NO744456L - - Google Patents

Description

"Procedure for the Preparation of New Heterocyclic Compounds".

in

The present invention relates to a method for the production of new heterocyclic compounds of formula I

in their optically active forms or in the form of their racemates, wherein R₂ is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, and acid addition salts thereof.

If means lower alkyl or lower alkoxy, this contains 1 h carbon atoms,

The peculiarity of the method according to the invention is that

a) compounds of formula II

in which R^ denotes bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R 2 stands for lower alkyl, is subjected to acid cleavage and the resulting mixture of compounds of formula I in which R^ has the above-mentioned meaning, and compounds of formula III

in which R. means bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, is divided in a manner known per se, or

b) compounds of formula III, in which R^ has the above meaning, at temperatures below 0°C are treated with hydrogen halide

and then the reaction product formed is hydrolysed, or

c) if, in the case of the preparation of the compound of formula t

IN

bromates vincamine in the form of its optically active forms or in the form of its racemate,

and if desired, possible racemates of the compounds of formula I are separated into their optical antipodes and/or the thus obtained compounds of formula I are optionally transferred into their acid addition salts.

The reaction can e.g. take place in such a way that compounds of formula II in which R 1 and R 2 have the above meaning, at temperatures between 0 and 80°C, preferably at temperatures between 10 and 60°C, are reacted with a hydrogen halide solution, e.g. hydrochloric acid in methanol, aqueous hydrogen iodide or hydrogen bromide in glacial acetic acid. The compounds of formula I and of formula III, in which R has the above-mentioned meaning, can then be isolated from the reaction mixture and purified in a manner known per se.

The reaction can also take place in such a way that compounds of formula III, in which R^ has the above meaning, at temperatures below 0.0°C, preferably at temperatures between -20 and -150°C, are reacted with absolute tbrt and halogen-free hydrogen halide. The preferred hydrogen halide is hydrogen bromide, but hydrogen chloride or hydrogen iodide can also be used. The solution is then evaporated to dryness, the residue is then slurried at temperatures below 0°C, preferably at temperatures between -20 and -150°C, in a suitable solvent which does not freeze at temperatures below 0°C, such as e.g. acetone or tetrahydrofuran, an aqueous mixture which does not freeze at temperatures below 0°C, consisting of a solvent, such as e.g. acetone or tetrahydrofuran, an organic base such as e.g. pyridine, sodium bicarbonate or alkali hydroxide and water, preferably in a ratio of 70:20:10 and heated to room temperature.

The compound of formula I formed can then be isolated from the reaction mixture and purified in a manner known per se.

In the case of the preparation of the compound of formula I', the bromination of vincamine takes place according to methods known per se, the introduction of bromine into the benzene nucleus being promoted by means of iron (III) chloride or bromide, boron tribromide, zinc (II) chloride, alimi- nium chloride or iodine. The reaction can e.g. occurs by suspending optically active or racemic vincamine in a solvent inert under the reaction conditions such as chloroform, chlorobenzene, methylene chloride, with the addition of one of the catalysts listed above and then adding dropwise - at temperatures of -20 to + 20°C - a solution of bromine in one of the solvents listed above.

The compound of formula I' formed can then be isolated from the reaction mixture and purified in a manner known per se.

The free bases of the compounds of formula I can be converted in the usual way into their acid addition salts and vice versa.

The previously unknown compounds of formula II used as starting material, in which R^ and Rg have the above meaning, are prepared by (S)-ethyl-(3-(p-toluenesulfonyloxy)-prop-1--yl)-malon- aldehyde acid ethyl ester-diethyl acetal of formula IV.

is reacted with a tryptamine derivative of formula V in which R_1 is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, the formed compound of formula VI in which R^ is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, is melted in the presence of imidazole, a compound of formula VII in which R^ is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy is formed. The last compound is treated under boiling with aqueous acetic acid, whereby a compound of formula VIII is formed in which R^ denotes bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy. Then, a dimethylphosphono-alkoxy-acetic acid methyl ester of formula IX in which R^ stands for a lower alkyl group is reacted in a solvent inert under the reaction conditions, such as e.g. 1,2 dimethoxyethane, tetrahydrofuran, dioxane, diethyl ether or dimethylformamide, in the presence of a strongly basic condensing agent, e.g. an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride or an alkali metal alcoholate such as potassium tert-butylate or sodium methylate, with a compound of formula VIII in which R^ has the above meaning, the resulting mixture of Z and E isomers of a compound of formula X in which R. means bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R 2 stands for. lower alkyl is isolated in a manner known per se from the reaction solution, then the isomer mixture is optionally separated chromatographically, then a bischler-napieral ring closure is carried out by dissolving in phosphorus oxychloride or polyphosphoric acid or a mixture of both and boiling for several hours under a nitrogen atmosphere or by dissolving in a mixture of phosphorus oxychloride dg polyphosphoric acid and an inert solvent, such as toluene, chlorobenzene or chloroform, and heating for several hours at temperatures between 60 and 120°C and then isolating the formed iminium salt with formula XI

in which R^ means bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R 2 stands for lower alkyl, in a manner known per se from the reaction solution. Then, possibly by precipitation with 10% aqueous sodium perchlorate from a metalionic solution or by distribution of the iminium salt with the general formula XI between 10% sodium perchlorate/methanol and methylene chloride, a transfer to the perchlorate is made and then a reduction is made.

The reduction takes place either catalytically or in the presence of

. organometallic compounds. The catalytic reduction through

preferably in a solvent that is inert under the reaction conditions, such as e.g. methanol or ethanol, with the addition of a weak base, such as potassium acetate or triethylamine. The reaction takes place preferably at room temperature and normal pressure. Of the usual hydrogenation catalysts, above all palladium catalysts, especially on supports, have proved beneficial. After completion of hydrogen absorption, the reaction mixture is worked up, e.g. in such a way that the catalyst is filtered off, the formed enolet of formula II in which R 1 and R 2 have the above-mentioned meaning, consisting of a mixture of Z and E isomers is isolated in a manner known per se from the filtrate, purified and the isomer mixture optionally separated kr:omat ogr af in sk.

However, the reduction can also be carried out with metal-organic compounds, preferably with lithium aluminum hydride. The reduction takes place preferably under the reaction conditions

inert solvent, preferably cyclic ethers or ethers with an open chain, such as e.g. tetrahydrofuran, dioxane, diethyl ether,

diglyme or dibutyl ether. The reduction is preferably carried out at temperatures between approximately 0 and 80°C. The cleavage of the reaction complex is then carried out in a manner known per se and the formed enolet of formula II, in which R 1 and R 2 have the above meaning, is isolated from the reaction mixture and purified.

The method according to the invention can be used both for the production of the optically active forms and for the production of the racemates of the compounds of formula I.

Optically active compounds are obtained from optically active intermediates according to the previously described progress small te.tr inn. If racemic intermediates are used, racemic end products are obtained, and these or their precursors can then be separated in a known manner into their optically active isomers, e.g. transfer racemic end products or their precursors by means of optically active bases or acids into the mixture of the diastereoisomeric salts and from there isolate the optical antipodes. The compounds of formula I in their optically active forms as well as in the form of their racemates as well as their acid addition salts are distinguished by interesting pharmacological properties and can consequently find application as medicine. In observational experiments with mice, an increase in irritation could be observed at doses of 10 to 100 mg/kg p.o. The sleep phases by electroencephalogram of rats showed a decreasing sleep and an increasing wakefulness at doses of 10 mg/kg to 30 mg/kg i.p. or p.o. Such changes are an expression of heightened liveliness and psychostimulation. ;Because of. these effects, the compounds are indicated for the treatment of disorders of vitality, especially for combating behavioral disorders due to cerebral vessel damage and cerebral sclerosis in geriatrics, and in the case of disturbances of consciousness due to head-skull injuries. The doses used vary, of course, depending on the compound used, the method of administration and the condition to be treated. In general, however, satisfactory results are obtained in animal experiments with a dose of 10 - 100 mg/kg body weight. For larger mammals, the daily dose is approximately 1 - 500 mg. If necessary, these doses can be administered in two to three partial doses of 0.5 - 30 mg of a compound of formula I alongside solid or liquid carrier substances or diluents or also as a retard form. ;In the following examples which illustrate the invention in more detail; all temperature indications are in °C" and are uncorrected. ;The optical rotation values refer to optically active compounds to measurements with chloroform as solvent. ;Example - 1 : ( . li+ S . 16S) - 10-fluoro-vincamine and HS .16S)-10-fluoro-apovincamine-; 3.86 g of a mixture of the Z- and E- isomers of 3~(1S,12bS)-1-e tyl-9-fluoro -1,2,3,1+, 6,7,12,1 2b-octahydro-indolo (2,3-a) quinolizin-1-yl)-2-methoxypropenoic acid methyl ester is added to 10 ml of 33% hydrogen- Br<p>mid in acetic acid and stirred under a nitrogen atmosphere for half an hour (in a bath at 60°C. Upon subsequent evaporation, a foam is formed. This is fed at 50°C/20mm and pulverized. The residue is dissolved in 20 ml of methylene chloride is added dropwise to 20 ml at 0°C in the presence of 2 N ammonia, the water phase is separated, then extracted with A. About ml of methylene chloride, the first and then the second organic phase, washed with 20 ml of it, the same washing water, combined, lined with 3§sodium sulfate and ti Steamed at 30°C/20mm. The remaining brown foam is chromatographed on 100 g silica gel 0.05 - 0.20 mm, added methylene chloride/methanol (99 L) on a long, thin column in $00 ml fractions of the same solvent mixture. Fractions 8-13 contain the main amount, fractions 1^-30 small amounts of (3S,16S)-10-fluoro-apovincamine, crystallizable from methanol. ;The following fractions 3"! - .36 are eluted with methylene chloride/methanol (98 : 2) and contain (3S ,.1 hS ,.16S)-1 C-fluor-vir.carnin. ;(^ S. rhS . 16S) - 10- fluorovincamine:;Melting point 218°C (decomposition); ( 3S. 16S)'- 10- f luor- apovincamine:;Melting point 17^°; (a)<2>° = + 155° (1%, CHCl^);NMR.- spectrum ( CDCl^. 100 MHz) :; ; The one used as starting material,, 3-(1S,12bS)-1-ethyl-9-fluoro-1,2,3,^,6,7,12,12b-octahydr p-indolo ('2,3 - a) quinolizin-1-yl)-2-methoxypropenoic acid methyl ester is prepared in the following way: a) CS)- V etvl- V. diethoxyzvmetvl- 1-( 2-( 5- fluoro- indol-Vyl)- etvl-2- pjperidone ;At a bath temperature of 30°C, 100 m mol of crude (S)-ethyl-(3-(p-toluenesulfpnyloxy)-prop-1-yl)-malonaldehyde acid ethyl ester-diethyl acetal are dissolved in 50 ml of dimethyl sulphoxide, a solution of 17, 82 g of 5-fluoro-tryptamine in 50 ml of dimethyl sulphoxide is added slowly with stirring and it is stirred for 16 hours at 30°C. (Then it is added dropwise at 23°C under o stirring 200 ml of a 2N sodium carbonate solution and 100 ml of toluene. The resulting mixture is filtered and washed with 50 ml of toluene. The water phase of the filtrate is separated, then extracted with: 50 ml of toluene and the two toluene phases are washed in sequence with 200 ml of the same mixture of water/ethanol (80:20). The combined toluene phases are stirred with 20 g of sodium sulphate, filtered; and evaporated at Uo°C/20 mm, whereby crude (S)-2-ethyl-2-diethoxy-methyl-5- (2- (5-fluoro-indol-3-yl).ethylamino)- pent anacid (ethyl st) is like a yellow, clear oil. The product thus obtained can be used without further purification for the reaction with imidazole. This raw material is mixed with 100 g of imidazole. The mixture is melted at 100°C and allowed to stand for 20 hours under a nitrogen atmosphere at 130°C. After cooling the reaction mixture to 100°C, 80 ml of toluene are added to the melt at 100°C. as a stirrable mass. This is added dropwise at 0°C with stirring and intense cooling 300 ml 6 N hydrochloric acid. The water phase is separated cold, then extracted with 50 ml toluene and the two toluene phases are washed with 100 ml of the same aqueous ;- 2 N ammonia solution. The combined toluene phases give after evaporation at <I>fO°C/20 mm ep. yellowish oil which is chromatographed on ;50 parts silica gel with methylene chloride methanol (98:2) in fractions of 25' parts. The combined residues of fractions 8-10 give after crystallization from ethyllace(tat : hexane (20 : 80) at 0°C white crystals. ;Melting point 101°C; (a)<2>° = + 6.7° ( 1%, CHCl^);b) ( S) - V ethyl- 3- f ormyl- 1 - ( 2- ( 5- fluoro- indole- V vi) - ethyl) - 2- plper idone; One mixes 39.05 g (S)-3-ethyl-3-diethoxymethyl-1-(2-(5-fluoro-indol-3-yl)ethyl)-2-piperidone with 80 ml of 99% acetic acid and 20 ml of water. The mixture is brought to a boil under a stream of nitrogen over the course of half an hour. After cooling, the solvent is evaporated, the oily residue is then taken up for substantial removal of water and acetic acid two more times in each time 50 ml of toluene and evaporated again, After crystallization from ethyl acetate : he.xane (1 : 2) ; at 0° Brownish crystals are obtained. ;Melting point 116°C; (a)<2>° = - 31.5° (1%, CHCl^);c.) 3- CS) - V ethyl- 1 - ( 2- ( 5- f luor- indole- Vvi)- ethyl) - 2-oxo- Vpiperidyl) - 2- methoxys-propene acid methyl ester; To a suspension of 360 mg of sodium hydride in 10 ml of abs. room temperature, a solution of 3.16 g of (S)-3-ethyl-3-formyl-N-(2-(5-fluoro-indol-3-yl)-ethyl)-2-piperidone in 10 ml is added dropwise to the reaction solution abs. tetrahydrofuran. The reaction mixture is then stirred for a further two hours at room temperature, poured onto ice and extracted with methylene chloride. The organic phases are dried and evaporated. A yellowish oil is obtained consisting of a mixture of Z- and E-isomers of 3~ ( S)-3-ethyl-1-(2-(5-fluoro-indol-3-yl)ethyl)-2-oxo-3-piperidyl)-2-methoxy-propenic acid ester. d) CS)- 1- ethyl- 9- fluoro- 1-( 2- methoxy- 2- methoxycarbonyl- vinyl)- 2. 3 A. ; 6. 7. 12- hexahydro- 1H- indolo ( 2. 3- a) quinolizin- 5- ium-- perchlorate;<i>+.025 g of an E-/Z-isomer' mixture of 3-( (S)- 3-Ethyl-1-(2-(5-fluoro-indole 3-yl)ethyl-2-oxo-3-piperidyl)-2-methoxy-propene sulfmethyl ester is dissolved in 5 ml of phosphorus oxychloride and boiled for .3 hours under nitrogen. then evaporated at 20 mm and 60° and then for 15 min at 60° C in high vacuum. After absorption in 10 ml of chloroform, the evaporation is repeated in the same way, the crude iminium chloride remaining as a yellowish-brown foam. 20 g Silica gel 0.05 - 0.20 mm methylene chloride is added to a column, the crude iminium chloride is dissolved in methylene chloride at 30°C and added to the column. Then it is washed with methylene chloride briefly to review the clearly visible, dark brown zone at the column outlet (100 - 200 ml). Then elute with 120 ml of methylene chloride/methanol (90 : 10) and this eluate is evaporated at 30°C/20 mm to foam. ; 5.0 ml of sodium chloride 10% in water is brought to 0°C and the solution of the above foam in 5 ml methanol drop by drop pes while stirring. The pale yellow precipitate is filtered at 0°C, washed twice each time. times 20 ml of water and sucked dry on a filter. From the residue, distil at 20 ml and 30°C bath temperature water until a solution is formed. This is added dropwise at 0°C with 5 ml of sodium perchlorate (10%), the precipitate is filtered cold, washed six times with 20 ml of 0°C water each time and sucked dry on a filter. It is then dried, whereby the compound mentioned in the title is obtained in the form of a mixture of E and Z isomers. ; e) . 3-( MS. 12bS)- 1-. etvl- 9- fluoro- 1 . 2. 3 . k. 6. 7 . 12. 12b- octahydro-;X-, - / ;indolo( £.- 3- a) quinolizine- 1- vl)- 2- methoxy- T) roi3enoic acid methyl ester; E- and Z-isomer mixture of (S)-1- ethyl-9-fluoro-1-(2-methoxy-2-methoxycarbonylvinyl)-2,3,^,6,7,12-hexahydro-1H-indolo(2,3-a)quinoli,zin-5-ium- perchlorate is dissolved at 30°C in 10 ml of methylene chloride/ethanol (80:20) and the solution is added to a hydrogenated mixture of 982 mg of potassium acetate, 2 g of Pd-10% on charcoal and 8 ml of ethanol as well as 2 ml of water . With stirring, the mixture is then hydrogenated at room temperature and normal pressure until the hydrogen consumption after absorption of 8 m mol of hydrogen has practically stopped. /j20 mm, the residue is dissolved in 20 ml of methylene chloride, 20 ml of 2 N ammonia is added at 0°C and distributed. The organic phase is separated, then extracted with 10 ml of methylene chloride, the first and second methylene chloride phases are washed with 20 ml of the same water, combined and dried with sodium sulfate.It is evaporated at 30°C/20 mm and pulverized, dried in high vacuum to obtain in the form of a yellow-brown residue in crude form a mixture of Z- and E-isomer ends of 3-(1S ,12bS>1 -ethyl-9-.fluoro-1,2,3,!+,6,7,12,12b-octahydro-indolo(2,3-aquinolizin-1-yl)-2-methoxy-propenic acid methyl ester.; Example 2 : ( 3S . 16S)- 10-fluorovincamine; To 35^,^ mg of (3S, 16S)-10-fluoro-apovincamine condense at -78°C; 1 ml absolute tort and bromine-free hydrogen bromide. After 15 min. stirring at -78°C, the formed solution is evaporated to dryness at 20 mm pressure and -78°C, the reaction vessel is relieved with dry nitrogen and the evacuation and unloading are repeated two more times. ;The residue is slurried at -78°C first in 5 ml of acetone of -78°C, then 1.5 ml of 10-N-potassium hydroxide is added with intense stirring at -<]>+0°C, the formed grotesque mixture is stirred for 1 hour at -^0 C and neutralized while stirring with 1 g of solid carbon dioxide. It is then distributed between 20 ml of methylene chloride and 7 ml of 2-N-Ammonia, the water phase is then extracted with 10 ml of methylene chloride and both methylene chloride phases are washed successively with 5 ml of the same washing water, dried over sodium sulphate and evaporated. ;The rest consists of (3S, 1^-S, 16S)- 10-fluoro-vincamine together with some (3S,' l6S)-10-fluoro-apovincamine and (3S , 1,4-R, l6S)-10-fluoro- 1)+-epivincamine as by-products. Crystallization of toluene gives (3S, 1^S, - 16S)-10-fluorovincamine, which has the properties indicated under example 1. In an analogous way, starting from (3R516R)-10-fluoro-apovincamine, (3R, 1-R, 16R)-.10-fluoro-vincamine with the same properties as (3S, 1^-S, 16S )-10-fluorine vincamine but with the direction of rotation reversed. ;In an analogous way, starting from rac.-10fluoro-apovincamine, rac,-10-fluoro-vincamine is obtained. Melting point: 230°C (decomposition). ;Example 3-'( 3S. 16S)- 1O- methoxy- apovincamine ;( 3S . 16S)- 1O- hydroxy- apovincamine ;( 3S , 1 kS , 16S)- 10- methoxy-vincamln and ;( 3S , 1 ^ - S , 16S) - 10-hydroxyvincamln; 3.985 g of a mixture of Z- and E-isomers of 3-(1S,12bS)-1-ethyl-9-methoxy-1,2,3, h, 6 ,7,12,12b-octahydro-indolo(2,3-a)quinolizin-1-yl)-2-methoxypropenoic acid methyl ester is added to 10 ml of 33% hydrogen bromide in acetic acid and stirred for half an hour in a bath of 60°C under nitrogen atmosphere. Upon subsequent evaporation, a foam is formed. This is dried at 50°C/20mm and pulverized. The residue is dissolved in 20 ml of methylene chloride, 20 ml of stirred 2-N ammonia is added dropwise at 0°C, the water phase is separated, further extracted with 10 ml of methylene chloride, the first and then the second organic phase is washed with 20 ml of the same washing water, combined, dried with 3 g of sodium sulphate and evaporate at 30°C/20 mm. -The remaining brown foam is chromatographed on 100 g of silica gel, 0.05 - 0.20-mm, followed by methylene chloride-methanol (96:^-) on a long, thin column, in 100 ml fractions with methylene chloride, containing h - 10 % methanol. The products are eluted in the following order: With methylene chloride/methanol (96:^f) (3S , 16S)-10-methoxy-apovincamine, then (3S ,1IfS,16S)-10-methoxy-vincamine; with methylene chloride/methanol (90:10) first (3S,16S)-10-hydroxy-apovincamine and "then (3S , 1J+S , 16S)-10-hydroxyvincamine. ;(3S,16S)-10-methoxy -apovincamine can be crystallized as hydrobromide from isopropyl alcohol and (3'S , 16S)-10-hydroxy-apovincamine as a base from toluene.;( 3S . 16S)- 10- methoxy-apovincamine; Melting point (hydrobromide) = 235°C (decomposition); (a)^(^ase)<=>+ 109° (0.25%, CHCl 3 ).;MR.- spectrum (CDCl^, 100 MHz): ;(3S.16S)-10-hydroxy-apovincamine; Melting point = 226°C '(cleavage): (a)2° = + .121° (0.25%, CHCl^) ;NMR.- spectrum (CDCl^, 100 MHz):; ; ( 3&, I^ S .l6S)- 10- methoxyvincamine ;Melting point 160°: (a)<2>° = + 16.2° (0.3%, GHCl^) ;NMR.- spectrum (CDC^, 100 MHz):; ( 3S. 1^- S. l6S)- 10- hydroxyvincamine Melting point (hydrogen fumarate) = 207° (cleavage); (<a>)<2>° (Base) = + 25.1° (0.25% , CHGl^). ;NMR.- spectrum (CDCl^, 100" MHz):; ; The starting material used 3-(("1S,12bS)-1-ethyl-9-methoxy-1,2,3,h,6,7,12,12b-octahydro-indolo(2,3-a)-quinolizine- 1-yl)-2-methoxy-propenoic acid methyl ester' can be prepared in the following way: a) (S)-3-ethyl-3-formvl-1- (2- (5-me. toxy-indole-3-vi) - etvl) - 2- ' ;- piperidone; With a bath temperature of 30°C, 100 m mol of crude (S)-ethyl-(3-(p-toluenesulfonyloxy)-prop-1-yl)-malonaldehyde acid ethyl ester is dissolved - G diethyl acetal in 50 ml dimethyl sulphoxide, a solution of 19502 g 5-methoxy-tryptamine in 50 ml dimethyl sulphoxide is added slowly with stirring and it is stirred for 16 hours at 30° C. Then, at 23° C with stirring, 200 ml of a .2 N sodium carbonate solution and 100 ml of toluene. The resulting mixture is filtered and washed with 50 ml of toluene. The water phase of the filtrate is separated, re-extracted with 50 ml of toluene and the two toluene phases are washed successively with 200 ml of the same mixture water/ethanol (80:20).The combined toluene phases are stirred with 20g sodium sulfate, filter s and evaporated at Ko°C / 20 mm, leaving crude (S)^2-ethyl-2-diethoxymethyl-5-(2-(5-methoxy-indole-3-yD-ethylamino)-pentanoic acid ethyl ester as a brown oil. The product thus obtained can be used without further purification for the conversion into imidazole. This raw material is mixed with 100 g of imidazole. The mixture is melted at 100°C and set aside for 20 hours under a nitrogen atmosphere at 130°C. After cooling the reaction solution to 100°C, the melt is poured into 80 ml of toluene at 100°C. The solution cooled during stirring begins to form crystals at high °C and is present at 0 °C as a still stirrable solid. This is added dropwise at 0°C with stirring and intense stirring to 300 ml of 6 N hydrochloric acid. The water phase is separated cold, then extracted with 50 ml of toluene and the two toluene phases are washed with 100 ml of the same aqueous 2 N ammonia solution. The combined toluene phases give, after evaporation at hO°C / 20 mm, a brown oil. This oil is mixed with 80 ml of 99% acetic acid and 20 ml of water. The mixture is brought to a boil under a nitrogen atmosphere for about half an hour. After cooling, the solvent is evaporated, the oily residue is then taken up for extensive removal of water and acetic acid; two more times in each time 50 ml of toluene and re-evaporate. ;En crude chromatography on 10 parts of silica gel 0.05 - 0.20 mm with methylene chloride: methanol = 98 : 2 in fractions, corresponding to 5 parts, gives in fractions 5 - 12 a yellow oil, which can be crystallized from ethyl acetate/hexane = 3 : 7 with 0°C. One 1. obtains white crystals of (S),-3-ethyl-3-formyl-1-(2-(5-methoxy-indol-3-yl)-ethyl)-2-piperidone. ;Melting point = 108°C; ' (oc)2° = - 2^,3° (1%, CHCl^)...;b) ' 3-( S)- 3- etvl- 1-( 2- C?- methoxy- indole- 3 - yl)- ethyl).- 2- 6xo- 3-' piperidyl)- 2- methoxy-propenic acid nrethyl ester; To a suspension of 360 mg of sodium hydride in 10 ml of abs. tetrahydrofuran is added dropwise while excluding moisture at room temperature 35l85g dimethylphosphonomethoxyacetic acid methyl ester. After 30 min., stirring at room temperature, a solution of 3.28 g of (S)-3-ethyl-3-formyl-N-(2-(5-methoxy-indol-3-yl)- ethyl-2-piperidone in 10 ml abs. ; tetrahydrofuran. ,, ' The reaction mixture is then stirred for 2 hours at room temperature, poured onto ice and, extracted with methylene chloride. The organic phases are evaporated to dryness. This is obtained - a yellowish oil consisting of a mixture of fats and the E isomers; of 3-(S)-3-ethyl-1-(2-(5-methoxy-indole-3-yD-ethyl-2-oxo-3- piperidyl)-2-methoxy-propensy<r>ernetyl ester. ;c) ( S)- 1^ ethyl- 9- methoxy- 1-( 2- methoxy- 2- methoxy- carbonylvinyl)- 2, 3. 6, 7 , 12- hexahydro- 1H- indolo-( 2. 3- a) quinolizine- 5- ium- perchlorate ;<l>+,1<I>f5g of a mixture of the Z- and E-isomers of 3-(S)- 3-Ethyl-1-(2-(5-methoxy-indol-3-yD ethyl)-2-oxo-3-piperidyl)-2-methoxy-propene-acid methyl ester treated analogously to example 1 d, whereby a Isomer mixture of the compound mentioned above in the title is obtained. d) 3-(1S. 12bS)- 1 - ethyl- 9- methoxy- 1. 2. 1. ^, 6, 7, 12. 1 2b- octahydro- indolo-( 2, 3- a) quinolizin- 1 - yl)- 2- methoxy- the propens acids are the ;E-and' Z-isomer mixture of (S)-1-ethyl-9-methoxy-1-(2-methoxy-me toxycarbonylv inyl) -2,3,1+,6,7,1 2- hexahydro-1H-indolo (2,3-a)quinolizin-5-ium perchlorate is treated analogously to example 1e, whereby a mixture of the Z- and E-isomers, of 3~(1S,12bS)-1ethyl-9-methoxy -1,2,3,k,6,7,12,12b-octahydroindolo(2,3-a)quinolizin-1-yl)-2-methoxy-propenoic acid methyl ester is obtained. ;Example h: . ( 3S . 1 ^- S , 16S) - 10- methoxy-vincamine; To M+7, ^- mg (3S, 16S)-10-methoxy-apovincamine hydrobromide condense at -78°C 1 ml absolute tort and bromine-free hydrogen bromide. After 15 min. stirring at - 78°C, the solution formed is evaporated at 20 mm pressure and 78°C to dryness, the reaction container is relieved with dry nitrogen and the evacuation and unloading are repeated two more times. The residue is slurried at - 78°C, first in 5 ml of acetone at - 78°C, then 1.5 ml of 10-N-potassium hydroxide is added with intense stirring at - hO°C, the formed grotesque mixture is stirred for 1 hour at - . If0°C and neutralized while stirring with 1 g of solid carbon dioxide. Then distribute between 20 ml of methylene chloride and 7 ml of 2 N ammonia, the water phase is then extracted with 10 ml of methylene chloride. and both methylene chloride phases are washed in succession with 5 ml of the same washing water, dried with sodium sulphate and evaporated. ;The rest consists of (3S, 1^-S , 16S)-10-methoxy-vincamine together with some (3S ,16S)-10-methoxy-apovincamine and (3S,1<l>fR,l6S)-10-methoxy -1lf-epivincamine as by-products. By crystallization from isopropyl-1-alcohol, (3S,1*+S,16S)-10-methoxy-vincamine is obtained with the data given in example 3.

Analogously, starting from (3R,16R)-1O-methoxy-apovincamine, (3Rj1^R516R)-10-methoxy-vincamine is obtained with the same properties as (3S , 1^fS , 16S)-10-methoxy-vincamine but with reverse direction of rotation. In an analogous way, starting from rac.-10-methoxy-apovincamine, rac.-10-methoxy-vincamine is obtained; melting point: 230°C (decomposition).

Example 5: (3S-1^-S,16S)-10-hydroxyvincamine

To 357.'?+ mg of (3S,16S)-10hydroxy-apovincamine, 1 ml of absolute tort and bromine-free hydrogen bromide is condensed at - 78°C. After 15 min. stirring at - 78°G, the solution formed is evaporated at 20 mm pressure and - 78°C to dryness, the reaction vessel is relieved with dry nitrogen and the evacuation and unloading are repeated two more times.

The residue is slurried at - 78°C, first in 5 ml of acetone of - 78°C, then 1.5 ml of 10-N-potassium hydroxide is added with intense stirring at - kO°C, the resulting slurry-like mixture is stirred for 1 hour at - hO° C and neutralized while stirring with 1 g of solid carbon dioxide. It is then distributed between 20 ml of methylene chloride and 7 ml of 2 N ammonia, the water phase is then extracted with 10 ml of methylene chloride and both methylene chloride phases are washed one after the other, with 5 ml of the same washing water, - dried with sodium sulfate - and evaporated.

The remainder consists of QS, 1 U-S ,l6S)-10-hydroxy-vincamine together with some (3S , 16S)-10-hydroxy- apbv fncamine and (3S , 1 >+R, 16S)-10-hydroxy-1 h ~, épivincamine as by-products. By crystallization from isopropyl alcohol in the presence of fumaric acid, crystals of (3S,1^-^,16.S)-10-hydroxyvincamine hydrogen fumarate are obtained. Isopropyl alcohol with the data given in example 3. Analogously, starting from (3R,16R)-10-hydroxy-apov-incamine, (3R,1!+R,16R)-10-hydroxy-vincamine with the same properties as (3S-1U-S , 16S ) -10-hydroxy-vincamine but with the direction of rotation reversed.

In an analogous manner, starting from rac.-1O-hydroxy-apovincamine, rac.-10-hydroxy-vincamine is obtained; melting point 230°C (decomposition).

Example 6: (3S, 1U-S, 16S)-11-bromovincamine

1U-.19 g of (3'S, 1U-S,16S)-vincamine and 10.81 g of iron trichloride hexahydrate are suspended at 0°C in 80 ml of chloroform and, with stirring, 1-1 ml of a 1-M solution of bromine in chloroform. After half an hour of further stirring at 0°C ■ 120 ml of 2-N-ammonia are added, the rust-brown precipitate is filtered off, the two phases of the filtrate are separated, the aqueous phase is further extracted with 10 ml of methylene chloride, the organic phases are washed with water, combined, dried with sodium sulfate and evaporated.

When the residue is taken up in 80 ml of isopropyl alcohol, a spontaneous crystallization occurs. These crude crystals of (3S,1U-S,16S)-11-bromovincamine are isolated at 0°C.

Pure (3S , 1 U-S ,16S)-11-bromo-vincamine is obtained by chromatography

of the crude crystals on silica gel with methylene chloride: methanol = 98:2 as solvent and subsequent crystallization from isopropyl alcohol.

-Melting point 21U-°C (decomposition); (a)2° = + 8.7° (1%, CHCl^)

NMR spectrum (CDCl3, 100 MHz):

In an analogous way, starting from rac-vincamine, rac-11-bromo-vincamine is obtained; melting point: 230°C (decomposition).

Example 7: ( 3S. 1U- S. 16S)- 9- fluorovincamine

To 35^,U- mg (3S,16S)-9-fluoro-apoVincamine is condensed at - 78°C

1 ml absolute tort and bromine-free hydrogen bromide. After 15 min. stirring at - 78°C, the formed solution is evaporated at 20 torr and

- 78°C to dryness and dried for 16 hours under these conditions. The residue was slurried at - 78°C, first in 5 ml of acetone of - 78°C, then under intense • stirring at - U-0°C added 1.5 ml of 10-N aqueous potassium hydroxide, the formed grotesque mixture was stirred further for 1 hour at -<!>+0°C, neutralized while stirring with ~1 g of solid carbon dioxide, distributed between 20 ml of methylene chloride and 7 ml of 2-N-ammonia, the aqueous phase was post-extracted with 10 ml of methylene chloride, the organic phases are washed with water, dried with sodium sulfate and evaporated.

The rest consists of (3S , 1 U-S , 16S)-9-fluorine-vincamine, ■ mixed with a little (3S ,16SJ-9-fluorine-apovincamine and (3S , 1U-R, 16S)-9-fluorine -1U--epivincamine as by-products Crystallization from toluene gives (3S,1U-S,16S)-9-fluoro-vincamine).

Melting point 210 °C (decomposition); (<x)2° = + 6.0° (1%, CHCl^).

NMR spectrum (CDCl3, 100 MHz):

Analogously, starting from (3R,16R)-9-fluoro-apovincamine, (3R,1<U>-R,16R)-9-fluoro-vincamine with the same properties as (3S, 1 U-S ,16S)- 9-fluorine vincamine but with the direction of rotation reversed.

Example 8: ( 3S . 1U- S . 16S)- 11 - chlorovincamine

Analogous to example 1, reaction of a mixture of the Z and E isomers of 3-(1S,12bS)-1-ethyl-1O-chloro-1,2,3,h,6,7,12,12b- Octahydro-indolo(2,3-a)quinolizin-1-yl)-2-methoxypropenoic acid methyl ester with hydrogen bromide in acetic acid (3S , 1 U-S , 16S )-11-chlorovincamine.

Melting point 222°C (decomposition); (a)<2>° = + 1.7° (0.1%, CHCl^)

NMR spectrum (CDCl3, 100 MHz):

Example 9: (3S, 1U-S, 16S)-9-hydroxyvincamine

Analogously to example 1, reaction of a mixture of the Z- and °E-isomers of 3-(1S, 1 2bS)-1-ethyl-8-hydroxy-1,2,3,U-,6,7,12 ,12b-octahydro-indolo(2,3-a)quinolizin-1-yl)-2-methoxypropenoic acid methyl ester with hydrogen bromide in acetic acid (3S , 1 U-S ,16S)-9-hydroxyvincamine.

Melting point 220°C (decomposition) from methylene chloride; (a)<2>£ = + 13.5<0>(1%, CHCl^).

NMR spectrum (CD^SOCD^, 100 MHz):

Example 10: ( 3S , 1 U- S. 16S)- 1 2- methylvincamine

Analogous to example 1, a mixture of the Z and E isomers of 3-(1S,12bS)-1-ethyl-11-methyl-1,2,3, h,6,7,12, 1 2b is obtained by reacting -octahydro-indolo;(2,3-a)-quinolizin-1-yl)-2-me toxypropenic acid methyl ester with hydrogen bromide in acetic acid ('3S , 1-U-S , 16S)-1 2-methyl-vincamine.

Melting point 22^°C .(cleavage) ; (cc)<2>° = + 7.6° (1%, CHCl^)

NMR spectrum (CDCl3, 90 MHz):

Claims (1)

1. Process for the preparation of new heterocyclic compounds of formula I in their optically active forms or in the form of their racemates and their acid addition salts, characterized by ata) compounds of formula II in which R^ means bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R^ stands for lower alkyl, is subjected to acid cleavage and the resulting mixture of compounds of formula I, in which R^ has the above meaning, and compounds of formula III in which R^ means bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, is divided in a manner known per se, or •b) compounds of formula III in which R^ has the above-mentioned meaning, at temperatures below 0°C are treated with hydrogen halide and then hydrolyze the formed reaction product, orc) in the case of the preparation of the compound of formula I' brominated■vincamine in its optically active forms or in the form of its racemate, then any possible racemates of the compounds of formula I are separated into their optical antipodes and/or the thus obtained compounds of formula I are optionally transferred into their acid addition salts.