PREPARATION OF ENANTIOMERICALLY PURE MIRTAZAPINE AND SALTS THEREOF

INTRODUCTION

Aspects of the present application relate to processes for the preparation of enantiomerically pure mirtazapine, including intermediates and salts thereof. Particular aspects relate to preparation of esmirtazapine, including intermediates and salts thereof.
Mirtazapine has a chemical name 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine and is represented by structural Formula I. It has one chiral center and hence the R- and S-isomers are represented by structural Formulae II and III, respectively.

Formula I Formula II Formula III

Mirtazapine belongs to the piperazino-azepine group of compounds and is used in the treatment of major depressive disorder. Esmirtazapine, which is the S-isomer of mirtazapine, is being developed for the potential treatment of insomnia and of vasomotor symptoms associated with menopause.

U.S. Patent No. 4,062,848 discloses mirtazapine and processes for its preparation. It also discloses optical resolution of mirtazapine using optically active 0,0-dibenzoyltartaric acid, in the presence of ethanol and ether as solvents.

International Application Publication No. WO 2005/102352 A1 discloses a pharmaceutical formulation comprising pharmaceutically suitable non-sublimating and solid salts of an enantiomer of mirtazapine and a method for its manufacture.

International Application Publication No. WO 2009/008303 A1 discloses the resolution of mirtazapine using optically active tartaric acid, in the presence of methanol and water.
D. F. Smith et al., in "PET neuroimaging of [11C]mirtazapine enantiomers in pigs," European Neuropsychopharmacology, 16(5), 350-357 (2006) discloses resolution of desmethylmirtazapine with (-)-di-p-toluoyltartaric acid in a mixture of acetone and water, to obtain S-(+)-desmethylmirtazapine.

There is a continuing need to develop alternative and simplified processes for preparing enantiomerically pure isomers of mirtazapine and its salts, which processes are suitable for commercial manufacturing in high purity and yield.

SUMMARY

Aspects of the present application provide processes for optical resolution of mirtazapine, using di-p-toluoyltartaric acid (herein after referred to as "DPTTA"). Several variants of the process are described.

In an aspect, this application provides a compound, which is a salt of enantiomerically pure mirtazapine with DPTTA, and processes for its preparation.

In an embodiment, the application provides processes for the preparation of enantiomerically pure mirtazapine DPTTA salt, embodiments comprising:

a) reacting mirtazapine with an optically pure DPTTA in the presence of a
solvent, to form a diastereomeric salt; and

b) recovering an enantiomerically pure mirtazapine DPTTA salt, as a solid.

In an aspect, the application provides processes for the preparation of
esmirtazapine or a pharmaceutically acceptable salt thereof, embodiments comprising:

a) reacting esmirtazapine DPTTA salt with a base in an aqueous solvent medium;

b) recovering esmirtazapine from the mixture; and

c) optionally, converting esmirtazapine into a pharmaceutically acceptable salt.

In an aspect, the application relates to processes for the preparation of esmirtazapine maleate, comprising reacting esmirtazapine with maleic acid, in the presence of a suitable solvent.

Aspects of the present application also relate to pharmaceutical compositions comprising enantiomerically pure mirtazapine or a salt thereof, obtained by a process described in this application.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an X-ray powder diffraction pattern of crystalline esmirtazapine (-)-DPTTA salt, prepared according to Example 1.

Fig. 2 is an X-ray powder diffraction pattern of crystalline esmirtazapine (+)-DPTTA salt, prepared according to Example 5.

Fig. 3 is an X-ray powder diffraction pattern of crystalline esmirtazapine, prepared according to Example 6.

Fig. 4 is an X-ray powder diffraction pattern of crystalline esmirtazapine maleate, prepared according to Example 7.

DETAILED DESCRIPTION

"Mirtazapine" refers to the racemic mixture of R- and S- isomers having ratio from 30:70 to 70:30. "Esmirtazapine" refers to the S-isomer of mirtazapine, and "R-mirtazapine" refers to the R-isomer of mirtazapine.

"Enantiomerically pure" as used herein refers to a compound having enantiomeric purity greater than about 90% w/w, or greater than about 95% w/w, or greater than about 99% w/w, as determined using high performance liquid chromatography (HPLC).

In an aspect, this application provides a compound, which is a salt of enantiomerically pure mirtazapine with DPTTA, and processes for its preparation.

