This invention relates to an improved process for the preparation of S(+)-ibuprofen and its salts from the mixtures of R(-) and S(+)2-(4-isobutylphenyl)propionic acid (racemic ibuprofen) to yield S(+) 2-(4-lsobutylphenyl) propionic acid and its salts in greater yield and high optical purity. The invention particularly relates to an improved process for the isolation of S(+)ibuprofen and its salts thereof employing N-alkyI or N-cycloalkyI or N-aralkyl-D-glucamlnes as a resolving agent.
Hitherto the resolution of racemic ibuprofen to yield S-(+)-ibuprofen is effected by various methods, some of which are described below.
Friedel-Crafts alkylation of isobutyl benzene with optically pure S-(+)-R0CH(CH3)C00R was carried out to give S-(+)-ibupr6fen in low yields (20%). (Piccolo Oreste; Spreafico Franca; Visentin Griusppina; Valoti Ermano J. Org. Chem; 1985 50 (20). 3945). An enantioselective process is also known for preparing optically active alpha aryl alkanoic acids such as S(-f)ibuprofen through an intermediate ketal formation.(Giordano Clandio Eur pat, EP, 118, 913). Asymmetric synthesis of aryl propanoic acids is also carried out employing a-hydroxy esters such as (S)ethyl lactate, as chiral reagents.(Larsen, Robert D; Carley Edward G, Davis, pau; Reider, Pan J, etal J. Am. chenj. SOC, 1989 111(10). 7650).
Palladium catalysed hydro-carboxylation of isobutyl- styrene in the presence of S-(+)-1,l'-binaphthyl-2, 2'diyl hydrogen phosphate afforded Ibuprofen in 94% yield but the optical yield was only 2% (S-configuration). {Alper, Jong, Tae; Alper, Howard J. Am cliem. soc., 112 (7). 2803. Alper Howard PCT Int. Appl. WO 91, 03, 452).

Phase transfer catalysed carbonylation of isobutylphenylacetylene in the presence of cobalt-chloride,potassium cyanide and nickel cyanide afforded a-phenylpropionic acid with good selectivity. (Lee, Jong, Tae; Alper, Howard Tetra Hedron Lett good selectivity. (Lee, Jong. Tae; Alper, Howard Tetra Hedron Lett., 1991. 32 (15). 1769). Asymmetric hydrogenation of 2-(4-isobutylphenyl)acrylic acid by the use of a ruthenium complex combined with a chiral phosphine produced S-(+)-ibuprofen with an optical purity of 67%.{Manimaran, T; Klobucar, W. Dirk; Kolicti Charles.H.; U.S PatNa 5,177,231 Manimaran, T; Klobucar, W. Dirk; Kolich Charles.H. U.S. Pat.No. 5.202.472. Manimaran. T; Klobucar, W. Dirk; Kolich Charles.H. U.S. Pat.No. 5.190,905). S(+)ibuprofen was also prepared by regeoselective carbonylation of isobutyl-phenylacetylene followed by hydrogenation. Enzymatic processes for the resolution of racemic ibuprofen have also been reported.
A single step photochemical rearrangement of a-chloro propiophenones to S-(+)-lbuprofen has also been reported with moderate optical yields(/»/per, Howard; Hamel. Nathalie J. Am. Chem. Soc., 1990(112(7). 2803).
Another method to resolve the racemic mixture of ibuprofen involves the use of a-phenylethylamine as the resolving agent. But the yield of product obtained by such process has low optical purity (82%) [Journal of organic chemistry 402; 179-187 (1987)]. Crystallization of the sodium salts of optically enriched mixtures was also attempted but the yields were low.
The S-(+)-ibuprofen was also obtained from its racemic ester by using an esterase enzyme produced by a micro-organism that is capable of selectively hydrolyzing the esters of the racemate. [European patent No. 195717].

