HRP920776A2 - PROCESS FOR OBTAINING 1 BETA-ETHYL-1 ALPHA(HYDROXYMETHYL)-1,2,3,4,6,7,12,12b ALPHA-OCTAHYDRO-INDOLO (2,3-a) QUINOLIZINE AND NEW INTERMEDIATES - Google Patents

Description

Field of invention

The invention belongs to the field of preparative chemistry.

Technical problem

This invention relates to a new process for obtaining 1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12bα-octahydro-indolo(2,3-a) quinolizine and new intermediates. More precisely, the invention relates to a process for obtaining (-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4-6,7,12bα-octahydro-indo!o(2,3-a)quinolysine formulas (I)

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and to the new intermediates obtained in this procedure.

State of the art

The compound of formula (I) which has a peripheral vasodilator effect is well known, its preparation and medicinal effect are described in British Patent Specification No. 2,174,701.

Racemic l-ethyl-1-(acyloxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo(2,3-a)quinolysine derivatives used as starting materials in the process described in British Patent Specification no. 2,174,701 can be obtained by the process described in British Patent Specification No. 1,499,546 by reacting 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolism of formula (II)

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with formaldehyde used in large excess. In this case, the racemic form of the compound of formula (I) is obtained. As described in British Patent Specification No. 2,174,701, a therapeutically effective χ-ethyl derivative of formula (I) can be obtained by acylating the racemic compound, then separating the acylated compound thus obtained and then deacylating the special β-ethyl form in 4 reaction steps. The yield of the pharmaceutically ineffective α-ethyl derivative isolated in the separation step is only about 25%, calculated for the starting hexahydro-indolo (2,3-a)quinolysine of formula (II) when considering the yield data described in examples 1 and 2 of British Patent Specification no. . 2,174,701.

The object of the invention is to carry out a rational synthesis route with which the starting 1-ethyl-hexahydroindolo(2,3-a)quinolysine of the formula (II) can be converted into the corresponding β-ethyl derivative in a simpler way with an excellent yield and, optionally, α- the ethyl derivative consumed in the earlier process can be recycled to the beginning of the synthesis pathway.

In the course of our experiments to carry out this rational route of synthesis, we surprisingly found that by reacting 1-ethyl-hexahydro-indolo(2,3-a)quinolysine of formula (II) with about an equimolar amount of formaldehyde and H with its polymerized form, racemic 1-( hydroxy-methyl)-1,2,3,4,6,7-hexahydro-indolo(2,3-a)quinolysine of formula (III)

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a new compound is obtained, from which the target compound can be obtained, in two different ways in a simple way, by reducing the new indolo-quinolisinium salt of formula (IV),

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where X- represents the residue of an optically active acid, thus obtained or

a) after treatment with a separation agent in an amount smaller than the equimolar amount, or

b) after treatment with a separation agent in an amount greater than the equimolar amount.

The resolving agent is an optically active acid. Such acids are well known in the art.

Description of the solution to the technical problem

This invention provides a process for obtaining (-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo-(2,3-a)quinolysine of formula (I). This procedure is characterized by:

1) by reacting 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolism of formula (II) with about an equimolar amount of formaldehyde or with its polymerized form and, subsequently if desired isolated, new racemic 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolysine of formula (III) obtained

a) is treated with a separation agent in an amount smaller than the equimolar amount and new compounds obtained 1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a The quinolizyme-5 salt of formula (IV) is reduced, or

b) is treated with a separation agent in an amount greater than the equimolar amount, diastereomeric salt pairs of the formula (IV) and

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where X- is defined as before, and the newly obtained 1β-ethyl-1α-hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a) quinolizine-5-salt of formula (IV) is reduced to the compound of formula (I), and, if desired, new 1α-ethyl-1β-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2, The obtained 3-a) quinolizine-5-salt of formula (V) is converted into the starting compound of formula (II) by treatment with alkali metal hydroxide, or

