FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
1. TITLE OF THE INVENTION: New-route of Synthesis of rn-Bromoanisole
2. APPLICANT(S)

(a) NAME: Adhirath Sanjay Wagh
(b) NATIONALITY: Indian
(c) ADDRESS: Matru Darshan, Opposite Vasant market, Old Gangapur Naka, Nashik-422 005, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which is to be performed.
4. DESCRIPTION (Description shall start from next stage.)
Field of invention:
The invention relates to the field of synthetic chemistry. Background of Invention:
3-Bromoanisole or meta-bromoanisole (MBA) is an intermediate in the pharmaceutical field. In particular, it is used for producing the analgesic drug tramadol, tapentadol, raloxifene, etc. Among the few known methods for preparing MBA, the most frequently encountered one is based on the methylation of 3-bromophenol. Hewett, J. Chem. Soc. 50-52 (1936)' and Natelson, Gottfried, J. Amer. Chem. Soc. 61, 1001-1002 (1939)' gave synthesis of m-bromophenol by diazotization starting from m-bromoaniline or m-aminophenol. Berti et al., Ann. Chim., 49, 1237, 1248 (1959)" reported a method for preparing MBA from meta-anisidine, via a diazotization reaction.Kadaba et al in J. Org.

Chem,22; 333-334 (1957)'"reported sequence of reaction of nitrobenzene by sulfonation, alkali fusion, reduction, acidification, diazotization and replacement by bromo group and etherification to get MBA. The yield is low (only 21.5%) and this lengthy route of synthesis cause serious environmental pollution. These methods which use m-amino phenol followed by diazotization (i.e. Sandmeyer's reaction involving cuprous bromide) provide maximum yields up to 70%.
The important difficulty of the known processes for the industrial preparation of MBA with m-amino phenol as starting material is that it inexpensive and insufficiently. Lie et aliv in patent CN 101333153 B disclosed a method with steps.
(1) The preparation of m-bromonitrobenzene, with bromination under the catalytic action of H2O2. The use of H2O2 helps to reduce requirement of bromine. The quantity of bromine is reduced by half compared with that used in the traditional technology.
(2) During the preparation of 3-bromoaniline, FeCl3 with activated carbon catalyst and hydrazine hydrate is used. The reaction between the FeCl3 and hydrazine hydrate provides hydrogen source and the reaction is homogeneous. This reduces the iron sludge/mud generation as compared to traditional technology. The m-bromophenol is methylated to get MBA. The methylation of m-bromophenol can be done with dimethyl sulfate under solvent-free conditions. Or else can be carried out in alkaline condition followed by extraction with ether. .
Other processes for m-bromonitrobenzene include methods developed by Johnson and Gauerke, v"Organic Synthesis", Coll. Vol. 1, 123-124 (1956) by bromination of nitrobenzene with bromine in the presence of iron powder. Tronov et al.vi (Chem. Abstr. 55:8347i and 49:13133d), used bromine, sulphuric, nitric and acetic acid. Also using bromine and catalysts such as aluminum, sulphur and tellurium was reported by Derbyshire and Waters,vii J. Chem. Soc, 573-577 (1950); with hypobromous acid by Harrison, et al viiiixU.S. Pat. No. 4,418,228 and J. Org. Chem., 46, 2169-2171 using potassium bromate by Gelmont and Zilberman U.S. Pat. No. 6380440 Bl using bromine in oleum. The bromination of nitrobenzene by any of these ways is a painstaking process.
The recently disclosed method of MBA synthesis also uses m-nitrobenzene. Gemlmont and ZilbermanxU.S. Patent No. 6380440 Bl had reported a one-step preparation of m-bromoanisole and others from the corresponding m-substituted nitrobenzene by nucleophilic aromatic substitution of the nitro group with sodium or potassium methoxide, employing an effective amount of a phase-

