sekundære base fra eksempel 12(a) methyle res reduktivt. 3-Butyl-3-(m-methoxyphenyl)-1-methylhexahydro--lH-azepin, der fremkommer som en rå olie fra reaktionsblandingen, omdannes til oxalatet (5,01 g), smeltepunkt 147-150°C. Fundet: C = 65,5%, H » 8,6%, N = 3,75.30 (b) 7.14 g of the secondary base of Example 12 (a) is methylated reductively. 3-Butyl-3- (m-methoxyphenyl) -1-methylhexahydro-1H-azepine, which is obtained as a crude oil from the reaction mixture, is converted to the oxalate (5.01 g), mp 147-150 ° C. Found: C = 65.5%, H »8.6%, N = 3.75.
35 kræver: C = 65,6%, H = 8,6%, N = 3,8%.35 requires: C = 65.6%, H = 8.6%, N = 3.8%.
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Eksempel 13 3-Butyl-3-(m-hydroxyphenyl)-1-methylhexahydro-lH-azepin 4.1 g af oxalatet fra eksempel 12(b) opvarmes under 5 tilbagesvaling med 40 ml 50%'s hydrogenbromidsyre i 2 timer. Produktet isoleres ved den i eksempel 1 beskrevne metode og omdannes til den frie base. Omkrystallisation fra petroleums-ether (kogepunkt 80-100°) giver 1,7 g 3-butyl-3-(m-hydroxyphenyl) -1-methylhexahydro-lH-azepin, smeltepunkt 116-118°C.Example 13 3-Butyl-3- (m-hydroxyphenyl) -1-methylhexahydro-1H-azepine 4.1 g of the oxalate of Example 12 (b) is heated under reflux with 40 ml of 50% hydrogen bromic acid for 2 hours. The product is isolated by the method described in Example 1 and converted to the free base. Recrystallization from petroleum ether (boiling point 80-100 °) gives 1.7 g of 3-butyl-3- (m-hydroxyphenyl) -1-methylhexahydro-1H-azepine, mp 116-118 ° C.
10 Fundet: C = 78,0%, H — 10,5%, N = 5,25%.Found: C = 78.0%, H - 10.5%, N = 5.25%.
C17H27NO kræver: c = 78,1%, H = 10,4%, N = 5,4%.C17 H27 NO requires: c = 78.1%, H = 10.4%, N = 5.4%.
Eksempel 14 15 3-Ethyl-3-(m-methoxyphenyl)-hexahydro-lH-azepin 9.1 g af azepinonen fra eksempel 4(b) i 50 ml tørt tetrahydrofuran og 50 ml ether sættes dråbevis til en omrørt suspension af 7,5 g aluminiumlithiumhydrid i 50 ml tør ether. Efter opvarmning under tilbagesvaling i 3 timer oparbejdes 20 reaktionsblandingen på den i eksempel 7 (a) beskrevne måde og destilleres, hvorved der fås 7,66 g 3-ethyl-3-(m-methoxyphenyl) -hexahydro-lH-azepin som en farveløs olie, kogepunkt 108-110°C/0,01 mm Hg.Example 14 3-Ethyl-3- (m-methoxyphenyl) hexahydro-1H-azepine 9.1 g of the azepinone of Example 4 (b) in 50 ml of dry tetrahydrofuran and 50 ml of ether are added dropwise to a stirred suspension of 7.5 g. aluminum lithium hydride in 50 ml of dry ether. After refluxing for 3 hours, the reaction mixture is worked up in the manner described in Example 7 (a) and distilled to give 7.66 g of 3-ethyl-3- (m-methoxyphenyl) hexahydro-1H-azepine as a colorless oil, boiling point 108-110 ° C / 0.01 mm Hg.
25 Eksempel 15 3-Ethyl-3-(m-hydroxyphenyl)-hexahydro-lH-azepin 2.2 g af produktet fra eksempel 14 opvarmes under tilbagesvaling med 50%'s hydrogenbromidsyre i 1 1/2 time. Reak- 30 tionsblandingen inddampes til tørhed og geninddampes med 3 portioner propan-2-ol. Den fremkomne olie opløses i propan--2-ol og fortyndes med ether. 2,5 g 3-ethyl-3-(m-hydroxyphenyl) -hexahydro-lH-azepin fås som hydrobromid, smeltepunkt 183-185°C.Example 15 3-Ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine 2.2 g of the product of Example 14 is heated under reflux with 50% hydrogen bromic acid for 1 1/2 hours. The reaction mixture is evaporated to dryness and re-evaporated with 3 portions of propan-2-ol. The resulting oil is dissolved in propane-2-ol and diluted with ether. 2.5 g of 3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine are obtained as hydrobromide, mp 183-185 ° C.
35 Fundet: C = 55,9%, H = 7,43%, N = 4,35%.Found: C = 55.9%, H = 7.43%, N = 4.35%.
C14H21NO'HBr kræver:C = 56,0%, H = 7,4%, N = 4,7%.C14H21NO'HBr requires: C = 56.0%, H = 7.4%, N = 4.7%.
Eksempel 16 16 150849 o; 3-Ethyl-3-(m-hydroxyphenyl)-1-methylhexahydro-lH-azepin (a) 5,13 g af azepinen fra eksempel 14 methyleres reduk- 5 tivt. Den fremkomne, rå olie omdannes til 4,9 g af hydrobro-midet, smeltepunktet 142-143°C. Omkrystallisation fra propan--2-ol hæver smeltepunktet for det fremkomne 3-ethyl-3-(m--methoxyphenyl)-1-methylhexahydro-lH-azapin-hydrobromid til 143-144°C.Example 16 16 150849 o; 3-Ethyl-3- (m-hydroxyphenyl) -1-methylhexahydro-1H-azepine (a) 5.13 g of the azepine of Example 14 is reductively methylated. The resulting crude oil is converted to 4.9 g of the hydrobromide, mp 142-143 ° C. Recrystallization from propan-2-ol raises the melting point of the resulting 3-ethyl-3- (m-methoxyphenyl) -1-methylhexahydro-1H-azapine hydrobromide to 143-144 ° C.
10 Fundet: C = 58,8%, H = 8,2%, N = 4,0%.Found: C = 58.8%, H = 8.2%, N = 4.0%.
C15H23NO,HBr kræver: c = 58,6%, H = 8,0%, N = 4,3%.C 15 H 23 NO, HBr requires: c = 58.6%, H = 8.0%, N = 4.3%.