2) by reacting 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine of formula (II) with about an equimolar amount of formaldehyde or with its polymerized form and with a separating agent in the amount less than an equimolar amount, then a new 1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolysine-5-yl salt of the formula ( IV) reduces to the compound of formula (I), or

3) by reacting 1-ethyl-1,2,3,4,6,7-hexahydro-indolo(2,3-a)quinolysine-5 salt of formula (IIa),

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where X- is defined as before, with about an equimolar amount of formaldehyde in the presence of base, and reduction of the new 1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indole(2, 3-a) quinolizine-5 salts of formula (IV) thus obtained, where X- is as defined above,

and optionally by releasing the free base of formula (I). Further, a new compound of formula (III) was provided,

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eg 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolysine. Also provided is a new compound of formula (IV),

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where X- is as defined earlier. Also provided is a new compound of formula (V),

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where X- is as defined earlier.

The starting compound of formula (II) reacts with about an equimolar amount, preferably 0.9 to 1.1 mol, of formaldehyde or with its polymerized form, eg paraformaldehyde, at a temperature close to room temperature. Paraformaldehyde is added to a solution of the starting compound of formula (II) in an aprotic or dipolar aprotic solvent or a mixture thereof. The new racemic compound of formula (III) obtained in this way reacts after isolation, or preferably without isolation, with the separation agent taken in an amount smaller than the equimolar quantity according to procedure variant 1a) in order to obtain the salt of the new 1β-ethyl-1α-(hydroxymethyl)-1,2 .

The above reaction with formaldehyde and treatment with a separating agent is carried out at near room temperature in a dipolar aprotic solvent such as acetone, methyl ethyl ketone, methyl isopropyl ketone, acetonitrile, dimethyl formamide, preferably acetone, or in an aprotic solvent such as methanol, ethanol , propanol, isopropanol, preferably isopropanol, or in a mixture of these two types of solvents, preferably in acetone containing ethanol or isopropanol.

The resolution of the new compound of formula (III) is carried out with an optically active acid, preferably (-)-Ldibenzoic acid.

The reduction of the new compound of formula (IV) can be carried out in a known manner with a chemical reducing agent, such as sodium borohydride, or with catalytic hydrogenation using preferably palladium on coal as a catalyst. When the reduction is carried out with a chemical reducing agent in a water-dissolved solvent, such as methanol 1H ethanol, the target compound of formula (I) precipitates the reaction mixture by adding water. When the reduction is carried out with catalytic hydrogenation, the target compound is isolated after the release of the free base. The free base is released in a known manner by adding an inorganic base, such as alkali metal hydroxide or ammonium hydroxide.

By carrying out the above procedure, the compound of formula (IV) is obtained from the starting compound of formula (III) with a very good yield close to 90%, from which the β-ethyl target compound of formula (I) is obtained by the reduction described above. In this way, the starting compound of formula (II) can be converted into the target compound of formula (I) with a yield greater than 80% (calculated, for example, on the basis of the yield data of examples 13 and 8) which shows, when compared with the number of reaction stages and yields from the procedure according to the British patent specification no. 2,174,701, except for the advantages of the process of this invention.

According to variant Ib) of the procedure, the new racemic compound of formula (III) obtained in the initial reaction is separated with a separation agent used in an amount greater than the equimolar amount. In this case, resolution is performed in a suitable separation system of choice, such as D-tartaric acid in water, or L-dibenzoyl tartaric acid in an aprotic dipolar solvent, such as acetone, at a temperature close to room temperature. When using the last system of the set, L-dibenzoyl tartrate acid can preferably be replaced with a cheaper acid, such as acetic acid, in an equimolar amount of about 0.5.

The starting compound of formula (II) can be obtained again from the new 1α-ethyl-1β-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolysine-5 -'s salts of formula (V), obtained after isolation, by treatment with a suitable base, although the therapeutically ineffective stereoisomer of the target compound can be obtained by reduction of this salt. The basic treatment can be carried out with an organic base, such as triethyl amine or dialkyl aniline, or with an inorganic base, such as ammonia or alkali metal hydroxide, preferably in a heterogeneous phase system containing an aqueous base and an organic solvent insoluble in water such as chlorinated aliphatic and aromatic hydrocarbons, eg dichloromethane, chloroform, dichloroethane and chlorobenzene, or aromatic hydrocarbons eg benzene, toluene and xylene; sodium hydroxide solution can preferably be used as an aqueous base.

The reaction is preferably carried out at a temperature that does not exceed 40°C, during 30 to 60 minutes.

If desired, the compound of formula (II) obtained is isolated in the form of acid addition salts, such as perchlorate, oxalate or (-)-L-dibenzoyl tartrate, and used again as a starting material for obtaining a therapeutically effective P-ethyl derivative.

The meaning of variant 1b) of the procedure through the discovery of the British patent specification no. 2,174,701 lies in the fact that the spent, therapeutically ineffective stereoisomer is not formed at all due to the corresponding deficiencies of the stereoisomer of formula (V) obtained in the synthesis as a side product is converted into the starting compound of formula (II).

Thus, the utilization of polyazide hexahydro-indolo(2,3-a)quinolysine of formula (II) is about 60 to 70%, calculated for the final product.

According to variant 2) of the procedure, the starting compound of formula (II) reacts with an almost equimolar amount of paraformaldehyde in a suitably selected solvent or solvent mixture in the presence of a separation agent used in a smaller than equimolar amount of the starting compound of formula (II), preferably (-)-L-dibenzoyl tartrate acid, then the compound of formula (IV) crystallizes from the reaction mixture in the reaction stage once within a reaction time of several hours with a very good yield of almost 80%, in an optical purity of almost 100%.

According to variant 3) of the procedure, it can also be processed by reacting the salt of the starting compound of formula (II) obtained with an optically active acid, preferably (1-ethyl-1,2,3,4,6,7-hexahydro-12H-indole (2,3 -a)quinolizin-5-jeva)2 (-)-L-dibenzoyl tartrate, e.g., a compound of formula (IIa), in a suitably selected solvent or solvent mixture, with an approximately equimolar amount of formaldehyde in the presence of 0.01 to 0.10 equimolar amount of a suitably selected base , such as the starting compound of formula (II), itself or triethyl amine, preferably the compound of formula (II), to obtain the compound of formula (IV), in crystalline form, after stirring the reaction mixture for several hours, with the yield and purity used above.

According to a variant of the procedure, the separation reagent is introduced into the reaction in the form of a salt of the starting compound of formula (II).

Solvents or solvent mixtures used in variants 2) and 3) of the procedure can be the same as defined in variant 1) of the procedure.

Treatment with a separation agent as described in variants 1a), 2) and 3) of the procedure leads to an asymmetric transformation based on the following; when a compound of formula (II) reacts with an equimolar amount of formaldehyde, a "racemic adduct" of formula (III) is formed. The racemic adduct of formula (III) is in dynamic equilibrium with the compound of formula (II). If less than an equimolar amount of resolving agent is added to this equilibrium mixture, preferably one of the diastereomeric salts of the racemic adduct of formula (III) crystallizes into the other diastereomeric salt contained in the solvent and becomes racemic through the dynamic equilibrium procedure described above. This equilibrium exists in basic form and therefore a slight excess of base is required in relation to the used neutralizing acid.

Summarizing the advantages of variants 1), 2) and 3) of the process according to the present invention as compared to the process described in British Patent Specification No. 2,174,701, it can be pointed out that the target compound can be obtained in two reaction steps instead of 4, and with significantly better yields. If variant 1b) of the procedure is carried out, the therapeutically effective β-ethyl compound is obtained with very good yields and also the therapeutically ineffective antipode, which was previously waste, can be used.

The starting compounds of formulas (II) and (IIa) are known from the reference Wenkert, e E. et al.: J. Am. Chem. Soc., 87. 1580 (1965).

The invention is elucidated in more detail with the following non-limiting examples.

