SE193653C1

SE193653C1 -

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Publication number: SE193653C1
Authority: SE
Publication date: 1964-01-01

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Uppfinnare: A Brossi och 0 Schnider Prioritetbegdrd iron den 20 september 1957 (Schweiz) Foreliggande uppfinning avser ett forfarande for framstallning av substituerade 2-hydroxibensolalkinoliziner med den allmanna formeln R.— HO R, van i R, och R, beteckna vate, en alkoxigrupp eller tillsammans en alkylendioxigrupp, R3 betecknar en alkylgrupp, som eventuellt innehaller eterartat, bundet syre, och van i R, betecknar en med alkyl-, aryl- eller alkoxigrupper eventuellt substituerad etinyl-, vinyl-. eller etylgrupp, och av salter av dessa foreningar. Inventors: A Brossi and Schnider Priority Iron, September 20, 1957 (Switzerland) The present invention relates to a process for the preparation of substituted 2-hydroxybenzolalkinolizines having the general formula R 1 - HO R, van in R, and R, denote vate, an alkoxy group or together an alkylenedioxy group, R 3 represents an alkyl group which optionally contains ethereal, bonded oxygen, and van in R, represents an ethinyl-, vinyl-, optionally substituted by alkyl, aryl or alkoxy groups. or ethyl group, and of salts of these compounds.

Det utmarkande for fiireliggande forfarande dr att man omsater en 2-oxo-benso[alkinolizin med den allmanna formeln II 0 van i R,, R, och Ra ha den angivna betydelsen, med en metallorganisk acetylenforening, hydrolyserar kondensationsprodukten, hydrerar eventuellt den bildade tertiara karbinolen ph katalytisk vag och overfor eventuellt till ett salt. The distinguishing feature of the present process is that reacting a 2-oxo-benzo [alkinolizine of the general formula II in R 1, R 2, and R a 'has the indicated meaning, with an organometallic acetylene compound, hydrolyzing the condensation product, optionally hydrating the formed tertiary the carbinol ph catalytic vague and possibly transfer to a salt.

Framstallningen av de sasom utgangsforeningar anvanda kinolizinketonerna, vilka i den aromatiska ringen kunna innehalla en eller tva, eventuellt med varandra forenade alkoxigrupper och vilka i 3-stallning kunna vara substituerade med en alkyl-, alkenyl- eller aralkylgrupp, som eventuellt innehaller eterartat, bundet syre, kan ske enligt uppgifterna i Rely. Chim, Acta 41 (1958), p. 119 ff. The preparation of the starting compounds using the quinolizine ketones, which in the aromatic ring may contain one or two, optionally joined alkoxy groups and which in the 3-position may be substituted by an alkyl, alkenyl or aralkyl group, which may contain ethereal, bonded oxygen , can be done according to the information in Rely. Chim, Acta 41 (1958), pp. 119 ff.

Enligt uppfinningen omsdttas dessa kinolizinketoner med en metallorganisk acetylenforening, vars etinylgrupp kan vara substituerad med alkyl-, aryl- eller alkoxigrupper. Exempel pa sadana metallorganiska acetylenforeningar aro litiumacetylid, natriumacetylid, acetylen-magnesiumbromid, alkalisalter av alkoxiacetylen och fenylacetylen, och fenylacetylen-magnesiumbromid. Omattningen genomfores ldmpligen i ett losningsmedel. Für alkaliacetyliderna lampar sig sarskilt flytande ammoniak, for acetylen-magnesiumhalogeniderna eter, tetrahydrofuran, dioxan och anisol. Alkinyl-karbinolerna utvinnas genom avdunstning av ltisningsmedlet och kristalliseras exempelvis ur diisopropyleter eller di-n-butyleter. According to the invention, these quinolizine ketones are reacted with an organometallic acetylene compound, the ethinyl group of which may be substituted by alkyl, aryl or alkoxy groups. Examples of such organometallic acetylene compounds are lithium acetylide, sodium acetylide, acetylene-magnesium bromide, alkali salts of alkoxyacetylene and phenylacetylene, and phenylacetylene-magnesium bromide. The feed is usually carried out in a solvent. For the alkali metal acetylides, especially liquid ammonia is used, for the acetylene-magnesium halides ether, tetrahydrofuran, dioxane and anisole. The alkinyl carbinols are recovered by evaporation of the antiseptic and crystallized, for example, from diisopropyl ether or di-n-butyl ether.

