FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of 4-bromophenyl acetic acid of formula I, a key intermediate in the Active Pharmaceutical Ingredients.

The present invention relates to an improved, commercially viable process for the preparation of 4-bromophenyl acetic acid of formula I without compromising the high yield and high purity.

The present invention relates to an improved process for the preparation of 4-bromophenyl acetic acid of formula I starting from low cost raw material 4-bromotoluene.

BACKGROUND OF THE INVENTION:

Phenylacetic acids and its substituted derivatives are very important compounds as they are showing broad range of biological activity, i.e., antibacterial, analgesic, virucidal, prostaglandin synthetase response, plant growth regulater, etc. 4-bromophenylacetic acid is the key starting material for Bilastine, Mecitentan , terfenadine and fexofenadine.
4-bromophenyl acetonitrile is used as a key intermediate in the preparation of 4-bromophenylacetic acid. 4-bromophenyl acetonitrile is also used in the synthesis of Brompheniramine, an antihistamine drug.

According to Tetrahedran Letters, 41 (2000) 7601 the article describes a process for the preparation of Phenylacetic acids by rhodium-catalyzed carbonylation; phenylacetic acids are prepared using benzyl halide derivative in the presence of a catalytic amount of the dimer of chloro(l,5-cyclpoctadiene)rhodium(I) in formic acid;

According to Applied Catalysis A: General, 165 (1997) 133, the article describes the hydrogenation of mandelic acid derivatives to the corresponding phenylacetic acid derivatives catalyzed by Pd/C: The hydrogenolysis of the C-0 bond of mandelic acid derivatives catalysed by 5% Pd/C, in the presence of hydrochloric or sulphuric acids as cocatalysts, was carried out in water or ethanol:

According to Journal, Bulletin of the Chemical Society of Japan 67 (1994) 2339, the article .describes a process for carbonylation of benzyl chloride in the presence of the water-soluble complex PdCh [PPli2(m-C6H4S03Na)]2, and surfactants under two-phase conditions:

According to Organic Syntheses 1922, 2, 63, the article describes synthesis of phenylacetic acid by acidic hydrolysis of phenyl acetonitrile:

According to Organic Syntheses 32: 92; Coll. Vol. 4, p. 760, the article describes the synthesis of of phenyl acetic acid by acidic hydrolysis of phenyl acetonitrile via formation of phenyl acetamide:
According to Moghaddam F.M., Ghaffarzadeh M., Mohammad D.G., J. Chem. Res. Synop., 5 (2000) 228, the article describes induced Willgerodt-Kindler reactions of styrenes

According to Synthetic Communication, 31 (2001) 317, (Willgerodt-Kindler Reaction) the article describes microwave-assisted rapid hydrolysis and preparation of thioamides by Willgerodt-Kindler reaction:
http://www.fundanow.co m/subiects/science 0475.htm describes a photochemical free radical reaction for the synthesis of 4- bromophenylacetic acid comprising generation of chlorine radicle using light and reacting
with 4-bromotoluene and followed by reacting with potassium cyanide and followed by hydrolysis.

According to Journal of Applied Chemistry and Biotechnology, 24 (1974) 105 the article describes the production of phenylacetic acid by liquid phase oxidation of acetophenone with sulphur in the presence of aqueous ammonia. The liquid phase oxidation of acetophenone by aqueous ammonia and sulphur to phenylacetamide and/or phenylacetic acid was investigated in a stainless steel autoclave maintained under autogenous pressure.

According to Synthetic Communications 33(1), 59-63 (2003), the article describes PTC mediated Willgerodt-Kindler Reaction. The reaction has been carried out at 100°C taking triethyl benzyl ammonium chloride (TEBA) as phase transfer catalyst. When thiomorpholides have been hydrolyzed with TEBA under basic conditions the hydrolysis takes place in 8 hr to afford phenylacetic acids.

