The first step is the preparation of benzoic hcmisuccinate of the formula (4) (formed as glass like substance) by esterification of benzoic of the formula (2) with succinic aniiydridc of the formula (3) at a temperature of 120 °C. This inlcrmcdialc is recovered from the reaction mixture using ether. The second step is the stylization of the hcmisuccinate of the formula (4) with ammonia or an equivalent thereof such as ammonium acetate to produce oxaprozin of the formula (1).
The above process has the following disadvantages :
1. The process involves the isolation of the intermediate benzoin hcmisuccinate and then reacting further with ammonia or equivalent thereof such as NH4O Ac.
2. In the process, benzoic and succinic anhydride were heated together at 120 °C which temperature succinic anhydride sublimes and deposits on the walls and necks of the flask / reactor leading to the choking. Such deposition adversely effects the reaction as it reduces the availability of succinic anhydride for the reaction. Further such sublimation poses additional problems of safety of the reaction.
3. The process employs ether for extraction of the glass like solid of the benzoin hcmisuccinate of the formula (4) formed during the esterification stage. The benzoin

hcmisuccinatc of the formula (4) was isolated by extraction with dilute aqueous sodium carbonate solution, followed by acidification. This methodology not only increases the number of steps thereby making the process uneconomical but also the extraction of the glass like solid of the benzoic hemisuccinate of the formula (4) is very tedious and laborious job because the hemisuccinate dissolves very slowly in saturated sodium bicarbonate solution with effervescence.
4. After the cyclisation of the hemisuccinate of the formula (4) with ammonium acetate in acetic acid, the product is isolated by pouring the solution into water. By this process recovery, recycling of the used acetic acid is not possible. It also poses additional problems of waste disposal as effluents generated are highly acidic. This adds up to the cost of production as well as environmental problems.
5. The Oxaprozin was recrystallized from methanol. Methanol being polar and low boiling organic solvent, the non-polar impurities like tetra phenyl praline present in Oxaprozin formed during the process cannot be eliminated and thus production of pharmaceutically acceptable quality of oxaprozin is not possible. In addition to this recycling of methanol was poor because of its low boiling point.
ES 548,254, discloses another process for the preparation of oxaprozin which consists of 5 steps as shown in scheme II


The first step was the esterification of benzoic of the formula (2) with chloropropionyl chloride of the formula (5) to give keto ester of the formula (6), which was refluxed with ammonium acetate and acetic acid to give chloromethyl biphenyl oxazole of the formula (7). Conversion of the compound of formula (7) to the Grignard reagent followed by carboxylation with dry CO2 gave Oxaprozin of the formula (1).
This process has many disadvantages :
1. The number of steps have increased from two (described in US patent No. 3,578,671)
to five which increases the cost of the process.
2. The major problem connected with the sublimation of succinic anhydride encountered
with procedure described in the process disclosed in US Patent no 3,578,671 was
addressed by the use of chloropropionyl chloride as an alternative reagent in the
synthesis. This reagent is not only expensive resulting in escalating the cost of the
process but also is lachrymatory posing additional problems of safety and health.

3. In the synthesis, Grignard reagent was prepared from the compound of formula (7). This methodology not only increases the number of steps, but also the makes the process complex from handling point of view.
Huaxue Yanj U. (Yu Ying Yong, 1996, 8(3), 457-9), describes the sequential synthesis of Oxaprozin in tliree steps starting from benzaldehyde of the formula (8) or benzoic of the formula (2) in 63% overall yield. In this process the starting material benzoic was synthesised from benzaldehyde using catalytic quantities of thiamine hydrochloride, diethylamide, sodium hydroxide instead of conventionally used cyanides. This reaction is shown in scheme III.

