Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF MIRTAZAPINE

Abstract This invention relates to an Improvea process for the preparetion of mirtazapine of Formula I, which involves the cyclization of pyridine carbinol compound of Formula ll, with sulfuric acid in an organic solvent.
Full Text

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Mirtazapine of Formula 1

BACKGROUND OF THE INVENTION
Mirtazapine of Formula I, also known as 2-methyl-1,2,3,4,10,14b-hexahydrobenzo[c]pyrazino(l,2-a)pyrido[3,2-f]azepine, is an antidepressant drug suitable for oral administration. Mirtazapine belongs to piperazinoazepine group of compounds.
US patent 4,062,848 has disclosed the method to prepare Mirtazapine from pyridine carbinol intermediate of Formula n, namely l-(3-hydroxymethylpyridyl-2)-2-phenyl-4-

methylpiperazine, by treating it with sulfuric acid. This pyridine carbinol intermediate has been prepared in three steps starting from l-methyl-3-phenylpiperazine. Subsequently, the cyclization to prepare Mirtazapine has been carried out by adding dropwise concentrated sulfuric acid to pyridine carbinol compound of Formula II {Example I of US '848).
In an alternate approach in Example IV of US patent 4,062,848, the structurally related pyridine carbinol compound of Formula HI has been added in portions to


concentrated sulfuric acid to carry out cyclization to prepare azepine compound, namely 2-methyl-1,2,3,4,10,14b-hexahydrobenzo [c]pyrazino[ 152-a]pyrido [3,4-f] azepine.
Further, European Patent, EP 1 238 977 claims a process wherein pyridine carbinol compound of Formula II has been added in divided portions to sulfuric acid to produce Mirtazapine.
However, there are certain drawbacks in the disclosed processes. The dropwise addition of concentrated sulfuric acid to crystalline pyridine carbinol compound results in formation of big lumps, making stirring difficult and thereby the reaction control would not be easy to obtain Mirtazapine having high purity. Alternatively, as described in EP 1 238 977, the addition of pyridine carbinol compound in several divided portions has to be carried out very slowly to ensure the complete dissolution of each individual portion of pyridine caibinol compound in sulfuric acid to prevent formation of lumps. Further, the addition of crystalline pyridine carbinol compound to sulfuric acid in several divided portions is inconvenient from the safety viewpoint. In the preparation of Mirtazapine, it is important that ring closure reaction is carried out till the complete disappearance of pyridine carbinol compound is confirmed, as it is difficult to remove any uncyclized carbinol from Mirtazapine by known purification procedures. It is difficult to complete the cyclization reaction in the prior art processes because of the problem of lumps formation and this results in Mirtazapine not having high purity.
In view of the above, it is an object of the present invention to provide a simple and efficient process to prepare Mirtazapine which is easy to operate on commercial scale.


in an organic solvent and adding this solution to sulfuric acid.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of highly pure Mirtazapine. The pyridine carbinol compound of Formula II is prepared by the methods known in the prior art, such as reported in US patent 4,062,848.
According to the instant invention, pyridine carbinol compound of Formula II is dissolved in an organic solvent before treating it with sulfuric acid to prepare Mirtazapine. The suitable organic solvents to prepare a solution of pyridine carbinol compound are chlorinated hydrocarbons such as methylene chloride, chloroform, chlorobenzene and the like. The most preferable solvent is methylene chloride for preparing solution of carbinol compound. The amount of solvent used should be enough to dissolve the pyridine carbinol compound at 30°C to 40°C.

More specifically, Mirtazapine is prepared by slow addition of pyridine carbinol solution to sulfuric acid and the addition is preferably carried out under nitrogen atmosphere. Sulfuric acid used to carry out the cyclization reaction is favorably concentrated sulfuric acid having concentration 97% to 99%. The amount of sulfuric acid is 1.5 to 3 parts by volume per part of the pyridine carbinol compound, however preferably 2 parts by volume is enough to carry out the cyclization reaction.
The temperature during addition of pyridine carbinol solution to sulfuric acid is maintained between 30°C and 40°C to efficiently progress the ring closure reaction to produce Mirtazapine. The completion of ring closure reaction is confirmed by HPLC and the reaction is continued till unreacted pyridine carbinol compound is less than 0.1% and it usually takes 3 to 4 hours to achieve this.
Next, it is preferable to add the reaction mass in a thin stream to water, preferably at a temperature between 0°C and 30°C to suppress the formation of tarry mass. Thereafter, aqueous alkali such as sodium hydroxide, potassium hydroxide, ammonia and the like is added for the purpose of neutralization. Among these, aqueous sodium hydroxide solution is preferably added at a temperature between 20°C and 30°C to adjust the pH to 8.0 to 12.0. Thereafter, Mirtazapine is extracted into an organic solvent such as methylene chloride, chloroform and the like. Concentration of the Mirtazapine extract and addition of an aliphatic hydrocarbon or an ether results in crystallization of highly pure Mirtazapine.
The major advantage realized in the present cyclization conditions as compared to prior art procedures is the ease of addition of pyridine carbinol compound as a solution to sulfuric acid and thereby eliminating the chances of forming lumps. This results in faster completion of reaction and forms Mirtazapine of high purity.

The following specific example illustrates the process of the invention:
Example 1
PREPARATION OFMIRTAZAPINE
1 -(3-Hydroxymethylpyridyl-2)-2-phenyl-4-methylpiperazine (75 g) was dissolved in methylene chloride (150 ml) and the solution was added slowly to sulfuric acid (150 ml) at 30-40°C. The reaction mixture was stirred further for 3 hours at 30-40°C. The reaction completion was confirmed by HPLC (unreacted pyridine carbinol compound was not detected). Thereafter, reaction mixture was cooled and added to water (750 ml) slowly keeping the temperature below 30°C. The pH of the reaction mixture was adjusted to 10.0 with 20% w/w aqueous sodium hydroxide solution. The contents were further diluted with methylene chloride (600 ml) and organic layer was separated. The aqueous layer was extracted once again with methylene chloride (225 ml). The combined methylene chloride extract was concentrated to remove methylene chloride. The concentrated mass was diluted with diisopropyl ether (160 ml) and cooled to 5°C, Mirtazapine was recovered by filtration, washed with diisopropyl ether (25 ml) and dried at 55-60°C under reduced pressure. Yield: 64 g (91% of theory). The Mirtazapine thus obtained had a chromatographic purity of 99.96% and an assay of 99.6% w/w.




WE CLAIM
1. An improved process for the preparation of Mirtazapine of Formula 1,

which comprises dissolving the pyridine carbinol compound of Formula II

in an organic solvent and treating this solution with sulfuric acid.
2. The process according to claim 1, wherein the solution of pyridine carbinol compound
is added to the sulfuric acid.
3. The process according to claim 1, wherein the pyridine carbinol compound is
dissolved in chlorinated hydrocarbon,
4. The process according to claim 3, wherein the chlorinated hydrocarbon is methylene
chloride.


Documents:

794-che-2004-abstract.pdf

794-che-2004-claims duplicate.pdf

794-che-2004-claims original.pdf

794-che-2004-correspondnece-others.pdf

794-che-2004-correspondnece-po.pdf

794-che-2004-description(complete) duplicate.pdf

794-che-2004-description(complete) original.pdf

794-che-2004-form 1.pdf

794-che-2004-form 19.pdf

794-che-2004-form 3.pdf

794-che-2004-form 5.pdf

794.1.jpg

794.jpg


Patent Number 205206
Indian Patent Application Number 794/CHE/2004
PG Journal Number 26/2007
Publication Date 29-Jun-2007
Grant Date 22-Mar-2007
Date of Filing 09-Aug-2004
Name of Patentee AUROBINDO PHARMA LIMITED,
Applicant Address PLOT NO-2, MAITRIVIHAR COMPLEX,(REGD. OFFICE), AMEERPET, HYDERABAD 500 038,
Inventors:
# Inventor's Name Inventor's Address
1 VIJAY KUMAR HANDA PLOT NO-2, MAITRIVIHAR COMPLEX,(REGD. OFFICE), AMEERPET, HYDERABAD 500 038,
2 DIVVELA VENKATA NAGA SRINIVASA RAO PLOT NO-2, MAITRIVIHAR COMPLEX,(REGD. OFFICE),,AMEERPET,HYDERABAD-500 038,,ANDHRA PRADESH,,
3 MEENAKSHISUNDERAM SIVAKUMAR. PLOT NO-2, MAITRIVIHAR COMPLEX,(REGD. OFFICE),,AMEERPET,HYDERABAD-500 038,,ANDHRA PRADESH,,
PCT International Classification Number A61K 31/55
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA