DK141624B

DK141624B - Analogous process for preparing morphinan derivatives.

Info

Publication number: DK141624B
Application number: DK440172AA
Authority: DK
Inventors: Irwin J Pachter; Bernard R Belleau; Ivo Monkovic
Original assignee: Bristol Myers Co
Priority date: 1971-09-08
Filing date: 1972-09-06
Publication date: 1980-05-12
Also published as: DE2243961A1; CH590845A5; CA999578A; FR2154481B1; GB1412130A; NL162072C; SE403286B; DE2265256C2; DE2243961C2; SE7506292L; DD100255A5; MY7900027A; JPS5310596B2; IE36687L; YU227772A; BE788478A; KE2911A; DE2265255C2; CY980A; JPS4834864A

Description

01) FREMLÆ8GEL8ESSKRIFT 1M624 DANMARK lntc|! c 07 D 221/28 (21) Ansøgning nr, 4401/72 (22) Indleveret den 6· SeP· 1972 1^1 (23) Løbedag 6· Ββρ. 1972 ν' (44) Ansøgningen fremlagt og „ fremlaggeleesskriftet offentliggjort den 1 2 · maj 19°001) SUBMISSION STATEMENT 1M624 DENMARK lntc |! c 07 D 221/28 (21) Application No, 4401/72 (22) Filed on 6 · SeP · 1972 1 ^ 1 (23) Race Day 6 · Ββρ. 1972 ν '(44) The application submitted and the' Writing Notice published on 1 2 · May 19 ° 0

DIREKTORAT^ FORDIRECTORATE ^ FOR

PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begeeret fre denPATENT AND TRADEMARK (30) Priority requested

8. sep. 1971, 178837, USSep 8 1971, 178837, US

13. jan. 1972, 217633, USJan 13 1972, 217633, US

(71) BRISTOL-MYERS COMPANY, J>^5 Park Avenue, New York, N.Y. 10022, US.(71) BRISTOL-MYERS COMPANY, J> ^ 5 Park Avenue, New York, N.Y. 10022, US.

(72) Opfinder: Irwin J. Pachter, 101 Woodberry Lane, Fayetteville, N.Y., US: Bernard R. Belleau, 1076 Chelsea Drive, Ottawa, CA: Ivo Monkovio, 44 des Acacias,"Oandiac, Quebec, CA.(72) Inventor: Irwin J. Pachter, 101 Woodberry Lane, Fayetteville, N.Y., US: Bernard R. Belleau, 1076 Chelsea Drive, Ottawa, CA: Ivo Monkovio, 44 of Acacias, "Oandiac, Quebec, CA.

(74) Fuldmægtig under sagens behandling:(74) Plenipotentiary in the proceedings:

Th. Ostenfeld Patent bureau A/s.__ (64) Analogifremgangsmåde til fremstilling af morphinanderivater.Th. Ostenfeld Patent bureau A / s .__ (64) Analogous process for the preparation of morphinan derivatives.

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte morphinanderivater, der er nyttige som analgetika og/eller narkotiske antagonister.The present invention relates to an analogous process for the preparation of novel morphinan derivatives useful as analgesics and / or narcotic antagonists.

(-)-14-Hydroxy-3-methoxy-N-methylmorphinan og derivater deraf er omtalt af Y.K. Sawa og H. Tada i Tetrahedron, 24, pp. 6185-6196. I dette skrift angives forbindelsen 14-hydroxy-3-methoxy-N-methylmorphinan at være fremstillet ud fra 14-hydroxydehydrothebainon, et opium alkaloid.(-) - 14-Hydroxy-3-methoxy-N-methylmorphinan and derivatives thereof are disclosed by Y.K. Sawa and H. Tada in Tetrahedron, 24, pp. 6185-6196. In this specification, the compound 14-hydroxy-3-methoxy-N-methylmorphinane is stated to be prepared from 14-hydroxydehydrothebainone, an opium alkaloid.

Beskrivelsen til USA patent nr. 3.166.559 omhandler forbindelser med den generiske formel: 2 141624 fssSJ \ A Ca'Phc ) HQ V og r^N-CH,U.S. Patent No. 3,166,559 discloses compounds of the generic formula: 2,61624 fssSJ \ A Ca'Phc) HQ V and r ^ N-CH,

/Tvv \7~\ B/ Tvv \ 7 ~ \ B

ro' r1 hvor R betegner et hydrogenatom eller en (lavere)alkylgruppe (f.eks. methyl, ethyl, propyl), betegner et hydrogenatom, en aryloxygruppe (f.eks. phenyloxy, naphthyloxy) eller substitueret phenyloxy eller substitueret naphthyloxy, hvor substituenten er (lavere)alkyl (f.eks. methyl, ethyl, propyl), (lavere)alkoxy (f.eks. methoxy, ethoxy, propoxy), nitro eller amino, X betegner et hydrogenatom eller en hydroxylgruppe, og hvor der i formel B findes en eller to dobbeltbindinger i C-ringen.wherein R represents a hydrogen atom or a (lower) alkyl group (e.g., methyl, ethyl, propyl), represents a hydrogen atom, an aryloxy group (e.g., phenyloxy, naphthyloxy) or substituted phenyloxy or substituted naphthyloxy, wherein the substituent is (lower) alkyl (e.g., methyl, ethyl, propyl), (lower) alkoxy (e.g., methoxy, ethoxy, propoxy), nitro or amino, X represents a hydrogen atom or a hydroxyl group, and wherein in the formula B contains one or two double bonds in the C-ring.

I beskrivelsen til britisk patent nr. 1.028.407 omtales forbindelser med den generiske formelIn the specification of British Patent No. 1,028,407, compounds of the generic formula are mentioned

r~ti-CH9-Yr ~ ti-CH9-Y

ro' Vro 'V

hvor R betegner en alkylgruppe, som ikke indeholder mere end S carbon-atomer (f.eks. methyl, ethyl, propyl), R* betegner et hydrogenatom eller en aryloxygruppe (f.eks. phenyloxy eller naphthyloxy), R" betegner en methylengruppe, en carbonylgruppe eller en ketaliseret carbonyl-gruppe (f.eks. ethylendioxymethylen eller diethoxymethylen), X betegner et hydrogenatom eller en hydroxylgruppe, og Y betegner en alkylgruppe med ikke mere end 5 carbonatomer (f.eks. methyl, ethyl eller propyl), en arylgruppe (f.eks. phenyl eller naphthyl) eller en aralkylgruppe, hvor alkylbestanddelen ikke indeholder mere end 5 carbonatomer (f.eks. benzyl eller phenethyl), hvilke forbindelser udviser forskellige farmakologiske aktiviteter, såsom analgesisk aktivitet, antitussiv aktivitet og anti-inflammatorisk aktivitet.wherein R represents an alkyl group containing no more than S carbon atoms (e.g., methyl, ethyl, propyl), R * represents a hydrogen atom or an aryloxy group (e.g., phenyloxy or naphthyloxy), R "represents a methylene group , a carbonyl group or a ketalized carbonyl group (e.g. ethylene dioxymethylene or diethoxymethylene), X represents a hydrogen atom or a hydroxyl group, and Y represents an alkyl group having no more than 5 carbon atoms (e.g., methyl, ethyl or propyl), an aryl group (e.g., phenyl or naphthyl) or an aralkyl group wherein the alkyl component contains no more than 5 carbon atoms (e.g., benzyl or phenethyl) exhibiting various pharmacological activities such as analgesic activity, antitussive activity, and anti-inflammatory activity.

3 14162Λ3 14162Λ

Den foreliggende opfindelse angår nu en analogifremgangsmåde til fremstilling af morphinanderivater med formlen: nfifThe present invention now relates to an analogous process for the preparation of morphinan derivatives of the formula: nfif

UU

hvor R1 betegner -CH2-CH=CH2, -CH2~-<] eller -CH2 “O , R2 betegner H eller alkyl med 1-6 carbonatomer eller et farmaceutisk anvendeligt syreadditionssalt deraf, hvilken fremgangsmåde er ejendommelig ved, at man A) omsætter en forbindelse med formlen:wherein R 1 represents -CH 2 -CH = CH 2, -CH 2 ~ - <] or -CH 2 "O, R 2 represents H or alkyl of 1-6 carbon atoms or a pharmaceutically useful acid addition salt thereof, which process is characterized by reacting A) a compound of the formula:

. f~~INH. f ~~ INH

,nÆ> (II) u 2' hvor R betegner alkyl med 1-6 carbonatomer, med et alkylerings-eller acyleringsmiddel med formlen: W- z - x hvor W betegner en gruppe i form af -CH=CH2,-<^] eller-^^> , z be-, n>> (II) u 2 'where R represents alkyl of 1-6 carbon atoms, with an alkylating or acylating agent of the formula: W- z - x where W represents a group in the form of -CH = CH 2, - <^] or - ^^>, z be-

It tegner carbonyl (-C-) eller -CH2-, og X betegner chlor, brom eller iod, i et inert organisk opløsningsmiddel i nærværelse af en organisk tertiær amin til dannelse af en forbindelse med formlen: z ’w R20''k^iJv‘)K (III) u 2' hvor R , Z og W har den ovennævnte betydning og 4 141624 oIt represents carbonyl (-C-) or -CH 2 -, and X represents chlorine, bromine or iodine, in an inert organic solvent in the presence of an organic tertiary amine to form a compound of the formula: z 'w R 20 iJv ') K (III) u 2' where R, Z and W have the above meaning and 4

IIII

B) såfremt Z betegner carbonyl (-C-)omsætter forbindelsen (III) med lithiumaluminiumhydrid i et inert organisk opløsningsmiddel til dannelse af en forbindelse med formlen:B) if Z represents carbonyl (-C-) reacting the compound (III) with lithium aluminum hydride in an inert organic solvent to form a compound of the formula:

-N-CHg-W-N-CH-W

fT I A0Ii CIV) R^o ·,fT I A0Ii CIV) R ^ o ·,

UU

21 hvor R og W har den ovenfor angivne betydning, eller et farmaceutisk anvendeligt syreadditionssalt deraf, hvorefter man, om ønsket spalter etherfunktionen i forbindelse (IV) · ved behandling med hydrogenbromidsyre, bortribromid eller pyridinhydrochlorid til dannelse af forbindelsen med formlen: -N-R1 θβ °Η fu) HO *i u hvor R har den ovenfor angivne betydning, eller et farmaceutisk anvendeligt syreadditionssalt deraf.21 wherein R and W are as defined above, or a pharmaceutically useful acid addition salt thereof, whereupon, if desired, the ether function of compound (IV) is cleaved by treatment with hydrobromic acid, boron tribromide or pyridine hydrochloride to give the compound of formula: -N-R1 θβ ° Η fu) HO * iu where R has the meaning given above, or a pharmaceutically useful acid addition salt thereof.

