Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF 2-ARYL PROPIONIC ACIDS

Abstract An improved proccrs for the preparation of 2- nryl propionic acid which comprises reading an aicohol having the general formula 1 of the drawing accompanying this sp-citlcalion , wherein RI may be aryl , subsliluled aryl, napthy I or substituted caplhyl, R2, R3, R4 and R5 may independently be hydrogen , alkyl, aryl, aryl alkyl. cycle aliphatic with or without subslilucrits, a halidc source selected from the group consisting of hatide suits or hydrohalic acid in the range of 5 to 500 moles a proionic acid such as herein described in the ransic of 5 to 500rnoles, varer in the concentration range of 1 to 6 °/c(v/v), hetrogcnous ruthenium cobait or nickel metal as a caldyst wherein the concentration of melat is 1 irole of metal for 500 lo 50000 nicies of alcohol and a phesphing ligand in the ramie of 20 lo 50 moles in an organic solvent such as herein described in the carbon monoxide atmosphere in an autoclave at atamperature rauging between 30 to 130° C, for a period tanging between 50 to 1500 psig cooling the reaction mixture to ambient temperature, flushing the catoclave with nitrogen , sepurating the catalysl, removing the solvent by conventional methods arid isolating the 2- aryl propionic acid of the formula II of the drawing accompanying (he specification wherein R1 , R2, R3, R4 and R5 bas the same meaning as defined above.
Full Text This invention relates to an improved process for the preparation of 2- aryl propionic acid . Particularly this invention relates to the improved process for conversion of aryl olefins having the general formula 1 of the drawing accompanying this specification wherein R1 may be aryl, substituted aryl, napthyl or substituted napthyl, R2,R3, R4 and R5 may independently be hydrogen , alkyl aryl, arylalkyl, cycloaliphatic with or without substituents , to the corresponding 2- aryl propionic acid of the formula II of the drawing accompanying the specification using a heterogenous ruthenium, cobalt or nickel catalyst system.
A majority of the 2- aryl propionic acid are well known non steroidal anti inflammatory drugs. The conventional synthesis of ibuprofen involves six steps which use hazardous chemicals like sodium cyanide and the waste material produced require down stream treatments for disposal. Recently Hoechst Celanese Corporation has feveloped a novel environmentally benign three step catalytic route for the synthesis of ibuprofen in which carbonylation of para isobutyl phenyl ethanol is the key step. In the processes described in the patented literature the catalysts used were mainly Pd( PPh3)2Cl2: or PdCl2 or Pd( Oac)2 along with excess phosphine ligands ( EP 0, 400 892 A3, EP 0, 284.3 10 AI) which gave lower reaction rates ( TOP = 25-35 h -1) and lower selectivity to ibuprofen (56-69%) under mild conditions (130° C, 1000 psig). Higher selectivity ( > 95 %) was obtained only at very high pressure of 2000 to 4500 psig and the rates still remained low. Us patent 5,536874 and the publication J. chem.. Tech. Biotechnol 1997, 70, 83-91 describes the carbonylation of p- IBPE (ibuprofen) in a two phase system wherein one phase in an aqueous medium which contains a water
soluble palladium complex and an acid promoter. These processes also have disadvantages such as low reaction rates (TOF= 0.1 to 0.4 h-1) and lower ibuprolen selectivity (59-74%) under mild reaction conditions (90°C, 450 to 900 psig). The patents, EP 387 502 (1990)and EP 361 021 (1990) report the ysc of homogeneous Nickel catalysts but only in the presence of corrossive iodide promoters and gives low reaction rates and selectivity under even high pressure conditions. Another major problem assocoated with all these processes is the difficulty of catalyst separation and recycle.
The inventors of the present invention have observed that the use of a new catalyst system comprising of a heterogeneous ruthenium, cobalt or nickel catalyst, a phosphine ligand, a protonic acid and a halidc source provide an improved catalyst system for the carbonylation of compounds of general formula I to corresponding 2-arylpropionic acids. The use of such a catalyst system gives high reaction rates and high selectivity to 2-arylpropionic acids under mild reaction conditions with easy separation of and efficient recycle of the catalyst Another added advantage of this catalyst system is the low cost of the metals.
