DK151020B - PROCEDURE FOR THE PREPARATION OF APOVINCAMIC ACID ESTERS - Google Patents
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- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
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Description
i 151020in 151020
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af racemiske eller optisk aktive apovincaminsyreestere med den almene formelThe present invention relates to a particular process for the preparation of racemic or optically active apovincamic acid esters of the general formula
Cccjx S?Cccjx S?
10 R10 R
1 2 hvor R og R uafhængigt af hinanden betegner alkylgrup-per med 1-6 kulstofatomer.12 where R and R are independently alkyl groups having 1-6 carbon atoms.
Fremgangsmåde ifølge opfindelsen er ejendommelig ved 15 at man ved en temperatur på 80-150°C omsætter et hydroxy-amino-E-homo-eburnan med den almene formelThe process according to the invention is characterized in that at a temperature of 80-150 ° C, a hydroxy-amino-E-homo-eburnane of the general formula is reacted
CcCsXCcCsX
20 1 II20 1 II
HO-HN*wi JL .HO-HN * wi JL.
r^ooc?r ^ OOC?
KK
1 2 hvor R og R har de ovenfor angivne betydninger, eller 25 et syreadditionssalt deraf med en organisk sulfonsyre i et aprotisk organisk opløsningsmiddel.Wherein R and R are as defined above, or an acid addition salt thereof with an organic sulfonic acid in an aprotic organic solvent.
1 2 I definitionerne af R og R som alkylgrupper med 1-6 kulstofatomer menes både ligekædede og grenede alkylgrupper med 1-6 kulstofatomer, fx metyl, ætyl, n-propyl, 30 isopropyl, n-butyl og sek-butyl.1 2 In the definitions of R and R as alkyl groups having 1-6 carbon atoms are meant both straight and branched alkyl groups having 1-6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and sec-butyl.
Det er velkendt at apovincaminsyrestrene med den 1 2 almene formel I, hvor R og R har de ovenfor angivne betydninger, har værdifulde farmakologiske egenskaber, og navnlig at (+)-apovincaminsyreætylester er en fremra-35 gende vasodilator.It is well known that the apovincamic acid esters of the general formula I, wherein R and R have the meanings given above, have valuable pharmacological properties, and in particular that (+) - apovincamic acid ethyl ester is a prominent vasodilator.
Ifølge ungarnsk patentskrift nr. 163.443 fremstilles disse forbindelser ved at man underkaster det farmaceutisk aktive vincamin hydrolyse og omdanner den dannede vincaminsyre til den tilsvarende ester. Ud fra den såle 151020 2 des- fremstillede vincaminsyreester fremstilles den tilsvarende apovincaminsyreester ved fraspaltning af vand.According to Hungarian Patent No. 163,443, these compounds are prepared by subjecting the pharmaceutically active vincamine hydrolysis and converting the resulting vincamic acid to the corresponding ester. From the sole decomposed vincamic acid ester, the corresponding apovincamic acid ester is prepared by decomposing water.
Ved en anden fremgangsmåde omdanner man først vincamin til apovincamin ved fraspaltning af vand og hydrolyserer 5 derefter apovincaminet og omdanner den dannede apovincamin-syre til den ønskede ester.In another method, vincamine is first converted to apovincamine by decomposition of water and then hydrolyzed the apovincamine and converted the apovincaminic acid formed to the desired ester.
En ulempe ved begge disse varianter af den kendte fremgangsmåde er at vincamin først må fremstilles ved en mangetrinssyntese, og ud fra denne forbindelse kan ^0 de tilsvarende apovincaminsyreestere kun opnås i et udbytte på højst 60%.A disadvantage of both of these variants of the known process is that vincamine must first be produced by a multi-step synthesis, and from this compound, the corresponding apovincamic acid esters can only be obtained in a yield of not more than 60%.
En yderligere fremgangsmåde, angivet i offentliggjort japansk patentansøgning nr. 53-061757, fremstilles 1 2 forbindelser med den almene formel I, hvor R og R har 15 de ovenfor angivne betydninger, ved omsætning af det tilsvarende 14-oxo-15-hydroxyimino-3a,16a-E-homo-eburnan med den tilsvarende alkohol i nærværelse af en syre.A further process, disclosed in Japanese Patent Application Laid-Open No. 53-061757, prepares 12 compounds of general formula I wherein R and R have the above meanings by reacting the corresponding 14-oxo-15-hydroxyimino-3a , 16a-E-homo-eburnan with the corresponding alcohol in the presence of an acid.
Den vigtigste ulempe ved denne fremgangsmåde består i at der ved den anvendte reaktionstemperatur, der 20 overstiger 100-104°C, også vindes en stor mængde af den til den anvendte alkohol svarende æter. Hvis der fx- bruges ætylalkohol som alkoholen ved reaktionen, dannes der også store mængder diætylæter på grund af tilstedeværelsen af den dehydratiserende syre. Dannelse af æter er 25 en særlig ulempe i de teknologier der skal bruges industrielt, da tilstedeværelse af ætere fører til forøget risiko- -for brand og eksplosion og derfor fører til yderligtgående sikkerhedskrav.The main disadvantage of this process is that at the reaction temperature used exceeding 100-104 ° C, a large amount of the ether corresponding to the alcohol used is also obtained. For example, if ethyl alcohol is used as the alcohol in the reaction, large amounts of diethyl ether are also formed due to the presence of the dehydrating acid. The formation of ether is a particular disadvantage in the technologies to be used industrially, as the presence of ether leads to increased risk of fire and explosion and therefore leads to extreme safety requirements.
En yderligere ulempe ved denne fremgangsmåde er 30 at der i almindelighed bruges den stærkt aggressive koncentrerede svovlsyre til dehydratiseringen, hvorfor der indtræder bireaktioner som nedsætter udbyttet og på den anden side også forringer slutproduktets kvalitet.A further disadvantage of this process is that the highly aggressive concentrated sulfuric acid is generally used for dehydration, which is why side reactions occur which reduce the yield and on the other hand also degrade the quality of the final product.
Det har nu vist sig at hvis der som udgangsforbin-35 delse bruges en forbindelse der allerede indeholder den estergruppe som svarer til den ønskede apovincaminsyreester med den almene formel I, så behøver der ikke at være alkohol til stede og følgelig finder der ikke nogen æterdannelse sted. Til dette øjemed kan der med udmær- 151020 3 ket resultat anvendes forbindelser med den almene formel 1 2 II/ hvor R og R har de allerede angivne betydninger.It has now been found that if, as a starting compound, a compound already containing the ester group corresponding to the desired apovincamic acid ester of the general formula I is used, then there should be no alcohol present and, consequently, no ether formation takes place . For this purpose, compounds of the general formula 1 2 II / wherein R and R have the meanings already indicated can be used with excellent results.
Udgangsforbindelsen med den almene formel II kan, i henhold til en fremgangsmåde der er angivet i belgisk 5 patentskrift nr. 883.576, fremstilles ud fra de tilsvarende hexahydroindolo-quinoliziniumforbindelser med mety-lenmalonsyrediestere. Ved fremgangsmåden ifølge den fore-liggende opfindelse kan forbindelserne med den almene formel II bruges som sådanne eller i form af deres syre-10 additionssalte med uorganiske eller organiske syrer, fortrinsvis i form af hydrokloridet.The starting compound of the general formula II can be prepared from the corresponding hexahydroindoloquinolizinium compounds with methylmalonic acid diesters according to a process disclosed in Belgian Patent Specification No. 883,576. In the process of the present invention, the compounds of general formula II may be used as such or in the form of their acid addition salts with inorganic or organic acids, preferably in the form of the hydrochloride.
Det har desuden vist sig at hvis koncentreret svovlsyre erstattes med de mindre korrosive organiske sulfon-syrer, nedsættes faren for korrosion på det anvendte ud-15 styr i betydelig grad.In addition, it has been found that if concentrated sulfuric acid is replaced by the less corrosive organic sulfonic acids, the risk of corrosion on the equipment used is significantly reduced.