Fbr overforing till alkenyl- eller alkylkarbinoler behandlas alkinyl-karbinolerna i ett lampligt losningsmedel, sasom alkohol eller attikester, i narvaro av en hydreringskatalysator, t. ex. platinaoxid, raney-nickel, palladium-kol eller lindlarkatalysator med vatgas. Before transfer to alkenyl or alkyl carbinols, the alkinyl carbinols are treated in a suitable solvent, such as alcohol or attic esters, in the presence of a hydrogenation catalyst, e.g. platinum oxide, raney nickel, palladium-carbon or lindlark catalyst with hydrogen gas.

De tertidra karbinolerna utgora farglosa, kristallina, basiska ftireningar. De aro ringa losliga i vatten men bilda vattenlbsliga kristallina salter med sedvanliga organiska och oorganiska syror, t. ex. vinsyra, citronsyra, fosforsyra, svavelsyra, metansulfonsyra, bromvatesyra och saltsyra. Savai baserna som salterna utmarka sig av en kraftig narkospotentierande och i hjarnan serotoninfrigorande verkan. Man erhaller armed ett liknande verkningsspektrum, som med vissa rauwolfiaalkaloider. FOreningarna skola anvandas sasom 2— — lakemedel eller sasom mellanprodukter for syntes av lakemedel. The tertiary carbinols form colorless, crystalline, basic compounds. They are slightly soluble in water but form water-soluble crystalline salts with customary organic and inorganic acids, e.g. tartaric acid, citric acid, phosphoric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid and hydrochloric acid. The savai bases as the salts are distinguished by a strong anesthetic potentiating and in the brain serotonin-releasing effect. Armed is obtained with a similar spectrum of action as with certain rauwolfia alkaloids. The compounds should be used as 2 - - drugs or as intermediates for the synthesis of drugs.

De tertiara karbinolerna kunna erhallas i olika isomera former. Foreliggande uppfinning omfattar framstallning av alla bildade isomerer. The tertiary carbinols can be obtained in various isomeric forms. The present invention encompasses the preparation of all isomers formed.

Uppfinningen askadligglires narmare medelst fiiljande exempel, van i temperaturerna angivas i Celsiusgrader. The invention is further illustrated by the following examples, in which the temperatures are given in degrees Celsius.