(b) 2,85 g af methoxyforbindelsen fra eksempel 16(a) opvarmes under tilbagesvaling med 15 ml 80%'s hydrogenbromid-syre i 2 timer og oparbejdes på den i eksempel 9 beskrevne 15 måde. 2,47 g 3-ethyl-3-(m-hydroxyphenyl)-1-methylhexahydro--ΙΗ-azepin fås som hydrobromid, smeltepunkt 221-222°C.(b) 2.85 g of the methoxy compound of Example 16 (a) is heated under reflux with 15 ml of 80% hydrogen bromide acid for 2 hours and worked up in the manner described in Example 9. 2.47 g of 3-ethyl-3- (m-hydroxyphenyl) -1-methylhexahydro-ΙΗ-azepine are obtained as hydrobromide, mp 221-222 ° C.
Fundet: C = 57,4%, H = 7,8%, N = 4,3%.Found: C = 57.4%, H = 7.8%, N = 4.3%.
C15H23NO,HBr kræver c = 57,4%, H = 7,7%, N = 4,5%.C15H23NO, HBr requires c = 57.4%, H = 7.7%, N = 4.5%.
20 Eksempel 17 3-(m-Hydroxyphenyl)-3-propylhexahydro-lH-azepin 6,1 g af produktet fra eksempel 7 opvarmes under tilbagesvaling med 40 ml 50%’s hydrogenbromidsyre i 2 1/2 time.Example 17 3- (m-Hydroxyphenyl) -3-propylhexahydro-1H-azepine 6.1 g of the product of Example 7 is heated under reflux with 40 ml of 50% hydrogen bromic acid for 2 1/2 hours.
25 Produktet oparbejdes som beskrevet i eksempel 16(b), hvorved der fås 5,88 g hydrobromid af 3-(m-hydroxyphenyl)-3-propyl-hexahydro-lH-azepin, smeltepunkt 74-78°C, som et hygroskopisk, fast stof.The product is worked up as described in Example 16 (b) to give 5.88 g of hydrobromide of 3- (m-hydroxyphenyl) -3-propyl-hexahydro-1H-azepine, mp 74-78 ° C, as a hygroscopic, solid.
Fundet: C = 57,4%, H = 7,8%, N = 4,5%.Found: C = 57.4%, H = 7.8%, N = 4.5%.
30 C15H23NO,HBr kræver: C = 57,4%, H = 7,7%, N = 4,5%.C15H23NO, HBr requires: C = 57.4%, H = 7.7%, N = 4.5%.
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Eksempel 18 l-Carbethoxy-3-(m-hydroxypheny1)-3-propyl-hexahydro-lH-azepln 1 ml ethylchlorformiat i 10 ml chloroform sættes til en 5 afkølet opløsning af 3,14 g af det ifølge eksempel 17 fremkomne produkt i 10 ml chloroform og 2,03 g triethylamin. Efter endt tilsætning omrøres reaktionsblandingen ved stuetemperatur i 2 timer. Ether tilsættes til bundfældning af triethyl-amin-hydrochlorid/hydrobromidet, og filtratet vaskes med vand.Example 18 1-Carbethoxy-3- (m-hydroxyphenyl) -3-propyl-hexahydro-1H-azeplin 1 ml of ethyl chloroformate in 10 ml of chloroform is added to a cooled solution of 3.14 g of the product of Example 17 in 10 ml. ml of chloroform and 2.03 g of triethylamine. After completion of the addition, the reaction mixture is stirred at room temperature for 2 hours. Ether is added to precipitate the triethylamine hydrochloride / hydrobromide and the filtrate is washed with water.
10 Inddampning giver et glas, som destilleres, kogepunkt 210-220°C (badtemperatur) ved 0,005 mm Hg, hvorved der fås 1,54 g viskos olie.Evaporation gives a glass which is distilled, boiling point 210-220 ° C (bath temperature) at 0.005 mm Hg to give 1.54 g of viscous oil.
Fundet: C = 70,2%, H = 8,9%, N = 4,3%.Found: C = 70.2%, H = 8.9%, N = 4.3%.
C18H27N03 kræver: c = 70,8%, H = 8,9%, N = 4,6%.C18 H27 NO3 requires: c = 70.8%, H = 8.9%, N = 4.6%.
1515
Eksempel 19 l-Allyl-3-(m-hydroxyphenyl)-3-propylhexahydro-lH-azepin En blanding af 4,3 g af produktet fra eksempel 17 20 1,655 g 3-bromprop-l-en og 8,1 g vandfrit kaliumcarbonat i 100 ml butan-2-on opvarmes under tilbagesvaling og omrøring i 16 timer. Reaktionsblandingen afkøles, og det faste materiale fjernes ved filtrering. Fjernelse af opløsningsmidlet giver en olie, som opløses i syre og ekstraheres med ether; disse 25 etherekstrakter kasseres. Syrelaget gøres basisk med koncentreret ammoniakopløsning og ekstraheres med ether. Efter tørring fjernes etheren, hvorved der fås en viskos olie, som giver 2,5 g af et krystallinsk toluen-o-sulfonatsalt, smeltepunkt 126-127°C.Example 19 1- Allyl-3- (m-hydroxyphenyl) -3-propylhexahydro-1H-azepine A mixture of 4.3 g of the product of Example 17 20 1.655 g of 3-bromoprop-1-ene and 8.1 g of anhydrous potassium carbonate in 100 ml of butan-2-one is heated under reflux and stirred for 16 hours. The reaction mixture is cooled and the solid is removed by filtration. Removal of the solvent gives an oil which is dissolved in acid and extracted with ether; these 25 ether extracts are discarded. The acid layer is made basic with concentrated ammonia solution and extracted with ether. After drying, the ether is removed to give a viscous oil to give 2.5 g of a crystalline toluene-o-sulfonate salt, mp 126-127 ° C.
30 Fundet: C = 67,5%, H = 8,0%, N = 3,0%.Found: C = 67.5%, H = 8.0%, N = 3.0%.
C18N27NO,C7H8°3S kræver; c = 67,4%, H = 8,0%, N = 3,0%.C18N27NO, C7H8 ° 3S requires; c = 67.4%, H = 8.0%, N = 3.0%.