Scheme III
The first step involves the esterification of benzoin of the formula (2) with succinic anhydride of the fonnula (3), in pyridine medium at 95 °C temp to produce the intermediate hemisuccinate of the formula (4). The hemisuccinate of the formula (4) was subsequently cyclised to Oxaprozin of the formula (I) using ammonium acetate in acetic acid medium.
This process is short and sequential but the use of pyridine as a base or medium at eslerification stage even though addresses the problem of sublimation to some extent. This poses a problem of health and safety in bulk handling as pyridine has a very strong

disagreeable odour and toxic in nature. In addition to this recovery and recycling of acetic acid and pyridine was not possible as aqueous work up was employed to isolate the product.
Considering the wide application of Oxaprozin as anti-inflammatory agent, we directed our research towards development of an improved process for the preparation of Oxaprozin using minimal number of steps in a single pot reaction. The main objective of tlie present invention is, therefore, to provide an improved process for the preparation of oxaprozin of the formula (1), which is very simple and economical.
Another objective of the present invention is to provide an improved process for the preparation of oxaprozin, which prevents the sublimation of succinic anliydride, thereby making the process more efficient and economical.
Yet another objective of the present invention is to provide an improved process for the preparation of oxaprozin which docs not employ pyridine in the reaction thereby making the process safe.
The invention has been developed based on our finding that (i) the sublimation of succinic anhydride in the esterification reacfion with benzoin can be prevented by employing hydrocarbon solvents, (ii) pyridine as a medium can be replaced by the use of the above said hydrocarbon solvent, and (iii) the possibility of in situ conversion of the glass Hke intermediate benzoin hemisuccinate formed in the esterification reaction of benzoin and succinic anliydride into Oxaprozin.
Accordingly, the present invention provides an improved process for the preparation of the formula (1) Oxaprozin, which comprises, esterifiying benzoin of the formula (2) with succinic anhydride of the formula (3) in the presence of a hydrocarbon solvent at a temperature in the range of 100-140 °C to produce the hemisuccinate of the formula (4) which is then cyclised in an inert atmosphere with ammonia or an ammonia generating
agent to produf« Oxanrnzin


Scheme IV
The hydrocarbon solvent such as heptane, octane, decane, toluene, xylene and tetralin may be used, preferable solvent being toluene. The reaction is smooth and facile, when benzoin vs solvent ratio of 1 : 0.188 to 1 : 0.3 w/v is employed. Preferable ratio of these reactants is 1 : 0.188 w/v. The reaction rate is very slow, when benzoin Vs solvent ratio of 1 : 0.5; 1 : 1 w/v is employed. The cyclization reaction may be earned out with or without the use of solvent and also with or without isolating the intermediate,. The ammonia generating agent, such as urea, or an ammonium salt may be used. In the case of use of ammonium salt, ammonium acetate in glacial acetic acid is found to be very effective. The inert atmosphere in the cyclization step may be maintained by using inert gases such as N2, Ar, He and the like.
In the process of the present invention Oxaprozin of the formula (1) is produced in the yield of 65 % with pharmaceutically acceptable quality.

The present invention is described in detail in the examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example -1 :
Step (i): Preparation of Benzoin hemisuccinate of the formula (4)
106 g of benzoin, 60 g of succinic anhydride and 20 ml of toluene were taken into necked round bottom flask fitted with a mechanical stirrer and a refluxing condenser under nitrogen atmosphere. The reaction mass was slowly heated to 120-130 °C in about 1 h without stirring. After the desired temperature is reached, the reaction mass was maintained at oil bath temperature of 120-130 °C under stirring for 10 h and N2 atmosphere. The reaction was monitored by TLC. The temperature of the reaction mass was brought to 60-70 °C and 200 ml of fresh toluene was added under stirring. The temperature of the reaction mass was further brought to 0-5 °C temperature and the precipitated solid, benzoin hemisuccinate was filtered and dried under reaction to obtain 109 g of pure benzoin hemisuccinate of the formula (4) (Y = 70%, m.p. 88-89 °C, P = 99 % by HPLC).
Step (ii): Preparation of 4,5-diphcnyl-2-oxazoIe propionic acid of the formula (1).
125 g of the Benzoin hemisuccinate obtained by the process described in step (I) above, 235 ml of glacial acetic acid and 39.5 g of ammonium acetate were taken into 1 L four necked round bottom flask fitted with a mechanical stirrer and reflux condenser under N2 atmosphere. The reaction mass was heated slowly to 120-130 °C and maintained at this temperature for 8 h under stirring under N2 atmosphere. The reaction was monitored by TLC and the temperature of the reaction mass was brought to room temperature by cooling the reaction mass to 15-17 °C with ice and maintain this temperature for 60 min. under efficient stirring. The precipitated crude Oxaprozin of the formula (1) was filtered and dried the product after thorough washing with DM water (800 ml x 3). The product

