NO131149B

NO131149B -

Info

Publication number: NO131149B
Application number: NO657/73A
Authority: NO
Inventors: Jardar Vartdal
Original assignee: Jardar Vartdal
Priority date: 1970-06-30
Filing date: 1973-02-19
Publication date: 1975-01-06
Also published as: NO129074B; DK129187B; CA957461A; GB1348649A; NO131149C; IS2169A7; SE366633B; CA949321A; DK129187C; IS2014A7

Description

Fremgangsmåte for fremstilling av nye skopinetere. Procedure for the production of new skopineters.

Foreliggende oppfinnelse angår fremstilling av nye skopinetere med den alminnelige formel I The present invention relates to the production of new scopineters with the general formula I

hvor R, er lavere alkyl, med rett eller for-grenet kjede, og R2 er et hydrogen eller halogenatom, og deres syreaddisjonssalter og kvaternære ammoniumforbindelser. where R 1 is lower alkyl, straight or branched chain, and R 2 is a hydrogen or halogen atom, and their acid addition salts and quaternary ammonium compounds.

Syreaddisjonssaltene av de nye skopinbenzhydryletere med formel er stabile krystallinske salter og kan fremstilles ved å bringe de basiske skopinbenzhydryletere til å reagere med farmakologisk anvendelige anorganiske eller organiske syrer, f. eks. saltsyre, hydrobromsyre, hydrojodsyre, svo-velsyre, fosforsyre, salpetersyre, benzoesy-re, benzensulfonsyre, naftalensulfonsyre, naftalen-l,5-disulfonsyre, salicylsyre, gly-kolsyre, eddiksyre, ravsyre, mandelsyre, ni-kotinsyre, tartarsyre, levulinsyre, stearin-syre, myresyre, palminsyre, sitronsyre, iso-sitronsyre, maleinsyre, glutarsyre, maleinsyre, pimelinsyre, melkesyre o. 1. The acid addition salts of the new scopine benzhydryl ethers of formula are stable crystalline salts and can be prepared by reacting the basic scopine benzhydryl ethers with pharmacologically useful inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, benzoic acid, benzenesulfonic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, salicylic acid, glycolic acid, acetic acid, succinic acid, mandelic acid, nicotinic acid, tartaric acid, levulinic acid, stearic acid, formic acid, palmic acid, citric acid, iso-citric acid, maleic acid, glutaric acid, maleic acid, pimelic acid, lactic acid etc. 1.

De frie skopineterbaser som er fremstilt i henhold til oppfinnelsen lar seg lett omdanne til kvaternære amoniumsalter. I denne hensikt omsettes N-alkyl-6,7-p-epoksy-nortropin-3-benzhydryleterbasen med et lavere derivat av et farmakologisk an-vendelig anion f. eks. metylbromid, metyl-klorid, metyljodid, dimetylsulfat, dietylsul-fat o. 1. Da den farmakologiske aktivitet for det kvaternære ammoniumsalt av N-alkyl-6,7-(3-epoksy-nortropin-3-benzhydryl skyldes kationet, kan det brukes hvilket som helst anion som er farmakologisk an-vendelig. The free scopine ether bases produced according to the invention can be easily converted into quaternary ammonium salts. For this purpose, the N-alkyl-6,7-p-epoxy-nortropine-3-benzhydryl ether base is reacted with a lower derivative of a pharmacologically useful anion, e.g. methyl bromide, methyl chloride, methyl iodide, dimethyl sulfate, diethyl sulfate, etc. 1. Since the pharmacological activity of the quaternary ammonium salt of N-alkyl-6,7-(3-epoxy-nortropin-3-benzhydryl) is due to the cation, it can be used any anion that is pharmacologically useful.

Tropinbenzhydryletere er eksempelvis kjent fra U.S. patent nr. 2 595 405 som beskriver fremstillingen av eteren ved å brin- Tropine benzhydryl ethers are, for example, known from the U.S. patent no. 2 595 405 which describes the preparation of the ether by burning

ge tropin til å reagere med difenyldiazo-metan og fra U.S. patent nr. 2 706 198 som viser fremstillingen av denne eter ved å bringe tropin til å reagere med difenylha-lometan i et surt miljø og videre beskriver reaksjonen mellom tropin- og ring-halo-gensubstituerte difenylhalometaner. ge tropine to react with diphenyldiazomethane and from the U.S. patent no. 2,706,198 which shows the preparation of this ether by reacting tropine with diphenylhalomethane in an acidic environment and further describes the reaction between tropine and ring-halogen substituted diphenylhalomethanes.

Disse kjente tropinbenzhydryletere i form av sine sure salter har forskjellige farmakodynamiske egenskaper. Ved siden av acetylcholin-hemmende virkning har de også utpreget antihistamin-virkning. These known tropine benzhydryl ethers in the form of their acid salts have different pharmacodynamic properties. In addition to their acetylcholine-inhibiting effect, they also have a pronounced antihistamine effect.

Disse tidligere tropinetere er først og fremst karakteristiske ved den lange va-righet av antihistamin-aktiviteten, men mindre ved intensiteten, se U.S. patent nr. These earlier tropineters are primarily characterized by the long duration of the antihistamine activity, but less so by the intensity, see U.S. Pat. patent no.

2 782 200, spalte 2, linjene 10—12. I denne 2 782 200, column 2, lines 10-12. In this

henseende er deres virkning overlegen overfor virkningen av de typiske antihist-aminer som anvendes som terapeutika. respect, their effect is superior to the effect of the typical antihistamines used as therapeutics.

Det var derfor å vente at de nye N-al-tyl-6,7-p-epoksy-nortropin-3-benzhydryletere (skopinetere) ville ha lignende farmakodynamiske egenskaper som benzhy-dryltropineterne. It was therefore to be expected that the new N-al-tyl-6,7-p-epoxy-nortropine-3-benzhydryl ethers (scopine ethers) would have similar pharmacodynamic properties to the benzhy-dryltropine ethers.

De nye etere som er utledet fra N-alkyl-6,7-(3-epoksynortropin-3-benzhydryl- The new ethers derived from N-alkyl-6,7-(3-epoxynortropin-3-benzhydryl-

eter (skopineter) og som er fremstilt ved fremgangsmåten i henhold til oppfinnelsen har nye og fullstendig ukjente farmakodynamiske egenskaper da de på den ene ether (scopine ether) and which are produced by the method according to the invention have new and completely unknown pharmacodynamic properties as they on the one hand

side bare har svak atropin- eller skopol-aminlignende aktivitet, men på den annen side skiller de seg fullstendig fra de nevnte alkaloider ved sin utpregete stimulerende aktivitet på spinalreflekser. on the one hand only have weak atropine- or scopol-amine-like activity, but on the other hand they differ completely from the aforementioned alkaloids by their distinct stimulating activity on spinal reflexes.

Intravenøs administrering av 2—10 mg/kg skopinbenzhydryleter øker utpregete mono-og polysynaptiske spinalreflekser på spinale såvel som intakte narkoti-serte katter. Muskelkontraksjonen som fremkalles ved direkte stimulering av mo-tornerven blir ikke påvirket av denne for-bindelse. Disse eksperimenter viser at den nye og hittil ukjente skopinbenzhydryleter fremmer spinalreflekser på grunn av direkte påvirkning av spinalsynapsis. Intravenous administration of 2-10 mg/kg scopine benzhydryl ether increases pronounced mono- and polysynaptic spinal reflexes in spinal as well as intact anesthetized cats. The muscle contraction induced by direct stimulation of the motor nerve is not affected by this connection. These experiments show that the new and hitherto unknown scopine benzhydryl ether promotes spinal reflexes due to direct action on spinal synapses.

De tidligere ukjente skopinbenzhydryletere som er fremstilt i henhold til oppfinnelsen kan derfor anvendes f. eks. i tera-pien av lidelser i ryggmargen hvor spinal-refleksene er svekket. På grunn av den fremmende virkning på reflekser og på grunn av denne stimulerende og opphis-sende virkning kan forbindelsene også brukes som centralstimulanter for å behandle lidelser i det centrale nervesystem, spesielt tilstander av psykisk depresjon. The previously unknown scopine benzhydryl ethers which have been prepared according to the invention can therefore be used, e.g. in the therapy of disorders in the spinal cord where the spinal reflexes are weakened. Because of the promoting effect on reflexes and because of this stimulating and exciting effect, the compounds can also be used as central stimulants to treat disorders in the central nervous system, especially states of mental depression.

De nye skopinbenzhydryletere med formel I kan fremstilles ved at et difenylmetanderivat med den alminnelige formel II The new scopine benzhydryl ethers of formula I can be prepared by adding a diphenylmethane derivative of the general formula II

hvor R., har samme betydning som i formel I, X er et hydrogenatom og Y er et klor- eller bromatom eller XY er en diazorest, N.,, omsettes med N-alkyl-nortro-pinderivater som har en epoksydring og har den alminnelige formel III hvor R, har samme betydning som ovenfor. En annen måte for fremstilling av de nye skopinbenzhydryletere med formel I består i at difenylmetanderivatet med formel II omfattes med de stereoisomere former av eventuelt acylerte N-alkyl-6-hydroksy-nortropiner som har formel IV hvor R, har samme betydning som ovenfor og A er et hydrogenatom eller en acylrest som lett lar seg avspalte etterpå, hvoretter epoksydringen innføres i de dannete benzhydryletere, idet den eventuelle til-stedeværende acylgruppe avspaltes, de re-sulterende stereoisomere former av N-alkyl-6-hydroksy-nortropin-3-benzhydryletere med formel V hvor R, og R2 har samme betydninger som i fromel I blir reagert med sulfonsyreklorider med formel VI hvor Z er en alifatisk eller alkylaromatisk rest for å danne sulfonsyreestere med formel VII where R., has the same meaning as in formula I, X is a hydrogen atom and Y is a chlorine or bromine atom or XY is a diazo residue, N.,, is reacted with N-alkyl nortropine derivatives having an epoxide ring and having the general formula III where R has the same meaning as above. Another way of producing the new scopine benzhydryl ethers of formula I consists in the diphenylmethane derivative of formula II being included with the stereoisomeric forms of optionally acylated N-alkyl-6-hydroxy-nortropines of formula IV where R has the same meaning as above and A is a hydrogen atom or an acyl residue which can easily be cleaved afterwards, after which the epoxidation is introduced into the formed benzhydryl ethers, with the eventual acyl group being cleaved off, the resulting stereoisomeric forms of N-alkyl-6-hydroxy-nortropine-3-benzhydryl ethers with formula V where R, and R 2 have the same meanings as in formula I are reacted with sulfonic acid chlorides of formula VI where Z is an aliphatic or alkylaromatic residue to form sulfonic acid esters with formula VII

hvor Z hår samme betydning som i formel VI og R, og R2 har samme betydning som i formel I. where Z has the same meaning as in formula VI and R, and R2 has the same meaning as in formula I.

Sulfonsyreesterne med formel VII blir omdannet ved behandling med en orga-nisk base og de oppnådde stereoisomere former av 6,7-tropenyl-3-benzhydryletere med formel VIII hvor R, og R., har samme betydning som i formel I epoksyderes med trifluorpered-diksyre og de oppnådde forbindelser over-føres eventuelt til sine syreaddisjonssalter og kvaternære ammoniumforbindelser. The sulfonic acid esters with formula VII are converted by treatment with an organic base and the obtained stereoisomeric forms of 6,7-tropenyl-3-benzhydryl ethers with formula VIII where R, and R., have the same meaning as in formula I are epoxidized with trifluoropered- acetic acid and the compounds obtained are optionally transferred to their acid addition salts and quaternary ammonium compounds.

I de foregående forbindelser angir fortegnene a og p de stereoisomere former av de 7-leddete cykloalkaner som bærer 1,5-imino-broen-N-R,, og forbindelser som In the preceding compounds, the signs a and p indicate the stereoisomeric forms of the 7-membered cycloalkanes bearing the 1,5-imino-bridge-N-R,, and compounds which

I IN

er merket p i forhold til substituenten inneholder denne substituent på samme side av planet for den 7-leddete ring i forhold til festepunktet for 1,5-cyklo-iminobroen, mens forbindelser som er merket « i forhold til substituenten inneholder denne substituent på den annen side av planet for den 7-leddete ring i forhold til festepunktet for 1,5-cyklo-iminobroen. is labeled p relative to the substituent contains this substituent on the same side of the plane of the 7-membered ring relative to the point of attachment of the 1,5-cycloimino bridge, while compounds labeled « relative to the substituent contain this substituent on the other side of the plane of the 7-membered ring relative to the attachment point of the 1,5-cycloimino bridge.

I nortropin er hydroksylet i 3-stillingen på den annen side av planet for den 7-leddete ring i forhold til den side hvor 1,5-cykloiminobroen er festet, og nomenklaturen blir Nortropan-3a-ol, mens i Nor-pse-udo-tropin ligger hydroksylet i 3-stillingen på samme side av planet for den 7-leddete ring i forhold til festepunktet for 1,5-cyk-loiminobroen, og nomenklaturen blir i dette tilfelle Nor-tropan-3p-ol. In nortropine, the hydroxyl in the 3-position is on the other side of the plane of the 7-membered ring relative to the side where the 1,5-cycloimino bridge is attached, and the nomenclature becomes Nortropan-3a-ol, while in Nor-pse-udo -tropine, the hydroxyl in the 3-position is on the same side of the plane of the 7-membered ring in relation to the attachment point for the 1,5-cyclo-loimino bridge, and the nomenclature in this case becomes Nor-tropan-3p-ol.

Denne nomenklatur for identifisering av de stereoisomere former for de forbindelser som er beskrevet her, deriblant de nye forbindelser som er fremstilt i henhold til oppfinnelsen, følger den som er fore-slått for nomenklaturen for stereoidene og triterpenoidene og er beskrevet i Journal of the Chemical Society (London) 1953 på side 721. This nomenclature for the identification of the stereoisomeric forms of the compounds described here, including the new compounds prepared according to the invention, follows that proposed for the nomenclature for the steroids and triterpenoids and is described in the Journal of the Chemical Society (London) 1953 at page 721.

Fremstillingen av de nye forbindelser som oppnås ved fremgangsmåten kan illu-streres ved følgende eksempler hvor alle temperaturverdier er i Celsiusgrader. The production of the new compounds obtained by the method can be illustrated by the following examples where all temperature values are in degrees Celsius.

Eksempel 1: Skopinbenzhydryleter : Example 1: Scopine benzhydryl ether:

(6,7|5-epoksy-tropin-3a-benzhydryleter) (6,7|5-epoxy-tropine-3a-benzhydryl ether)

En oppløsning av 3 g skopin i 5 cm:! vannfri benzen ble oppvarmet under til-bakeløp til 80—85° i 5 timer med difenyl-diazometan (fremstilt av 7,5 g benzofenon-hydrazon og 8,5 g kvikksølv-(II)-oksyd). Den avkjølte blanding ble så behandlet med 45 cm» benzen og 600 cm» 0,5 pst. vandig iskjølet saltsyre. A solution of 3 g of skopin in 5 cm:! anhydrous benzene was heated under reflux to 80-85° for 5 hours with diphenyldiazomethane (prepared from 7.5 g of benzophenone hydrazone and 8.5 g of mercuric (II) oxide). The cooled mixture was then treated with 45 cm" of benzene and 600 cm" of 0.5% aqueous ice-cooled hydrochloric acid.

Etter omhyggelig rysting ble benzenlaget skilt fra og den vandige saltsyre-oppløsning ble deretter vasket med 60 ems benzen og med tilsammen 120 cm» eter. Det vandige lag ble så kjølet sterkt og gjort alkalisk med 30 pst. vandig natriumhy-droksyd og den alkaliske vandige oppløs-ning ekstrahert med tilsammen 500 cm» benzen. After careful shaking, the benzene layer was separated and the aqueous hydrochloric acid solution was then washed with 60 ems of benzene and with a total of 120 cm" of ether. The aqueous layer was then cooled strongly and made alkaline with 30% aqueous sodium hydroxide and the alkaline aqueous solution extracted with a total of 500 cc of benzene.

De kombinerte benzenekstrakter ble tørket over magnesiumsulfat, benzen ble fjernet i vakuum og hydrokloridet fremstillet fra den oljeaktige rest av skopinbenzhydryleter ved behandling med meta-nolsk saltsyre under kjøling. Skopinbenzhydryleter-hydrokloridet ble krystallisert ved oppløsning i metanol og tilsetning av eter og deretter omkrystallisert fra metanoleter. The combined benzene extracts were dried over magnesium sulfate, the benzene was removed in vacuo and the hydrochloride prepared from the oily residue of scopine benzhydryl ether by treatment with methanolic hydrochloric acid under cooling. The scopine benzhydryl ether hydrochloride was crystallized by dissolution in methanol and addition of ether and then recrystallized from methanol ether.

Smp. 212—214° (sp) fra metanol/eter. Temp. 212-214° (sp) from methanol/ether.

Eksempel 2: Skopinbenzhydryleter. Example 2: Scopine benzhydryl ether.

(6,7p-epoksy-3a-benzhydryleter). (6,7p-epoxy-3a-benzhydrylether).

En oppløsning av 13,6 g difenyl-brommetan i 6 cm» abs. benzen ble satt dråpevis ved 110° under røring i løpet av en time til en blanding av 10 g 6 p-acetoksy-tropin og 2,6 g natriumkarbonat. Deretter ble blandingen holdt på 125° i ytterligere 4 timer med ytterligere røring. Etter av-kjøling ble 100 cm» vann og 100 cm» benzen tilsatt, blandingen ble rystet, benzenlaget skilt fra og den vandige del ekstrahert igjen med tilsammen 160 cm» benzen. De kombinerte benzenekstrakter ble så rystet ut med tilsammen 240 cm» is-kjølet vandig 2N-saltsyre, den vandige saltsyreekstrakt ble vasket med 90 cm» eter og gjort alkalisk under kjøling med 30 pst. vandig natriumhydroksydoppløs-ning. Den ble rystet ut med tilsammen 380 cm» benzen, de kombinerte benzenekstrakter ble tørket over magnesiumsulfat og benzenen fordampet i vakuum. Resten, 6p-acetoksy-tropin-3ra-benzhydryleter ble krystallisert fra benzen/petroleumeter. A solution of 13.6 g of diphenyl-bromomethane in 6 cm» abs. benzene was added dropwise at 110° with stirring over the course of one hour to a mixture of 10 g of 6 p-acetoxytropine and 2.6 g of sodium carbonate. The mixture was then held at 125° for a further 4 hours with further stirring. After cooling, 100 cm" of water and 100 cm" of benzene were added, the mixture was shaken, the benzene layer separated and the aqueous part extracted again with a total of 160 cm" of benzene. The combined benzene extracts were then shaken out with a total of 240 cc of ice-cooled aqueous 2N hydrochloric acid, the aqueous hydrochloric acid extract was washed with 90 cc of ether and made alkaline under cooling with 30% aqueous sodium hydroxide solution. It was shaken out with a total of 380 cm" of benzene, the combined benzene extracts were dried over magnesium sulfate and the benzene evaporated in vacuo. The residue, 6β-acetoxytropin-3α-benzhydrylether was crystallized from benzene/petroleum ether.

Smp. 109—111° fra benzen. Temp. 109—111° from benzene.

En oppløsning av 10,0 g 6p-acetoksy-tropin-3a-benzhydryleter i 40 cm» etanol og 20 cm» vandig 3N-natriumhydroksyd-oppløsning ble varmet i en time til 70°. Etanol ble så fjernet i vakuum hvorpå en olje skilte seg ut. Den vandige alkaliske destilleringsrest ble rystet ut med tilsammen 100 cm» kloroform, de forente kloroformekstrakter vasket med 40 cm» mettet natriumkloridoppløsning og tørket over magnesiumsulfat og kloroform fjernet i vakuum. Resten, 6p-hydroksy-tropin-3«-benzhydryleter ble krystallisert fra benzen og omkrystallisert fra benzen/petroleumeter eller benzen. Smp. 134—136°. A solution of 10.0 g of 6β-acetoxytropine-3α-benzhydrylether in 40 cm" of ethanol and 20 cm" of aqueous 3N sodium hydroxide solution was heated for one hour at 70°. Ethanol was then removed in vacuo whereupon an oil separated. The aqueous alkaline distillation residue was shaken out with a total of 100 cc of chloroform, the combined chloroform extracts washed with 40 cc of saturated sodium chloride solution and dried over magnesium sulfate and chloroform removed in vacuo. The residue, 6β-hydroxytropine-3'-benzhydrylether was crystallized from benzene and recrystallized from benzene/petroleum ether or benzene. Temp. 134-136°.

6|3-mesyloksy-tropin-3a-benzhydryleter ble fremstillet ved at en oppløs-ning av 12,0 g 6|3-hydroksy-tropin-3a-benzhydryleter i 36 cm» vannfri kloroform og 3,0 cm.3 abs. pyridin ble behandlet med 2,88 cm» metansulfonsyreklorid, hvorved den ble varm. Reaksjonsblandingen fikk stå ved romtemperatur i 50 min., ble så holdt svakt kokende under tilbakeløp i 5 timer. Etter kjøling ble reaksjonsblandingen behandlet med 85 ems kloroform og rystet ut med tilsammen 200 ems vann i fem omganger. Kloroformoppløsningen ble så tørket over magnesiumsulfat, kloroformen fjernet i vakuum, og resten 6(3-mesyl-oksy-tropin-3a-benzhydryleter krystallisert fra litt benzen ved tilsetting av petroleumeter. Smp. 87—89° fra benzen/petroleumeter. 6|3-Mesyloxy-tropine-3a-benzhydryl ether was prepared by dissolving 12.0 g of 6|3-hydroxy-tropine-3a-benzhydryl ether in 36 cm» of anhydrous chloroform and 3.0 cm.3 abs. pyridine was treated with 2.88 cm» of methanesulfonic acid chloride, heating it. The reaction mixture was allowed to stand at room temperature for 50 min., then was kept gently boiling under reflux for 5 hours. After cooling, the reaction mixture was treated with 85 ems chloroform and shaken out with a total of 200 ems water in five rounds. The chloroform solution was then dried over magnesium sulphate, the chloroform removed in vacuo, and the residue 6(3-mesyl-oxy-tropine-3a-benzhydrylether) crystallized from a little benzene by the addition of petroleum ether. Mp. 87-89° from benzene/petroleum ether.

Forestringen med metansulfonsyreklorid kunne også utføres i nærvær av trietylamin:: 0,24 cm3 metansulfonsyreklorid ble satt til oppløsning av 1,0 g 6(3-hydroksy-tropin-3a-benzhydryleter i 2 cm.3 abs. kloroform og 0,13 g trietylamin, og blandingen fikk stå ved romtemperatur i 18 timer. Deretter ble den varmet til svak koking under tilbakeløp i nye 5 timer. Etter kjøling ble reaksjonsblandingen behandlet med 6 cm3 kloroform og rystet ut med tilsammen 21 cm» vann i fem omganger. Kloformoppløsningen ble tørket over magnesiumsulfat og kloroformen fordampet i vakuum. Resten ble kromatografert over aluminiumoksyd, hvorved 6(3-mesyl-oksy-tropin-3a-benzhydryleter ble vasket med en oppløsningsmiddelblanding av benzen/petroleumeter (4 : 1). Smp. 88— 90° fra benzen/petroleumeter. The esterification with methanesulfonic acid chloride could also be carried out in the presence of triethylamine:: 0.24 cm3 of methanesulfonic acid chloride was added to a solution of 1.0 g of 6(3-hydroxy-tropine-3a-benzhydryl ether in 2 cm.3 abs. chloroform and 0.13 g triethylamine, and the mixture was allowed to stand at room temperature for 18 hours. It was then heated to a gentle reflux under reflux for another 5 hours. After cooling, the reaction mixture was treated with 6 cm3 of chloroform and shaken out with a total of 21 cm3 of water for five times. The chloroform solution was dried over magnesium sulfate and the chloroform evaporated in vacuo. The residue was chromatographed over alumina, whereby 6(3-mesyl-oxy-tropine-3a-benzhydryl ether was washed with a solvent mixture of benzene/petroleum ether (4 : 1). M.P. 88— 90° from benzene/petroleum ether.

Ved å behandle en metanoloppløsning av 6(3-mesyloksy-tropin-3a-benzhydryleter med den beregnete mengde naftalen-1,5-disulfonsyre, oppløst i metanol, ble det oppnådd 6(3-mesyloksy-tropin-3a-benzhydryleter-naftalen-l,5-disulfonat. Smp. 194 By treating a methanol solution of 6(3-mesyloxy-tropine-3a-benzhydryl ether with the calculated amount of naphthalene-1,5-disulfonic acid, dissolved in methanol, 6(3-mesyloxy-tropine-3a-benzhydryl ether-naphthalene- 1,5-disulfonate, mp 194

—195° (sp) fra metanol/eter. 6(3-mesyloksy-tropin-3a-benzhydryleter ble omdannet til 6,7-tropenyl-3a-benzhydryleter ved at 2,25 g 6|3-mesyloksy-tropin-3a-benzhydryleter, 4,5 cm3 trietylamin og 0,3 cm3 dietylanilin ble lukket inn under nitrogen i et trykkrør og oppvarmet til 125—135° i to timer. Innholdet i trykk-røret ble så kjølet sterkt og den flytende del dekantert. Den lysegule oppløsning ble konsentrert i vakuum, opptatt i 50 cm3 kloroform og vasket to ganger med 20 cm3 vandig mettet natriumkarbonatoppløsning. Kloroformoppløsningen ble tørket over magnesiumsulfat og kloroformen og det gjenværende trietylamin ble fjernet i vakuum. 6.7 tropenyl-3a-benzhydryleter kunne bare destilleres med delvis spalting. Kp. 175—185° ved et trykk på 0,05 mm Hg. 6,7-tropenyl-3a-benzhydryleter ble epoksydert ved at 420 mg trifluoreddiksyre under kjøling ble satt til en oppløsning av 125 g 6,7-tropenyl-3a-benzhydryleter i 20 cm» acetonitril, hvorpå blandingen ble behandlet ved en høyeste temperatur på 25° i 30 min. under røring, med en oppløsning av trifluor-pereddiksyre fremstillet av 1,56 g trifluoracetanhydrid og 0,22 g 90 pst. hydrogenperoksyd, i 10 cm3 metylenklorid. Reaksjonsblandingen ble rørt i ytterligere 30 min. ved romtemperatur og så rystet ut med tilsammen 100 ems vann. Den vandige oppløsning ble gjort alkalisk med 30 pst. vandig natriumhydroksydopp-løsning, og ekstrahert med tilsammen 150 ems kloroform. Kloroformekstraktene ble kombinert, tørket over magnesiumsulfat og kloroformen fordampet i vakuum. Hydrokloridet ble fremstillet fra den oljeaktige rest med den beregnete mengde metanolisk saltsyre, idet skopinbenzhydryleterhydrokloridet krystalliserte ut ved tilsetting av en liten mengde eter. Etter omkrystallisering fra metanol/eter, smeltet forbindelsen ved 212 —214° (sp). -195° (mp) from methanol/ether. 6(3-Mesyloxy-tropine-3a-benzhydryl ether was converted to 6,7-tropenyl-3a-benzhydryl ether by adding 2.25 g of 6|3-mesyloxy-tropine-3a-benzhydryl ether, 4.5 cm3 of triethylamine and 0.3 cm3 of diethylaniline was enclosed under nitrogen in a pressure tube and heated to 125-135° for two hours. The contents of the pressure tube were then cooled sharply and the liquid part decanted. The pale yellow solution was concentrated in vacuo, taken up in 50 cm3 of chloroform and washed twice with 20 cm3 of aqueous saturated sodium carbonate solution.The chloroform solution was dried over magnesium sulfate and the chloroform and the residual triethylamine was removed in vacuo. 6.7 tropenyl-3a-benzhydrylether could only be distilled with partial cleavage. Kp. 175—185° at a pressure of 0.05 mm Hg. 6,7-tropenyl-3a-benzhydryl ether was epoxidized by adding 420 mg of trifluoroacetic acid under cooling to a solution of 125 g of 6,7-tropenyl-3a-benzhydryl ether in 20 cm" of acetonitrile, after which the mixture was treated at a highest temperature of 25° for 30 min. with stirring, with a solution of trifluoroperacetic acid prepared from 1.56 g of trifluoroacetic anhydride and 0.22 g of 90% hydrogen peroxide, in 10 cm 3 of methylene chloride. The reaction mixture was stirred for an additional 30 min. at room temperature and then shaken with a total of 100 ems of water. The aqueous solution was made alkaline with 30% aqueous sodium hydroxide solution, and extracted with a total of 150 ems of chloroform. The chloroform extracts were combined, dried over magnesium sulfate and the chloroform evaporated in vacuo. The hydrochloride was prepared from the oily residue with the calculated amount of methanolic hydrochloric acid, the scopine benzhydryl ether hydrochloride crystallising out by the addition of a small amount of ether. After recrystallization from methanol/ether, the compound melted at 212-214° (mp).

Etter tilsetting av den beregnete mengde oksalsyre til en metanoloppløsning av skopinbenzhydryleter (fremstillet fra hydrokloridet), krystalliserte det sure oksa-lat av skopinbenzhydryleter med 1 mol krystalliserings-metanol ved tilsetting av litt eter. After adding the calculated amount of oxalic acid to a methanol solution of scopine benzhydryl ether (prepared from the hydrochloride), the acid oxalate of scopine benzhydryl ether crystallized with 1 mole of crystallization methanol by adding a little ether.

Skopinbenzhydryleter, fremstillet fra 1 g hydroklorid på den vanlige måte, ble Scopine benzhydryl ether, prepared from 1 g of hydrochloride in the usual manner, was

oppløst i 3 cm» aceton og behandlet med 3 cm3 metylbromid for å fremstille det dissolved in 3 cm» of acetone and treated with 3 cm3 of methyl bromide to prepare it

kvaternære ammoniumsalt. Etter henstand i 15 timer ved romtemperatur, be-gynte skopinbenzhydryleter-brommetylat å skille seg ut som krystaller etter noen tid. Det ble filtrert av og omkrystallisert fra metanol/aceton/eter. Smp. 214—215° (sp). quaternary ammonium salt. After standing for 15 hours at room temperature, scopine benzhydryl ether bromomethylate began to separate as crystals after some time. It was filtered off and recrystallized from methanol/acetone/ether. Temp. 214—215° (sp).

Det 6|3-acetoksytropin som ble benyttet som utgangsmaterial ble fremstillet på følgende måte: 25 g 6(3-hydroksy-tropinon ble oppløst i 150 cm3 rent vannfritt pyridin og 100 ems eddikanhydrid og fikk stå ved romtemperatur (20—25°) i 48 timer. Derpå ble ho-veddelen av pyridinet og overskudd av eddikanhydrid fjernet i vakuum, og resten opptatt i 150 cm» kloroform og vasket to ganger med 50 cm.3 iskjølet mettet vandig natriumkarbonat-oppløsning. Kloro-formoppløsningen ble så tørket over vannfritt magnesiumsulfat, kloroformen fjernet i vakuum og resten destillert i høyvakuum hvoretter 6(3-acetoksy-tropinon gikk over mellom 129° og 132° ved 0,8 mm Hg. The 6|3-acetoxytropine that was used as starting material was prepared in the following way: 25 g of 6(3-hydroxytropinone was dissolved in 150 cm3 of pure anhydrous pyridine and 100 ems of acetic anhydride and allowed to stand at room temperature (20-25°) in 48 hours. The bulk of the pyridine and excess acetic anhydride were then removed in vacuo, and the residue taken up in 150 cc of chloroform and washed twice with 50 cc of ice-cooled saturated aqueous sodium carbonate solution. The chloroform solution was then dried over anhydrous magnesium sulfate, the chloroform removed in vacuo and the residue distilled in high vacuum after which 6(3-acetoxy-tropinone passed between 129° and 132° at 0.8 mm Hg.

Hydrobromid: Smp. 192—194° (sp) fra metanol/eter. Hydrobromide: mp. 192-194° (mp) from methanol/ether.

Hydrokloridet av 6|3-acetoksy-tropinon etter krystallisering fra metanol/eter hadde et smp. på 199—200° (sp). The hydrochloride of 6|3-acetoxytropinone after crystallization from methanol/ether had a m.p. at 199-200° (sp).

En oppløsning av 5,6 g 6|3-acetoksy-tropinon i 15 cm» ren vannfri metanol ble hydrert i en autoklav i 8 timer ved 45c med Raneynikkel ved et utgangs-vann-stofftrykk på 60 atm. A solution of 5.6 g of 6|3-acetoxytropinone in 15 cm" of pure anhydrous methanol was hydrated in an autoclave for 8 hours at 45°C with Raney nickel at an outlet water-substance pressure of 60 atm.

Katalysatoren ble filtrert av, oppløs-ningsmidlet fjernet i vakuum og rester destillert i høyvakuum, hvorpå 6[3-acetoksytropin gikk over mellom 130° og 133c ved 0,08 mm Hg. Forbindelsen var litt hy-groskopisk. The catalyst was filtered off, the solvent removed in vacuo and the residue distilled in high vacuum, whereupon 6[3-acetoxytropine transitioned between 130° and 133° at 0.08 mm Hg. The compound was slightly hygroscopic.

6|3-acetoksy-tropin-naftalen-l,5-di-sulfonat: Smp. 237—239° (sp) fra metanol/eter. 6|3-acetoxy-tropine-naphthalene-1,5-di-sulfonate: M.p. 237-239° (mp) from methanol/ether.

Eksempel 3. Example 3.

Skopinbenzhydryleter. Scopine benzhydryl ether.

( 6, 7fi- epoksy- tropin- 3a- benzhydryleter). ( 6, 7fi- epoxytropin- 3a- benzhydryl ether).

En oppløsning av 4,0 g (1/50 mol) 6(3-acetoksy-tropin, fremstillet som beskrevet i eksempel 2, i 5 cm3 benzen ble varmet under tilbakeløp til 85—90° i 5 timer med difenyl-diazo-metan, fremstillet fra 7,9 g benzofenon-hydrazon og 8,8 g kvikksølv-(II)-oksyd. Den kjølte reaksjonsblanding ble så behandlet med 100 cm» benzen og 850 cm» 0,5 pst. vandig iskjølt saltsyre. Etter rysting ble benzenlaget skilt fra og det vandige lag ble deretter vasket med nye 100 cm» benzen og så med tilsammen 250 cm» eter. Deretter ble den sure vandige oppløsning gjort alkalisk med 30 pst. vandig natriumhydroksydoppløsning under sterk kjøling og deretter ekstrahert med tilsammen 800 cm3 benzen. De kombinerte benzenekstrakter ble tørket over magne-simsulfat og benzenen ble fjernet i vakuum. Resten, 6|3-acetoksy-tropin-3a-benzhydryleter ble krystallisert fra en blanding av benzen og petroleumeter. Smp. 109—110°. Det blandete smeltepunkt med et produkt fremstillet fra 6(3-acetoksy-tropin med difenyl-brommetan viste ingen synking. A solution of 4.0 g (1/50 mol) of 6(3-acetoxytropine, prepared as described in Example 2, in 5 cm3 of benzene was heated under reflux to 85-90° for 5 hours with diphenyl-diazo-methane , prepared from 7.9 g of benzophenone hydrazone and 8.8 g of mercuric (II) oxide. The cooled reaction mixture was then treated with 100 cm" of benzene and 850 cm" of 0.5% aqueous ice-cooled hydrochloric acid. After shaking, the benzene layer was separated and the aqueous layer was then washed with a new 100 cm" of benzene and then with a total of 250 cm" of ether. The acidic aqueous solution was then made alkaline with 30% aqueous sodium hydroxide solution under strong cooling and then extracted with a total of 800 cm3 of benzene . The combined benzene extracts were dried over magnesium sulfate and the benzene was removed in vacuo. The residue, 6|3-acetoxy-tropine-3α-benzhydryl ether, was crystallized from a mixture of benzene and petroleum ether. M.p. 109-110°. The mixed m.p. with a product prepared from 6(3-acetoxy-tropine with diphenyl-bromomethane shown e no sinking.

Videre opparbeiding ble utført slik som beskrevet i eksempel 2. Sluttproduk- Further processing was carried out as described in example 2. Final product

tet, skopinbenzhydryleterhydroklorid smeltet ved 212—214° (sp). tet, scopine benzhydryl ether hydrochloride melted at 212-214° (sp).

Eksempel 4. Example 4.

Skopinbenzhydryleter. Scopine benzhydryl ether.

(6,7-epoksy-tropin-3a-benzhydryleter). (6,7-epoxy-tropine-3a-benzhydrylether).

En oppløsning av 2,47 g difenyl-brommetan i 6 cm» abs. benzen ble langsomt, under omrøring ved 110° i løpet av en time satt til en blanding av 2,76 g 6(3-fenyl-karbamoyloksy-tropin, fremstillet som angitt av G. Fodor m. fl. i J. Chem: Soc. 1957, 1349, og 0,53 g natriumkarbonat. Deretter ble reaksjonsblandingen, under videre røring holdt på 125° i ytterligere 5 timer. Så ble 100 cm3 benzen og 100 cm» vann tilsatt, hvorved utskilling av krystaller fant sted. Etter kort henstand i kulde ble den filtrert, filtreringsresten ble opp-løst i 40 cm» kloroform og rystet med 20 ems 30 pst. vandig natriumhydroksydopp-løsning. Kloroformdelen ble skilt fra, tør-ket over kaliumkarbonat, og kloroformen fjernet i vakuum. Etter rensing via hydrokloridet og frigjøring av basen på vanlig måte, smeltet 6(3-fenyl-karbamoyl-oksy-tropin-3a-benzhydryleter ved 154—156° etter omkrystallisering fra benzen/petroleumeter. 6(3-fenyl-karbamoyloksy-tropin-3a-benzhydryleter ble ved vakuumoppvarm-ning omdannet til 6(3-hydroksy-tropin-3a-benzhydryleter på følgende måte: 1,5 g 6(3-fenyl-karbamoyloksy-tropin-3a-benzhydryleter ble langsomt varmet i en destilleringskolbe ved høyvakuum ved 0,05 mm Hg. Ved en temperatur på 195° kunne det legges merke til gassutvikling i de smeltete stoff, og samtidig minsket va-kuumet til 0,3 mm Hg. Ved en temperatur på mellom 230 og 240° ved 0,15 mm Hg destillerte 6(3-hydroksy-tropin-3a-benzhydryleter som en f arveløs olje som størknet som krystaller i den kjølete mottager. Smp. 132—134° etter omkrystallisering fra benzen /petroleumeter. A solution of 2.47 g of diphenyl-bromomethane in 6 cm» abs. benzene was added slowly, with stirring at 110° over the course of one hour, to a mixture of 2.76 g of 6(3-phenyl-carbamoyloxytropine, prepared as indicated by G. Fodor et al. in J. Chem: Soc . 1957, 1349, and 0.53 g of sodium carbonate. Then, with further stirring, the reaction mixture was kept at 125° for a further 5 hours. Then 100 cm3 of benzene and 100 cm3 of water were added, whereby crystals separated out. After a short standstill in the cold, it was filtered, the filtration residue was dissolved in 40 cm" of chloroform and shaken with 20 ml of 30% aqueous sodium hydroxide solution. The chloroform part was separated, dried over potassium carbonate, and the chloroform removed in vacuo. After purification via the hydrochloride and liberation of the base in the usual manner, 6(3-phenyl-carbamoyl-oxy-tropine-3a-benzhydrylether) melted at 154-156° after recrystallization from benzene/petroleum ether. 6(3-phenyl-carbamoyloxy-tropine-3a-benzhydryl ether was converted by vacuum heating into 6(3-hydroxy-tropine-3a-benzhydryl ether in the following way: 1.5 g of 6(3-phenyl-carbamoyloxy-tropine-3a -benzhydryl ether was slowly heated in a distillation flask under high vacuum at 0.05 mm Hg. At a temperature of 195° gas evolution could be noticed in the molten substance, and at the same time the vacuum was reduced to 0.3 mm Hg. At a temperature of between 230 and 240° at 0.15 mm Hg, 6(3-hydroxy-tropine-3a-benzhydryl ether) distilled as a colorless oil which solidified as crystals in the cooled receiver. M.p. 132—134° after recrystallization from benzene/petroleum ether .