Anvendelse af organisk sulfonsyre i stedet for koncentreret svovlsyre nedsætter også bivirkningerne på grund af korrosion, så ikke blot udbyttet men også kvaliteten af slutproduktet forbedres. Kvalitetsforbedringen 20 er af særlig betydning fordi de forbindelser med den almene formel I, der fremstilles ved fremgangsmåden, er beregnet til farmaceutisk anvendelse.The use of organic sulfonic acid in place of concentrated sulfuric acid also reduces the side effects due to corrosion, so that not only the yield but also the quality of the final product is improved. The quality improvement 20 is of particular importance because the compounds of the general formula I prepared by the process are intended for pharmaceutical use.
Som alifatiske sulfonsyrer kan der anvendes sulfon-syrer med en alifatisk kulstofkæde med 1-12 kulstofato-25 mer, fx metansulfonsyre, ætansulfonsyre eller dodecylsul-fonsyre. Anvendelige aromatiske sulfonsyrer er bl.a. sulfonsyrer med en eller flere aromatiske ringe, der kan være substitueret med en eller flere ens eller forskellige substituenter, fx benzensulfonsyre, p-toluensulfonsyre, 30 α-naftylsulfonsyre og ø-naftylsulfonsyre. Pr. 1 mol af en forbindelse med den almene formel II bruges der fortrinsvis 2-3 mol af en sulfonsyre.As aliphatic sulfonic acids, sulfonic acids may be used with an aliphatic carbon chain having 1 to 12 carbon atoms, for example methanesulfonic acid, ethanesulfonic acid or dodecylsulfonic acid. Useful aromatic sulfonic acids include sulfonic acids with one or more aromatic rings which may be substituted by one or more identical or different substituents, for example benzenesulfonic acid, p-toluenesulfonic acid, α-naphthylsulfonic acid and iso-naphthylsulfonic acid. Pr. 1 mole of a compound of general formula II is preferably used 2-3 moles of a sulfonic acid.
Som opløsningsmiddel kan der bruges aprotiske organiske opløsningsmidler såsom eventuelt halogenerede aroma-35 tiske kulbrinter, fx benzen, toluen, xylen eller klorbenzen, eller cykliske ætere som fx dioxan.As a solvent, aprotic organic solvents such as optionally halogenated aromatic hydrocarbons such as benzene, toluene, xylene or chlorobenzene, or cyclic ethers such as dioxane may be used.
Reaktionen udføres ved en temperatur på 80-150°C, fortrinsvis 100-120°C. Reaktionstiden er en funktion af temperaturen.The reaction is carried out at a temperature of 80-150 ° C, preferably 100-120 ° C. The reaction time is a function of temperature.
151020 4151020 4
Reaktionen udføres fortrinsvis under vandfri betingelser.The reaction is preferably carried out under anhydrous conditions.
Ved fremgangsmåden ifølge opfindelsen kan der fremstilles racemiske og optisk aktive forbindelser med den 5 almene formel I, idet man går ud fra henholdsvis racemiske eller optisk aktive forbindelser med den almene formel II.In the process of the invention, racemic and optically active compounds of general formula I can be prepared, starting from racemic or optically active compounds of general formula II, respectively.
En hovedfordel ved fremgangsmåden ifølge opfindelsen i forhold til de kendte fremgangsmåder består i at 10 man ved den foreliggende fremgangsmåde kan fremstille apovincaminsyreestre med den almene formel I ud fra let tilgængelige forbindelser, ved hjælp af i ringe grad korrosivt virkende reaktanter der er lette at håndtere, og med forbedret udbytte og i høj renhed. Fremgangsmåden 15 er let at udføre i industriel målestok og indebærer ingen sikkerhedsproblemer.A major advantage of the process according to the invention in relation to the known processes is that in the present process it is possible to prepare apovincamic acid esters of the general formula I from readily available compounds by means of low-corrosion-reactive materials which are easy to handle. and with improved yield and high purity. The method 15 is easy to perform on an industrial scale and poses no safety concerns.
Ved den mest foretrukne udførelsesform for fremgangsmåden ifølge opfindelsen koges en forbindelse med den almene formel II eller et syreadditionssalt, fortrins-20 vis hydrokloridet deraf med tør p-toluensulfonsyre i toluen i 1-2 timer.In the most preferred embodiment of the process of the invention, a compound of the general formula II or an acid addition salt, preferably the hydrochloride thereof, is boiled with dry p-toluenesulfonic acid in toluene for 1-2 hours.
Fremgangsmåden ifølge opfindelsen skal i det følgende belyses nærmere ved nogle udførelseseksempler.The process according to the invention will now be described in more detail by some exemplary embodiments.
25 Eksempel 1 70 g (0,1 mol) (-)-la-(karbometoxyætyl)-la-ætyl-1,2,3,4,6,7,12,12b-oktahydroindolo-[2,3-a]-quinoliz in-D-dibenzoyltartrat suspenderes i 300 ml toluen. Til sus-30 pensionen sættes der 70 ml koncentreret vandig ammonium-hydroxyopløsning og reaktionsblandingen omrøres ved stuetemperatur i 10 minutter. Toluenfasen skilles fra den vandige fase og tørres ved azeotrop destillation, hvorefter blandingen suppleres op til 300 ml med toluen. Til 35 toluenopløsningen sættes der 36 ml (31 g) t-butylnitrit og 25 g natrium-t-butylat og blandingen omrøres under nitrogenatmosfære ved 30°C i 25 minutter. Til reaktionsblandingen sættes der 300 ml ætanol og der omrøres ved 60°C i 1 time. pH reguleres til 2 ved hjælp af en 36%s 40 vandig saltsyreopløsning ved stuetemperatur, blandingen 151020 5 afkøles til 0°C og det udfældede stof frafiltreres ved denne temperatur og vaskes med 2 x 100 ml vand. Det dannede produkt lufttørres og behandles derefter med 150 ml 10%s vandig ammoniumhydroxydopløsning. Produktet fra-5 filtreres, vaskes med 3 x 50 ml vand og tørres. Der vindes 20 g (-)-14-ætoxykarbonyl-14-hydroxyamino-3a,16a-eburnan med smp. 172-173°C; udbytte 52%. [a]^ = -144,1° (c = 1 i kloroform).Example 1 70 g (0.1 mole) of (-) - 1α- (carbomethoxyethyl) -la-ethyl-1,2,3,4,6,7,12,12b-octahydroindolo- [2,3-a] Quinoliz in-D-dibenzoyl tartrate is suspended in 300 ml of toluene. To the suspension is added 70 ml of concentrated aqueous ammonium hydroxy solution and the reaction mixture is stirred at room temperature for 10 minutes. The toluene phase is separated from the aqueous phase and dried by azeotropic distillation, after which the mixture is added up to 300 ml with toluene. To the toluene solution is added 36 ml (31 g) of t-butyl nitrite and 25 g of sodium t-butylate and the mixture is stirred under a nitrogen atmosphere at 30 ° C for 25 minutes. To the reaction mixture is added 300 ml of ethanol and stirred at 60 ° C for 1 hour. The pH is adjusted to 2 by means of a 36% 40 aqueous hydrochloric acid solution at room temperature, the mixture is cooled to 0 ° C and the precipitate is filtered off at this temperature and washed with 2 x 100 ml of water. The resulting product is air dried and then treated with 150 ml of 10% aqueous ammonium hydroxide solution. The product is filtered off, washed with 3 x 50 ml of water and dried. 20 g of (-) - 14-ethoxycarbonyl-14-hydroxyamino-3a, 16a-eburnane are obtained with m.p. 172-173 ° C; yield 52%. [α] D = -144.1 ° (c = 1 in chloroform).
10 Eksempel 2 19 g (0,05 mol) (-)-14-ætoxykarbonyl-14-hydroxy-amino-3a,16a-eburnan, fremstillet ifølge eksempel 1, og 19,8 g (0,125 mol) tør p-toluensulfonsyre koges i 350 ml tør toluen i 1,5 timer. Reaktionsblandingen afkøles 15 til 20°C hvorefter der tilsættes 200 ml vand og blandingens pH-værdi reguleres til 9 med ca. 20 ml koncentreret aitmo-niumhydroxydopløsning. Den organiske fase fraskilles og den vandige fase ekstraheres med 50 ml toluen. Toluenfaserne forenes, tørres over vandfrit natriumsulfat og fil-20 treres og filtratet affarves med 1 g aktiveret kul og filtreres. Filtratet inddampes til tørhed i vakuum, ind-dampningsremanensen opløses i 20 ml ætanol, koges i 1 minut og krystalliseres efter afkøling til 0°C. Der vindes 16,6 g (+)-apovincaminsyreætylester med smp. 144-146°C.Example 2 19 g (0.05 mole) of (-) - 14-ethoxycarbonyl-14-hydroxy-amino-3a, 16a-eburnane, prepared according to Example 1, and 19.8 g (0.125 mole) of dry p-toluenesulfonic acid are boiled in 350 ml of dry toluene for 1.5 hours. The reaction mixture is cooled to 15 to 20 ° C, then 200 ml of water is added and the pH of the mixture is adjusted to 9 with approx. 20 ml of concentrated ammonium hydroxide solution. The organic phase is separated and the aqueous phase is extracted with 50 ml of toluene. The toluene phases are combined, dried over anhydrous sodium sulfate and filtered and the filtrate is decolorized with 1 g of activated carbon and filtered. The filtrate is evaporated to dryness in vacuo, the evaporation residue is dissolved in 20 ml of ethanol, boiled for 1 minute and crystallized after cooling to 0 ° C. 16.6 g (+) - apovincamic acid ethyl ester is obtained with m.p. 144-146 ° C.
25 Udbytte 95%. [a]j^ = +(144,1-145,1)° (c = 1 i kloroform).Yield 95%. = + (144.1-145.1) ° (c = 1 in chloroform).
Renhed 99,8-100,1% (i iseddikesyre i nærværelse af en indikator med perklorsyre til titrering).Purity 99.8-100.1% (in glacial acetic acid in the presence of a perchloric acid indicator for titration).
Eksempel 3 30 Vand elimineres ved azeotrop destillation fra en opløsning af 47,5 g (0,25 mol) p-toluensulfonsyrehydrat i 400 ml toluen. Derefter sættes der 42 g (0,1 mol) (-)- 14-ætoxykarbonyl-14-hydroxyamino-3a,16a-eburnan-hydroklo-rid til den tørre blanding der derefter tilbagesvales 35 i 2 timer under omrøring. Reaktionsblandingen afkøles til +10°C, der tilsættes 100 ml vand, 30 ml 25%s vandig (r) ammoniumhydroxydopløsning og 2 g "Celite" ^ , hvorpå re- 151020 6 aktionsblandingen omrøres ved +10°C i 5 minutter hvorefter den filtreres. Filtratets vandige fase og toluenfase adskilles, den vandige fase ekstraheres med 50 ml toluen og toluenfaserne forenes. De forenede toluenfaser vaskes 5 med 50 ml vand, tørres over 20 g vandfrit natriumsulfat og filtreres. Filtratet inddampes til tørhed i vakuum, til inddampningsresten sættes der 40 ml ætanol, den dannede opløsning koges i 1 minut og afkøles derefter til 0°C. Blandingen henstår ved 0°C i 1 time hvorefter det 10 udfældede produkt frafiltreres, vaskes ved dækning med 2 x 20 ml ætanol med en temperatur på 0°C og tørres. Der vindes 30 g (86%) (+)-apovincaminsyreætylester med smp. 