Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF BUPROPION HYDROCHLORIDE
Abstract	The present invention relates to an improved, industrially advantageous process for the preparation of Bupropion hydrochloride of Formula I, which comprises the bromination of m-chloropropiophenone in chlorinated solvent in the presence of a catalyst to prepare a bromo compound, which on treatment with tert-butylamine give bupropion base and further treating with isopropyl alcohol hydrogen chloride mixture (IP A-HCI) to prepare bupropion hydrochloride.

Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF BUPROPION HYDROCHLORIDE

Abstract

The present invention relates to an improved, industrially advantageous process for the preparation of Bupropion hydrochloride of Formula I, which comprises the bromination of m-chloropropiophenone in chlorinated solvent in the presence of a catalyst to prepare a bromo compound, which on treatment with tert-butylamine give bupropion base and further treating with isopropyl alcohol hydrogen chloride mixture (IP A-HCI) to prepare bupropion hydrochloride.

Full Text	FIELD OF THE INVENTION: The present invention relates to an improved industrially advantageous process for the preparation of Bupropion hydrochloride of Formula I, BACKGROUD OF THE INVENTION; Bupropion hydochloride, also known as l-(3-chlorophenyl)-2-[(l,l-dimethyl-ethyl)amino]-l-propanone hydrochloride is a clinically efficacious antidepressant agent and it has the chemical structure as depicted in formula I. Bupropion and its preparation have been first disclosed in US patent 3,819,706. The process disclosed in this patent comprises the condensation of m-chlorobenzonitrile (II) with ethyl magnesium bromide (III) in refluxing ether to give m-chloropropiophenone (IV), which is then halogenated to yield 3'-chloro-2-halopropiophenone (V). Alternatively, the 3'-chloro-2-halopropiophenone (V) is prepared by the halogenation of propiophenone followed by chlorination in the ring by means of sulphuryl chloride and aluminum chloride. Further the 3'-chloro-2-halopropiophenone (V) is reacted with tert-butylamine in acetonitrile to prepare Bupropion (VI) as shown in Scheme 1. In the exemplified process, the hydrochloride salt of Bupropion is prepared in ether using excess of concentrated hydrochloric acid and thereafter ether layer is separated and washed with water. The acidic aqueous layer is concentrated in vacuo to crystallize Bupropion hydrochloride, which is isolated and recrystallized from a mixture of isopropanol and absolute ethanol. International publication WO 2004/024674 Al discloses the preparation of Bupropion hydrochloride by the reaction of 3'-chloropropiophenone with bromine in the presence of tert-butylamine to prepare Bupropion free base, which is converted to its hydrochloride by treating with aqueous hydrochloric acid. The acidic aqueous phase is concentrated under reduced pressure and the residue is crystallized from isopropanol to obtain Bupropion hydrochloride. Both the above processes involve the concentration of acidic aqueous solution in vacuo, leading to the decomposition of product resulting in low yields. In view of the above, there is a clear need to find an alternative, industrially viable process for the production of Bupropion hydrochloride. Surprisingly we have found a new simple process for the preparation of highly pure Bupropion hydrochloride in high yields by concentrating the alcoholic solutions. SUMMARY OF THE INVENTION Accordingly, the present invention relates to a simple and an industrially advantageous process for the preparation of Bupropion hydrochloride, of formula I in chlorinated solvents such as carbon tetrachloride, chloroform and methylene chloride in the presence of a catalyst to prepare a compound of formula VII, - treating the compound of formula VII which is optionally isolated, with tert- butylamine to prepare bupropion base of formula VI, - treating bupropion base in an organic solvent with isopropyl alcohol hydrogen chloride mixture to prepare bupropion hydrochloride of Formula I. DETAILED DESCTIPTION OF THE INVENTION; The present invention relates to a simple industrial process for the preparation of highly pure Bupropion hydrochloride in high yields where isopropyl alcohol hydrogen chloride is used advantageously for hydrochloride salt formation. Specifically, 3'-chloropropiophenone is brominated in methylene chloride in the presence of catalyst. The catalyst can be acidic catalyst and preferably p-toluenesulphonic acid is used. It is advantageous to use catalyst because in the presence of catalyst, the initiation of reaction is smooth and fast, hence the formation of 3'-chloro-2,2-dibromopropiophenone impurity is less. The product 3'-chloro-2-bromopropiophenone is optionally isolated and further treated with tert-butylamine to prepare Bupropion base. The hydrochloride formation is advantageously carried out in organic solvents. Bupropion base is dissolved in organic solvent such as alcohols, ethers, esters and hydrocarbons and preferably toluene and to this solution, isopropyl alcohol hydrogen chloride mixture is added slowly. Isopropyl alcohol hydrogen chloride mixture is prepared by passing anhydrous hydrogen chloride gas in isopropyl alcohol. The concentration of hydrogen chloride in isopropyl alcohol hydrogen chloride can be 10-40% w/w and preferably 20-30% w/w is used. Optionally the toluene solution is treated with activated carbon to improve colour. The amount of hydrochloric acid required is 0.7 to 1.6 mole / more of Bupropion base, preferably 1 mole / mole of Bupropion base is used. The product isolated has a purity of greater than 99.8%, which can be further crystallized in isopropyl alcohol. Major advantages realized in the present invention are high yield and high purity. Further no concentration of acidic aqueous solution is required to crystallize Bupropion hydrochloride thus avoiding lower yield. Further use of catalyst during bromination minimizes formation of 3'-chloro-2,2-dibromopropiophenone impurity. The following examples illustrated the process of the invention: Example 1 PREPARATION OF BUPROPION HYDROCHLORIDE Stepl Preparation of Bupropion base To a mixture of 3'-chloropropiophenone (50 g) and p-toluenesulphonic acid (0.75 g) in methylene chloride (200ml) a solution of bromine (49.82g) in methylene chloride (50 ml) was added at 15-20°C. After completion of reaction, the reaction mass was diluted with water. The layers were separated and washed the methylene chloride layer with sodium sulfite solution and concentrated. To the resulting 3'-chloro-2-bromopropiophenone, tert-butylamine (151.8g) was added and stirred at 45-50'C till completion of the reaction. The excess of tert-butylamine was distilled out under reduced pressure and the resulting reaction mass was dissolved in methylene chloride. The reaction mixture was basified with aqueous sodium hydroxide solution and separated. The methylene chloride layer was concentrated to obtain 64g of the bupropion base having purity 97.59% by HPLC. Step! Preparation of Bupropion Hydrochloride Bupropion base (64g) was dissolved in toluene (205ml) and cooled to 0-5^C. To this solution isopropyl alcohol hydrogenchloride (IPA-HCl; 43.2g; 24.8% w/w) was added slowly at 0-10°C and stirred the reaction mass for further 30-40 minutes. The product, which crystallized out during this period was filtered, washed with toluene, isopropanol and recrystallized from isopropanol to obtain 50.6 g of bupropion hydrochloride having purity 99.95% by HPLC. WE CLAIM; 1. A process for the preparation of Bupropion hydrochloride, of Formula I which comprises the bromination of compound of formula IV, in chlorinated solvent selected from carbon tetrachloride, chloroform and methylene chloride, in the presence of a catalyst to prepare a compound of formula VII, - treating the compound of formula VII with tert-butylamine to prepare bupropion baseof formula VI, and " treating bupropion base in an organic solvent with isopropyl alcohol hydrogen chloride mixture (IPA-HCl) to prepare bupropion hydrochloride of formula I. 2. The process according to claim 1, wherein the catalyst used for bromination is p- toluenesulfonic acid. 3. The process according to claim 1, wherein the solvent used during Bupropion hydrochloride formation is selected from alcohols, ethers, esters and hydrocarbons and the like or mixture thereof 4. The process according to claim 3, wherein the solvent used is toluene.

Full Text

FIELD OF THE INVENTION:
The present invention relates to an improved industrially advantageous process for the preparation of Bupropion hydrochloride of Formula I,

BACKGROUD OF THE INVENTION;
Bupropion hydochloride, also known as l-(3-chlorophenyl)-2-[(l,l-dimethyl-ethyl)amino]-l-propanone hydrochloride is a clinically efficacious antidepressant agent and it has the chemical structure as depicted in formula I.

