AU2005201117A1 - Novel synthesis and crystallization of piperazine ring-containing compounds - Google Patents

Description

S&FRef: 573449D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Teva Pharmaceutical Industries Ltd., of 5 Basel Street P.O. Box 3190, 49131, Petah Tiqva, Israel Anita Liberman Claude Singer Nina Finkelstein Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Novel synthesis and crystallization of piperazine ringcontaining compounds The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c NOVEL SYNTHESIS AND CRYSTALLIZATION OF PIPERAZINE RING-CONTAINING COMPOUNDS FIELD OF THE INVENTION The present invention relates to synthetic organic chemistry, particularly, to synthesis of piperazine ring-containing compounds, such as mirtazapine, and to the S crystallization of mirtazapine from different solvents and solvent systems.

BACKGROUND OF THE INVENTION Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,l-a]pyrido[2,3-c][2] benzazepine, having the formula I:

'N

N

CH

3

I

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

Mirtazapine may be made by methods described in U.S. Patent No. 4,062,848.

By a process of U.S. Patent No. 4,062,848 ("the '848 patent"), the mirtazapine intermediate 1-(3-hydroxymethylpyridyl-2-4-methyl-2-phenyl-piperazine is made by a three step process starting with a 2,3-substituted pyridine derivative. Therefore, as shown in Scheme 1, when starting with 2-amino-3-cyano-pyridine, the process of the '848 patent requires four synthetic steps to make mirtazapine. It is desirable to have a process for making mirtazapine that requires fewer steps, and therefore requires less reagent, solvent and time.

Scheme 1

N

N NH 2 Step 1 Step 2

KOH_

EtOH 2-amino- 3-cyano-pyridine

COOH

N

N

N

OH

3 1 -carboxymethylpyr 4-methyl-2-pheriyl-pipe N-methyl-i -phenyl- 2,2'-iminodiethyl chloride 4-mel SStep 3 ,HOH- Step LiAIH 4 N H 2

SO

N

N

N

CH3 idyl-2)- I -(3-hydroxymethylpyridyl-2)- ~razine 4-methyl-2-phenyl-piperazine

OH

3 -yanomethylpyridyl-2)thyl-2-phenyi-piperazine 4 4

N;N

N

OH

3 Mirtazapine t By the process of U.S. Patent No. 4,062,848 ("the 848 patent"), the

O

0mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by the hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine under highly Sbasic conditions of 25 moles of potassium hydroxide (KOH) per mole of nitrile, at high it 5 temperature and for long reaction times of 24 hours. These harsh reaction conditions necessitate a great effort in purifying the resulting product as well as creating environmental waste disposal issues associated with neutralizing and disposing of large volumes of concentrated basic solutions. The highly basic conditions and long reaction times make the Sprocedure of the '848 patent very costly, especially in terms of reactor time.

D According to the methods of U.S. Patent No. 4,062,848, crude mirtazapine is C recrystallized only in ether and petrol ether 40-60. The solvents ether and petrol ether 40-60 are both very difficult to handle in large scale production.

SUMMARY OF THE INVENTION The present invention is directed to a method for the preparation of

R

1 mirtazapine, comprising the steps of: reacting a compound of the formula N R2

CH

2 I

R

3 with a compound of the formula H 3 C to form a compound of the formula

\R

1 n N

N

N

CH

3 and

N)

adding a ring closing reagent to the compound of the formula CH 3 to form mirtazapine, wherein 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.

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

Further, it has now been discovered that the mirtazapine intermediate 1-(3carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolysis of the nitrile 1- 3 -cyanopyridyl-2)-4-methyl-2-phenyl-piperazine using new more favorable reaction conditions. The new reaction conditions of the present invention include a low mole to mole ratio of potassium hydroxide to nitrile and shorter reaction times.

The present invention relates to a improved process for making 1-(3carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing 1-(3-cyanopyridyl-2)-4methyl-2-phenyl-piperazine comprising the step of reacting 1-(3-cyanopyridyl-2)-4-methyl-2phenyl-piperazine with a base wherein 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.

In a preferred embodiment of the present invention, the ratio of the 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.

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

tl In another embodiment of the present invention, the mixture of the 1-(3-

O

Scyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 1300 C.

In another embodiment of the present invention, the hydrolysis of 1-(3cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in a mixture water and a solvent t l 5 selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.

The present invention also relates to improved processes for making Smirtazapine from crude mirtazapine comprising the steps of heating a mixture of crude CI mirtazapine and solvent; and isolating mirtazapine.

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

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

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

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for preparing piperazine ringcontaining compounds, such as mirtazapine, as described in Scheme 2 below. The process of the present invention is advantageous over prior art processes due to, inter alia, the higher yield, smaller number of steps in relation to the alternative methods, and minimized raw material costs.

Scheme 2 R' R' R NN R -N

N

N R 2 C H2 R3 H3C

N

CH

3

CH

3 I In IV I Mirtazapine More particularly, the present invention relates to the process of making mirtazapine from compounds of the formulae II, III and IV. In the process of the present invention the compound of formula II in Scheme 2 above, wherein R' denotes hydroxymethyl, chloromethyl, bromomethyl or iodomethyl, and R 2 denotes amine, preferably

-NH

2 is reacted with the compound of formula III in Scheme 2 above, wherein R 3 denotes chloro, fluoro, bromo or iodo, to form the compound of formula IV wherein R 1 is defined as 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 is added to 0 the solvent mixture and the resulting mixture is heated. Preferably the reaction mixture is S heated to the reflux temperature of the solvent. The mixture is heated to form the compound of formula IV. Mirtazapine is then prepared by ring closure of the compound of formula IV.

Ring closure of the compound of formula IV may be performed using a ring-closing reagent.

Suitable ring closing reagents are dehydrating or dehydrohalogenating agents. Dehydrating or dehydrohalogenating agents that may 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, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.

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

In a preferred embodiment of the present invention the compounds of the formulae II, III and IV are compounds of the formulae II', III' and IV' respectively as shown in Scheme 3 below. In an embodiment of the present invention, 2-amino-3-hydroxymethyl pyridine is reacted with N-methyl-l-phenyl-2,2'-iminodiethyl chloride to form 1-(3hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine. In the present invention, 2-amino- 3-hydroxymethyl pyridine is added to a solvent. Suitable solvents include 1,2dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and dimethylsulfoxide. N-Methyl-l-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-(3hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is formed and the reaction is complete. A suitable time is about six to about 24 hours. The 1-(3-hydroxymethylpyridyl-2)- 4-methyl-2-phenyl-piperazine is then converted to mirtazapine by ring closure.

The ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenylpiperazine is performed under strongly dehydrating OH) conditions, 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 agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred.

Scheme 3

CH

2 0 H r-r S CHOH CI CH

CH

2 N NH 2

CI

H 3 C CH

H

.3

CH

II III' IV' I 2-amino- N-methyl- -phenyl- 1-(3-hydroxymethylpyridyl-2)- Mirtazapine 3-hydroxymethyl 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine pyridine The present invention also provides new processes for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrile 1-(3cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrile is hydrolyzed by base using a new low mole to mole ratio of base to the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2phenyl-piperazine and (ii) hydrolyzed using short reaction times.

Where the present invention provides improved methods for makinig the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine, the nitrile 1- (3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is dissolved in a mixture of water and organic solvent. Preferred organic solvents include polar aprotic solvents and alcohols. Polar aprotic organic solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide 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 (for example 12:1 KOH:nitrile) is preferred. Amounts of base, such as potassium hydroxide, in the ratio of about 9 moles of potassium hydroxide per one mole of nitrile (9:1 KOH:nitrile), to about 12 moles of potassium hydroxide per mole of nitrile (12:1 KOH:nitrile) are preferred.

In the present invention, the mixture of the nitrile 1-(3-cyanopyridyl-2)-4methyl-2-phenyl-piperazine, solvent and base is heated to at least about 130 0 C. Reaction temperatures of about 130 0 C to about 1500 are preferred. In an embodiment of the present invention, the reaction may be conducted under pressure to facilitate the attainment of high temperatures. A pressure of at least about 3 atmospheres is preferred. Pressures of at least about 3 atmospheres to about 4 atmospheres are more preferred. The reaction mixture is heated until the reaction is complete. The completion of the reaction may be monitored by HPLC. The amount of time needed for the completion of the hydrolysis of the nitrile varies with the temperature of the reaction. Higher reaction temperatures generally require shorter reaction times, while lower reaction temperatures generally requires longer reaction times.

SWhile not limiting the reaction time of the present invention, preferred reaction times of the present invention may be from about 2 hours to about 8 hours. 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-(3cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and filtration of the reaction mixture.

In an additional embodiment of the present invention, the reaction mixture of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, and potassium hydroxide, is heated while using a minimum amount of water, such as about 0.25-1 mL of water per gram of KOH, and small amounts of an aprotic solvent such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, such as about 0.1 to 0.5 grams of aprotic solvent per gram of nitrile, under very concentrated conditions or almost neat conditions at atmospheric pressure. The mirtazapine intermediate, -(3-cyanopyridyl-2)-4-methyl-2phenyl-piperazine is isolated following washing and filtration of the reaction mixture.

The new processes of the present invention for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrile 1-(3cyanopyridyl-2)-4-methyl-2-phenyl-piperazine significantly reduce the quantity of potassium hydroxide used, from 25 moles of potassium hydroxide per mole of the nitrile as in the '848 patent, to about 12 moles or less of potassium hydroxide to one mole of the nitrile. The reduction in the amount of base needed considerably simplifies the work-up of the reaction and minimizes environmental problems.

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

It has been discovered 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. According to 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 those solvents with water. Additional preferred solvents also include toluene, hexane, and methylene chloride. Solvent mixtures of water and ethanol are more preferred. Solvent mixtures of ratios of about 1:1 to about 1:4 ethanol:water are preferred.

In the present 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 being used in any particular embodiment of the present invention. For example, in an embodiment of the present invention where toluene is the solvent, a temperature of about 110°C is suitable. Purified mirtazapine precipitates upon cooling of the reaction mixture. Filtration and drying of the resulting precipitate yields 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 precipitation of mirtazapine. The precipitate is purified by filtration, washing and drying to yield purified mirtazapine. The crystallized mirtazapine may be a water adduct thereby containing up to 3 water by weight w/w).

The solvents and solvent systems of the present invention are suitable for large scale reactions, and are more suitable for large scale reactions than ether or petrol ether 40-60.

Additionally, the crystallization yield can be substantially improved when using the solvent system of the present invention.

Mirtazapine and mirtazapine intermediates, 1-(3-cyanopyridyl-2)-4-methyl-2phenyl-piperazine and 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine each contain an asymmetric carbon atom, as a result of which separate optical isomers may be prepared in addition to a racemic mixtures. Processes of the present invention include these optical D isomers just as the racemic mixtures are included in the invention.

."A

;_In accordance with the present invention, mirtazapine produced by the process of the present invention may be prepared as pharmaceutical compositions that are particularly S useful for the treatment of depression. Such compositions comprise a therapeutically effective amount of mirtazapine with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.

D

EXAMPLES

SThe following examples are given for the purpose of illustrating the present D invention and shall not be construed as being limitations on the scope or spirit of the invention.

EXAMPLE 1 Preparation of 1-(3-Hydroxymethylpyridyl-2)-4-Methyl-2-Phenyl-Piperazine In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer 1 g (0.008 mole) of 2-amino-3-hydroxymethyl pyridine and 20 mL of 1,2dichloroethane were charged. The mixing is started and to the suspension 2.8 g (0.012 mole) of N-methyl-l-phenyl-2,2'-iminodiethyl-chloride are added. The reaction mixture is heated to reflux C) and maintained at this temperature for six hours.

After six hours the reaction mixture is cooled and the solvent (1,2dichloroethane) is removed by dry distillation. A yellowish powder is obtained which contains 1.8 g 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine (yield This powder can be used without additional purification for the preparation of mirtazapine.

EXAMPLE 2 Preparation of Mirtazapine In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer 1.8 g of 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine are added to -5 mL of concentrated sulfuric acid that was previously cooled to 10 0 C. The obtained solution is mixed at room temperature for 4 hours, then heated for one hour to about 500 to 600 C. After cooling, the reaction mass is added to 25 g of ice under mixing and neutralized with a concentrated ammonia solution or sodium hydroxide. The formed precipitate is separated by filtration. The mother liquor is evaporated to dryness under vacuum. Both the formed 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 is obtained which contains 1.35 g ofmirtazapine (yield Example 3 SPreparation of Mirtazapine 1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (1.8 g) is added to -5 mL of concentrated sulfuric acid. The resulting solution is mixed at 350 C for 6 hours.

After cooling, the reaction mixture is added to 25 g of ice under mixing and basified with a 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 (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) is dissolved in 340 mL of ethanol and 34 mL of water. Potassium hydroxide flakes, 85% (113 are added and the reaction mixture is heated in an autoclave to 1400 C. The pressure increases to 3-4 atmospheres and the reaction mixture is maintained under pressure with mixing for 5 hours.

After 5 hours, the reaction mixture is cooled, the ethanol is removed from the mixture by vacuum distillation, fresh water and toluene are added and the 2 phases are separated. The water solution is neutralized with hydrochloric acid (HC1) to pH 6.5-7. At pH 6.5-7 the water is evaporated and toluene is added. The inorganic salts are filtered and the toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl- 2phenyl-piperazine (yield: D Example Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine SPotassium hydroxide (150 g of KOH flakes, 85%) and 75 mL of water and g of DMSO are added to 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) and the reaction mixture is heated to 145-1500 C and mixed for 8 hours. After 8 hours, the inorganic phase containing water and potassium hydroxide (KOH) is separated and the organic phase, containing mainly a product oil, is cooled. Fresh water and toluene are added and the two phases are separated. The aqueous solution is neutralized with HC1 to pH 6.5-7. At pH 6.5-7, the water is evaporated and toluene is added. The inorganic salts are filtered and the S toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl- 2-phenyl-piperazine (yield: Example 6 Recrystallization ofMirtazapine Mirtazapine (20 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 100 C. The resulting filter cake is washed with a solution of water:ethanol and dried at 600 C under a vacuum. Crystallized mirtazapine, 18 g, is obtained in 90% yield.

Table 1 sets forth a summary of additional experiments generally following procedures described above wherein the Yield is the percent yield of mirtazapine crystals from crude mirtazapine and the Purity is the percent purity as compared to a mirtazapine standard.

Table 1. Purification of Crude MirtazaDine by Recrvstallization Solvent system Ratio of solvents Conditions Yield' ml:ml/g hexane 10 reflux toluene 3 reflux 32 toluene 2 reflux 53 acetone/water 6:25 250 C 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 acetone-water 3:2 reflux 53 ethanol/water 1:1.3 reflux ethanol/water 1.3:1.75 reflux 90.3 ethanol/water 1:4 reflux 100 ethanol/water 1.1:1.2 reflux 87.8 ethanol/water 0.8:0.9 reflux 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 Sg mirtazapine crystals 100 mirtazapine crude 100 Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rule of law.

Claims (43)

1. A method for the preparation of mirtazapine, comprising the steps of: R 1 reacting a compound of the formula N R 2 with a compound of I R3 the formula H3 C N s to form a compound of the formula ,and adding a ring closing reagent to the compound of the formula to form mirtazapine wherein 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.

2. The method of claim 1, wherein R' is hydroxymethyl, R 2 is -NH 2 and R 3 is s chloro.

3. The method of claim 1, wherein said a 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, to zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.

4. The method of claim 2, wherein said ring closing reagent is sulfuric acid. The method of claim 1 which further comprises the step of heating.

6. A method for the preparation of mirtazapine, comprising the steps of: 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 a ring closing reagent to the 1-(3-hydroxymethylpyridyl-2)-4- methyl-2-phenyl-piperazine to form mirtazapine.

7. The method of claim 6, wherein said a 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 wherein the ring closing reagent is sulfuric acid.

9. The method of claim 6 further comprising the step of heating.

10. A process for making 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising the step of reacting 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base wherein 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. to 11. The process of claim 10 wherein the ratio of the 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 process of claim 10 wherein the base is potassium hydroxide or sodium hydroxide

13. The process of claim 12 wherein the mixture of the 1-(3-cyanopyridyl-2)-4- methyl-2-phenyl-piperazine and the base is heated to at least about 130 0 C.

14. The process of claim 13 wherein the mixture is heated to about 130 0 C to about 150 0 C.

15. The process of claim 12 wherein the hydrolysis is carried out in water and an aprotic polar solvent.

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, S isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.

17. The process of claim 12 wherein the hydrolysis is carried out at a pressure of about 3 to about 4 atmospheres pressure. 0

18. The process of claim 12 wherein the hydrolysis is carried out at almost neat 0 conditions.

19. A process for recrystallized mirtazapine from crude mirtazapine comprising the steps of: 1 0 heating a mixture of crude mirtazapine and a solvent; cooling the mixture such that purified mirtazapine precipitatis; and isolating the recrystallized mirtazapine. The process of claim 19 wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, and mixtures thereof.

21. The process of claim 20 further comprising the step of adding water to the mixture of mirtazapine and solvent to facilitate precipitation of mirtazapine.

22. The process of claim 19 where in the solvent is selected from the group consisting of toluene, hexane, and methylene chloride, and mixtures thereof.

23. The process of claim 20 wherein the solvent is ethanol.

24. The process of claim 19 wherein the recrystallized mirtazapine is a mirtazapine water adduct. The product of the process of claim 24.

26. Mirtazapine prepared according to the process of claim 1.

27. A pharmaceutical composition comprising a therapeutically effective amount of mirtazapine of claim 26 and a pharmaceutically acceptable carrier.

28. A method for the treatment of depression, comprising the step of administering to a human subject in need of such treatment the pharmaceutical composition of claim 27.

29. A pharmaceutical composition that includes an active ingredient comprising a water adduct of mirtazapine, wherein the pharmaceutical composition is in a solid dosage form. The pharmaceutical composition according to claim 29, wherein the active ingredient comprises a water adduct of mirtazapine containing up to about 3% by weight water.

31. A method of treating depression by administering to a human patient in need of such treatment a pharmaceutical composition according to claim 29 or

32. Use of a water adduct of mirtazapine for the manufacture of a medicament in solid dosage form for treating depression.

33. A crystalline adduct of mirtazapine and water containing up to about 3% by weight water.

34. The adduct of mirtazapine and water according to claim 33 prepared by precipitation from a solvent comprising water and either an alcohol or acetone. The adduct of mirtazapine and water according to claim 34, wherein the solvent comprises water and an alcohol.

36. The adduct of mirtazapine according to claim 35, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropyl alcohol.

37. The adduct of mirtazapine and water according to claim 35, wherein the solvent comprises water and ethanol.

38. The adduct of mirtazapine and water according to claim 37, wherein the solvent is an about 1:1 to about 1:4 ethanol:water mixture.

39. A crystallised adduct of mirtazapine and water prepared by: crystallizing mirtazapine from a solution comprising water; recovering crystallized mirtazapine; and drying the crystallized mirtazapine until the crystallized mirtazapine contains up to about 3 percent water. [R:\LIBH]04914.doc:LG The adduct of mirtazapine and water according to claim 39, wherein the solution also comprises an alcohol.

41. The adduct of mirtazapine and water according to claim 40, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropyl alcohol. s 42. The adduct of mirtazapine and water according to claim 41, wherein the alcohol is ethanol.

43. The adduct of mirtazapine and water according to claim 42, wherein the solution comprises a ratio of ethanol:water ranging from about 1:1 to about 1:4.

44. A process for preparing a mirtazapine water adduct, comprising suspending crude mirtazapine in a solvent to form a mixture; (ii) heating the mixture to reflux to form a solution; (iii) adding water dropwise to the solution to obtain mirtazapine in the form of a mirtazapine water adduct; and (iv) isolating the mirtazapine water adduct.

45. The process according to claim 44, wherein the solvent is an alcohol.

46. The process according to claim 45, wherein the alcohol is methanol, ethanol or isopropanol.

47. The process according to claim 44, wherein the solvent is acetone.

48. A mirtazapine water adduct prepared according to the process of any one of claims 44 to 47.

49. The mirtazapine water adduct of claim 48 containing up to 3% water by weight. A pharmaceutical composition comprising a therapeutically effective amount of the mirtazapine water adduct according to claim 48 or 49, and a pharmaceutically acceptable carrier.

51. A method for treating depression, comprising the step of administering to a human subject in need of such treatment the pharmaceutical composition according to claim

52. Use of the mirtazapine water adduct according to claim 48 or 49 for the manufacture of a medicament for treating depression. Dated 15 March, 2005 Teva Pharmaceutical Industries Ltd. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON (R:\LIBH04914.doc:LUG