De omhandlede forbindelser med den almene formel (I) har uventet vist sig at være værdifulde som analgetika og/eller narkotiske antagonister.The present compounds of general formula (I) have unexpectedly been found to be valuable as analgesics and / or narcotic antagonists.

Det foretrækkes, at o f 1. R i trin A betegner methyl, det inerte organiske opløsningsmiddel er methylenchlorid, dichlorethan eller en (lavere)alkanol, den organiske tertiære amin er pyridin eller triethylamin, og reaktionen udføres ved en temperatur i intervallet fra ca. 15°C til ca. tilbagesvalingstemperatur, eller 2. det organiske opløsningsmiddel i trin A er methanol, ethanol, n-propanol eller isopropanol, den tertiære amin er triethylamin, og reaktionen udføres ved ca. tilbagesvalingstemperatur i fra ca. 5 til ca. 20 timer.It is preferred that o f 1. R in Step A represents methyl, the inert organic solvent is methylene chloride, dichloroethane or a (lower) alkanol, the organic tertiary amine is pyridine or triethylamine, and the reaction is carried out at a temperature in the range of ca. 15 ° C to approx. reflux temperature, or 2. the organic solvent of step A is methanol, ethanol, n-propanol or isopropanol, the tertiary amine is triethylamine, and the reaction is carried out at ca. reflux temperature in from approx. 5 to approx. 20 hours.

De ifølge opfindelsen fremstillede forbindelser indeholder morphi- nanbasiskernen, som nummereres og angives ved følgende planformel: 5 U1624 ΙιίΆ* 5The compounds of the invention contain the morphine base nucleus which is numbered and denoted by the following plan formula: 5 U1624 ΙιίΆ * 5

Skønt der er tre asymmetriske carbonatomer (markeret med stjerner) i morphi-nanmolekylet, er kun to diastereoisomere (racemiske) former mulige, fordi iminoethanosystemet knyttet til stilling 9.og 13, geometrisk er bundet til en cis-(1,3-diaksial)-fusion. Disse racemater kan derfor kun afvige ved ringenes B og C samlingspunkt med andre ord ved konfigurationen af carbonatom 14. Den eneste variable vil være cis- og transforbindelsen imellem 5 (13)- og 8 (14)-bindingerne (Analgetics, Ed. George de Stevens, Academic Press, New York, side 137 (1965). Når 5 (13)- og 8 (14)-bindingerne indbyrdes er i transstilling, har man forbindelser, der almindeligvis betegnes som "isomorphinaner". På den anden side har man, når 5 (13)- og 8(14)-bindingerne indbyrdes er i cis-stilling, forbindelser der almindeligvis betegnes som "morphinaner". Anvendelsen af en grafisk angivelse har til hensigt at indbefatte den dl-raceraiske blanding og de adskilte d- og 1-isomere deraf.Although there are three asymmetric carbon atoms (marked with asterisks) in the morphine molecule, only two diastereoisomeric (racemic) forms are possible because the iminoethano system attached to positions 9 and 13 is geometrically bound to a cis- (1,3-diaxial) fusion. In other words, these racemates can differ only at the junction of rings B and C in the configuration of carbon atom 14. The only variable will be the cis and trans link between the 5 (13) and 8 (14) bonds (Analgetics, Ed. George de Stevens, Academic Press, New York, page 137 (1965) When the 5 (13) and 8 (14) bonds are in trans position, there are compounds commonly referred to as "isomorphinans". When the 5 (13) and 8 (14) bonds are mutually in the cis position, compounds commonly referred to as "morphinans". The use of a graphical indication is intended to include the dl raceric mixture and the separate d- and 1-isomers thereof.

Betegnelsen "farmaceutisk anvendeligt syreadditionssalt" har til hensigt at indbefatte alle de uorganiske og organiske syresalte af de ifølge opfindelsen fremstillede forbindelser, hvilke salte almindeligvis anvendes til fremstilling af ikke-toxiske salte af farmaceutiske præparater indeholdende aminfunktioner. Belysende eksempler på sådanne salte er salte dannet ved at blande forbindelsen med formel I med saltsyre, svovlsyre, salpetersyre, phosphorsyre, phosphorsyrling, hydrogenbromid-syre, maleinsyre, æblesyre, ascorbinsyre, citronsyre eller vinsyre, pamoinsyre (pamoic acid), laurinsyre, stearinsyre, palmitinsyre, oliesyre, myristinsyre, laurylsvovlsyre, naphthalinsulfonsyre, linolsyre eller linolensyre og lignende.The term "pharmaceutically useful acid addition salt" is intended to include all the inorganic and organic acid salts of the compounds of the invention, which salts are commonly used to prepare non-toxic salts of pharmaceutical preparations containing amine functions. Illustrative examples of such salts are salts formed by mixing the compound of formula I with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphoric acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, citric or tartaric acid, pamoic acid, lauric acid, palmitic acid, oleic acid, myristic acid, lauryl sulfuric acid, naphthalene sulfonic acid, linoleic or linolenic acid and the like.

6 14TS24 I det foreliggende betyder betegnelsen "inert organisk opløsningsmiddel" et organisk opløsningsmiddel, som ikke deltager i reaktionen, således at det fremkommer uomdannet fra reaktionen. Sådanne opløsningsmidler er methylenchlorid, chloroform, dichlorethan, tetrachlormethan, benzen, toluen, ether, ethylacetat, xylen, tetrahydrofuran, dioxan, dimethylacetamid, dimethylforamid og lignende, når der anvendes et syrehalogenid. Når der udføres en alkyleringsreaktion kan det benyttede inerte opløsningsmiddel også indbefatte (lavere)alkanoler, såsom methanol, ethanol, n-propanol, isopropanol og lignende. Betegnelsen "organisk tertiær amin" betyder en som protonacceptor ved alkylerings-og acyleringsreaktioner almindeligt anvendt tertiær amin. Sådanne aminer er tri(lavere)alkylaminer, f.eks. trimethylamin, triethylamin og lignende, pyridin, dimethylanilin, N-methylpiperidin og lignende.6 14TS24 In the present term, the term "inert organic solvent" means an organic solvent which does not participate in the reaction so as to appear unchanged from the reaction. Such solvents are methylene chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene, ether, ethyl acetate, xylene, tetrahydrofuran, dioxane, dimethylacetamide, dimethylforamide and the like when an acid halide is used. When carrying out an alkylation reaction, the inert solvent used may also include (lower) alkanols such as methanol, ethanol, n-propanol, isopropanol and the like. The term "organic tertiary amine" means a tertiary amine commonly used as a proton acceptor in alkylation and acylation reactions. Such amines are tri (lower) alkylamines, e.g. trimethylamine, triethylamine and the like, pyridine, dimethylaniline, N-methylpiperidine and the like.

Udgangsmaterialet morphinaner med formel (II) kan fremstilles på følgende måde: Man A) omsætter en forbindelse med formlen: •2Jl ju« Jl (v) ? hvor R' betegner alkyl med 1-6 carbonatomer, med trifluoreddike-syreanhydrid eller trifluoracetylhalogenid, hvor halogenidet er chlor, brom eller iod, i et inert organisk opløsningsmiddel til dannelse af en forbindelse med formlen: COCF-j ftXJu 2 hvor R' har den ovennævnte betydning.The starting material morphinans of formula (II) can be prepared as follows: Man A) translates a compound of formula: • 2Jl ju «Jl (v)? represents alkyl of 1-6 carbon atoms, with trifluoroacetic anhydride or trifluoroacetyl halide, wherein the halide is chlorine, bromine or iodine, in an inert organic solvent to form a compound of the formula: COCF-j ftXJu 2 where R 'has it the aforementioned meaning.

B) epoxidiserer forbindelse (VI) med en perbenzoesyre i et inert organisk opløsningsmiddel ved fra ca. 10°C til ca. 40°C til dannelse af en forbindelse med formlen: 7 141624 iFo tvn) 2 hvor RT har den ovennævnte betydning, C) deacylerer forbindelse (VII) ved behandling med natrium-borhydrid i en (lavere)alkanol til dannelse af en forbindelse med formlen: CVHI) 2 hvor Rf har den ovennævnte betydning, og D) omsætter forbindelse (VIII) med lithiumaluminiumhydrid ved forøget temperatur i et inert organisk opløsningsmiddel til dannelse af en forbindelse med formlen: <"> u 2 hvor R’ har den ovennævnte betydning.B) epoxidizes compound (VI) with a perbenzoic acid in an inert organic solvent at from ca. 10 ° C to approx. 40 ° C to form a compound of formula: 7 wherein RT has the above meaning, C) deacylates compound (VII) by treatment with sodium borohydride in a (lower) alkanol to form a compound of formula : CVHI) 2 where Rf has the above meaning and D) converts compound (VIII) with lithium aluminum hydride at elevated temperature in an inert organic solvent to give a compound of formula: wherein R 'has the above meaning.

