HRP20010747A2 - Novel synthesis and crystallization of piperazine ring-containing compounds - Google Patents

Description

Reference to a related application

This application is supported in the U.S. Provisional Application No. 60/130,047, received April 19, 1999.

Field of invention

This invention relates to synthetic organic chemistry, in particular to the synthesis of compounds containing a piperazine ring, such as mirtazapine, and to the crystallization of mirtazapine from various solvents and solvent systems.

Background of the invention

Mirtazapine 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino[2,1a]pyrido[2,3c]benzazepine, having formula I:

[image]

was approved by the U.S. Food and Drug Administration, under the trade name Remeron®, for the treatment of depression. Mirtazapine has a tetracyclic chemical structure unrelated to other classes of antidepressants such as selective serotonin inhibitors, tricyclic or monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine group of compounds.

Mirtazapine can be prepared using methods described in U.S. Pat. Patent number 4,062,848. The mirtazapine intermediate 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine can be prepared using the procedure of U.S. Pat. Patent No. 4,062,848 ("848 patent"), in three steps starting with a 2,3-substituted pyridine deriv. Therefore, as shown in Scheme 1, when starting with 2-amino-3-cyano-pyridine, the process of the "848 patent requires 4 synthetic steps to make mirtazapine. It is desirable to have a process for preparing mirtazapine that requires fewer steps, and consequently fewer reagents, solvents, and time.

[image]

Using the procedure from the U.S. Patent number 4,062,848 ("848 patent") prepared the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolysis of nitrile 1-(3-cyanopyridyl-2)-4-methyl-2 -phenyl-piperazine under highly basic conditions of 25 moles of potassium hydroxide (KOH) per mole of nitrate, at high temperature and through a long reaction time of 24 h. These strict reaction conditions require a great effort in the purification of the resulting g product as well as the generation of harmful waste associated with the neutralization and disposal of a large volume of concentrated base solutions. Highly basic conditions and a long reaction time make the "848 patent" process very expensive, especially in terms of reactor time.

In line with the U.S. meta ladies. Patent number 4,062,848, crude mirtazapine is recrystallized only in ether and benzine ether 40-60. Solvents ether and benz ether 40-60 are very difficult to handle in terms of large production.

Summary of the invention

This invention is directed to a method for preparing mirtazapine, and includes the steps:

reaction of a compound of the formula

[image]

with the compound formula

[image]

to obtain a compound of the formula

[image]

and, adding a ring-closing reagent to a compound of the formula

[image]

to obtain mi rt a zapi n, where R is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl, and iodomethyl; R 2 is amine; and R 3 is selected from the group consisting of chloro, fluoro, bromo and iodo.

A preferred embodiment of the present invention is directed to a method for preparing mirtazapine, comprising the steps of reacting 2-amino-3-hydroxymethylpyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2) -4-methyl-2-phenyl piperazine, and adding sulfuric acid to 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to give mirtazapine.

It was further discovered that the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine can be prepared via the hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with the use of new, much more favorable conditions. The novel reaction conditions of this invention include a low mol/mol ratio of potassium hydroxide to nitrile and a shorter reaction time.

This invention relates to an improved process for the preparation of 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolysis of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising the reaction step of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base, with the base being present in a ratio of up to about 12 moles of base per one mole of 1-(3-cyanopyridyl-2)-4 -methyl-2-phenyl-piperazine.

In a preferred embodiment of the present invention, the ratio of base to 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to about 1 mole of 1-(3-cyanopyridyl-2)-4-methyl -2-phenyl-piperazine to about 9 moles of base to about 1 mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.

In another preferred embodiment of the present invention, the base is potassium hydroxide or sodium hydroxide.

In another embodiment of the present invention, the mixture of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 130°C.

In another embodiment of this invention, the hydrolysis of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in a mixture of water and a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.

The present invention also relates to an improved process for making mirtazapine from crude mirtazapine comprising the steps of (a) heating a mixture of crude mirtazapine and a solvent; and (b) isolation of mirtazapine.

In a preferred embodiment of the present invention, water is added to the heated mixture of mirtazapine and solvent to facilitate precipitation of the mirtazapine.

In an additional embodiment of this invention, preferred solvents are methanol, ethanol, isopropanol, acetone, toluene, and hexane and mixtures thereof.

In an additional embodiment of this invention, the preferred solvents are toluene, hexane and methylene chloride.

Detailed description of the invention

The present invention relates to a novel process for the preparation of compounds containing a piperazine ring, such as mirtazapine, as described below in Scheme 2. The process of the present invention has advantages over prior processes, inter alia, higher yields, fewer reaction steps compared to other methods, and minimized raw material costs.

Scheme 2

[image]

This invention, in particular, relates to a process for preparing mirtazapine from compounds of formulas II, III and IV. In the process of the present invention, the compound of formula II from scheme 2 above, where R1 denotes hydroxymethyl, chloromethyl, bromomethyl or iodomethyl, and R1 denotes amine, preferably -NH2, is reacted with the compound of formula III from scheme 2 above, where R3 denotes chloro, fluoro, bromo or iodo, to give a compound of formula IV wherein R 1 is as defined above.

In the process of the present invention, the compound of formula II is dissolved in a solvent such as methylene chloride. The compound of formula III was added to the solvent mixture and the resulting mixture was heated. Preferably, the reaction mixture is heated to the reflux temperature of the solvent. The mixture was heated to form a compound of formula IV. Mirtazapine was then prepared by ring closure of the compound of formula IV. Ring closure of a compound of formula IV can be performed using a ring closing reagent. Suitable ring-closing reagents are dehydrating or dehydrohalogenating substances. Dehydrating or dehydrohalogenating substances that can be added to the reaction mixture for this purpose include acids such as sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis acids, such as aluminum chloride, ferric chloride, zinc chloride, stannous chloride, titanium chloride, boron trifluoride, antimony pentachloride, and zirconium tetrachloride.

Dehydrating substances that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred. A particularly preferred dehydrohalogenating substance is aluminum chloride.

In a preferred embodiment of the present invention, compounds of formulas II, III, and IV are compounds of formulas II', III', and IV as shown in Scheme 3 below. In one embodiment of the present invention, 2-amino-3-hydroxymethyl pyridine is reacted with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to give 1-(3-hydroxymethylpyridyl-2)-4-methyl-2- phenyl-piperazine. In this invention, 2-amino-3-hydroxymethyl pyridine (II') is added to the solvent. Suitable solvents include 1,2-dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and dimethyl sulfoxide.

N-methyl-1-phenyl-2,2'-imidodiethyl chloride (III') is added to the solvent mixture and the resulting mixture is heated. Preferably, the reaction mixture is heated to the reflux temperature of the solvent. The mixture is heated until 1-(3-hydroxymethylpyridinium-2)-4-methyl-2-phenyl-piperazine is formed and the reaction is complete. A suitable time is around 6 to around 24 hours. 1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is then converted to mirtazapine via ring closure.

Ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine is performed under strongly dehydrating conditions (R1=OH), preferably at an elevated temperature. Suitable dehydrating agents include acids such as sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide and phosphorus pentoxide. Dehydrating substances that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred.

Scheme 3

[image]

This invention also provides a novel process for the preparation of the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrile (I) is hydrolyzed by base using a new mol/mol ratio of base to nitrile 1-(3-cyanopyridine-2)-4-methyl-2-phenyl-piperazine and (ii) is hydrolyzed using a short reaction time.

Wherein the present invention provides an improvement in methods for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine nitrile dissolves in a mixture of water and an organic solvent. Preferred organic solvents include polar aprotic solvents and alcohols. Polar aprotic organic solvents such as dimethylformamide, dimethylacetamide and dimethyl sulfoxide and the like are preferred. Preferred alcohols are methanol, ethanol, propanol, isopropanol, butanol and the like. A suitable amount of base, such as potassium hydroxide or sodium hydroxide, is added to the reaction mixture. An amount of base, such as potassium hydroxide or sodium hydroxide, of up to about 12 moles of base per mole of nitrile (eg 12:1 KOH nitrile) is preferred. Amounts of base, such as potassium hydroxide, in a ratio of about 9 moles of potassium hydroxide per mole of nitrile (9:1 KOH:nitrile), to about 12 moles of potassium hydroxide per mole of nitrile (12:1 KOH:nitrile).

In this invention, a mixture of nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, solvent and base is heated to at least 130°C. Temperatures from about 130°C to about 150°C are preferred. In one embodiment of the present invention, the reaction may be carried out under pressure to facilitate the attainment of high temperatures. A pressure of at least about 3 atmospheres is desirable. Even more preferred are pressures of at least about 3 atmospheres to about 4 atmospheres. The reaction mixture is heated until the reaction is complete. Completion of the reaction can be monitored by HPLC. The amount of time required to complete nitrile hydrolysis varies with reaction temperature. Higher reaction temperatures generally require shorter reaction times, while lower reaction temperatures generally require longer reaction times. Although we do not limit the reaction time of this invention, the preferred reaction time of this invention may be from about 2 h to about 8 h. Upon completion of the reaction, the pH of the reaction mixture is lowered, preferably to a pH of about 6 to about 7. Preferably, the pH is lowered with hydrochloric acid.

The mirtazapine intermediate, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine was isolated after washing and filtering the reaction mixture.

In an additional embodiment of this invention, the reaction mixture of nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl piperazine, and potassium chloride, is heated using a minimum amount of water of about 0.25-1 ml of water per gram KOH, and small amounts of aprotic solvent such as dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, of about 0.1-0.5 grams of aprotic solvent per gram of nitrile, under highly concentrated conditions or near-undiluted conditions at atmospheric pressure. The mitrtazapine intermediate, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine was isolated after washing and filtering the reaction mixture.

The new process of this invention for the preparation of the intermediate product of mirtazapine, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine from nitrile-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine and 1- (3-Cyanopyridyl-2)-4-methyl-2-phenyl piperazine significantly reduces the amount of potassium hydroxide used, from 25 moles of potassium hydroxide per mole of nitrile as in the "848 patent, to about 12 moles or less of potassium hydroxide per mole of nitrile . Reducing the required amount of base simplifies the performance of the reaction and minimizes environmental problems.

The present invention also provides new methods for preparing pure mirtazapine by purifying crude mirtazapine by recrystallization. After ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine to give mirtazapine, the crude product, mirtazapine, is purified by recrystallization.

It has been found that common solvents such as toluene or methylene chloride and solvent systems such as alcohol-water can be used in the recrystallization of crude mirtazapine. In accordance with the present invention, crude mirtazapine is suspended in a suitable solvent. Preferred solvents include methanol, ethanol, isopropanol, and acetone and mixtures thereof, or mixtures of one or more of said solvents with water. Additional preferred solvents also include toluene, hexane, and methylene chloride. Solvent mixtures of water and ethanol are more preferred. Solvent mixtures in ratios of about 1:1 to about 1:4 ethanol:water are preferred.

In the present invention, the suspension of crude mirtazapine and the solvent is heated to a suitable temperature, suitable temperatures include, for example, the reflux temperature of the solvent system used in any embodiment of the present invention. For example, in one embodiment of the present invention where toluene is the solvent, a temperature of 110°C is suitable. After the cooling of the reaction mixture, the purified mirtazapine is precipitated. Filtration and drying of the resulting precipitate gives purified, recrystallized mirtazapine.

In a further example, crude mirtazapine is suspended in a solvent such as ethanol, and the mixture is heated to reflux. Water is then added dropwise and the solution is cooled to facilitate the precipitation of mirtazapine. The precipitate is purified by filtration, washing and drying to obtain purified mirtazapine. Crystallized mirtazapine can attract water and therefore contain up to 3% water by weight (3% w/w).

The solvents and solvent systems of this invention are suitable for large-scale reactions, and are more suitable than ether or 40-60 benzine ether. In addition, the crystallization yield can be significantly improved if the solvent system of the present invention is used.

Mirtazapine and the mirtazapine intermediates, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl piperazine and 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl piperazine each possess an asymmetric carbon atom, which separate optical isomers can be made in addition to racemic mixtures. The process of this invention includes these optical isomers as well as the racemic mixtures included in this invention.

In accordance with the present invention, mirtazapine produced by the process of the present invention can be prepared in the form of pharmaceutical compositions which are particularly useful in the treatment of depression. Such preparations contain a therapeutically effective amount of mirtazapine with a pharmaceutically acceptable carrier and/or excipients known to those skilled in the art.