Methods utilizing the multiphase extractive membrane bioreactors fabricated with poly acrylonitrile have also been developed to selectively produce S(+) ibuprofen.
It Is also known that, benzotriazole derivatives containing aminoalkyi side chains are useful as resolving agents for the resolution of racemic mixture of ibuprofen.
Sodium salt of ibuprofen sulfomethyl ester was resolved using a proteinase to give S(+)ibuprofen in 39% yield.
The racemic forms of ibuprofen was also resolved using optically active 1-p-nitrophenyl-2-amino-propane-1,3-diol to give a diastereomeric salt which was decomposed to give S-(+)-lbuprofen. [Ger.DE 3, 814, 887]. .
Among the various methods employed for the resolution of racemeic mixtures of ibuprofen to give S(+)-ibuprofen in greater yield and higher chiral purity, the use of a-phenylethylamine as the resolving agent appears to be the most promising one. A number of reports claimed the utility of this chiral amine under a variety of experimental conditions.( Rossi, Richard, F; Heefiner, Danald.L : Zepp, Charles, M; U.S.Pat..No.5,73,895).
All the above mentioned processes produce S(+) 2-(4-isobutylphenyl) propionic acid in moderate to good yields but with low chiral purity(i.e less than 90%) Most of the methods employ costly catalysts and lengthy and tedious procedures making the processes of obtaining S(+)ibuprofen uneconomical for using them on a commercial scale.
Further the above said methods of resolution of racemic ibuprofen suffer from one or more of the following drawbacks.

a. Poor yields of S-(+)-ibuprofen.
b. Low chiral purity of S-(+)-ibuprofen.
c. Lengthy reaction times.
d. Relatively costlier resolving agents, catalysts and other chemicals
involved.
e. Repeated recrystallisations.
Therefore research work for the development of an economical and simpler process for the resolution of racemic mixtures of ibuprofen is being carried out through out the world to obtain pure form of S-(+)-ibuprofen in greater yields with higher chiral purity.
The above said circumstances and the increasing demand for S(+)ibuprofen inspired us to develop an improved process for the resolution of racemic mixtures of ibuprofen avoiding the above said drawbacks of the hitherto known processes.
The main object of the present invention, therefore, is to provide an improved process for the resolution of racemic ibuprofen to obtain S(+)-ibuprofen with greater yield and higher chiral purity.
The invention is based on our finding that N-alkyl-D-glucamines where the alkyl group has 4 to 36 carbon atoms, preferably 4 to 18 carbon atoms, N-cycloalkyl-D-glucamines where the alkyl group has 3 to 9 carbon atoms or N-aralkyl-D-glucamines where the aralkyl group has 7 to12 carbon atoms or salts thereof can be used for the resolution of racemic mixtures of ibuprofen.The

preferred glucamines which fall with in the scope of this invention are N-sec-butyl D-glucamine, N-octyl D-glucamine and N-benzyl-D-glucamine.
The process of resolution according to the process of the present invention is carried out in an organic solvent having a pronounced difference between the solubilities of the salts of S(+)2-(4-isobutylphenyl)propionic acid and the corrresponding salts of R(-)2-(4-isobutylphenyl) propionic acid with the above said glucamine The formation of the solution of the salt of S (+) ibuprofen and the salt of R(-)ibuprofen formed during the reaction with the said glucamine, is effected by heating the reaction mixture. The solvent employed should be such that, the salt of S(+)ibuprofen formed during the reaction with the said glucamine should have less solubility in the solvent employed than that of the corresponding salt of R(-)ibuprofen. This is essential so as to precipitate out the salt of S(+)ibuprofen from the solution. On cooling the solution, the less soluble salt of S(+)ibuprofen starts crystallizing out and can be separated.
Accordingly, the present invention provides an improved process for the preparation of S(+)ibuprofen and salts thereof from the racemic mixtures of ibuprofen which comprises :
a. preparing a solution of racemic mixtures of ibuprofen in a solvent.
b. adding a resolving agent selected from N-alkyl-D-glucamine N-
cycloalkyl-D-glucamine or N-aralkyl-D-glucamine to the solution of
racemic mixtures of ibuprofen in the solvent.
c. heating the resultant mixture so as to obtain a clear solution.

d. cooling the solution to room temperature or to a further lower
temperature so as to precipitate the salt of the S(+)ibuprofen formed
with the resolving agent used.
e. filtering the reaction mixture
f. suspending the precipitate in water and adjusting the pH by adding a
mineral acid or an organic acid.
g. heating the suspension to a temperature in the range of 50-80°C and
maintaining the suspension at that temperature for a period ranging
from 30minutes to 3hours.
h. cooling the suspension to room temperature i. extracting the S(+) ibuprofen with an organic solvent by conventional method.
Suitable solvents which can be employed for the preparation of the salt include C1 to C10 alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, isobutanol etc..Other solvents such as N,N- dimethyl formamide, N,N-dimethyl acetamide and dimethylsulfoxide can also be employed. Water can be added as a co-solvent to the reaction mixture, if needed, to solubilize all the reagents, thus making the reaction mixture a homogeneous solution. The solution is cooled slowly to ambient or below ambient temperature to selectively precipitate the salt of S(+)2-(4-isobutyphenyl)propionic acid. The salt is separated by filtration. This salt can further be purified by suspending it in the same solvent and heating to the boiling temperature of the solvent. The salt enriched with salt of S(+)-ibuprofen with the resolving agent separates on cooling which can be separated