Example 1

(±)-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-indolo(2,3-a)quinolysine (III)

37.8 g (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydroindolo(2,3-a)-quinolizline is dissolved in 100 ml of acetone, 5 g of paraformaldehyde is added there and the mixture is stirred at room temperature for 1.5 hours. Then 30 ml of distilled water is added to the mixture over 15 minutes and the mixing is continued for another hour at 0°C. The settled compound from the title obtained in the form of orange-colored crystals is filtered and washed in two parts with a total of 20 ml of acetone, at 0°C. Mass: 34.13 g (80.7%), melting point: 111-113°C.

Example 2

a) (-)-1α-ethyl-1β-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolizin-5-jeva-(+)- D-tartartrate (V)

8.6 g (0.0573 mol) of (+)-D-tartaric acid was dissolved in 160 ml of distilled water and 16.1 g (0.057 mol) (±)-1-ethyl-1-(hydroxymethyl)-1,2,3,4, 6,7-hexahydro-indolo-(2,3-a)quinolysine as obtained in Example 1 is added thereto.

The mixture is stirred at room temperature for 10 minutes to obtain a homogeneous solution.

This solution is filtered through celite, if necessary, and allowed to stand for 2 hours. The settled crystalline product from the title is filtered and washed in two parts, all with 10 ml of acetone. Mass: 10.2 g, melting point: 103-105°C, yield: 82.7%. (a) 20D: -81.7° (c=1, methanol).

b) (+)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolizin-5-jeva-(+)- D-tartrate (IV)

The aqueous mother liquor obtained as described in point a) above is cooled to 10°C and allowed to stand for 24 hours. The settled compound obtained in the form of crystals is filtered and washed in 2 parts completely with 10 ml of acetone. Mass: 7.2 g, melting point: 136-139°C, yield: 58.4%, (a)20D: +117° (c=1, methanol).

Example 3

(-)-1β-ethyl-lα-(hydroxymethyl)-1,2,3,4,6,7-hexa-hydro-indolo(2,3-a)quinolysine

obtained as in example 1 is suspended in 50 ml of acetone. Then a solution of 2 g of acetic acid and 8.5 g (0.0226 mol)

(-)-L-dibenzoyl tartaric acid mono-hydrate in 30 m! of methanol is added there under stirring. The mixture is stirred for 3 hours and filtered at 20°C, then washed under acetone. The title compound is obtained in the form of crystals. Mass: 10g, melting point: 172-174°C, (a)20D: -83.2° (c=1, DMF), base content: 59.3% by titration with HCIO4. The yield is 84.1%, calculated for the base content.

Example 4

(-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydroindolo-(2,3-a)quinolisin-5-jeva)2 (-)L-dibenzoyl tartrate ( IV)

37.8 g (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydroindolo(2,3-a)quinolysine is dissolved in 100 ml of acetone, 5.2 g of paraformaldehyde is added to the solution and the mixture is stirred during 1.5 hours at room temperature. Then 50 ml of acetone is added to the mixture, followed by a solution of 6 g of acetic acid and 28 g (0.0745 mol) of (-)-L-dibenzoyl tartaric acid monohydrate in 100 ml of methanol. The mixture is stirred for 3 hours and the settled crystalline product of the title is filtered at 20°C and washed under acetone. Mass: 28 g, melting point: 171-173°C.

(a) 20 D: -82.7° (c=1, DMF), base content: 59.2% by titration with nClO4. The yield is 78.37%, calculated for the base content.

Example 5

1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolysine-5-yl perchlorate (II, salt)

21.6 g (-)-1α-ethyl-1β-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolysin-5-ene (+)-D -tartrate obtained as in example 2a), is suspended in a mixture of 100 ml of water and 100 ml of dichloromethane. 12 ml of concentrated aqueous ammonia is added to the mixture with vigorous stirring and stirring is continued for 15 minutes. Then 10 ml of a 25% aqueous solution of sodium hydroxide is added and vigorous stirring is continued for a further 15 minutes. The organic phase is separated and the aqueous phase is extracted with 30 ml of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered from the drying agent and evaporated. The residue is dissolved in 40 ml of methanol and acidified to pH for 1-2 hours with a 60% aqueous solution of perchloric acid. The settled compound from the title obtained in the form of crystals is filtered at 0°C and washed in two parts completely with 10 ml of cold methanol. Mass: 14.95 g (85%). Melting point: 179-180°C.