Exempel 1. I en lOsning av 1,7 g Minna 11000 ml flytande ammoniak inledes torr acetylengas, tills den i bOrjan bla lOsningen är ayfargad. Man. tillsatter sedan en lOsning av 35 g 2-oxo-3-etyl9,10 -dimetoxi -1,2,3,4,6,7 -hexahydro -11bH -ben - so [alkinolizin i 1200 ml absolut eter och skakar reaktionsblandningen Over natten i en autoklav vid rumstemperatur. Efter avdunstning av ammoniaken skakar man eterlosningen med mattad ammoniumkloridlosning, tvattar med vatten, torkar over natriumsulfat och indunstar i vakuum. Aterstoden ibises i aceton och forsattes med alkoholisk saltsyralosning till lackmussur reaktion. Darvid utkristallisera 38 g av en hydroklorid, som efter omkristallisering ur metanol-eter smalter yid 257-259°. Ur en yattenlosning ay hydrokloriden utskiljes genom tillsats av natriumkarbonatlosfling 2-hydroxi-2-etiny1-3-ety1-9,10-dimetoxi-1,2, 3, 4,6,7-hexahydro-11bH-benso[a]kinolizin, som efter torkning och omkristallisering ur dttikester smatter vid 1° . 15,8 g ay hydrokloriden av 2-hydroxi-2-etiny1- 3-ety1-9,10-dimetoxi-1,2,3,4,6,7-hexahydro-11bHbenso[a]kinolizin losas i 200 ml aceton och hydreras Over 5 g palladiumkolkatalysator (5 %). Efter upptagning av 2 moler vate avskiljer man katalysatorn, indunstar, uppkokar med aceton, nutschar och omkristalliserar ur etanol-eter. Man erhailer 13,5 g 2-hydroxi-2,3-diety1-9,10-dimetoxi1,2,3,4,6,7-hexahydro-1 I bH-b enso [a ]-kinolizinhydroklori d med smaltpunkten 192-194°. Den ur en vattenlosning av hydrokloriden med natriumkarhonatlOsning utskilda kristallina basen smalter efter torkning och omkristallisering ur isopropyleter vid 124-125°. Example 1. In a solution of 1.7 g of Minna 11000 ml of liquid ammonia, dry acetylene gas is introduced until it is initially colored, inter alia, with the solution. MAN. then add a solution of 35 g of 2-oxo-3-ethyl9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH -benzo [alkinolizine] in 1200 ml of absolute ether and shake the reaction mixture overnight. in an autoclave at room temperature. After evaporation of the ammonia, the ether solution is shaken with matt ammonium chloride solution, washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is ibised in acetone and continued with alcoholic hydrochloric acid solution to litmus reaction. Thereby crystallize out 38 g of a hydrochloride, which after recrystallization from methanol-ether melts at 257-259 °. From a surface solution of the hydrochloride, 2-hydroxy-2-ethyl-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine is separated by the addition of sodium carbonate solution. which after drying and recrystallization from dttikester smacks at 1 °. 15.8 g of the hydrochloride of 2-hydroxy-2-ethynyl-3-ethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bHbenzo [a] quinolizine are dissolved in 200 ml of acetone and hydrogenated Over 5 g of palladium-carbon catalyst (5%). After uptake of 2 moles of hydrogen, the catalyst is separated off, evaporated, boiled with acetone, nuts and recrystallized from ethanol-ether. 13.5 g of 2-hydroxy-2,3-diethyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-1H bH-b enso [a] quinolizine hydrochloride, m.p. 194 °. The crystalline base separated from an aqueous solution of the hydrochloride with sodium carbonate solution melts after drying and recrystallization from isopropyl ether at 124-125 °.

Exempel 2. I en losning av 470 mg Edam i 300 ml flytande ammoniak inledes acetylen till avfargning. Darefter tillsatter man en losning ay 22 g 2-oxo-3-isobuty1-9,10-dimetoxi-1,2,3,4,6,7- hexahydro-11b1I-benso[a]kinolizin i 1500 ml absolut eter. Man skakar Over natten i en autoklay och upparbetar sedan pa i exempel 1 beskrivet satt. Efter upplosning av aterstoden i isopropyleter utkristallisera spontant 16 g 2-hydroxi-2-eti-ny1-3-isobuty1-9,10-dimetoxi-1,2,3,4,6,7-hexahydro-11bH-benso[a]kinolizin med smaltpunkten 124-- 125°. Den i aceton med alkoholisk saltsyra beredda hydrokloriden smaller vid 251-252° under svartfargning. Example 2. In a solution of 470 mg of Edam in 300 ml of liquid ammonia, acetylene is initiated for decolorization. Then a solution of 22 g of 2-oxo-3-isobutyl- 9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bI-benzo [a] quinolizine in 1500 ml of absolute ether is added. Shake overnight in an autoclay and then work up in the manner described in Example 1. After dissolving the residue in isopropyl ether, 16 g of 2-hydroxy-2-ethyl-1,3-isobutyl- 9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] spontaneously crystallize out. quinolizine with a melting point of 124-125 °. The hydrochloride prepared in acetone with alcoholic hydrochloric acid narrows at 251-252 ° during blackening.

Katalytisk hydrering ay 2-hydroxi-2-etiny1-3- isobuty1-9,10-dimetoxi -1,2,3,4, 6,7-hexahydro -11 - bH-benso [a ]kinolizin-hydroklorid enligt uppgifterna i exempel 1 ger 2-hydroxi-2-ety1-3-isobutyl9,10 -dimetoxi -1,2,3,4,6,7 -hexahydro -11bH -ben - so [alkinolizin-hydroklorid med smdltpunkten 216 —218°. Den ur en vattenlosning av hydrokloriden pa sedvanligt satt utskilda fria basen smaller efter omkristallisering ur isopropyleter yid 121-122°. Catalytic hydrogenation of 2-hydroxy-2-ethinyl-3-isobutyl- 9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11-bH-benzo [a] quinolizine hydrochloride according to the data in Example 1 gives 2-hydroxy-2-ethyl-3-isobutyl9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH -benzo [alkinolizine hydrochloride, m.p. 216-218 °. The free base separated from an aqueous solution of the hydrochloride in the usual manner narrows after recrystallization from isopropyl ether at 121-122 °.