There are several other processes reported in the literature for preparation of 4- Bromophenylacetonitrile such as Journal of Agricultural and Food Chemistry, 63(13), 3377- 3386; 2015, Angewandte Chemie, International Edition, 53(39),. 10510-10514; 2014, Tetrahedron Letters, 55(32), 4424-4426; 2014, Journal of Molecular Catalysis A: Chemical, 365, 80-86; 2012, Catalysis Communications, 18, 102-105; 2012, Comptes Rendus Ghimie, 13(12), 1468-1473; 2010, Tetrahedron Letters, 51(25), 3274-3276; 2010, Journal of the Iranian Chemical Society,5(Suppl.), S26-S32; 2008, Tetrahedron Letters, 50(1), 55-56; 2009,
WO2008020203, Bulletin of the Chemical Society of Japan, 79(7), 1106-1117; 2006', Synlett, (20), 3160-3162; 2005, Chemistry Letters, 33(9), 1192-1193; 2004, Synlett, (12), 2110-2112; 2002, Angewandte Chemie, International Edition, 41(17), 3265-3267; 2002, Canadian Journal of Chemistry, 79(11), 1556-1561; 2001 Journal of the Chemical Society,Chemical
Communications, (7), 439-40; 1984

There are also several other processes reported in the literature for preparation of 4-bromophenyl acetic acid such as Chem Cat Chem, 6(6), 1589-1593; 2014, DEI02012224021, Journal of Organic Chemistry, 76(22), 9519 9524; 2011, Tetrahedron

Letters, 51(46), 6045-6048; 2010, Science of Synthesis, 20a, 137-172; 2006, Huaxue Yanjiu, 19(3), 48-50; 2008, Guangzhou Huaxue, 33(4), 37-41; 2008, Journal of Organic Chemistry, 69(17), 5547-5554; 2004, Synthetic Communications, 19(11-12), 2151-7; 1989, Tetrahedron Letters, 25(48), 5529-32; 1984

Although, all these methods have some limitations such as long reaction times, hazardous reaction conditions and use of microwave ovens which are not commonly available in all the research laboratories, low yield and low purity and more over the prior available all the literature can't be suggesting a Industrially / commercially viable process. Therefore in view of the above said limitations and their pharmaceutical and biological importance, there is an intense demand to develop efficient, robust, economical method for the synthesis of phenyl acetic acids and its substituted derivatives and under mild reaction conditions and commercially viable process.

Considering the importance of 4-bromophenyl acetic acid, there is need for a simple, economical and industrially viable process for the preparation of 4-bromophenyl acetic acid, with a view to find a simple process, applicant diligently worked and identified a simple, robust and economical process for the preparation of 4-bromophenyl acetic acid starting from 4-bromotoluene.

OBJECT OF THE INVENTION:

An object of the present invention relates to an improved process for the preparation of 4-bromophenyl acetic acid improved process for the preparation of 4-bromophenyl acetic acid starting from 4-bromotoluene, a cheaply and commercially available raw material.

A preferred object of the present invention relates to a process for the preparation of 4-bromophenyl acetic acid having purity 99.9%.

Another preferred object of the present invention relates to 4-bromophenyl acetonitrile
having purity 99.9%. _ _

SUMMARY OF THE INVENTION:

The present invention relates to a process for the preparation of 4-bromopheny 1 acetic acid of formula I, starting from 4-bromotoluene. The present invention is an improved, robust, economically viable process and provides the target compound in high yield and high purity.

The present invention relates to a process for the preparation of 4-bromopheny 1 acetic acid of formula I:
Comprising the steps of:

a) Treating the 4-bromotoluene of formula III:
In the presence of free radical generating agent and a phase transfer catalyst to obtain a reaction mass;

b) Cyanating the obtained reaction mass of step a) with agent such as Sodium cyanide in a solvent mixture of toluene and water optionally in the presence of a phase transfer catalyst to obtain 4-Bromophenylacetonitrile of formula II:

c) Optionally purifying the 4-Bromophenylacetonitrile of formula II using alcohol;

d) Hydrolyzing the 4-Bromophenylacetonitrile of formula II with aqueous base selected from sodium hydroxide and
Potassium hydroxide to obtain a reaction mass; and . ■'

e) Adjusting the pH of reaction mass of step d) with a suitable acid in the range of 2-4. and jsolatinsthe hiehlv oure 4-bromophenyl acetic acid of formula I.