144-146°C. [a]p° = +(141-146)° (c = 1 i kloroform).Example 3 Water is eliminated by azeotropic distillation from a solution of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate in 400 ml of toluene. Then, 42 g (0.1 mole) of (-) - 14-ethoxycarbonyl-14-hydroxyamino-3a, 16a-eburnane hydrochloride is added to the dry mixture which is then refluxed for 2 hours with stirring. The reaction mixture is cooled to + 10 ° C, 100 ml of water, 30 ml of 25% aqueous ammonium hydroxide solution and 2 g of "Celite" . The aqueous and toluene phases of the filtrate are separated, the aqueous phase is extracted with 50 ml of toluene and the toluene phases are combined. The combined toluene phases are washed with 50 ml of water, dried over 20 g of anhydrous sodium sulfate and filtered. The filtrate is evaporated to dryness in vacuo, to the evaporation residue is added 40 ml of ethanol, the resulting solution is boiled for 1 minute and then cooled to 0 ° C. The mixture is left at 0 ° C for 1 hour after which the 10 precipitated product is filtered off, washed by covering with 2 x 20 ml ethanol at a temperature of 0 ° C and dried. 30 g (86%) of (+) - apovincamic acid ethyl ester are obtained with m.p. 144-146 ° C. [α] p ° = + (141-146) ° (c = 1 in chloroform).
Beregnet for C22H25N2°2 (35°/44): 15 C 75,33 H 7,45 N 7,99Calculated for C 22 H 25 N 2 ° 2 (35 ° / 44): 15 C 75.33 H 7.45 N 7.99
Fundet: C 75,31 H 7,42 N 7,90%.Found: C, 75.31; H, 7.42; N, 7.90%.
Eksempel 4 20 ' På samme måde som beskrevet i eksempel 3, men ud fra 38 g (0,1 mol) (-)-14-ætoxykarbonyl-14-hydroxyamino-3a,J6a-eburnan vindes der 31,5 g (90%) ( + )-apovincaminsyreætylester med smp. 144-146°C. [a]^0 = +(141-146)° (c = 1 i kloroform) .· 25Example 4 20 'In the same manner as described in Example 3, but from 38 g (0.1 mole) of (-) - 14-ethoxycarbonyl-14-hydroxyamino-3a, J6a-eburnane, 31.5 g (90%) is obtained. ) (+) -apovincamic acid ethyl ester with m.p. 144-146 ° C. [.alpha.] D @ 20 = + (141-146) ° (c = 1 in chloroform)
Eksempel 5 På samme måde som beskrevet i eksempel 3, men med anvendelse af 400 ml benzen i stedet for 400 ml toluen som opløsningsmiddel og under udførelse af reaktionen 30 i 12 timer vindes der 23,4 g (67,0%) (+)-apovincaminsyreætylester med smp. 141-145°C. [a]^ = +(141-144)° (c = 1 i kloroform).Example 5 In the same manner as described in Example 3, but using 400 ml of benzene instead of 400 ml of toluene as solvent and in the course of the reaction 30 for 12 hours, 23.4 g (67.0%) (+) is obtained. -apovincamic acid ethyl ester with m.p. 141-145 ° C. [α] D = + (141-144) ° (c = 1 in chloroform).
Eksempel 6 35 På samme måde som beskrevet i eksempel 4, men med anvendelse af 400 ml xylen i stedet for 400 ml toluen som opløsningsmiddel og under udførelse af reaktionen 7 151020 i 30 minutter ved en temperatur på 140°C vindes der 30,5 g (87,3%) (+)-apovincaminsyreætylester med smp. 144-146°C.Example 6 35 In the same manner as described in Example 4, but using 400 ml of xylene instead of 400 ml of toluene as solvent and in carrying out the reaction 7 for 30 minutes at a temperature of 140 ° C, 30.5 g are obtained. (87.3%) (+) - apovincamic acid ethyl ester with m.p. 144-146 ° C.
