HU204526B - Process for producing 1-ethyl-indolo(2,3-a)quinolizine derivatives and acid additional salts - Google Patents

Abstract

The present invention relates to a novel process for the preparation of 1-ethylindolo [2,3-a] quinolizine of formula (Ia) and acid addition salts of formula (Ib), wherein X is an acid residue, such that: (a) Ha), 1-alkyl-1- (alkoxycarbonyl ethyl) -1,2,3,4,6,7-hexahydroindolo [2,3-a] quinolizine of formula IIb or IIc - wherein R is C 1 alkyl; X is an acid residue; organic dipolar-aprotic or aprotic solvent, optionally with a carbon atom EN 204 526 A Scope of the specification: 6 pages (including 1 sheet)

Description

The present invention relates to a novel process for the preparation of the 1-ethylindolo [2,3-a] quinolysinium derivative of formula (Ia) and its acid addition salts of general formula (Ib):

X is for the production of an acid residue by:

a) 1-alkyl-1- (alkoxycarbonylethyl) -1,2,3,4,6,7-hexahydroindolo [2,3-a] selected from formula (IIa), (IIb) or (IIc); quinolizine derivative - wherein

R is C 1 -C 4 alkyl;

X is an acid residue treated with an organic base in an organic dipolar aprotic or aprotic solvent, optionally in the presence of an alkanol, or

b) heating a compound of formula (Hb) or IIc, where R is as defined above, optionally in the presence of an organic dipolar aprotic or aprotic solvent, and optionally converting the resulting compound to an acid addition salt.

The hexahydro-12H-indolo [2,3-a] quinolizine derivative of the formula (Ia) and its acid addition salts prepared by the novel process of the present invention are known compounds, e.g. E. Wenkert et al. A. C. S. 87, 1580-89 (1965)]. These compounds are important intermediates in the synthesis of pharmaceutically valuable indole alkaloids (vincamine, vincamon) and their derivatives such as Cavinton. (Hungarian Patent No. 181,495).

In the formulas (IIa), (IIb) and (IIc), R as a C 1 -C 4 alkyl group is a straight or branched chain group such as methyl, ethyl, η-propyl, i-propyl, η-butyl, sec-butyl -, tert-butyl groups. X may be any organic or inorganic acid residue such as perchlorate or oxalate.

Starting materials of formula (II) can exist in three forms depending on the method of isolation. With acids, they form a crystalline imium salt of formula (IIa). The so-called "zwitter ion" material of formula (Hb) is a red oil which can be isolated as a base by liberating it from the acid addition salt of formula (Ha). When the red oil of formula (Hb) is treated with an alcohol of ROH, the so-called "alcohol adduct" of formula (IIc) precipitates in crystalline form.

The major unresolved problem in the production process of the therapeutic octahydroindolo [2,3-a] quinolizine and eburnan backbone compounds (vincamine, vincamone, apovincamic acid esters) was that only the In position 1, the enantiomer containing the alkyl group at the a-position may be used: the other enantiomer, i.e. half of the substance, is wasted.

It is an object of the present invention to provide a process for the re-use of an undesired enantiomer.

It was surprisingly found that the alkoxycarbonylethyl side chain in position 1 was cleaved by base or heat to form the derivative of formula (Ia).

Such cleavage of molecules of this structure has never been described in the literature.

The side-chain cleavage is surprising because, to date, base is used to form a lactam in an anhydrous medium (L. Szabó, Gy. Kalaus, Cs. Szántay, Archive, Dér Pharmacie 316. 629-630, 1983). In the presence of base and water, the saponification of the ester group would be expected. Ultimately, we would expect deep disintegration of the molecule upon exposure to heat.

In the process of the invention, the starting compounds of formula (IIa) (IIb) or (IIc) may be racemic compounds containing both enantiomers. Their preparation is described in Hungarian Patent Application No. 171,660. Preferably, however, optically active derivatives prepared according to Hungarian Patent Application No. 185,262 are used when cleavage can be carried out on any enantiomer, but it is most preferable to start from the enantiomer containing the alkyl group at the 1-position, since the unused enantiomer can be converted in good yield into an important intermediate for the synthesis of therapeutic compounds.

The novel process according to the invention is described in detail below.

In process (a), the starting compound (IIa), (IIb) or (IIc) is dissolved in an organic dipolar aprotic solvent such as dimethylformamide or an aprotic solvent such as tetrahydrofuran and the starting compound (IIb) or (IIc) 0.1 molar equivalent to 1.5 molar equivalent of an organic base such as sodium methylate, triethylamine, potassium tert-butylate, preferably potassium tert-butylate, is added to the compound of formula (I). It has been found to be advantageous to add some alcohol such as methanol to the solvent. The reaction is carried out at room temperature to about 100 ° C, optionally under nitrogen. At 50-100 ° C, the reaction time is 2-3 hours.

In process (b), the starting compound (IIb) or (IIc), alone or in one of the solvents listed in process (a), such as dimethylformamide or tetrahydrofuran, is heated and the cleavage reaction is also carried out. The optimum reaction temperature is 160-180 ° C and the reaction is complete within about 10-20 minutes.

HU 204 526 A

The resulting compound of formula (Ia) is optionally isolated in the form of an acid addition salt (Ib), preferably in the form of a chlorate or oxalate, or reused as a starting material in the synthesis of pharmaceutically active indole alkaloids or derivatives thereof (e.g. Cavinton). (Hungarian Patent No. 181,495).

The following examples illustrate the process of the present invention without limiting its scope to these examples.

Example 1 1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-ium oxalate

3.00 g (8.08 mmol) of the racemic 1-ethyl-1-methoxycarbonylethyl, 2,3,4,6,7-hexahydroindolo [2,3-a] quinolizin-5-ium compound in methanol ( He) dissolved in 12 ml of absolute dimethylformamide, after dissolution, 1.6 ml of absolute methanol and 0.90 g (8.0 mmol) of potassium tert-butylate are added. The mixture was stirred under an N ₂ atmosphere in an external bath at 75 ° C for 2 hours 45 minutes. After cooling, wash in a shaking funnel with 30 mL of ethyl acetate and shake vigorously with 30 mL of water. The aqueous portion was extracted with ethyl acetate (2 x 10 mL). The combined organic phases are shaken with water (15 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. (Dimethylformamide may still be present). The residue was dissolved in 3 ml of ethanol and 1.0 g (7.93 mmol) of 2 aqueous crystalline oxalic acid was added and the mixture was kept at 0 ° C overnight. The title compound is filtered off with suction and washed with a little cold ethyl acetate.

Yield: 1.24 g (45%)

Melting point: 174-176 ° C.

It is identical to the authentic pattern in all its physical and chemical properties.

Example 2 1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium oxalate

0.88 g (2.0 mmol) of racemic 1-ethyl-1-methoxycarbonylethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-perchlorate (Ha The mixture was stirred for 5 minutes in a mixture of 5 ml of dichloromethane and 5 ml of 2% sodium hydroxide. The organic layer was filtered over potassium carbonate and evaporated in vacuo. The residue (Hb) was dissolved in 5 ml of tetrahydrofuran, 0.4 ml of methanol and 0.22 g (1.96 mmol) of potassium tert-butylate were added. The reaction mixture was allowed to stand at room temperature for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 mL) and extracted with water (5 mL). The organic layer was filtered over potassium carbonate and evaporated. The residue (0.6 g) was dissolved in ethanol (2 mL) and oxalic acid dihydrate (0.25 g, 2.0 mmol) was added. The precipitated crystals are filtered off with suction and washed with a little cold ethanol.

Yield: 0.11 g (16%) of the title compound.

Example 3 1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium oxalate

0.76 g (2.0 mmol) of the methanolic adduct of racemic 1-ethyl-1-methoxycarbonylethyl-1,2,3,4,6,7-hexahydro-indolo [2,3-a] quinolizin-5-ium ( IIc) Heat in 4 ml of dimethylformamide in an oil bath at 130 ° C for 20 minutes. After cooling, ethyl acetate (15 mL) was added, washed in a funnel and extracted with water (15 mL). The organic phase was dried over anhydrous potassium carbonate, filtered and evaporated. The residue was dissolved in 2 ml of ethanol and 0.25 g (2.0 mmol) of oxalic acid dihydrate was added. In a refrigerator, 70 mg of the title compound precipitates.

Yield: 10%.

Example 4 1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium oxalate

0.50 g (1.13 mmol) of racemic 1-ethyl-1-tert-butoxycarbonylethyl-1,2,3,4,6,7-hexahydro-indolo [2,3-a] quinolizin-5ium isopropyl of its alcohol adduct (IIc) was heated in a 160 ° C oil bath for 8 minutes. The residue was dissolved in ethanol (1.5 mL) and oxalic acid hydrate (0.15 g, 1.19 mmol) was added. In a refrigerator 0.14 g of the title compound precipitates.

Yield: 36%.

Example 5 1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium oxalate

1.92 g (4.0 mmol) of 1-ethyl-1-tert-butoxycarbonylethyl-1,2.3.4.6.7-hexahydro-12H-indolo [2,3-a] quinolizine-5-perchlorate (Ha) for 5 minutes was stirred in a mixture of 10 ml of dichloromethane and 10 ml of 2% sodium hydroxide. The organic layer was dried over anhydrous potassium carbonate, filtered and concentrated in vacuo. The residue was dissolved in xylene (35 mL). The mixture is refluxed for 2 hours by continuously bubbling dry nitrogen gas through the solution. The solvent was evaporated in vacuo and the residue was dissolved in 3 ml of ethanol. Add 0.50 g (3.96 mmol) of oxalic acid dihydrate and leave to stand in a refrigerator.

Yield: 0.37 g (27%) of the title compound.

Example 6 1-Ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-ium oxalate

The methanolic adduct (IIc) of ,00β-ethyl-loc-methoxycarbonylethyl-1,2.3.4.6.7-hexahydro-indolo [2,3-a] quinolizin-5-ium (3.00 g, 8.08 mmol) having a specific [ _α ] ₅₄₆ = + 23 ° (c = 1.00, DMF), dissolved in 12 ml of absolute dimethylformamide, after dissolution, 1.6 ml of absolute methanol and 0.90 g (8.0 mmol) of potassium tert-butylate are added. . The mixture was stirred under an N ₂ atmosphere in an external bath at 75 ° C for 2 hours 45 minutes. After cooling, shake vigorously in a shaking funnel with 30 mL of ethyl acetate and 30 mL of water. The aqueous portion was extracted with ethyl acetate (2 x 10 mL). The combined organic phases are shaken with 15 ml of water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 3 ml of ethanol and 1.0 g (7.93 mmol) of oxalic acid dihydrate was added. The mixture was allowed to stand at 0 ° C overnight and the racemic 1-ethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizine-5-iumoxalate precipitated. suction, wash with a little cold ethanol.

Yield: 1.24 g (45%).

Melting point: 181 ° C.

HU 204 526 A

Example 7 1-Ethyl-2,3,4,6,7-hexahydroindolo [2,3-a] quinolizine

0.88 g (2.0 mmol) of racemic 1-ethyl-1-methoxycarbonylethyl-1,2,3,4,6,7-hexahydro-12H-indolo [2,3-a] quinolizin-5-ium perchlorate (Ha The mixture was stirred for 5 minutes in a mixture of 5 ml of dichloromethane and 5 ml of 2% sodium hydroxide. The organic layer was filtered over potassium carbonate and evaporated in vacuo. The residue (IIb) is dissolved in 5 ml of tetrahydrofuran, 0.4 ml of methanol and 0.22 g (1.96 mmol) of potassium tert-butylate are added. The reaction mixture was allowed to stand at room temperature for 3 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (5 mL) and extracted with water (5 mL). The organic layer was filtered over potassium carbonate and evaporated. The residue was 0.6 g of a dark red oil which was the title enamine base.

Claims (3)

A process for the preparation of the l-ethylindolo [2,3-a] quinolizine derivative of formula (Ia) and its acid addition salts of formula (Ib) X is for the production of an acid residue, characterized in that: a) 1-alkyl-1- (alkoxycarbonylethyl) -1,2,3,4,6,7-hexahydroindolo [2,3-a] selected from the group consisting of formula (IIa), (IIb) or (IIc). quinolizine derivative - wherein R is C 1 -C 4 alkyl, X is an acid residue; treated with an organic base in an organic dipolar aprotic or aprotic solvent, optionally in the presence of a C 1A alkanol, or b) heating a compound of formula (IIb) or (IIc), where R is as defined above, optionally in the presence of an organic dipolar aprotic or aprotic solvent, and optionally converting the resulting compound to an acid addition salt. Process (a) according to Claim 1, characterized in that the reaction is carried out as a base in the presence of an alkali metal alkoxide having 1, 2 or 3 carbon atoms. Process (a) according to claim 1, characterized in that the alkali metal alkoxide is used in an amount of 0.1 to 1.5 molar equivalents relative to the starting compound (IIb) or (IIc).