transfer catalyst, in a medium of a non-polar aprotic solvent, under aerobic conditions, at a temperature of 50-65 °C. This methoxy denization process was very sensitive to the type of phase-transfer catalyst. The phase-transfer catalyst used is tetra-n-butyl ammonium bromide12. The recovery of TBAB is not quantitative. Rising price of TBAB, KOH and NaOH are also the factors of concern.
The principal disadvantage of the known processes for the industrial preparation of MBA is that they are based on expensive and insufficiently accessible starting materials and/or costly catalysts. It is a purpose of this invention to provide a new and convenient route for the preparation of MBA. The method involves conversion of mixture of p-chloronitrobenzene (PNCB) and o-chloronitrobenzene (MNCB) to mixture of p-anisidine and o-anisidine followed by direct bromination under simple conditions to m-bromoanisidine. Prior art:
m-Bromoanisole is important intermediate for Tramadol ( postsurgical analgesic ).The literature reports for the synthesis of m-Bromoanisole covers various routes of synthesis, e.g:
1. m-Aminophenol to m-Bromophenol to m-Bromoanisole
2. m-Bromonitrobenzene to m-Bromoanisole by phase transfer catalyst
At present the conventional route is in commercial practice. The route 2 suffers from few drawbacks like the painstaking bromination of nitrobenzene as well as there are several issues related to bromination process. This process is very cumbersome and few isomers are also formed. The present investigation reports a new simple and cost effective method for the synthesis of m-bromoanisidine. Nitration of chlorobenzene gives 60:40 mixture of p-nitrochlorobenzene and o-nitrochlorobenzene is well known in industrial practice. The ortho-para mixture is produced in commercial scale by several manufacturers which is further separated to p-nitrochlorobenzene and o-nitrochlorobenzene.
Object of the invention:
Object of the invention is to develop novel, simple and cost effective method for synthesis of m-bromoanisole or 3-bromoanisole.
A summary of the invention:
The present investigation utilizes the p-nitrochlorobenzene and o-nitrochlorobenzene mixture available commercially. This mixture is converted to p-nitroanisole / o-nitroanisole by treatment

with sodium methoxide at elevated temperature and pressure. This mixture is further hydrogenated to o-anisidine / p-anisidine. Bromination of this mixture at lower temperature gives a mixture of 3 products viz. 2-bromo-4-methoxyaniline, 2-methoxy-4-bromoaniline, 2-methoxy-6-bromoaniline.This mixture is deaminated using sodium nitrite, hydrochloric acid, ethanol and copper powder to a single product m-Bromoanisole in 70% yield.
A brief description of the accompanying drawing:
The drawings in the sheet consist of structural formulas of m-Bromoanisole and the synthetic scheme for the synthesis of the same.
Detailed description of the invention:
The present investigation reports a new simple and cost effective method for the synthesis of m-bromoanisidine. Nitration of chlorobenzene gives 60:40 mixture of p-nitrochlorobenzene and o-nitrochlorobenzene is well known in industrial practice. The ortho-para mixture is produced in commercial scale by several manufacturers which is further separated to p-nitrochlorobenzene and o-nitroch!orobenzene.
The present investigation utilizes the p-nitrochlorobenzene and o-nitrochlorobenzene mixture available commercially. This mixture is converted to p-nitroanisole / o-nitroanisole by treatment with sodium methoxide at elevated temperature and pressure. This mixture is further hydrogenated to o-anisidine / p-anisidine. Bromination of this mixture at lower temperature gives a mixture of 3 products viz. 2-bromo-4-methoxyanilineJ 2-methoxy-4-bromoaniline, 2-methoxy-6-bromoaniline.This mixture is deaminated using sodium nitrite, hydrochloric acid, ethanol and copper powder to a single product m-Bromoanisole in 70% yield.
Important points in synthesis
• m-amino phenol cost of amino phenol is expensive
• Second step is Sandmeyer's reaction involving cuprous bromide
• Yield of bromination by snadmeyers is maximum 70% Cost of MBA is more than Rs2000.
• Bromination of nitrobenzene is painstaking process Rising price of TBAB, KOH and NaOH.
• Recovery of TBAB is not qualitative.
• Margins are under pressure