Bupropion and its preparation have been first disclosed in US patent 3,819,706. The process disclosed in this patent comprises the condensation of m-chlorobenzonitrile (II) with ethyl magnesium bromide (III) in refluxing ether to give m-chloropropiophenone (IV), which is then halogenated to yield 3'-chloro-2-halopropiophenone (V). Alternatively, the 3'-chloro-2-halopropiophenone (V) is prepared by the halogenation of propiophenone followed by chlorination in the ring by means of sulphuryl chloride and aluminum chloride.

Further the 3'-chloro-2-halopropiophenone (V) is reacted with tert-butylamine in acetonitrile to prepare Bupropion (VI) as shown in Scheme 1. In the exemplified process, the hydrochloride salt of Bupropion is prepared in ether using excess of concentrated hydrochloric acid and thereafter ether layer is separated and washed with water. The acidic aqueous layer is concentrated in vacuo to crystallize Bupropion hydrochloride, which is isolated and recrystallized from a mixture of isopropanol and absolute ethanol.

International publication WO 2004/024674 Al discloses the preparation of Bupropion hydrochloride by the reaction of 3'-chloropropiophenone with bromine in the presence of tert-butylamine to prepare Bupropion free base, which is converted to its hydrochloride by treating with aqueous hydrochloric acid. The acidic aqueous

phase is concentrated under reduced pressure and the residue is crystallized from isopropanol to obtain Bupropion hydrochloride.
Both the above processes involve the concentration of acidic aqueous solution in vacuo, leading to the decomposition of product resulting in low yields.
In view of the above, there is a clear need to find an alternative, industrially viable process for the production of Bupropion hydrochloride. Surprisingly we have found a new simple process for the preparation of highly pure Bupropion hydrochloride in high yields by concentrating the alcoholic solutions.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to a simple and an industrially advantageous process for the preparation of Bupropion hydrochloride, of formula I

in chlorinated solvents such as carbon tetrachloride, chloroform and methylene chloride in the presence of a catalyst to prepare a compound of formula VII,

- treating the compound of formula VII which is optionally isolated, with tert-
butylamine to prepare bupropion base of formula VI,

- treating bupropion base in an organic solvent with isopropyl alcohol hydrogen
chloride mixture to prepare bupropion hydrochloride of Formula I.
DETAILED DESCTIPTION OF THE INVENTION;
The present invention relates to a simple industrial process for the preparation of highly pure Bupropion hydrochloride in high yields where isopropyl alcohol hydrogen chloride is used advantageously for hydrochloride salt formation. Specifically, 3'-chloropropiophenone is brominated in methylene chloride in the presence of catalyst. The catalyst can be acidic catalyst and preferably p-toluenesulphonic acid is used. It is advantageous to use catalyst because in the presence of catalyst, the initiation of reaction is smooth and fast, hence the formation of 3'-chloro-2,2-dibromopropiophenone impurity is less. The product 3'-chloro-2-bromopropiophenone is optionally isolated and further treated with tert-butylamine to prepare Bupropion base. The hydrochloride formation is advantageously carried out

in organic solvents. Bupropion base is dissolved in organic solvent such as alcohols, ethers, esters and hydrocarbons and preferably toluene and to this solution, isopropyl alcohol hydrogen chloride mixture is added slowly. Isopropyl alcohol hydrogen chloride mixture is prepared by passing anhydrous hydrogen chloride gas in isopropyl alcohol. The concentration of hydrogen chloride in isopropyl alcohol hydrogen chloride can be 10-40% w/w and preferably 20-30% w/w is used. Optionally the toluene solution is treated with activated carbon to improve colour. The amount of hydrochloric acid required is 0.7 to 1.6 mole / more of Bupropion base, preferably 1 mole / mole of Bupropion base is used. The product isolated has a purity of greater than 99.8%, which can be further crystallized in isopropyl alcohol.
Major advantages realized in the present invention are high yield and high purity. Further no concentration of acidic aqueous solution is required to crystallize Bupropion hydrochloride thus avoiding lower yield. Further use of catalyst during bromination minimizes formation of 3'-chloro-2,2-dibromopropiophenone impurity.
The following examples illustrated the process of the invention:
Example 1
PREPARATION OF BUPROPION HYDROCHLORIDE
Stepl
Preparation of Bupropion base
To a mixture of 3'-chloropropiophenone (50 g) and p-toluenesulphonic acid (0.75 g) in methylene chloride (200ml) a solution of bromine (49.82g) in methylene chloride (50 ml) was added at 15-20°C. After completion of reaction, the reaction mass was

diluted with water. The layers were separated and washed the methylene chloride layer with sodium sulfite solution and concentrated. To the resulting 3'-chloro-2-bromopropiophenone, tert-butylamine (151.8g) was added and stirred at 45-50'C till completion of the reaction. The excess of tert-butylamine was distilled out under reduced pressure and the resulting reaction mass was dissolved in methylene chloride. The reaction mixture was basified with aqueous sodium hydroxide solution and separated. The methylene chloride layer was concentrated to obtain 64g of the bupropion base having purity 97.59% by HPLC.
Step!
Preparation of Bupropion Hydrochloride
Bupropion base (64g) was dissolved in toluene (205ml) and cooled to 0-5^C. To this solution isopropyl alcohol hydrogenchloride (IPA-HCl; 43.2g; 24.8% w/w) was added slowly at 0-10°C and stirred the reaction mass for further 30-40 minutes. The product, which crystallized out during this period was filtered, washed with toluene, isopropanol and recrystallized from isopropanol to obtain 50.6 g of bupropion hydrochloride having purity 99.95% by HPLC.

WE CLAIM;
1. A process for the preparation of Bupropion hydrochloride, of Formula I

which comprises the bromination of compound of formula IV,

in chlorinated solvent selected from carbon tetrachloride, chloroform and methylene chloride, in the presence of a catalyst to prepare a compound of formula VII,

- treating the compound of formula VII with tert-butylamine to prepare bupropion baseof formula VI,

and " treating bupropion base in an organic solvent with isopropyl alcohol hydrogen chloride mixture (IPA-HCl) to prepare bupropion hydrochloride of formula I.
2. The process according to claim 1, wherein the catalyst used for bromination is p-
toluenesulfonic acid.
3. The process according to claim 1, wherein the solvent used during Bupropion
hydrochloride formation is selected from alcohols, ethers, esters and
hydrocarbons and the like or mixture thereof
4. The process according to claim 3, wherein the solvent used is toluene.

Documents:

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Patent Number

279844

Indian Patent Application Number

1323/CHE/2004

PG Journal Number

05/2017

Publication Date

03-Feb-2017

Grant Date

31-Jan-2017

Date of Filing

06-Dec-2004

Name of Patentee

M/S. AUROBINDO PHARMA LIMITED

Applicant Address

PLOT NO. 2, MAITRIVIHAR COMPLEX(REGD OFFICE), AMEERPET, HYDERABAD-500 038.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAMESH DANDALA	PLOT NO. 2, MAITRIVIHAR COMPLEX(REGD OFFICE), AMEERPET, HYDERABAD-500 038.
2	BUDIDET SANKAR REDDY	AUROBINDO PHARMA LIMITED, PLOT NO. 2, MAITRIVIHAR COMPLEX(REGD OFFICE),AMEERPET,HYDERABAD-500 038.
3	SENTHIL KUMAR NATARAJAN	AUROBINDO PHARMA LIMITED, PLOT NO. 2, MAITRIVIHAR COMPLEX(REGD OFFICE), AMEERPET, HYDERABAD-500 038.
4	MEENAKSHISUNDERAM SIVAKUMARAN	AUROBINDO PHARMA LIMITED, PLOT NO. 2, MAITRIVIHAR COMPLEX(REGD OFFICE), AMEERPET, HYDERABAD-500 038.

PCT International Classification Number

C07C 221/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA