ES2900563T3 - Process for the preparation of enantiomers of pirlindol and its salts - Google Patents

Abstract

A process for the synthesis of enantiomers of pirlindole of formula II and III **(See formula)** or a pharmaceutically acceptable salt 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 **(See formula)** and a compound of formula X **(See formula)** 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 the enantiomer (R)-8-methyl-3-((R)-1-phenylethyl)-2,3,3a,4,5,6- hexahydro-1H-pyrazino[3,2,1-jk]carbazole IX **(See formula)** and subjecting the compound of formula VII or IX to catalytic hydrogenolysis to give pirlindole enantiomers of formula II or III or their pharmaceutically acceptable salts.

Description

DESCRIPTION

Process for the preparation of enantiomers of pirlindol and its salts

technical field

The present invention relates to an improved process for the preparation of pirlindole enantiomers, or a pharmaceutically acceptable salt thereof.

Background

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

Compound of formula I

also described as Pyrazidole™ represents a new class of original tetracyclic antidepressants, the 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 and safe short-acting drug.

Pirlindole is a selective, reversible inhibitor of MAO-A. In vitro evidence suggests catalytic oxidation of pirlindole to dehydropyrlindole by MAO-A. Dehydropyrlindole may be a more potent, slowly reversible inhibitor of MAO-A and this could explain the persistence of MAO-A inhibition in vivo (MAO-The mother of all amine oxidases, John PM Finberg et al. 1998, Springer) .

The chemical structure of pirlindole is composed of a stereogenic center indicating the existence of two enantiomers, (R)-pirlindol and (S)-pirlindol.

Although the pharmacological data and clinical use of pirlindole was done on the racemate, recently there has been increasing interest in the pharmacological profile of each enantiomer (WO 2015/171005 A1).

International Patent Publication WO 2015/171003A1 filed May 9, 2014 discloses a resolution of racemic pirlindole to optically active pirlindole. The Resolution-Racemization-Recycling (RRR) synthesis described involves derivatization by preparation of 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 it is a very efficient process for preparing preclinical or laboratory scale batches of (R)- or (S)-pirlindol, it is not economically convenient on an industrial scale because the process relies on pirlindole racemate as the starting material.

Andreeva et al. ( Pharmaceutical Chemistry 1992 , 26, 365-369) discloses the first isolation of pirlindole enantiomers in isolated form. The (R)-pirlindole of formula II

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

was also isolated as a hydrochloride salt, though via asymmetric synthesis from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one IV

The compound of formula IV was reacted with the chiral auxiliary (S)-(-)-a-methylbenzylamine to give (S)-6-methyl-N-(1-phenylethyl)-2,3,4,9-tetrahydro Asymmetric -1H-carbazole-1-imine V

The compound of formula V was subjected to stereoselective reduction with sodium borohydride in ethanol. According to Andreeva et al. the reaction could proceed via direct intramolecular hydride transfer after formation of a complex between the compound of formula V and the reducing agent to give (S)-6-methyl-N-((S)-1-phenylethyl) -2,3,4,9-tetrahydro-1H-carbazole-1-amine VI

The compound of formula VI is reacted with ethylene glycol ditosylate by ethylene bridging 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

The alkaline agent is sodium hydride (NaH), in the presence of dimethylsulfoxide (DMSO) or dimethylformamide (DMF).

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

The cyclization reaction occurs at room temperature over a period of 4.5 hours.

The compound of formula VII was subjected to catalytic hydrogenolysis conditions to give the desired hydrochloride salt of the compound of formula III.

The hydrogenolysis reaction was catalyzed by palladium on carbon (Pd content 0.1 g, 9 mol%) and was carried out 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.

Work-up conditions for the hydrogenolysis reaction involved neutralization with ammonia solution followed by recrystallization from benzene. The hydrochloride salt of the compound of formula III was formed by the addition of hydrochloric acid to a solution of the free base in ethanol.

The process gave (S)-pirlindole hydrochloride in 10% final yield relative to intermediate VI.

Mixing sodium hydride with DMSO generates dimsyl anion. This anion is most often used on a laboratory scale, but since it is unstable its use on a large scale must be done with specific precautions. The decomposition of the dimsyl anion is exothermic. Decomposition of the dimsyl anion is reported to start even at 20°C, and above 40°C it decomposes at an appreciable rate (Lyness, WI et al., US Pat.

3,288,860 1966, Cl. 260-607).

It is described in 'Sax &Lewis's Dangerous Properties of Industrial Materials' that the 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 from a pilot plant reactor containing sodium hydride and DMF from 50°C. Accelerating rate calorimetry (ARC) tests showed exothermic activity as low as 26 °C. Similar behavior was also seen with DMA. De Wall, G. et al., Chem. Eng. News 1982, 60(37), 5, describes a similar incident, where the leak started at 40°C, and rose to 100°C in less than 10 minutes, evaporating most of the DMF.

There is a need for safe, industry-friendly and environmentally friendly processes for the preparation of pirlindole enantiomers. These facts are disclosed for the purpose of illustrating the technical problem addressed by the present disclosure.

P. Yu lvanov et al "New approach to the synthesis of pyrazidol" discloses a synthetic method on which the production of the antidepressant pyrazidol (I) is based, including the alkylation phase of 6-methyl-1-oxotetrahydrocarbazole (II) by bromo-acetaldehyde acetal; subsequent transformations of the N-alkylated ketocarbazole (III) produce the formation of pyrazidol.

AI Bokanov et al "Synthesis of heterocycles on the basis of iminotetrahydrocarbazoles. i. 3-benzyl-8-methy-2-oxo-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2, ijk]carbazone" discloses that the reaction of 6-methyl-1-oxo-1,2,3,4-tetrahydrocarbazole and benzylamine gave 1-benzylimino-6-methyl-1,2,3,4-tetrahydrocarbazole which was converted by two methods to a pyrazinocarbazole derivative.

AV lvachchenko et al "New heterocyclic hepatitis C virus (HCV) inhibitors containing A 2-Aminomethyl-1-H-Indole Fragment" discloses that a focused library of heterocyclic compounds including a 2-aminomethyl-1H-benzimidazole fragment (1 -19), 2-aminomethylindole (20-83), benzofuran-2-ylmethylamine (84-92), or 2-piperazin-1-ylmethylbenzoxazole (93) for their ability to inhibit hepatitis C virus (HCV) in vitro.

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

Document EP 2597097 A1 discloses novel antiviral active components, pharmaceutical composition, antiviral drug, and method for the prophylaxis and treatment of viral diseases, in particular caused by hepatitis C virus (HCV) with the general formula:

General description

The process disclosed herein provides an industrially applicable synthesis of pirlindole enantiomers or pharmaceutically acceptable salts thereof. The present disclosure relates to the transformation of the compound of formula VI ((S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-1- amine) in 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, in particular DMI with sodium hydride (NaH), are as follows: DMI is thermally stable towards NaH and as such this mixture can be safely heated, resulting in conversion rates and increased reaction yields of, for example, the compound of formula VI to the compound of formula VII (see Tables 1 and 2). Work-up of this reaction involves the addition of methanol (MeOH) to precipitate the compound of formula VII. As DMI is very soluble in dichloromethane (DCM), extraction of the mother liquor with dichloromethane allows the recovery of DMI which can later be reused.

Catalytic hydrogenolysis of the compound of formula VII obtained by this process yields the highly pure crude compound of formula III ((S)-pirlindole) which requires simple purification steps, since basification is not necessary.

The present disclosure refers to a process for the synthesis of pirlindol enantiomers of formula II and III

or a pharmaceutically acceptable salt 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-phenNetyl)-2,3,4,9-tetrahydro-1H-carbazole-1-amine

and a compound of formula X

where 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-phenNetN)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole VII or the enantiomer (R)-8-methyl-3-((R)-1-phenNetN)-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 now disclosed process and also in the reaction conversion of compound VI or VIII to compound VII or IX, respectively.

In one embodiment and for even better results, the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X may be from 1:1:1 to 5:1:3. More particularly the molar ratio 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.

In one embodiment and for even better results, the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X may 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.

In one embodiment and for even better results, the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X may be 4:1:2.

In one embodiment and for even better results, the suitable alkaline agent may be sodium hydride.

In one embodiment and for even better results, L of the compound of formula X may preferably be -OTs.

In one embodiment and for even better results, the pharmaceutically acceptable salt of the pirlindol III or II enantiomer may be acetate salt, hydrochloride salt, hydrobromide salt, mandelate salt, citrate salt, succinate salt, tartrate salt, malonate salt, salt maleate, methanesulfonate salt, lactate salt, ethanesulfonate salt, glutamate salt or phosphate salt.

In one embodiment and for even better results, the pharmaceutically acceptable salt may be hydrochloride salt or methanesulfonate salt.

In one embodiment and for even better results, the pharmaceutically acceptable salt may be lactate salt, ethanesulfonate salt, mandelate salt, citrate salt, or succinic salt.

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-carbazole-1-amine, or its enantiomeric compound of formula VIII (R)-6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazoM -amine, and the compound of formula X, can be carried out at temperatures between 50 °C and 120 °C, preferably at 60 °C.

In one embodiment and to obtain even better results, the catalytic hydrogenolysis can be carried out at temperatures between 20-70°C, preferably at 50°C.

In one embodiment and for even better results, the catalytic hydrogenolysis can be carried out for 2-8 hours, preferably 5 hours.

Detailed description

The present invention provides a process for the synthesis of pirlindole enantiomers that are readily convertible to the corresponding acid salts.

In one embodiment, the process of the present invention uses the intermediate of formula VI, (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro- 1H-carbazole-1-amine

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

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

with a chiral auxiliary (S)-(-)-a-methylbenzylamine, followed by: 2-stereoselective reduction with sodium borohydride. The compound of formula VI can be cyclized to give 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 subjected to catalytic hydrogenolysis to give the compound of formula III (S)-pirlindole.

In one embodiment, the present invention relates to the preparation of (R)-pirlindole 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-carbazoM-amine VIII

is obtained from the condensation of the compound of formula IV with (R)-(+)-a-methylbenzylamine. The compound of formula VIII can be cyclized to give the compound of formula IX

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

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

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

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 is -OTs. .

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

In one embodiment, the compound of formula X may 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 phosphorous 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.

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

In one embodiment, suitable solvents for the preparation of the compound 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 for even better results, the solvent is DMI.

In one embodiment, preferably the molar ratio between the cyclization reaction components alkaline agent, intermediate VI, and compound X is between 1:1:1 and 5:1:3, more preferably, and for even better results , is 4:1:2 (see table 1).

In one embodiment, the cyclization reaction occurs at a temperature between 50°C and 120°C, preferably 60°C.

In one embodiment, the cyclization reaction occurs for 1 to 20 hours, preferably 1 to 5 hours, more preferably 2 hours.

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

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 a process according to the invention can be subjected to catalytic hydrogenolysis or acid phenylethyl cleavage. Catalytic hydrogenolysis in a mixture of acidified organic solvents gives the compound of formula II (R)-pirlindol. Catalytic hydrogenolysis is under hydrogen pressure or transfer hydrogenolysis conditions.

In one embodiment, preferably the acidic phenylethyl cleavage is carried out by an acidic cleavage agent such as boron or aluminum trihalide. More preferably the acid cutting agent is boron trichloride, boron tribromide or aluminum chloride.

In one embodiment, preferably the catalytic hydrogenolysis uses a heterogeneous catalyst and occurs under hydrogen pressure. Preferably the heterogeneous catalyst is palladium on carbon. More preferably, the heterogeneous catalyst will have a palladium content of about 3.2 mole %. Preferably the hydrogen pressure for catalytic hydrogenolysis is between 500-2000 KPa (5-20 bar), more preferably it is 700 KPa (7 bar). Preferably the temperature for catalytic hydrogenolysis can be between 20-70°C. More preferably the temperature is 50 °C. Preferably the catalytic hydrogenolysis lasts for a period of 2 to 8 hours, more preferably 5 hours. The suitable catalytic hydrogenolysis acidified solvent mixture may be a mixture of organic solvents selected from ethyl acetate, DMF, MeOH, ethanol, isopropanol (¡PrOH) and DCM, preferably the solvent mixture is composed of a mixture of a protic solvent. with DCM, more preferably MeOH with DCM.

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).

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

In one embodiment, the crude high purity compound of formula III, or formula II, obtained does not require any base neutralization and is rapidly recrystallized from water and/or a protic solvent.

A specific embodiment of the present invention is a process that includes the following steps:

placing the compound of formula X in DMI;

carefully add the alkali metal hydride;

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

add MeOH to the ice-water cooled reaction mixture in the previous step;

let the suspension stir at 0 °C;

filter the solid compound of formula VII or the compound of formula IX and wash with water-MeOH;

extract mother liquor with DCM;

evaporate the DCM to allow the DMI solvent to recover;

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

The process of the invention is suitable for industrial use and has an ecological advantage such as the possibility of recycling the solvent involved in the process (DMI).

Pharmaceutically accepted salts according to the invention include the therapeutically active non-toxic acid salt form which the compounds of formula II and III are able to form.

In one embodiment, the acid addition salt form of a compound of formula II or III that occurs in its free form as a base may be obtained by treating the free base with an appropriate 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, succinic, tartaric, glutamic, p-toluenesulfonic, cyclamic, ethanesulfonic acid , 1,2-ethanedisulfonic and the like.

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

In one embodiment, the compounds of formula II or III, and their salts 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.

In all the previously mentioned domains the optically active center can assume both the 'R' and 'S' configuration.

The compounds of formula I, II and III and all intermediates have one or two stereogenic centers in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation being used in correspondence with the rules described in Pure Appl. Chem. 45 (1976) 11-30.

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

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

For the purposes of this invention, it is considered enantiomerically pure when the enantiomeric purity is equal to or greater than 97%.

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 was carried out as follows.

In one embodiment, ethylene glycol ditosylate (73 g, 197 mmol) and DMI (240 mL) were charged to a 2 L three-neck round bottom flask equipped with a magnetic stirrer. To the resulting clear solution, NaH (60% suspension in mineral oil, 15.8 g, 394 mmol) was carefully added. To the resulting suspension, a solution of VI ((S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazole-1 -amine) (30 g, 95.5 mmol) in DMI (60 mL) at 60 °C. The mixture was stirred for 1 h at 60 °C. The mixture was cooled to room temperature, then MeOH was added slowly with ice-water cooling. A white precipitation appeared, and the resulting suspension was stirred and then filtered. The filtrate was washed with water-MeOH. The product was dried in vacuo to give 24.9 g of compound of formula VII (75.2 mmol, yield: 76%). Purity >99.9% area (HPLC).

In one embodiment, the preparation of the compound (S)-pyrlindole hydrochloride salt, compound of formula III, was carried out as follows.

In one embodiment, the 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 the 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 completion (HPLC) the suspension was filtered through a pad of celite, and the filter cake washed with MeOH. The resulting solution was checked for pH (<3) and evaporated to give the crude hydrochloride salt of the compound of formula III. To the crude material iPrOH was added and the suspension was allowed to stir at reflux. The suspensions were filtered, and the product was dried in vacuo to give (S)-pyrlindole hydrochloride salt, 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)+.

The data reported in Tables 1 and 2 comprise isolated yields or reaction conversions. Reaction conversion reflects the conversion of reactant to product, can be obtained by HPLC analysis and is reported as area %.

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

In one embodiment and for even better results, the combination of DMI and the molar ratios disclosed in Tables 1 and 2 surprisingly provide even higher yields and comparative reaction conversions of compound VI or VIII to compound VII or IX, respectively.

Table 1 . Comparative Yields Using DMI as Solvent

a Reagent conversion was determined by HPLC analysis [area %]

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.

Claims (14)

1. A process for the synthesis of pirlindole enantiomers of formula II and III

or a pharmaceutically acceptable salt 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 a compound of formula X

where 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 the 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 to give pirlindole enantiomers of formula II or III or pharmaceutically acceptable salts thereof. 2. The process according to claim 1, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 1:1:1 to 5:1:3. 3. The process according to any preceding claim, 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. The process according to any preceding claim, 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. The process according to any preceding claim, 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. The process according to any preceding claim, 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 any of claims 1-4, wherein the molar ratio of the suitable alkaline agent: intermediate VI or VIII: compound of formula X is 4:1:2. 8. The process according to any of the previous claims, wherein the suitable alkaline agent is sodium hydride. 9. The process according to any of the previous claims, wherein the compound of formula X is ethane-1,2-diyl bis(4-methylbenzenesulfonate). 10. The process according to any of the preceding claims, wherein the pharmaceutically acceptable salt is 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 process according to claim 10, wherein the pharmaceutically acceptable salt is hydrochloride salt or methanesulfonate salt. 12. The process according to claim 10, wherein the pharmaceutically acceptable salt is lactate salt, ethanesulfonate salt, mandelate salt, citrate salt or succinate salt. 13. The process according to any of the previous claims, wherein the cyclization step is carried out at temperatures between 50 °C and 120 °C, preferably at 60 °C. 14. The process according to any of the previous 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.