Enantiomerically pure mirtazapine may be esmirtazapine or R-mirtazapine and the DPTTA may be (+)-DPTTA or (-)-DPTTA. Accordingly, the present application provides esmirtazapine (+)-DPTTA salt, esmirtazapine (-)-DPTTA salt, R-mirtazapine (+)-DPTTA salt, and R-mirtazapine (-)-DPTTA salt.

In an aspect, the application provides processes for the preparation of enantiomerically pure mirtazapine DPTTA salts, embodiments comprising:

a) reacting mirtazapine with an optically pure DPTTA in the presence of a
solvent, to form a diastereomeric salt; and

b) recovering an enantiomerically pure mirtazapine DPTTA salt, as a solid.

Step a) involves reaction of mirtazapine with an optically pure DPTTA in the
presence of solvent to form a diastereomeric salt.

Optically pure DPTTA that may be used in the present process includes (+)-DPTTA or (-)-DPTTA, with enantiomeric purity greater than about 95%, or greater than about 99%.

DPTTA that may be used in the present process may in any solid form including anhydrous, monohydrate, and the like.

Suitably, mirtazapine and optically pure DPTTA may be dissolved individually, then both the solutions are combined, or mirtazapine and optically pure DPTTA may be dissolved in the solvent together.

Quantities of optically pure DPTTA may range from about 0.5 to about 3 moles, per mole of mirtazapine.

Quantities of solvent used for the process may be from about 5 mL to about 50 mL, or about 10 mL to about 20 mL, per gram of mirtazapine.

The process of step a) is suitably carried out at temperatures ranging from about 25°C to about boiling temperature of the solvent used, or about 55°C to 65°C.

It has been observed that either (+)-DPTTA or (-)-DPTTA may be used for salt formation with esmirtazapine and R-mirtazapine.

Depending upon the solvent medium used for the resolution process, enantiomerically pure mirtazapine DPTTA salt is obtained in the form of a solid.

In embodiments, esmirtazapine (+)-DPTTA salt or R-mirtazapine (-)-DPTTA salt is recovered as a solid, when the solvent medium comprises an aqueous ethanol.

In embodiments, esmirtazapine (-)-DPTTA salt or R-mirtazapine (+)-DPTTA salt is recovered as a solid when the solvent medium comprises an aqueous methanol.

In embodiments, mirtazapine may be reacted with (+)-DPTTA in an aqueous methanol solvent medium to recover R-mirtazapine (+)-DPTTA salt as a solid, and the filtrate enriched with esmirtazapine is then reacted with (+)-DPTTA in an aqueous ethanol solvent to recover esmirtazapine (+)-DPTTA salt in high yield. Similarly, this process may be carried out using (-)-DPTTA also.

Step b) involves recovering enantiomerically pure mirtazapine DPTTA salt as a solid.
For solid isolation to occur, the reaction mixture may be maintained further at temperatures lower than the reaction temperatures, such as, for example, about 25°C to about 35°C, for a period of time as desired for a required extent of isolation of the solid product. The exact cooling temperatures and times required for complete isolation can be readily determined by a person skilled in the art, and will also depend on parameters such as concentrations and temperatures of the solution or slurry. Optionally, isolation may be enhanced by methods such as further cooling, partial removal of the solvent from the mixture, by combining an anti-solvent with the reaction mixture, by seeding with solid product obtained previously, or a combination thereof.

The solid product obtained is recovered from the reaction mixture using suitable techniques, such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed with a solvent to wash out the mother liquor.

If desired, the obtained wet solid may be dried further. Drying may be done in a tray dryer, air oven, vacuum dryer, spin flash dryer, fluidized bed dryer, flash dryer, etc. The drying may be carried out at temperatures ranging from about 50°C to about 75°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon and helium. The drying may be done for any desired times to get the desired product, such as from about 30 minutes to about 2 hours, or longer.

The filtrate contains the other isomer DPTTA salt, which may be recovered by distilling the solvent or any other suitable technique.

If desired, the enantiomerically pure mirtazapine DPTTA salt obtained above may be further purified by recrystallizing in a solvent comprising about 30-50% v/v aqueous alcohol.

Suitable alcoholic solvents include methanol, ethanol, isopropanol, and the like. The quantities of solvent used for the purification may be from about 5 mL to about 15 mL, or about 6 mL to about 10 mL, per gram of enantiomerically pure mirtazapine DPTTA salt.
Suitably, reaction temperatures, durations, and recoveries of the purified product may be carried out as described above during a resolution process.

In embodiments, esmirtazapine (-)-DPTTA salt is in crystalline form. The crystalline form may be characterized by an X-ray powder diffraction ("XRPD") pattern having peaks located at about 5.1, 7.2, 8.2, 10.4, 11.9, 18.6, 20.6, and 20.9, ± 0.2 degrees 2 theta.

The crystalline form of esmirtazapine (-)-DPTTA salt may be further characterized by an XRPD pattern substantially as depicted in Fig. 1.

In embodiments, esmirtazapine (+)-DPTTA salt is in crystalline form. The crystalline form may be characterized by an XRPD pattern having peaks located at about 5.1, 7.2, 8.2, 10.4, 11.9, 18.6, 20.6, and 20.9, ± 0.2 degrees 2 theta.

The crystalline form of esmirtazapine (+) DPTTA salt may be further characterized by an XRPD pattern substantially as depicted in Fig. 2.

X-ray powder diffraction patterns described herein are obtained using a Bruker AXS, DS Advance Powder X-ray powder diffractometer, with copper K-alpha radiation.

In an aspect, the present application provides processes for the preparation of esmirtazapine or a pharmaceutically acceptable salt thereof, embodiments comprising:

a) reacting esmirtazapine DPTTA salt with a base, in an aqueous solvent medium;

b) recovering esmirtazapine from the reaction mixture; and

c) optionally, converting esmirtazapine into a pharmaceutically acceptable salt.

Step a) involves reacting esmirtazapine DPTTA salt with a base in an aqueous solvent medium.

Esmirtazapine DPTTA salts that may be used in step a) include esmirtazapine (+)-DPTTA salt and esmirtazapine (-)-DPTTA salt. Esmirtazapine DPTTA salts may be prepared by any processes, including processes described in the present application.

Suitable bases that can be used step a) include, but are not limited to: alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; bicarbonates of alkali metals, such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and any mixtures thereof. These bases can be used in the form of solids, or in the form of aqueous solutions.

Suitably, aqueous solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding base can be used. Any concentration is useful, which will convert the acid addition salt to the free base.

Suitably, the pH of the reaction mixture may range from about 7 to about 14, or from about 10 to about 12.

Suitable temperatures for conducting the reaction range from about 10°C to about 50°C, or about 25°C to about 35°C.

Step b) involves recovering esmirtazapine from the reaction mixture.

Suitable solvents that can be used for extraction of the free base from aqueous solutions include, but are not limited to, water immiscible solvents such as: halogenated hydrocarbons such as dichloromethane, ethylene dichloride, chloroform, and the like; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, cyclohexane, and the like; esters such as ethyl acetate, propyl acetate, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tertiary-butyl ether, and the like; and any mixtures thereof.

After extraction completion, the organic layer containing the free base is separated and may be progressed to further processing steps directly, or it can be concentrated to isolate the free base. The distillation may be done with or without applying vacuum at temperatures in the range of about 30°C to about 100°C or about 40°C to about 70°C.

The desired product may be recovered by scraping from the vessel or, by dissolving and crystallization from a suitable solvent.

Suitable solvents that may be used for crystallization include, but are not limited to: alcohols such as methanol, ethanol, isopropanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; esters such as ethyl acetate, propyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof.
A solid product obtained can be recovered using suitable techniques, such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed with a solvent to wash out the mother liquor.

The obtained solid may be dried, and drying may be done in a tray dryer, air oven, vacuum dryer, spin flash dryer, fluidized bed dryer, flash dryer, etc.. The drying may be carried out at temperatures from about 30°C to 65°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon and helium. The drying may be conducted for any desired times to get the desired product purity, such as from about 1 hour to about 5 hours, or longer.

The crystalline form of esmirtazapine obtained by processes described herein may be characterized by a XRPD pattern having peaks located at about 9.2, 10.5, 12.5, 14.6, 15.5, 18.4, 19.5, 20.5, 22.4, 22.9, and 23.5, ± 0.2 degrees 2 theta.

The crystalline form of esmirtazapine obtained by a process as in Example 6 hereof may also be characterized by its XRPD pattern substantially as depicted in Fig. 3.

Step c) involves converting esmirtazapine into a pharmaceutical acceptable salt.
Pharmaceutically acceptable acids that can be used include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, and the like.
In embodiments, the acid is maleic acid and the resulting acid addition salt is esmirtazapine maleate.