9 Π 1 [α]β = +(141-146)° (c = 1 i kloroform).9 Π 1 [α] β = + (141-146) ° (c = 1 in chloroform).
55
Eksempel 7 På den måde der er beskrevet i eksempel 3, men med anvendelse af 400 ml klorbenzen i stedet for 400 ml toluen som opløsningsmiddel og under udførelse af reaktio-10 neri ved 130°C i 40 minutter, vindes der 3 0,8 g (88%) ( + )- apovincaminsyreætylester.Example 7 In the manner described in Example 3, but using 400 ml of chlorobenzene instead of 400 ml of toluene as the solvent and carrying out the reaction at 130 ° C for 40 minutes, 3,8 g are obtained. (88%) (+) - apovincamic acid ethyl ester.
Eksempel 8 15 På den i eksempel 3 beskrevne måde, men med anven delse af 43 g (0,25 mol) tør p-toluensulfonsyre i stedet for 47,5 g (0,25 mol) p-toluensulfonsyrehydrat og 400 ml dioxan i stedet for 400 ml toluen, vindes der 18,0 g (51,5%) (+)-apovincaminsyreætylester med smp. 141-143°C.Example 8 In the manner described in Example 3, but using 43 g (0.25 mole) of dry p-toluenesulfonic acid instead of 47.5 g (0.25 mole) of p-toluenesulfonic acid hydrate and 400 ml of dioxane instead for 400 ml of toluene, 18.0 g (51.5%) of (+) - apovincamic acid ethyl ester is obtained with m.p. 141-143 ° C.
20 [a= +(140-143)° (c = 1 i kloroform).[Α = + (140-143) ° (c = 1 in chloroform).
Eksempel 9 På den måde der er beskrevet i eksempel 3, men ved udskiftning af 47,5 g (0,25 mol) p-toluensulfonsyre-25 hydrat med 27,5 g (0,25 mol) ætansulfonsyre vindes der 30,0 g (86%) (+)-apovincaminsyreætylester med smp. 144-146°C. [a]p° = +(141-146)° (c = 1 i kloroform).Example 9 In the manner described in Example 3, but by replacing 47.5 g (0.25 mole) of p-toluenesulfonic acid hydrate with 27.5 g (0.25 mole) of ethanesulfonic acid, 30.0 g is obtained. (86%) (+) - apovincamic acid ethyl ester with m.p. 144-146 ° C. [α] p ° = + (141-146) ° (c = 1 in chloroform).
Eksempel 10 På den måde der er beskrevet i eksempel 3, men ved udskiftning af 48 g (0,25 mol) p-toluensulfonsyrehy-drat med 39,5 g (0,25) benzensulfonsyre vindes der 30,5 g (87,5%) (+)-apovincaminsyreætylester med smp. 144-146°C. [a]p° = +(141-146)° (c = 1 i kloroform).Example 10 In the manner described in Example 3, but by replacing 48 g (0.25 mol) of p-toluenesulfonic acid hydrate with 39.5 g (0.25) benzenesulfonic acid, 30.5 g (87.5) is obtained. %) (+) - apovincamic acid ethyl ester with m.p. 144-146 ° C. [α] p ° = + (141-146) ° (c = 1 in chloroform).
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU802208A HU183207B (en) | 1980-09-10 | 1980-09-10 | Process for preparing apovincaminic acid esters |
| HU220880 | 1980-09-10 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK396881A DK396881A (en) | 1982-03-11 |
| DK151020B true DK151020B (en) | 1987-10-12 |
| DK151020C DK151020C (en) | 1988-02-29 |
Family
ID=10958296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK396881A DK151020C (en) | 1980-09-10 | 1981-09-08 | PROCEDURE FOR THE PREPARATION OF APOVINCAMIC ACID ESTERS |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5780384A (en) |
| AT (1) | AT382616B (en) |
| AU (1) | AU544436B2 (en) |
| BE (1) | BE890274A (en) |
| CA (1) | CA1162543A (en) |
| CH (1) | CH646167A5 (en) |
| DD (1) | DD201680A5 (en) |
| DE (1) | DE3135728C2 (en) |
| DK (1) | DK151020C (en) |
| ES (1) | ES8206522A1 (en) |
| FI (1) | FI69628C (en) |
| FR (1) | FR2489824B1 (en) |
| GB (1) | GB2086886B (en) |
| GR (1) | GR75030B (en) |
| HU (1) | HU183207B (en) |
| IL (1) | IL63720A0 (en) |
| IT (1) | IT1146707B (en) |
| NL (1) | NL8104044A (en) |
| NO (1) | NO813067L (en) |
| NZ (1) | NZ198318A (en) |
| PT (1) | PT73644B (en) |
| SE (1) | SE443141B (en) |
| SU (1) | SU1114336A3 (en) |
| YU (1) | YU41987B (en) |
| ZA (1) | ZA816100B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2052449B1 (en) * | 1992-12-22 | 1995-02-16 | Covex Sa | NEW PROCEDURE FOR THE PREPARATION OF THE ETHYL APOVINCAMINATE. |
| WO2002074613A1 (en) | 2001-03-15 | 2002-09-26 | Honda Access Corporation | Saddle bag installation structure of motorcycle |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2389625B1 (en) * | 1977-05-06 | 1980-04-18 | Roussel Uclaf | |
| HU179292B (en) * | 1978-12-01 | 1982-09-28 | Richter Gedeon Vegyeszet | Process for preparing ester derivatives of apovincaminic acid |
| HU181495B (en) * | 1979-05-31 | 1983-07-28 | Richter Gedeon Vegyeszet | Process for producing hydroxy-imino-eburnane derivatives |
-
1980
- 1980-09-10 HU HU802208A patent/HU183207B/en not_active IP Right Cessation
-
1981
- 1981-08-31 AT AT0376081A patent/AT382616B/en not_active IP Right Cessation
- 1981-09-01 NL NL8104044A patent/NL8104044A/en not_active Application Discontinuation
- 1981-09-02 ZA ZA816100A patent/ZA816100B/en unknown
- 1981-09-02 IL IL63720A patent/IL63720A0/en not_active IP Right Cessation
- 1981-09-04 IT IT68172/81A patent/IT1146707B/en active
- 1981-09-07 DD DD81233097A patent/DD201680A5/en not_active IP Right Cessation
- 1981-09-08 CH CH579581A patent/CH646167A5/en not_active IP Right Cessation
- 1981-09-08 BE BE0/205907A patent/BE890274A/en not_active IP Right Cessation
- 1981-09-08 FI FI812785A patent/FI69628C/en not_active IP Right Cessation
- 1981-09-08 SE SE8105338A patent/SE443141B/en not_active IP Right Cessation
- 1981-09-08 DK DK396881A patent/DK151020C/en not_active IP Right Cessation
- 1981-09-08 GR GR65987A patent/GR75030B/el unknown
- 1981-09-09 NZ NZ198318A patent/NZ198318A/en unknown
- 1981-09-09 AU AU75092/81A patent/AU544436B2/en not_active Ceased
- 1981-09-09 NO NO813067A patent/NO813067L/en unknown
- 1981-09-09 CA CA000385471A patent/CA1162543A/en not_active Expired
- 1981-09-09 ES ES505325A patent/ES8206522A1/en not_active Expired
- 1981-09-09 JP JP56141112A patent/JPS5780384A/en active Granted
- 1981-09-09 DE DE3135728A patent/DE3135728C2/en not_active Expired - Fee Related
- 1981-09-09 FR FR8117112A patent/FR2489824B1/en not_active Expired
- 1981-09-09 GB GB8127201A patent/GB2086886B/en not_active Expired
- 1981-09-09 PT PT73644A patent/PT73644B/en not_active IP Right Cessation
- 1981-09-09 SU SU813333370A patent/SU1114336A3/en active
- 1981-09-10 YU YU2181/81A patent/YU41987B/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |