CZ20013658A3 - Synthesis and crystallization of compounds containing piperazine ring - Google Patents

Abstract

The present invention is directed to methods for the preparation of piperazine ring-containing compounds, particularly mirtazapine. According to the present invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base where the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridly-2)-4-methyl-2-phenyl-piperazine may be made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at least about 130 DEG C. The method of the present invention also includes reacting 2-amino-3-hydroxymethyl pyridine 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 the 1-(3-hydroxymethylpyridyl-2)-phenyl-4-methylpiperazine to form mirtazapine. The present invention also relates to new processes for recrystallization of mirtazapine form crude mirtazapine.

Description

Technical field

The invention relates to synthetic organic chemistry, in particular to the synthesis of piperazine ring containing compounds, for example mirtazapine, and the crystallization of mirtazapine from various solvents and solvent systems.

BACKGROUND OF THE INVENTION

Mirtazapine, ie 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] [2] benzazepine, having the formula I

CH ₃ has been approved by the US Food and Drug Administraton under the trademark Remeron for the treatment of depression. Mirtazapine has a tetracyclic chemical structure that is not related to other classes of antidepressants, such as selective reuptake serotonin inhibitors, tricycles or monoamine oxidase inhibitors. Mirtazapine belongs to the compounds of the piperazinoazepine group.

Mirtazapine can be prepared by the methods described in US Patent 4,062,848. Using the method described in U.S. Pat. No. 4,062,848, a three-step process is performed in which the process is as described in U.S. Pat

The starting material uses a 2,3-substituted pyridine derivative to prepare the 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine intermediate mirtazapine. Thus, as shown in Reaction Scheme 1, when 2-amino-3-cyanopyridine is used as the starting material, four synthetic steps are required to obtain mirtazapine in the process of U.S. Patent 4,062,848. Thus, it is desirable to develop a process for producing mirtazapine that requires fewer steps and hence less reagent, solvent and time.

Reaction Scheme 1

/ h ₃ c ch ₂ -ch ₂

Step 2

KOH

EtOH

1- (3-cyanomethylpyridyl-2 ', 4'-methyl-2-phenylpiperazine)

2-Aithiino-3-cyanopyridine

N-methyl-1-phenyl-2,2' -iminodiethyl chloride

1- (3-Carboxymethyl-pyridyl-2) -4-methyl-2-phenyl-piperazine

1- (3-Hydroxymethylpyridyl-2)

-4-methyl-2-phenylpiperazine mirtazapine

01-3188-01-Ce

In the process of U.S. Pat. No. 4,062,848, the 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine intermediate mirtazapine is prepared by hydrolyzing 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile under highly basic conditions. 25 moles of potassium hydroxide per mol of nitrile at high temperature and long reaction time (24 hours). These demanding reaction conditions require a great deal of effort to purify the resulting product and, in addition, pollute the environment with waste resulting from the neutralization and use of large volumes of concentrated alkaline solutions. Highly basic conditions and long reaction times make the process of US Patent 4,062,848 expensive, with a major disadvantage being especially the long reaction time.

According to the process described in U.S. Patent 4,062,848, crude mirtazapine is recrystallized only from ether and petroleum ether 40-60. Handling of both solvents, i. ether and petroleum ether 40-60 is very difficult in industrial production.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of mirtazapine which comprises reacting a compound of formula (I) with a compound of formula (r):

H ₃ C ·

01-3188-01-Ce to form a compound of formula

and adding a ring-closing agent to the obtained compound to form mirtazapine, wherein R ¹ is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R ² is an amine; and R ³ is selected from the group consisting of chlorine, fluorine, bromine and iodine.

In a preferred embodiment of the process for preparing mirtazapine, 2-amino-3-hydroxymethylpyridine is reacted with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to give 1- (3-hydroxymethylpyridyl-2) -4-methyl-2- phenylpiperazine to which sulfuric acid is added to form mirtazapine.

It has now been found that the 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine intermediate mirtazapine can be prepared by hydrolyzing 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile using the new, more favorable reaction conditions. The novel reaction conditions of the invention include a low molar ratio of potassium hydroxide to potassium. nitrile and shorter reaction times.

The invention further relates to an improved process for the preparation of 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine by hydrolysis of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine, which comprises

01-3188-01-Ce reacting 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine with a base wherein the base is present in a ratio of up to about 12 moles of base to 1 mole of 1- (3-cyanopyridyl) -2) -4-methyl-2-phenylpiperazine.

In a preferred embodiment of the invention, the ratio of base to 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine ranges from about 12 moles of base to 1 mol of 1- (3-cyanopyridyl-2) -4-methyl-2. -phenylpiperazine to about 9 moles of base to 1 mol of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine.

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

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

In another embodiment of the invention, the hydrolysis of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine 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 invention also relates to an improved process for producing mirtazapine from crude mirtazapine, comprising (a) heating a mixture of crude mirtazapine and a solvent and (b) isolating mirtazapine.

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

In another embodiment of the invention, preferred solvents are methanol, ethanol, isopropanol, acetone, toluene and hexane, as well as mixtures thereof.

01-3188-01-Ce

In another embodiment of the invention, the solvents are toluene, hexane and methylene chloride.

advantageous

The invention relates to a novel process for the preparation of piperazine ring containing compounds such as mirtazapine, the process of the invention being outlined in Reaction Scheme 2. The advantage of the process of the invention over the prior art is, inter alia, higher yield, less steps compared to alternative methods and reduced raw material costs.

Reaction Scheme 2

mirtazapine

More particularly, the invention relates to a process for the preparation of mirtazapine from compounds of formulas II, III and IV. In Reaction Scheme 2, which suggests the process of the invention, the substituents of formula II have the following meanings: R ¹ denotes hydroxymethyl, chloromethyl, bromomethyl or iodomethyl and R ² denotes

01-3188-01-Ce amine, preferably an amine group. The compound of formula II is reacted with a compound of formula III wherein R ³ is chlorine, fluorine, bromine or iodine to form a compound of formula IV wherein R ^{1 is} as defined above.

In carrying out the process of the invention, the compound of formula II is dissolved in a solvent such as methylene chloride. A compound of formula III is added to a mixture of a compound of formula II and a solvent and the resulting mixture is heated. Preferably, the reaction mixture is heated to the reflux temperature of the solvent. The mixture is heated to form a compound of formula IV. Mirtazapine is then obtained by ring closure of a compound of formula IV. The ring closure of the compound of formula IV can be carried out using a ring closure agent. Suitable ring-closing agents are dehydrating or dehydrohalogenating agents. Dehydrating or dehydrohabogenating agents 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), phosphorous oxychloride, phosphorous trioxide, phosphorous pentoxide and Lewis acids such as aluminum chloride, ferric chloride, zinc chloride, tin tetrachloride, titanium tetrachloride, boron trifluoride, antimony chloride, and zirconium chloride.

Particularly preferred dehydrating agents are sulfuric acid and phosphorus derivatives such as PPA, and phosphorus oxychloride. Concentrated sulfuric acid appears to be most preferred. A particularly preferred dehydrohalogenating agent is aluminum chloride.

01-3188-01-Ce

In a preferred embodiment of the process according to the invention, the compounds of the formulas II, III and IV are compounds of the formulas II ', III' and III ', respectively. IV ', which are shown in Reaction Scheme III below. In one embodiment of the invention, 2-amino-3-hydroxymethylpyridine is reacted with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to give 1- (3-hydroxymethylpyridyl-2) -4-methyl-2- phenylpiperazine. In carrying out the process of the invention, 2-amino-3-hydroxymethylpyridine (II ') is added to the solvent. Suitable solvents include 1,2-dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and dimethylsulfoxide. To the obtained solvent mixture was added N-methyl-1-phenyl-2,2'-imidodiethyl chloride (III ') and the resulting mixture was warmed. The reaction mixture is preferably heated to the reflux temperature of the solvent. The mixture is heated until 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine is formed and the reaction is complete. A suitable reaction time is about 6 to 24 hours. 1- (3-Hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine is then converted to the ring closure ring.

phosphorous. In particular, sulfuric acid and

Ring closure of 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine is carried out under strongly dehydrating (R1 ⁼ OH) conditions, preferably at elevated temperature. Suitable dehydrating agents include acids such as sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus pentoxide, and oxide. Most preferred is concentrated sulfuric acid.

