FIELD OF THE INVENTION:

The present invention relates to an improved process for preparation of mirtazapine, wherein 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine is subjected to cyclization in the presence of a solvent to get mirtazapine.

BACKGROUND OF THE INVENTION:

Mirtazapine acts as an antagonist at central presynaptic a2-adrenergic autoreceptors and heteroreceptors, thereby possibly resulting in increased central noradrenergic and serotonergic neurotransmission. Mirtazapine is a potent antagonist of serotonin type 2 (5-HT2) and type 3 (5-HT3) receptors, but the drug does not exhibit any significant affinity for serotonin type IA (5-HT1A) or type IB (5-HTIB) receptors. Mirtazapine is a potent antagonist of histamine (H1) receptors, is a moderate antagonist at muscarinic receptors and exhibits moderate peripheral a2-adrenergic blocking activity. Because of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated antidepressant agent.

The present invention relates to 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c][2] benzazepine, also known as mirtazapine (Formula I)

Formula (I)

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 is sold under the trademark REMERON® and is available in two dosage forms: tablets and orally disintegrating tablets. Both dosage forms of REMERON® are indicated for the treatment of major depressive disorder.

Mirtazapine is first disclosed in US 4062848, wherein concentrated sulfuric acid is added to 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II at room temperature. After completion of the reaction, water is added followed by neutralized with aqueous ammonia solution, extracted with chloroform and concentrated.

Mirtazapine is isolated from petroleum ether solvent.
In this process reaction is carried out in neat condition without solvent medium. The reaction mass in this process is not homogeneous and leads to formation of lumps. Thus the process is not suitable for industrial implementation.

WO00/62782 application is disclosed the process of Mirtazapine, wherein 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II is added to concentrated sulfuric acid at room temperature for 4 hours followed by heating to about 50° to 60°C. After completion of the reaction, water is added followed by neutralized with aqueous ammonia solution and extracted with dichloromethane. Mirtazapine is isolated by evaporation of the solvent.

EP 1209159 A2 is disclosed the process of Mirtazapine, wherein 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II is added to the concentrated sulfuric acid in divided portions at 5° to 30°C and that the mixture is stirred at 30° to 40°C for 8 hours. After the completion of the reaction crude mirtazapine is isolated by acid base treatment and finally Mirtazapine is obtained from a mixture of methanol and heptane.

The above two processes are not suitable for industrial implementation in terms of controlling the reaction temperature and impurities. It is important to take into account that the compound of formula II is added as a solid to the sulfuric acid, which is highly exothermic and it leads to number of impurities.

WO2006008302 disclosed the process of mirtazapine, wherein 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II is suspended in water and added to concentrated sulfuric acid. After the completion of the reaction water is added followed by neutralization with aqueous ammonia solution and Mirtazapine is extracted into ethyl acetate. Though this process is suitable for industrial scale up, but it requires more number of purifications to get pure mirtazapine.

According to the prior art processes addition of compound of formula II as a solid to concentrated sulfuric acid is highly exothermic and reaction is not homogeneous as formation of lumps during the addition. Reaction completion time is more as per the prior art processes, which leads to decomposition of the product in sulfuric acid and ultimately end up with lot more impurities with poor yields. Accordingly, there is a need for a process useful to the preparation of mirtazapine in improved yield and purity in an industrial scale.

The present process overcomes the problems associated with the prior art processes. The present invention provides mirtazapine with improved yield and purity, further this process is cost effective, industrially feasible.

SUMMARY OF THE INVENTION:

Main aspect of the present invention is to provide a process for the preparation of mirtazapine comprising the steps of:
a) dissolving 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II in a first organic solvent,
b) adding the solution of step a) into sulfuric acid,
c) diluting the reaction mass with water and separating the aqueous layer,
d) adjusting aqueous layer pH with a base,
e) extracting the product into second organic solvent, and
f) isolating mirtazapine.
The present invention is shown in the below scheme.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for preparing mirtazapine, wherein 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-nnethylpiperazine of formula II is dissolved in organic solvent and slowly added to concentrated sulfuric acid at room temperature. After the completion of the reaction, aqueous layer is separated and adjusted the pH to basic.
Mirtazapine is extracted with another organic solvent, concentrated the solvent and finally pure mirtazapine isolated from isopropyl ether.

One embodiment of the present invention is to provide a process for the preparation of mirtazapine comprising the steps of:

a) dissolving 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II in a first organic solvent,
b) adding the solution of step a) into sulfuric acid,
c) diluting the reaction mass with water and separating the aqueous layer,
d) adjusting aqueous layer pH with a base,
e) extracting the product into second organic solvent, and
f) isolating mirtazapine.

According to the present invention 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II is dissolved in first organic solvent selected from dichloromethane, chloroform, dichlorethane or mixture thereof. This solution is added to concentrated sulfuric acid at ambient temperature and the reaction is maintained for about 2 hours at 25-40°C. After completion of the reaction, aqueous layer is separated adjusted the pH to basic, preferably to 9.5 to 10.5. Mirtazapine is extracted into second organic solvent selected from toluene, dichloromethane, ethyl acetate or ether and evaporated to get residue. Isopropylether is added to the residue and filtered the obtain Mirtazapine.

According to the prior art processes addition of 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II as a solid to concentrated sulfuric acid is highly exothermic and reaction is not homogeneous as lumps are forming during the addition. Reaction completion time is more as per the prior art processes, which leads to decomposition of the product in sulfuric acid and formation of more impurities, which leads to poor yield and quality.

According to the present invention, the reaction is carried out in the presence of an organic solvent, wherein the reaction mass is homogeneous mixture and there is no formation of lumps. Exothermicity is controlled while slow addition of compound of formula II in organic solvent. According to the present invention, reaction mass is washed with chlorinated organic solvent before neutralizing the solution. This will wash out all the possible impurities formed during reaction. In the present invention, reaction completion time is very less and it completes in 4hrs with more than 90% of yield, which ultimately reduce the cost of the product.

According to the present invention mirtazapine having the particle size d90 is more than 150microns, preferably more than 300microns.
According to the present invention mirtazapine having the particle size d50 is more than 50 microns, preferably more than 100 microns.
According to the present invention mirtazapine having the particle size d10 is less than 10 microns, preferably more than 7 microns.

ADVANTAGES OF THE PRESENT INVENTION:

1. Addition of 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II as a liquid into sulfuric acid, the exothermicity is low when compared to solid addition to concentrated sulfuric acid without dilution.
2. Present invention avoids the lumps formation during the reaction.
3. Reaction time is less as compared to prior art process.
4. Due to less reaction time the formation of impurities is less and leads to good yield and purity.

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

Example 1: Preparation of 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine

To a stirred solution of dimethylformamide (50ml) and Potassium fluoride (25g) was added 1-methyl-3- phenyl piperazine at 25-30°C followed by 2-chloro nicotinonitrile. Heated the mixture to 135-140°C and maintained for 8 hrs. distilled out the dimethylformamide below 80°C. Water and ethyl acetate was added and the pH of the solution was adjusted to 6.8-7.2 with ammonia solution. The product was extracted into ethyl acetate and distilled out ethyl acetate below 60°C to get title compound.

Example 2: Preparation of 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine

To a stirred solution of dimethylformamide (50ml) and Potassium fluoride (150g) was added 1-methyl-3- phenyl piperazine (150g) at 25-30°C, followed by 2-chloro nicotinonitrile (115.7g). Heated the mixture to 138-142°C and maintained the reaction for 12 hrs. Dimethylformamide was distilled out the below 80°C. Cool the mass to 40°C. The product was extracted into ethanol and moved to next step.