In embodiments, the present application relates to processes for the preparation of esmirtazapine maleate, comprising reacting esmirtazapine with maleic acid in the presence of a suitable solvent.

Esmirtazapine used in the present process may be obtained by a process described hereinabove, or from any other processes known in the art. Suitably, any polymorphic form of esmirtazapine may be used, viz. crystalline, amorphous, or mixtures thereof.

Suitable solvents that may be used in this process include, but are not limited to: alcohols such as methanol, ethanol, isopropanol, and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, and the like; ethers such as diethyl ether, diisopropyl ether, and the like; esters such as ethyl acetate, propyl acetate, and the like; nitriles such as acetonitrile, propionitrile, and the like; water; and any mixtures thereof.

Esmirtazapine may be mixed with about 2 mL to about 6 mL of the solvent, per gram of esmirtazapine.

Quantities of maleic acid may range from about 0.5 to about 3 moles or about 1 to about 2 moles per mole of esmirtazapine.

The reaction may be carried out at temperatures from about 20°C to about 40°C. The mixture may be stirred for any desired time periods, to get the desired product, such as from about 30 minutes to about 2 hours, or longer.

The solid product obtained is recovered from the reaction mixture using suitable techniques such as decantation, filtration by gravity or by suction, centrifugation, and the like. The crystals so isolated can carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired, the crystals can be washed with a solvent to wash out the mother liquor.

The obtained wet solid may be dried. Drying may be done using a tray dryer, air oven, vacuum dryer, spin flash dryer, fluidized bed dryer, flash dryer, etc. The drying may be carried out at temperatures from about 40°C to 70°C, with or without vacuum, and in the presence or absence of an inert atmosphere like nitrogen, argon, neon and helium. The drying may be done for any desired times to get the desired product purity, such as from about 30 minutes to about 2 hours, or longer.

Esmirtazapine maleate obtained by a process described in this application is in the form of a crystalline solid, and can be characterized by an XRPD pattern substantially in accordance with the pattern of Fig. 4.

Crystalline esmirtazapine maleate obtained by a process described in this application can also be characterized by an XRPD pattern having significant peaks located at about 7.8, 10.6, 12.6, 13.8, 15.3, 18.5, 20.6, 21.3, 22.0, and 29.4, ± 0.2 degrees 26.

Esmirtazapine maleate obtained according to process embodiments of the present invention has a particle size distribution where D50 is less than about 50 urn.

The D10, D50 and D90 values are useful ways for indicating a particle size distribution. D90 refers to at least 90 volume percent of the particles having a size smaller than the said value. Likewise, D10 refers to 10 volume percent of the particles having a size smaller than the said value. D50 refers to 50 volume percent of the particles having a size smaller than the said value. Methods for determining D10, D50 and D90 include laser diffraction, such as using equipment from Malvern Instruments Ltd. of Malvern, Worcestershire, United Kingdom.

Esmirtazapine maleate obtained according to embodiments of the present invention has: D10 less than about 20 m, or less than about 15 m; D50 less than about 50m, or less than about 35 m; and D90 less than about 100m, or less than about 70 rn. There is no specific lower limit for any of the D values.

Esmirtazapine and its salts, such as a maleate salt, prepared in accordance with the present invention contains less than about 0.2%, or less than about 0.1%, by weight of the corresponding impurities, including R-mirtazapine, as characterized by HPLC analysis.
The present application also relates to pharmaceutical compositions comprising enantiomerically pure mirtazapine or a salt thereof, obtained by a process described in this application.

Pharmaceutical compositions comprising enantiomerically pure mirtazapine or salts thereof, and their combinations with pharmaceutically acceptable excipients may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; and liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using process steps such as direct blending, dry granulation, wet granulation, or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.

Pharmaceutically acceptable excipients that are useful for preparing formulations include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidones, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcellulosess, ethyl celluloses, methyl celluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided for purposes of illustration only, and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Example 1: Preparation of esmirtazapine (-)-DPTTA salt, using aqueous methanol.
Mirtazapine (50 g) is charged into a 3 L round bottom flask, followed by the addition of methanol (600 ml_). The mixture is stirred for about 15 minutes. (-)-DPTTA monohydrate (152 g) is added and stirring is continued. Water (175 mL) is added slowly over about 15 minutes. The mixture is heated to about 60-65°C and stirred for 20 minutes to obtain a clear solution. The solution is cooled to 25-30°C and maintained for about 45 minutes. The formed solid is filtered and the wet solid is washed with a mixture of methanol (100 mL) and water (30 mL). The solid is dried at 60-65°C for 3 hours, to get 96.4 g of dry solid.

The dry solid (96 g, purity 99.15% by chiral HPLC) is charged into a round bottom flask and methanol (576 mL) is added. The mixture is heated to 60°C and then water (192 mL) is added. The mixture is stirred at 60-65°C for 25 minutes, then cooled to 25-35°C and stirred for 35 minutes. The formed solid is filtered and washed with a mixture of methanol (115 mL) and water (48 mL). The solid is suction dried for 30 minutes and further dried for 2 hours at 60-65°C, to get 86.1 g of the title compound as a crystalline solid.

Purity by chiral HPLC: 99.89%.

Example 2: Preparation of esmirtazapine.

The salt obtained in Example 1 (83 1 g) is charged into a 2 L round bottom flask and water (415 5 mL) is added. The pH is adjusted to about 10 using 40% aqueous NaOH (12.3 g) and the mixture is stirred for about 10 minutes. The mixture is extracted with dichloromethane (200 mL, then 150 mL). The combined organic layer is dried with sodium sulfate and distilled completely under vacuum at 45-50°C, to get 23.5 g of the title compound as a residue.

Purity by chiral HPLC: 99.84%.

Example 3: Preparation of esmirtazapine maleate.

Esmirtazapine obtained in Example 2 (10.5 g) and ethanol (34.8 mL) are charged into a 250 mL round bottom flask and the mixture is stirred. A mixture of maleic acid (4.6 g) and ethanol (34.8 mL) is added and the mixture is stirred for 90 minutes at 25-35°C. The formed solid is filtered and washed with ethanol (5 mL). The wet solid is dried at 60°C for about 3 hours, to get 11.4 g of the title compound as a crystalline solid.

Purity by chiral HPLC: 99.99% w/w.

Example 4: Preparation of esmirtazapine maleate.

Esmirtazapine (1.5 g) and the solvent (10 mL) are charged into a 250 mL round bottom flask and the mixture is stirred for 15 minutes. A mixture of maleic acid (0.65 g) and the solvent (5 mL) is added and the mass is stirred for 1 hour at 25-35°C. The formed solid is filtered and washed with solvent (5 mL). The wet solid is dried at 40°C under vacuum, to get the title compound as a crystalline solid. Yield and purity details of the products obtained are given in the following table. All of the products have XRPD patterns substantially similar to Fig. 4.

Example 5: Preparation of esmirtazapine (+)-DPTTA salt using aqueous ethanol.
Mirtazapine (50.0 g) is charged in to a 5 L round bottom flask, followed by the addition of ethanol (270 mL) and water (480 ml_). The mixture is stirred for about 5 minutes. A mixture of (+)-Di-p-toluoyl-D-tartaric acid(DPTTA) monohydrate (142 g) and ethanol (500 mL) is added and the mass is stirred for about 15 minutes. Petroleum ether (1 L) is added and the mass is maintained at 25-30°C for about 16 hours. The formed solid is filtered and the wet solid is suction dried for about 30 minutes. The solid is further dried at 60-65°C for 1 hour, to get 99.1 g of dry solid.

The solid (purity 93.26% by chiral HPLC) is charged into a round bottom flask and methanol (495 mL) is added. The mixture is heated to 45°C and water (187 mL) is added. The mixture is heated to 60-65°C and maintained for 25 minutes. The mixture is cooled to 25-35°C and maintained for 1 hour, then is filtered and the solid is washed with a mixture of methanol (15 mL) and water (5.5 mL). The solid is suction dried for 30 minutes and further for 1 hour at 60-65°C, to get 57.6 g of the title compound as a crystalline solid.

Example 6: Preparation of esmirtazapine.

The salt obtained in Example 5 is charged into a 500 mL round bottom flask and water (200 mL) is added. The pH is adjusted to about 10 using NaOH. The mixture is stirred for about 10 minutes. The mixture is extracted with methyl-t-butyl ether (2x100 mL). The combined organic layer is distilled completely under vacuum at 45-50°C. The obtained residue is dried at 40-55°C for 3-4 hours, to get 12.6 g of the title compound.

Purity by chiral HPLC: 99.47%.

SOR: + 518.4°. (C= 0.1% w/v in methanol at 20°C)

Example 7: Preparation of esmirtazapine maleate.

