DESC:Field of The Invention
The present invention relates to an improved process for the preparation of Mirtazapine having the structural formula (I).

The present invention also relates to novel intermediate of formula (V) which is useful in the preparation of Mirtazapine.

(V)

Background of the Invention

Mirtazapine is a tetracyclic piperazino-azepine antidepressant agent. It is initially approved for the treatment of a major depressive disorder (MDD) in the Netherlands in 1994. This drug was manufactured by Organon Inc.

Mirtazapine is chemically known as 1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine. Food and Drug Administration granted marketing Authorisation for Mirtazapine in United States under the brand name “REMERON” for the treatment of major depressive disorder.

Mirtazapine and its process is first disclosed in US 4062848. The synthetic procedure involves three steps starting with a 2,3-substituted pyridine derivative. This patent discloses the condensation of 2-chloro-3-cyanopyridine with 1-methyl-3-phenyl-piperazine in presence of DMF to give 1- (3-cyano-2-pyridyl) - phenyl-4-methylpiperazine, then hydrolysed in presence of potassium hydroxide to give 1- (3-carboxy-2-pyridyl) -2-phenyl-4-methylpiperazine followed by reduction with lithium aluminum hydride in tetrahydrofuran to obtain [1- (3-hydroxymethyl-2-pyridyl) -2-phenyl-4-methylpiperazine and finally cyclized in presence of a strong dehydrating agent to obtain Mirtazapine.

Handling of lithium aluminum hydride at commercial level is difficult and removal of substantial amounts of unwanted side products is costly and time consuming. It is desirable to have a process for making Mirtazapine with less reagents, solvent and time.

Various processes for the preparation of Mirtazapine is disclosed in US 7297790, US 6723845, US 6660730, US 6552189, US 6545149, US 6339156, CN 1220691, CN 1429819, CN 101654454, CN 102432594 and CN 105367571.

The reported processes for Mirtazapine suffer from many disadvantages which includes difficulty in achieving purity, tedious and cumbersome workup procedures, multiple crystallizations or isolation steps and purifications etc. All these disadvantages effect the overall yield as well as the quality of the final product.

In view of all these disadvantages, there is a significant need to develop a stable, commercially viable process for the preparation of highly pure Mirtazapine with good yield.

Summary of The Invention

The main objective of the present invention is to provide a well optimized, cost effective, novel and an efficient process for the preparation of Mirtazapine with higher yields and purity.

In one embodiment, the present invention provides a process for the preparation of Mirtazapine of formula (I).

which comprises:
a) chlorination of compound of formula (II)

(II)
with chlorinating agent in presence of solvent to obtain compound of formula (III);

(III)

b) condensation of compound of formula (III) with compound of formula (IV)

(IV)
in presence of a base and solvent to obtain compound of formula (V);

(V)

c) reduction of compound of formula (V) with a reducing agent in a solvent to obtain compound of formula (VI);

(VI)

d) cyclization of compound of formula (VI) in presence of sulfuric acid to obtain Mirtazapine of formula (I).

In yet another embodiment, the present invention provides a process for the preparation of isopropyl 2-(4-methyl-2-phenylpiperazin-1-yl) nicotinate of formula (V)

.
(V)
which comprises:
a) chlorination of compound of formula (II)

(II)
with chlorinating agent in presence of solvent to obtain compound of formula (III);

(III)

b) condensation of compound of formula (III) with compound of formula (IV)

(IV)
in presence of a base and solvent to obtain compound of formula (V).

In yet another embodiment, the present invention provides a process for the preparation of compound of formula (VI) which is useful in the preparation of Mirtazapine.

(VI)
which comprises:
a) reduction of compound of formula (V)

(V)

with a reducing agent in a solvent to obtain compound of formula (VI)

In yet another embodiment, the present invention provides the following novel intermediate of formula (V) which is useful in the preparation of Mirtazapine.

(V)

Detailed Description of the Invention

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

The term “chlorinating agent” means thionyl chloride, oxaloyl chloride or pivaloyl chloride.

The term “base” means inorganic or organic base like sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, triethylamine, diisopropylethylamine or pyridine.

The term “reducing agent” as used herein refers to sodium borohydride, lithium aluminum hydride, diborane, vitride reagent or lindlar catalyst.

