RS62667B1 - Process for the preparation of pirlindole enantiomers and its salts - Google Patents

Description

Description

Technical field

[0001] This invention relates to an improved process for obtaining the enantiomers of Pirlindole, or their pharmaceutically acceptable salts.

Basis of the invention

[0002] Pyrlindole (8-methyl-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole) of formula I

also described as Pyrazidol<TM>represents a new class of original tetracyclic antidepressants, pyrazinocarbazole derivatives. The drug was synthesized and characterized in the late 1960s and marketed as an antidepressant in 1975. Current clinical trials have shown it to be a very effective short-acting and safe drug.

[0003] Pirlindole is a selective, reversible inhibitor of MAO-A. In vitro evidence indicates the catalytic oxidation of pyrlindole to dehydro-pyrlindole by MAO-A. Dehydro-pyrlindole may be a more potent slowly reversible MAO-A inhibitor and this could explain the persistence of MAO-A inhibition in-vivo (MAO-mother of all amine oxidases, John P.M. Finberg et al. 1998, Springer).

[0004] The chemical structure of Pirlindole consists of one stereogenic center indicating the existence of two enantiomers, (R)-Pirlindole and (S)-Pirlindole.

[0005] Although the pharmacological data and clinical use of Pirlindole have been carried out on the racemate, recently there is an increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 A1).

[0006] International patent publication WO 2015/171003A1 filed on May 9, 2014 discloses the resolution of racemic pyrlindole into optically active pyrlindole. The described Resolution-Racemization-Recycling (RRR) synthesis involves derivatization by preparing pairs of diastereomers in the form of salts from an optically active organic acid. These diastereomers can be separated by conventional techniques such as crystallization. Although this procedure is very efficient for the preparation of either preclinical batches of (R)- or (S)-pirlindole on a laboratory scale, it is not economically feasible on an industrial scale because the process relies on the racemate Pirlindole as a starting material.

[0007] Andreeva et al. (Pharmaceutical Chemisry 1992, 26, 365-369) discloses the first isolation of the Pirlindole enantiomer in isolated form. (R)-Pyrilindole of formula II

was isolated as the hydrochloride salt from the racemic base by fractional crystallization of the racemic salt of pyrlindole with (+)-camphor-10-sulfonic acid. (S)-Pyrilindol of formula III

was also isolated as the hydrochloride salt albeit by asymmetric synthesis from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one IV

[0008] A compound of formula IV was reacted with the chiral auxiliary (S)-(-)-α-methylbenzylamine to give the asymmetric (S)-6-methyl-N-(1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-imine V

[0009] The compound of formula V is subjected to stereoselective reduction with sodium borohydride in ethanol. According to Andreeva et al., the reaction can take place through directed intramolecular hydride transfer after complexation between a compound of formula V and a reducing agent to give (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine VI

[0010] The compound of formula VI was reacted with ethylene glycol ditosylate via ethylene bridge formation under alkaline conditions to give (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole VII

[0011] The alkaline agent is sodium hydride (NaH), in the presence of dimethyl sulfoxide (DMSO) or dimethylformamide (DMF).

[0012] The ratio between the alkaline agent, the compound of formula VI and ethylene glycol ditosylate is 1.2:1:1.

[0013] The cyclization reaction takes place at room temperature over a period of 4.5 hours.

[0014] The compound of formula VII is subjected to catalytic hydrogenolysis conditions to obtain the desired hydrochloride salt of the compound of formula III.

[0015] The hydrogenolysis reaction is catalyzed by

in palladium on charcoal (Pd content 0.1 g, 9 mol%) and reduced in methanol. The conversion of the compound of formula VII to the compound of formula III was carried out under a hydrogen pressure of 1.8-2.0 MPa at 22 °C for a period of 17 h.

[0016] Processing conditions for the hydrogenolysis reaction included neutralization with ammonia solution followed by recrystallization with benzene. The hydrochloride salt of the compound of formula III is formed by adding hydrochloric acid to a solution of the free base in ethanol.

[0017] The process gave (S)-pyrlindole hydrochloride with a final yield of 10% relative to intermediate VI.

[0018] Mixing sodium hydride with DMSO generates the dimsil anion. This anion is very commonly used on a laboratory scale, but because it is unstable, its use on a large scale should be under certain precautions. Decomposition of dimsil anion is exothermic. Decomposition of the dimsil anion has been reported to begin as early as 20°C, and above 40°C it decomposes at a significant rate (Lyness, W.I. et al., US 3,288,860 1966, CI.260-607).

[0019] In "Sax & Levis's Dangerous Properties of Industrial Materials" it is reported that a mixture of DMF and sodium hydride gives a violent reaction with ignition above 50 °C. Buckey, J. et al., Chem. Eng. News 1982, 60(28), 5, describes thermal runaway of a pilot plant reactor containing sodium hydride and DMF of 50 °C. Accelerated calorimetry (ARC) tests showed exothermic activity already at 26 °C. A similar behavior was observed with DMA. De Wall, G. et al., Chem. Eng. News 1982, 60(37), 5, reports a similar incident, where an uncontrolled temperature rise topped 40 °C, and rose to 100 °C in less than 10 minutes, with almost all of the DMF boiling off.

[0020] There is a need for safe, industrial and environmentally acceptable processes for the preparation of Pirlindole enantiomers. These facts are disclosed to illustrate the technical problem addressed by this disclosure.

[0021] P. Yu Ivanov et al "New approach to the synthesis of pyrazidol" describes the synthesis method on which the production of the antidepressant pyrazidol (I) is based, includes the alkylation phase of 6-methyl-I-oxotetrahydrocarbazole (II) using bromo-acetaldehyde acetal; subsequent transformations of N-alkylated ketocarbazole (III) lead to the formation of pyrazidol.

[0022] A.I. Bokanov with collaborators "Synthesis of heterocycles on the basis of iminotetra-hydrocarbazoles. i.

3-benzyl-8-methy 2-oxo-2,3,3a,4,5,6-hexahydro-1H-pyrazino [3,2,i-j-k] carbazone" reveals the reaction of 6-methyl-1-oxo-1,2,3,4-tetrahydro-carbazole and benzylamine to give 1-benzylimino-6-methyl-1,2,3,4-tetrahydrocarbazole, which was converted into the deriv. pyrazinocarbazole.

[0023] A.V. Ivachtchenko et al "New heterocyclic hepatitis C virus (HCV) inhibitors containing A 2-Aminomethyl-1-H Indole Fragment" disclosed a focused library of heterocyclic compounds including 2-aminomethyl-1H-benzimidazole (1-19), 2-aminomethylindole (20-83), benzofuran-2-ylmethylamine (84-92) or 2-piperazin-1-ylmethylbenzoxazole (93) fragment which was screened for ability to inhibit hepatitis C virus (HCV) in vitro.

[0024] Document EP 1044976 A1 discloses a process for the synthesis of pyrlindole hydrochloride, which is characterized in that 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride is cyclized to obtain 1,2,5,6-tetrahydro-8-methylpyrazine[3,2,1-j,k]-4H-carbazole of formula (VI) which is subjected to reduction.

[0025] Document EP 2597097 A1 discloses new antiviral active components, pharmaceutical composition, antiviral drug and method for the prophylaxis and treatment of viral diseases, especially caused by hepatitis C viruses (HCV) with the general formula:

General description

[0026] The process disclosed herein provides an industrially applicable synthesis of pyrlindole enantiomers or pharmaceutically acceptable salts thereof. This disclosure relates to the transformation of the compound of formula VI ((S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine) into the compound of formula VII ((S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole) which can be carried out in a dipolar aprotic solvent such as 1,3-dimethyl-2-imidazolidinone (DMI). The advantages of using DMI with a suitable alkaline agent, particularly DMI with sodium hydride (NaH) are as follows: DMI is thermally stable to NaH and as such this mixture can be heated under safe conditions, leading to increased conversion rates and reaction yields of, for example, a compound of formula VI to a compound of formula VII (see Tables 1 and 2). The work-up procedure for this reaction involves the addition of methanol (MeOH) to precipitate the compound of formula VII. Since DMI is very soluble in dichloromethane (DCM), extraction of the mother liquor with dichloromethane allows obtaining DMI that can be reused later.

[0027] Catalytic hydrogenolysis of the compound of formula VII obtained by this process gives the crude compound of formula III ((S)-pyrlindole) of high purity which requires simple purification steps, since basification is not necessary.

[0028] The present invention relates to a process for the synthesis of pyrlindole enantiomers of formula II and III

or pharmaceutically acceptable salts thereof, comprising the steps of:

cyclization between the compound of formula VI (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine or its enantiomeric compound of formula VIII (R)-6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine

and compounds of formula X

wherein L is a leaving group selected from -OTs, -OMs, -OTf, -Cl or -Br, -I in 1,3-dimethyl-2-imidazolidinone (DMI), in the presence of a suitable alkaline agent to give (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole VII or its enantiomer. (R)-8-methyl-3-((R)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole IX

and subjecting the compound of formula VII or IX to catalytic hydrogenolysis. Unexpectedly, the use of DMI provides a significant increase in the yield of the process now disclosed, as well as in the conversion reaction of compound VI or VIII to compound VII or IX, respectively.

[0029] In one embodiment and in order to obtain even better results, the molar ratio of suitable alkaline agent:intermediate VI or VIII:compound of formula X can be from 1:1:1 to 5:1:3. More precisely, the molar ratio is 1:1:1; 1:1:1.2; 1:1:1.5; 1:1:2; 1:1:3; 1.2:1:1; 1.2:1:1.2; 1.2:1:1.5; 1.2:1:2; 1.2:1:3; 2.2:1:1; 2.2:1:1.2; 2.2:1:1.5; 2.2:1:2; 2.2:1:3; 2:1:1; 2:1:1.2; 2:1:1.5; 2:1:2; 2:1:3; 3:1:1; 3:1:1.2; 3:1:1.5; 3:1:2; 3:1:3; 4:1:1; 4:1:1.2; 4:1:1.5; 4:1:2; 4:1:3; 5:1:1; 5:1:1.2; 5:1:1.5; 5:1:2; 5:1:3.

[0030] In one embodiment and in order to obtain even better results, the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X can be from 2.2:1:1.2 to 4:1:2, preferably from 3:1:1.2 to 4:1:1.5, even more preferably from 3:1:1.2 to 4:1:1.2.

[0031] In one embodiment and in order to obtain even better results, the molar ratio of suitable alkaline agent:intermediate VI or VIII:compound of formula X can be 4:1:2.

[0032] In one embodiment and to obtain even better results, a suitable alkaline agent can be sodium hydride.

[0033] In one embodiment and in order to obtain even better results, L of the compound of formula X can preferably be -OTs.

[0034] In one embodiment and in order to obtain even better results, the pharmaceutically acceptable salt of the enantiomer of Pirlindol III or II can be an acetate salt, a hydrochloride salt, a hydrobromide salt, a mandelate salt, a succinate salt, a citrate salt, a malonate salt, a maleate salt, a methanesulfonate salt, a lactate salt, an ethanesulfonate salt, a glutamate salt or a phosphate salt.

[0035] In one embodiment and in order to obtain even better results, the pharmaceutically acceptable salt may be a hydrochloride or methanesulfonate salt.

[0036] In one embodiment and in order to obtain even better results, the pharmaceutically acceptable salt may be a lactate salt, an ethanesulfonate salt, a mandelate salt, a citrate salt or a succinic acid salt.

[0037] In one embodiment and to obtain even better results, the cyclization step between the compound of formula VI (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine or its enantiomeric compound of formula VIII (R)-6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine and compounds of formula X can be made at temperatures between 50 °C and 120 °C, preferably at 60 °C.

[0038] In one embodiment and in order to obtain even better results, catalytic hydrogenolysis can be performed at temperatures between 20-70 °C, preferably at 50 °C.

[0039] In one embodiment and in order to obtain even better results, catalytic hydrogenolysis can be performed for 2-8 hours, preferably 5 hours.

Detailed description

[0040] The present invention provides a process for the synthesis of enantiomers of Pirlindole which are easily converted into the corresponding acid salts.

[0041] In one embodiment, the process of the present invention utilizes an intermediate compound of formula VI, (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine

[0042] The compound of formula VI can be prepared in two steps:

1-condensation of compounds of formula IV, 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one

with the chiral auxiliary (S)-(-)-α-methylbenzylamine, followed by: 2-stereoselective reduction with sodium borohydride.

[0043] A compound of formula VI can be cyclized to give a compound of formula VII, (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole

which can be subjected to catalytic hydrogenolysis to give a compound of formula III (S)-Pyrlindole.

[0044] In one embodiment, this invention relates to the preparation of (R)-pyrlindole of formula II wherein the enantiomer of the compound of formula VI, (R)-6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine VIII

obtained by condensation of compounds of formula IV with (R)-(+)-a-methylbenzylamine. A compound of formula VIII can be cyclized to give a compound of formula IX

which can be subjected to catalytic hydrogenolysis to give a compound of formula II (R)-pyrlindole.

[0045] In one embodiment, the present invention relates to a cyclization reaction that produces an intermediate compound of formula VII, (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole.

[0046] In one embodiment, a compound of formula VI is reacted with a compound of formula X wherein L is a leaving group in a suitable solvent and in the presence of a suitable alkaline agent.

[0047] In one embodiment, examples of leaving groups include, but are not limited to, sulfonic alcohols such as -OTs, -OMs, -OTf, or halogens such as -Cl, Br, -I, preferably L -OTs.

[0048] In one embodiment, the compound of formula X is ethane-1,2-diyl bis(4-methylbenzenesulfonate).

[0049] In one embodiment, a compound of formula X can be prepared in situ from ethylene glycol in the presence of a suitable reagent, for example, one selected from the group consisting of thionyl chloride, sulfonyl halides, such as sulfonyl chloride, sulfonyl anhydride and phosphorus halides. Preferably, the reagent is selected from the group consisting of thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, trifluoromethanesulfonic anhydride, phosphoryl chloride, phosphorus tribromide, and phosphorus pentachloride. More preferably, the reagent is p-toluenesulfonyl chloride.

[0050] In one embodiment, a suitable alkaline agent according to the invention is selected from, but not limited to, carbonate or hydride salts of an alkali metal such as cesium carbonate or sodium hydride, or even phosphate salts of alkali metals such as potassium triphosphate. Preferably, and for even better results, the alkaline agent is sodium hydride.

[0051] In one embodiment, suitable solvents for the preparation of compounds of formula VII according to the invention are selected from polar aprotic cyclic urea solvents such as DMI and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU). Preferably, and to obtain even better results, the solvent is DMI.

[0052] In one embodiment, it is preferable that the molar ratio between the components of the cyclization reaction of the alkaline agent, intermediate VI and compound X is between 1:1:1 and 5:1:3, more preferably, and to obtain even better results, it is 4:1:2 (see Table 1).

[0053] In one embodiment, the cyclization reaction takes place at a temperature between 50 °C and 120 °C, preferably at 60 °C.

[0054] In one embodiment, the cyclization reaction takes place for 1 to 20 hours, preferably 1 to 5 hours, more preferably 2 hours.

[0055] In one embodiment, intermediate VII (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazine[3,2,1-jk]carbazole obtained by the process according to the invention can be subjected to catalytic hydrogenolysis or acid phenyl ethyl cleavage. Catalytic hydrogenolysis in an acidified mixture of organic solvents gives the compound of formula III (S)-Pirlindole. Catalytic hydrogenolysis is under hydrogen pressure or under transfer hydrogenolysis conditions.

[0056] In one embodiment, intermediate IX (R)-8-methyl-3-((R)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole obtained by the process of the present invention can be subjected to catalytic hydrogenolysis or acid phenyl-ethyl cleavage. Catalytic hydrogenolysis in an acidified mixture of organic solvents gives the compound of formula II (R)-pyrlindole. Catalytic hydrogenolysis is under hydrogen pressure or under transfer hydrogenolysis conditions.

[0057] In one embodiment, the preferred acidic phenyl ethyl cleavage is performed using an acidic cleavage agent such as boron or aluminum trihalide. A more preferred acidic cleaving agent is boron trichloride, boron tribromide or aluminum chloride.

[0058] In one embodiment, it is preferred that the catalytic hydrogenolysis uses a heterogeneous catalyst and that it takes place under hydrogen pressure. Preferably, the heterogeneous catalyst is palladium on charcoal. More preferably, the heterogeneous catalyst has a palladium content of approximately 3.2 mol%. Preferably, the hydrogen pressure for catalytic hydrogenolysis is between 500-2000 kPa (5-20 bar), more preferably 700 kPa (7 bar). Preferably, the temperature for catalytic hydrogenolysis can be between 20-70 °C. It is preferable for the temperature to be 50 °C. It is preferable that the catalytic hydrogenolysis lasts for a period of 2 to 8 hours, more preferably 5 hours. A suitable acidified solvent mixture for catalytic hydrogenolysis can be a mixture of organic solvents selected from ethyl acetate, DMF, MeOH, ethanol, isopropanol (iPrOH) and DCM, preferably the solvent mixture is composed of a mixture of a protic solvent with DCM, more preferably MeOH with DCM.

[0059] In one embodiment, the catalytic hydrogenolysis is carried out at 20-70 °C, preferably for 2-8 hours and with a hydrogen pressure between 500-2000 KPa (5-20 bar).

[0060] In one embodiment, acidification of the solvent mixture preferably occurs by absorption of HCl gas.

[0061] In one embodiment, the resulting high purity crude compound of formula III, or formula II, does not require any base neutralization and is immediately recrystallized from water and/or a flowable solvent.

[0062] One specific embodiment of the present invention is a process that includes the following steps:

placing a compound of formula X in DMI;

careful addition of the alkali metal hydride;

adding a mixture of (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine (compound of formula VI) or (R)-6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine (compound of formula VIII) in DMI to the previously obtained combination at a temperature and time sufficient to allow the reaction;

adding MeOH to the reaction mixture cooled with ice and water in the previous step;

allowing the suspension to stir at 0 °C;

filtering the solid compound of formula VII or compound of formula IX and washing with water-MeOH; extraction of mother liquor with DCM;

evaporation of DCM to leave the regenerated DMI solvent;

subjecting the compound of formula VII or the compound of formula IX to catalytic hydrogenolysis to obtain the compound of formula III or formula II in salt form.

[0063] The process of the present invention is suitable for industrial application and shows an environmental advantage such as the possibility of recycling the solvent involved in the process (DMI).

[0064] Pharmaceutically acceptable salts of the present invention include the therapeutically active, non-toxic acid salt form that the compounds of formula II and III can form.

[0065] In one embodiment, the acid addition salt form of a compound of formula II or III which occurs in free form as a base can be obtained by treating the free base with a suitable acid such as an inorganic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, nitric acid and the like; or an organic acid, such as, for example, acetic, citric, anhydrous citric, mandelic, hydroxyacetic, lactic, pyruvic, maleic, malonic, fumaric, malic, methanesulfonic, amber, tartaric, glutamic, p-toluenesulfonic, cyclamic, ethanesulfonic, 1,2-ethanedisulfonic acid, and the like.

[0066] In one embodiment, the salt form can be converted to the free form by treatment with a base.

[0067] In one embodiment, the compounds of formula II or III and salts thereof may be in the form of a solvate, which is included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates, and the like.

[0068] In all the scopes mentioned above, the optically active center can have both 'R'- or 'S'- configurations.

[0069] The compounds of formula I, II and III and all intermediates have one or two stereogenic centers in their structure. This stereogenic center can be present in the R or S configuration, the aforementioned R and S notation being used according to the rules described in Pure Appl. Chem. 45 (1976) 11-30.

[0070] The invention relates to all stereoisomeric forms such as enantiomeric and diastereomeric forms of compounds of formula I, II and III and intermediates.

[0071] In one embodiment, the preparation of a compound of formula III or a compound of formula II starting from a compound of formula IV can be carried out in a series of separate reactions in which each intermediate is isolated, or can be carried out as a telescopic synthesis.

[0072] For the purposes of this invention, enantiomerically pure is considered when the enantiomer purity is equal to or greater than 97%.

[0073] In one embodiment, the preparation of (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole, compound of formula VII is carried out in the following manner.

[0074] In one embodiment, ethylene glycol ditosylate (73 g, 197 mmol) and DMI (240 mL) were poured into a 2 L, three-neck, round-bottomed flask equipped with a magnetic mixing cup. NaH (60% suspension in mineral oil, 15.8 g, 394 mmol) was carefully added to the resulting clear solution. A solution of VI ((S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine) (30 g 98.5 mmol) in DMI (60 mL) at 60 °C was added dropwise to the obtained suspension. The mixture was stirred for 1 h at 60 °C. The mixture was cooled to room temperature, then MeOH was slowly added while cooling with ice water. A white precipitate appeared, and the resulting suspension was stirred and then filtered. The filtered product was washed with water-MeOH. The product was dried under vacuum to obtain 24.9 g of the compound of formula VII (75.2 mmol, yield: 76%). Purity >99.9 surface% (HPLC).

[0075] In one embodiment, the preparation of the hydrochloride salt of (S)-pyrlindole, a compound of formula III, is carried out as follows.

[0076] In one embodiment, free amine VII ((S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole) (8.32 g, 25 mmol) was dissolved in DCM (42 mL) and excess HCl in MeOH (42 mL) was added. The solvents were evaporated under reduced pressure to dryness to give a yellow oil. The residue was dissolved in MeOH (120 mL) and added to a dispersion of Pd/C (1.74 g, ~50% water) in MeOH (20 mL). The reaction mixture was stirred at 50 °C under a hydrogen pressure of 750 kPa (7.5 bar) for 5 h. After the end of the brush (HPLC), the suspension was filtered through a celite pad, and the filter cake was washed with MeOH. The pH of the resulting solution was checked (<3) and evaporated to give the crude hydrochloride salt of the compound of formula III. To the crude material was added iPrOH and the suspension was allowed to stir under reflux. The suspensions were filtered and the product dried under vacuum to give the hydrochloride salt of (S)-Pirlindole, compound of formula III (5.11 g, 19.5 mmol, yield: 77%). Purity > 99.5% (HPLC). Enantiomeric purity 99.5% (Chiral HPLC). MS (ESI): m/z 227.2 (M+H)<+>.