DETAILED DESCRIPTION OF THE INVENTION:

In an embodiment of the present invention, the invention relates to a process for the preparation of 4-bromophenyl acetic acid of formula I starting from 4-bromotoluene.

The present invention relates to a process for the preparation of 4-bromophenyl acetic acid which comprises bromiriation of 4-bromotoluene to give l-bromo-4-(bromomethyl) benzene, followed by cyanation with a cyanating agent to give 4-bromophenyl
Acetonitrile which on hydrolysis yields 4-bromophenyl acetic acid.
The present invention relates to a process for the preparation of 4-bromophenyl acetic acid as shown in the scheme given below:

In an embodiment of the present invention relates to a process for the preparation of 4-bromophenyl acetic acid of formula I:
Comprisinjg the steps of:

a) Treating the 4-bromotoluene of formula III:

In the presence of free radicle generating agent and a phase transfer catalyst to obtain a reaction mass;

b) Cyanating the obtained reaction mass of step a) with agent such as Sodium cyanide in a solvent mixture of toluene and
water optionally in the presence of a phase transfer catalyst to obtain 4-Bromophenylacetonitrile of formula II:

c) Optionally purifying the 4-Brombphenylacetonitrile of formula II using alcohol;

d) Hydrolyzing the 4-Bromophenylacetonitrile of formula II with aqueous base selected from sodium hydroxide and potassium hydroxide to obtain a reaction mass; and

e) Adjusting the pH of reaction mass of step d) with a suitable acid in the range of 2-4 and isolating the highly pure 4-bromophenyl acetic acid of formula I. In an embodiment, the present invention relates to a process for the preparation of 4-bromophenyl acetic acid wherein the bromination is carried in the presence of free radical generating agent.

In a preferred embodiment, the free radical generating agent is selected from peroxides of formula ROORi, wherein R and Ri are independently selected from hydrogen, Ci-6 alkyl, Ci-6 alkoxy, C6-12 aryl, Ce-n aryloxy, Ci-6 alkyl carbonyl and C7.13 aryloxy carbonyl. Preferably hydrogen peroxide or benzoyl peroxide.

In an embodiment of the present invention, cyanating agent used is selected from sodium cyanide and potassium cyanide.

In an embodiment the phase transfer catalyst used in the process of present, invention is selected from tetrabutylammonium bromide, benzyl trimethyl ammonium chloride, tetrabutylammonium chloride and tetrabutylammonium hydrogen sulphate;

Preferably tetrabutylammonium bromide; More preferably tetrabutylammonium chloride.

The present invention describes a process for the preparation of 4-Bromophenylacetonitrile having purity greater than 99% comprising purification 4-Bromophenylacetonitrile in the presence of alcohol selected from straight chain or branched Ci-6 alcohols. Preferably methanol, ethanol, n-propanol and isopropanol; More preferably Isopropanol.

In an embodiment the present invention relates to a process for the preparation of 4-Bromophenylacetonitrile having purity greater than 99%.

In an embodiment the present invention relates to a process for the preparation of 4-Bromophenylacetonitrile having purity greater than 99.9%.

The present invention relates to a process for the preparation of 4-bromophenyl acetic acid comprising hydrolysis of 4-Bromophenylacetonitrile in the presence of a base.

In an embodiment of the present invention the base is selected from sodium hydroxide or potassium hydroxide.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way.