• Advantages of developed method
• Relatively cheaper availability of o/p anisidine mixture The reason being the cost of seprataion of PNCB/ONCB is obviated
• Direct bromination under simple conditions to monoibromo anisidine
• Isomer free MBA in 70 to 80%
• Cost effective process compared to existing industrial process.
EXPERIMENTAL PART
The different steps involved in the newly developed method of synthesis of m-bromoanisole are
illustrated below:
Examples:
i. Stepl:
A) 236.4 gm of equivalent mixture of o/p-nitrochlorobenzene was taken in 4710 ml of methanol
containing sodium methoxide (122.49gm), copper oxide(5.9gm),TBAB (tetra butyl ammonium
bromide ) (23.55g) . Pressure raised to 6 kg. Reaction was carried out for 6-8 hours. Check the GC
for the presence of p-nitrochlorobenzene and o-nitrochlorobenzene and the autoclave is cooled
toroom temperature . The methanol removed under vacuum and the residue is treated with 2364ml
of water acidify to pH 1 and extract with 2 X 300ml ethyl acetate. The extract was dried on
anhydrous NaSO4 and concentrated to yield a mixture o/p-Nitroanisidine. The GC purity 98%
(aggregate).
B) 236.4 gm of equivalent mixture of o/p-nitrochlorobenzene was taken in 4710 ml of methanol
containing 112.3 gm of sodium methoxide , copper oxide (5.955gm), TBAB (tetra butyl ammonium
bromide) (23.55 gm). Pressure raised to 6 kg .reaction was carried out for 6-8 hours. Check the GC
for the presence of p-nitrochlorobenzene and o-nitrochlorobenzene and the autoclave is cooled to
room temperature. The methanol removed under vacuum and the residue is treated with 2364 ml of
water. Acidify to pH 1 and extract with 2 X 300ml ethyl acetate. The extract was dried on anhydrous
NaSO4 and concentrated to yield a mixture o/p-nitroanisidine. The GC purity 98% ( aggregate )
ii. Step-2 A) The concentrate bottom of example 1 A or 1 B dissolved in methanol and hydrogenated over

nickel catalyst (3 to 5 % of the starting of o/p-nitroanisidine) between 3-5 kg H2 pressure. The completion of reaction check by GC .The catalyst was filtered and reaction mass was concentrated and taken as such for next batches.
B) The concentrate bottom of example 1A or 1B dissolved in methanol and hydrogenated over nickel catalyst (5 to 7 % of the starting of o/p-nitroanisidine) between 3-5 kg H2 pressure. The completion of reaction check by GC .The catalyst was filtered and reaction mass was concentrated and taken as such for next batches.
ii. Step-3.
A) The o/p-anisidine mixture is monobrominated by bromine/acetic acid 184725 gm of aggregate mixture dissolved in 775.84ml of acetic acid and 820.2 ml of chloroform. 264 gm of bromine was dissolved in chloroform and added to 0° c over the period of 6-8 hr. The reaction mass stirrer and allowed to 2 hr. and water was added neutralize to pH 6 by addition of sodiumcarbonate. The reaction mass was extracted with 3 x 200L chloroform. The chloroform was removed under vacuum the brominated mass weighs about 272 gm. The residue was as such for step-4.
B) The o/p-anisidine mixture is mono-brominated by bromine / acetic acid. 184.8gm of aggregate mixture dissolved in 775.8ml of acetic acid and 820.179 ml of chloroform. 208 gm of bromine was dissolved in chloroform and added to 0 c over the period of 8-10 hr. The reaction mass stirred and allowed to stand for 2 hr and water was added neutralize to pH 6 by addition of sodium carbonate. The reaction mass was extracted with 3 x 200 ml chloroform. The chloroform was removed under vacuum the brominated mass weighs about 272gm. The residue was used as such for step-4.
v. Step-4 A) The residue of step-3 dissolved in 4410ml of aqueous 15% H2SO4, equivalent amount of ethanol was added. It was diazotized at 0°C using 103.5 gm of Sodium nitrite after the addition of Sodium nitrite completed, 10% by weight of monobromoanisidine copper powder was added and the mixture is heated to 60°C vigorous evaluation of acetaldehyde and nitrogen takes place. The reaction is cooled after 3 hr. and dilute with Hit water followed by extraction with chloroform (3 x 50 ml). The chloroform extract was washed by 3 x 50ml 5% Na2CO3 solution. The extract was dried chloroform is removed. The yield obtain is = 197 gm of m-bromoanisole

B)The residue of step-3 dissolved in 4410 ml of aqueous 15% H2SO4, equivalent amount of ethanol was added. It was diazotized at 0°C using 103.5gm of sodium nitrite. After the addition of Sodium nitrite completed. 1855ml of 30% hypophosphorus acid was added and stirred overnight at 0-5°C. The reaction was cooled for 3hr and diluted with 1L water followed by extraction with chloroform (3 x 50ml). The chloroform extract was washed by 3 x 50 ml, 5% Na?C03 solution. The extract was dried and chloroform is removed.
The yield obtain is 192gm of m-bromoanisole. Example 1> 4-methoxyphenylurea:-
Dissolve 12.3 gm of p-anisidine in 10 ml of glacial acetic acid diluted to 100 ml contained in a 250 ml conical flask, and add with stirring a solution of 6.5 gm of sodium cyanate in 50 ml of warm water.AUow to stand for 30 minutes, then cool in ice, and hold for 30 minutes. Filter at pump, wash with water and dry at 100°C . The 4-methoxyphenyl urea weighs 15.7gm. M.P. 162-164°C . Example 2:-
2-bromo-4-methoxy phenyl urea:-
Dissolve 16.6 gm 4-methoxyphenylurea in 55 ml glacial acetic acid in 500 ml round bottom flask and bring the reaction mixture temperature to 0 C . Meantime, in another flask dissolve 17 gm (5.3 ml) of bromine in 25 ml of glacial acetic acid. Add bromine solution slowly with constant stirring maintaining reaction mixture temperature in 0°C to 5°C . When all the bromine has been added, solution will have an orange colour due to the slight excess of bromine. Allow the final reaction mixture to stand at room temperature for 30 minutes with stirring. Pour the reaction mixture into 400 ml of water and rinse the flask with about 100 ml water. Stirr mixture well. Filter crystalline precipitate over Buchner funnel, wash thoroughly with ice cold water. Dry at 100 C. 2-bromo-4-methoxy phenyl urea (melting point more than 300°C) weighs 17.13 gm Example 3:-
2-bromo-4-methoxy phenyl urea:-
Dissolve 16.6 gm 4-methoxyphenylurea in 55 ml glacial acetic acid in 500 ml round bottom flask, and bring the reaction mixture temperature to 10°C. Meantime, in another flask dissolve 17 gm (5.3 ml) of bromine in 25 ml of glacial acetic acid. Add bromine solution slowly with constant stirring maintaining reaction mixture temperature in I0°C to 20°C. When all the bromine has been added, solution will have an orange colour due to the slight excess of bromine. Allow the final reaction

mixture to stand at room temperature for 30 minutes with stirring. Pour the reaction mixture into 400 ml of water and rinse the flask with about 100 ml water. Stirr mixture well. Filter crystalline precipitate over Buchner funnel, wash thoroughly with ice cold water. Dry at 100°C. 2-bromo-4-methoxy phenyl urea (melting point more than 300°C) weighs 17.13 gm Example 4>
2-bromo-4-methoxy phenyl urea:-
Dissolve 16.6 gm 4-methoxyphenylurea in 55 ml glacial acetic acid in 500 ml round bottom flask, and bring the reaction mixture temperature at room temperature. Meantime, in another flask dissolve 17 gm (5.3 ml) of bromine in 25 ml of glacial acetic acid. Add bromine solution slowly with constant stirring maintaining reaction mixture temperature at room temperature. When all the bromine has been added, solution will have an orange colour due to the slight excess of bromine. Allow the final reaction mixture to stand at room temperature for 30 minutes with stirring. Pour the reaction mixture into 400 ml of water and rinse the flask with about 100 ml water. Stirr mixture well. Filter crystalline precipitate over Buchner funnel; wash thoroughly with ice cold water. Dry at 100°C. 2-bromo-4-methoxy phenyl urea (melting point more than 300 C) weighs 17.13 gm
Example 5:-
2-bromo-4-methoxy aniline:-
Boil a mixture of 24.5 gm 2-bromo-4-methoxy phenyl urea and 75 ml of 70 %w/w sulphuric acid under reflux for 3 to 4 hours or until test sample remains clear upon dilution with 3 times its volume of water. The 2-bromo-4-methoxy aniline remains as soluble sulphate salt. Pour the clear hot solution into 500 ml cold water and precipitate the 2-bromo-4-methoxy aniline by adding excess of concentrated ammonia solution. When cold, filter the crystalline precipitate at pump, wash it well with water and drain thoroughly and dry. 2-bromo-4-methoxy aniline weighs 16.33 gm. M.P. 58-60°C Example 6:-3-bromo anisole:-
To a cold mixture of 400 ml methanol and 100 ml concentrated sulphuric acid contained in a 2.5-litre three-necked flask, provided with an efficient mechanical stirring, add 135 gm of 2-bromo-4-methoxy aniline. Stir the solution and cool to 5°C , then add slowly a solution of 74 gm of sodium nitrite in 135 ml of water. Do not allow temperature to rise above I0°C. Continue the stirring for 20 minutes after all the nitrite solution has been added in order to complete the diazotization. Add 17.5 gm copper powder to the diazotized solution, and replace the stirrer by double surface condenser. Warm the flask

carefully on water bath until a vigorous evolution of gas commences. When the reaction has subsided, again warm the flask gently, and finally heat on a boiling water bath for 10 minutes. Remove methanol under mild vacuum on water bath. Add 300 ml cold water in to reaction mixture and extract with 250 ml toluene. Distill out toluene under vacuum followed by 3-bromo anisole (112-116°C at 0.5 mmHg). Weight 78.48 gm. GC-99.8%.
Example 7:-
2-methoxyphenyIurea:-
Dissolve 12.3 gm of o-anisidine in 10 ml of glacial acetic acid diluted to 100 ml in a 250 ml conical
flask, and add with stirring a solution of 6.5 gm of sodium cyanate in 50 ml of warm water. Allow to
stand for 30 minutes, then cool in ice, and hold for 30 minutes. Filter at pump, wash with water and
dry at 100°C. The 2-methoxyphenyl urea was distilled under vacuum and a fraction boiling between
176-180°C at 0.3-0.5 mmHg .yield 15.7gm.
Example 8:-
4-bromo-2-methoxy phenyl urea:-
Dissolve 16.6 gm 2-methoxypheny!urea in 55 ml glacial acetic acid in 500 ml round bottom flask, and bring the reaction mixture temperature to 0°C. Meantime, in another flask dissolve 17 gm (5.3 ml) of bromine in 25 ml of glacial acetic acid. Add bromine solution slowly with constant stirring maintaining reaction mixture temperature in 0°C to 5°C. When all the bromine has been added, solution will have an orange colour due to the slight excess of bromine. Allow the final reaction mixture to stand at room temperature for 30 minutes with stirring. Pour the reaction mixture into 400 ml of water and rinse the flask with about 100 ml water. Stirr mixture well. Filter crystalline precipitate over Buchner funnel, wash thoroughly with ice cold water. Dry at 100 C. 4-bromo-2-methoxy phenyl urea (M.P.dec.273°C) weighs 18.00 gm.
Example 9:-
4-bromo-2-methoxy phenyl urea:-
Dissolve 16.6 gm 2-methoxyphenylurea in 55 ml glacial acetic acid in 500 ml round bottom flask, and
bring the reaction mixture temperature to 10°C . Meantime, in another flask dissolve 17 gm (5.3 ml) of
bromine in 25 ml of glacial acetic acid. Add bromine solution slowly with constant stirring
maintaining reaction mixture temperature in 10°C to 20°C . When all the bromine has been added,

solution will have an orange colour due to the slight excess of bromine. Allow the final reaction mixture to stand at room temperature for 30 minutes with stirring. Pour the reaction mixture into 400 ml of water and rinse the flask with about 100 ml water. Stirr mixture well. Filter crystalline precipitate over Buchner funnel, wash thoroughly with ice cold water. Dry at 100 C. 4-bromo-2-methoxy phenyl urea (M.P.dec.273°C) weighs 18.00 gm.
Example 10:-
4-bromo-2-methoxy phenyl urea:-
Dissolve 16.6 gm 2-methoxyphenylurea in 55 ml glacial acetic acid in 500 ml round bottom flask , and bring the reaction mixture temperature at room temperature . Meantime, in another flask dissolve 17 gm (5.3 ml) of bromine in 25 ml of glacial acetic acid. Add bromine solution slowly with constant stirring maintaining reaction mixture temperature at room temperature. When all the bromine has been added, solution will have an orange colour due to the slight excess of bromine. Allow the final reaction mixture to stand at room temperature for 30 minutes with stirring. Pour the reaction mixture into 400 ml of water and rinse the flask with about 100 ml water. Stirr mixture well. Filter crystalline precipitate over Buchner funnel, wash thoroughly with ice cold water. Dry at 100 C. 4-bromo-2-methoxy phenyl urea (M.P.dec.273°C) weighs 18.00 gm.
Example 11 :-
4-bromo-2-methoxy aniline:-
Boil a mixture of 24.5 gm 4-bromo-2-methoxy phenyl urea and 75 ml of 70 % w/w sulphuric acid under reflux for 3 to 4 hours or until test sample remains clear upon dilution with 3 times its volume of water. The 4-bromo-2-methoxy aniline remains as soluble sulphate salt. Pour the clear hot solution into 500 ml cold water and precipitate the 4-bromo-2-methoxy aniline by adding excess of concentrated ammonia solution. When cold, filter the crystalline precipitate at pump, wash it well with water and drain thoroughly and dry. 4-bromo-2-methoxy aniline weighs 16.33 gm. M.P. 56-57 C
Example 12:-
3-bromo anisole:-
To a cold mixture of 400 ml methanol and 100 ml concentrated sulphuric acid contained in a 2.5-litre
three-necked flask, provided with an efficient mechanical stirring, add 135 gm of 4-bromo-2-methoxy
aniline. Stir the solution and cool to 5°C, then add slowly a solution of 74 gm of sodium nitrite in 135

ml of water. Do not allow temperature to rise above 10oC. Continue the stirring for 20 minutes after all the nitrite solution has been added in order to complete the diazotization. Add 17.5 gm copper powder to the diazotized solution, and replace the stirrer by double surface condenser. Warm the flask carefully on water bath until a vigorous evolution of gas commences. When the reaction has subsided, again warm the flask gently, and finally heat on a boiling water bath for 10 minutes. Remove methanol under mild vacuum on water bath. Add 300 ml cold water in to reaction mixture and extract with 250 ml toluene. Distill out toluene under vacuum followed by 3-bromo anisole (112-116°C at 0.5 mmHg). Weight 78.21 gm. GC-99.84 %.

5. CLAIMS
I claim the following:
1. Production of m-bromo anisole (3-bromoanisole) using a mixture of o/p-nitrochlorobenzenes (2/4-nitrochlorobenzene).
2. Production of m-bromo anisole (3-bromoanisole) using a mixture of o/p-anisidines.
3. Manufacturing of m-bromo anisole (3-bromoanisole) using 4-methoxy phenylurea.
4. Manufacturing of m-bromo anisole (3-bromoanisole) using 2-methoxy phenylurea.