01-3188-01-Ce

Reaction Scheme 3

'II' '

2-Amino-3-hydroxymethylpyridine III '

N-methyl-1-phenyl-2,2 ' -iminodiethyl chloride

mirtazapine

IV '

1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine

The invention also provides novel processes for preparing the 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine intermediate mirtazapine from 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile, wherein the nitrile ( i) hydrolyzed with a base using a new low molar ratio of base to 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile; and (ii) hydrolyzed with short reaction times.

In carrying out improved methods for preparing the 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine intermediate mirtazapine, 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile is dissolved in a mixture of water and an organic solvent . Preferred organic solvents include polar aprotic solvents and alcohols. Preferred aprotic organic solvents are, for example, dimethylformamide, dimethylacetamide and dimethylsulfoxide. Preferred alcohols are methanol, ethanol, propanol, isopropanol, butanol and the like. To the reaction mixture. an appropriate amount of a base such as potassium hydroxide or sodium hydroxide is added. Advantageous

The amount of base, such as potassium hydroxide or sodium hydroxide, is up to about 12 moles of base per mole of nitrile (e.g., 12: 1 KOH to nitrile). The amount of the base such as potassium hydroxide is preferably from about 9 moles of potassium hydroxide per mole of nitrile (9: 1 KOH to nitrile) to about 12 moles of potassium hydroxide per mole of nitrile (12: 1 KOH to nitrile).

In carrying out the process of the invention, the mixture of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile, solvent and base is heated to at least about 130 ° C. Preferred reaction temperatures are about 130 ° C to 150 ° C. In one embodiment of the invention, the reaction can be carried out at elevated pressure to facilitate high temperatures. A preferred pressure is about at least 0.3 MPa. A preferred pressure is about 0.3 MPa to 0.4 MPa. Heat the reaction mixture until the reaction is complete. The completion of the reaction can be monitored by HPLC. The time required to complete the hydrolysis of the nitrile will vary depending on the reaction temperature used. Higher reaction temperatures generally require shorter reaction times, while lower reaction temperatures generally require longer reaction times. Although the reaction time is not particularly limited in the process of the invention, approximately two to eight hours reaction times are preferred. After completion of the reaction, the pH of the reaction mixture is lowered, preferably to about 6 to 7. Preferably, the pH is lowered by the addition of hydrochloric acid. The mirtazapine 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine intermediate was isolated by subsequent rinsing and filtration of the reaction mixture.

In another embodiment of the invention, the reaction mixture of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine and potassium hydroxide nitrile is heated using a minimum amount of water, for example about 0.25 ml to 1 ml water per g KOH, a

01-3188-01-Ce of a small amount of aprotic solvent, such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, added in an amount of about 0.1 g to 0.5 g aprotic solvent per g nitrile, in an almost concentrated state atmospheric pressure. The mirtazapine 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine intermediate was isolated by subsequent rinsing and filtration of the reaction mixture.

The novel methods of producing 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine intermediate mirtazapine from 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine nitrile significantly reduce the amount of potassium hydroxide used from 25 moles. potassium hydroxide per mole of nitrile (U.S. Patent 4,062,848) to about 12 moles or less of potassium hydroxide per mole of nitrile. Reducing the amount of base required greatly simplifies the processing of the reaction mixture and minimizes environmental pollution problems.

The invention also provides novel methods for producing pure mitrazapine by purification of crude mirtazapine by recrystallization. After ring closure of 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine, the crude mirtazapine obtained is purified by recrystallization.

It has been found that conventional solvents such as toluene or methylene chloride and solvent systems such as an alcohol / water mixture can be used to recrystallize the crude mirtazapine. According to the invention, the crude mirtazapine is suspended in a suitable solvent. Preferred solvents include methanol, ethanol, isopropanol and acetone as well as mixtures thereof or mixtures of one or more of these solvents with water. Other preferred solvents also include toluene, hexane and methylene chloride. Solvent mixtures of water and ethanol are preferred. Particularly preferred are solvent mixtures,

Wherein the ethanol to water ratio ranges from about 1: 1 to 1: 4.

In carrying out the process of the invention, the suspension of crude mirtazapine and solvent is heated to a suitable temperature. Suitable temperatures include, for example, the reflux temperature of the solvent system used in a particular embodiment of the invention. In an embodiment of the invention where toluene is used as the solvent, a suitable temperature is, for example, about 110 ° C. Purified mirtazapine precipitates upon cooling the reaction mixture. Filtration and drying of the resulting precipitate yields purified recrystallized mirtazapine.

In another exemplary embodiment, the crude mirtazapine is suspended in a solvent such as ethanol and the mixture is heated to reflux temperature. Water is then added dropwise and the solution is cooled to facilitate the precipitation of mirtazapine. The precipitate obtained is purified by filtration, rinsing and drying to give purified mirtazapine. Recrystallized mirtazapine may be an aqueous adduct and may thus contain up to 3 wt. water.

Solvents and solvent systems that can be used in the processes of. of the invention are suitable for industrial scale reactions and are more suitable for these industrial reactions than ether or petroleum ether 40-60. Moreover, the crystallization yield is greatly increased by the use of the solvent system according to the invention.

Mirtazapine and mirtazapine intermediates, i.e. 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine and 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine, contain an asymmetric carbon atom, so Separate optical isomers may also be prepared in racemic mixtures. Thus, methods are within the scope of the invention

01-3188-01-Ce comprising these optical isomers as well as methods involving racemic mixtures.

According to the invention, pharmaceutical compositions of mirtazapine can be prepared which are particularly suitable for the treatment of depression. These compositions comprise a therapeutically effective amount of mirtazapine with pharmaceutically acceptable carriers and / or excipients known to those skilled in the art.

The following examples are illustrative only, and are not intended to limit the scope of the invention as set forth in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine

1 g (0.008 mol) of 2-amino-3-hydroxymethylpyridine and 20 ml of 1,2-dichloroethane were introduced into a 50 ml three-necked flask equipped with a mechanical stirrer, condenser and thermometer. 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 temperature (about 80 ° C) and held at this temperature for 6 h.

After six hours, the reaction mixture was cooled and the solvent (1,2-dichloroethane) was removed by dry distillation. A yellowish powder was obtained which contained 1.8 g of 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine (80% yield). This powder can be used without further purification to prepare mirtazapine.

01-3188-01-Ce

Example 2

Preparation of mirtazapine

To a 50 ml three-necked flask equipped with a mechanical stirrer, condenser and thermometer containing approximately 5 ml of concentrated sulfuric acid pre-cooled to 10 ° C was added 1.8 g of 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine . The resulting solution was stirred for 4 h at room temperature, then warmed to about 50 ° C to 60 ° C and held at that temperature for 1 h. After cooling, the reaction mixture was added to 25 g of ice with stirring and neutralized with concentrated ammonia solution or sodium hydroxide. The resulting precipitate was isolated by filtration. The mother liquor was evaporated to dryness under vacuum. The resulting precipitate and the residue from the mother liquor were suspended (each) in approximately 20 mL of isopropanol. The combined isopropanol extracts were evaporated to dryness. An oil was obtained which contained 1.35 g of mirtazapine (80% yield).

Example 3

Preparation of mirtazapine

1- (3-Hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine (1.8 g) was added to approximately 5 mL of concentrated sulfuric acid. The resulting solution was stirred at 35 ° C for 6 h. After cooling, the reaction mixture was added to 25 g of ice with stirring and basified with concentrated ammonia solution or sodium hydroxide solution to pH 10. The isolated precipitate was extracted in methylene chloride and the extract was evaporated to dryness. 1.6 g of mirtazapine were obtained (95% yield).

01-3188-01-Ce

Example 4

Preparation of 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine

1- (3-Cyanopyridyl-2) -4-methyl-2-phenylpiperazine (54 g) was dissolved in 340 ml of ethanol and 34 ml of water. To the reaction mixture was added 85% potassium hydroxide (113 g) as a flake, and the reaction mixture was heated to 140 ° C in an autoclave. The pressure in the autoclave was increased to 0.3 MPa to 0.4 MPa and the reaction mixture was stirred at this pressure for 5 hours. After this time, the reaction mixture was cooled, ethanol was removed by vacuum distillation, fresh water and toluene were added, and the two phases formed were separated. The aqueous solution was neutralized by addition of hydrochloric acid to a pH of 6.5 to 7. At pH 6.5 to 7, the water was evaporated and toluene was added. The inorganic salts were filtered off and the toluene solution gave after evaporation to dryness 52 g of 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine (90% yield).

Example 5

Preparation of 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine

To 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine (54 g) was added potassium hydroxide (150 g KOH flakes, 85%) 75 mL water and 6.5 g DMSO and the reaction mixture was warmed to 145 ° C to 150 ° C and stirred at this temperature for 8 hours. After eight hours, the inorganic phase containing water and potassium hydroxide was separated and the organic phase containing mainly the product as an oil was cooled. Fresh water and toluene were added and the resulting two phases were separated. The aqueous solution was neutralized by addition of hydrochloric acid to a pH of 6.5 to 7. At pH 6.5 to 7, the water was evaporated and toluene was added. The inorganic salts were filtered off

01-3188-01-Ce _: N, and the toluene solution gave after drying to dryness 52 g of 1- (3-carboxypyridyl-2) -4-methyl-2-phenylpiperazine (90% yield).

Example 6

Recrystallization of mirtazapine

Mirtazapin. (20 g) obtained in Examples 2 and 3 was suspended in 20 ml of ethanol and heated to reflux temperature. At reflux temperature, 40 ml of water was added dropwise to the solution over one hour, after which the solution was cooled to 10 ° C. The resulting filter cake was rinsed with a 2: 1 solution of water and ethanol and dried at 60 ° C under vacuum. 18 g of recrystallized mirtazapine were obtained in 90% yield.

Table 1 summarizes further experiments generally carried out as described above, wherein "% yield" refers to the percentage yield of mirtazapine crystals obtained from crude mirtazapine.

01-3188-01-What?

ί.

7 J _; ,

Table 1 Purification of crude mirtazapine by recrystallization Solvent system Solvent ratio ml: ml / g Conditions Yield ¹ Hexane 10 reflux 55 Toluene 3 reflux 32 Toluene 2 reflux 53 Acetone / water 6:25 Deň: 22 ° C 65 Ethanol / water 7:10 reflux 67 Methanol / water 2.25: 1.5 reflux 67 Ethanol / water 1.5: 2 reflux 72 Isopropyl / water 1.65: 2 reflux 60 Acetone / water 3 - 2 reflux 53 Ethanol / water 1: 1.3 reflux 70 Ethanol / water 1.3: 1.75 reflux 90, 3 Ethanol / water 1: 4 reflux 100 ALIGN! Ethanol / water 1.1: 1.2 reflux 87.8 Ethanol / water 0.8: 0.9 reflux 90 Ethanol / water 0.8: 1 reflux 57 Ethanol / water 0.6: 0.7 reflux 89, 1 Ethanol / water 0.35: 0.7 reflux 91, 5 Ethanol / water 0.6: 0.69 reflux 87 Ethanol / water 2: 2.8 reflux 95, 6

ί g mirtazapine crystals 100% / g crude mirtazapine 100%

01-3188-01-Ce

Claims (26)

PATENT CLAIMS 1. í m, (a) A method for preparing mirtazapine comprising: reacting a compound of formula with a compound of formula to form a compound of formula a (b) adding a ring-closing agent to the obtained compound to form mirtazapine, wherein R ¹ is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R ² 01-3188-01-Ce means chlorine, amine; fluorine and R ³ is selected from bromine and iodine. from the set consisting of from the atom 2. Way according to claim 1, marked by that R ¹ is a hydroxymethyl group, R ² means amino and R ³ represents chlorine. 3. Way according to claim 1, marked by the agent closing circle select from the group consisting of sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorous oxychloride, phosphorus pentoxide, phosphorous pentoxide, Lewis acids, aluminum chloride, ferric chloride, zinc chloride, tin tetrachloride, titanium tetrachloride, boron trifluoride, antimony chloride and zirconium chloride. 4. The process of claim 2 wherein the ring-closure agent is sulfuric acid. 5. The method of claim 1, further comprising heating. 6. A process for the preparation of mirtazapine comprising: (a) reacting 2-amino-3-hydroxymethylpyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 01-3188-01-Ce 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine; and (b) adding a ring closure agent to 1- (3-hydroxymethylpyridyl-2) -4-methyl-2-phenylpiperazine to form mirtazapine. 7. The method of claim 6, wherein the ring-closing agent is selected from the group consisting of sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus oxychloride, phosphorus pentoxide, phosphorus pentoxide, Lewis. acids, aluminum chloride, ferric chloride, zinc chloride, tin tetrachloride, titanium tetrachloride, boron trifluoride, antimony tetrachloride and zirconium chloride. 8. The method of claim 6, wherein the ring-closing agent is sulfuric acid. The method of claim 6, further comprising heating. A process for the production of 1- (3-carboxypyridyl-2) -4-methyl-2-hydrolysis by 1- (3-cyanopyridyl-2) -4-methyl-2, characterized in that it comprises 1- (3-cyanopyridyl-2) -phenylpiperazine. 4-methyl-2-phenylpiperazine is reacted with a base wherein the base is present in a ratio of up to 12 moles of base per mole of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine. 01-3188-01-Ce 11. The process of claim 10 wherein the ratio of base to 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine ranges from about 12 moles of base to about 1 moles of 1- (3-cyanopyridyl-). 2) -4-methyl-2-phenylpiperazine to about 9 moles of base to about 1 mol of 1- (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine. 12. The process of claim 10 wherein the base is potassium hydroxide or sodium hydroxide. The method of claim 12, wherein the mixture of 1-, (3-cyanopyridyl-2) -4-methyl-2-phenylpiperazine and base is heated to a temperature of at least 130 ° C. The method of claim 13, wherein the mixture is heated to a temperature of about 130 ° C to 150 ° C. Process according to claim 12, characterized in that the hydrolysis is carried out in water and an aprotic solvent. by the polar 16. The process of claim 12 wherein the hydrolysis 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. 01-3188-01-Ce The process according to claim 12, wherein the hydrolysis is carried out at 0.4 MPa. characterized in that the pressure is about 0.3 MPa to 100 bar Process according to claim 12, characterized in that the hydrolysis is carried out under substantially anhydrous conditions. 19. A process for recrystallizing mirtazapine from crude mirtazapine comprising: (a) heating the mixture of crude mirtazapine and solvent; (b) cooling the mixture to precipitate purified mirtazapine; and (c) recovering the recrystallized mirtazapine. 20. The process of claim 19 wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, and mixtures thereof. 21. The method of claim 20, further comprising adding water to the mixture of mirtazapine and a solvent to facilitate the precipitation of mirtazapine. 22. The process of claim 19 wherein the solvent is selected from the group consisting of toluene, hexane, and methylene chloride, as well as mixtures thereof. 01-3188-01-Ce ²³ She / · '//': 23. The process of claim 20 wherein the solvent is ethanol. 24. The method of claim 19 wherein the recrystallized mirtazapine is a mirtazapine water adduct. The product of claim 24. Mirtazapine prepared by the method of claim 1. 27. A pharmaceutical composition comprising a therapeutically effective amount of mirtazapine according to claim 26 and a pharmaceutically acceptable carrier. 28. A method of treating depression comprising administering the pharmaceutical composition of claim 27 to a human subject in need thereof.