FORM-3A
THE PATENTS ACT, 1970
COMPLETE
SPECIFICATION
SECTION 10
TITLE NOVEL PROCESS FOR THE PREPARATION OF 3' CHLOROPROPIOPHENONE

APPLICANT :- BOMBAY DRUGS AND PHARMAS LTD, NAIR BAUG, AKURLI ROAD,
KANDIVALI (E) , MUMBAI 400 001, MAHARASHTRA, INDIA
M/S STRIDES ARCOLAB LIMITED
201, DE VAVRATA, SECTOR 17, VASHI,
NAVI MUMBAI - 400 703, INDIA.
The following Specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed : -

3. NOVEL PROCESS FOR THE PREPARATION OF
3' -CHLOROPROPIOPHENONE
This invention relates to a novel process for the preparation of 3 '-Chloropropiophenone (I). The process herein described is particularly suitable for large scale manufacture of 3'- Chloropropiophenone.
BACKGROUND OF THE INVENTION
3'-Chloropropiophenone [I] is used as a key intermediate for the preparation of Bupropione Hydrochloride (II) [United States Patent No. 3,885,046 (1975), Canadian Patent No. 977,778(1975)]. Bupropione Hydrochloride has been in commercial use as an anti-depressant drug. A new indication for bupropione as a smoke ceasant was recently established, thereby the combination of these two indications make these compound extremely commercially significant.
Bupropione Hydrochloride was originally developed and marketed by Glaxo-wellcome as an anti-depressant drug under the brand name of Wellbrutin. The introduction of new and better anti-depressants like Fluoxetine (Prozac of Lilly), Sertaline (zoloft of Pfizer), Peroxetine (paxil of Smith-Kline Beecham) and Fluoxamine (Luvox of Solvay) etc. in market, made therapy cost unviable for wellbutrin, forcing price reduction to sustain market growth. Simultaneously as aforesaid a new indication for bupropione namely smoking ceasation has been recently established. A new product namely "Zyban" has been brought for this indication combined with the already known indications. The combination of antidepressant and smoking ceasation made bupropione a commercially important molecule compelling the commercial use of bupropione
The above described commercial developments prompted inventing newer and cheaper processes for the manufacture of bupropione commercially. The only known method for the manufacture of bupropione commercially. The only known method ( for the synthesis of Bupropione HC1 is through 3-Chloropropiophenone. This method is described herebelow(l).
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3'-Chloropropiophenone (I) on bromination with bromine (Br2) in presence of
catalytic quantity of aluminium chloride (AICI3) gave a-Bromo-3.'-Chloropropiophenone (1). The latter on reaction with t-Butyl amine (2) in acetonitrile gave Bupropione (3). Bupropione thus obtained is converted into 'Bupropione.HCl (4) on exposure to HCl alcohol followed by usual work-up.

The industrial significance of 3'- Chloropropiophenone as a key intermediary in preparation of Bupropione.HCl and the commercial viability of latter resulted in exploring the possibility of developing a cheaper, one step and industrially viable process for the large scale manufacture of 3'-Chloropropiophenone. A suitable solvent has been used for arriving at the desired low level temperature.
Various methods so far known for the preparation of 3'-Chloropropiophenone are described herebelow. These methods include the preparation of 3'-Chloropropiophenone from 3-Chlorobenzonitrile (4), Propiophenone (8) and 3-chlorobenzoic acid (12). All of these methods have got atypical disadvantages associated therewith.
The known method of preparation of 3'-Chloropropiophenone from 3-Chlorobenzonitrile is as follows: -
3-Chlorobenzonitrile (6) on reaction with Grignard reaction with Grignard reagent derived from ethyl bromide (4) and Magnesium in tetrahydrofurane as a solvent gives Grignard complex (7). The latter on hydrolysis with Aq. acid and usual work-up gave 3'-Chloropropiophenone (I).

The above described method represents a process for the synthesis of the said compound which is viable for laboratory preparations. However when it comes to commercial application, the said process has got a number of limitations. Certain of such limitations are described herebelow: -
a) The said synthesis involves Grignard reaction, and large scale operations will be hazardous
and unviable.
b) All raw materials, required for the synthesis, like 3-Chlorobenzonitrile, ethyl bromide,
magnesium metal as well as THF as solvent are quite expensive ruling out the economic
viability of the product.
The known method for the preparation of 3'-Chloropropiophenone from propiophenone (8) is as follows: -
Propiophenone (8) on nitration gives m-nitropropiophenone (9, major) along with O/P-nitropropiophenone. m-Nitropropiophenone separated by fractionation, hydrogenated in presence of catalyst under pressure to afford m-Aminopropiophenone (11). The latter on diazotization followed by sand mayer reaction gave 3'-Chloropropiophenone (I).

The above described process has got various disadvantages. It is neither synthetically simple nor commercially viable as it suffers from the following disadvantages: -
a) It is a multi step process, involving precise fractionation for separation of isomers.
b) The process involves nitration as well as fractionation of nitration mixture by distillation as well as hydrogenation is potentially dangerous operation and demands specialised facilities.
c) The process involves nitration as well as diazotization steps are associated with large amount of effluent generation.
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d) Over all yield achieved is only ~ 47%
Yet another process for the preparation of 3'-Chloropropiophenone is from 3-Chlorobenzoic Acid (12). This process is best described in the following manner.
3-Chlorobenzoic Acid (12) on reaction with Propionic acid (13) in presence of Iron powder at 250°C/45 mins. furnished 3'-Chloropropiophenone (I).

3-Chlorobenzoic acid Propionic Acid Iron powder I) 3'-Chloropropiophenone
(12) (13) yield 42%
This method suffers from various disadvantages including the following: -
a) The process results in low yield.
b) The very high temperature and involves hydrogen gas evolution at such an high
temperature over a short period and hence will prove very dangerous on commercial
scale and could be run away reaction leading to explosion and fire.
DESCRIPTION OF THIS INVENTION
It was against this background the present invention was brought out .All the known methods reported above for title compound has inbuilt chlorine atom on the 3-position of aromatic ring of the substrate or introduced it through sand-mayer reaction on 3-Aminopropiophenone.
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However, there is no literature report is available using elemental chlorine for selective introduction at 3-position of propiophenone. The general method of introduction of Bromine at 3-position of aromatic ring of a carbonyl compound is as follows;

The above described process involves addition of bromine on to the aluminium chloride complex of the carbonyl compound and is indicated below.

The above process has been commercially used for introduction of bromine at 3-portion with respect to carbonyl moiety on aromatic ring. But there is no prior art available on 3-chloropropiophenone using aluminum chloride complex of propiophenone and introduction of chlorine atom selectively at 3-position
This lead to employing the process of selective meta chlorination of propiophenone aluminum chloride and a systematic investigation of chlorination of propiophenone aluminum chloride complex with a view to bring out a novel, commercially viable and useful process for the preparation of 3'-Chloropropiophenone. The schematic reaction process is given below:-
Anhydrous Aluminum Chloride on addition to propiophenone (6) in Ethylene
Dichloride (EDC) produced Propiophenone-AlCh complex. C12 gas was then purged
at controlled temperature of 13° C to 18°C gave rise to a mixture of chlorinated
propiophenone with m-chloropropiophenone-AlCh complex (23) as major component
with minor o/p complex (24). The latter on hydrolysis with aq. acid, gave 3'-
Chloropropiophenone (I).
The solvent used in this reaction is Ethylene Dichloride and the catalyst used is Aluminium Chloride. Chlorination occurs in Propiophenone AICI3 Complex solution in appropriate quantity of Chlorine Gas. The resultant outcome are m-chloropropiophenone AICI3 complex (23) as the major component and other o/p complex (23) as minor component. This is achieved by metachlorination process.
In aromatic situations there are two positions where the substituents are attacked, one is the ortho/para and the other is the meta position. In the present invention the meta position is more stable than the ortho/para position. The hydrolysis process occurs in the presence of acid (HC1) to get pure 3-chloropropiophenone and regenerates the AICI3 catalyst.

REACTION SCHEME

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EXAMPLE:
A process for the preparation of 3' chloropropiophenone involving charged ethylene dichloride (EDC) and aluminum chloride (224gms), cooled to 20°C, added propiophenone (150 gm) below 20°C over 30 min purged Ch gas (63) betn. the temp. 13 -18°C during 3 hrs. Reaction mass monitored by GC, after completion of reaction, the residue mass decomposed with ice & HC1, the residue was extracted with EDC (100 ml x 2) org Layer washed with alkali followed by water, dried over Na2So4 removed the EDC under reduced pressure, the crude product when fractionated gave (122.6 fm 65.00%) 3-Chloropropiophenone white crystalline solid, GC 99.9%, M.P. 46 – 47OC.
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We Claim:
1. A process for the preparation of 3-Chloropropiophenone comprising:
Reacting propiophenone with anhydrous aluminum chloride in presence of ethylene dichloride (EDC) below 20°C, over 30 minutes Cl2 gas being purged at controlled temperature of 13°C to 18°C.
2. A process for the preparation of 3-Chloropropiophenone as substantially
herein described with reference to the Example.

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