EXAMPLES:

Example-1: Preparation of 4-Bromophenylacetonitrile:

To a 500ml round bottom flask added 4-bromotoluene (lOgm), benzoyl peroxide (0.2gm) slowly raise the temperature up to 120°C, then added liquid bromine (7.2gm) for 4-5 hours duration. Maintain it for another 1-2 hours, check the TLC, If complies then the whole reaction mass cool to 90-100°C and then the reaction mass saturated with sodium carbonate (pH~6.0-8.5). The saturated reaction mass is added with aqueous sodium cyanide (2.25gm) in water (80ml), and tetrabutylammonium chloride (TBAC, 0.2gm). After the addition the reaction mass maintain for 6-8 hours at 90-100°C, once reaction completed (GC monitoring) then the reaction mass settle for separation, the separated organic layer directly taken for high vacuum distillation ( 110°C to 160°C) the main fraction obtained was subjected for isopropyl alcohol purification to achieve obtain4-Bromophenylacetonitrile (4.5-5.5gm )(99.9% high purity).

Example-2: Preparation of 4-Bromophenylacetic acid

To a 500 ml round bottom flask 4-Bromophenylacetonitrile of example lis added andaddedwith sodium hydroxide (2.25gm)in 25ml water under reflux conditions (90-100°C) and maintained for 6-8 hours. After completion of TLC, cool the reaction mass to room temperature, wash with 5-15 ml of toluene followed by carbon treatment to remove color & base organic impurities and then adjust the pH 2-3 to aqueous reaction mass to get the pure 4-bromophenylacetic acid as a white to half white solid after drying at 65-73°C, with purity 99.9% and yield 98%.

We Claim:

1. A process for the preparation of 4-bromophenyl acetic acid of formula I:
Comprising the steps of:

a) Treating the 4-bromotoluene of formula III:
In the presence of free radicle generating agent and a phase transfer catalyst to obtain a reaction mass;

b) Cyanating the obtained reaction mass of step a) with cyanating agent such as Sodium cyanide in a solvent mixture of toluene and water optionally in the presence of a phase transfer catalyst to obtain 4-Brombphenylacetonitrile of formula II:

c) Optionally purifying the 4-Bromophenylacetonitrile of formula II using alcohol;

d) Hydrolyzing the 4-Bromophenylacetonitrile of formula II with aqueous base selected from sodium hydroxide and potassium hydroxide to obtain a reaction mass; and ; i( ;

e) Adjusting the pH of reaction mass of step d) with a suitable acid in the range of 2-4 and isolating the highly pure 4-bromophenyl acetic acid of formula I.

2. The process as claimed in claim 1, wherein the step a) is carried in the presence of free radicle generating agent selected from benzoyl peroxide and hydrogen peroxide; preferably Benzoyl peroxide.

3. The process as claimed in claim 1, wherein the step a) and step b) are carried in the presence of phase transfer catalyst selected from tetrabutylammonium bromide, benzyl trimethyl ammonium chloride, and tetrabutylammonium chloride and tetrabutylammonium hydrogen sulphate.

4. The process as claimed in claim 1, the phase transfer catalyst used is selected from tetrabutylammonium chloride and tetrabutylammonium bromide.

5. The process as claimed in claim 1, where in the step a) is carried at a temperature ranging 50-150°C.

6. The process as claimed in Claim 1, where in the reaction mass of step a) is subjected to high vacuum distillation.

7. The process as claimed in claim 1, the process for the purification of 4-Bromophenylacetonitrile by recrystallization in the presence of alcohol selected from straight chain or branched Ci_6 alcohols.

8. The process claimed in claim 7, wherein the process is carried in the presence of alcohol selected from methanol, ethanol, n-propanol and isopropanol; preferably Isopropanol.

9. The compound obtained as per process as claimed in claim 7, the 4-Bromophenylacetonitrile is having purity 99.9% by HPLC.

10. An improved process for the preparation of highly pure 4-bromophenyl acetic acid of formula I, prepared according to the examples as described herein.