18 15084918 150849
Eksempel 20Example 20
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3-(m-Hydroxyphenyl)-3-methylhexahydro-lH-azepin 12,64 g af produktet ifølge eksempel 8(a) i 120 ml 5 50%'s vandig hydrogenbromidsyre opvarmes under tilbagesvaling i 1 time. Syren fjernes ved inddampning under formindsket tryk, og produktet tørres ved azeotrop destillation med propan--2-ol. Produktet (15,6 g) krystalliserer som sit hydrobromid, et hvidt, fast stof, ud fra propan-2-ol, smeltepunkt 203-204°C.3- (m-Hydroxyphenyl) -3-methylhexahydro-1H-azepine 12.64 g of the product of Example 8 (a) in 120 ml of 50% aqueous hydrobromic acid are heated at reflux for 1 hour. The acid is removed by evaporation under reduced pressure and the product is dried by azeotropic distillation with propane-2-ol. The product (15.6 g) crystallizes as its hydrobromide, a white solid, from propan-2-ol, mp 203-204 ° C.
10 Fundet: C = 54,3%, H = 6,8%, N = 4,75%.Found: C = 54.3%, H = 6.8%, N = 4.75%.
C13H19NO,HBr c = 54,55%, H = 7,0%, N = 4,5%.C 13 H 19 NO, HBr c = 54.55%, H = 7.0%, N = 4.5%.
Eksempel 21 15 l-Allyl-3-(m-hydroxyphenyl)-3-methyl-hexahydro-lH-azepin 2,86 g af produktet fra eksempel 20 opvarmes under tilbagesvaling og omrøring med en blanding af 2,8 g vandfrit kali-umcarbonat, 1,21 g 3-bromprop-l-en og 100 ml butan-2-on i 20 timer. Det faste stof fjernes ved filtrering, og filtratet 20 inddampes til en viskos olie. Olien opløses i ether, og det basiske materiale isoleres på sædvanlig måde. Destillation giver 1,62 g af en viskos olie, kogepunkt 160-165°C/0,001 mm Hg.Example 21 1-Allyl-3- (m-hydroxyphenyl) -3-methyl-hexahydro-1H-azepine 2.86 g of the product of Example 20 are heated under reflux and stirred with a mixture of 2.8 g of anhydrous potassium carbonate. , 1.21 g of 3-bromoprop-1-ene and 100 ml of butan-2-one for 20 hours. The solid is removed by filtration and the filtrate 20 is evaporated to a viscous oil. The oil is dissolved in ether and the basic material is isolated in the usual manner. Distillation gives 1.62 g of a viscous oil, boiling point 160-165 ° C / 0.001 mm Hg.
Fundet: C = 78,4%, H = 9,5%, N = 5,65%.Found: C = 78.4%, H = 9.5%, N = 5.65%.
25 C16H23NO kræver: C = 78,3%, H = 9,45%, N = 5,7%.C 16 H 23 NO requires: C = 78.3%, H = 9.45%, N = 5.7%.
Eksempel 22 3-(m-Acetoxyphenyl)-3-ethylhexahydro-lH-azepin 30 1,5 g af azepin-hydrobromidet fra eksempel 15 opvar mes i et lukket rør med en blanding af hydrogenbromid i 5 ml iseddike og 3 ml acetylbromid i 2 timer ved 100°C. Røret afkøles, og reaktionsblandingen inddampes til tørhed ved stuetemperatur og formindsket tryk. 25 ml propan-2-ol til-35 sættes og afdampes ligeledes ved stuetemperatur. Remanensen omkrystalliseres fra en blanding af propan-2-on og ether, 150849Example 22 3- (m-Acetoxyphenyl) -3-ethylhexahydro-1H-azepine 30 1.5 g of the azepine hydrobromide of Example 15 are heated in a sealed tube with a mixture of hydrogen bromide in 5 ml glacial acetic acid and 3 ml of acetyl bromide in 2 hours at 100 ° C. The tube is cooled and the reaction mixture is evaporated to dryness at room temperature and reduced pressure. 25 ml of propan-2-ol is added and evaporated at room temperature as well. The residue is recrystallized from a mixture of propan-2-one and ether, 150849
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19 hvorved der fås 1,36 g hvidlige nåle, smeltepunkt 120-125°C. Produktet omkrystalliseres fra en blanding af propan-2-on-og ether, hvorved der fås 725 mg 3-(m-acetoxyphenyl)-3-ethyl-hexahydro-lH-azepin, smeltepunkt 125-130°C (bliver ikke klar).19 to give 1.36 g of whitish needles, mp 120-125 ° C. The product is recrystallized from a mixture of propan-2-one and ether to give 725 mg of 3- (m-acetoxyphenyl) -3-ethylhexahydro-1H-azepine, m.p. 125-130 ° C (not clear).
5 Fundet: C = 56,1%, H = 7,1%, N = 4,0%.Found: C = 56.1%, H = 7.1%, N = 4.0%.
C16H23N02'HBr kræver: C = 56,15%, H = 7,1%, N = 4,1%.C 16 H 23 NO 2 · H2 Br requires: C = 56.15%, H = 7.1%, N = 4.1%.
Eksempel 23 10 3-(m-Acetoxyphenyl)-l-acetyl-3-ethylhexahydro-lH-azepinExample 23 3- (m-Acetoxyphenyl) -1-acetyl-3-ethylhexahydro-1H-azepine
Azepin-hydrobromidet fra eksempel 15 opvarmes under tilbagesvaling i 3 timer med 5 ml acetylbromid og 10 ml 45%1 s hydrogenbromid i eddikesyre. Eddikesyren og acetylbro-midet fjernes under formindsket tryk, og de sidste spor fjer-15 nes ved samdestillation med toluen. Remanensen destilleres, hvorved der fås 0,47 g af et bleggult glas, kogepunkt 170-180°C/0,5 mm Hg.The azepine hydrobromide of Example 15 is heated under reflux for 3 hours with 5 ml of acetyl bromide and 10 ml of 45% 1 sec hydrogen bromide in acetic acid. The acetic acid and acetyl bromide are removed under reduced pressure and the last traces are removed by co-distillation with toluene. The residue is distilled to give 0.47 g of a pale yellow glass, boiling point 170-180 ° C / 0.5 mm Hg.
Fundet: C = 71,25%, H = 8,4%, N = 4,6%.Found: C = 71.25%, H = 8.4%, N = 4.6%.
C18H25N03 dræver: C = 71,25%, H = 8,31%, N = 4,6%.C18 H25 NO3 kills: C = 71.25%, H = 8.31%, N = 4.6%.