Acyleringsmidlet i trin A) er fortrinsvis trifluoreddikesyre-anhydrid, og det inerte organiske opløsningsmiddel er fortrinsvis ether, dioxan eller tetrahydrofuran, især tør ether, i trin B) er perbenzoesyren fortrinsvis m-chlorperbenzoesyre, som anvendes i et molært overskud på ca. 101 i methylenchlorid eller dichlorethan ved ca. stuetemperatur, i trin C) er den (lavere)alkanol fortrinsvis methanol, ethanol, n-propanol eller isopropanol, især absolut ethanol, i hvilket trin der anvendes en temperatur ved ca. tilbagesvalingstemperatur i fra ca. 3 til ca. 10 minutter, og i trin D) er det organiske opløsningsmiddel fortrinsvis ether, dioxan eller især tetrahydrofuran, i hvilket trin der anvendes en temperatur ved ca. tilbagesvalingstemperatur i fra ca. 10 til ca. 60 minutter, fortrinsvis ca. 15 minutter.The acylating agent of step A) is preferably trifluoroacetic anhydride, and the inert organic solvent is preferably ether, dioxane or tetrahydrofuran, especially dry ether, in step B), the perbenzoic acid is preferably m-chloroperbenzoic acid used in a molar excess of approx. 101 in methylene chloride or dichloroethane at ca. room temperature, in step C), the (lower) alkanol is preferably methanol, ethanol, n-propanol or isopropanol, especially absolute ethanol, in which step a temperature is used at approx. reflux temperature in from approx. 3 to approx. 10 minutes, and in step D), the organic solvent is preferably ether, dioxane or especially tetrahydrofuran, in which step a temperature is used at approx. reflux temperature in from approx. 10 to approx. 60 minutes, preferably approx. 15 minutes.

U1&24 8U1 & 24 8

Udgangsmaterialerne med formel (V) kan fremstilles ved en fremgangsmåde, hvor man A) dehydrerer en forbindelse med formlen: ^ι^-^Γί-οο2κ10 , [ f βΟ, ΛΤΥΊ 2 10 hvor R* har den ovenfor anførte betydning og R betegner (lavere) alkyl, med et dehydreringsmiddel til dannelse af en forbindelse med formlen: rf% rø • ^The starting materials of formula (V) can be prepared by a process in which A) dehydrates a compound of formula: ^ ι ^ - ^ Γί-οο2κ10, [f βΟ, ΛΤΥΊ 2 10 where R * has the meaning given above and R represents ( lower) alkyl, with a dehydrating agent to form a compound of the formula: rf% red

. I. IN

2 10 hvor R* og R har den ovennævnte betydning, og B) hydrolyserer forbindelse (X) ved behandling med et alkali-metalhydroxid i en højtkogende alkanol med 6 til 12 carbonatomer ved en temperatur ved ca. tilbagesvalingstemperatur.Wherein R * and R are as defined above, and B) hydrolyzes compound (X) by treatment with an alkali metal hydroxide in a high boiling alkanol having 6 to 12 carbon atoms at a temperature of approx. reflux temperature.

I trin A) er dehydreringsmidlet fortrinsvis POCl^, thionylchlorid eller KHSO^, i en tertiær amin i form af pyridin, n-methylpiperidin, triethylamin eller N,N-dimethylanilin, og hvor • 2 R betegner CH^, ligger temperaturen fortrinsvis i intervallet fra ca. 15°C til ca. 40°C, og i trin B) er hydroxidet fortrinsvis natrium- eller kaliumhydroxid.In step A), the dehydrating agent is preferably POClOC, thionyl chloride or KHSO ^, in a tertiary amine in the form of pyridine, n-methylpiperidine, triethylamine or N, N-dimethylaniline, and where 2R represents CH₂, the temperature is preferably in the range. from approx. 15 ° C to approx. 40 ° C, and in step B) the hydroxide is preferably sodium or potassium hydroxide.

Det er i teknikken velkendt, at det er muligt for nogle narkotiske analgetica forbindelser at besidde både agonistiske og antagonistiske egenskaber. En agonist er en forbindelse, som efterligner et narkotisk analgeticum og besidder analgetiske egenskaber. En antagonist er en forbindelse, som modvirker de analgetiske og euphoriske egenskaber hos et narkotisk analgeticum. Det er muligt for en forbindelse at besidde begge egenskaber. Et godt eksempel på en sådan forbindelse er cyclazocin.It is well known in the art that it is possible for some narcotic analgesic compounds to possess both agonistic and antagonistic properties. An agonist is a compound that mimics a narcotic analgesic and possesses analgesic properties. An antagonist is a compound that counteracts the analgesic and euphoric properties of a narcotic analgesic. It is possible for a connection to possess both properties. A good example of such a compound is cyclazocin.

9 U16249 U1624

Hydrochloridsaltene af forbindelse (18 ), (19.), (19 a), (19 b) og ( 21) (se eksemplerne nedenfor) afprøvedes in vivo til bestemmelse af deres agonistiske og/eller antagonistiske egenskaber.The hydrochloride salts of compounds (18), (19.), (19 a), (19 b) and (21) (see the examples below) were tested in vivo to determine their agonistic and / or antagonistic properties.

Af den efterfølgende tabel fremgår resultaterne af afprøvningerne. Sammenligningsforbindelserne er pentazocin: 2-dimethylalkyl-5,9-dimethyl-2,-hydroxybenzomorphan, nalorphin: 7,8-didehydro-4,5-epoxy-17-(2-propenyl)morphinan-3,6-diol, levallorphan: 17-allyl-morphinan-3-ol, cyclazocin: 2-cyclopropylmethyl-5,9-dimethyl-2'-hydroxybenzomorphan og naloxon: 17-allyl-4,5a-epoxy-3-14-dihydroxy-morphinan-6-on. De angivne talværdier er det antal mg/kg legemsvægt af forbindelsen, som frembringer en agonistisk eller antagonistisk virkning hos 50¾ af de mus og rotter, som anvendtes ved afprøvningen (ed50).The following table shows the results of the tests. Comparative compounds are pentazocin: 2-dimethylalkyl-5,9-dimethyl-2, -hydroxybenzomorphan, nalorphine: 7,8-didehydro-4,5-epoxy-17- (2-propenyl) morphinan-3,6-diol, levallorphan: 17-allyl-morphinan-3-ol, cyclazocin: 2-cyclopropylmethyl-5,9-dimethyl-2'-hydroxybenzomorphan and naloxone: 17-allyl-4,5a-epoxy-3-14-dihydroxy-morphinan-6-one . The indicated numerical values are the number of mg / kg body weight of the compound which produces an agonistic or antagonistic effect in 50¾ of the mice and rats used in the test (ed50).

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Det fremgår tydeligt af afprøvningen, at forbindelserne (19) (19a)og (21) besidder svag subkutan analgetisk virkning, men er relativt kraftige parenterale antagonister. Samtidig udviser forbindelse (18) kraftig analgesi, men svag antagonisme ved parenteral indgivelse.It is clear from the assay that compounds (19) (19a) and (21) possess weak subcutaneous analgesic action but are relatively potent parenteral antagonists. At the same time, compound (18) exhibits strong analgesia but weak antagonism on parenteral administration.

De kraftigste narkotiske antagonister ifølge tabellen er^-3,14-dihydroxy-N-cyclopropylmethylmorphinan (19 a). Forbindelsen er aktiv både oralt og parenteralt. Det normale parenterale dosisinterval for voksne mennesker ligger fra ca. 0,25 til 10 mg tre til fire gange pr; dag. Oralt ligger dosen i intervallet fra ca. 2 til ca. 50 mg tre eller fire gange pr. dag.The most potent narcotic antagonists of the table are ^ -3,14-dihydroxy-N-cyclopropylmethylmorphinan (19a). The compound is active both orally and parenterally. The normal parenteral dose range for adult humans ranges from approx. 0.25 to 10 mg three to four times per; day. Orally, the dose ranges from approx. 2 to approx. 50 mg three or four times per day. day.

Det har været angivet i litteraturen, at forbindelsen haloperidol, 4/4-(p-chlorphenyl)-4-hydroxypiperiding7-4'-fluorbutyrophenon (Merck Index, 8th Edition, side 515) har fundet nogen experimentel anvendelse ved afbødningen af narkotikamisbrug-abstinenssymptomer. Det kan derfor være ønskværdigt at kombinere haloperidol med de ifølge opfindelsen fremstillede narkotiske antagonister, især^-3,14-dihydroxy-N-cyclopropylmethylmorphinan til dannelse af et produkt, som ikke kun modvirker narkotikamisbrug, men samtidig tilvejebringer støtteterapi i fravær af opiater.It has been reported in the literature that the compound haloperidol, 4 / 4- (p-chlorophenyl) -4-hydroxypiperiding7-4'-fluorobutyrophenone (Merck Index, 8th Edition, page 515) has found some experimental use in the alleviation of drug abuse withdrawal symptoms. . Therefore, it may be desirable to combine haloperidol with the narcotic antagonists of the invention, especially β-3,14-dihydroxy-N-cyclopropylmethylmorphinan to form a product which not only counteracts drug abuse but at the same time provides support therapy in the absence of opiates.

Haloperidol indgives almindeligvis oralt i en mængde på fra 0,5 til 5,0 mg to eller tre gange daglig afhængende af sygdomsgraden. En dosis haloperidol i dette interval vil blive indgivet samtidig med en effektiv dosis af den narkotiske antagonist til frembringelse af det ønskede resultat.Haloperidol is usually administered orally in an amount of from 0.5 to 5.0 mg two or three times daily depending on the degree of disease. A dose of haloperidol in this range will be administered concomitantly with an effective dose of the narcotic antagonist to produce the desired result.

Andre kombinationer vil indbefatte de narkotiske antagonister i kombination med beroligende midler, såsom chlordiazepoxid og diazepam, eller phenathiaziner, som chlorpromazin, primazin eller methotrime-prazin.Other combinations will include the narcotic antagonists in combination with sedatives such as chlorine diazepoxide and diazepam, or phenathiazines such as chlorpromazine, primazine or methotrime prazine.