Exempel 3. 6,8 g av enligt exempel 2 erhallna 2-hydroxi-2-etiny1-3-isobuty1-9,10-dimetoxi-1,2,3, 4,6,7-hexahydro-11bH-benso[a]kinolizin lOsas i 100 ml metanol och hydreras Over 2 g palladiumkol-katalysator (5 %), tills 1 mol vate upptagits. 490 ml vatgas upptagas pa 35 minuter. Efter avfiltrering ay katalysatorn och indunstning omkristalliserar man ur diisopropyleter. Man erhaller 5,1 g 2-hydroxi-2-yiny1-3-isobuty1-9,10-dimetoxi1,2,3,4,6,7-hexahydro-11bH-benso[a]kinolizin med smaltpunkten 86°. Den i aceton med alkoholisk saltsyra beredda hydrokloriden smaller vid 244 245°. Example 3. 6.8 g of 2-hydroxy-2-ethinyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,6-hexahydro-11bH-benzo [a] obtained according to Example 2 quinolizine is dissolved in 100 ml of methanol and hydrogenated over 2 g of palladium-carbon catalyst (5%), until 1 mole of water is taken up. 490 ml of hydrogen is taken up in 35 minutes. After filtration of the catalyst and evaporation, it is recrystallized from diisopropyl ether. 5.1 g of 2-hydroxy-2-ylinyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine with a melting point of 86 ° are obtained. The hydrochloride prepared in acetone with alcoholic hydrochloric acid narrows at 244 245 °.

Fortsatt hydrering ger under upptagning ay 1 mol \Tate den i exempel 2 beskrivna etyl-karbinolen. Continued hydrogenation gives the ethyl carbinol described in Example 2 while taking up 1 mole of Tate.

Exempel 4. I en losning ay 1,6 g natrium i 250 ml flytande ammoniak inledes torr acetylengas, tills losningen Or avfargad. Man tillsatter sedan en losning av 11 g 2-oxo-3-isobuty1-9,10-dimetoxi- 1,2,3,4,6,7-hexahydro-11bH-bensoi 750 ml absolut eter och orndir 2 timmar. Ammoniaken avdunstas Over natten under stdndig omrOring. Aterstoden forsattes med mattad vattenhaltig ammoniumkloridlosning, yarefter eterlesningen avskiljes, tvattas med vatten, torkas Over natriumsulfat och industas. Aterstoden ger efter upptagning i diisopropyleter 6,5 g etinylkarbinol med smaltpunkten 125°, som Or identisk med den enligt exempel 2 framstallda produkten. I moderluten kan en isomer forening pavisas genom papperskromatografering. Example 4. In a solution of 1.6 g of sodium in 250 ml of liquid ammonia, dry acetylene gas is introduced until the solution Or is decolorized. A solution of 11 g of 2-oxo-3-isobutyl- 9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzoyl 750 ml of absolute ether is then added and allowed to stand for 2 hours. The ammonia is evaporated overnight with constant stirring. The residue was continued with a molten aqueous ammonium chloride solution, after which the ether reading was separated, washed with water, dried over sodium sulfate and evaporated. The residue, after incorporation into diisopropyl ether, gives 6.5 g of ethinylcarbinol, m.p. 125 DEG, which is identical to the product prepared according to Example 2. In the mother liquor, an isomeric compound can be detected by paper chromatography.

Samma produkt erhalles Oven genom omsattning av ketonen med acetylenmonomagnesiumbromid (J. Chem. Soc. (London) 1956, p. 4765), varyid likaledes en blandning av de tva isomera etinylkarbinolerna erhalles. The same product is obtained. By reacting the ketone with acetylene monomagnesium bromide (J. Chem. Soc. (London) 1956, p. 4765), a mixture of the two isomeric ethinyl carbinols is also obtained.

