FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"AN IMPROVED PROCESS FOR PREPARATION OF MIRTAZAPINE AND
ITS INTERMEDIATE"
2. APPLICANT
(a) NAME: WATSON PHARMA PRIVATE LIMITED
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 201/301, Corporate Enclave, HDO-Corporate Bldg.,
B Wing, B. D. Sawant Marg, Chakala, Off Western Express Highway, Andheri (East), Mumbai - 400 099, Maharashtra, India.
3.PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to an improved process for preparing Mirtazapine and its intermediate l-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, a key intermediate used in the manufacture of Mirtazapine.
BACKGROUND OF THE INVENTION
The present invention relates to 1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,l-a]pyrido[2,3-c][2] benzazepine, also known as Mirtazapine (Formula I)


CH3
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 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 1A (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.
Mirtazapine can be manufactured by methods described in US Patent No. 4,062,848 ("the '848 patent") (assigned to Akzona Incorporated). The '848 patent discloses a process for
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preparing Mirtazapine by adding concentrated sulfuric acid to l-(3-hydroxymethylpyridyI-2)-2-phenyl-4-methylpiperazine of Formula II.

l-(3-hydroxymethylpyridyl-2)-2-phenyI-4-methylpiperazine of Formula II also known as a pyridinemethanol compound, is a key raw material for the manufacture of Mirtazapine. US Patent No. 4,062,848 describes a process for preparation of the pyridinemethanol compound by reducing a pyridinecarboxylic acid of Formula III:
using Lithium aluminium hydride.
European Patent No. 1238977 discloses a process for preparation of the pyridinemethanol by reducing the potassium pyridinecarboxylate represented by Formula IV:

using Lithium aluminium hydride.
Both of the above processes use Lithium aluminium hydride as a reducing agent, which is a pyrophoric substance and a potential hazard in the scale-up and commercial manufacturing of the pyridinemethanol compound.
US Patent Publication No. 2003/0069417 Al discloses a process for the preparation of pyridinemethanol by reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-
3 -

phenyl-2,2'-iminodiethyl chloride. But the process is economically infeasible because of the expensive raw materials.
Since the above processes have various drawbacks, there is a need for a process useful for the preparation of the pyridinemethanol compound which is commercially scalable, non-hazardous and can be commercially viable.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for preparing l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine or pyridinemethanol compound which is a key raw material in the manufacture of Mirtazapine.
The present invention provides a process for preparing pyridinemethanol compound of Formula II, which is scalable, free from hazardous pyrophoric chemicals and commercially viable. The present invention provides a process for preparing pyridinemethanol compound comprising:
(a) hydrolysis of l-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine in presence of potassium hydroxide in a mixture of water and methanol to give l-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine of Formula III;
(b) reduction of l-(3-carboxypyridyl-2)-4-rnethyl-2-phenylpiperazine of Formula III using sodium bis(2-methoxyethoxy)aluminum hydride as a solution in toluene in a suitable solvent to give l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of Formula II; and
(c) treatment of l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of Formula II with sulfuric acid to give Mirtazapine of Formula I.
The above process is nonhazardous since it avoids use of highly reactive and flammable reagents such as Lithium Aluminium Hydride.
DESCRIPTION OF THE INVENTION
One aspect of the present invention is to provide an improved process for the preparation of l-(3-hydroxymethylpyridyI-2)-2-phenyl-4-methylpiperazine or pyridinemethanol compound which involves:
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(a) hydrolyzing the compound l-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine
in alkaline condition in one or more suitable solvents selected from the group consisting
of water, C1 to C3 alcohols, or mixtures thereof under heating. The hydrolysis is carried
out using one or more alkali metal bases selected from the group consisting of potassium
hydroxide or sodium hydroxide, or mixtures thereof, in a molar ratio ranging from about
10 moles to about 20 mole, more preferably about 18 to 20 moles. The reaction is carried
out by heating to a temperature range between about 60° C to about 90° C, preferably
between about 85° C to about 88° C for about 5 to about 10 hours, more preferably
between about 6 to about 8 hours to provide (after conventional work up) the product 1-
(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine of Formula III;
(b) Reacting a suspension of l-(3-carboxypyridyl-2)-4-methyI-2-phenylpiperazine of Formula III in toluene with a solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene at a suitable temperature for about 4 to about 6 hours to give (after conventional work up) l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methy!piperazine of Formula II. The sodium bis(2-methoxyethoxy)aluminum hydride is used in a range of about 2 mole equivalent to about 5 mole equivalent, more preferably from about 3 to about 3.5 mole equivalent with respect to l-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine. The reaction is carried out at a reaction temperature of about 25° C to about 30° C for a period of from about 4 to about 6 hours;
(c) Quenching the reaction mass of above step (b) with approximately 2 volumes of methanol and approximately 3 volumes of about 30 to about 50% w/v of an aqueous solution of sodium sulfate (preferably about 50% w/v) to decompose any unreacted reducing agent and thereby converting the decomposed reducing agent into a granular solid which is easily filtered and separated from the reaction mixture; and
d) Isolating the product by concentrating the clear toluene filtrate obtained from above step (c) and adding hexane to obtain l-(3-hydroxymethylpyridyI-2)-2-phenyI-4-methylpiperazine of Formula II.