Esmirtazapine (2.0 g) and ethanol (10 mL) are charged into a 100 mL round bottom flask and the mixture is stirred. A mixture of maleic acid (0.88 g) and ethanol (10 mL) is added and the mixture is stirred for 1 hour at 25-35°C. The formed solid is filtered and washed with ethanol (10 mL). The wet solid is dried at 40°C under vacuum, to get 2.6 g of the title compound as a crystalline solid.

Example 8: Preparation of R-mirtazapine (+)-DPTTA salt using aqueous methanol. Mirtazapine (25.0 g) is charged into a 1 L round bottom flask, followed by the addition of methanol (300 ml_). (+)-DPTTA monohydrate (76.0 g) and water (100 mL) is added and the mmixture is heated to 60-65°C. The mixture is maintained for about 30 minutes at 60-65°C, then cooled to 25-35°C and stirred for about 1 hour. The formed solid is filtered and washed with a mixture of methanol (30 mL) and water (10 ml_). The solid is suction dried for 20-30 minutes and further dried at 60-65°C for 1 hour, to get 48.4 g of the title compound.

Example 9: Recovery of esmirtazapine (+)-DPTTA salt from a filtrate.

The filtrate obtained in Example 8 is distilled below 65°C under vacuum. Water (300 mL) is added to the residue and pH is adjusted to about 9 using sodium hydroxide (12 g). The mixture is extracted with dichloromethane (2x250 mL) and solvent is distilled completely from the organic layer, to get 15 g of esmirtazapine enriched free base.

The free base (10.0 g) is charged into a 1 L round bottom flask, followed by the addition of ethanol (54 mL) and water (96 mL), and the mixture is stirred for 10 minutes. Ethanol (100 mL) and (+)-DPTTA monohydrate (30.5 g) are added. The mixture is maintained for about 3 hours at 25-35°C. The formed solid is filtered and washed with a mixture of methanol (15 mL) and water (10 mL). The solid is suction dried for 20-30 minutes and further dried at 60-65°C for 1 hour, to get 35.2 g of the title compound.

Purity by chiral HPLC: 98.97%.

Example 10: Preparation of esmirtazapine.

The salt obtained in Example 9 is charged into a 500 mL round bottom flask and water (100 mL) is added. The pH is adjusted to about 10 using sodium hydroxide (4 g). The mixture is stirred for about 10 minutes. The mixture is extracted with dichloromethane (2x100 mL). The combined organic layer is distilled completely under vacuum at 45-50°C. The obtained residue is further dried at 40-55°C for 3-4 hours, to get 8 g of the title compound.

Purity by chiral HPLC: 99.03%.

We Claim:

1. A process for the preparation of enantiomerically pure Esmirtazapine or a salt
thereof, comprising the step of:

a) reacting mirtazapine with an optically pure di-p-toluoyltartaric acid in a solvent;

b) recovering an enantiomerically pure mirtazapine di-p-toluoyltartaric acid salt;

c) reacting esmirtazapine di-p-toluoyltartaric acid salt with a base in an aqueous solvent;

d) recovering the resulting esmirtazapine freebase as solid; and

e) optionally, reacting esmirtazapine freebase with an acid to afford an acid addition salt of esmirtazapine.

2. The process according to claim 1, wherein di-p-toluoyltartaric acid in step a) comprises (+) - di-p-toluoyltartaric acid or (-) - di-p-toluoyltartaric acid

3. The process according to claim 1, wherein in step a) an amount of a di-p-toluoyltartaric acid is in a ratio from about 0.5 to about 3.0 moles, per mole of mirtazapine

4. The process according to claim 1, wherein a solvent in step a) comprises an alcohol or aqueous alcohol

5. The process according to claim 1, wherein a base in step c) comprises an alkali metal or alkaline earth metal hydroxide, carbonate, or bicarbonate, or an amine

6. The process according to claim 1, wherein esmirtazapine di-p-toluoyltartaric acid salt in step c) comprises esmirtazapine (+)-di-p-toluoyltartaric acid salt or esmirtazapine (-)-di-p-toluoyltartaric acid.

7. The process of claim 1, wherein an acid in step e) comprises hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, oxalic acid, tartaric acid, succinic acid, fumaric acid or maleic acid.

8. The process of claim 7, wherein an acid is maleic acid.

7. The process of claim 1, wherein the obtained Esmirtazapine or its salt has enantiomeric excess of at least about 99% by weight.

10. A pharmaceutical composition containing esmirtazapine obtained by claim 1 and one or more pharmaceutically acceptable excipients.