by filtration. The crystalline salt obtained is suspended in water and acidified to pH 2 with a mineral acid such as hydrochloric acid or sulphuric acid or an organic acid such as acetic acid. The suspension is heated to a temperature in the range of 50-80°C and held at that temperature for about 5-10 minutes and then the resulting mass is cooled to ambient temperature. The fine white crystalline S(+)-ibuprofen formed is filtered or extracted with solvents such as n-hexane, benzene or dichloromethane. The product can be recrystallised from aqueous methanol or ethanol. Alternatively the pH of the salt suspension in water, can be adjusted to 8-10 with a strong base such as sodium hydroxide or potassium hydroxide. The suspension is heated to 50-80°C and filtered to recover the resolving agent. Then the S (+)ibuprofen is recovered by adjusting filtrate to acidic pH, preferably 2 to 3, using an acid as mentioned above.
The resolving agent so recovered can be recycled directly if required. The quantity of resolving agent used in the process of present invention may range between 50% and 100% (on a molar basis relative to the racemic mixture of ibuprofen [i.e.R(-)andS(+)2-(4-isobutylphenyl) propionic acid] used. The remaining part of the resolving agent can be replaced with a less expensive inorganic base such as sodium hydroxide, potassium hydroxide, ammonia etc. or an organic base such as triethylamine, tributylamine, etc.
In an embodiment of present invention, N-n-octyl D-glucamine is the preferred resolving agent so as to obtain S(+)2-(4-isobutylphenyl) propionic acid [S(+)ibuprofen] of high optical purity [98 to100%e.e. (enantiomeric excess)] in greater yield ( around 90%) and the resolving agent can be recovered to an extent of 95 - 99%.

The details of the invention are given in the examples given below which are provided by way of illustration only and should not be construed to limit the scope of the invention.
Example 1 : Racemic ibuprofen (25g), N-n-octyl-D-glucamine (36g) and isopropyl alcohol (200ml) are mixed and boiled. The reaction mixture is cooled to 0°C and is maintained for 1 hour. The solid separated is filtered and washed with chilled isopropyl alcohol. The wet salt is taken in isopropyl alcohol (40ml),and the resulting supention is refluxed for 15minutes.This suspention is cooled to room temperature, the salt of S(+)-ibuprofen with N-octyl-D-glucamine is filtered.washed with chilled isopropyl alcohol and dried, yield 25 g. M.R : 138-140°C; [α]D = (-) 118 (c=1 in methanol).
Example 2 A mixture of racemic ibuprofen (41.2g), N-sec.butyl-D-glucamine(47.4g) and methyl alcohol (125ml) are mixed and heated to 55°C and maintained until clear solution is obtained. The solution is cooled to 0-5°C and maintained for about 4 hours to precipitate the salt. The precipitated salt of S(+)-ibuprofen with N-sec.butyl-D-glucamine is filtered and recrystallised from methanol(80ml) and dried. Yield 36.5 g M.R. 138-140°C ; [α]D (-) 12.3 (c=1 in methanol)
Example 3.
Racemic ibuprofen(226.5g.), N-benzyl D-glucamine(300g) are taken in
methyl alcohol (900ml) and heated to reflux temperature. The reaction mixture is
cooled to ambient temperature in about 6 hours and precipitated salt is filtered. The
salt so obtained is suspended in methyl alcohol (250ml), heated and maintained at

60°C for about 10 minutes and cooled to 25°C. The salt of S(+)-ibuprofen with N-benzyl-D-glucamine is filtered and dried, yield 200 g.; M.R. 124-126°C; ND (-) 7.8°(c=1 in methanol).
Example-4 The salt of S(+)ibuprofen with N-n-octyl-D-glucamine(25g) obtained in example 1 is suspended in water(150ml) and the pH is adjusted to 2.0 by adding hydrochloric acid. The reaction mixture is heated and maintained at 60-70°C for about 10 minutes and then cooled to ambient temperature. The S-(+)-ibuprofen, liberated in the reaction, is extracted with n-hexane. The hexane extract is concentrated and cooled. The S(+)ibuprofen separated is filtered and dried. Yield lOg; M.R. 49-51 °C; [α]D-(+)69°(c = 2.5 in methanol); chiral purity 99.67%(by HPLC).
Example 5. The salt of S(+) ibuprofen with N-sec.butyl-D-glucamine (36.5g) (obtained in example 2) is suspended in water (300ml) and acidified with dilute sulphuric acid to pH 2 at ambient temperature. The precipitated S(+) ibuprofen is filtered, washed with water and dried. The dried product is recrystallised from aqueous ethanol. Yield 16.0 g.; M.R. 48-50°C ; (c = 2.5 in methanol) [α]D (+)57°; chiral purity 97.5%(by HPLC).
Example 6 The S(+)ibuprofen salt with N-benzyl-D-glucamine(200g) (obtained in experiment No.3) is suspended in water(3200ml) and heated to 70°C. The aqueous mass is adjusted to pH 2 with hydrochloric acid. The liberated S(+) ibuprofen is extracted with 600 ml of n-hexane. The hexane extract is concentrated and cooled to precipitate the S(+) ibuprofen. The S(+)ibuprofen is filtered and dried. Yield 84.3g.

M.R.48-49°C(c = 2.5 in methanol); [α]D (+)57°; chiral purity 97.6%.( by HPLC)
Example 7;
A mixture of racemic ibuprofen (82.4g.), N-n-octyl D-glucamine (119g.)
and ethanol (825ml) is warmed for complete dissolution. The reaction mass is cooled
to 0°C and maintained at this temperature until the salt precipitation is complete.
The solid separated is collected by filtration and washed with cold ethanol. This
solid is suspended in water (1300ml) and the pH is adjusted to 2.0 with
hydrochloricacid. The reaction mixture is maintained at 50-80°C for about 10
minutes and then it is cooled to ambient temperature. The S(+)-ibuprofen liberated
is extracted with n-hexane. The hexane extract is concentrated and the S(-i-)-
ibuprofen liberated is filtered and dried. Yield 33.8 gr; M.P. 49-51°C; [ah (+)58.4° (c=2.5 in methanol); chiral purity 99.49% (by HPLC).
Example 8;
Racemic ibuprofen(25 g) ,N-n-octyl-D-glucamine (36g) and 2-propanol (200ml) are mixed together and heated to 70-75°C. The reaction mixture is cooled to 40°C to precipitate the solid. This is filtered and recrystallised from 2-propanol(125ml). The solid is suspended in 150ml water and pH of the solution is adjusted to 2.0 with cone, hydrochloric acid. The reaction mixture is maintained at 60-70°C for about 10 minutes and cooled to ambient temperature. The S-(+)-ibuprofen is extracted with n-hexane from the reaction mixture. The hexane extract is concentrated and cooled. The S-(+)-ibuprofen is filtered and dried. Yield 9.85g.; M.R.49-51°C; [a]D(+)58.5°(c=2.5 in methanol); chiral purity.99.36%(by HPLC)

Example 9 :
Racemic ibuprofen(25g),N-n-octyl-D-glucamine(36g) are dissolved in dimethyl formamide (75ml) and stirred the solution for 1 hour. The solid separated in the reaction mixture is filtered. The solid thus collected is suspended in water(150ml). The pH of the suspension is adjusted approximately to 2.0. The reaction mixture is heated and maintained at 70°C for 10 minutes and then cooled to ambient temperature. The S-(+)-lbuprofen thus liberated is extracted with n-hexane and the hexane extracts are concentrated. S-(+)-ibuprofen separated upon cooling the concentrate is filtered and dried. Yield 11.3g ; M.R. 49-51°C; [a]D.(+) 58° (0=2.5 in methanol); chiral purity.98.7 % (by HPLC).
Example 10: Racemic ibuprofen(41.2g), N-n-octyl glucamine (28.5g) and sodium hydroxide (3.2g) in methanol (200ml) are heated to boiling temperature for complete dissolution. The reaction mixture is cooled to 0°C. The salt separated as solid is filtered and washed with cold methanol. The salt so obtained is recrystallised from methanol (250 ml) The recrystallised salt is suspended in water (150 ml) and the pH is adjusted to 2.5. The solution is maintained at 60-70°C for 10 minutes and then cooled to ambient temperature. The S-(+)-ibuprofen thus liberated is extracted with n-hexane. The hexane extracts are mixed and concentrated. S-(+)-ibuprofen is separated on cooling the concentrate. It is collected by filtration and dried. Yield.17.2g.;M.R.49-51°C ; [a]D.(+) 58.3°(c = 2.5 in methanol) chiral purity 99.21%.
Example 11 Racemic ibuprofen (41.2g), N-n-octyl-D-glucamine (28.5g) and triethylamine (8.1g) are heated in methanol (200ml) until a clear solution is obtained.

The clear solution is cooled to 0°C to precipitate the salt which is filtered and washed with cold methanol. The solid thus obtained is suspended in water (150ml),the pH adjusted to 2.0 with sulphuric acid and maintained at 60-70°C for 10 minutes. After cooling to ambient temperature, S-(+)-ibuprofen is filtered and recrystallised from aqueous methanol.Yield : 17.6g. M.R.49-51°C[a]D (+) 58.2°(c=2.5 in methanol) and chiral purity more than 99.12%(by HPLC).
ADVANTAGES OF THE PRESENT INVENTION:
1. The resolving agents employed are cheaper.
2. The reaction times required for resolution are shorter.
3. The yields of S(+)ibuprofen are higher ( 80-90 %).
4. The chiral purity is more than 98%.
5. The resolving agents can easily be recovered and reused
6. The salts prepared are novel and are also useful as anti-inflamatory agents.
The above advantages make the process of the present invention cheaper and economical and useful for its employment on a commercial scale.

We claim
1. An improved process for the preparation of S(+)ibuprofen and salts thereof from the racemic mixtures of ibuprofen which comprises :
a. preparing a solution of racemic mixtures of ibuprofen in a solvent.
b. adding a resolving agent selected from N-alkyl-D-glucamine
N-cycloalkyI- D-glucamine or N-aralkyl-D-glucamine to the solution of
racemic mixtures of ibuprofen in the solvent.
c. heating the resultant mixture so as to obtain a clear solution.
d. cooling the solution to room temperature or to a further lower
temperature so as to precipitate the salt of the S(+)ibuprofen formed
with the resolving agent used.
e. filtering the reaction mixture
f. suspending the precipitate in water and adjusting the pH by adding a
mineral acid or an organic acid.
g. heating the suspension to a temperature in the range of 50-80°C and
maintaining the suspension at that temperature for a period ranging
from 30minutes to 3hours.
h. cooling the suspension to room temperature
i. extracting the S(+) ibuprofen with an organic solvent by conventional method.
2. An improved process as claimed in claim 1 wherein the N-alkyl-D-glucamine used has in the alkyl group 4 to 36 carbon atoms preferably 4-18 carbon atoms.

3. An improved process as claimed in claim 1 wherein the N-cyclo-alkyl-D-glucamlne used has in the alkyl group 3 to 9 carbon atoms.
4. An improved process as claimed in claim 1 wherein the N-aralkyl-D-glucamine used has in the alkyl group 7 to 12 carbon atoms.
5. An improved process as claimed in claims 1-4 wherein the solvent used is selected from Ci to Cio alcohols, dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide.
6. An improved process as claimed in claims 1-5 wherein water is used along with the solvent to prepare the solution of racemic mixtures of ibuprofen and the resolving agent.
7. An improved process as claimed in claims 1-6 wherein the resolving agent is used along with an inorganic base such as sodium hydroxide, potassium hydroxide, ammonia or with an organic base such as triethylamine and tributylamine.
8. An improved process as claimed in claims 1-7 wherein the pH is adjusted by employing a mineral acid such as hydrochloric acid, sulphuric acid or an organic acid such as acetic acid .
9. An improved process as claimed in Claims 1-8 when the salt of S(+) ibuprofen is purified by suspending it in the same solvent used in step (5), heating and cooling.
10. An improved process as claimed in claims 1-9, wherein S(+)ibuprofen is separated from the reaction mixture by heating the suspention to a temperature in the range of 50°C to 80°C maintaining the mixture at

that temperature for a period of 10 minutes,cooling, filtering, and drying.
11. An improved process as claimed in claims 1-10 wherein the
S(+) -ibuprofen is separated by suspending the salt in water,adjusting
the pH in the range of 8-10 with a base such as potassium- hydroxide
or sodium hydroxide, heating the suspention to a temperature in the
range of 50-80°C, filtering, adjusting the pH of the suspension to
around 2 by adding a mineral acid such as hydrochloric acid, sulphuric
acid or an organic acid such as acetic acid.
12. An improved process for the preparation of S(+)ibuprofen and salts
thereof from the racemic mixture of ibuprofen substantially as herein
described with reference to the examples.