The term “solvent” as used herein refers to hydrocarbon solvent, ester solvent, ether solvents, alcohol solvents, chlorinated solvents, polar aprotic solvents or water.

Accordingly, the present invention provides a process for the preparation of Mirtazapine of formula (I).

The main embodiment of the present invention provides an improved process for the preparation of Mirtazapine of formula (I), which as shown in the Scheme-I given below.

Scheme-I

In step-1, chlorination of compound of formula (II) with a chlorinating agent in presence of solvent to obtain compound of formula (III).

The chlorinating agent used in this reaction can be selected from the group consisting of thionyl chloride, oxalyl chloride or pivaloyl chloride. Preferably using thionyl chloride. This reaction is carried out at a temperature of 60 °C to 90 °C, preferably at 70 °C to 80 °C. The duration of the reaction may range from 2 hours to 5 hours, preferably for a period of 4 hours.

The solvent used in the reaction can be selected from group consisting of hydrocarbons, alcoholic solvents, preferably using isopropanol.

In step-2, compound of formula (III) is condensed with compound of formula (IV) in presence of a base and a solvent to obtain compound of formula (V). The base used in this reaction can be selected from the group consisting of alkali hydroxide, alkali carbonates or alkali bicarbonates. Preferably using sodium bicarbonate.

This reaction is carried out at a temperature of 120 °C to 160 °C, preferably at 140 °C to 150 °C. The duration of the reaction may range from 20 hours to 32 hours, preferably for a period of 25 hours to 30 hours.

The solvent used in the reaction can be selected from the group consisting of hydrocarbons, ether solvents, ester solvents, alcoholic solvents or chloro solvents. preferably using diglyme.

In step-3, compound of formula (V) reduced by using a reducing agent and solvent to obtain compound of formula (VI).

Reducing agent used in this reaction can be selected from the group consisting of sodium borohydride, lithium aluminium hydride, diborane, vitride reagent or lindlar catalyst; Preferably using vitride reagent.

The solvent used in the reaction can be selected from the group consisting of hydrocarbons, ether solvents, ester solvents, alcoholic solvents or chloro solvents. preferably using toluene.

The duration of the reaction may range from 1 hour to 4 hours. Preferably for a period of 2 hours to 2.5 hours.

In step-4, compound of formula (VI) is cyclized in presence of sulfuric acid to obtain mirtazapine. This compound is purified by using solvent.

This reaction is carried out at a temperature of 30 °C to 50 °C, preferably at 30 °C to 35 °C. The duration of the reaction may range from 4 hours to 8 hours; preferably for a period of 5 hours to 6 hours.

In yet another embodiment the present invention provides an improved process for the preparation of compound of formula (V) as shown in the Scheme-II given below:

Scheme-II

In step-1, chlorination of compound of formula (II) with a chlorinating agent in presence of solvent to obtain compound of formula (III).

The chlorinating agent used in this reaction can be selected from thionyl chloride, oxalyl chloride, pivaloyl chloride. Preferably using thionyl chloride.

This reaction is carried out at a temperature of 60 °C to 90 °C., preferably at 70 °C to 80 °C. The duration of the reaction may range from 2 hours to 5 hours, preferably for a period of 4 hours.

The solvent used in the reaction can be selected from the group consisting of hydrocarbons or alcoholic solvents preferably using isopropanol.

In step-2, compound of formula (III) is condensed with compound of formula (IV) in presence of a base and a solvent to obtain compound of formula (V).

The base used in this reaction can be selected from the group consisting alkali hydroxide, alkali carbonates, alkali bicarbonates. Preferably using sodium bicarbonate.

This reaction is carried out at a temperature of 120 °C to 160 °C. preferably at 140 °C to 150 °C. The duration of the reaction may range from 20 hours to 32 hours, preferably for a period of 25 hours to 30 hours.

The solvent used in the reaction can be selected from the group consisting of hydrocarbons, ether solvents, ester solvents, alcoholic solvents or chloro solvents. preferably using ether solvents like diglyme.

In yet another embodiment, the present invention provides the following novel intermediate of formula (V) which is useful in the preparation of Mirtazapine.

(V)

EXPERIMENTAL PORTION

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

Example-1: Process for the preparation of Mirtazapine

Stage-1: Synthesis of Isopropyl 2-chloro nicotinic ester

A mixture of Toluene (200 ml), 2-chloro nicotinic acid (100 grams) and thionyl chloride (90.65 grams), DMF (1 mL) was stirred for 10 minutes at 25-30 °C. The resulting reaction mixture was heated to 70-80°C and stirred for 4 hours at the same temperature. Volatiles were removed under reduced pressure. Cooled the reaction mixture to 40-50 °C. Isopropanol (100 mL) was added to the resulted reaction mixture at 40-50 °C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 70-80 °C and stirred for 60 minutes at the same temperature. Volatiles were removed under reduced pressure. Toluene (50 mL) and water (200 mL) were added to the resulting crude at 25-30 °C and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were separated, and aqueous layer was extracted with toluene. Combine the organic layers and 10% sodium bi carbonate solution was added. Both the organic and aqueous layers were separated. Volatiles were evaporated from the organic layer under reduced pressure to get the title compound.
Yield: 92-97 %.

Stage-2: Synthesis of Isopropyl 2-(4-methyl-2-phenylpiperazin-1 yl) Nicotinate

A mixture of Isopropyl 2-chloro nicotinic ester (100 grams, obtained in stage-1), diglyme (25 mL), sodium bicarbonate (31.5 grams) and 1-methyl-3-phenyl piperazine (110.32 grams) was stirred for 10 minutes at 25-30 °C. Heated the reaction mixture to 140-150 °C and stirred for 30 hours at the same temperature. After consumption of the starting material, toluene (400 mL) and water (400 mL) were added to the resulting reaction mixture at 25-30 °C. Both the organic and aqueous layers were separated, and aqueous layer was extracted with toluene. Combine the organic layers and water was added to it at 25-30 °C. Acidified the resulting reaction using 6N hydrochloric acid and stirred for 15 minutes. Both the organic and aqueous layers were separated. Aqueous layer was basified using aqueous sodium hydroxide solution. Toluene was added to the resulting reaction mixture at 25-30 minutes and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were separated. Volatiles were removed from the organic layer under reduced pressure to get the title compound.

Stage-3: Synthesis of (2-(4-Methyl -2-phenylpiperazin-1-yl) pyridine-3-yl) methanol

Isopropyl 2-(4-methyl-2-phenylpiperazin-1yl) nicotinate (Obtained in stage-2) was dissolved in toluene (180 mL) at 25-30 °C and stirred for 10 minutes at the same temperature. Cooled the reaction mixture to 0-10 °C and vitride reagent [70 % Sodium bis(2-methoxyethoxy) aluminium hydride (173 grams)] in toluene solution was slowly added to the resulting reaction mixture over a period 30-60 minutes at 0-10 °C. Heated the reaction mixture to 60-65 °C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-10 °C and aqueous sodium hydroxide solution was added slowly to the resulting reaction mixture within 15 minutes at the same temperature. Raised the temperature of reaction mixture to 60-65 °C and stirred for 30 minutes at the same temperature. Cooled to 25-35°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated, and aqueous layer was extracted with toluene. Combine the organic layers and added activated carbon (5 grams) to it at 25-35°C. Filtered the reaction mixture and volatiles were removed from the obtained filtrate under reduced pressure. Ethyl acetate (150mL) was added to the obtained crude compound at 25-30 °C. Heated the reaction mixture to 70-80°C and stirred for 15-30 minutes at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 95-105% w/w.

Stage-4: Synthesis of Mirtazapine

Sulfuric acid (26 mL) was slowly added to (2-(4-Methyl -2-phenylpiperazin-1-yl) pyridine-3-yl) methanol (13 grams, obtained in stage-3) at 10-15 °C. Raised the reaction mixture temperature to 30-35 °C and stirred for 6 hours at the same temperature. After consumption of starting material, water (130 mL) was added to the reaction mixture. The resulting reaction mixture was basified using aqueous sodium hydroxide solution at 25-30°C and stirred for 2 hours at the same temperature. Filtered the reaction mixture and followed by water slurry.

Acetone (26 mL) was added to the obtained wet compound at 25-30 °C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to reflux temperature and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30 °C. Water was added to the resulting reaction mixture. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound.

Yield: 90 %.

Example-2: Process for the preparation of isopropyl 2-(4-methyl-2-phenylpiperazin-1-yl) nicotinate of formula-V

Stage-1: Synthesis of Isopropyl 2-chloro nicotinic ester

A mixture of 2-chloro nicotinic acid (100 grams) and thionyl chloride (150 mL) was stirred for 10 minutes at 25-30 °C. The resulting reaction mixture was heated to 80-90°C and stirred for 3 hours at the same temperature. Volatiles were removed under reduced pressure. Cooled the reaction mixture to 35-45 °C. Isopropanol (200 mL) was added to the resulted reaction mixture at 35-45 °C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 70-80 °C and stirred for 60 minutes at the same temperature. Volatiles were removed under reduced pressure. Toluene (300 mL) and water (500 mL) were added to the resulting crude at 25-30 °C and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were separated, and aqueous layer was extracted with toluene. Combine the organic layers and 10% sodium bi carbonate solution was added. Both the organic and aqueous layers were separated. Volatiles were evaporated from the organic layer under reduced pressure to get the title compound.

Yield: 92.3 %

Stage-2: Synthesis of Isopropyl 2-(4-methyl-2-phenylpiperazin-1 yl) Nicotinate

A mixture of Isopropyl 2-chloro nicotinic ester (25 grams, obtained in stage-1), diglyme (6.25 mL), sodium bicarbonate (7.87 grams) and 1-methyl-3-phenyl piperazine (27.53 grams) was stirred for 10 minutes at 25-30 °C. Heated the reaction mixture to 70-75 °C and stirred for 22 hours at the same temperature. After consumption of the starting material, toluene (425 mL) and water (600 mL) were added to the resulting reaction mixture at 25-30 °C. Both the organic and aqueous layers were separated, and aqueous layer was extracted with toluene. Combine the organic layers and water was added to it at 25-30 °C. Acidified the resulting reaction using 6N hydrochloric acid and stirred for 15 minutes. Both the organic and aqueous layers were separated. Aqueous layer was basified using aqueous sodium hydroxide solution. Toluene was added to the resulting reaction mixture at 25-30 minutes and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were separated. Volatiles were removed from the organic layer under reduced pressure to get the title compound.

Yield: 89.6 %
,CLAIMS:1. An improved process for the preparation of Mirtazapine of formula (I)

which comprises:
a) chlorination of compound of formula (II)

(II)
with chlorinating agent in presence of solvent to obtain compound of formula (III);

(III)

b) condensation of compound of formula (III) with compound of formula (IV)

(IV)
in presence of a base and solvent to obtain compound of formula (V);

(V)

c) reduction of compound of formula (V) with a reducing agent to obtain compound of formula (VI);

(VI)
d) cyclization of compound of formula (VI) in presence of sulfuric acid to obtain Mirtazapine of formula (I).

2. The process for the preparation of isopropyl 2-(4-methyl-2-phenylpiperazin-1-yl)nicotinate of formula (V)
.
(V)
which comprises:
a) chlorination of compound of formula (II)

(II)
with chlorinating agent in presence of solvent to obtain compound of formula (III)

(III)

b) condensation of compound of formula (III) with compound of formula (IV)

(IV)
in presence of a base and solvent to obtain compound of formula (V).

3. The process for the preparation of isopropyl 2-(4-methyl-2-phenylpiperazin-1-yl)-nicotinate of formula (V)

.
(V)
which comprises:

a) condensation of compound of formula (III)

(III)
with compound of formula (IV)

(IV)
in presence of a base and solvent to obtain compound of formula (V).

4. The process for the preparation of compound of formula (VI) which is useful in the preparation of Mirtazapine.

(VI)
which comprises:
a) reduction of compound of formula (V)

(V)

with a reducing agent in a solvent to obtain compound of formula (VI)

5. The process as claimed in claims 1 to 2, wherein the chlorinating agent is selected from group consisting of thionyl chloride, oxalyl chloride or pivaloyl chloride.

6. The process as claimed in claims 1 to 3, wherein the solvent is diglyme (diethylene glycol dimethyl ether).

7. The process as claimed in claim 1, wherein the reducing agent is selected from the group consisting of sodium borohydride, lithium aluminum hydride, diborane, vitride reagent or lindlar catalyst.

8. The process as claimed in claim 4, wherein the reducing agent is selected from the group consisting of lithium aluminum hydride, sodium borohydride, potassium borohydride or sodium bis(2-methoxyethoxy) aluminium hydride.

9. The process as claimed in any of claims 1 to 3 wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate or potassium bicarbonate.

10. A compound of formula (V)

(V)