Det blandete smeltepunkt ved 6(3-hydroksy-tropin-3a-benzhydryleter fremstillet fra 6(3-acetoksy-tropin-3a-benzhydryleter ved forsåping med etanolisk natrium-hydroksydoppløsning (eksempel 2) viste ingen synking. The mixed melting point of 6(3-hydroxytropine-3α-benzhydryl ether prepared from 6(3-acetoxytropine-3α-benzhydryl ether) by saponification with ethanolic sodium hydroxide solution (Example 2) showed no lowering.

De videre reaksjoner kan utføres på samme måte som beskrevet i eksempel 2, hvorved det oppnås skopinbenzhydryleterhydroklorid som smelter ved 212—214° The further reactions can be carried out in the same way as described in example 2, whereby scopine benzhydryl ether hydrochloride is obtained which melts at 212-214°

(sp). (sp).

Eksempel 5. Example 5.

Skopinbenzhydryleter. Scopine benzhydryl ether.

(6,7-epoksy-tropin-3a-benzhydryleter). (6,7-epoxy-tropine-3a-benzhydryl ether).

En oppløsning av 9,4 g difenylbrom-metan i 6 ems abs vannfri benzen ble langsomt, under røring, ved 110° i løpet av en time satt til en blanding av 3,0 g 3a, 6|3-dihydroksy-tropan og 0,1 g natriumkarbonat. Deretter ble blandingen holdt på 125° i ytterligere 5 timer hvorved det langsomt dannet seg en hard masse. Etter kjøling ble 100 cm» vann og 100 cm» benzen satt til reaksjonsblandingen og rystet godt. En krystallinsk del som er uoppløse-lig i denne oppløsningsmiddelblanding, og som er 6|3-hydroksy-tropin-3a-benzhydryleter-hydrobromid ble filtrert av og omkrystallisert fra metanol/eter. Smp. 237 —239° (sp). A solution of 9.4 g of diphenylbromomethane in 6 ems abs of anhydrous benzene was added slowly, with stirring, at 110° over the course of one hour to a mixture of 3.0 g of 3a, 6|3-dihydroxytropane and 0 .1 g of sodium carbonate. The mixture was then held at 125° for a further 5 hours whereby a hard mass slowly formed. After cooling, 100 cm" of water and 100 cm" of benzene were added to the reaction mixture and shaken well. A crystalline portion insoluble in this solvent mixture, which is 6|3-hydroxytropine-3α-benzhydryl ether hydrobromide, was filtered off and recrystallized from methanol/ether. Temp. 237 —239° (sp).

Den fri base ble fremstillet fra hydro-bromidet på kjent måte: Smp. 134—135° fra benzen/petroleumeter. The free base was prepared from the hydrobromide in a known manner: mp. 134—135° from benzene/petroleum ether.

Det blandete smeltepunkt med et produkt fremstillet fra 6(3-acetoksy-tropin og difenyl-brommetan og etterfølgende forsåping for å fjerne acetylet i 6(i-stillingen viste ingen synking. The mixed melting point with a product prepared from 6(3-acetoxytropine and diphenyl-bromomethane and subsequent saponification to remove the acetyl at the 6(i) position showed no sinking.

Den isomere 3a-hydroksy-tropin-6(3-benzhydryleter ble oppnådd fra filtratet (benzen/vann-blanding) på vanlig opp-arbeidingsmåte, og etter omkrystallisering fra en blanding av aceton og petroleumeter, smeltet det ved 146—148°. The isomeric 3α-hydroxytropine-6(3-benzhydryl ether) was obtained from the filtrate (benzene/water mixture) by the usual work-up, and after recrystallization from a mixture of acetone and petroleum ether, it melted at 146-148°.

Hydrobromid: Smp. 217—219° (sp) fra metanol/eter. Hydrobromide: mp. 217-219° (mp) from methanol/ether.

6p-hydroksy-tropm-3a-benzhydryleter som ble oppnådd i dette eksempel ble videre bragt til å reagere slik som beskrevet i eksempel 2. Sluttproduktet, skopinbenzhydryleterhydroklorid, hadde smp. 212— 214° (sp). The 6β-hydroxytropin-3α-benzhydryl ether obtained in this example was further reacted as described in example 2. The end product, scopine benzhydryl ether hydrochloride, had m.p. 212— 214° (sp).

Eksempel 6. Example 6.

N- etyl- norskopin- benzhydryleter. N- ethyl- norscopine- benzhydryl ether.

(N-etyl-6,7(3-epoksy-nortropin-3a-benzhydryleter). (N-ethyl-6,7(3-epoxy-nortropine-3a-benzhydrylether).

En oppløsning av 3,7 g difenylbrom-metan i 6 cm<3> abs. benzen ble satt dråpevis ved 110° under røring i løpet av en time til en blanding av 3,2 g N-etyl-6p-acetoksy-nortropin og 0,8 g natriumkarbonat. Deretter ble blandingen holdt på 125° i ytterligere 4 timer under videre røring. Etter kjøling ble 50 cm1 vann og 50 cm3 benzen tilsatt, blandingen ble rystet omhyggelig, benzenlaget skilt fra og den vandige del ekstrahert med tilsammen 80 cm3 benzen. De kombinerte benzenekstrakter ble rystet ut med en samlet mengde på 150 cm<3> iskjølet vandig 2N-saltsyre, den vandige saltsure ekstrakt ble vasket med 50 cm3 eter og gjort alkalisk under kjøling med 30 pst. vandig natriumhydroksydopp-løsning. Det alkaliske vandige miljø ble rystet ut med tilsammen 200 cm3 benzen, de kombinerte benzenekstrakter ble tørket over magnesiumsulfat og benzenen fjernet i vakuum. Resten ble oppløst i 50 cm<3> vannfri eter og behandlet med tørr hydrogenbromidgass inntil det ble oppnådd sur reaksjon med pH-3. Bunnfallet ble snart krystallinsk og ble oppsamlet på et filter og tørket. Etter omkrystallisering fra en metanol-eterblanding var smeltepunktet for N-etyl-6p-acetoksy-nortropin-3a-benzhydryleter-hydrobromid 186—189° (sp). A solution of 3.7 g of diphenylbromomethane in 6 cm<3> abs. benzene was added dropwise at 110° with stirring over the course of one hour to a mixture of 3.2 g of N-ethyl-6β-acetoxy-nortropine and 0.8 g of sodium carbonate. The mixture was then held at 125° for a further 4 hours with further stirring. After cooling, 50 cm1 of water and 50 cm3 of benzene were added, the mixture was shaken carefully, the benzene layer was separated and the aqueous part was extracted with a total of 80 cm3 of benzene. The combined benzene extracts were shaken out with a total amount of 150 cm3 of ice-cooled aqueous 2N hydrochloric acid, the aqueous hydrochloric acid extract was washed with 50 cm3 of ether and made alkaline under cooling with 30% aqueous sodium hydroxide solution. The alkaline aqueous environment was shaken out with a total of 200 cm 3 of benzene, the combined benzene extracts were dried over magnesium sulphate and the benzene removed in vacuo. The residue was dissolved in 50 cm<3> of anhydrous ether and treated with dry hydrogen bromide gas until an acidic reaction with pH-3 was obtained. The precipitate soon became crystalline and was collected on a filter and dried. After recrystallization from a methanol-ether mixture, the melting point of N-ethyl-6β-acetoxy-nortropine-3α-benzhydryl ether hydrobromide was 186-189° (sp).

En oppløsning av 1,0 g N-etyl-6p-acetoksy-nortropin-3a-benzhydryleter i 12 cm» etanol og 10 cm» vandig 3N-natrium-hydroksydoppløsning ble kokt i 2 timer, hvoretter det ble oppnådd en klar oppløs-ning. Så ble etanol fjernet i vakuum, resten opptatt i 20 cm3 vann og ekstrahert med en samlet mengde på 100 cm3 kloroform. De kombinerte kloroformekstrakter ble vasket med 20 cm3 mettet natriumklo-ridoppløsning, tørket over magnesiumsulfat og kloroformen fordampet i vakuum. Resten, N-etyl-6p-hydroksy-nortropin-3a-benzhydryleter ble krystallisert fra benzen/ petroleumeter. Smp. 129—131°. A solution of 1.0 g of N-ethyl-6β-acetoxy-nortropine-3α-benzhydryl ether in 12 cm" of ethanol and 10 cm" of aqueous 3N sodium hydroxide solution was boiled for 2 hours, after which a clear solution was obtained . Ethanol was then removed in vacuo, the residue taken up in 20 cm3 of water and extracted with a total amount of 100 cm3 of chloroform. The combined chloroform extracts were washed with 20 cc saturated sodium chloride solution, dried over magnesium sulfate and the chloroform evaporated in vacuo. The residue, N-ethyl-6β-hydroxy-nortropine-3α-benzhydryl ether was crystallized from benzene/petroleum ether. Temp. 129—131°.

En oppløsning av 3,0 g N-etyl-6(3-hydroksy-nortropin-3a-benzhydryleter i 9 cm3 abs. kloroform og 0,72 cm'1 abs. pyridin ble behandlet med 0,67 cm<3> metansulfonsyreklorid, hvorved den ble varm. Reaksjonsblandingen fikk stå ved romtemperatur i 1 time og ble deretter holdt svakt kokende under tilbakeløp i 3 timer. Etter kjø-ling ble reaksjonsblandingen behandlet med 21 cm3 kloroform og rystet ut med tilsammen 40 cm5 8 pst. vandig natrium-karbonatoppløsning i 6 porsjoner. Kloro-formoppløsningen ble så tørket over magnesiumsulfat, kloroformen fjernet i vakuum og resten kromatografert over aluminiumoksyd, hvorved N-etyl-6p-mesyl-oksy-nortropin-3a-benzhydryleter ble frigjort med en oppløsningsmiddelblanding av benzen/petroleumeter (1 : 1). A solution of 3.0 g of N-ethyl-6(3-hydroxy-nortropine-3a-benzhydrylether in 9 cm3 abs. chloroform and 0.72 cm'1 abs. pyridine was treated with 0.67 cm<3> methanesulfonic acid chloride, whereupon it became warm. The reaction mixture was allowed to stand at room temperature for 1 hour and was then kept at a gentle boil under reflux for 3 hours. After cooling, the reaction mixture was treated with 21 cm3 of chloroform and shaken out with a total of 40 cm5 of 8% aqueous sodium carbonate solution in 6 portions. The chloroform solution was then dried over magnesium sulfate, the chloroform removed in vacuo and the residue chromatographed over alumina, whereby N-ethyl-6β-mesyl-oxy-nortropine-3α-benzhydrylether was liberated with a solvent mixture of benzene/petroleum ether (1 : 1).

For identifisering ble naftalen-1,5-disulfonatet fremstillet. Smp. 180—191° For identification, the naphthalene-1,5-disulfonate was prepared. Temp. 180-191°

(sp) fra metanol/eter. (sp) from methanol/ether.

Naftalen-l,5-disulfonat kunne også fremstilles fra den rå N-etyl-6p-mesyl-oksy-nortropin-3a-benzhydryleter uten rensing ved kromatotgrafering over alu- i miniumoksyd. Etter fjerning av kloroform i vakuum, ble 1,86 g av den oljeaktige rest 1 oppløst i 1 cm3 abs. metanol og behandlet i med en oppløsning av 0,89 g 76 pst. nafta-len-l,5-disulfonsyre i 1 cm3 abs. metanol. 1 Etter å ha stått i flere timer i kulden, ble ( det krystallinske bunnfall av saltet filtrert av og omkrystallisert fra metanol. Smp. 1 180—181° (sp). ]Naphthalene-1,5-disulfonate could also be prepared from the crude N-ethyl-6p-mesyl-oxy-nortropin-3a-benzhydryl ether without purification by chromatography over aluminum oxide. After removal of chloroform in vacuo, 1.86 g of the oily residue 1 was dissolved in 1 cm 3 of abs. methanol and treated with a solution of 0.89 g of 76% naphthalene-1,5-disulfonic acid in 1 cm3 abs. methanol. 1 After standing for several hours in the cold, ( the crystalline precipitate of the salt was filtered off and recrystallized from methanol. Mp. 1 180-181° (sp). ]

5,2 g N-etyl-6|3-mesyloksy-nortropin- i 3a-benzhydryleter, 10,4 g trietylamin og 0,4 cm3 dietylanilin ble innelukket under 1 nitrogen i et trykkrør og varmet til 125— ( 135° i 2 timer. Innholdet i trykkrøret ble 5.2 g of N-ethyl-6|3-mesyloxy-nortropine- in 3a-benzhydryl ether, 10.4 g of triethylamine and 0.4 cm3 of diethylaniline were enclosed under 1 nitrogen in a pressure tube and heated to 125— ( 135° for 2 hours.The contents of the pressure tube became

så kjølet sterkt og den flytende del ble de- i kantert. Denne lysebrune oppløsning ble < konsentrert i vakuum,- opptatt i 50 cm<3>] kloroform og vasket to ganger, hver gang med 25 cm3 vandig mettet natriumkarbo- 1 natoppløsning. Kloroformoppløsningen ble i tørket over magnesiumsulfat og kloro- 1 formen og den gjenværende trietyl- i amin fjernet under nedsatt trykk. 610 i mg trifluoreddiksyre ble under kjøling ! satt til en oppløsning av 1,9 g av i resten, N-etyl-6,7-nortropenyl-3a-benz- i hydryleter i 20 cm3 metylenklorid og blan- i dingen ble så behandlet med en høyeste : temperatur på 25° i løpet av 30 min., under i røring med en oppløsning av trifluorper- ] eddiksyre, (fremstillet av 2,25 g trifluor-eddikanhydrid og 0,32 g 90 pst. vandig hydrogenperoksyd) i 10 cm<3> metylenklorid. Røringen ble fortsatt ved romtemperatur i ytterligere 30 min., reaksjonsblandingen i ble ekstrahert med tilsammen 100 cm3 vann, den vandige oppløsning ble gjort alkalisk med 30 pst. vandig natriumhy-droksydoppløsning og ekstrahert med tilsammen 150 cm<3> kloroform. De kombinerte kloroformekstrakter ble tørket over magnesiumsulfat, og kloroformen fjernet i vakuum. Den oljeaktige rest, 714 mg, ble kromatografert over aluminiumoksyd, hvorved N-etyl-norskopin-3a-benzhydryleter ble frigjort med en blanding av benzen/petroleumeter (1 : 4). For identifisering ble det fremstilt N-etyl-norskopin-3a-benzhydryleter-naftalen-l,5-disulfonat. Smp. 234—236° (sp) fra metanol/eter. then cooled strongly and the liquid part was decanted. This light brown solution was concentrated in vacuo, taken up in 50 cm<3>] chloroform and washed twice, each time with 25 cm3 of aqueous saturated sodium carbonate solution. The chloroform solution was dried over magnesium sulfate and the chloroform and the remaining triethylamine removed under reduced pressure. 610 in mg trifluoroacetic acid was under cooling ! added to a solution of 1.9 g of in the residue, N-ethyl-6,7-nortropenyl-3a-benz- i hydrylether in 20 cm3 of methylene chloride and the mixture was then treated at a highest : temperature of 25° in during 30 min., while stirring with a solution of trifluoroperacetic acid, (prepared from 2.25 g of trifluoroacetic anhydride and 0.32 g of 90% aqueous hydrogen peroxide) in 10 cm<3> of methylene chloride. Stirring was continued at room temperature for a further 30 min., the reaction mixture was extracted with a total of 100 cm 3 of water, the aqueous solution was made alkaline with 30% aqueous sodium hydroxide solution and extracted with a total of 150 cm 3 of chloroform. The combined chloroform extracts were dried over magnesium sulfate, and the chloroform removed in vacuo. The oily residue, 714 mg, was chromatographed over alumina, whereby N-ethyl-norscopine-3a-benzhydrylether was liberated with a mixture of benzene/petroleum ether (1:4). For identification, N-ethyl-norscopine-3a-benzhydryl ether-naphthalene-1,5-disulfonate was prepared. Temp. 234-236° (sp) from methanol/ether.

Det N-etyl-6(3-acetoksy-nortropin som ble benyttet som utgangsmaterial ble fremstillet på følgende måte: En vandig saltsur oppløsning av maur-syredialdehyd, fremstillet ved hydrolyse av 88,0 g 2,5-dietoksy-3-hydroksy-tetrahydro-furan med 2 liter vandig 0,1 N-saltsyre, ble satt til en oppløsning av 150 g aceton di-karboksylsyre, 82,0 g etylaminhydroklorid og 340,0 g natriumacetat i 10 liter vann. DH-verdien for blandingen ble innstillet på 1,0. Etter å ha stått i 48 timer ved romtemperatur, var den utvikling av CO., som fant sted sluttet og pH-verdien hadde ste-det til 5,0. 2,5 kg kaliumkarbonat ble opp-øst i den mørkebrune reaksjonsblanding, 3g oppløsningen ekstrahert med tilsammen 1 liter kloroform. Kloroformekstrakten ble The N-ethyl-6(3-acetoxy-nortropine which was used as starting material was prepared in the following way: An aqueous hydrochloric acid solution of formic acid dialdehyde, prepared by hydrolysis of 88.0 g of 2,5-diethoxy-3-hydroxy- tetrahydrofuran with 2 liters of aqueous 0.1 N hydrochloric acid was added to a solution of 150 g of acetone dicarboxylic acid, 82.0 g of ethylamine hydrochloride and 340.0 g of sodium acetate in 10 liters of water. The DH value of the mixture was set of 1.0. After standing for 48 hours at room temperature, the evolution of CO. which had taken place had ceased and the pH had reached 5.0. 2.5 kg of potassium carbonate was precipitated into the dark brown reaction mixture, 3g of the solution was extracted with a total of 1 liter of chloroform. The chloroform extract was

:ørket over magnesiumsulfat, oppløsnings-midlet ble fordampet og resten destillert ander høyvakuum, hvorved N-etyl-6(3-hydroksy-nortropin gikk over ved 100—112° ved et trykk på 0,8 mm Hg som en lysegul olje som krystalliserte i mottageren. For videre rensing kan N-etyl-6p-hydroksy-nortropinon omkrystalliseres fra en blanding av benzen og petroleumeter eller sub-limeres i vakuum. Smp. 94—96°. :dried over magnesium sulfate, the solvent was evaporated and the residue distilled under high vacuum, whereby N-ethyl-6(3-hydroxy-nortropine passed at 100-112° at a pressure of 0.8 mm Hg as a pale yellow oil which crystallized in the receiver. For further purification, N-ethyl-6p-hydroxy-nortropinone can be recrystallized from a mixture of benzene and petroleum ether or sublimed in vacuo. M.P. 94-96°.

5,0 g N-etyl-6|3-hydroksy-nortropinon ble oppløst i 30 cm<3> abs. pyridin og 100 cm<3 >acetanhydrid og fikk stå ved romtemperatur i 48 timer. Deretter ble den største del av pyridinet og overskuddet av acetanhy-dridet fjernet i vakuum, resten opptatt i 50 cm3 kloroform og vasket to ganger hver 5.0 g of N-ethyl-6|3-hydroxy-nortropinone was dissolved in 30 cm<3> abs. pyridine and 100 cm<3 >acetic anhydride and allowed to stand at room temperature for 48 hours. Then the largest part of the pyridine and the excess of the acetic anhydride were removed in vacuo, the remainder taken up in 50 cm3 of chloroform and washed twice each

gang med 20 cm<3> iskjølet, mettet vandig natriumkarbonatoppløsning. Kloroform-oppløsningen ble tørket over magnesiumsulfat, kloroform ble fordampet i vakuum og resten destillert i høyvakuum hvorpå N-etyl-6|3-acetoksy-nortropinon destillerte mellom 120—123° ved 0,01 mm Hg. times with 20 cm<3> of ice-cold, saturated aqueous sodium carbonate solution. The chloroform solution was dried over magnesium sulfate, the chloroform was evaporated in vacuo and the residue distilled in high vacuum whereupon N-ethyl-6|3-acetoxy-nortropinone distilled between 120-123° at 0.01 mm Hg.

Hydrobromid: Smp.: 187—188° (sp) Hydrobromide: mp: 187—188° (sp)

fra metanol/eter. from methanol/ether.

En oppløsning av 4,5 g N-etyl-6p-acetoksy-nortropinon i 15 cm<3> abs. metanol ble hydrert i en autoklav ved 45° i 8 timer med Raneynikkel ved et begynnelsestrykk på 55 atm. Katalysatoren ble fjernet ved filt-rering, oppløsningsmidlet fjernet i vakuum og resten destillert i høyvakuum hvorpå N-etyl-6|3-acetoksy-nortropin gikk over mellom 124—128° ved 0,03 mm Hg. A solution of 4.5 g of N-ethyl-6p-acetoxy-nortropinone in 15 cm<3> abs. methanol was hydrogenated in an autoclave at 45° for 8 hours with Raney nickel at an initial pressure of 55 atm. The catalyst was removed by filtration, the solvent removed in vacuo and the residue distilled in high vacuum whereupon N-ethyl-6|3-acetoxy-nortropine transitioned between 124-128° at 0.03 mm Hg.

Eksempel 7. Example 7.

Skopin-( 4'- klorbenzhydryl) eter. Scopine-(4'-chlorobenzhydryl) ether.

[6,7(3-epoksy-tropin-3«-(4'-klor-benzylhydryl) eter. ] [6,7(3-epoxy-tropine-3'-(4'-chloro-benzylhydryl) ether. ]

En oppløsning av 9,4 g 4-klor-difenyl-klormetanol i 6 cm<3> abs. benzen ble satt dråpevis ved 110° under røring i løpet av 2 timer til en blanding av 7,9 g 6p-acetoksy-tropin og 2,0 g natriumkarbonat. Deretter ble reaksjonsblandingen holdt på 125° i ytterligere 5 timer. Etter kjøling ble det tilsatt 100 cm<3> vann og 100 cm<3> benzen, blandingen ble rystet omhyggelig, benzenlaget ble skilt fra og den vandige del ble ekstrahert igjen med tilsammen260 cm» benzen. De kombinerte benzenekstrakter ble rystet ut med tilsammen 360 cm<3> is-kjølt vandig 2N-saltsyre, den vandige saltsure ekstrakt ble vasket med 200 cm3 eter og gjort alkalisk under kjøling med 30 pst. vandig natriumhydroksydoppløsning. Det alkaliske vandige miljø ble rystet ut med tilsammen 500 cm<3> benzen, de forente benzenekstrakter ble tørket over magnesiumsulfat og benzen fjernet under nedsatt trykk. Den gjenværende 6(3-acetoksy-tropin-3a-(4'-klor-benzhydryl)eter ble iden-tifisert som naftalen-l,5-disulfonat. Smp. 234—235° (sp). A solution of 9.4 g of 4-chloro-diphenyl-chloromethanol in 6 cm<3> abs. benzene was added dropwise at 110° with stirring over 2 hours to a mixture of 7.9 g of 6β-acetoxytropine and 2.0 g of sodium carbonate. The reaction mixture was then held at 125° for a further 5 hours. After cooling, 100 cm<3> of water and 100 cm<3> of benzene were added, the mixture was shaken thoroughly, the benzene layer was separated and the aqueous part was extracted again with a total of 260 cm<3> of benzene. The combined benzene extracts were shaken out with a total of 360 cm<3> of ice-cooled aqueous 2N hydrochloric acid, the aqueous hydrochloric acid extract was washed with 200 cm3 of ether and made alkaline under cooling with 30% aqueous sodium hydroxide solution. The alkaline aqueous environment was shaken out with a total of 500 cm<3> of benzene, the combined benzene extracts were dried over magnesium sulphate and the benzene removed under reduced pressure. The remaining 6-(3-acetoxytropin-3α-(4'-chloro-benzhydryl)ether was identified as naphthalene-1,5-disulfonate. mp 234-235° (mp).

Fra den benzenoppløsning som ble ekstrahert med vandig 2N-saltsyre kunne det oppnås en annen porsjon 6(3-acetoksy-tropin-3a-(4'-klor-benzhydryl)eter under anvendelse av følgende fremgangsmåte: Benzenoppløsningen ble tørket over magnesiumsulfat, og benzenen fjernet i vakuum. Resten ble opptatt i vann, den vandige oppløsning vasket med eter og mettet under kjøling med kaliumkarbonat. Den alkaliske blanding ble filtrert og filtratet deretter ekstrahert flere ganger med kloroform. De kombinerte kloroformekstrakter ble tørket over magnesiumsulfat, kloroformen fjernet i vakuum. Den oljeaktige rest ble oppløst i vannfri metanol og behandlet med tørr hydrogenbromidgass inntil det ble oppnådd sur reaksjon med pH = 2. Eter ble tilsatt og blandingen holdt i noen tid i kulden, hvor 6[3-acetoksy-tropin-3a-(4'-klor-benzhydryl)eterhydro-bromid krystalliserte ut. Smp. 242—243°From the benzene solution extracted with aqueous 2N hydrochloric acid, another portion of 6(3-acetoxytropin-3a-(4'-chloro-benzhydryl)ether could be obtained using the following procedure: The benzene solution was dried over magnesium sulfate, and the benzene removed in vacuo. The residue was taken up in water, the aqueous solution washed with ether and saturated under cooling with potassium carbonate. The alkaline mixture was filtered and the filtrate then extracted several times with chloroform. The combined chloroform extracts were dried over magnesium sulfate, the chloroform removed in vacuo. The oily residue was dissolved in anhydrous methanol and treated with dry hydrogen bromide gas until an acidic reaction with pH = 2 was obtained. Ether was added and the mixture kept for some time in the cold, where 6[3-acetoxy-tropin-3a-(4' -chloro-benzhydryl)ether hydrobromide crystallized out, mp 242-243°

(sp) fra metanol/eter. (sp) from methanol/ether.

En oppløsning av 2,1 g 6(3-acetoksy-tropin-3a- (4'-klor-benzhydryl) -eter-naf-talen-l,5-disulfonat i 10 cm3 etanol og 20 cm3 vandig 3N-natriumhydroksydoppløs-ning ble kokt i 4i/2 time på dampbad, hvorpå en klar oppløsning ble oppnådd. Deretter ble etanol fjernet under nedsatt trykk, resten opptatt. i 20 ems vann og 30 cm3 kloroform. Noe biprodukt med smp. over 300° ble filtrert fra. Kloroformlaget av filtratet (kloroform/vannblanding) ble skilt fra og den vandige del ble ekstrahert igjen med tilsammen 100 cm<3> kloroform. De kombinerte kloroformekstrakter ble tør-ket over magnesiumsulfat og kloroformen fjernet i vakuum. Den gjenværende 6(3-hydroksy-tropin-3a- (4'-klor-benzhydryl) - eter ble krystallisert fra en blanding av benzen/petroleter. Smp. 96—98°. A solution of 2.1 g of 6(3-acetoxy-tropine-3a-(4'-chloro-benzhydryl)-ether-naphthalene-1,5-disulfonate in 10 cm 3 of ethanol and 20 cm 3 of aqueous 3N sodium hydroxide solution was boiled for 41/2 hours on a steam bath, whereupon a clear solution was obtained. Then ethanol was removed under reduced pressure, the residue taken up. in 20 ems of water and 30 cm3 of chloroform. Some by-product with m.p. above 300° was filtered off. The chloroform layer of the filtrate (chloroform/water mixture) was separated and the aqueous part was extracted again with a total of 100 cm<3> chloroform. The combined chloroform extracts were dried over magnesium sulfate and the chloroform removed in vacuo. The remaining 6(3-hydroxytropine -3α-(4'-chloro-benzhydryl)-ether was crystallized from a mixture of benzene/petroleum ether, mp 96-98°.

En oppløsning av 4,7 g 6|3-hydroksy-tropin-3a-(4'-klor-benzhydryl)eter i 19 cm3 abs. pyridin ble behandlet med 1,0 cm<3> metansulfonsyreklorid hvorved den ble varm. Reaksjonsblandingen fikk stå ved romtemperatur i 1 time og ble så holdt svakt kokende under tilbakekjøling i 2 timer. Etter kjøling ble reaksjonsblandingen behandlet med 45 cm<3> kloroform og rystet ut med en samlet mengde på 90 cm3 8 pst. vandig natriumkarbonatoppløsning i 6 porsjoner. Kloroformoppløsningen ble så tørket over magnesiumsulfat og kloroformen fjérnet i vakuum. Resten ble behandlet med den beregnete mengde av en metanoloppløs-ning av naftalen-l,5-disulfonsyre hvoretter 6(5-mesyloksy-tropin-3a-(4'-klorbenzhydryl)eter-naftalen-l,5-disulfonat ble skilt ut i krystallinsk form. Smp. 185—187° (sp) etter omkrystallisering fra metanol. A solution of 4.7 g of 6|3-hydroxy-tropine-3a-(4'-chloro-benzhydryl) ether in 19 cm 3 of abs. pyridine was treated with 1.0 cm<3> of methanesulfonic acid chloride, heating it. The reaction mixture was allowed to stand at room temperature for 1 hour and was then kept at a gentle boil under reflux for 2 hours. After cooling, the reaction mixture was treated with 45 cm3 of chloroform and shaken out with a total amount of 90 cm3 of 8% aqueous sodium carbonate solution in 6 portions. The chloroform solution was then dried over magnesium sulfate and the chloroform removed in vacuo. The residue was treated with the calculated amount of a methanol solution of naphthalene-1,5-disulfonic acid, after which 6(5-mesyloxytropin-3a-(4'-chlorobenzhydryl)ether-naphthalene-1,5-disulfonate was separated into crystalline form, mp 185-187° (sp) after recrystallization from methanol.

3,0 g 6|3-mesyloksy-tropin-3a-(4'-klor-benzyhydryl)eter, 5,8 g trietylamin og 0,2 cm3 dietylanilin ble innelukket under nitrogen i et trykkrør og oppvarmet til 125— 135° i 2 timer. Innholdet i trykkrøret ble så kjølet sterkt og den flytende del dekantert. Denne gule oppløsning ble konsentrert i vakuum, opptatt i 40 cm3 kloroform og vasket to ganger, hver gang med 20 cm3 vandig mettet natriumkarbonat-oppløsning. Kloroformoppløsningen ble tør-ket over magnesiumsulfat, og kloroformen og den gjenværende trietylamin ble fjernet under nedsatt trykk. 300 mg trifluoreddiksyre ble satt under kjøling til en oppløsning av 0,98 g av den gjenværende 6,7-tropenyl-3a-(4'-klor-benzhydryl)eter i 10 cm3 metylenklorid, og blandingen ble 3.0 g of 6|3-mesyloxytropin-3α-(4'-chloro-benzyhydryl)ether, 5.8 g of triethylamine and 0.2 cm3 of diethylaniline were enclosed under nitrogen in a pressure tube and heated to 125-135° in 2 hours. The contents of the pressure tube were then cooled strongly and the liquid part decanted. This yellow solution was concentrated in vacuo, taken up in 40 cc of chloroform and washed twice, each time with 20 cc of aqueous saturated sodium carbonate solution. The chloroform solution was dried over magnesium sulfate, and the chloroform and the remaining triethylamine were removed under reduced pressure. 300 mg of trifluoroacetic acid was added under cooling to a solution of 0.98 g of the remaining 6,7-tropenyl-3a-(4'-chloro-benzhydryl) ether in 10 cm 3 of methylene chloride, and the mixture was

deretter behandlet ved en høyeste temperatur på 25° i løpet av 30 min., under rø-ring med en oppløsning av trifluorpered-diksyre (fremstillet av 1,1 g trifluoreddik-anhydrid og 0,15 g 90 pst. vandig hydrogenperoksyd) i 5 cm<3> metylenklorid. Røring ble fortsatt ved romtemperatur i ytterligere 30 min., reaksjonsblandingen ble ekstrahert med en samlet mengde på 40 cm<3> vann, den vandige oppløsning ble gjort alkalisk med 30 pst. vandig natriumhydroksydopp-løsning og ekstrahert med en samlet mengde på 100 cm<3> kloroform. De kombinerte kloroformekstrakter ble tørket over magnesiumsulfat, og kloroformen fjernet i vakuum. Fra den oljeaktige rest ble skopin-(4'-klorbenzhydryl)eter isolert på vanlig måte som naf talen-1,5-disulfonat. Smp. 223—228° (sp) fra metanol/eter. then treated at a maximum temperature of 25° during 30 min., while stirring with a solution of trifluoroperacetic acid (prepared from 1.1 g of trifluoroacetic anhydride and 0.15 g of 90% aqueous hydrogen peroxide) in 5 cm<3> methylene chloride. Stirring was continued at room temperature for a further 30 min., the reaction mixture was extracted with a total amount of 40 cm<3> of water, the aqueous solution was made alkaline with 30% aqueous sodium hydroxide solution and extracted with a total amount of 100 cm<3> 3> chloroform. The combined chloroform extracts were dried over magnesium sulfate, and the chloroform removed in vacuo. From the oily residue, scopine-(4'-chlorobenzhydryl)ether was isolated in the usual manner as naphthalene-1,5-disulfonate. Temp. 223-228° (mp) from methanol/ether.

Eksempel 8. Example 8.

Skopinbenzhydryleter. Scopine benzhydryl ether.

(6,7-epoksy-tropin-3a-benzhydryleter). (6,7-epoxy-tropine-3a-benzhydryl ether).

En oppløsning av 0,96 g difenylbrom-metan i 3 cm<3> vannfri benzen ble satt dråpevis ved 110° under røring i løpet av iy2 time til en blanding av 0,6 g skopin og 0,3 g natriumkarbonat. Deretter ble reaksjonsblandingen holdt på 125° i ytterligere 3 timer med videre røring. Etter kjøling ble 50 cm<3> vann og 50 cm3 benzen satt til, blandingen ble rystet omhyggelig, benzenlaget skilt fra, og den vandige del ekstrahert igjen med nye 200 cm3 benzen. De forente benzenekstrakter ble rystet ut med tilsammen 250 cm<3> iskjølet vandig 2N-saltsyre, den vandige ekstrakt ble vasket med 50 cm3 eter og gjort alkalisk under kjøling med vandig 30 pst. natriumhydroksydopp-løsning. Det alkaliske vandige miljø ble rystet ut med tilsammen 350 cm3 benzen, de kombinerte benzenekstrakter tørket over magnesiumsulfat, og benzenen fjernet i vakuum. Resten av skopinbenzhydryleter ble behandlet med en beregnet mengde metanolvannstoffklorid, hvorpå hydrokloridet krystalliserte ut etter tilsetting av eter. Etter rekrystallisering fra metanol/ eter smeltet skopinbenzhydryleterhydrokloridet ved 209—212° (sp) og viste ingen synking i blandet smeltepunkt med en prøve som var fremstillet i henhold til eksempel 1. A solution of 0.96 g of diphenylbromomethane in 3 cm<3> of anhydrous benzene was added dropwise at 110° with stirring over 1y2 hours to a mixture of 0.6 g of scopine and 0.3 g of sodium carbonate. The reaction mixture was then kept at 125° for a further 3 hours with further stirring. After cooling, 50 cm<3> of water and 50 cm3 of benzene were added, the mixture was shaken carefully, the benzene layer was separated, and the aqueous part was extracted again with a new 200 cm3 of benzene. The combined benzene extracts were shaken out with a total of 250 cm3 of ice-cooled aqueous 2N hydrochloric acid, the aqueous extract was washed with 50 cm3 of ether and made alkaline under cooling with an aqueous 30% sodium hydroxide solution. The alkaline aqueous environment was shaken out with a total of 350 cm 3 of benzene, the combined benzene extracts dried over magnesium sulfate, and the benzene removed in vacuo. The residue of scopine benzhydryl ether was treated with a calculated amount of methanolic hydrogen chloride, whereupon the hydrochloride crystallized out after addition of ether. After recrystallization from methanol/ether, the scopine benzhydryl ether hydrochloride melted at 209-212° (sp) and showed no depression in mixed melting point with a sample prepared according to Example 1.

Claims

Process for the production of new scopineters, which stimulate the spinal reflexes, and which have the general formula

as well as their acid addition salts and quaternary ammonium compounds, where R, is a lower alkyl group and R2 is a hydrogen or halogen atom, characterized in that a diphenylmethane derivative with formula where R, has the same meaning as above, X is a hydrogen atom, and Y is a chlorine or bromine atom, or XY is a diazo residue, N„ is either reacted with N-alkyl nortropine derivatives, which already have an epoxide ring, and has the general formula where R, has the same meaning as above, or with the stereoisomeric forms of optionally acylated N-alkyl-6-hydroxy-nortropines with the general formula where R, has the same meaning as above, and A is a hydrogen atom or an acyl residue which can easily be cleaved afterwards, after which the epoxidation is introduced into the formed benzhydryl ethers, with the acyl group possibly present being cleaved off, the formed stereoisomeric forms of N-alkyl- The 6-hydroxy-nortropine-3-benzhydryl ether of formula is reacted with sulfonic acid chlorides with the general formula Z - so2ci where Z is an aliphatic or alkylaromatic residue, to form sulfonic acid esters of formula where R7, R2 and Z have the same meaning as above, these are treated with organic bases, and the obtained stereoisomeric forms of the 6,7-tropenyl-3-benzhydryl ether with formula where R, and R2 have the same meaning as above, are epoxidized with trifluoroperacetic acid, and the compounds obtained are optionally transferred to their acid addition salts and quaternary ammonium compounds.