appears as off-white crystalline solid weighs about 93-104 g, yield 79-88 %, m.p. 158-159 °C (rep. 161-165 °C) 97-98 % assay by potentiometric titration. The crude was purified by dissolving in 3 L of toluene at rcfluxing, decolorising with activated charcoal and filtering the hot toluene layer on celite bed. The filtered MLs are cooled to 10 °C under stirring for 2 h and the precipitated pure Oxaprozin was filtered and dried at 60-65 °C in hot air oven. The dried pure Oxaprozin appears as white crystalline solid, weights about 77-84 g, yield 65-71 %, m.p. 162-163 °C, 99.3-99.8 % assay by potentiometric titration. The total impurities meiy range from 0.2 to 0.4 % as per TLC at X, 254 nm as described in JP XIII, p 542. The IR spectrum as KBr shows the following absorption bands at 3460 cm"' (broad 0-H stretch), 2926 cm"' (C-H stretch), 1720 cm"' (-CO stretch -in - COOH). The 'H NMR spectrum in CH2OD (TMS internal standard) shows the following signals at 6 2.8 (t, 3H, -CH2-COOH), 5 3.2 (t, 3H, -CH2-CH2-COOH), 6 7.3-7.7 (m, lOH, aromatic protons)
Example 2 : One pot preparation of 4,5-dipIienyl-2-oxazole propionic acid of the formula (1)
106 g of benzoin, 60 g of succinic anhydride and 20 ml of toluene were taken into 1 L four necked round bottom flask, fitted with a mechanical stirrer and a refluxing condenser under nitrogen atmosphere. The reaction mass was slowly heated to 120-130 °C in about 1 h without any stirring. When the desired temperature of 120-130 °C was reached, maintain the reaction mass under stirring for 10 h at this temperature under N2 atmosphere. Progress of the reaction was monitored by TLC. The reaction mass was brought to 60-70 °C and 39.5 g of ammonium, 235 ml of glacial acetic acid were added at this temperature under stirring and N2 atmosphere. The reaction mass was maintained at 120-130 °C for 8 h under stirring. The reaction was monitored for completion. The reaction mass was brought to room temperature followed by cooled the reaction mass to 15-17 °C with ice and maintain this temperature for 1 h under efficient sfirring. Filter the precipitated crude Oxaprozin solid by washing with 20 ml of acetic acid, followed by demineralised water (800 ml x 3) till the filtrate shows pH of 5.5-6.0. After washings, the

product was dried in hot air oven at 60-70 °C till MC reaches 0.5 %. The product appears as off-white crystalline solid, weighs about 115-128 g, yield 79-88 %, m.p 158 -159 °C (rep. 161-165 °C), 97-98 % assay by potentiometric titration. The impure Oxaprozin 93-104 g was purified by dissolving in 3 L of toluene at reflux, decolorising with activated charcoal and filtering the decolorised hot toluene layer on celite bed. The bed washed with 2 x 100 ml hot toluene. The filtered toluene is collected and cooled to 10 °C under stimng for 2 h and the precipitated pure Oxaprozin was filtered and dried at 60-65 °C in hot air oven. The dried pure Oxaprozin appears as white crystalline solid, weights about 95-102 g, yield 65-70 %, m.p. 162-163 °C, 99.3-99.8 % assay by potcnUomctiic titration. The total impurities may range from 0.2 - 0.4 % as per TLC at X -254 nm as described in JP XIII, p 542. The product confirms to the structure by IR & 'H NMR spectral data.
Example 3 : One pot preparation of 4,5-diplienyl-2-oxazolepropionic acid of the formula (I)
106 g benzoin, 60 g of succinic anhydride and 20 ml of xylene were taken into 1 L of four necked round flask fitted with a reflux condenser of mechanical stirrer under nitrogen atmosphere. The reacUon mass was slowly heated to 120-130 °C in about 1 h without any stining. When the desired temperature of 120-130 °C was reached, maintain the reaction mass under stirring for 10 h at this temperature under N2 atmosphere. Progress of the reaction was monitored by TLC. The reaction mass was brought to 60-70 °C and 39.5 g of ammonium, 235 ml of glacial accfic acid were added at this temperature under sfirring and N2 atmosphere. The reaction mass was maintained at 120-130 °C for 8 h under stirring. The reaction was monitored for completion. The reaction mass was brought to room temperature followed by cooled the reaction mass to 15-17 °C with ice and maintain this temperature for 1 h under efficient stirring. Filter the precipitated crude Oxaprozin solid by washing with 20 ml of acetic acid, followed by demineralised water (800 ml X 3) till the filtrate shows pH of 5.5 - 6.0. After washings, the product was dried in hot air oven at 60-70 °C till MC reaches 0.5 %. The product appears as off-white

crystalline solid, weighs about 115-128 g, yield 79-88 %, m.p 158-159 °C (rep. 161-165 °C), 97-98 % assay by potentiometric titration. The impure Oxaprozin 93-104 g was purified by dissolving in 3 L of toluene at reflux, decolorising with activated charcoal and filtering the decolorised hot toluene layer on celite bed. The bed washed with 2 x 100 ml hot toluene. The filtered toluene is collected and cooled to 10 °C under stiiring for 2 h and the precipitated pure Oxaprozin was filtered and dried at 60-65 °C in hot air oven. The dried pure Oxaprozin appears as white crystalline solid, weights about 95-102 g, yield 65-70 %, m.p. 162-163 °C, 99.3-99.8 % assay by potentiometric titration. The total impurities may range from 0.2 - 0.4 % as per TLC at X, 254 nm as described in JP XIII, p 542. The product confinns to the structure by IR & 'H NMR spectral data.
Advantages of the present invention :
1. The process is cost effective and is simple, clean, commercially viable and ecofi"iendly.
2. The process employs inert hydrocarbon solvent like heptane, toluene or xylene in place of pyridine. Such a reaction prevents the sublimation of succinic anhydride and also avoids the usage of toxic pyridine.
3. It is not necessary to isolate the hemisuceinate of the formula (4) and can be directly converted to Oxaprozin. Thus the laborious process of ether extraction of th(| glass like solid hemisuceinate formed at esterification stage is avoided. In addition the step of isolation of hemisuceinate ester of the formula (4) by aqueous NaiCOs extraction and liberating with cone. HCl are not required thus making the process simple and economical.
4. Recovery of unused solvent is possible and can be reused, thereby making the process cost effective.

5. The employment of single solvent system namely hydrocarbon solvent both in the
reaction and for recrystallization results in simplicity of the reaction and economics of the
process.
6. The purification methodology using toluene eliminates the non-polar impurities like tetraphenyl pyrazine fornied in the synthesis, thus making the process more effective and in overall improvement in yield inspitc of using inexpensive chemicals and simplified steps.
7. The process results in the preparation of the final product in 99.3-99.4 % purity with a phamiaceutically acceptable quality.

We claim :
1. An improved process for the preparation of Oxaprozin of the formula (I)

(1)
which comprises :
(i). tisterifiying benzoic often formula (2)

with succinic anhydride of the formula (3)

in the presence of a hydrocarbon solvent at a temperature in the range of 100-140 °C to produce the hemisuccinate of the formula (4)

(ii). the hemisuccinate of the formula (4) is then cyclical in an inert atmosphere with
ammonia or an ammonia generating agent to produce Oxaprozin of he formula (1).
2). A process according to claim 1, wherein the hydrocarbon solvent used is selected
from heptane, octane, decade, toluene, xylene, and terrain.
3). A process according to claims 1-3, wherein the solvent used in the cyclisation step
is selected from ammonium generating agent or ammonium salt.

4). An improved process for the preparation of Oxaprozin of the formula (1), substantially as herein described with reference to the examples.