THE PATENT OFFICE

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ql laq INDIAN PATENT SPECIFICATION

(51) Int. CI : C I)7 C - 25/00,25t24 ’11) DocumentNo. IN t O

A Date of document : 25.08.2000
(52) Ind. CI. 32 F, (1) (42) Dote of Publication : G. tl. 02...

(21) Application No. 780 MUM 2000 (71) Applicant : BOMBAY DRUGS & PHARMAS LTD,
NAIR BAUG,AKURLI ROAD,KANDIVLI (E),
MUMBAI 400 001, MAHARASHTRA, ]INDIA.
(22) Date of filing : 25.08.2000

(72) Inventors :
(1) DR.GOPAKIJMAR G.NAIR
{2) DR.V.D.PATIL
(3) K.R.MORE
(74) Agent : MYs. LEX ORRIS
Claims : 02
Text : 12 Pages : Drgs .NIL Sheet EXAJVIINER : SttRI N.RAMCHANDER

(54)Title : NOVEL PROCESS FOR THE PREPARATION OF YCHLOROPROPIOPHENONE.

(57) Abstract : A Process for the preparation of 3"chloropropiophenone by way of selective

metachlorination of propiophenone aluminum chloride complex at a

controlled 13 degree-18 degree C in chlorinated aliphatic solvent:. The

pmcess produces as yield as high as 65% therefore particularly suitable of

commercial production.

PRICE : THIRTY RUPEES

 Form 1

THE PATENT ACT, 1970

(39 of 1970)

Application for Grant of a Patent

[See sections 5(2), 7, 54, and 135 and rule 33A]

We,

(a) Bombay Drugs and Pharmas Limited,

(a) Nair Bang, Akurli Road, Kandivile (E), Mumbai 400 001, State of
Maharashtra, India

(b) Nationality - Indian

2 Hereby declare -

(a) that we are in possession of an invention titled "Novel Process for

the Preparation of 3’Chloropropiophenone"

(b) that the complete specification relating to this inventions ts filed

with this application

(c) That there is no lawful ground of objection to grant of a patent to

us

3 Further declare that the inventors for the said inventions are

Nair, Dr. Gopakumar, G.

(b) Nair Bang, Akurli Road, Kandivile (E), Mumbai - 400 001
(c) Indian National

{a) Patil, Dr. V. D.,

(b) Nalr Bang, Akurh Road, Kandlvde (E), Mumba1 - 400 00l
(c) Indian Nanonal

(a} More, K. R.,

(b) Nalr Baug, Akurh Road, Kandwde (E), Mumbai 400 001
(c) Indian Nanonal
4. We, claim the priority from the applications filed in convention countries,
particulars of which are as follows:

Not Applicable

5. We state that the said invention is an improvement in or modification of the

invention, the particulars of which are as follows and of which I/We are the
applicant/patentee:

Not Applicable

6 We state that the application is divided out of my/our application, the

particulars of which are given below and pray that this application deemed to
have been filed on ................... under 16 of the Act.

Not Applicable

7. That we are the assignee of the tr e and first inventors

8. That our address for service in India is as follows:

l x Orbls,
Intellectual Property Attorneys,
B-l! 39,
Malviya Nagar,
New Delhi-100 017

9 Following declaration was given by the inventors or applicants in the

convention country

We, the true and first inventors for this invention decLare that the apphcant
herein is our assignee

Dr. Gepakumar, 6. Nair

Nair Baug, Akurli Road, Kandivile (E), Mumbai - 400 001

Dr. V. D. Paril
Nair Bang, .Ak rh Rodd, Kzndivile (E), Mumbai 400 001

K. R. -h re
Nan1 B u .\kuth l(t Itl K,1 nd1 de ll ) NItHnba1 4rill Ib111
 10 That to the best of" our knowledge, information and belief the fact that and
matters stated herein are correct and that here is no lawful ground of objection
to the grant ofpatem to us on this application

11 Following are the attachment with the application

(a) Complete specification [3 copies]

(c) Power of Attorney in Form 26 in original

(b) Declaration as to lnventorship in Form 5 [in original]

We request that a patent may be granted to us for the said invention

Dated this the 25th Day of Au

Vasudevan Nair
Patent Attorney

LEX ORBIS
[Intellectual Property Attorneys]
B - 1/39, Malviya Nagar
New Delhi - 110 017

To,
The Controller of Patent,
The Patent Office,
At Mumhai
5. abstract
A process for the preparation of 3’-Chlosophepnone by way of defective
metachlodnation of propiophenone aluminum chloride complex at a controlled 13o -
lS°C in chlorinated aliphatic solvent. The process ¢ as yield as high as 65%

therefore particularly suitable of commercial production.

 THE PATENTS ACT,1970

COMPLETE

SPECIFICATION
SECTION 10

The following Speeifieation particularly describes 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 hloroprepiophenone [I] is used as a key intermediate for the preparation of

Buproplone Hydrnohkirid¢ (II) [United States Patent No. 3,885,046 (1975), Canadian
Patent No. 977,77g(1975)]. Bupropione Hydrochloride has been in commercial use as
an anfi-depressmat drug. A new indication for bepropione as a smoke peasant was
recently established, thereby the combination of these two indications make these
compound extremely commercially si ficant.

Bupropione Hydrochloride was originally developed and marketed by Glaxo-

wellcome as an anti-depressant drag under the brand name of Wellbrutin. The
introdttetion of new and better anti-depressants like Fluoxetine (Prozac of Lilly),
Serteline (zoloR of Pfizer), Peroxetine (paxil of Smith-Kline Beecham) and
Fluoxamlne (Luvox of Solvay) etc. in market, made therapy cost unvlable 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 anti-
depressant and smoking eeasatlon made bupropione a commercially important
molecule compelling the commercial use of bupropinne

The above described commercial developments prompted inventing newer and

cheaper processes for the manufacture of bepropione commercially. The only known
method for the manufacture of bupropione commercially. The only known method
for the synthesis of Bupropione HCI is through 3-Cbteropropiophenone. This method
is described berebelow(l).

2
3’-Chloropropiophenone (1) on bromination with bromine (Br2 ) in presence of
catalytic quantity of aluminium chloride (AICI ) 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.HCI (4) on exposure to HCI alcohol followed by
usual work-up

Br2/Alcl3
tm

ar

C( CI

I) 3’-Chloropropiophenone ( I ) ct-Bromo-3’ -Chloropropiophenone

121 [31

CH3

CH3 CH3
C fr’{3 NH2 /CH3CN HCI/AlcohoI,.
CH3
C(
t-Butyl am ne/Acelonitnle

(11) Buproplone HCI

(41

Ct
..g-
I h "111dlJMr1al Ngnllicance of - ( hh)Ioproph llht’no]IL" ,I’ a k mlemlcd]ar,, ff

preparanon of Buproplone f{CI and the commercial \taNht of latte1 resulted m exploring the

poss]Nhty of developing a cheaper, one step and mdusmallv sable process for the large scale

manufacture of 3’-Chloroproplophenone A suitable solvent has been used for arrtvtng at the

desired low level temperature

Various methods so far known for the preparalmn of -Chloropropmphenone are described

herebelow These methods include the preparatmn of 3’-Chloroproplophenone from 3-

Chtorobenzonitrile (4), Proplophenone (g) and 3-chlorobenzotc actd (I2) All of these

methods have got atypical disadvantages associated therewith

The known method of preparation of 3’-Chloroproptophenone from 3-Chlorobenzomtnle Is as

follows -

3-Chlorobenzonitrile (6) on reaction with Grignard reaction with Gfignard 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’-

Chloroproptophenone (l)

THF (5) C
CH3 CH2 Br + Mg " CH3 CH2 MgBr
3-Chlorobenzonitrd (6)
Ethyl bromide Magnesium
(4)
N MgBr
H÷/H-,O

Cl
Cl
(7)

I) 3 ’ -Chloropropiophenone
bitch IS viable for laboratory separation th e er hen it comes lo commerc]al applLcat )n,

d e said process has gol a number ol" hmHat*ons Certain of such limitations are described

herebelow -

a) The said synthesis invol’,es Gr*gnald reacuon, and Large scale operations will be hazardous
and unviable

b) All raw materials, required lbr Ihe synthesis, like 3-Chlorobenzonitrile, ethyl bromide,

magnesium metal as wet[ as THF as solves are qune expensive ruling out the economic

viability of the product

The known method for the preparation of 3’-Chloroprop ophenone fiom 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 reacmm gave 3’-Ch!oropropiophenone ([)

0 CHa 0
Fractionation
O Nitration
Ii.

NO2
NO2
O/P-Nitropropiophenone
m-nitropropiophennne (Minor)
(Major) (9) (10)

Propiophenone

(s)
 CH3

Hydrogenation
H2/Catalyst
Pressure NH2
No2 m-Aminopropiophenone (11 )
rn-nitropropiaphenane (9)