Fremstilling af udgangsmaterialer 3,4-dihydro-7-methoxy-2,2-tetramethylen-l(2H)-naphthalenon (2) 12 U162ÅPreparation of starting materials 3,4-dihydro-7-methoxy-2,2-tetramethylene-1 (2H) -naphthalenone (2) 12 U162Å

En nitrogenatmosfære opretholdtes under hele den følgende omsætning. Til en omrørt og til tilbagesvaling opvarmet suspension af 12 g (0,5 mol) natriumhydrid i 100 ml tør benzen sattes i løbet af 30 minutter 16,6 g (0,2 mol) vandfri t-amylalkohol. Reaktionsblandingen omrørtes og tilbage-svaledes i 15 minutter og derpå tilsattes dråbevis en opløsning af 35,2 g (0,2 mol) 7-methoxy-3,4-dihydro-l(2H)-naphthalenon i 100 ml tør benzen. Efter yderligere 15 minutter, tilsattes 54,0 g (0,25 mol) 1,4-dibrombutan i løbet af et tidsrum på 15 minutter efterfulgt af 100 ml tør benzen. Den resulterende reaktionsblanding omrørtes og til-bagesvaledes i 50 timer. Den afkøledes så, vaskedes to gange med vand, tørredes over vandfri natriumsulfat og koncentreredes ved formindsket tryk. Den residuale gule olie opløstes i 400 ml petroleumsether (kogepunkt 30-60°C), behandledes med trækul, filtreredes, og opløsningsmidlet afdampedes. Den resulterende klare lysegule olie (45,7 g) destilleredes ved formindsket tryk, og fraktionen kogende ved 120-123°C/ 0,05 mm Hg opsamledes. Denne fremgangsmåde gav 29,4 g (65%) farveløs spiroketon (2).Det infrarøde spektrum (IR) og det kernemagnetiske resonansspektrum (NMR) stemte overens med strukturen.A nitrogen atmosphere was maintained throughout the following reaction. To a stirred and refluxed suspension of 12 g (0.5 mole) of sodium hydride in 100 ml of dry benzene was added 16.6 g (0.2 mole) of anhydrous t-amyl alcohol over 30 minutes. The reaction mixture was stirred and refluxed for 15 minutes, then a solution of 35.2 g (0.2 mole) of 7-methoxy-3,4-dihydro-1 (2H) -naphthalenone in 100 ml of dry benzene was added dropwise. After an additional 15 minutes, 54.0 g (0.25 mol) of 1,4-dibromobutane was added over a period of 15 minutes followed by 100 ml of dry benzene. The resulting reaction mixture was stirred and refluxed for 50 hours. It was then cooled, washed twice with water, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residual yellow oil was dissolved in 400 ml of petroleum ether (boiling point 30-60 ° C), treated with charcoal, filtered and the solvent evaporated. The resulting clear pale yellow oil (45.7 g) was distilled off at reduced pressure and the fraction boiling at 120-123 ° C / 0.05 mm Hg was collected. This procedure yielded 29.4 g (65%) of colorless spiroketone (2). The infrared spectrum (IR) and the nuclear magnetic resonance spectrum (NMR) were consistent with the structure.

Analyse beregnet for C. 78,22; H. 7,88.Analysis calculated for C. 78.22; H. 7.88.

Fundet: C. 77,96; H. 7,93.Found: C, 77.96; H. 7.93.

l-hydroxy-7-methoxy-l,2,3,4-tetrahydro-2,2-tetramethylen-l-naphtha- lenacetonitril (5)1-Hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthalenacetonitrile (5)

CNCN

Til en omrørt opløsning af 13,8 ml (0,022 mol) 1,6 M n-butyllithium i hexan ved -80°C under nitrogen sattes hurtigt 13,8 ml vandfri tetra-hydrofuran (THF) øjeblikkeligt efterfulgt af en opløsning af 0,82 g (0,02 mol) acetonitril i 20 ml THF, som tilsattes i løbet af 7 minutter. Efter omrøring i 1 time ved -80°C, behandledes den resulterende hvide suspension i løbet af 5 minutter med en opløsning af 4,60 g (0,02 mol) spiroketon (2)i 20 ml THF. Kuldebadet fjernedes, og opløsningen omrørtes i 10 minutter, før den udhældtes i isvand syrnet med saltsyre.To a stirred solution of 13.8 ml (0.022 mol) of 1.6 M n-butyllithium in hexane at -80 ° C under nitrogen was quickly added 13.8 ml of anhydrous tetrahydrofuran (THF) immediately followed by a solution of 0 82 g (0.02 mole) of acetonitrile in 20 ml of THF which was added over 7 minutes. After stirring for 1 hour at -80 ° C, the resulting white suspension was treated over 5 minutes with a solution of 4.60 g (0.02 mol) of spiroketone (2) in 20 ml of THF. The cold bath was removed and the solution was stirred for 10 minutes before being poured into ice water acidified with hydrochloric acid.

13 14162413 141624

Lagene adskiltes, og det vandige lag ekstraheredes med tre 25 ml portioner benzen.The layers were separated and the aqueous layer was extracted with three 25 ml portions of benzene.

Efter tørring over vandfri natriumsulfat, opnåedes ved afdampning af opløsningsmidlet og omkrystallisation af det resterende faststof i chloroform 4,4 g (801) hvidt faststof(3) , smeltepunkt 140-142°C. IR- og NMR-spektrene stemte overens med strukturen.After drying over anhydrous sodium sulfate, by evaporation of the solvent and recrystallization of the residual solid in chloroform, 4.4 g (801) of white solid (3), mp 140-142 ° C, were obtained. The IR and NMR spectra were consistent with the structure.

sp

Analyse beregnet for 75,24; H. 7,80; N. 5,16.Analysis calculated for 75.24; H. 7.80; N, 5.16.

Fundet: C. 75,12; H. 7,91; N. 4,89.Found: C, 75.12; H. 7.91; N, 4.89.

1-(2-aminoethyl)-7-methoxy-l,2,3,4-tetrahydro-2,2-tetramethylen-1-naphthol (4)1- (2-aminoethyl) -7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene-1-naphthol (4)

Til en omrørt suspension af 0,57 g (0,015 mol) lithiumaluminium-hydrid i 20 ml vandfri tetrahydrofuran (THF) under nitrogenatmosfære sattes en opløsning af 2,71 g (0,01 mol) forbindelse (3). i 20 ml tetrahydrofuran. Reaktionsblandingen omrørtes i 4 timer ved stuetemperatur (r.t.). Den afkøledes så og behandledes med 0,6 ml vand efterfulgt af 0,6 ml 5N natriumhydroxid og til slut 1,8 al vand. Det uorganiske materiale frafiltreredes og vaskedes grundigt med ether. Filtratet ekstraheredes med to 15 ml portioner IN saltsyre. Ekstrakten blev gjort basisk med vandig ammoniak, og den frie base optoges i ether.To a stirred suspension of 0.57 g (0.015 mol) of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran (THF) under a nitrogen atmosphere was added a solution of 2.71 g (0.01 mol) of compound (3). in 20 ml of tetrahydrofuran. The reaction mixture was stirred for 4 hours at room temperature (r.t.). It was then cooled and treated with 0.6 ml of water followed by 0.6 ml of 5N sodium hydroxide and finally 1.8 all water. The inorganic material was filtered off and washed thoroughly with ether. The filtrate was extracted with two 15 ml portions of 1N hydrochloric acid. The extract was basified with aqueous ammonia and the free base was taken up in ether.

Efter tørring over vandfrit natriumsulfat og afdampning af opløsningsmidlet, opnåedes 2,2 g lysegul olie (4). Den omdannedes til oxalat-saltet i acetone og rekrystalliseredes i methanol. Denne fremgangsmåde gav 2,9 g (761) hvidt faststof indeholdende 1 mol krystallisations-methanol, smeltepunkt 178-180.After drying over anhydrous sodium sulfate and evaporation of the solvent, 2.2 g of pale yellow oil (4) was obtained. It was converted to the oxalate salt in acetone and recrystallized in methanol. This procedure gave 2.9 g (761) of white solid containing 1 mole of crystallization methanol, mp 178-180.

Ved et andet eksperiment opnåedes forbindelse (4) ud fra forbindelse (2) uden isolering af forbindelse (3) , som følger: 4,6 (0,02 mol) spiroketon(2) i 20 ml tetrahydrofuran omdannedes til nitrilen (3) i overensstemmelse med den ovenfor beskrevne' fremgangsmåde. Til den resulterende kolde opløsning (-80°C) af forbindelse 14 utm (3) sattes 1,14 g (0,03 mol) lithiumaluminiumhydrid i små portioner. Efter fuldførelse af tilsætningen, omrørtes reaktionsblandingen ved stuetemperatur i 4 timer. Efter oparbejdning som ovenfor, opnåedes 5,7 g (75¾ total) af oxalatsaltet af forbindelse (4¾ smeltepunkt 179-180°C. Ved begge fremgangsmåder stemte IR- og NMR-spektrene overens med det ønskede produkt.In another experiment, compound (4) was obtained from compound (2) without isolation of compound (3) as follows: 4.6 (0.02 mol) of spiroketone (2) in 20 ml of tetrahydrofuran was converted to the nitrile (3) in accordance with the method described above. To the resulting cold solution (-80 ° C) of compound 14 µm (3) was added 1.14 g (0.03 mole) of lithium aluminum hydride in small portions. After completion of the addition, the reaction mixture was stirred at room temperature for 4 hours. After working up as above, 5.7 g (75¾ total) of the oxalate salt of compound (4¾ melting point 179-180 ° C) were obtained. In both methods, the IR and NMR spectra were consistent with the desired product.

Analyse beregnet for (*17^25^2*CH^OH: C. 63,31; H. 7,70; N.3,69. Fundet: C. 63,41; H. 7,43; N.3,79.Analysis calculated for (* 17 ^ 25 ^ 2 * CH2 OH: C. 63.31; H. 7.70; N.3.69. Found: C. 63.41; H. 7.43; N.3 , 79th

4a-(2-aminoethyl)-1,2,5,4,4a,9-hexahydro-6-methoxyphenanthren (5) ®3oA[0|4a- (2-aminoethyl) -1,2,5,4,4a, 9-hexahydro-6-methoxyphenanthrene (5) ® 300A [0 |

Metode A:Method A:

Forbindelse (4) /1,50 g (0,00548/7 (fri base frigjort fra 2 g oxalatsalt) i 5 ml ether behandledes med 1,5 ml koncentreret HC1 under nitrogenatmosfære ved 55°-60°C i 5 timer. Til den afkølede blanding sattes i rækkefølge 10 ml ether og 10 ml vand. Efter omrystning, adskiltes de to lag. Det sure lag blev gjort alkalisk med vandig ammoniak og ekstraheredes med ether. Etherlaget tørredes (K^CO^) og koncentreredes til dannelse af 1,30 g lysegul olie(5). Den omdannedes til et oxalatsalt i acetone. Krystallerne frafiltreredes og vaskedes med en lille mængde methylenchlorid. IR- og NMR-spektrene stemte overens med strukturen.Compound (4) / 1.50 g (0.00548 / 7 (free base released from 2 g of oxalate salt) in 5 ml of ether was treated with 1.5 ml of concentrated HCl under nitrogen atmosphere at 55 ° -60 ° C for 5 hours). The cooled mixture was added successively to 10 ml of ether and 10 ml of water. After shaking, the two layers were separated. The acidic layer was made alkaline with aqueous ammonia and extracted with ether. The ether layer was dried (K 2 CO 2) and concentrated to give 1 , 30 g of pale yellow oil (5) It was converted to an oxalate salt in acetone The crystals were filtered off and washed with a small amount of methylene chloride, the IR and NMR spectra matched the structure.

Udbytte 1,7 g (961) hvidt faststof, smeltepunkt 18743°C.Yield 1.7 g (961) white solid, mp 18743 ° C.

Analyse beregnet for C/^NO.c. 65,69; H. 7,25; N. 4,03.Analysis calculated for C 65.69; H. 7.25; N, 4.03.

Fundet: C. 64,44; H. 7,47; N. 4-,43.Found: C, 64.44; H. 7.47; N. 4-, 43.

Metode B: 120 g af oxalatsaltet af forbindelse (4) opslæmmedes i 700 ml vand og dertil sattes 400 ml benzen og 60 ml koncentreret ammoniak. Blandingen omrørtes, indtil al faststoffet var forsvundet (ca. 15 minutter), og derpå adskiltes lagene. Det vandige lag ekstraheredes med 15 U1S24 yderligere 100 ml benzen, og de kombinerede benzenlag rystedes med 200 ml mættet natriumchloridopløsning, filtreredes over °S ^on" centreredes i vakuum. Den residuale olie (ca. 90 g) opløstes i 300 ml ether i en 1 liter rund kolbe, og under afkøling med et is-vandbad og omskvulpning tilsattes omhyggeligt 90 ml koncentreret HC1 og derpå tilbagesvaledes forsigtigt på dampbad i 3 timer i et lukket system under anvendelse af en oliebobler. Lagene adskiltes så, og til det vandige lag sattes 150 ml vand. Efter afkøling frafiltreredes faststoffet og vaskedes med 50 ml acetonitril til dannelse af 80-85 g af HC1-saltet. Fra moderluden kan en yderligere høst af produktet opnås ved frigørelse af den frie base og gentagelse af den ovenstående HC1-behandling. Produktet rekrystalliseredes som hydrochloridet i methanol-ether, smeltepunkt 135°C (dekomponering).Method B: 120 g of the oxalate salt of compound (4) was slurried in 700 ml of water and to this was added 400 ml of benzene and 60 ml of concentrated ammonia. The mixture was stirred until all the solid had disappeared (about 15 minutes) and then the layers were separated. The aqueous layer was extracted with an additional 100 ml of benzene and the combined benzene layers were shaken with 200 ml of saturated sodium chloride solution, filtered over ° C, centrifuged in vacuo. The residual oil (about 90 g) was dissolved in 300 ml of ether. 1 liter round flask, and while cooling with an ice-water bath and rinsing was carefully added 90 ml of concentrated HCl and then gently refluxed on a steam bath for 3 hours in a closed system using an oil bubbler. The layers were then separated and added to the aqueous layer. After cooling, the solid was filtered off and washed with 50 ml of acetonitrile to give 80-85 g of the HCl salt, from the mother liquor a further harvest of the product can be obtained by releasing the free base and repeating the above HCl treatment. The product was recrystallized as the hydrochloride in methanol-ether, mp 135 ° C (decomposition).

Analyse beregnet for C^y^jNO.HCl.CHjOH: C,66,34; H. 8,66; N. 4,29. Fundet: C. 66,34; H. 8,02; N. 4,46.Analysis calculated for C ^ y ^NO.HCl.CH₂OH: C, 66.34; H, 8.66; N, 4.29. Found: C. 66.34; H. 8.02; N, 4.46.

4a-[2-(ethoxycarbonylamino)-ethyl]-1,2,3,4,4a,9-hexahydro-6-methoxy-phenanthren (6) fQj |) HHCOfcEt4- [2- (ethoxycarbonylamino) ethyl] -1,2,3,4,4a, 9-hexahydro-6-methoxy-phenanthrene (6) f

Til en omrørt opløsning af 51,4 g (0,2 mol) amin (5)og 19,75 g (0,25 mol) pyridin i 200 ml methylenchlorid sattes dråbevis 27,125 g (0,25 mol) ethylchlorformiat ved is-vandbadtemperatur (5-10°C). Efter omrøring i 10 minutter ekstraheredes opløsningen med 100 ml fortyndet saltsyre efterfulgt af 100 ml vand. Methylenghloridopløsningen tørredes over vandfri natriumsulfat og inddampedes til dannelse af en olie, som opløstes i en ether-petroleumsetherblanding og filtreredes igennem en celit-trækulblanding til dannelse af en lysegul olie i kvantitativt udbytte (65,8 g). IR- og NMR-spektrene stemte overens med strukturen.To a stirred solution of 51.4 g (0.2 mole) of amine (5) and 19.75 g (0.25 mole) of pyridine in 200 ml of methylene chloride was added dropwise 27.125 g (0.25 mole) of ethyl chloroformate at ice-water bath temperature. (5-10 ° C). After stirring for 10 minutes, the solution was extracted with 100 ml of dilute hydrochloric acid followed by 100 ml of water. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated to give an oil which was dissolved in an ether-petroleum ether mixture and filtered through a celite charcoal mixture to give a pale yellow oil in quantitative yield (65.8 g). The IR and NMR spectra were consistent with the structure.

Analyse beregnet for ^g^yNO^: C. 72,9; H. 8,26; N. 4,25.Analysis calculated for g ^ ^NO ^: C, 72.9; H. 8.26; N. 4.25.

Fundet: C. 72,71; H. 8,27; N. 4,25.Found: C, 72.71; H. 8.27; N. 4.25.

16 utm 10,10a-a-epoxy-4a[2- (ethoxycarbonylamino)-ethyl] -1,2,5,4,4a,9,10 , 10a-octahydro-6-methoxyphenanthren (7)16 µm 10,10a-α-epoxy-4a [2- (ethoxycarbonylamino) ethyl] -1,2,5,4,4a, 9,10,10a-octahydro-6-methoxyphenanthrene (7)

Til en omrørt og afkølet (5-10°C) opløsning af 65,8 g (0,2 mol) af forbindelse(6) i 150 ml methylenchlorid sattes i små portioner 25 g (0,22 mol) 55! m-chlorperbenzoesyre. Den resulterende blanding fik lov at stå ved stuetemperatur i fem timer. Efter filtrering vaskedes filtratet med en 10! natriumsulfitopløsning, indtil en prøve for peroxider med iod-stivelsespapir var negativ. Opløsningen vaskedes så med en 5! vandig natriumhydrogencarbonatopløsning og til slut med vand og en mættet natriumchloridopløsning. Efter tørring over vandfri natriumsulfat, inddampedes methylenchloridopløsningen i vakuum. Den residuale gule olie optoges i ether, og den resulterende opløsning fortyndedes med petroleumsether. Den tågede blanding filtreredes igennem en celit-trækulblanding og inddampedes til tørhed til dannelse af en olie i en mængde på 65,8 g (95,4!). IR- og NMR-spektrene stemte overens med strukturen.To a stirred and cooled (5-10 ° C) solution of 65.8 g (0.2 mole) of compound (6) in 150 ml of methylene chloride was added in small portions 25 g (0.22 mole) of 55! m-chloroperbenzoic acid. The resulting mixture was allowed to stand at room temperature for five hours. After filtration, the filtrate was washed with a 10! sodium sulfite solution until a test for iodine starch paper peroxides was negative. The solution was then washed with a 5! aqueous sodium bicarbonate solution and finally with water and a saturated sodium chloride solution. After drying over anhydrous sodium sulfate, the methylene chloride solution was evaporated in vacuo. The residual yellow oil was taken up in ether and the resulting solution diluted with petroleum ether. The misty mixture was filtered through a celite charcoal mixture and evaporated to dryness to give an oil in an amount of 65.8 g (95.4 L). The IR and NMR spectra were consistent with the structure.

Analyse beregnet for ^20^27^41 C. 69,50; H. 7,88; N. 4,05.Analysis calculated for ^ 20 ^ 27 ^ 41 C. 69.50; H. 7.88; N. 4.05.

Fundet: C. 70,10; H. 7,97; N. 3,97.Found: C, 70.10; H. 7.97; N, 3.97.

N-ethoxycarbonyl-14-hydroxy-3-methoxyisomerphinan (8) XOTho£| 141624 17N-ethoxycarbonyl-14-hydroxy-3-methoxyisomerphinane (8) XOTho 141624 17

Den følgende omsætning udførtes under en nitrogenatmosfære. Til en omrørt og til tilbagesvaling opvarmet suspension af 1,76 g (73,34 mmol) natriumhydrid i 200 ml tør benzen sattes en opløsning af 5,87 g (66,67 mmol) tør t-amylalkohol i 50 ml tør benzen. Da hydrogenudviklingen var taget af (ca. 15 minutter) tilsattes i løbet af 4 timer dråbevis en opløsning af 23,0 g (66,67 mmol) epoxid (7) i 500 ml tør benzen. Efter fuldendelse af tilsætningen, omrørtes reaktionsblandingen og tilbagesvaledes i 18 timer. Efter afkøling tilsattes 400 ml isvand,og benzenlaget vaskedes med vand og derpå med en mættet natriumchloridopløsning. Efter tørring over vandfri natriumsulfat og inddampning ved formindsket tryk, opløstes den residuale olie i ether, og den resulterende opløsning fortyndedes med petroleumsether. Den uklare opløsning filtreredes gennem en celit-trækulbiånding og inddampedes til dannelse af 20,0 g (87¾) af en gul olie. En prøve destilleret wed 160°C/0,05 mm tryk gav en olie, som størknede ved henstand, smeltepunkt 50°C. IR- og NMR-spektrene stemte overens med strukturen.The following reaction was carried out under a nitrogen atmosphere. To a stirred and refluxed suspension of 1.76 g (73.34 mmol) of sodium hydride in 200 ml of dry benzene was added a solution of 5.87 g (66.67 mmol) of dry t-amyl alcohol in 50 ml of dry benzene. When the hydrogen evolution had subsided (about 15 minutes), a solution of epoxide (7) in 23 ml of dry benzene was added dropwise over 4 hours. After completion of the addition, the reaction mixture was stirred and refluxed for 18 hours. After cooling, 400 ml of ice water was added and the benzene layer was washed with water and then with a saturated sodium chloride solution. After drying over anhydrous sodium sulfate and evaporation at reduced pressure, the residual oil was dissolved in ether and the resulting solution diluted with petroleum ether. The turbid solution was filtered through a celite charcoal bond and evaporated to give 20.0 g (87¾) of a yellow oil. A sample distilled wed 160 ° C / 0.05 mm pressure gave an oil which solidified on standing, melting point 50 ° C. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for: ^0^27^4: C. 69,54; H. 7,88; N. 4,05.Analysis calculated for: δ O 27 4 4: C, 69.54; H. 7.88; N. 4.05.

Fundet: C. 69,21; H. 8,01; N, 3,95.Found: C, 69.21; H. 8.01; N, 3.95.

N-ethoxycarbonyl-3-methoxy- Δ! -morphinan (9) ^ν^/ΛΝ-COgEtN-ethoxycarbonyl-3-methoxy-Δl -morphinan (9) ^ ν ^ / ΛΝ-COgEt

Til en afkølet og omrørt opløsning af 48,0 g (0,139 mol) af den rå (8) -forbindelse i 96 ml tør pyridin sattes dråbevis 48 ml POClj under nitrogenatmosfære. Reaktionsblandingen fik lov at stå ved stuetemperatur i 7 dage, fortyndedes med 200 ml benzen og hældtes derpå omhyggeligt ud i isvand. Vandlaget ekstraheredes med 100 ml benzen.To a cooled and stirred solution of 48.0 g (0.139 mol) of the crude (8) compound in 96 ml of dry pyridine was added dropwise 48 ml of POClj under a nitrogen atmosphere. The reaction mixture was allowed to stand at room temperature for 7 days, diluted with 200 ml of benzene and then carefully poured into ice water. The water layer was extracted with 100 ml of benzene.

De kombinerede benzenekstrakter vaskedes med mættet natriumchloridopløsning og tørredes så over vandfri natriumsulfat. Fjernelsen af opløsningsmidlet gav en brun olie, som opløstes i ether. Den resulterende opløsning fortyndedes først med petroleumsether (kogepunkt 30-60°C), indtil den blev uklar og filtreredes så igennem en celit-trækulblånding. Afdampning af opløsningsmidlet gav 36,0 g (79¾) farveløs olie. IR- og NMR-spektrene stemte overens med strukturen.The combined benzene extracts were washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. The removal of the solvent gave a brown oil which was dissolved in ether. The resulting solution was first diluted with petroleum ether (bp 30-60 ° C) until it became cloudy and then filtered through a celite charcoal mixture. Evaporation of the solvent gave 36.0 g (79¾) of colorless oil. The IR and NMR spectra were consistent with the structure.

141624 18141624 18

Analyse beregnet for C. 73,37; Η- 7,70; Ν· 4,28.Analysis calculated for C. 73.37; Η- 7.70; 4 · 4.28.

Fundet: C. 73,22; Η. 8,33; N. 4,12.Found: C, 73.22; Η. 8.33; N, 4.12.

3-methoxy- A8’^-morphinan (10)3-Methoxy-A8 + - morphinan (10)

OISLAND

En blanding af 32,7 g C0,1 mol) rå(9)-forbindelse, 160 ml n-octanol og 28,0 g KOH-perler tilbagesvaledes under nitrogenatmosfære i 45 minutter. Efter afkøling behandledes blandingen med vand og ether (600 ml). Vandlaget bortkastedes, og det organiske lag ekstraheredes med 300 ml 2N HC1 og 2 x 300 ml vand. De kombinerede vandige ekstrakter gjordes basiske med vandig ammoniak, og den frie base optages i ether til dannelse af 20 g råt produkt efter tørring over K^CO^ og inddampning. Produktet omdannedes til et oxalatsalt i vandfri ether. Det resulterende salt rekrystalliseredes i en acetone-methanolblanding til dannelse af 12 g produkt (34,81), smeltepunkt 180-182°C. Rekrystallisation i en methanol-acétoneblanding gav en prøve smeltende ved 187-389°C. IR-og NMR-spektrene stemte overens med strukturen.A mixture of 32.7 g of 0.1 mole crude (9) compound, 160 ml of n-octanol and 28.0 g of KOH beads was refluxed under nitrogen atmosphere for 45 minutes. After cooling, the mixture was treated with water and ether (600 ml). The water layer was discarded and the organic layer was extracted with 300 ml of 2N HCl and 2 x 300 ml of water. The combined aqueous extracts were basified with aqueous ammonia and the free base was taken up in ether to give 20 g of crude product after drying over K 2 CO 2 and evaporation. The product was converted to an oxalate salt in anhydrous ether. The resulting salt was recrystallized in an acetone-methanol mixture to give 12 g of product (34.81), mp 180-182 ° C. Recrystallization in a methanol-acetone mixture gave a sample melting at 187-389 ° C. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for ci7H21N0*C2H2° : C* 66>07» H. N. 4>06·Analysis calculated for c17H21NO * C2H2 °: C * 66> 07 »H. N. 4> 06 ·

Fundet: C. 66,28; H. 6,72; N. 4,11.Found: C. 66.28; H. 6.72; N, 4.11.

5-methoxy-N-trifluoracetyl- Δ8»14 -morphinan (11) Λϊ-COCFj 141624 195-methoxy-N-trifluoroacetyl-Δ8 »14 -morphinane (11) Λϊ-COCF₂

Til en opløsning af 5,1 g (20 nmol) af den sekundære aain(iø)i 60 ml tør ether tilsattes 24 g (280 mmol) Na^O^. Blandingen afkøledes og omrørtes kraftigt og 32 ml (228 mmol) trifluoreddikesyreanhydriø tilsattes så hurtigt som muligt uden at herredømmet over reaktionen mistedes. Kølebadet fjernedes, og den kraftige omrøring fortsattes i .20 minutter. Reaktionsblandingen udbældtes i chloroform, det overskydende anhydrid destrueredes med is, og chloroform-H)plø§ningen vaskedes med vand, tørredes, og inddampedes til dannelse af en olie vejende 6,33 g. Olien dækkedes med 15 ml ether, og den krystalliserede ved henstand. Den filtreredes til dannelse af et faststof vejende 4,96 g (701), smeltepunkt 94-96-C. IR- og NMR-spektrene stemte overens med strukturen.To a solution of 5.1 g (20 nmol) of the secondary amine (iu) in 60 ml of dry ether was added 24 g (280 mmol) of Na 2 O 2. The mixture was cooled and stirred vigorously and 32 ml (228 mmol) of trifluoroacetic acid anhydride was added as quickly as possible without losing control of the reaction. The cooling bath was removed and vigorous stirring was continued for 20 minutes. The reaction mixture was precipitated in chloroform, the excess anhydride was destroyed with ice, and the chloroform-H solution was washed with water, dried and evaporated to give an oil weighing 6.33 g. The oil was covered with 15 ml of ether and crystallized at standing. It was filtered to give a solid weighing 4.96 g (701), mp 94-96-C. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for Cj^gH^NO^: C. 64,95; H. 5,74; N. 3,99.Analysis calculated for C CjHH ^NO ^: C, 64.95; H, 5.74; N. 3.99.

Fundet: C. 65,34; H. 6,76; N. 3,03.Found: C, 65.34; H. 6.76; N. 3.03.

8,14-epoxy-5-methoxy-N-trifluoracetyliBondiinan (12) 1 S • '8,14-Epoxy-5-methoxy-N-trifluoroacetylBondiinane (12) 1S

Fremgangsmåden er den samme, som fremgangsmåden beskrevet ved fremstillingen af forbindelse (7) »og der anvendes følgende materialer: 3,85 g (10,96 mmol) forbindelse XX, 2,07 g (12 mmol) 851 m-chlorperbenzoesyre, og 30 ml methylenchlorid. Reaktionstiden var 6 timer.The process is the same as the process described in the preparation of compound (7) and the following materials are used: 3.85 g (10.96 mmol) of compound XX, 2.07 g (12 mmol) of 851 m-chloroperbenzoic acid, and ml of methylene chloride. The reaction time was 6 hours.

Efter den sædvanlige oparbejdelse dækkedes den residuale olie med 5 ml ether. Der fremkom krystaller, som samledes ved filtrering.After the usual work-up, the residual oil was covered with 5 ml of ether. Crystals were obtained which collected by filtration.

En analytisk prøve fremstilledes ved rekrystallisation i methanol, smeltepunkt 102-105°C, udbytte: 3,35 g (82,61). IR- og NMR-spektrene stemte overens med strukturen.An analytical sample was prepared by recrystallization in methanol, mp 102-105 ° C, yield: 3.35 g (82.61). The IR and NMR spectra were consistent with the structure.

Analyse beregnet for CjgK^gFjNO^: C. 62,12; H. 5,49; N. 3,82.Analysis calculated for C C CK ^ gFFNO ^: C, 62.12; H. 5.49; N, 3.82.

Fundet: C. 62,07; H. 5,38; N. 3,73.Found: C, 62.07; H. 5.38; N, 3.73.

2020

nrs2Anrs2A

8,14-epoxy-3-methoxymorphinan (13)8,14-epoxy-3-methoxymorphinan (13)

En blanding af 1,0 g (2,72 mmol) epoxid (12) og 0,103 g (2,72 mmol) natriumborhydrid i 5 ml absolut ethanol tilbagesvaledes i S minutter. Efter afkøling symedes reaktionsblandingen med fortyndet saltsyre og ekstraheredes så med ether. Det vandige lag fraskiltes og gjordes alkalisk ved tilsætning af vandig ammoniak og ekstraheredes så med methylenchlorid. De resulterende ekstrakter tørredes over Na2SO^ og koncentreredes i vakuum til dannelse af 800 mg olie (13), som ikke rensedes yderligere, men anvendtes direkte ved den næste omdannelse.A mixture of 1.0 g (2.72 mmol) of epoxide (12) and 0.103 g (2.72 mmol) of sodium borohydride in 5 ml of absolute ethanol was refluxed for 5 minutes. After cooling, the reaction mixture was stitched with dilute hydrochloric acid and then extracted with ether. The aqueous layer was separated and made alkaline by the addition of aqueous ammonia and then extracted with methylene chloride. The resulting extracts were dried over Na 2 SO 4 and concentrated in vacuo to give 800 mg of oil (13), which was not further purified but used directly in the next conversion.

IR- og NMR-spektrene stemte overens med strukturen.The IR and NMR spectra were consistent with the structure.

14-hydroxy-3-methoxymorphinan (14)14-hydroxy-3-methoxymorphinan (14)

En opløsning af 800 mg amin-epoxid ( 13 .) i 10 ml tetrahydrofuran sattes dråbevis ved stuetemperatur til en suspension af 500 mg lithium-aluminiumhydrid i 5 ml tør tetrahydrofuran. Efter fuldendelse af tilsætningen omrørtes reaktionsblandingen og tilbagesvaledes i 15 minutter. Oparbejdning som sædvanlig gav 700 mg olie, som opløstes i ether og den resulterende opløsning filtreredes igennem en celit-trækul-blanding. Filtratet behandledes med en mættet opløsning af saltsyre i ether til dannelse af 720 mg hvidt hydrochloridsalt., som efter re-krystallisation i methanol smeltede ved 243-244°C (dekomponering).A solution of 800 mg of amine epoxide (13) in 10 ml of tetrahydrofuran was added dropwise at room temperature to a suspension of 500 mg of lithium aluminum hydride in 5 ml of dry tetrahydrofuran. After completion of the addition, the reaction mixture was stirred and refluxed for 15 minutes. Work-up as usual yielded 700 mg of oil which was dissolved in ether and the resulting solution filtered through a celite charcoal mixture. The filtrate was treated with a saturated solution of hydrochloric acid in ether to give 720 mg of white hydrochloride salt, which after recrystallization in methanol melted at 243-244 ° C (decomposition).

Analyse beregnet for C17H23N02.HC1.l/2CH3OH: C. 64,50; H. 8,04; N.4,30. Fundet: C. 64,18; H. 7,81; N.4,25.Analysis calculated for C 17 H 23 NO 2 .HCl 1 / 2CH 3 OH: C, 64.50; H. 8.04; N.4,30. Found: C. 64.18; H. 7.81; N.4,25.

2121

U1S2AU1S2A

Fremgangsmåden ifølge opfindelsen illustreres yderligere gennem de følgende eksempler.The process of the invention is further illustrated by the following examples.

Eksempel 1 N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan Cl5) 0 uExample 1 N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinane Cl

Til en omrørt og afkølet opløsning af 400 mg (0,00146 mol) af aminoalkoholen (14) i 0,16 g (0,002 mol) tør pyridin og 5 ml methylen-chlorid sattes dråbevis en opløsning af 0,19 g (0,0016 mol) syréchlorid af cyclobutylcarboxylsyre i 5 ml methylenchlorid. Efter omrøring i 10 minutter vaskedes reaktionsblandingen successivt med koldt fortyndet saltsyre, fortyndet vandig natriumhydroxid,vand og til slut med en mættet vandig natriumchloridopløsning. Efter tørring over Na2SO^ og afdampning af opløsningsmidlet opnåedes 400 mg af en olie, som krystalliserede ved henstand. Olien behandledes aed en lille mængde kold ether og filtreredes til dannelse af 320 mg (61,61) krystaller, som efter rekrystallisation i methanol smeltede ved 183-185°C. IR- og NMR-spektrene stemte overens med strukturen.To a stirred and cooled solution of 400 mg (0.00146 mol) of the amino alcohol (14) in 0.16 g (0.002 mol) of dry pyridine and 5 ml of methylene chloride was added dropwise a solution of 0.19 g (0.0016 mole) acid chloride of cyclobutyl carboxylic acid in 5 ml of methylene chloride. After stirring for 10 minutes, the reaction mixture was washed successively with cold dilute hydrochloric acid, dilute aqueous sodium hydroxide, water and finally with a saturated aqueous sodium chloride solution. After drying over Na 2 SO 4 and evaporation of the solvent, 400 mg of an oil was obtained which crystallized on standing. The oil was treated with a small amount of cold ether and filtered to give 320 mg (61.61) crystals which, after recrystallization in methanol, melted at 183-185 ° C. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for C. 74,33; H. 8,22; N. 3,94.Analysis calculated for C. 74.33; H. 8.22; N, 3.94.

Fundet: C. 74,19; H. 8,40; N. 3,75.Found: C, 74.19; H. 8.40; N, 3.75.

N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan Γ161 14t624 22N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan Γ161 14t624 22

Til en suspension a£ 1,0 g lithiumalMiiniuahydrid i 5 ml tør tetrahydrofuran sattes ved stuetemperatur under nitrogenatmosfære en opløsning af 2,14 g ( 6 mmol) amid (15) i 25 ml tetrahydrofuran.To a suspension of 1.0 g of lithium aluminum hydride in 5 ml of dry tetrahydrofuran was added at room temperature under nitrogen atmosphere a solution of 2.14 g (6 mmol) of amide (15) in 25 ml of tetrahydrofuran.

Reaktionsbiandingen tilbagesvaledes så i 30 minutter og oparbejdedes som sædvanlig til dannelse af 2,0 g olie, som opløstes i ethek, og den resulterende opløsning filtreredes igennem en celit-trækuiblanding.The reaction mixture was then refluxed for 30 minutes and worked up as usual to give 2.0 g of oil, which was dissolved in ethics, and the resulting solution was filtered through a celite-wood mixture.

Behandling med tør HCl-gas gav 2,04 g hydrochlorid, smeltepunkt 235-237°C (dekomponering). Rekrystallisation i methanol forøgede smelte punktet til 248-250°C (dekomponering). IR- og NMR-spektrene stemte overens med strukturen.Dry HCl gas treatment gave 2.04 g of hydrochloride, mp 235-237 ° C (decomposition). Recrystallization in methanol increased the melting point to 248-250 ° C (decomposition). The IR and NMR spectra were consistent with the structure.

Analyse beregnet for C^Hj^NO^.HCl. 1/21^0: C. 68,28; H. 8,60; N. 3,62. Fundet: C. 68,25; H. 8,40; N. 3,75.Analysis calculated for C 1/21: C. 68.28; H. 8.60; N. 3.62. Found: C. 68.25; H. 8.40; N, 3.75.

Det analoge N-cyclopropylmethyl-14-hydroxy-3-methoxymorphinan-hydrochlorid (forbindelse 17) smelter ved 223-225°C. Rekrystallisation i methanol-ether forøgede smeltepunktet til 259-260°C. IR- og NMR-spektrene stemte overens med strukturen.The analog N-cyclopropylmethyl-14-hydroxy-3-methoxymorphinane hydrochloride (compound 17) melts at 223-225 ° C. Recrystallization in methanol ether increased the melting point to 259-260 ° C. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for ^.H^.HCl.l/ZHjO: C. 67,671 H. 8,37; N. 3,76.Calcd. For C .HHHCl.l / ZH₂O: C, 67.671; H, 8.37; N, 3.76.

„ Λ C, 67,70; H. 8,02; N. 3,72.C, 67.70; H. 8.02; N, 3.72.

Fundet:found:

Eksempel 2 N-cyclobutylmethyl-5,14-dihydroxymorphinan (18)Example 2 N-cyclobutylmethyl-5,14-dihydroxymorphinane (18)

En blanding af 1,0 g (2,58 mmol) forbindelse (16) og 10 ml 48¾ HBr tilbagesvaledes under nitrogenatmosfære i fem minutter. Efter afkøling fortyndedes reaktionsblandingen med vand og gjordes basisk med vandig ammoniumhydroxid. Den vandige basiske blanding ekstrahere-des med chloroform og de forenede chloroformekstrakter tørredes over vandfri natriumsulfat. Efter afdampning af opløsningsmidlet optoges den residuale olie (730 mg) i tør ether, og den resulterende opløsning filtreredes igennem celit-trækul. Filtratet behandledes med en mættet opløsning af hydrogenchlorid i tør ether. Det således opnåede hydrochloridsalt opsamledes ved filtrering og rekrystallisere- 23 «'·« des i en methanol-acetoneblanding til dannelse af 565 mg ¢56,5%) krystaller smeltende ved 272-274°C (dekomponering). IR- og NMR-spektre-ne stemte overens med strukturen.A mixture of 1.0 g (2.58 mmol) of compound (16) and 10 ml of 48¾ HBr was refluxed under a nitrogen atmosphere for five minutes. After cooling, the reaction mixture was diluted with water and basified with aqueous ammonium hydroxide. The aqueous basic mixture is extracted with chloroform and the combined chloroform extracts are dried over anhydrous sodium sulfate. After evaporation of the solvent, the residual oil (730 mg) was taken up in dry ether and the resulting solution filtered through celite charcoal. The filtrate was treated with a saturated solution of hydrogen chloride in dry ether. The hydrochloride salt thus obtained was collected by filtration and recrystallized in a methanol-acetone mixture to give 565 mg of 56.5% crystals melting at 272-274 ° C (decomposition). The IR and NMR spectra were consistent with the structure.

Analyse beregnet for C2^H2gN02.HCl.l/2CH2(HI: C. 67,97; H. 8,49; N.3,49. Fundet: C. 68,10; H. 8,14; N.3,80.Analysis calculated for C₂ ^H₂gNO₂. HCl / 2CH₂ (HI: C, 67.97; H, 8.49; N.3.49; Found: C, 68.10; H, 8.14; N.3 , 80th

Den analoge N-cyclopropylmethyl-3,14-dihydroxymorphinan (forbindelse 19) smelter ved 157-159°C. Hydrochloridsaltet rekrystalliseret i methanol-acetone har et smeltepunkt på 179-181 C i!forbindelse med svind, som begynder ved 163°C. Produktet indeholder 1/2 molekyle krystallisationsmethanol. IR- og NMR-spektrene stemte overens med strukturen.The analog N-cyclopropylmethyl-3,14-dihydroxymorphinane (compound 19) melts at 157-159 ° C. The hydrochloride salt recrystallized from methanol-acetone has a melting point of 179-181 ° C with shrinkage starting at 163 ° C. The product contains 1/2 molecule of crystallization methanol. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for C2qH2^N02.HC1.1/2CH20H: C.67,32; H. 8,37; N.3,83. Fundet: C.67,56; H. 8,20; N.3,90.·Analysis calculated for C₂qH₂ ^NO₂. HCl.1 / 2CH₂OH: C.67.32; H. 8.37; N.3,83. Found: C.67.56; H. 8.20; N.3,90. ·

Eksempel 3 N-allyl-14-hydroxy-3-methoxymorphinan (20)Example 3 N-allyl-14-hydroxy-3-methoxymorphinan (20)

UU

Til en omrørt blanding af 900 mg (3,3 mmol) aminoalkohol (14) og 1>7 g (16,5 mmol) triethylamin i 12 ml absolut ethanol sattes ved stuetemperatur og under nitrogenatmosfære en opløsning af 0,605 g (5 mmol) allylbromid. Efter fuldendelse af tilsætningen tilbagesvale-des reaktionsblandingen i 18 timer og inddampedes så til tørhed.To a stirred mixture of 900 mg (3.3 mmol) of amino alcohol (14) and 1> 7 g (16.5 mmol) of triethylamine in 12 ml of absolute ethanol was added at room temperature and under a nitrogen atmosphere a solution of 0.605 g (5 mmol) of allyl bromide. . After completion of the addition, the reaction mixture was refluxed for 18 hours and then evaporated to dryness.

Resten blandedes med en 201 vandig natriumcarbonatopløsning,og den resulterende blanding ekstraheredes med adskillige portioner ether.The residue was mixed with a 201 aqueous sodium carbonate solution and the resulting mixture extracted with several portions of ether.

De forenede etherekstrakter tørredes over Na2SO^ og inddampedes til dannelse af 940 mg olie, som opløstes i ether. Den resulterende opløsning filtreredes igennem en celit-trækulblanding, og filtratet koncentreredes ved formindsket tryk. Den resterende olie omdannedes i ether til hydrochloridsaltet. Rekrystallisation fra en methanol-etherblan-ding gav 600 mg af et hvidt faststof smeltende ved 244-346°C (dekompo-nering). Udbytte var 51,9¾. IR- og NMR-spektrene stemte overens med strukturen.The combined ether extracts were dried over Na 2 SO 4 and evaporated to give 940 mg of oil which was dissolved in ether. The resulting solution was filtered through a celite charcoal mixture and the filtrate was concentrated at reduced pressure. The remaining oil was converted into ether to the hydrochloride salt. Recrystallization from a methanol-ether mixture gave 600 mg of a white solid melting at 244-346 ° C (decomp.). Yield was 51.9¾. The IR and NMR spectra were consistent with the structure.

Analyse beregnet for C2QH27N02.HC1: C. 68,65; H. 8,07; N. 4,00.Analysis calculated for C₂QH₂NNO₂HCl: C, 68.65; H. 8.07; N. 4.00.

Fundet: C. 68,01; H. 7,97; N. 3,90.Found: C. 68.01; H. 7.97; N. 3.90.

24 14162Λ24 14162Λ

Eksempel 4 N-allyl-3,14-dihydroxymorphinan (21) HCr^^^i -Example 4 N-allyl-3,14-dihydroxymorphinane (21) HCr

kJkJ

Til en opløsning af 3,814 g (12,135 mmol) forbindelse (20) i 90 ml tør CE^C^ ved -80°C sattes under nitrogenatmosfære dråbevis en opløsning af 9,4252 g (37,42 mmol) BBr^ i 20 ml tør CE^C^· Den resulterende reaktionsblanding fik langsom lov til at antage stuetemperatur i 18 timer. Den dekomponeredes med is-vand, lagene adskiltes, og CH7C17-opløsningen vaskedes med vand og mættet natriumchloridopløsning.To a solution of 3.814 g (12.135 mmol) of compound (20) in 90 ml of dry CE ° C at -80 ° C was added dropwise under a nitrogen atmosphere a solution of 9.4252 g (37.42 mmol) of BBr ^ in 20 ml of dry The resulting reaction mixture was slowly allowed to reach room temperature for 18 hours. It was decomposed with ice-water, the layers were separated and the CH7C17 solution washed with water and saturated sodium chloride solution.

L· i* 'L · i * '

Den tørredes og .inddampedes til dannelse af 3,76 g olie. Denne omdannedes i acetone til HCl-saltet deraf. Det opnåede HCl-salt rekrystallise-redes i vand-acetone til dannelse af 1,15 g hvidt faststof. Moderluden koncentreredes, og forbindelsen omdannedes til den frie base. Den frie base kromatograferodes på A^O^ (Act. 4) og elueredes med CHCl^ til dannelse af en fraktion (1,35 g), som omdannedes til HCl-saltet deraf. HCl-saltet rekrystalliseredes i ^O-acetone, hvilket gav 950 mg. IR-og NMR-spektrene stemte overens med strukturen.It was dried and evaporated to give 3.76 g of oil. This was converted in acetone to the HCl salt thereof. The resulting HCl salt was recrystallized in water-acetone to give 1.15 g of white solid. The mother liquor was concentrated and the compound was converted to the free base. The free base is chromatographed on A₂O ^ (Act. 4) and eluted with CHCl ^ to give a fraction (1.35 g) which is converted to the HCl salt thereof. The HCl salt was recrystallized from 2 O-acetone to give 950 mg. The IR and NMR spectra were consistent with the structure.

Totale udbytte: 2,10 g (50%).Total yield: 2.10 g (50%).

Analyse beregnet for C^g^tjNC^.HCl.l/^CHjOH: C. 66,56; H. 8,02; N. 3,98. Fundet: C. 66,65; H. 7,76; N. 3,88.Analysis calculated for C ^ gH₂ tjNC ^HCl.1 / CH₂OH: C, 66.56; H. 8.02; N, 3.98. Found: C. 66.65; H. 7.76; N, 3.88.

Spaltning af dl-3,14-Dihydroxy-N-cyclopropylmethylmorphinan i dens optiske d og/^-isomere.Cleavage of dl-3,14-Dihydroxy-N-cyclopropylmethylmorphinane in its optical d and / - isomers.

A). J/-Z,14-Dihydroxy-N-cyclopropylmethylmorphinan (19a) dl-3,14-dihydroxy-N-cyclopropylmethylmorphinan (7,835 g,; 25 mmol) i form af den frie base opløstes i 15 ml varm methanol. Hertil sattes en opløsning af 3,75 g (25 mmol) ^-vinsyre i 15 ml varm methanol. Den resulterende opløsning fortyndedes med 30 ml acetone og fik lov at stå ved 5°C i 60 timer til krystallisering. Opløsningen filtreredes, hvilket gav 3,2 g af et krystallinsk faststof (A). Moderluden inddampedes til tørhed og gjordes basisk med vandig ammoniak, hvilket gav ca. 5,0 g fri base (B).A). J / Z, 14-Dihydroxy-N-cyclopropylmethylmorphinan (19a) dl-3,14-dihydroxy-N-cyclopropylmethylmorphinan (7,835 g,; 25 mmol) as the free base was dissolved in 15 ml of warm methanol. To this was added a solution of 3.75 g (25 mmol) of tartaric acid in 15 ml of warm methanol. The resulting solution was diluted with 30 ml of acetone and allowed to stand at 5 ° C for 60 hours for crystallization. The solution was filtered to give 3.2 g of a crystalline solid (A). The mother liquor was evaporated to dryness and basified with aqueous ammonia to give approx. 5.0 g of free base (B).

Claims

The solid (A) was recrystallized nine times in methanol-acetone to give 500 mg of tartrate salt; [α] 22 D -63.2375 (C. 0.4; MeOH). The free base was released with ammonia and recrystallized from CH 2 Cl 2, m.p. 178-180 ° C, weight 300 mg; ZsZp2 = δ 91.26 (C, 0.4408; CHCl 3). This is the isomer (19a). B). d-3,14-Dihydroxy-N-cyclopropylmethylmorphinane (19b). The free base (B), 5.0 g obtained in step A above, was dissolved in hot methanol and an equivalent amount of d-tartaric acid dissolved in hot methanol was added. This yielded 5.0 g of tartrate salt, which was recrystallized seven times in methanol-acetone; + q / 22 s +63.679 (C. 0.4028, MeOH). The free base was released from the tartrate salt and the base was recrystallized in CHCl 3, mp 178-179 ° C; weight 650 mg; + ό 2 + + 91.83 ° C. (C. 0.4168, CHCl 3). This is the d-isomer compound (19b). Analogous process for preparing morphinan derivatives of formula: J - N-R1 O wherein R1 represents -CH2-CH = CH2, -CH2 or -CH2 R2 represents H or alkyl of 1-6 carbon atoms or a pharmaceutically useful acid addition salt thereof by substituting A) a compound of formula: ΓΓ ^ ΓΝΗ W W „O 2 26 nt & 24 wherein R represents alkyl of 1-6 carbon atoms, with an alkylation or acylating agent of formula: W - Z - X wherein W represents a Z represents carbonyl (-C-) or -CH 2 - and X represents chlorine, bromine or iodine, in an inert organic solvent in the presence of an organic tertiary amine to form a compound of formula: (IH) u 2 'wherein R, Z and W have the above meaning and O II B) if Z represents carbonyl (-C-), the compound (III) reacts with lithium aluminum hydride in an inert organic solvent. to give a compound of formula: -N-CH 2 -WCl * OH (IV) u 2 'wherein R and W have the meaning given above, or a pharmaceutically useful acid addition salt thereof, whereupon, if desired, the ether function of compound (IV) is cleaved by treatment with hydrobromic acid, boron tribromide or pyridine hydrochloride to give the compound of the formula: -N-R1