(e) l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine of Formula II is then treated with concentrated sulfuric acid to obtain Mirtazapine of Formula I.
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EXAMPLES
Example 1
Preparation of l-(3-carboxypyridyl-2)-4-methyl-2-phe nylpiperazine (III)
175 grams (0.63 mole) of ]-(3-cyanopyridyl-2)-4-methy!-2-phenylpiperazine was dissolved in 1150 ml methanol. 650 grams (11.6 mole) of Potassium hydroxide was slowly added to the reaction mixture under stirring to get a clear solution. 250 ml water was added and the reaction mixture was heated to reflux at 85° C to 90° C. The reaction mixture was maintained under reflux for 24 hours. The reaction mixture was then cooled to 50° C. The reaction mixture was concentrated under vacuum to remove methanol completely. The thick brown mass obtained was then cooled to about 25° C and 350 ml of water was added and the reaction mass stirred for 15 minutes. The pH of the reaction mass was adjusted to about 7 using concentrated hydrochloric acid and maintaining temperature between 20° C to 30° C. The resulting suspension obtained was stirred for 30 minutes at 20° C to 30° C. The solids were filtered and dried at 60° C for 4 to 5 hours. The dried solids were then suspended in 475 ml of isopropyl alcohol and the reaction mixture was heated to reflux and stirred at reflux temperature for about 30 minutes. The reaction mixture was filtered hot to remove the insoluble inorganics. The clear filtrate was then concentrated under vacuum to get a thick slurry. The resulting slurry was then cooled to about 10°C and filtered. The product was washed with 100ml n-hexane. The wet product was dried at 60°- 70°C to get 90 grams of l-(3-carboxypyridyl-2)-4-methyI-2-phenyIpiperazine.
Example 2
Preparation of l-(3-hydroxymethylpyridyI-2)-2-phenyl-4-methylpiperazine (II)
50 grams (0.168 mole) of l-(3-carboxypyridyl-2)-4-methyl-2-phenylpiperazine was suspended in 500 ml anhydrous toluene. The reaction mixture was cooled to 15° C. 178 ml of sodium bis(2-methoxyethoxy)aluminum hydride or Vitride (65% solution in toluene) was slowly added to the reaction mixture maintaining the temperature between 15 to 20° C in about 1 to 2 hour. The temperature of the reaction mixture was then raised to 25° C and the reaction mixture was stirred for 5 hours at 25 to 30° C. The reaction
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mixture was cooled to 10° C and methanol 100 ml, was slowly added to the reaction mixture maintaining temperature below 30° C. The reaction rnass was further stirred at 25 to 30° C for 1 hour. 150 ml aqueous solution of sodium sulfate (50%) was added to the reaction mixture at about 30° C. The reaction mixture was then heated to about 60° C and stirred for 1 hour. The reaction mass was filtered to remove the inorganic obtained. The inorganic were washed with 200 ml toluene. The clear filtrate and the washings were collected together and the layers were separated. The upper toluene extract was then washed with 200 ml water. The toluene extract was dried over anhydrous sodium sulfate and then concentrated under vacuum maintaining temperature below 65° C till thick slurry is obtained. Hexane, 100 ml, was added and the reaction mass was cooled to 10° C. The product obtained was filtered and washed with 25 ml hexane. The wet solids were dried at about 60°C-65°C to get 40 grams of l-(3-hydroxyrtiethyIpyridyl-2)-2-phenyl-4-methylpiperazine.
Example 3
Preparation of Mirtazapine (I) from l-(3-hydroxymethylpyridyI-2)-2-phenyl-4-methylpiperazine (II)
100 ml of concentrated sulfuric acid was cooled to about15° C. 50 grams (0.18 mole) of l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine was added slowly to the sulfuric acid and the temperature was maintained below 20° C. The temperature was then raised to 30° C and the reaction mixture was stirred for 12 hours maintaining the temperature between 25 to 30° C. The reaction mass was then quenched in 1 liter of ice-cold water. The pH of the reaction mixture was adjusted to about 10-11 using 20-25% aqueous Ammonia solution maintaining the temperature below 30° C. 500 ml ethylacetate was added to the reaction mixture and stirred for about 15 minutes at 30° C. The layers were separated and the aqueous layer was back extracted with 100 ml ethylacetate. All the ethylacetate extracts were combined together and heated to reflux under stirring. 5 grams of activated charcoal was added and the reaction mixture was stirred under reflux temperature for 30 minutes. The reaction mixture was filtered hot over a hyflo bed. Water 1.6 ml was added to the clear filtrate and heated to about 50° C. The reaction mass was stirred at 50° C for 30 minutes and then concentrated under vacuum to keep about 100 ml
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ethylacetate in the reaction mixture. Isopropyl ether 150 ml, was added to the reaction mass and heated to reflux. 5 grams of activated carbon was added and the reaction mixture was stirred under reflux for 30 minutes. The reaction mixture was filtered hot over a hyflo bed. The clear filtrate was cooled under stirring to about 30° C and further chilled to about 5° C. The reaction mass was stirred at 5 to 10° C for 1 hour. The solids crystallized were filtered and washed with 25 ml chilled isopropyl ether. The product obtained was suck dried for 30 minutes and then dried at 65° C under vacuum to get 40 grams of Mirtazapine having HPLC purity of more than 99.8%.
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We claim,
1. A process for the manufacture of Mirtazapine comprising:
a. Hydrolysis of l-(3-cyanopyridyl-2)-4-methyl-2-phenylpiperazine in
alkaline conditions under reflux to give l-(3-carboxypyridyl-2)-4-methyl-
2-phenylpiperazine;
b. Reduction of l-(3-carboxypyridyl-2)-4-methyl-2-phenyIpiperazine using
sodium bis(2-methoxyethoxy)aluminum hydride in an organic solvent to
give 1 -(3-hydroxymethylpyridyl-2)-2-phenyi-4-methylpiperazine; and
c. Cyclization of 1 -(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine
under acidic conditions to give Mirtazapine.
2. The process of claim 1, wherein the hydrolysis step is carried out using one or more alkali metal bases.
3. The process of claim 2, wherein the one or more alkali metal bases are selected from the group consisting of potassium hydroxide, sodium hydroxide, or mixtures thereof in a molar ratio from about 10 moles to about 20 moles.
4. The process of claim 3, wherein the molar ratio is from about 18 to about 20 moles.
5. The process of claim 2, wherein the reaction is carried out between about 60° C to about 90° C.
6. The process of claim 5, wherein the reaction is carried out between about 85° C to about 88° C.
7. A process for the manufacture of l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine comprising:
a. Suspending 1-(3-carboxypyridyl-24-methy1-2-phenylpiperazine in an
organic solvent;
b. Adding sodium bis(2-methoxyethoxy)aluminum hydride as a reducing
agent;
c. Quenching the excess of reducing agent after the completion of the
reaction; and
d. Isolating the l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine
in an organic solvent.
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8. The process of claim 7, wherein the sodium bis(2-methoxyethoxy)aluminum
hydride is added in a range of about 2 mole equivalent to about 5 mole equivalent
with respect to the l-(3-carboxypyridyl-24-methyl-2-phenylpiperazine.
9. The process of claim 8, wherein the sodium bis(2-methoxyethoxy)aluminum hydride is added in a range of about 3 mole equivalent to about 3.5 mole equivalent with respect to the 1-(3-carboxypyridyI-2)-4-methyI-2-phenylpiperazine.
10. The process of claim 7, wherein the quenching step comprises use of methanol and an aqueous solution of sodium sulfate.
11. The process of claim 10, wherein 2 volumes of methanol are used.
12. The process of claim 10, wherein the concentration of the aqueous solution of sodium sulfate is about 30% w/v to about 50% w/v.
13. The process of claim 10, wherein the concentration of the aqueous solution of sodium sulfate is about 50% w/v.
14. The process of claim 10, wherein about 3 volumes of aqueous solution of sodium sulfate are used.
Dated this 22nd day of October 2008
Dr. Gopakumar G. Nair Agent for the Applicant
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