FORM2THE PATENTS ACT, 1970(39 of 1970)&The Patents Rules, 2003PROVISIONAL SPECIFICATION(See section 10; rule 13)
1. Title of the invention - AN IMPROVED PROCESS FOR PREPARING BUPROPION HYDROCHLORIDE.
2. Applicant(s)(a) NAME:(b) NATIONALITY:(c) ADDRESS : ALEMBIC LIMITEDAn Indian Company.Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

Field of the invention:
The present invention relates to an improved process for preparing Bupropion Hydrochloride of formula (I). The present invention also provides a process for purification of Bupropion hydrochloride.

Background of the invention:
The chemical name of Bupropion is l-(3-Chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propanone and formula is C13H18CINO and molecular weight is 239.74. The current pharmaceutical product containing this drug is being sold by Glaxosmithkline using the tradename Wellbutrin SR, in the form of tablets.
Bupropion is used as Antidepressant. It acts as dopamine reuptake inhibitor. It is also used as antiobesity drug. It is used in treatment of attention deficit hyperactivity disorder(ADHD), neuropathic pain and smoking cessation. It also aid to treatment of substance dependency.
US patent 3,819,706 describes a process for the preparation of Bupropion Hydrochloride which is as shown in the scheme below.

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The process involves reacting m-chlorobenzonitrile (II) with ethyl magnesium bromide and subsequent hydrolysis with dilute hydrochloric acid gives m-chloropropiophenone (IV) which is further reacted with bromine in methylene chloride to give m-chloro-α-bromopropiophenone (V). This compound on reaction with t-butylamine in acetonitrile and subsequent treatment with hydrochloric acid gives bupropione hydrochloride (I). In this process when the reaction of m-chloropropiophenone with bromine is conducted in methylene chloride, hydrobromide gas is evolved. To trap this hydrobromide gas special kind of arrangement is nessasary to set up like basic trap or acid scavenger or any other equivalent method. This makes the process at industrial level inconvenient. The amount of hydrogen bromide in the effluent obtained after work up procedure can also be a problematic while draining it for ETP with lots of neutralizing compound. Moreover reaction of m-chloro-α-bromopropiophenone (V) with t-butylamine is also very slow. This is also a factor which adds up to increase of overall cost of the production. The product is purified by recrystallization from mixture of IPA and absolute ethanol.
It is therefore, a need to develop a process which not only overcomes the disadvantages of the prior art but also be economical, operationally simple and industrially applicable.
Present inventors have directed their research work towards developing a process for the preparation of Bupropion hydrochloride which is devoid of the above disadvantages. In the process of present invention, the generated hydrogen
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bromide is dissolved in water and need not special kind of apparatus to trap it. While doing work up the hydrogen bromide remains in water layer and can be easily removed from product which remains in organic layer. The use of catalyst such as N-methyl pyrrolidone (NMP) or N, N-dimethyl formamide (DMF) increases the rate of reaction for formation of bupropion. The present inventors also found improved purification method for bupropion hydrochloride.
Summary of the invention:
It is therefore an object of the present invention to provide an improved process for the preparation of Bupropion Hydrochloride.
Another object of the present invention is to provide a process which gives bupropion hydrochloride with high purity.
Another object of the present invention is to provide a process which is simple and easy to handle at an industrial scale.
Yet another object of the present invention is to provide a process for purification of bupropion hydrochloride.
Accordingly, present invention provides an improved process of preparation of Bupropion Hydrochloride comprising steps of:
(i) reacting m-chloropropiophenone (IV) with bromine in water and optionally in the presence of acid to obtain m-chloro-a-bromopropiophenone (V);
(ii) reacting the m-chloro-α-bromopropiophenone (V) with t-butylamine in the presence of catalyst such as N-Methyl pyrrolidone (NMP) or N,N-dimehtyl formamide (DMF) to provide bupropion;
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(iii) reacting bupropion with Hydrochloric acid to give bupropion hydrochloride.
Another aspect of the present invention provides a process for purification of bupropion hydrochloride comprising steps of
(a) stirring impure bupropion hydrochloride with methanol and filtering through hyflobed;
(b) removing methanol from filtrate;
(c) adding isopropyl alcohol to the mass obtained after removal of methanol;
(d) isolating the solid.
Detailed description of the invention:
The present invention provides an improved process of preparation of Bupropion Hydrochoride comprising steps of:
(i) reacting m-chloropropiophenone (IV) with bromine in water and optionally in the presence of acid to obtain m-chloro-a-bromopropiophenone (V);
(ii) reacting the m-chloro-α-bromopropiophenone (V) with t-butylamine in the presence of catalyst such as N-Methyl pyrrolidone (NMP) or N,N-dimehtyl formamide (DMF) to provide bupropion;
(iii) reacting bupropion with Hydrochloric acid to give bupropion hydrochloride.
In the process of present invention, bromine is reacted with m-chloropropiophenone (IV) in water at about 20° to about 35°C during 30 to 60 minutes via dropwise addition. This reaction can also be carried out in the presence of acid like hydrochloric acid or aluminium chloride. Generally the
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reaction completes within 1-3 hours. The progress of the reaction is monitored by TLC. After completion of reaction, organic solvent such as toluene, xylene or ether and sodium thiosulphate solution is added to the reaction mass. The organic layer is separated. The organic layer is twice washed with water and then with brine. The organic layer thus obtained is taken for next step. The organic layer containing m-chloro-α-bromopropiophenone (V) is reacted with t-butylamine in the presence of catalyst such as N-Methyl pyrrolidone (NMP) or N,N-dimehtyl formamide (DMF). NMP acts as catalyst and facilitates to increases the rate of the reaction. The reaction is carried out at about room temperature to about 80°C, preferably 60°C to 65°C for 3 to 6 hours. The progress of the reaction is monitored by TLC. After completion of the reaction, water is added to the reaction mixture. The organic layer is separated and washed twice with water and then with brine. To this organic layer HC1 in isopropanol (IPA-HC1) is added at about 0°C to about 10°C till pH 2 is obtained. The reaction mixture is stirred for about 1 hour at the same temperature. The resulting solid bupropion hydrochloride is isolated by conventional methods such as filtration, decantation or centrifugation.
The product obtained by above process is having purity greater than 99% by HPLC.
The synthetic reaction scheme of the present invention is as shown below.

Another aspect of the present invention provides a process for purification of bupropion hydrochloride comprising steps of
(a) stirring impure bupropion hydrochloride with methanol and filtering through hyflobed;
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(b) removing methanol from filtrate;
(c) adding isopropyl alcohol to the mass obtained after removal of methanol;
(d) isolating the solid.
"Impure bupropion hydrochloride" means bupropion hydrochloride having purity 99.8% or less. Isolation of the solid can be done by filtration, decantation or centrifugation methods. Preferably, it is done by filtration.
In the process of present invention, the purification can be achieved by stirring impure bupropion hydrochloride with methanol at ambient temperature about 20°C to about 35°C. Most of the product dissolves in methanol. The solution is filtered through hyflobed to remove any kind of undissolved particles or impurity. Methanol is evaporated from filtrate to give solid mass to which isopropyl alcohol is added. The isopropyl alcohol is distilled out. This is repeated twice to remove trace amount of methanol. Finally isopropyl alcohol is added to solid mass and heated to reflux for 30 min. The suspension is cooled at about 25°C to about 35°C and stirred for 1 hour at the same temperature. The solid product is isolated by conventional methods such as filtration, decantation or centrifugation. The solid is washed with isopropyl alcohol and suck dried. The product is dried in vacuum dryer at 70°C to 75°C till LOD is obtained below 0.5%.
The product purified by above process is having purity about 99.9% pure.
The following examples illustrate the invention further. It should be understood, however, that the invention is not confined to the specific limitations set forth in the individual examples but rather to the scope of the appended claims.
Example-1
(a) Preparation of m-chloro-α-bromopropiophenone
Bromine (46.45g) was added to a stirred suspension of m-chloro propiophenone (100g) in D.M. water (500ml) dropwise during 30 to 60min at 20°C to 35°C. The
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reaction mixture was stirred for 1 hour at 20°C to 35°C. The progress of the reaction was monitored on TLC. After completion of reaction, toluene (500ml) and sodium thiosulphate solution was added to the reaction mixture and stirred for 30min at the same temperature. The organic layer was separated and washed with water (500mlx2) and brine (500ml). The organic layer was taken for next step.
(b) Preparation of bupropion
N-methyl pyrrolidone (NMP) (100ml) was added to organic layer obtained in step (a) and stirred at 20°C to 35°C. Tertiary butyl amine (108.3g) was added to the above reaction mixture and heated to 60°C to 65°C for 3 hours. The progress of the reaction was monitored on TLC. After completion of reaction, water (500ml) was added and stirred for 30min at 20°C to 35°C. The organic layer was separated and washed with water (500mlx2) and brine (500ml). This organic layer was taken for next step i.e. hydrochloride salt preparation.
(c) Preparation of bupropion hydrochloride
The organic layer obtained in step (b) was cooled to 0°C to 10°C. Isopropanol
saturated with hydrochloric acid (IPA-HC1) was added slowly until pH 2 of the
reaction is obtained. The reaction mixture was stirred for 1 hour at the same
temperature. The solid was filtered and washed with toluene (100ml). The solid
was suck dried and dried in oven at 70°C to 75 °C to give bupropion hydrochloride
(120g).
HPLC purity: 99.8%
Example-2
Impure bupropion hydrochloride (120g) was stirred with methanol (360ml) at 20 to 35°C. The mixture is filtered through hyflobed. The hyflobed was washed with methanol (120ml). The combined filtrate was distilled completely to get mass. To
the mass, isopropyl alcohol (60ml) was added and distilled out under vacuum at 55°C to 60°C. Again isopropyl alcohol (60ml) was added and distilled out under
vacuum at 55°C to 60°C. Isopropyl alcohol (600ml) was added and heated to
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reflux for 30 min. The suspension was cooled to 25°C to 35°C and stirred for 1 hour. The solid was filtered and washed with isopropyl alcohol (120ml) and suck dried. The solid was dried in vacuum dryer at 70°C to 75°C till LOD is obtained below 0.5% to get pure bupropion hydrochloride (l00g)
HPLC purity: 99.9%
Dated this 12th day of February 2007

Ashwini Sandu
Of S. Majumdar & Co. Applicant's agent

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