[0077] The data disclosed in Tables 1 and 2 include isolated yields or reaction conversions. The reaction conversion reflects the conversion of the reactant to the product, can be obtained by HPLC analysis and expressed as % area.

[0078] In one embodiment, the combination of DMI, and in particular the use of DMI and a molar ratio of 1:1:1 alkaline agent:intermediate VI or VIII:compound of formula X, provides an unexpected increase in yield and reaction conversion of compound VI or VIII to compound VII or IX, respectively. Preferably, for even better results, the use of DMI and a molar ratio of 1.2:1:1 - 4:1:2 alkaline agent:intermediate VI or VIII:compound of formula X provides an unexpected increase in yield and reaction conversion of compound VI or VIII to compound VII or IX, respectively.

[0079] In one embodiment and to obtain even better results, the combination of DMI and molar ratios disclosed in Tables 1 and 2 surprisingly gives even higher yields and comparable reaction conversions of compounds VI or VIII to compounds VII or IX, respectively.

Table 2. Comparative yields using a molar ratio of alkaline agent:intermediate VI or VIII:compound of formula X of 1.2:1:1 with different solvents

Solvent Yield (%) of compound VI or VIII to compound VII or IX, respectively

DMSO 23.8

DMI 31

Claims (14)

Patent claims 1. Process for the synthesis of pyrlindole enantiomers of formulas II and III or pharmaceutically acceptable salts thereof, comprising the steps of: cyclization between the compound of formula VI (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine or its enantiomeric compound of formula VIII (R)-6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine and compounds of formula X wherein L is a leaving group selected from -OTs, -OMs, -OTf, -Cl or -Br, -I in 1,3-dimethyl-2-imidazolidinone (DMI), in the presence of a suitable alkaline agent to give (S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1Hpyrazino[3,2,1-jk]carbazole VII or the enantiomer (R)-8-methyl-3-((R)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1Hpyrazino[3,2,1-jk] carbazole IX and subjecting the compound of formula VII or IX to catalytic hydrogenolysis to obtain the enantiomers of Pirlindole of formula II or III or pharmaceutically acceptable salts thereof. 2. Process according to patent claim 1, wherein the molar ratio suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 1:1:1 to 5:1:3. 3. A process according to any of the preceding claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 1.2:1:1 to 5:1:3. 4. A process according to any of the preceding claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 2.2:1:1.2 to 4:1:2. 5. A process according to any of the preceding claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 3:1:1.2 to 4:1:1.5.6. 6. A process according to any of the preceding claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 3:1:1.2 to 4:1:1.2. 7. The process according to claims 1-4, wherein the molar ratio suitable alkaline agent: intermediate VI or VIII: compound of formula X is 4:1:2. 8. A process according to any of the preceding claims, wherein the suitable alkaline agent is sodium hydride. 9. A process according to any of the preceding claims, wherein the compound of formula X is ethane-1,2-diyl bis(4-methylbenzenesulfonate). 10. The method according to any of the preceding claims, wherein the pharmaceutically acceptable salt is an acetate salt, hydrochloride salt, hydrobromide salt, mandelate salt, citrate salt, succinate salt, tartrate salt, malonate salt, maleate salt, methanesulfonate salt, lactate salt, ethanesulfonate salt, glutamate salt or phosphate salt. 11. The method according to claim 10, wherein the pharmaceutically acceptable salt is a hydrochloride or methanesulfonate salt. 12. The method according to claim 10, wherein the pharmaceutically acceptable salt is a lactate salt, an ethanesulfonate salt, a mandelate salt, a citrate salt or a succinate salt. 13. The process according to any of the preceding claims, wherein the cyclization step is carried out at temperatures between 50°C and 120°C, preferably at 60°C. 14. The method according to any of the preceding claims, wherein the catalytic hydrogenolysis is carried out at 20-70 °C, preferably for 2-8 hours and with a hydrogen pressure between 500-2000 KPa. Published and printed by: Institute for Intellectual Property, Belgrade, Kneginje Ljubice 5