Example 6

(1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolysine-5-yl)2(-)L-dibenzoyl tartrate (KII, salt)

The procedure is as in example 5 with the difference that the rest of the free solvent is dissolved in 60 ml of acetone, 9.45 g of (-)-L-dibenzoyl tartaric acid monohydrate is added to the solution and the last one is stirred for 15 mm under reflux. The title compound obtained in the form of crystals is filtered at 10°C and washed in two parts under 10 ml of acetone. Mass: 17.3 g (80.7, melting point: 128-132°C.

Example 7

1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo (2,3-a) quinolin-3-ene perchlorate (II, salt)

The mother liquor containing acetone and methanol obtained in Example 11 is evaporated under vacuum. 70 ml of dichloromethane and 100 ml of water, a further 10 ml of concentrated aqueous ammonia and 8 ml of a 25% aqueous solution of sodium hydroxide are added there with stirring. After stirring for 0.5 hours, the organic phase is separated and the aqueous phase is extracted in two parts completely with 30 ml of dichloromethane. The combined extracts are evaporated, 20 m! of methanol is added to the residue and the resulting solution is acidified to pH 1-2 by adding a 60% aqueous solution of perchloric acid. The settled product from the title at 0°C and washed in two portions completely under 10 ml of cold methanol. Mass: 12.33 g (87%), melting point: 178-180°C.

From the salt obtained from the corresponding free base, e.g. 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine, in the form of a solution in an organic solvent can easily be obtained by phase distribution between an organic solvent insoluble in water, such as dichloromethane or chloroform, and water using a strong base.

The procedure in this example is also suitable for processing the mother's fluid obtained in examples 2,3,4,10 and 12.

Example 8

(-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12,12a-octahydro-indolo(2,3-a)quinolysine (I)

47.63 g (-)-(1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolizin-5jev) 2 (-)- The L-dibenzoyl tartrate obtained as in example 13, which has a base content of 59.2%, is suspended in 800 ml of methanol. Next, 6.5 g of sodium borohydride is mixed in small portions into the suspension with stirring until it becomes colorless. The mixture is concentrated to a third of its original volume under vacuum and 800 ml of water is added thereto. The settled white substance is filtered, washed until neutral with water and dried in a vacuum desiccator. Mass: 27.8 g (98%), mp: 228-230°C, (a)20D: -108.4° (c-1, DMF).

Example 9

(-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo(2,3-a)quinolysine (I)

4.3 g (+)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H indolo(2,3-a)quinolisin-5-ene-(+)-D -tartrate obtained as in example 2b) is suspended in 70 ml of methanol. A total amount of 0.7g of sodium borohydride is added to the suspension under stirring in small portions at a temperature of 20°C until the solution becomes colorless. Then 300 ml of water is added to the mixture, the settled substance is filtered and washed until neutral with water. Mass: 2.74 g (97%), melting point: 228-230°C. (a) 20D: -108.7° (c=1, DMF).

Example 10

(-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12bα-octahydro-indolo(2,3-a)quinolysine (I)

10 s (-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolysin-5-ene)2-(- )-L-dibenzoyl tartrate (base content: 59.3%) is suspended in a mixture of 40 ml of dimethyl formamide and ml of methanol. 1 ml of glacial acetic acid and 0.5 g of 10% palladium on charcoal are added and the mixture is hydrogenated with elemental hydrogen until hydrogen uptake ceases. The catalyst is filtered and the filtrate is washed twice completely with 10 ml of methanol. Methanol is removed from the filtrate by atmospheric distillation and the residue is poured slowly into a mixture of 3 ml of concentrated aqueous ammonia and 120 ml under vigorous stirring. The settled substance weighing 5.75 g (97%) is filtered and washed neutrally with water. The obtained product is crystallized from dimethyl formamide. Its melting point is 228-230°C, (a)20 D:-108.4°

Example 11

(-)-(1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-bexahydro-12H-indolo-(2,3-a)quinolizin-5-jev)2-(- )-L-dibenzoyl tartrate (IV)

14.1 g (0.5 mol) of (±)-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-indolo(2,3-a)quinolysine obtained as in example 1 is suspended in 50 ml of acetone and a solution of 8.5 g (0.0226 mol) (-)-L-dibenzoyl tartaric acid monohydrate in 20 ml of methanol is added there under stirring. The mixture is stirred at room temperature for 10 hours, filtered at 20°C, the settled title compound obtained in the form of crystals is washed in two parts completely with 20 ml of a 5:2 mixture of acetone and methanol and dried. Mass: 18.7 g, melting point: 170-172°C, (a)20 D:-60.4° (c=1, DMP). Base content is 59.2% by titration with HCIO4. The yield is 78.5%, calculated for the base content. The mother fluid can be processed as described in Example 7.

Example 12

(-)-(1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolisin-5-jev)2(-)- L-dibenzoyl tartrate (IV)

37.8 g (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine is dissolved in 100 ml of acetone, 5.2 g (0.173 mol) of paraformaldehyde is added there and the mixture is stirred at room temperature for 1.5 hours. Then 50 ml of acetone and a solution of 26 g (0.069 mol) of (-)-L-dibenzoyl tartaric acid monohydrate in 60 ml of methanol were added to the solution. Then the mixture is stirred for 10 hours and the title product obtained in the form of crystals is filtered at 20°C and washed in two parts completely under 60 ml of a 5:2 mixture of acetone and methanol and dried. Mass: 52.5 g, melting point: 170-172°C. (a) 20 D: -79.7° (c=1, DMF). Base content is 58% by titration with HCIO4. The yield is 73%, calculated for the base content.

Example 13

(-)-(1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolizin-5-jev)2-(- )-L-dibenzoyl tartrate (IV)

37.8 g (0.15 mol) of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a) quinolizine reacts with 5.4 g (0.18 mol) of paraformaldehyde in 100 ml of acetone at 20°C for 1 hour, then a solution of 26 g (0.069 mol) of (-)-L-dibenzoyl tartaric acid monohydrate in 100 ml of ethanol is added to the mixture. This is stirred for 10 hours at 20°C. The settled compound from the title is filtered and washed in two portions completely under 50 ml of ethanol. Mass: 61 g, melting point: 170-172°C, (a)20D: -74.1° (c=1, DMF) Base content is 57.6 % and the yield is 89%, calculated for the base content.

Example 14

(-)-(1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolizin-5-jev)2(-) -L-dibenzoyl tartrate (IV)

The procedure described in Example 12 is followed except that equal amounts of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine, paraformaldehyde and (-)-L-dibenzoyl tartaric acid is simultaneously added to 150 ml of acetonitrile and the resulting mixture is stirred at 20°C for 24 hours. After following the procedure as described in example 13, the title compound is obtained in an amount of 54.8 g. Yield: 80%.

Example 15

(-)-(1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolizin-5-jev)2(-) -L-dibenzoyl tartrate (IV),

17.3 g of (1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a)quinolizin-5-jev)2(-)-L-dibenzoyl tartrate and 1.35 g of paraformal aldehyde is suspended in the direction of 160 ml of acetonitrile and 10 ml of methanol, 0.4 g of triethylamine is added there and the mixture is stirred at room temperature for 24 hours. From the reaction mixture, the compound from the title is filtered at 0°C in the form of crystals, washed completely in two portions with 10 ml of methanol and dried. Mass: 14.4 g, yield: 78%.

Claims (10)

1. Process for obtaining (-)-lβ-ethyl-lα-(hydroxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo(2,3-a)quinolysine of formula (I) [image] characterized by the reaction of 1-ethyl-2,3,4,6,7,12-hexahydro indolo (2,3-a)quinolism of formula (II) [image] with about an equimolar amount of formaldehyde or with its polymerized form and, after isolation if new racemic 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2, 3-a) quinolysine of formula (III) [image] obtained is treated with a separation agent in an amount smaller than the equimolar amount and the new 1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolysine -5 salts of formula (IV) [image] where X- represents the residue of an optically active acid, thus obtained is reduced, and the free base of formula (I) is, if desired, released. 2. Process for obtaining (-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo(2,3-a)quinolysine of formula (I) [image] characterized by the reaction of 1-ethyl-2,3,4,6,7,12-hexahydro(2,3-a)quinolysine of the formula (II) [image] if with an equimolar amount of formaldehyde or with its polymerized form and, after isolation if desired, the newly obtained racemic 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2, 3-a) quinolysine of the formula (III) is treated with a separation agent in an amount greater than the equimolar amount, then a pair of diastereomeric salts of the formulas (IV) and (V) [image] where X;- represents the residue of an optically active acid, the newly obtained 1β-ethyl-1α-(hydroxy methyl)-1,2,3,4,6,7-hexahydro-12H-indolo(2,3-a) The quinolizine-5 salt of formula (IV) is reduced to the compound of formula (I), and, if desired, the newly obtained 1α-ethyl-1β-(hydroxymethyl)-1,2,3,4,6,7-hexahydro -12H-indolo-(2,3a) quinolizine - 5 - salt of formula (V) is converted into the starting compound of formula (II) by treatment with alkali metal hydroxide. 3. Procedure for obtaining (-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo(2,3-a)quinolysine of formula (I) [image] indicated by the reaction of 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine of formula (II) [image] with about an equimolar amount of formaldehyde or with its polymerized form and with a separating agent in an amount smaller than the equimolar amount, reducing the new 1β-ethyl-1α-hydroxymethyl-1,2,3,4,6,7-hexahydro-12H-indolo-( 2,3-a) quinolysine-5 salts of formula (IV) [image] thus obtained, where X- represents an optically active acid residue and, if desired, by releasing the free phase of formula (I). 4. Procedure for obtaining (-)-1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7,12,12bα-octahydro-indolo(2,3-a)quinolism of formula (I) [image] indicated by the fact that 1-ethyl-1,2,3,4,6,7-hexahydro indolo(2,3-a)quinolysine-5-salt of the formula (IIa) reacts [image] where X- is the residue of an optically active acid, with about an equimolar amount of formaldehyde or with its polymerized form, in the presence of a base, by reducing the new 1β-ethyl-1α-(hydroxymethyl)- 1,2,3,4,6,7-hexa hydro -12H-indolo(2,3-a)quinolysine-5 salts of formula (IV) [image] thus obtained, where X- is the residue of an optically active acid, and, if desired, by releasing the free base of formula (I). 5. The process as claimed in any one of claims 1 to 4, characterized in that 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine of formula (II) reacts ), or its formed salt with an optically active acid, with paraformaldehyde in the presence of a maximum of 0.1 equimolar amount of base, at a temperature close to room temperature, in a protic or dipolar aprotic solvent or in a mixture of these solvents. 6. A process as claimed in any one of claims 1 to 4, characterized in that the reduction of 1β-ethyl-1α-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo( 2,3-a)quinolysine-5 salts of formula (IV) with a chemical reducing agent, preferably with sodium borohydride, or with catalytic hydrogenation, optionally in the presence of palladium on a charcoal catalyst. 7. The process as required in claim 4, characterized in that the starting compound 1-ethyl-2,3,4,6,7,12-hexahydro-indolo(2,3-a)quinolysine of the formula (II) is used as a base ) only. 8. 1-ethyl-1-(hydroxymethyl)-1,2,3,4,6,7-hexahydro-12H-indolo-(2,3-a)quinolysine of formula (III) [image] 9. Compound of formula (IV) [image] where X- is an optically active acid residue. 10. Compound formula [image] where X- is an optically active acid residue.