Example 3: Preparation of 1-(3-Carboxypyridyl-2)-4-Methy1-2-Phenyl-Piperazine

1-(3-cyanopyridy1-2-)-4-methyl-2-phenyl-piperazine (20g) was dissolved in ethanol (100ml). Potassium hydroxide flakes (15g) were added and the mixture heated to 100X to 110°C and maintained the reaction for 32 hours. After completion of the reaction, ethanol was distilled out; water and toluene were added and separated the water layer. The water solution is neutralized with con hydrochloric acid to pH 7.5 and washed with chloroform. Aqueous layer pH was adjusted to 4-4.5 with dilute hydrochloric acid and extracted with chloroform. The chloroform layer was given charcoal treatment and distilled out the chloroform below 50°C. ethanol was added to the residue, refluxed for 30min and cooled the mass to 10°C. the obtained solid was filtered and washed with ethanol.

Example 4: Preparation of 1-(3-Carboxypyridyl-2)-4-Methy1-2-Phenyl-Piperazine

1-(3-cyanopyridy1-2-)-4-methyl-2-phenyl-piperazine (20g) was dissolved in ethanol (100ml). Sodium hydroxide flakes (600g) were added and the mixture was heated to 100°C to 110°C and maintained the reaction for 42 hours. After completion of the reaction, ethanol was distilled out; water and toluene were added and separated the water layer. The water solution is neutralized with concentrated hydrochloric acid to pH 7.2 and washed with chloroform. Aqueous layer pH was adjusted to 4-4.5 with dilute hydrochloric acid and extracted with chloroform. The chloroform layer was given charcoal treatment and distilled out the chloroform below 50°C. Ethanol was added to the residue, refluxed for 30min and cooled the mass to 10°C. The obtained solid was filtered and washed with ethanol.

Example 5: Preparation of 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine

1-3- carboxypyridyl-2)-methyl- 2- phenyl piperazine (100g) was added to the mixture of toluene (1530ml) and vitride (275.2g) at 15°C to 25°C for about 1-2 hrs. The reaction was monitored at 65-70°C for 30- 45 minutes, water was slowly added to the reaction mass and allowed to separate the layers. The compound was extracted into toluene and washed with

EDTA solution. Toluene was distilled out under vaccum below 65°C. fresh toluene was added followed by n-hexane and raised the temperature to 65°C for about 15min. The mixture was cooled to 0-2°C and the obtained mass was filtered, washed with n-hexane.

Example 6: Preparation of anhydrous mirtazapine

1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine (50g) was dissolved in chloroform (100ml). This solution was added to conc, sulfuric acid (180g) for the period of 1-2hrs at 20-25°C. The reaction was maintained at 35-38°C for 1-2hrs and quenched with water. Chloroform layer was separated, toluene was added to the aqueous layer and pH was adjusted to 9.5-10.5 with sodium hydroxide solution at 25°C. compound was extracted into toluene and given charcoal treatment. Toluene layer was distilled out completely, Isopropylether was added. The mixture was heated to reflux and maintained for 10-15min. Cooled the mixture to 2°C and the obtained solid was filtered to get anhydrous mirtazapine (Yield 90%).

WE CLAIM:

1. process for the preparation of mirtazapine comprising the steps of:
a) dissolving 1-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of formula II in a first organic solvent,
b) adding the solution of step a) into sulfuric acid,
c) diluting the reaction mass with water and separating the aqueous layer,
d) adjusting aqueous layer pH with a base,
e) extracting the product into second organic solvent, and
f) isolating mirtazapine.

2. The process according to claim 1, wherein the first organic solvent in step a) is selected from dichloromethane, chloroform or toluene.

3. The process according to claim 1, wherein the solution is slowly added in step b) over the period of 1-2 hrs at 20-25° C.

4. The process according to claim 1, wherein said pH is adjusted to 9.5-10.5.

5. The process according to claim 1, wherein said alkaline base used for the pH adjustment is selected from sodium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate.

6. The process according to claim 1, wherein second organic solvent in step e) is selected from toluene, ethyl acetate, dichloromethane, chloroform or ether.

7. The process according to claim 1, wherein mirtazapine is purified from isopropylether.

8. The process according to claim 1, wherein mirtazapine having the particle size d90 more than 150 microns, d50 is more than 50 microns and d10 is less than 10 microns.