2020
Eksempel 24 3- (m-Hydroxyphenyl)-3-isopropylhexahydro-lH-azepin (a) 6,8 g 6-(methoxyphenyl)-6-methylhexahydro-2H-azepin-2- 25 -on i 150 ml tetrahydrofuran reduceres med 5,0 g lithium- aluminiumhydrid som beskrevet i eksempel 7(a). Produktet destilleres, hvorved der fås 6,1 g farveløs olie, kogepunkt 110-112°C/0,01 mm Hg. Produktet kan omdannes til et hydrobro-mid og omkrystalliseres fra en blanding af propan-2-on og 30 ether, smeltepunkt 170-171°C.Example 24 3- (m-Hydroxyphenyl) -3-isopropylhexahydro-1H-azepine (a) 6.8 g of 6- (methoxyphenyl) -6-methylhexahydro-2H-azepine-2- 25 -one in 150 ml of tetrahydrofuran is reduced by 5 , 0 g of lithium aluminum hydride as described in Example 7 (a). The product is distilled to give 6.1 g of colorless oil, boiling point 110-112 ° C / 0.01 mm Hg. The product can be converted to a hydrobromide and recrystallized from a mixture of propan-2-one and 30 ether, mp 170-171 ° C.
Fundet: C = 58,65%, H = 8,0%, N = 4,3%.Found: C = 58.65%, H = 8.0%, N = 4.3%.
C16H25NO/HBr kræver: C = 58,6%, H = 8,0%, N = 4,3%.C 16 H 25 NO / HBr requires: C = 58.6%, H = 8.0%, N = 4.3%.
20 150849208
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(b) 2,5 g af azepinen fra del (a) opvarmes under tilbage svaling med 10 ml 50%'s vandig saltsyre i 1 time. Opløsningsmidlet fjernes under formindsket tryk, og de sidste spor af vand fjernes ved azeotrop destillation med propan-2-ol.(b) 2.5 g of the azepine from part (a) is heated under reflux with 10 ml of 50% aqueous hydrochloric acid for 1 hour. The solvent is removed under reduced pressure and the last traces of water are removed by azeotropic distillation with propan-2-ol.
5 2,08 g af 3-(m-hydroxyphenyl)-3-isopropylhexahydro-lH-aze- pinen fås som hydrobromid i form af farveløse nåle, smeltepunkt 95-98°C fra en blanding af propan-2-ol og ether.2.08 g of 3- (m-hydroxyphenyl) -3-isopropylhexahydro-1H-azepine are obtained as hydrobromide in the form of colorless needles, mp 95-98 ° C from a mixture of propan-2-ol and ether.
Fundet: C = 57,4%, H = 8,1%, N = 4,0%.Found: C = 57.4%, H = 8.1%, N = 4.0%.
Ο^Η^ΝΟ,ΗΒγ kræver: C = 57,3%, H = 7,7%, N = 4,5%.Ο ^ Η ^ ΝΟ, ΗΒγ requires: C = 57.3%, H = 7.7%, N = 4.5%.
1010
Eksempel 25 3-(m-Hydroxyphenyl)-l-methyl-3-isopropylhexahydro-lH-azepin (a) 3,0 g 3-(m-methoxyphenyl)-3-isopropylhexahydro-lH-15 -azepin omsættes med 3 ml 40%'s vandigt formaldehyd i nærværelse af 2,0 g 10%'s palladium på trækul i 80 ml ethanol i en Parr-hydrogenator. Efter oparbejdning anvendes 3,0 g råt produkt til næste eksperiment.Example 25 3- (m-Hydroxyphenyl) -1-methyl-3-isopropylhexahydro-1H-azepine (a) 3.0 g of 3- (m-methoxyphenyl) -3-isopropylhexahydro-1H-15-azepine are reacted with 3 ml. % aqueous formaldehyde in the presence of 2.0 g of 10% palladium on charcoal in 80 ml of ethanol in a Parr hydrogenator. After working up, 3.0 g of raw product is used for the next experiment.
(b) 3,0 g produkt fra ovennævnte omsætning opvarmes under 20 tilbagesvaling med 50%'s vandigt hydrogenbromid i 1 time.(b) 3.0 g of product from the above reaction is heated under reflux with 50% aqueous hydrogen bromide for 1 hour.
Opløsningsmidlet fjernes under formindsket tryk, og produktet opløses i vand og omdannes til den frie base. Efter ekstraktion med benzen, tørring og fjernelse af opløsningsmidlet fås 3,0 g 3-(m-hydroxyphenyl)-l-methyl-3~isopropylhe-25 xahydro-lH-azepin som et fumarat, smeltepunkt 180-182°C.The solvent is removed under reduced pressure and the product dissolved in water and converted to the free base. After extraction with benzene, drying and removal of the solvent, 3.0 g of 3- (m-hydroxyphenyl) -1-methyl-3-isopropylhexahydro-1H-azepine is obtained as a fumarate, m.p. 180-182 ° C.
Fundet: C = 66,0%, H = 8,3%, N = 3,8%.Found: C = 66.0%, H = 8.3%, N = 3.8%.
C16H25NO,C4H4°4 kræver: c = 66#1%' H = 8,0%, N = 3,85%.C16H25NO, C4H4 ° 4 requires: c = 66 # 1%, H = 8.0%, N = 3.85%.
Eksempel 26 30 -Butyl-3-(m-hydroxyphenylj-hexahydro-lH-azepin 1,61 g af azepinen fra eksempel 12(a) opvarmes under tilbagesvaling med 5 ml 50%'s vandig hydrogenbromidsyre i 1 1/2 time. Opløsningsmidlet afdampes til en olie under for-35 mindsket tryk, og produktet tørres ved gentagen inddampning med portioner af propan-2-ol. 1,64 g hydrobromid af 3-butyl-3-(m- 2i 150849 o -hydroxyphenyl)-hexahydro-lH-azepin fås som hvidlige, hygroskopiske nåle, smeltepunkt 88-94°c.Example 26 -Butyl-3- (m-hydroxyphenylj-hexahydro-1H-azepine 1.61 g of the azepine of Example 12 (a) is heated under reflux with 5 ml of 50% aqueous hydrogen bromic acid for 1 1/2 hours. is evaporated to an oil under reduced pressure, and the product is dried by repeated evaporation with portions of propan-2-ol. 1.64 g of hydrobromide of 3-butyl-3- (m-2-hydroxyphenyl) -hexahydro-hydroxyphenyl. 1 H-azepine is available as whitish, hygroscopic needles, mp 88-94 ° c.
Fundet: C = 58,35%, H = 8,2%, N = 4,0%.Found: C = 58.35%, H = 8.2%, N = 4.0%.
C16H25NO/HBr kræver: c = 58,7%, H = 8,0%, N = 4,3%.C 16 H 25 NO / HBr requires: c = 58.7%, H = 8.0%, N = 4.3%.
55
Eksempel 27 1-Ally 1-3-ethy1- 3- (m-hydroxyphenyl) -hexahydro-lH-azepinExample 27 1-Ally 1-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine
En blanding af 3,0 g 3-ethyl-3-(m-hydroxypheny1)-hexahy-10 dro-lH-azepin-hydrobromid, 1,2 g allylbromid og 3,0 g kalium-carbonat i 40 ml acetone opvarmes under tilbagesvaling i 16 timer. Overskydende acetone fjernes under formindsket tryk, 1 ml eddikesyreanhydrid tilsættes, der opvarmes i 1 time til 100°C og gøres derpå basisk med natriumcarbonatop-15 løsning. Den udfældede olie ekstraheres over i ether, som derpå ekstraheres med fortyndet saltsyre. Syreekstrakten gøres derpå basisk og ekstraheres igen med ether. Den organiske ekstrakt tørres over magnesiumsulfat og inddampes i vakuum, hvorved der fås 2,6 g råt allylderivat.A mixture of 3.0 g of 3-ethyl-3- (m-hydroxyphenyl) hexahydro-10H-azepine hydrobromide, 1.2 g of allyl bromide and 3.0 g of potassium carbonate in 40 ml of acetone is heated at reflux. for 16 hours. Excess acetone is removed under reduced pressure, 1 ml of acetic anhydride is added, heated for 1 hour to 100 ° C and then basified with sodium carbonate solution. The precipitated oil is extracted into ether, which is then extracted with dilute hydrochloric acid. The acid extract is then made basic and extracted again with ether. The organic extract is dried over magnesium sulfate and evaporated in vacuo to give 2.6 g of crude allyl derivative.
2o Remanensen opløses i den minimale mængde iso-propanol, og derpå tilsættes 50%'s hydrogenbromidsyre, indtil opløsningen er svagt sur. Den udfældede brune olie krystalliseres fra en blanding af acetone og ether og omkrystalliseres derpå fra en blanding af ethanol og ether, hvorved der fås 1,55 g 25 l-allyl-3-ethyl-3-(m-hydroxyphenyl)-hexahydro-lH-azepin som hydrobromid, smeltepunkt 141-142°C.The residue is dissolved in the minimum amount of iso-propanol and then 50% hydrogen bromide acid is added until the solution is slightly acidic. The precipitated brown oil is crystallized from a mixture of acetone and ether and then recrystallized from a mixture of ethanol and ether to give 1.55 g of 25-1-allyl-3-ethyl-3- (m-hydroxyphenyl) -hexahydro-1H -azepine as hydrobromide, mp 141-142 ° C.
Fundet: C = 60,1%, H = 7,7%, N = 3,9%.Found: C = 60.1%, H = 7.7%, N = 3.9%.
C17H25NO'HBr kræver: C = 60,15%, H = 7,7%, N = 4,1%.C17H25NO'HBr requires: C = 60.15%, H = 7.7%, N = 4.1%.
30 Eksempel 28 3-Ethyl-l-formyl-3-(m-hydroxyphenyl)-hexahydro-lH-azepinExample 28 3-Ethyl-1-formyl-3- (m-hydroxyphenyl) -hexahydro-1H-azepine
En blanding af 1,5 g 3-ethyl-3-(m-hydroxyphenyl)-hexa-hydro-lH-azepin og 10 ml 95%'s myresyre opvarmes til 160°C i 35 16 timer. Afdampning i vakuum af overskydende myresyre giver en olieagtig remanens, som opløses i benzen, vaskes med vand, fortyndet natriumcarbonatopløsning og.vand, tørres over magnesiumsulfat og inddampes, hvorved der fås 1,2 g råt produkt.A mixture of 1.5 g of 3-ethyl-3- (m-hydroxyphenyl) -hexa-hydro-1H-azepine and 10 ml of 95% formic acid is heated to 160 ° C for 16 hours. Evaporation in vacuo of excess formic acid gives an oily residue which is dissolved in benzene, washed with water, diluted sodium carbonate solution and water, dried over magnesium sulfate and evaporated to give 1.2 g of crude product.
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Fraktioneret destillation giver derefter 0,5 g af produktet, kogepunkt 240-250°C/0,001 mm Hg.Fractional distillation then gives 0.5 g of the product, boiling point 240-250 ° C / 0.001 mm Hg.
Fundet: C = 72,4%, H = 8,65%, N = 5,6%.Found: C = 72.4%, H = 8.65%, N = 5.6%.
C15H21NC>2 kræver: C = 72,8%, H = 8,5%, N = 5,7%.C15H21NC> 2 requires: C = 72.8%, H = 8.5%, N = 5.7%.
55
Eksempel 29 l-Carbethoxy-3-ethyl-3-(m-hydroxyphenyl)-hexahydro-lH-azepin Til en omrørt og isafkølet opløsning af 4,0 g 3-ethyl-10 -3-(m-hydroxyphenyl)-hexahydro-lH-azepin-hydrobromid i 20 ml chloroform sættes en opløsning af 2,66 g triethylamin i 10 ml chloroform efterfulgt af dråbevis tilsætning af en opløsning af 1,44 g ethylchlorformiat i 10 ml chloroform.Example 29 1-Carbethoxy-3-ethyl-3- (m-hydroxyphenyl) hexahydro-1H-azepine For a stirred and ice-cooled solution of 4.0 g of 3-ethyl-10 -3- (m-hydroxyphenyl) hexahydro-hydroxide 1H-azepine hydrobromide in 20 ml of chloroform is added a solution of 2.66 g of triethylamine in 10 ml of chloroform followed by dropwise addition of a solution of 1.44 g of ethyl chloroformate in 10 ml of chloroform.
Den opløsning, der fremkommer efter omrøring i 2 timer ved 15 is-temperatur, får lov at henstå yderligere 16 timer ved stuetemperatur. Ether tilsættes for at bundfælde blandingen af triethylamin-hydrochlorid og triethylamin-hydrobromid, der derpå filtreres fra. Filtratet vaskes med vand, tørres over magnesiumsulfat, inddampes under formindsket tryk, og den tilba-20 geblivende røde olie underkastes fraktioneret destillation, hvorved der fås 2,1 g l-carbethoxy-3-ethy1-3-(m-hydroxyphenyl)--hexahydro-lH-azepin, kogepunkt 172-180°C/0,001 mm Hg.The solution obtained after stirring for 2 hours at 15 ice temperature is allowed to stand for an additional 16 hours at room temperature. Ether is added to precipitate the mixture of triethylamine hydrochloride and triethylamine hydrobromide which is then filtered off. The filtrate is washed with water, dried over magnesium sulfate, evaporated under reduced pressure and the residual red oil is subjected to fractional distillation to give 2.1 g of 1-carbethoxy-3-ethyl-3- (m-hydroxyphenyl) - hexahydro-1H-azepine, boiling point 172-180 ° C / 0.001 mm Hg.
Fundet: C = 70,3%, H = 8,8%, N = 4,9%.Found: C = 70.3%, H = 8.8%, N = 4.9%.
C17H24NO kræver: c = 70,35%, H = 8,3%, N = 4,8%.C 17 H 24 NO requires: c = 70.35%, H = 8.3%, N = 4.8%.
2525
Eksempel 30 3-Ethyl-3-(m-methoxyphenyl)-hexahydro-lH-azepinExample 30 3-Ethyl-3- (m-methoxyphenyl) hexahydro-1H-azepine
En opløsning af 12,3 g 6-ethyl-6-(m-methoxyphenyl)-30 -hexahydro-2H-azepin-2-on i 30 ml natrium-tørret benzen sættes dråbevis til 56 ml benzenopløsning af 40,34 g natrium-dihy-dro-bis-(2-methoxyethoxy)-aluminat. Blandingen opvarmes derefter under tilbagesvaling i 5 timer, og komplekset sønderdeles derpå ved tilsætning af 2 N natriumhydroxidopløsning.A solution of 12.3 g of 6-ethyl-6- (m-methoxyphenyl) -30-hexahydro-2H-azepin-2-one in 30 ml of sodium-dried benzene is added dropwise to 56 ml of benzene solution of 40.34 g of sodium-benzene. dihy-dro-bis (2-methoxyethoxy) aluminate. The mixture is then heated under reflux for 5 hours and the complex is then decomposed by the addition of 2N sodium hydroxide solution.
35 Det organiske lag skilles fra og ekstraheres derpå med fortyndet saltsyre. Den sure ekstrakt gøres basisk ved tilsætning af 0,880 ammoniakopløsning og ekstraheres med ether, som efterThe organic layer is separated and then extracted with dilute hydrochloric acid. The acidic extract is made basic by the addition of 0.880 ammonia solution and extracted with ether, which after
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23 150849 tørring over magnesiumsulfat inddampes under formindsket tryk, hvorved der fås 7,0 g 3-ethyl-3-(m-methoxyphenyl)--hexahydro-lH-azepin. Denne forbindelse er også blevet fremstillet ved lithiumaluminiumhydrid-reduktion af den samme 5 2H-azepin-2-on, som det er nærmere beskrevet i eksempel 4.Evaporation under magnesium sulfate was evaporated under reduced pressure to give 7.0 g of 3-ethyl-3- (m-methoxyphenyl) hexahydro-1H-azepine. This compound has also been prepared by lithium aluminum hydride reduction of the same 5 2 H-azepin-2-one as described in more detail in Example 4.
Som angivet ovenfor har forbindelserne med formel (XVIII) smertestillende virkning som vist ved standardforsøg på forsøgsdyr. Mange viser en smertestillende virkning, som svarer til virkningen af codeinphosphat, og synes ikke at 10 skabe tilvænning og at være fri for visse uønskelige bivirkninger, der hyppigt forekommer ved smertestillende midler, såsom tendens til at forårsage konvulsioner og/eller konstipa-tion.As indicated above, the compounds of formula (XVIII) have analgesic effect as shown in standard experiments on experimental animals. Many show an analgesic effect similar to that of codeine phosphate, and do not appear to be accustomed and free from certain undesirable side effects that are frequently encountered with painkillers, such as tendency to cause convulsions and / or constipation.
Nedenstående tabeller opsummerer nogle af de farmakolo-15 giske forsøg, der er udført. Forbindelser afprøvedes, hvad angår smertestillende virkning ved en modifikation af "rottehaleslaget" ifølge D'Amour and Smith, J. Pharm. 72^ : 74, 1941. Forsøgsmaterialet blev indgivet subcutant i et doseringsniveau på 25 mg/kg, og analgesi hos dyrene blev bestemt 20 som en procentdel af den totale* mulige analgesi, som kunne opstå i forsøgsperioden.The following tables summarize some of the pharmacological tests performed. Compounds were tested for analgesic effect by a modification of the "rat tail" according to D'Amour and Smith, J. Pharm. 72 ^: 74, 1941. The test material was administered subcutaneously at a dosage level of 25 mg / kg, and analgesia in the animals was determined as a percentage of the total * possible analgesia that could occur during the experimental period.
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24 1 5 0 8 4 924 1 5 0 8 4 9
Tabel ITable I
Forsøgsmateriale Totale mulige analgesi i % 20-30 30-40 40-50 50-60 60Test material Total possible analgesia in% 20-30 30-40 40-50 50-60 60
5 Codeinphosphat XCodeine Phosphate X
Produkt ifølge eksempel 9 XProduct of Example 9 X
Produkt ifølge eksempel 10 XProduct of Example 10 X
Produkt ifølge eksempel 11 XProduct of Example 11 X
Produkt ifølge eksempel 13 XProduct of Example 13 X
10 Produkt ifølge eksempel 15 XProduct of Example 15 X
Produkt ifølge eksempel 16(a) XProduct of Example 16 (a) X
Produkt ifølge eksempel 16(b) XProduct of Example 16 (b) X
Produkt ifølge eksempel 17 XProduct of Example 17 X
Produkt ifølge eksempel 18 XProduct of Example 18 X
15 Produkt ifølge eksempel 19 XProduct of Example 19 X
Produkt ifølge eksempel 20 XProduct of Example 20 X
Produkt ifølge eksempel 21 XProduct of Example 21 X
Produkt ifølge eksempel 22 XProduct of Example 22 X
Produkt ifølge eksempel 24 XProduct of Example 24 X
20 Produkt ifølge eksempel 26 XProduct of Example 26 X
Produkt ifølge eksempel 27 XProduct of Example 27 X
Tabel II sammenligner den analgetiske middeldosis (AD,-q), den konvulsive middeldosis (CD,-q) og den dødelige middeldo-25 sis (LD^q) af visse forbindelser med formel (XVIII) med de tilsvarende værdier for codeinphosphat og d-propoxyphen-hy-drochlorid. Ved disse forsøg blev forsøgsmaterialerne indgivet intraperitonealt til mus.Table II compares the analgesic mean dose (AD, -q), convulsive mean dose (CD, -q), and lethal mean dose (LD 2) of certain compounds of formula (XVIII) with the corresponding values for codeine phosphate and d. -propoxyphen-hy-hydrochloride. In these experiments, the test materials were administered intraperitoneally to mice.
25 1 5 0 8 4 925 1 5 0 8 4 9
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Tabel IITable II
CP50 CP50 5 Forsøgsmateriale AD50 CD50 L^50 AD50 AD50CP50 CP50 5 Test Material AD50 CD50 L ^ 50 AD50 AD50
Codeinphosphat 25,5 112 127 4,39 4,98 d-Propoxyphen-hydrochlorid 45,5 120 190 2,64 4,18Codeine Phosphate 25.5 112 127 4.39 4.98 d-Propoxyphene Hydrochloride 45.5 120 190 2.64 4.18
Produkt ifølge eksempel 11 22,8 53 150 2,32 6,48Product of Example 11 22.8 53 150 2.32 6.48
Produkt ifølge eksempel 15 15,92 X 61,24 X 3,85 10 Produkt ifølge eksempel 17 37 X 140 X 3,78Product of Example 15 15.92 X 61.24 X 3.85 Product of Example 17 37 X 140 X 3.78
Produkt ifølge eksempel 19 40,1 50,4 127,3 1,26 3,18Product of Example 19 40.1 50.4 127.3 1.26 3.18
Produkt ifølge eksempel 22 14,0 X 70 X 5,0Product of Example 22 14.0 X 70 X 5.0
Produkt ifølge eksempel 27 12,0 70,0 70,0 5,8 4,8 15 X Intet tegn på konvulsive egenskaber.Product of Example 27 12.0 70.0 70.0 5.8 4.8 15 X No evidence of convulsive properties.
En noget lignende sammenligning af disse forbindelsers analgetiske og toksiske egenskaber på basis af oral indgift til mus er vist i tabel III.A somewhat similar comparison of the analgesic and toxic properties of these compounds on the basis of oral administration to mice is shown in Table III.
2020
Tabel IIITable III
CP50 CP50CP50 CP50
Forsøgsmateriale AD50 CD50 LD50 AD50 AD50 25Test Material AD50 CD50 LD50 AD50 AD50 25
Codeinphosphat 54 410 410 7,59 7,59 d-Propoxyphen-hydrochlorid 125 - 285 2,28 2,28Codeine Phosphate 54 410 410 7.59 7.59 d-Propoxyphene Hydrochloride 125 - 285 2.28 2.28
Produkt ifølge eksempel 11 65 240 530 3,69 8,15Product of Example 11 65 240 530 3.69 8.15
Produkt ifølge eksempel 15 31,11 X 142,9 X 4,59 30 Produkt ifølge eksempel 17 68 X 600 X 8,82Product of Example 15 31.11 X 142.9 X 4.59 30 Product of Example 17 68 X 600 X 8.82
Produkt ifølge eksempel 19 160,3 254,6 360 1,59 2,24 X Intet tegn på konvulsive egenskaber.Product of Example 19 160.3 254.6 360 1.59 2.24 X No evidence of convulsive properties.
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150849150849
Det vil ses af ovenstående tabeller, at forbindelser med formel (XVIII) har meget kraftige smertestillende egenskaber, og at den smertestillende virkning nås hos i det mindste adskillige ved en dosering, der er meget mindre end de dødelige 5 eller konvulsive doser.It will be seen from the above tables that compounds of formula (XVIII) have very potent analgesic properties and that the analgesic effect is achieved in at least several at a dosage much less than the lethal or convulsive doses.
Det har vist sig, at forbindelserne ifølge eksemplerne 9, 10, 21 og 27 også udviser morphin-antagonistisk virkning. Dette er et stærkt tegn på, at sådanne forbindelser vil vise sig ikke at skabe tilvænning.It has been found that the compounds of Examples 9, 10, 21 and 27 also exhibit morphine antagonistic effect. This is a strong sign that such connections will prove not to be used.
10 Det har længe været kendt, at mange smertestillende mid ler, f.eks. codein, har konstiperende virkning, og dette er sædvanligvis temmelig uønsket. Der er blevet udført forsøg med et antal forbindelser med formel (XVIII) ved to metoder for at vurdere denne virkning. Formindskelse i antallet af eks-15 krementer fra individuelle rotter efter dosering med forbindelserne med formel (XVIII) tages som et mål for konstiperende virkning. En alternativ metode, der er blevet anvendt, har været bestemmelse af den hastighed, hvormed et indifferent, farvet stof (trækul) passerer gennem tyndtarmen efter dosering 20 med forsøgsforbindelse. I alle sådanne forsøg, der er blevet udført, viser forbindelserne med formel (XVIII) sig at være mindre konstiperende end codein.It has long been known that many pain relievers, e.g. codeine, has constipative effect, and this is usually quite undesirable. A number of compounds of formula (XVIII) have been tested by two methods to evaluate this effect. Decreases in the number of excretions from individual rats after dosing with the compounds of formula (XVIII) are taken as a measure of constipation effect. An alternative method that has been used has been the determination of the rate at which an inert colored dye (charcoal) passes through the small intestine after test compound dosage 20. In all such experiments performed, the compounds of formula (XVIII) are found to be less constipating than codeine.
Claims (5)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB3920168 | 1968-08-16 | ||
| GB3920168 | 1968-08-16 | ||
| GB4206068 | 1968-09-04 | ||
| GB4206068 | 1968-09-04 | ||
| GB4694/69A GB1285025A (en) | 1968-08-16 | 1969-01-28 | Hexahydroazepines |
| GB469469 | 1969-01-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK150849B true DK150849B (en) | 1987-07-06 |
| DK150849C DK150849C (en) | 1988-02-01 |
Family
ID=27254483
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK439969AA DK141401B (en) | 1968-08-16 | 1969-08-15 | Analogous process for preparing hexahydro-1H-azepine compounds or acid addition or quaternary ammonium salts thereof. |
| DK340571A DK150849C (en) | 1968-08-16 | 1971-07-09 | HEXAHYDRO-2H-AZEPIN-2-ONES USED AS INTERMEDIATES IN THE PREPARATION OF HEXAHYDRO-1H-AZEPINE DERIVATIVES OR ANY ACID ADDITION SALT OR QUATERNATE AMMONIUM SALT |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK439969AA DK141401B (en) | 1968-08-16 | 1969-08-15 | Analogous process for preparing hexahydro-1H-azepine compounds or acid addition or quaternary ammonium salts thereof. |
Country Status (18)
| Country | Link |
|---|---|
| JP (1) | JPS505197B1 (en) |
| AR (1) | AR194353A1 (en) |
| AT (1) | AT312611B (en) |
| BE (1) | BE737548A (en) |
| CH (3) | CH536843A (en) |
| DE (1) | DE1941534C3 (en) |
| DK (2) | DK141401B (en) |
| ES (1) | ES370497A1 (en) |
| FI (1) | FI51479C (en) |
| FR (1) | FR2015812A1 (en) |
| HU (1) | HU162512B (en) |
| IE (1) | IE33382B1 (en) |
| IL (1) | IL32801A (en) |
| IT (1) | IT1053698B (en) |
| NL (1) | NL164275C (en) |
| NO (2) | NO132046C (en) |
| SE (1) | SE366043B (en) |
| YU (2) | YU34124B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1319785A (en) * | 1970-02-06 | 1973-06-06 | Wyeth John & Brother Ltd | Hexahydroazepines |
| US3666752A (en) * | 1970-03-09 | 1972-05-30 | Bristol Myers Co | 4,4-diphenylhexahydroazepine compounds |
| DE2901180A1 (en) * | 1979-01-13 | 1980-07-24 | Basf Ag | HEXAHYDRO-1,4-OXAZEPINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| SE439186B (en) * | 1980-12-04 | 1985-06-03 | Olof Ohrnell | ELASTIC CLUTCH BETWEEN ONE INTERNAL AND EXTERNAL IN RELATION TO EACH CONCENTRIC ROW |
| DE3502667A1 (en) * | 1985-01-26 | 1986-07-31 | Klöckner-Humboldt-Deutz AG, 5000 Köln | Centrifugal oil filter for internal combustion engines |
| JPWO2005037269A1 (en) * | 2003-10-21 | 2006-12-28 | 住友製薬株式会社 | Novel piperidine derivatives |
| EP3402779A1 (en) * | 2016-01-15 | 2018-11-21 | Esteve Pharmaceuticals, S.A. | 3-ethyl-3-phenylazepane derivatives having multimodal activity against pain |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2740779A (en) * | 1956-04-03 | Substituted azacycloalkanes |
-
1969
- 1969-08-06 IE IE1102/69A patent/IE33382B1/en unknown
- 1969-08-08 IL IL32801A patent/IL32801A/en unknown
- 1969-08-14 IT IT20967/69A patent/IT1053698B/en active
- 1969-08-14 BE BE737548D patent/BE737548A/xx not_active IP Right Cessation
- 1969-08-14 FR FR6928129A patent/FR2015812A1/en not_active Withdrawn
- 1969-08-14 DE DE1941534A patent/DE1941534C3/en not_active Expired
- 1969-08-14 ES ES370497A patent/ES370497A1/en not_active Expired
- 1969-08-15 YU YU2102/69A patent/YU34124B/en unknown
- 1969-08-15 NL NL6912483.A patent/NL164275C/en not_active IP Right Cessation
- 1969-08-15 CH CH1241969A patent/CH536843A/en not_active IP Right Cessation
- 1969-08-15 NO NO3311/69A patent/NO132046C/no unknown
- 1969-08-15 HU HUWI160A patent/HU162512B/hu unknown
- 1969-08-15 JP JP44064669A patent/JPS505197B1/ja active Pending
- 1969-08-15 FI FI692393A patent/FI51479C/en active
- 1969-08-15 CH CH340773A patent/CH554865A/en not_active IP Right Cessation
- 1969-08-15 SE SE11395/69A patent/SE366043B/xx unknown
- 1969-08-15 DK DK439969AA patent/DK141401B/en not_active IP Right Cessation
- 1969-08-15 CH CH1056472A patent/CH554864A/en not_active IP Right Cessation
- 1969-08-18 AT AT789269A patent/AT312611B/en not_active IP Right Cessation
-
1971
- 1971-07-09 DK DK340571A patent/DK150849C/en not_active IP Right Cessation
- 1971-11-30 AR AR239343A patent/AR194353A1/en active
-
1975
- 1975-02-11 NO NO750442A patent/NO142395C/en unknown
- 1975-10-27 YU YU02716/75A patent/YU39170B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL32801A0 (en) | 1969-11-12 |
| IE33382B1 (en) | 1974-06-12 |
| NO132046C (en) | 1975-09-10 |
| FI51479C (en) | 1977-01-10 |
| FI51479B (en) | 1976-09-30 |
| CH536843A (en) | 1973-05-15 |
| NO142395B (en) | 1980-05-05 |
| DE1941534B2 (en) | 1979-11-15 |
| IL32801A (en) | 1973-06-29 |
| NO750442L (en) | 1970-02-17 |
| CH554864A (en) | 1974-10-15 |
| NO132046B (en) | 1975-06-02 |
| AR194353A1 (en) | 1973-07-13 |
| NL164275B (en) | 1980-07-15 |
| DK141401C (en) | 1980-09-08 |
| DE1941534A1 (en) | 1970-04-09 |
| FR2015812A1 (en) | 1970-04-30 |
| YU39170B (en) | 1984-08-31 |
| YU210269A (en) | 1978-06-30 |
| BE737548A (en) | 1970-02-16 |
| DK141401B (en) | 1980-03-10 |
| ES370497A1 (en) | 1972-04-16 |
| JPS505197B1 (en) | 1975-02-28 |
| NL6912483A (en) | 1970-02-18 |
| NO142395C (en) | 1980-08-13 |
| DE1941534C3 (en) | 1980-07-24 |
| DK150849C (en) | 1988-02-01 |
| HU162512B (en) | 1973-02-28 |
| NL164275C (en) | 1980-12-15 |
| IT1053698B (en) | 1981-10-10 |
| CH554865A (en) | 1974-10-15 |
| YU34124B (en) | 1978-12-31 |
| AT312611B (en) | 1974-01-10 |
| SE366043B (en) | 1974-04-08 |
| YU271675A (en) | 1982-02-28 |
| IE33382L (en) | 1970-02-16 |
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