DE2458164A1 - METHOD FOR PRODUCING NEW HETEROCYCLIC COMPOUNDS - Google Patents

Description

Process for the preparation of new heterocyclic compounds

The invention relates to processes for the preparation of new heterocyclic compounds of the formula I in their optically active forms or in the form of their racemates, in which. R .. bromine, fluorine, chlorine, hydroxyl, means lower alkyl or lower alkoxy, and their acid addition salts and also includes compounds of formula I and their acid addition salts.

If R is lower alkyl or lower alkoxy, this contains 1 to 4 carbon atoms.

The processes are characterized in that one

a) Compounds of the formula II in which R _{1 is} bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy

'50S826 / 0972

- 2 - ■ Case 100-4110

and R_ stands for lower alkyl, the acidic cleavage subject and the resulting mixture of compounds of the formula I, wherein R- has the above meaning has, and compounds of the formula III, wherein R, bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower Alkoxy means, separates in a manner known per se, or

b) Compounds of the formula III, in which R _{1 has the} above meaning, treated with hydrogen halide at temperatures below 0 ° and then hydrolyzed the resulting reaction product, or

c) that in the case of the preparation of the compound of the formula I ¹ vincamine is brominated in its optically active forms or in the form of its racemate

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

The reaction can be carried out, for example, that compounds of the formula II, wherein R ₁ and R _{0 have the} above meaning, with a hydrogen halide solution, for. B. hydrochloric acid in methanol, aqueous hydrogen iodide or hydrogen bromide in glacial acetic acid, at temperatures between 0 and 80 °, preferably at temperatures between 10 and 60 °. The resulting compounds of the formula I and of the formula III, wherein R-. obi ^ <B has meaning can then be isolated from the reaction mixture and purified in a manner known per se.

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The reaction can also be carried out in such a way that compounds of the formula III, in which R has the above meaning, are allowed to react with absolutely dry and halogen-free hydrogen halide ^{at temperatures below 0 °, preferably at temperatures between -20 and -150 c} . 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 at temperatures below 0 °, preferably at temperatures between -20 and -150 °, in a suitable solvent that does not freeze at temperatures below 0 °, such as. B. acetone or tetrahydrofuran, slurried, then with a water-containing mixture that does not freeze at temperatures below 0 °, consisting of a solvent, such as. B. acetone or tetrahydrofuran, an organic base, such as. B. pyridine, sodium hydrogen carbonate or alkali metal hydroxide and water, preferably in a ratio of 70: 20: 10, added and warmed to room temperature.

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

In the case of the preparation of the compound of the formula I ¹ , the bromination of vincamine takes place according to methods known per se, by introducing bromine into the benzene nucleus by means of iron (III) chloride or bromide, boron tribromide, zinc (II) chloride, aluminum chloride or Iodine is supported. The reaction can be carried out, for example, that one optically active or racemic

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Vincamine in a solvent that is inert under the reaction conditions, such as chloroform, chlorobenzene, methylene chloride, suspended with the addition of one of the catalysts listed above and then at temperatures of - A solution of bromine in one of the inert solvents listed above can be added dropwise at 20 to + 20 °.

The resulting compound of the formula I ¹ can then be isolated from the reaction mixture and purified in a manner known per se.

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

The previously unknown compounds of formula II used as starting material, in which R ₁ and R_ have the above meaning, are prepared by ethyl (S) -Aethyl- [3- (p-toluenesulfonyloxy) -prop-1-yl] -malonaldehydic acid ethyl ester diethyl acetal (Formula IV) with a tryptamine derivative of the formula V, in which R. is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, the resulting compound of the formula VI, in which R .. bromine, fluorine, chlorine, hydroxyl, means lower alkyl or lower alkoxy, melts in the presence of imidazole, a compound of the formula VII in which R, bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy is formed. The latter is treated with boiling with aqueous acetic acid, a compound of the formula VIII in which R _{1 is} bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy is formed. A dimethylphosphono-alkoxy-acetic acid is then

509826/0972

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methyl ester of the formula IX, in which R- is a lower alkyl group, in a solvent which is inert under the reaction conditions, such as, for. B. 1,2-dimethoxyethane, tetrahydrofuran, dioxane, diethyl ether or dimethylformamide, in the presence of a strongly basic condensing agent, e.g. B. 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-butoxide or sodium methylate, with a compound of the formula VIII, in which R has the above meaning, to isolate the resulting mixture of Z- and Ε- Isomers of a compound of the formula X in which R _{1 is} bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R _? stands for lower alkyl, in a manner known per se from the reaction solution, then separates the isomer mixture chromatographically, if desired, then carries out a Bischler-Napieralski.-ring closure 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 and polyphosphoric acid and an inert one. Solvents such as toluene, chlorobenzene or chloroform, and heating for several hours at temperatures between 60 and 120 ° by and then isolating the resulting eidnium salt of the formula XI, wherein R _{1 is} bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R is lower alkyl is, in a manner known per se, from the reaction solution. It is then optionally by precipitation with 10% aqueous sodium perchlorate from a methanolic solution or by distributing the iminium. salt of the general formula XI between 10% sodium

B09826 / 0972

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perchlorate / methanol and methylene chloride converted into the perchlorate and then reduced.

The reduction takes place either catalytically or in the presence of organometallic compounds. The catalytic reduction is preferably carried out in a solvent which is inert under the reaction conditions, such as B. methanol or ethanol, with the addition of a weak base such as potassium acetate or triethylamine. The reaction is preferably carried out at room temperature and normal pressure. From the usual hydrogenation catalysts In particular, palladium catalysts, in particular on supports, have proven their worth. After the Hydrogen uptake is the reaction mixture z. B. worked up in the manner by removing the catalyst filtered off, the resulting enol ether of the formula II, wherein R. and R_ have the above meaning, consisting of a mixture of Z and Ε isomers isolated from the filtrate in a manner known per se, purified and optionally the mixture of isomers is separated by chromatography.

But you can also reduce with organometallic compounds, preferably lithium aluminum hydride, carry out. The reduction is preferably carried out in a solvent which is inert under the reaction conditions, preferably cyclic or open-chain ethers, such as. B. tetrahydrofuran, dioxane, diethyl ether, Diglyme or dibutyl ether. The reduction is preferred carried out at temperatures between about 0 and 80 °. The decomposition of the reaction complex will then carried out in a manner known per se and

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the resulting enol ethers of the formula II, in which R. and R ₁ have the above meaning, isolated from the reaction mixture and purified. .

The inventive method can be used both for the production the optically active forms, as well as for the preparation of the racemates of compounds of the formula I. be used.

Optically active compounds are obtained from optically active intermediates according to those described above Procedural stages. If racemic intermediates are used, racemic end products are obtained, these or their precursors can then be separated into their optically active isomers in a known manner, by adding, for example, racemic end products or their precursors to the mixture using optically active bases or acids of the diastereoisomeric salts converted and the optical antipodes isolated therefrom.

The compounds of the formula I in their optically active forms and also in the form of their racemates and their Acid addition salts are characterized by interesting pharmacological properties and can be used as Find application of remedies.

The observation test on the mouse showed an increase in excitability at doses of 10 to 100 mg / kg p.o. observed v / ground. The phases of sleep in the electroencephalogram of the rat showed a decrease in sleep and an increase in wakefulness at doses of Io mg / kg up to 30 mg / kg i.p. or p.o. Such changes are an expression of an increase in vigilance and psychostimulation.

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Because of the above effects, the compounds are indicated for the treatment of disorders of vigilance, in particular to combat behavior disorders due to cerebral vascular damage and cerebral sclerosis in geriatrics, and for impaired consciousness due to head trauma.

The doses to be used naturally vary depending on the substance used, the type of administration and the condition to be treated. In general, however, satisfactory results are achieved in animal experiments with a dose of 10 to 100 mg / kg body weight. For larger mammals, the daily dose is around 1 up to 500 mg. These doses can, if necessary, be in 2 to proportions of 0.5-30 mg of a compound of the formula I. be administered in addition to solid or liquid carriers or diluents or as a sustained release form.

In the following examples, which explain the invention in more detail, but in no way its scope should restrict, all temperatures are given in degrees Celsius and are uncorrected.

The rotation values for all optically active compounds relate to measurements with chloroform as a solvent.

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Case 100-4110

Br "

- CH ^ OOC I ¹

CH ₃ OOC (RO) C = CIr j II

CH ₃ OOC III

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Case 100-4110

y \ COOC ₀ H, (C ₂ H ₅ O) ₂ CI

IV

CH ₂ -CH ₂ -NH ₂

VI

VII

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Case 100-4110

0H (VIII

P-CH

oOCH.

IX

CH ₃ OOC (R ₂ O) C = CH

XI

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Example 1: (3S, 14S, 16S) -lO-fluoro-vincamin and (3S, 16S) -10-fluoro-apovincamine

3.86 g of a mixture of the Z and Ε isomers of 3- [(IS, 12bS) -l-ethyl-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-indolo [2,3-a] quinolizin-1-yl] -2-methoxypropenoic acid methyl ester are mixed with 10 ml of 33% hydrogen bromide in acetic acid and under a nitrogen atmosphere half an hour in a bath of 60 touched. The subsequent evaporation creates a foam. This is dried at 50 ° / 20 mm and pulverized. The residue is dissolved in 20 ml of methylene chloride, 20 ml of which is stirred at 0 ° 2 N ammonia added dropwise, the water phase separated, extracted with 10 ml of methylene chloride, the 1st and then washed the 2nd organic phase with 20 ml of the same washing water, combined, with 3 g of sodium sulfate dried and evaporated at 30 ° / 20 mm. The remaining brown foam is 100 g Silica gel 0.05-0.20 mm, made up with methylene chloride / methanol (99: 1) on a long thin Column, chromatographed in 100 ml fractions of the same solvent mixture. The factions 8-13 contain the main amount, fractions 14 -

30 lower amounts of (3S, 16S) -10-fluoro-apovincamin, crystallizable from methanol. The following factions

31 - 36 are eluted with methylene chloride / methanol (98: 2) and contain (3S, 14S, 16S) -10-fluorovincamine.

(3S, 14S, 16S) -10-fluoro-vincamine: m.p. 218 ° (dec.); [α] ^ ° = - 4.1 ° (1%, CHCl ₃ )

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13 - Case 100-4110

NMR spectrum (CDCl ₃ , 100 MHz):

0.89 (T ₇ THzZH ₃ C (21) / 3 H)

1.17-3.44 (M '/ 14H)

below that at 2.10 + 2.20 (AB, 15Hz / H C (15))

3.80 (S / H COOC (22) / 3 H) '

3.88 (S / iIC (3) / 1H)

4.62 (S / HOC (14) / IH / interchangeable)

6.66 - 7.20 (M / HC (9.11.12) / 3H)

(3S, 16S) -lO-fluoro-apovincamin:

90
M.p. 174 °; [α] ^ ^υ = + 155 ° (1%, CHCl ₃ )

NMR spectrum (CDCl ₃ , 100 MHz):

1.01 (T, 7Hz / H ₃ C (21) / 3 H)

1.22 - 3.53 (M / 12 H)

below that at 1.91 (Q, 7Hz / H ₉ C (20))

3.93 (S / H ₃ COOC (22) / 3 H)

4.11 (S / HC (3) / 1H)

6/14 (S / HC (15) / 1 H)

6.70 - 7.27 (M / HC (9, ll _# 12) - / 3 H)

The 3 - [(IS, 12bS) -1 ethyl-9-fluoro-1,2,3,4,6,7,12,12b-octahydro-indolo used as starting material [2,3-a] quinolizin-1-yl] -2-methoxypropenoic acid methyl Ester is made as follows:

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100 mol of crude (S) -ethyl- [3 ~ (p-toluenesulfonyloxy) prop-1-yl] malonaldehyde ethyl ester diethyl acetal are dissolved at a bath temperature of 30.degree in 50 ml of dimethyl sulfoxide, slowly sets a solution of 17.82 g of 5-fluoro-tryptamine in with stirring 50 ml of dimethyl sulfoxide are added and stirred for 16 hours at 30 °. Then at 23 ° with stirring 200 ml of a 2 N sodium carbonate solution and 100 ml of toluene were added dropwise. The resulting mixture is filtered and washed with 50 ml of toluene. The water phase of the filtrate is separated off and extracted with 50 ml of toluene and washes the two toluene phases one after the other with 200 ml of the same mixture of water / Ethanol (80:20). The combined toluene phases are stirred with 20 g of sodium sulfate, filtered and evaporates at 40 ° / 20 mm, with crude (S) ^ -Aethyl ^ -diäthoxymethyi-S- [2- (5-fluoro-indol-3-yl) ethylamino] ethyl pentanoate remains as a yellow clear oil. The product obtained in this way can be used for sales without further purification used with imidazole.

This raw material is mixed with 100 g of imidazole. The mixture is melted at 100 ° and left at 130 ° for 20 hours under a nitrogen atmosphere. After cooling the reaction solution to 100, the melt is poured into 80 ml of toluene at 100 °. The solution, cooled with stirring, starts at 45

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To form crystals and is present at 0 ° as a still stirrable paste. This is added at 0 ° dropwise with stirring and intensive cooling with 300 ml of 6N hydrochloric acid. The water phase is separated cold, extracted with 50 ml of toluene and washed the two toluene phases with 100 ml of the same aqueous 2 N ammonia solution. The combined toluene phases give a yellowish color after evaporation at 40 ° / 20 mm OeI, which on 50 parts of silica gel with methylene chloride: methanol - 98: 2 in fractions is chromatographed by 25 parts. The combined residues of fractions 8-10 yield after crystallization from ethyl acetate: hexane - 20:80 at 0 ° "white crystals.

M.p. 101 °; [α] * "= + 6.7 ° (1%, CHCl ₃ )

39.05 g of (S) ~ 3-ethyl-3-diethoxymethyl-1- [2- (5-fluoro-indol-3-yl) -ethyl] -2-piperidone are mixed with 80 ml of 99% acetic acid and 20 ml of water. The mixture is left under nitrogen flow for 1/2 hour brought to the boil. After cooling, the solvent is evaporated; the oily residue will then to remove most of the water and acetic acid twice more in 50 ml of toluene and evaporated again. After crystallization from ethyl acetate: hexane -1: 2 at 0 °, brownish ones are obtained Crystals. ■

M.p. 116 °; [a] ^ ° = - 31.5 ° (1%, CHCl)

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c) 3 — Qs) -3-AethYl; l-l2 -_ (5-f luor-indole ^ S ^ l ^ äthYll-g ^

ester

To a suspension of 360 mg of sodium hydride in 10 ml of abs. Tetrahydrofuran is added dropwise with exclusion of moisture at room temperature, 3.185 g of methyl dimethylphosphonomethoxyacetate.

After stirring for 30 minutes at room temperature, the reaction solution is added dropwise with a Solution of 3.164 g of (S) -S-ethyl-S-formyl-N- [2- (5-fluoro-indol-3-yl) -ethyl] -2-pipcridone in 10 ml 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 concentrated a. A yellowish oil is obtained, consisting of a mixture of the Z and Ε isomers of 3- £ (S) -3-ethyl-1- [2- (5-fluoro-indol ~ 3-yl) ethyl] -2-oxo-3-piperidyl3 ™ 2-methoxy-propenoic acid methyl ester.

4.025 g of an E / Z isomer mixture of 3- £ (S) -3-ethyl-1- [2- (5-fluoro-indole-3-vl) ether-Z-oxo-a-piperidyli ^ -methoxy are dissolved propenoic acid methyl ester in 5 ml of phosphorus oxychloride and boil for 3 hours under nitrogen. The solution is then evaporated at 20 ram and 60 ° and

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- 17 - Case 100-4110

finally 15 minutes at 60 ° in a high vacuum. To Taking up in 10 ml of chloroform, the evaporation is repeated in the same way, with the crude iminium chloride remains as a yellow-brown foam. 20 g of silica gel 0.05-0.20 mm are mixed with methylene chloride attached to a column, the crude iminium chloride dissolved in methylene chloride at 30 ° and placed on the column given. It is then washed with methylene chloride until shortly before the clearly visible, dark brown zone at the column outlet (100 - 200 ml). Then with 120 ml of methylene chloride / Methanol (90:10) eluted and this eluate evaporated at 30 ° / 20 mm to form a foam.

50 ml 10% sodium perchlorate are introduced into water at 0 ° and the solution of the above 'foam in ¹ 5 ml of methanol added dropwise with stirring. The light yellow precipitate is filtered at 0 °, washed twice with 20 ml of water each time and sucked dry. Water is distilled off from the residue at a bath temperature of 20 mm and a bath temperature of 30 ° until a solution is formed. This is added dropwise to 50 ml of sodium perchlorate (10%) at 0 °, the precipitate is filtered cold, washed 6 times with 20 ml of water at 0 ° each time and sucked dry. It is then dried, the title compound being obtained in the form of an E and Z isomer mixture.

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The E and Z isomer mixture of (S) -l-ethyl-9-fluoro-1- (2-methoxy-2-methoxycarbony! Vinyl) -2,3,4, 6,7,12-hexahydro-1H-indolo [2,3-a] quinolizine-5-ium perchlorate one dissolves at 30 ° in 10 ml of methylene chloride / ethanol (80:20) and gives the Solution to a pre-hydrogenated mixture of 982 mg of potassium acetate, 2 g of Pd-IO% on charcoal and 8 ml of ethanol and 2 ml of water. The mixture is then hydrogenated at room temperature and normal pressure with stirring until the hydrogen consumption after uptake of 8 m mol Hydrogen has practically come to a standstill.

After filtration through Hyflo, washing with 20 ml of methylene chloride / ethanol (80:20), the filtrate is evaporated at 30 ° / 20 mm, the residue is dissolved in 20 ml of methylene chloride, and 20 ml of 2N ammonia are added at 0 ° and distributed. The organic phase is separated off, extracted with 10 ml of methylene chloride, and the 1st and 2nd methylene chloride phases are washed with 20 ml of the same water, combined and dried with sodium sulfate. It is evaporated at 30 ° / 20 mm, pulverized, dried in a high vacuum and obtained in the form of a yellow-brown residue in crude form, a mixture of the Z and Ε isomers of 3 - [(IS , 12bS) -1-Ethy1-9- fluoro-1,2,3,4,6,7,12,12 octahydro-indolo [2,3-a] quinolizin-1-yl] ~ 2-methoxypropenoic acid methyl ester.

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Example 2; (3S, 14S ', 16S) -IQ-fluoro-vincamin

1 ml of absolutely dry and bromine-free hydrogen bromide is condensed into 354 _f 4 mg of (3S, 16S) -10-fluoro-apovincamin at -78 °. After stirring for 15 minutes at -78 °, the resulting solution is evaporated to dryness at 20 mm pressure and -78 °, the reaction vessel is relieved of pressure with dry nitrogen and the evacuation and releasing are repeated twice.

The residue is first slurried at -78 ° in 5 ml of acetone at -78 °, then added vigorous stirring at - 40 ° with 1.5 ml of 10 N potassium hydroxide, stirs, the resulting paste for 1 hour at -40 ° and neutralized with stirring with 1 g of solid carbon dioxide. Then between 20 ml of methylene chloride and 7 ml of 2N ~ ammonia distributed, the Viasser phase extracted with 10 ml of methylene chloride and both methylene chloride phases washed successively with 5 ml of the same washing water, with sodium sulfate dried and evaporated.

The residue consists of (3 S, 14 S, 16 S) - · 10-fluorovincamine accompanied by little (3S, 16S) -10-fluoro-apovincamin and (3S, 14R, 16S) -10-fluoro-14-epivincamin as by-products. Crystallization from toluene gives (3S, 14S, 16S) 10-fluoro-vincamine, which has the properties given in Example 1.

In an analogous way, starting from (3R, 16R) -1O-, Fluoro-apovincamin (3R, 14R, 16R) -10-fluoro-vincamin with the same properties as (3S, 14S, 16S) -10-fluorovincamin but reversed sense of rotation.

In an analogous manner, starting from racr10-fluorapovincamine, one obtains raci-10-fluoro-vincamin; M.p .: 230 ° (decomp.).

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Example 3; (3S, 16S) -lQ-methoxy-apovincamine, (3S, 16S) -lO-hydroxy-apovincamin, (3S, 14 S, 16 S) -IQ-methoxy-vineartiin and (3S, 14S, 16S) -10-hydroxy-vincamine

3.985 g of a mixture of the Z and Ε isomers of 3 - [(IS, 12bS) -l-ethyl-9-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo [2 , 3-a] quinolizin-1-yl] -2-methoxypropen-.

acid methyl ester with 10 ml

33% hydrogen bromide in acetic acid was added and the mixture was stirred in a bath at 60 ° for half an hour under a nitrogen atmosphere. The subsequent evaporation creates a foam. This is dried and pulverized at 50 ° / 20 mm. The residue v.'ird dissolved in 20 ml of methylene chloride, added dropwise to 20 ml of 2N ammonia stirred at 0 ° , the aqueous phase separated off, re-extracted with 10 ml of methylene chloride, and the 1st and then the 2nd organic phase washed with 20 ml of the same washing water , combined, dried with 3 g of sodium sulfate and evaporated at 30 ° / 20 mm. The remaining brown foam is chromatographed on 100 g of silica gel 0.05-0.20 mm, made up with methylene chloride / methanol (96: 4) on a long thin column, in 100 ml fractions with methylene chloride containing 4 to 10% methanol .

The products are eluted in the following order: With methylene chloride / methanol (96: 4) (3S, 16S) -10-methoxy-apovincamine, then (3S, 14S, 16S) -10-methoxyvincamine; with methylene chloride / methanol (90:10) (3S, 16S) -10-hydroxy-apovincamine, then (3S, 14S, 16S) -10-hydroxy-vincamine.

(3S, 16S) -10-methoxy-apovincamin is available as a hydrobromide crystallizable from isopropyl alcohol, (3S, 16S) -1O-hydroxy-apovincamine as a base from toluene.

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Case 100-4110

(3S, 16S) -10-methoxy-apovincamine m.p. (hydrobromide) = 235 ° (dec.); MR spectrum (CDCl ₅ , 100 MHz):

1.02 (T, 7 Hz / H ₅ C (21) 1.20-3.44 (M / below at 1.92 (Q, 7 Hz / H ₂ C (20) 3.85 (S / H ₅ COC (IO) 3.93 4.13 6.10 6.78 6.91 7.13

(S / H ₅ C00C (22)

(S 'Jf HC (3)

(S / HC (15)

(Q, 9 + 3 Hz / HC (II)

(D, 3Hz / HC (9)

(D, 9 Hz / HC (12)

(Base) = + 109 ° (0.25

CHOI,)

/ 3H); 12 H);

/ 3 H); / 1 H); / IH); IH); / 1 H);
/ 1 H):

(3S, 16S) -10-hydroxy-apovincamine

= + 121 ° (0.25

M.p. = 226 ° (dec.)

NMR spectrum (CDCl ₅ , 100 MHz): 1.00 (T, 7 Hz / H ₅ C (21) 1.23-3.51 (M below at 1.92 (Q, 7 Hz / H ₂ C (20) 3.92 4.16 approx. 6.07 6.68 6.83 7.07 CHCl ₅ ).

(S / H ₅ COOC (22)

(S / HC (3)

(br.S / HO-C (IO), exchangeable.

(S / HC (15)

(Q, 9 + 2 Hz / HC (II)

(D, 2 Hz / HC (9) B09826 / 0972

(D, 9 Hz / HC (12).

/ 3 H);

/ 12 H);

/ 3H); / 1 H); / 1 H); / 1 H); / 1 H); / ¹ H); / 1 H).

case 100-4110

(3S, 14S, 16S) -10-methoxy-vincamine

M.p. 160 °; [a] ^ ° = + 16.2 ° (0.3 #, CHCl ₃ )

MR spectrum (CDCl ₃ , 100 14Hz):

0.90 (T, 7 Hz / H ₃ C (21) ·

1.12-3.43 (M.

below that at 2.09 + 2.20 (AB, 14 Hz / H ₂ C (l5)

3.80 + 3.82 (2 S / H ₅ COC (IO) H- H ₅ C00 (22)

3.88 (S / HC (3)

4.60 (S / HO-C (14) i interchangeable

6.72 (Q, 9 +3 Hz / HC (II) 6.86 - 7.20 (M / HC (9) + .HC (12))

/ 3 H);

/ 14 H);

/ 6 H); / 1 H); / 1 H); / IH); /.2 H).

(3S, 14S, 16S) -lO -hydrox y-vincamine

M.p. (hydrogen fumarate) = 207 ° (dec.); fO £ ⁰ (base) = + 25.1 ° (0.25 %> CHCl ₃ ).

NMR spectrum (CDCl ₇ , 100 MxIz):

0.89 (T, 7 Hz / H ₃ C (21) / 3 H);

1.14-3.51 (M / 14H);

below that at 2.11 + 2.21 (from, 14 Hz / H ₂ C (15));

· (S / H ₃ C00C (22) / 3 H);

(S / HC (3) / 1H);

3.82 ·

3.93

approx 4.7

6.64

6.77-7.03

(br. S / HO-C (IO) + HO-C (U), interchangeable / 2 H); (Q, 9 + 3 Hz / HC (H) / 1H);

(M / HC (9) + HC (12) / 2H).

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The 3 - [(IS, 12bS) -1-ethyl-9-methoxy-1,2,3,4,6,7,12,12b-octahvdro-indolo [2,3-a] used as starting material quinolizin-l-yl] -2-methoxypropenoic acid methyl ester is prepared as follows:

2-p_ip_eridon

At a bath temperature of 30 °, 100 m mol of crude (S) -Aethy1- [3- (p-toluenesulfonyloxy) -prop-1-y1] -malonaldehyde ethyl ester diethyl acetal are dissolved in 50 ml of dimethyl sulfoxide, slowly add a solution of 19.02 g of 5-methoxy-tryptamine while stirring in 50 ml of dimethyl sulfoxide and stirred for 16 hours at 30 °. Then at 23 ° under Stir 200 ml of a 2 N sodium carbonate solution and 100 ml Toluene added dropwise. The resulting mixture is filtered and rewashed with 50 ml of toluene. The water phase is separated of the filtrate, extracted "with 50 ml of toluene and washed the two toluene phases one after the other with 200 ml the same mixture of water / ethanol (80:20). The United Toluene phases are stirred with 20 g of sodium sulfate, filtered and evaporated at 40 ° / 20 mm> where crude (S) ~ 2-ethyl-2-diethoxymethyl-5- [2- (5-methoxy-indol-3-yl) ethylaminoj-pentanoic acid ethyl ester remains as brown oil. The product obtained in this way can be converted into imidazole without further purification be used.

You mix this raw material

with 100 g imidazole. The mixture is melted at 100 ° and for 20 hours under a nitrogen atmosphere

509826/0972

- 24 - Case 100-4110

Leave 130 °. After the reaction solution has cooled down At 100 °, the melt is poured into 80 ml of toluene at 100 °. The solution, cooled with stirring, begins to form crystals at 45 ° and is at 0 ° as still stirrable Porridge before. 300 ml of δ hydrochloric acid are added dropwise to this at 0 ° with stirring and intensive cooling. The Kasser phase is separated off cold, extracted with 50 ml of toluene and the two toluene phases are washed with 100 ml the same aqueous 2N ammonia solution. The combined toluene phases yield after evaporation at 40 ° / 20 mm a brown oil,

This oil is mixed with 80 ml of 99% strength Acetic acid and 20 ml of water. The mixture is under nitrogen current brought to the boil for 1/2 hour. After cooling, the solvent is evaporated off; the oily residue It is then taken up twice more in 50 ml of toluene each time to remove water and acetic acid and evaporated again.

A coarse chromatography on 10 parts of silica gel 0.05-0.20 µm with methylene chloride: methanol = 98: 2 in fractions, corresponding to 5 parts, yields a yellow oil in fractions 5-12, which turns out Lets ethyl acetate: hexane = 3: 7 crystallize at 0 °. White crystals of (S) -3-Ethyl-3-formyl-1- [2- (5-methoxy-indol-3-yl) -ethyl] -2-piperidone.

M.p. = 108 °; [ct] * ^U = - 24.3 * (1%, CHCl ₃ ).

50 9826/0 972

- 25 - Case 100-4110

To a suspension of 360 mg sodium hydride in 10 ml Section. Tetrahydrofuran is added dropwise with exclusion of moisture 3.185 g of methyl dimethylphosphonomethoxyacetate at room temperature.

After stirring for 30 minutes at room temperature, a solution of 3.284 g of (S) -3-ethyl-3-formyl-N- [2- (5-methoxy-indol-3-yl) -ethyl] -2 is added dropwise to the reaction solution -piperidone in 10 ml abs. Tetrahydrofuran. The reaction mixture is then stirred for a further two hours at room temperature, poured onto ice and extracted with methylene chloride. You dry them
organic phases and constricts. A yellowish oil is obtained, consisting of a mixture of the Z and sort of 3- £ (S) -3-ethyl-1- [2- (5-methoxy-indol-3-yl) ethyl] ^ - oxo -S
acid methyl ester.

4.145 g of a mixture of Z and
Ε-Isomers of 3- £ (S) -3-ethyl-1- [2- (5-methoxyindol-3-yl) ethyl] ^ -oxo-S-piperidyr ^ -methoxypropenoic acid methyl ester analogous to Example 1d, wherein
a mixture of isomers of the above title compound is obtained.

509826/0972

- 26 - Case 100-4110

The E and Z isomer mixture of (S) -l-ethyl-9-methoxy-1- (2-methoxy-2-methoxycarbonylvinyl) -2.3, 4,6,7,12-hexahydro-1H-indolo [2,3-a] quinolizine-5-ium perchlorate is treated analogously to Example 1 e, a mixture of the Z and Ε isomers of 3- [ (IS, 12bS) -1-ethyl-9-methoxy-1,2,3,4,6,7,12,12-octahydro-indolo [2,3-a] quinolizin-1-yl] -2-methoxypropenoic acid methyl ester is obtained.

Example 4; (3S, 14S, 16S) -IQ-methoxy-vincamine

447.4 mg (3S, 16S) -10-methoxy-apovincatnin-hydrobromide is added to

- 78 ° 1 ml of absolutely dry and bromine-free hydrogen bromide condensed. After 15 minutes of stirring at -78 ° the resulting solution at 20 irun pressure and -78 ° for Evaporated to dryness, dry the reaction vessel Nitrogen released and the evacuation and releasing repeated two more times.

The residue is first dissolved in 5 ml of acetone at -78 °

- Slurried 78 °, then added under intense Stirring at - 40 ° with 1.5 ml of 10 N potassium hydroxide, stir the resulting Mash 1 hour at -40 ° and neutralized with stirring with 1 g of solid carbon dioxide. Afterward is distributed between 20 ml of methylene chloride and 7 ml of 2N ammonia, the water phase is re-extracted with 10 ml of methylene chloride and both methylene chloride phases washed successively with 5 ml of the same wash water, with sodium sulfate dried and evaporated.

509826/0972.

- 27 - Case 100-4110

The residue consists of (3S, 14S, 16S) -10-methoxy-vincamine accompanied by little (33,16S) -lO-methoxy-apovincamin and (3S, 14R, 16S) -lO-methoxy-14-epivincamine as by-products. Crystallization from isopropyl alcohol gives (3S, 14S, 16S) -10-methoxy-vincamine with the data given in Example 3. "

Analogously, starting from (3R, 16R) -10-methoxy-apovincamin is obtained (3R, 14R, 16R) -10-methoxy-vincamine with the same properties as (3S, 14S, 16S) -10-methoxy-vincamine but reverse direction of rotation.

In an analogous manner, starting from raclO-methoxyapovincamine, one obtains rac-10-methoxy-vincamine; M.p .: 230 ° (decomp.),

Example 5; (3S, 14S, 16S) -IQ-hydroxy-vincamine

1 ml is added to 357.4 mg (3S, 16S) -10-hydroxy-apovincamin at -78 ° absolutely dry and bromine-free hydrogen bromide condenses. After 15 minutes of stirring at -78 °, the resulting Solution evaporated to dryness at 20 mm pressure and -78 °, the reaction vessel with dry nitrogen relieved and the evacuation and releasing repeated two more times.

The residue is first dissolved in 5 ml of acetone at -78 ° - 78 ° slurried, in it you put under intense Stir at - 40 ° with 1.5 ml of 10N potassium hydroxide, stir the resulting Mash 1 hour at -40 ° and neutralized with stirring with 1 g of solid carbon dioxide. Afterward - between 20 ml of methylene chloride and 7 ml of 2N Ammonia distributed, the * water phase with 10 ml of methylene chloride back-extracted and both methylene chloride phases washed successively with 5 ml of the same wash water, dried with sodium sulfate and evaporated.

50982 6/0972

- 28 - Case 100-4110

The residue consists of (38,148,16S) -10-hydroxyvincamine accompanied by a little (3S, 16S) -10-hydroxy-apovincamin and (38,14R, 16S) -lO-hydroxy-14-epivincamin as Byproducts. Crystallization from isopropyl alcohol in the presence of fumaric acid gives crystals of (3S, 14S, 16S) -10-Hydroxy-vincamine-hydrogen fumarate.Isopropyl alcohol with the data given in Example 3. Analogously, starting from (3R, 16R) -10-hydroxy-apovincamin is obtained (3R, 14R, 16R) ~ 1O-Hydroxy-vincamine with the same Properties like (3S, 14S, 16S) -10-hydroxy-vincamin but reverse direction of rotation.

In an analogous manner, starting from rac-io-hydroxyapovincamine is obtained racj-10-hydroxy-vincamine; M.p. 230 ° (decomp.).

Example 6; (38,148,16S) -11 -Bro m-vincamin

14.19 g (3S, 14S, 16S) -vincamine and 10.81 g iron trichloride hexahydrate were suspended at 0 ° in 80 ml of chloroform and 44 ml of a 1M solution of bromine in chloroform with stirring dripped. After stirring at 0 ° for half an hour, 120 ml of 2N ammonia were added, the rust-brown one The precipitate is filtered off, the two phases of the filtrate are separated, the aqueous phase with 40 ml of methylene chloride extracted, the organic phases washed with water, combined, dried with sodium sulfate and evaporated.

When taking up the residue in 80 ml of isopropyl alcohol spontaneous crystallization occurred. These crude crystals of (3S, 14S, 16S) -11-bromo-vincamin were at 0 ° isolated.

509826/0972

- 29 - "Case 100-4110

Pure (3S, 14S, 16S) -ll-bromovincamine was obtained from Chromatograph the crude crystals on silica gel with methylene chloride: methanol = 98: 2 as solvent and subsequent crystallization from isopropyl alcohol.

M.p. 214 ° (dec.); [a] * ° = + 8.7 ° (1%, CHCl) '

Nuclear Magnetic Resonance Spectrum (CDCI, 100 MHz): -

0.86 (T, 7 Hz / H ₃ CUl) / 3 H);

1.18-3.49 (M- / 14H); below that at about ". 2.07 + 2.16 (AB, 15 Hz / H C (15);

3.80 (ca, S / H COOC (-22) + HC (3) / 4H);

4.63 (S ■ / .HO-C (14), exchangeable / 1H);

7.04 - 7.48 (M / HC (9 + 10 +12) / 3H).

In an analogous manner, starting from racj-vincamine is obtained rll-bromovincamin; M.p .: 230 ° (decomp.)

Example 7 : (3S, 14S, 16S) -9-fluoro-vincamine

To 354.4 nag (3S, 16S) -9-fluoro-apovincamin was added 1 ml at -7.8 ° absolutely dry and bromine-free hydrogen bromide condenses. After 15 minutes of stirring at -78 ° was the resulting solution was evaporated to dryness at 20 Torr and -78 ° and under these conditions for 16 hours dried.

The residue was first dissolved in 5 ml of acetone at -78 ° slurried at -78 °, then with vigorous stirring at -40 ° with 1.5 ml of 10N ~ aqueous potassium hydroxide added, the resulting paste for 1 hour at -40 °

5098 2 6/0972

- 30 - Case 100-4110

weitergertihrt, neutralized with stirring with 1 g of solid carbon dioxide, distributed between 20 ml of methylene chloride and 7 ml of 2N ammonia, the aqueous phase with 10 ml
Extracting methylene chloride, the organic phases washed with water, dried with sodium sulfate and evaporated.

The residue consists of (3S, 14S, 16S) -9-fluoro-vincamin, accompanied by a little (3S, 16S) -g-fluoro-apovincamin and (3S, 14R, 16S) -9-fluoro-14 ~ epivincamin "as By-products. Crystallization from toluene gave (3S, 14S,
16S) -9-fluoro-vincamin.

M.p. 210 ° (dec.); [cc] ^ ⁰ = + 6.0 ° (1%, CHCl ₃ )
Nuclear Magnetic Resonance Spectrum (CDCI, 100 MHz):

0.88 (T, 7 Hz / H ₃ C (21) / 3H);

1.18-3.50 (M./14H); below that at about 2.09 + 2.17 (AB, 13 Hz / H ₂ C (15));

at 3.23 (H ₂ C (6));

3.79 (S / H ₃ COOC (22) / 3 H);

3.86 (S / HC (3) / 1H);

4.64 (S / HO-C (14), exchangeable / 1H);

6.57-7.20 (M / HC (IO + 11 + 12) / 3H)>

Analogously, starting from (3R, 16R) -9-fluorapovincamin, (3R, 14R, 16R) -9-fluorovincamin is obtained with the
same properties as (3S, 14S, 16S) -9-fluorovincamin but with the opposite direction of rotation.

509826/0972

- 31 - Case 100-4110

Example 8: (33,14S, 16S) -ll-chloro-viricamin

Analogously to Example 1, by reacting a mixture of the Z and Ε isomers of 3 - [(lS, 12bS) -1-ethyl-lO-chloro-1,2,3,4,6,7,12,12b-octahydro -indolo [2,3-a] quinolizin-1-yl] -2-methoxypropenoic acid methyl ester with Hydrogen bromide in acetic acid (3S, 14S, 16S) -11-chlorovincamine obtain.

M.p. 222 ° (dec.); [cc] * = + 1.7 ° (0.1%, CHCl ₃ )

NMR spectrum (CDCl ₃ , 100 MHz):

0.87 (T, 7 Hz / H ₃ C (21) / 3 H);

1.08 - 3.46 (M / 14 H)

below that at 2.07 + 2.17 (AB, Ί4 Hz / H ₂ C (15));

3.78 (S / H ₃ COOC (22)) and

3.82 (shoulder / HC (3) / together 4H) '; 4.55 (broad / H0-C (14), interchangeable / 1H); 6.94 - 7.40 (M / HC (9 + 10 + 12) / 3H).

Example 9; (3S, 14S, 16S) -9-hydroxy-vincamine

Analogously to Example 1, by reacting a mixture of the Z and Ε isomers of 3 - [(lS, 12bS) -l-ethyl-8-hydroxy-1,2,3,4,6,7,12,12b-octahydro -indolo [2,3-a] quinolizin-1-yl] -2-methoxypropenoic acid methyl ester with hydrogen bromide in acetic acid (3S, 14S, 16S) -9-hydroxyvincamine obtain.

Mp. 220 ° (decomp.) From methylene chloride; [α] ²⁰ = + 13.5 (1%, CHCl ₃ )

50 9826/097 2

- 32 - Case 100-4110

NMR. -S spectrum (CU ₃ SOCD ₃ , 100 MHz):

0.83 (T, 7 Hz / H ₃ C (21) / 3 H);

1.02-3.40 (M / 14H);

below at Z, 13 f 2.21 (AB., 15 Hz / H ₂ C (15));

at 3.10 (S / H ₂ C (6));

3.67 (S / H ₃ COOC (22) / 3 II);

3.71 (S / HC (3) / 1H);

5.69 (S / H CH ₂ Cl ₂ / 1H);

6.34 ■ (D, 7 Hz / HC (IO) / 1H);

6.50. (D, β Uz / I1C (12) / 1H);

6.60 (S / 110-0 (14), interchangeable / 1H);

6.73 (approx. Ϊ, + 7 Uv, / HC (II) / 1 H);

9.06 (S / H0 ~ C (9), interchangeable / 1H).

Example 10: (3S, 14S, 16S) -12-methyl-vincamine

Analogously to Example 1, by reacting a mixture of the Z and Ε isomers of 3 - [(lS, 12bS) -1-ethyl-ll-methyl-1,2,3,4,6,7,12,12b-octahydro -indolo [2,3-a] quinolizin-1-yl] -2-methoxypropenoic acid methyl ester obtained with hydrogen bromide in acetic acid (3S, 14S, 16S) -12-methyl-vincamine.

M.p. 224 ° (dec.); [α] * "= + 7.6 ° (1%, CHCl ₃ )

Nuclear Magnetic Resonance Spectrum _{(CDCl 3} , 9OMHz):

0.89 (t, 7 Hz / H ₃ C (21) / 3 H);

1.13-3.43 (M / 17H);

below that at 2.00 + 2.19 (AB, 14 Hz / H C (15));

at 2.47 (S / CH ₃ C (12).);

509826/09 7 2

- 33 - Case 100-4110

3.81 (S / H ₃ COOC (22) / 3H); 3.86 (S / HC (3) / 1H); 3.99 (S / HO-C (14), exchangeable / 1H);

6.82 - 7.44 (M "/ HC (9 + 10 + 11) - / 3H).

5 0 98 26/0972

Claims (5)

- 34 - Case 100-4110 claims: 1. New heterocyclic compounds of the formula I in • their optically active forms or in the form of their Racemates in which R is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, and their acid addition salts. 2. Process for the production of. new heterocyclic compounds of the formula I in their optically active Forms or in the form of their racemates vind their acid addition salts, characterized in that one a) Compounds of the formula II in which R, bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy and R "is lower alkyl, is subjected to acidic cleavage and the resulting mixture of compounds of the formula I in which R _{1 is} above Has meaning, and compounds of the formula III in which R- is bromine, fluorine, chlorine, hydroxyl, lower alkyl or lower alkoxy, separates in a manner known per se, or b) Compounds of the formula III, v / orin R as defined above has, treated with hydrogen halide at temperatures below 0 ° and then the resulting reaction product is hydrolyzed, or c) that in the case of the preparation of the compound of the formula I 'vincamine in its optically active Forms or brominated in the form of its racemate 509826/0972 - 35 - Case 100-4110 thereupon any racemates of the compounds of If desired, formula I separates into their optical antipodes and / or the compounds thus obtained of the formula I, if desired, converted into their acid addition salts. 3. (3S, 14S, 16S) -10-fluoro-vincamine and its acid addition salts 4. Remedies / characterized in that they contain the new heterocyclic compounds of the formula I. or contain their acid addition salts. 5. (3S, 14S, 16S) -ll-ßrom-vincam.in and its acid addition salts, - ■ - 3700 / BA / ER. SANDOZ-PATENT-GMBH ■) 50 9826/0972