O
CH3
1 ) Diezotization
2) Sand-Mayer
reaction
CI
(I) 3’Chloroproplophenone

The above described process has got various disadvantages It is no=thor syntheucally smlp[e

nor commercially viable as it suffers from the following disadvantages -

a) h is a multi step process, revolving precise fractionation for separation of isomers

b) The process involves nitration as well as fractionation of nitration mixture by dlstdlat=on as

swell as hydrogenation s potenually dangerous operation and demands speclahsed

t’dC1J1l leS

]he process Ill ol e ; llltldttt}ll d, ell a d1 azottzatlon steps are associated 1 th large

dl!lOtnlt l’et’l]L1 er1 l etl ,lllt}]l

d) Over all yield achieved is only 47%

Yet another process for the preparation of Y-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 rains fitrnished 3’-Chloropropiophenone (1)

+ H2
+ CH3 COOH + Fe 250°C/4 mins

Cl CI

3-Chlorobenzoic acid Propionic Acid Iron powder 1) 3’-Chlaropropiophenone

(12) f13) yield 42%

This method suffers from various disadvantages including the following: -

a) The process results in low yield

b) The very high temperature and imotves 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 Reading to explosion and fire

DESCRII ILQ.N. QI" Tills INVESTIGATION

h a against lh s background the presel]l ]n enlltln v as brought out All the known method

leporled aht e t i lille ctlmi ounLI h,t inht11 h :hl lrlrle atom rl he LpOSlliOrl o " iron/ l ic rlll

fltl1e st1 h Ildte tit irlttt dt1 c 2d n lhI L h dll1 ]-nla t21 reaction 11 At llnopropl phelqollc

-7-
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,

0
0
O
R ÷

BF O/P (Minor)
R = H/alkyl
(Major)

(14) (15) (16)

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

R R

+ AICI3

(14) (17)

AICI3 + HBr

gt
(]8)

HTO/H* +AI3" +3CL

BF
s
The above process has been commercially used for introduction of bromine at 3-
pofition with respect to carbonyl moiety on aromatic ring. But there is no prior art
available on 3-chloropropiophenone using aluminum chloride complex of
propiophenon¢ and introduction of chlorine atom selectively at 3-position

Fhis 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 Propinphenone-AICI3 complex. C12 gas was then purged

at eonta’olled temperature of 13° C to 18°C gave rise to a mixture of chlorinated

pmpiopbenone with m-chloropropiophanona-AIC13 complex (23) as major component
with minor o/p complex (24). The latter on hydrolysis with aq. acid, gave 3’-
Chlaropropiophenone (1).

The solvent used in this reaction is Ethylene Dichloride and the catalyst used is
Ainm:1ff um Chloride. Chlorination occurs in Propiophenona AICI3 Complex solution

in appropriate quantity of Chlorine Gas. The resultant outcome are m-

chloropropiophenona AIC13 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 rnela position. In the presen! 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-chioropropiophanone and regenerates the
AICI catalyst
REACTION SCHEME

OCHs + AICI3

(20)
Propiophenone (6)

i-’ cH3
" cH3 A "*" HCI

CIn n= 1 or 2
CI 2% 2’.5’-, 2’,3’-
(Ma)or) (Minor)

^ ( CH3 " + 3CI-

CH
+ C n0 +AI
,,

Cl
(I) 125)

3’- Chloropropiophenone 2 -, 2,5 2 3 -, chloroprop ophenone

10
EXAMPLE

A process for the preparation of 3’ chloropropiophenone involving charged ethylene

dichloride (EDC) and aluminum chloride (224gms), cooled to 20°C, added
propiophenone (I 50 gm) below 20°C over 30 rain purged CI2 gas (63) bern the temp

13 -18 C during 3 hrs. Reaction mass monitored by GC, after completion of reaction,
the residue mass decomposed with ice & HCI, the residue was extracted with EDC

(100 ml x 2) org Layer washed with alkali followed by water, dried over Na2 So4
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 - 47¢C.

//
We Claim:

1. A process for the preparation of 3-Chloropropiophenone comprising:

Reacting propiophenonc with anhydrous aluminum chloride in presence of

ethylene dichloride (EDC) below 20°C, over 30 minutes CI2 gas being purged at
conlmlled temperature of 13°C to 18aC.

2. A process for the preparation of 3-Chloropmpiopbenone as substantially

herein described with reference to the Example.

Dated this the 13th Day of December 2001

C ["XM:noj’N asudevan Nalr

Agent for the Applicant
LEX ORBIS
Intellectual Property Attorneys
B-II39, Malviya Nagar
New Delhi - 110 017

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