Exempel 5. 500 mg litium losas i 250 ml flytande ammoniak, varefter metylacetylen, som i farvag torkats med kalciumklorid inledes till ayfargning. Man Ulf& sedan en losning av 11 g 2- oxo-3-isobuty1-9,10-dimetoxi-1,2,3,4,6,7-hexahydro-11bH-benso[alkinolizin i 700 nil absolut eter. Efter 2 timmars omroring far blandningen sta. Over natten, varyid ammoniaken avdunstar. Vid upparbetning enligt exempel 4 erhaller man 9,5 g 2-hydroxi-2-metyletiny1-3-isobuty1-9,10-dimetoxi1,2,3,4,6,7-hexahydro-11bH-benso {a}kinolizinmed smdltpunkten 154°. Den i aceton med alkoholisk saltsyra beredda hydroklodden smalter vid 221222°. Vid katalytisk hydrering ay 3,9 g av denna forening i 100 ml metanol Over 200 mg platinaoxid-katalysator upptages den for upptagning av 2 moler beraknade mangden vatgas. Efter indunstning kristalliserar ur diisopropyleter 2- hydroxi-2-propy1-3-isobuty1-9,10-dimetoxi-1,2,3,4, 6,7-hexahydro-11bH-bensosom efter omkristallisering ur attikester smalter yid 117°. Hydrokloriden har smaltpunkten 198-200°. Example 5. 500 mg of lithium are dissolved in 250 ml of liquid ammonia, after which methyl acetylene, which has been dyed in color with calcium chloride, is started to dye. Then a solution of 11 g of 2-oxo-3-isobutyl- 9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [alkinolizine in 700 ml of absolute ether was added. After stirring for 2 hours, the mixture is allowed to stand. Overnight, the varied ammonia evaporates. In working up according to Example 4, 9.5 g of 2-hydroxy-2-methylethylene-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo {a} quinolizine with a melting point of 154 °. The hydrochloride prepared in acetone with alcoholic hydrochloric acid melts at 221222 °. Upon catalytic hydrogenation of 3.9 g of this compound in 100 ml of methanol, the amount of hydrogen gas calculated for the uptake of 2 moles is taken up over 200 mg of platinum oxide catalyst. After evaporation, 2-hydroxy-2-propyl-3-isobutyl-9,10-dimethoxy-1,2,3,4, 6,7-hexahydro-11bH-benzosome crystallizes from diisopropyl ether after recrystallization from attics, melting at 117 °. The hydrochloride has a melting point of 198-200 °.

Exempel 6. I en losning av 420 mg litium i 250 ml flytande ammoniak infOras 5,88 g n-butoxiacetylen och efter 2 timmars omroring en losning — —3 av 9,5 g 2-oxo-3-isobuty1-9,10-dimetoxi-1,2,3,4,6, 7-hexahydro-11bH-benso-[a]kinolizin i 700 ml absolut eter. Det enligt uppgifterna i exempel 4 erhallna extraktet kristalliseras ur petroleumeter. Man erhaller 2,8 g 2-hydroxi-2-n-butoxi-etiny1-3- 9,10 -dimetoxi-1,2,3,4,6,7-hexahydro-11bH-benso[a]kinolizin med smaltpunkten 84°. Katalytisk hydrering enligt exempel 1 ger 2-hydroxi-2-n butoxi-ety1-3-isobuty1-9,10,-dimetoxi-1,2,3,4,6,7- hexahydro-11bH-benso[a]kinolizin, vars hydro-. klorid smatter yid 204-°. Example 6. 5.88 g of n-butoxyacetylene are introduced into a solution of 420 mg of lithium in 250 ml of liquid ammonia and, after stirring for 2 hours, a solution of 9.5 g of 2-oxo-3-isobutyl-9,10 dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo- [a] quinolizine in 700 ml of absolute ether. The extract obtained according to the information in Example 4 is crystallized from petroleum ether. 2.8 g of 2-hydroxy-2-n-butoxy-ethylene-3-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine are obtained, m.p. °. Catalytic hydrogenation according to Example 1 gives 2-hydroxy-2-n-butoxy-ethyl-3-isobutyl-9,10,-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine, vars hydro-. chloride smatter yid 204- °.

Exempel 7. 700 mg litium losas i 400 ml flytande ammoniak och forsattas darefter droppvis med 10,2 g fenylacetylen. Efter 2 timmars omrbring tillsatter man en losning av 16 g 2-oxo-3-isobuty1- 9,10-dimetoxi-1,2,3,4,6,7-hexahydro -11bH-benso[a]-kinolizin i 600 ml absolut eter. Blandningen far sta. Over natten for avdunstning av ammoniaken och upparbetas sedan enligt exempel 4. Den erMina aterstoden loses i aceton och forsattes med alkoholisk saltsyra (till kongosur reaktion), varvid man erhaller 10 g 2-hydroxi-2-fenyletiny1-3-isobuty1-9,10 -dime toxi -1,2,3,4,6,7 -hexahydro -11bH benso[a]kinolizin-hydroklorid med smaltpunkten 240°. Example 7. 700 mg of lithium are dissolved in 400 ml of liquid ammonia and then added dropwise with 10.2 g of phenylacetylene. After stirring for 2 hours, a solution of 16 g of 2-oxo-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine in 600 ml is added absolute ether. The mixture gets stubborn. Overnight for evaporation of the ammonia and then worked up according to Example 4. The ermine residue is dissolved in acetone and continued with alcoholic hydrochloric acid (to congo acid reaction) to give 10 g of 2-hydroxy-2-phenylethynyl-3-isobuty1-9,10 -dime toxi -1,2,3,4,6,7 -hexahydro -11bH benzo [a] quinolizine hydrochloride with a melting point of 240 °.

Samma produkt erhalles om man omsatter isobutylketon i tetrahydrouran med fenylacetylenmagneciumbromid (J. Chem. Soc., 1956, p. 4765); dessutom erhalles en stereoisomer fOrening, vars hydroklorid smalter vid 273°. The same product is obtained by reacting isobutyl ketone in tetrahydrouran with phenylacetylene magnesium bromide (J. Chem. Soc., 1956, p. 4765); in addition, a stereoisomeric compound is obtained, the hydrochloride of which melts at 273 °.

Katalytisk hydrering av 4,56 g 2-hydroxi-2- fenyletiny1-3 -isobutyl -9,10 -dimetwd -1,2,3,4,6,7 - hexahydro-11bH-benso [a]kinolizin-hydroklorid i 70 ml metanol Over 4 g palladiumkolkatalysator (5 %) ger under upptagning av 2 moler vate 3,5 g 2 -hydroxi -2 -fenylety1-3 -isobuty1-9,10 -dimetoxi - 1,2,3,4,6,7 -hexallydro-11bH -benso[a]kinolizin - hydroklorid, som efter omkristallisering ur metanol-eter smatter vid 235°. Catalytic hydrogenation of 4.56 g of 2-hydroxy-2-phenylethylene-3-isobutyl-9,10-dimethyl-1,2,2,4,4,6,7-hexahydro-11bH-benzo [a] quinolizine hydrochloride in 70 ml of methanol Over 4 g of palladium-carbon catalyst (5%) yields 3.5 g of 2-hydroxy-2-phenylethyl-3-isobutyl- 9,10-dimethoxy - 1,2,3,4,6,7 -hexallydro-11bH -benzo [a] quinolizine hydrochloride, which after recrystallization from methanol-ether slaps at 235 °.

Exempel 8. Av 2-oxo-3-n-buty1-9,10-dimetoxi1,2,3,4,6,7-hexahydro-11bH-benso [a]kinolizin framstaller man enligt exempel 1 2-hydroxi-2- etiny1-3 -n -buty1-9,10 -dimetoxi -1,2,3,4,6, 7-hexa - hydro-11bH-benso [aJkinolizin, som har srnaltpunkten 115°. Den i aceton med alkoholisk saltsyra beredda hydrokloriden smalter yid 233234° under svartfargning. Example 8. From 2-oxo-3-n-butyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine, 2-hydroxy-2- Ethyl 3 -n-butyl-9,10-dimethoxy-1,2,3,4,6,7-hexa-hydro-11bH-benzo [a] quinolizine having a melting point of 115 °. The hydrochloride prepared in acetone with alcoholic hydrochloric acid melts at 233234 ° under black coloration.

Katalytisk hydrering enligt exempel 1 ger 2- hydroxi-2-ety1-3-n-buty1-9,10-dimetoxi-1,2,3,4,6, 7-hexahydro-11bH-benso [a]kinolizin-hydroklorid med smaltpunkten 214°. Den fria basen smalter yid 85°. Catalytic hydrogenation according to Example 1 gives 2-hydroxy-2-ethyl-3-n-butyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine hydrochloride with melting point 214 °. The free base melts at 85 °.

Exempel 9. I en losning av 160 mg litium i 100 ml flytande ammoniak inledes torr acetylengas till avfargning. Man tillsatter sedan en losning av 3,2 g 2 -oxo -3 -n-butyl-9 -metoxi -1, 2,3,4,6, 7-hexahydro11bH-benso[alkinolizin i 200 ml absolut eter. Efter skakning i en autoklav vid rumstemperatur dyer natten upparbetar man enligt exempel4 loser den erhallna aterstoden (3,0 g) i bensen och kromatograferar med en pelare av 30 g aluminiumoxid (aktivitet 2, neutral). Med bensen kan kristaLlint utgangsmaterial elueras. Med eter elueras totalt 600 mg 2-hydroxi-2-etiny1-3-n- buty1-9-metoci-1,2,3,4,6,7-hexahydro-11bH-ben-so [a]kinolizin, som efter omkristallisering ur attikester-petroleumeter smatter vid 144°. 200 mg 2-hydrwd-2-etiny1-3-n-butyl-9-metoxi1,2,3,4,6,7-hexahydro-11bH-benso[a]kinolizin ge yid katalytisk hydrering Over 200 mg palladiumkol-katalysator (5 %) under upptagning av 2 moler vate, 160 mg 2-hydrox.i-2-ety1-3-n-buty1-9- metoxi-1,2,3,4,6,7-hexahydro-11bH-benso [a]kinolizin, som efter omkristallisering ur isopropyleter smalter vid 131°. Example 9. In a solution of 160 mg of lithium in 100 ml of liquid ammonia, dry acetylene gas is initiated for decolorization. A solution of 3.2 g of 2-oxo-3-n-butyl-9-methoxy-1,2,3,4,6,7-hexahydro11bH-benzo [alkinolizine 'in 200 ml of absolute ether is then added. After shaking in an autoclave at room temperature overnight, work up according to Example 4, dissolve the obtained residue (3.0 g) in benzene and chromatograph with a column of 30 g of alumina (activity 2, neutral). With benzene, crystalline starting material can be eluted. A total of 600 mg of 2-hydroxy-2-ethinyl-3-n-butyl-9-methoci-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine is eluted with ether, which after recrystallization from attic ester petroleum ether at 144 °. 200 mg 2-Hydro-2-ethynyl-3-n-butyl-9-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [a] quinolizine by catalytic hydrogenation Over 200 mg palladium-carbon catalyst ( 5%) while taking up 2 moles of hydrogen, 160 mg of 2-hydroxy-2-ethyl-3-n-butyl-9-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo [ a] quinolizine, which after recrystallization from isopropyl ether melts at 131 °.

Exempel 10. I en losning av 130 mg litium i 100 ml flytande ammoniak inledes torr acetylengas till avfargning. Man tillsatter sedan en losning av 3 g 2-oxo-3-w-metoxibuty1-9,10-dimetoxi-1,2,3, 4,6,7-hexahydro-11bH-bensoi 250 ml absolut eter. Vid vidarebearbetning enligt exempel 4 erhaller man 3,0 g av ett extrakt, som efter upplosning i eter ger 1,1 g kristallin 2-hydroxi-2- etiny1-3-w-metoxibuty1-9,10-dimetoxi-1,2,3,4,6,7- hexahydro-11bH-benso [a jkinolizin. Produkten smalter efter omkristallisering vid 109°. Den i aceton med alkoholisk saltsyra beredda hydrokloriden smalter vid 223°. Example 10. In a solution of 130 mg of lithium in 100 ml of liquid ammonia, dry acetylene gas is initiated for decolorization. A solution of 3 g of 2-oxo-3-w-methoxybutyl-9,10-dimethoxy-1,2,3,4,6,7-hexahydro-11bH-benzoyl 250 ml of absolute ether is then added. Further processing according to Example 4 gives 3.0 g of an extract which, after dissolution in ether, gives 1.1 g of crystalline 2-hydroxy-2-ethinyl-3-w-methoxybutyl-9,10-dimethoxy-1,2, 3,4,6,7-hexahydro-11bH-benzo [a] quinolizine. The product melts after recrystallization at 109 °. The hydrochloride prepared in acetone with alcoholic hydrochloric acid melts at 223 °.

Katalytisk hydrering ay 500 mg 2-hydroxi-2- etiny1-3-w-metoxibuty1-9,10-climetwd-1,2,3,4,6, 7- hexoahydro-11bH-benso[a]kinolizin i metanol Over 250 ml palladium-kol-katalysator (5 %) ger under upptagning ay 2 moler vate 350 mg 2- hydroxi -2 -ety1-3 -w-metcaibutyl -9,10 -dimetoxi - 1,2,3,4,6,7-hexahydro-11bH-bensosom efter omkristallisering ur diisopropyleter smatter vid 98°. Catalytic hydrogenation ay 500 mg 2-hydroxy-2-ethinyl-3-w-methoxybutyl- 9,10-climethyd-1,2,3,4,6,7-hexoahydro-11bH-benzo [a] quinolizine in methanol Over 250 ml of palladium-carbon catalyst (5%) gives, during uptake ay 2 moles of hydrogen 350 mg of 2-hydroxy-2-ethyl-3 -w-methacibutyl-9,10-dimethoxy - 1,2,3,4,6,7 -hexahydro-11bH-benzosome after recrystallization from diisopropyl ether slams at 98 °.

Exempel 11. Man forfar enligt exempel 1 och omsatter 2-oxo-3-isobuty1-9,10-metylendioxi-1,2, 3,4,6,7-hexahydro-11bH -b ens o [a]kinolizin (smaltpunkten 115; oxalatet har smaltpunkten 182°) med litiumacetylid, hydrolyserar kondensationsprodukten och hydrerar pa katalytisk vag i narvaro av en palladium-kol-katalysator, varvid man erhaller 2-hydroxi-2-ety1-3-isobuty1-9,10-metylenclioxi-1,2,3,4,5,6,7-hexahydro-11bH-benso [alkinolizin med smaltpunkten 140-141°. Example 11. The procedure is as in Example 1, reacting 2-oxo-3-isobutyl-9,10-methylenedioxy-1,2,3,4,6,7-hexahydro-11bH -bene o [a] quinolizine (m.p. 115 The oxalate has a melting point of 182 DEG C. with lithium acetylide, hydrolyzes the condensation product and hydrates on a catalytic pathway in the presence of a palladium-carbon catalyst to give 2-hydroxy-2-ethyl-3-isobutyl-9,10-methyleneclioxy-1 2,3,4,5,6,7-hexahydro-11bH-benzo [alkinolizine, m.p. 140-141 °.

Claims

Patent claim:

A process for the preparation of substituted 2-hydroxy-benzo [a] quinolizines of the general formula L R-HO R, van in R, and R, representing hydrogen, an alkoxy group or together an alkylenedioxy group, R Represents an ethereal bonded oxygen optionally containing alkyl group and R represents an ethinyl, vinyl or ethyl group optionally substituted by alkyl, aryl or alkoxy groups, and of salts of these compounds, characterized in that a 2-oxo- benzo [a] quinolizine of the general formula V in R1, R2 and R, having the meaning given, with an organometallic acetylene compound, hydrolyses the condensation product, optionally hydrates the formed tertiary carbinol on catalytic vapor and 'Wee & optionally to a salt.

Process according to Claim 1, Urinated in that an alkali metal acetylide is used as the condensation component and the reaction is carried out in liquid ammonia.

3. Process according to claim 1, Urinary characterized in that an acetylene magnesium halide is used as the condensation component and the reaction is carried out in diethyl ether, tetrahydrofuran, dioxane or anisole.

4. A process according to claim 1, characterized in that palladium carbon is used as the hydrogenation catalyst. Request publications: Patents from Sweden 98 739, 166 67 4.