EXAMPLES

The following examples are presented for the purpose of illustrating the present invention and are not intended to limit the scope or spirit of the invention.

EXAMPLE 1

Preparation of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine

A 50 ml three-necked flask equipped with a mechanical stirrer, condenser and thermometer was charged with 1 g (0.008 mol) of 2-amino-3-hydroxymethyl pyridine and 20 ml of 1,2-dichloroethane. Stirring was started and 2.8 g (0.012 mol) of N-methyl-1-phenyl-2,2'-iminodiethyl chloride was added to the suspension. The reaction mixture was heated to reflux (-80°C) and maintained at this temperature for 6 hours. After six hours, the reaction mixture was cooled and the solvent (1,2-dichloroethane) was removed by dry distillation. A yellowish powder containing 1.8 g of 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine was obtained (80% yield). This powder can be used without further purification to make mirtazapine.

EXAMPLE 2

Preparation of mirtazapine

1.8 g of 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl piperazine was added to a 50 ml three-necked flask equipped with a mechanical stirrer, condenser and thermometer in 5 ml of concentrated sulfuric acid that had previously cooled to 10°C. The resulting solution is stirred at room temperature for 4 hours, then heated for one hour to about 50-60°C. After cooling, the reaction mass is added to 25 g of ice with stirring and neutralized with a concentrated solution of ammonia or sodium hydroxide. The resulting precipitate is separated by filtration. The mother liquor is evaporated to dryness under vacuum. The resulting precipitate and the residue from the mother liquor are each suspended in 20 ml of isopropanol. The combined isopropanol extracts are evaporated to dryness. An oil containing 1.35 g of mirtazapine is obtained (80% yield).

EXAMPLE 3

Preparation of mirtazapine

1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine (1.8 g) was added to 5 ml of concentrated sulfuric acid. The resulting solution is stirred at 35°C for 6 hours. After cooling, the reaction mixture is added to 25 g of ice with stirring and alkalized with concentrated ammonia solution or sodium hydroxide solution to pH = 10. The separated precipitate is extracted into methylene chloride and the extract is evaporated to dryness; 1.6 g of mirtazapine is obtained (95% yield).

EXAMPLE 4

Preparation of 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl piperazine

1-(3-Cyanopyridyl-2)-4-methyl-2-phenyl piperazine (54 g) was dissolved in 340 ml of ethanol and 34 ml of water. Potassium hydroxide beads, 85% (113 g), are added and the reaction mixture is heated in an autoclave to 140°C. The pressure is increased to 3-4 atmospheres and the reaction mixture is maintained under pressure with stirring for 5 hours. After 5 hours, the reaction mixture is cooled, ethanol is removed from the mixture by vacuum distillation, water and toluene are added and the 2 phases are separated. The aqueous solution is neutralized with hydrochloric acid (HCl) to pH = 6.5-7. At pH = 6.5-7, water is evaporated and toluene is added. The inorganic salts are filtered off and the toluene solution is evaporated to dryness to give 52 g of 1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine (yield: 90%).

EXAMPLE 5

Preparation of 1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine

Potassium hydroxide (150 g KOH granules, 85%) and 75 ml water and 6.5 g DMSO were added to 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) and the reaction mixture was heat up to 145-150°C and stir for 8 hours. After 8 hours, the inorganic phase containing water and potassium hydroxide (KOH) is separated and the organic phase, which mainly contains product oil, is cooled. Fresh water and toluene are added and the two phases are separated. The aqueous solution is neutralized with HCl to pH = 6.5-7. At pH = 6.5-7, water is evaporated and toluene is added. The inorganic salts are filtered off and the toluene solution is evaporated to dryness to give 52 g of 1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine (yield: 90%).

EXAMPLE 6

Recrystallization of mirtazapine

Mirtazapine (20 g), obtained as in examples 2 and 3, is suspended in 20 ml of ethanol and heated to reflux. At reflux, 40 ml of water is added dropwise to the solution over one hour, followed by cooling to 10°C. The resulting filter "cake" is washed with a solution of water and ethanol (2:1) and dried at 60°C under vacuum. Crystallized mirtazapine 18 g is obtained in an amount of 90%.

Table 1 shows a summary of additional experiments generally following the procedures described above where Yield% represents the yield of mirtazapine crystals from crude mirtazapine and Purity% represents the percent purity compared to the mirtazapine standard.

Table 1. Purification of crude mirtazapine by recrystallization.

[image] g of mirtazapine crystals 100%/g of raw mirtazapine 100%

Although some of the presently preferred embodiments of this invention have been described herein, it is understood by those skilled in the art that variations and modifications of the described embodiments may be made without departing from the scope and spirit of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the foregoing requirements and the applicable rules of the art.

Claims (28)

1. A method for preparing mirtazapine, characterized in that it contains the steps: (a) reaction of a compound of formula [image] by combining the formula [image] to obtain a compound of the formula [image] (b) adding a ring-closing reagent whose formula is [image] to obtain mirtazapine characterized in that R 1 is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R 2 is amine; and R 3 is selected from the group consisting of chloro, fluoro, bromo and iodo. 2. The method of claim 1, wherein R1 is hydroxymethyl, R2 is -NH2, and R is chloro. 3. The method of claim 1, characterized in that said ring-closing reagent is selected from the group consisting of sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide, Lewis acids, aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride. 4. The method of claim 2, characterized in that the ring-closing reagent is sulfuric acid. 5. The method of claim 1 further comprising a heating step. 6. A method for preparing mirtazapine, characterized by the fact that it contains the steps: (a) reaction of 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2'iminodiethyl chloride to give 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine, and (b) adding a ring-closing reagent to 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to give mirtazapine. 7. The method of claim 6, characterized in that said ring-closing reagent is selected from the group consisting of sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide, Lewis acids, aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride. 8. The method of claim 6 characterized in that the ring-closing reagent is sulfuric acid. 9. The method of claim 6 further comprising a heating step. 10. Process for preparing 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolysis of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine containing reaction step 1 -(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base characterized in that the base is present in a ratio of up to about 12 moles of base per mole of 1-(3-cyanopyridyl-2)-4-methyl- 2-phenyl-piperazine. 11. The method of claim 10 characterized in that the ratio of base to 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to about one mole of 1-(3-cyanopyridyl-2) -4-methyl-2-phenyl-piperazine to about 9 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine. 12. The method of claim 10 characterized in that the base is potassium hydroxide or sodium hydroxide. 13. The method of claim 12 characterized in that the mixture of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 130°C. 14. The method of claim 13 characterized in that the mixture is heated from about 130°C to about 150°C. 15. The method of claim 12 characterized in that the hydrolysis is carried out in water and an aprotic polar solvent. 16. The method of claim 12 characterized in that the hydrolysis is performed in a mixture of water and a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide. 17. The method of claim 12 characterized in that the hydrolysis is performed under a pressure of about 3 to about 4 atmospheres. 18. The method of claim 12 characterized in that the hydrolysis is carried out under almost clean conditions. 19. A process for recrystallization of mirtazapine from crude mirtazapine characterized by comprising the steps: (a) heating a mixture of crude mirtazapine and solvent; (b) cooling the mixture so that the purified mirtazapine precipitates; and (c) isolation of recrystallized mirtazapine. 20. The method of claim 19 characterized in that the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone and their mixtures. 21. The method of claim 20, characterized in that it comprises the step of adding water to the mixture of mirtazapine and solvent to facilitate the precipitation of mirtazapine. 22. The method of claim 19 characterized in that the solvent is selected from the group consisting of toluene, hexane, and methylene chloride, and their mixtures. 23. The method of claim 20 characterized in that the solvent is ethanol. 24. The method of claim 19 characterized in that the recrystallized mirtazapine is supplied from water. 25. The product characterized by the fact that the process from claim 24. 26. Mirtazapine characterized by the fact that it is prepared in accordance with the process of claim 1. 27. Pharmaceutical preparation characterized in that it contains a therapeutically effective amount of mirtazapine from claim 26, and a pharmaceutically acceptable carrier. 28. A method of treating depression, characterized in that the pharmaceutical preparation from claim 27 is applied to people who need such treatment.