The object of the present invention therefore is to provide an improved process for the preparation of 2-aryl propionic acids by the carbonylation of corresponding alcohols.
Accordingly the present invention provides an improved process for the preparation of 2- aryl propionic acid which comprises reacting an alcohol having the general formula 1 of the drawing accompanying this specification , wherein RI may be aryl, substituted aryl, napthyl or substituted napthyl, R2, R3, R4 and R5 may independently be hydrogen, alkyl, aryl, aryl alkyl, cyclo aliphatic with or without substituents, a halide source selected from the group consisting of halide salts or hydrohalic acid in the range of 5 to 500 moles a protonic acid such as herein described in the range of 5 to 500moles, water in the concentration range of 1 to 6 %(v/v) , hetrogenous ruthenium, cobalt or nickel catalyst wherein the concentration of metal is 1 mole of metal for 500 to 50000 moles of alcohol and a phosphine ligand in the range of 20 to 50 moles in an organic solvent such as herein described in the carbon monoxide atmosphere in an autoclave at a temperature ranging between 30 to 130° C, for a period ranging between 50 to 1500 psig, cooling the reaction mixture to ambient temperature, flushing the autoclave with nitrogen , separating the catalyst, removing the solvent by conventional methods and isolating the 2- aryl propionic acid of the formula II of of the drawing accompanying the specification wherein R1 , R2, R3, R4 and R5 has the same meaning as defined above.
In one embodiments of the present invention the catalyst used may be rhodium or iridium as metal powder or as supported metal form.
In another embodiment the supports used may be such as carbon, or any of the refractory oxides such as alumina, silica,titania, zirconia or clays and zeolites.
In yet another embodiment the phosphine ligand used may be any of the mono or diphosphines such as triphenyl phosphine, tris(p-tolyl)phosphine, tricyclohexyl phoshine, tris(p-chloro phenyl) phosphine, tris(p-fluoro phcnyl)phosphinc, tris(p-methoxy phenyl) phosphine, tributyl phosphine, trisisopropyl phosphine, bisdiphenyl phosphino ethane, bisdiphenyl phosphino propane and bisdiphenyl phosphino butane.
In another embodiment the halide source may be any of the halide salts such as lithium chloride, sodium chloride, potassium chloride, lithium iodide, lithium bromide, sodium bromide, sodium iodide, potassium bromide, potassium iodide, tetrabutyl ammonium chloride, tetrabutyl ammonium bromide and tctrabutyl ammonium iodide or hydro halic acids such as hydrochloric acid, hydrobromic acid and hydro iodic acid .
In yet another embodiment the protonic acid used may be any of the hydrohalic acids such as hydrochloric acid, hydrobromic acid and hydroiodic acid or other protonic acids such as para toluene sulphonic acid, methane sulphonic acid, triflouromethane sulphonic acid, formic acid, oxalic acid, acetic acid and trifluoro acetic acid.
In yet another embodiment the organic solvent may be the, aromatic hydrocarbons like, bcn/cnc, toluene, xylcnes, or kctoncs like methyl ethyl kctone, acetone or cyclic ethers such as tetrahydrofuran, dioxan, or nitriles such as acetonitrile or amides like N-methyl pyrrolidone.
In another embodiment the concentration of catalyst may be one mole of the metal for every 500 to 50000 moles of alcohol, preferably 1 mole for every 800 to 6000 moles, and more preferably one mole for every 1000 to 2000 moles of alcohol.
In still another embodiment the amount of halidc source per gram mole of metal may be in the range of 5 to 500 moles, preferably 20 to 300 moles, and more preferably 50 to 150 moles.
In another embodiment the amount of acid source per gram mole of metal may be in the range of 5 to 500 moles, preferably 20 to 300 moles, and more preferably 50 to 150 moles.
In yet another embodiment the amount of the phosphine ligand per gram mole of metal may be in the range of 20 to 50.
In yet another embodiment the amount of water may be in the range of 1 to 6 % (v/v) of the total reaction mixture, preferably 3 to 5 % (v/v).
In a feature of the invention, the reaction can be conveniently carried out in a stirred reactor with the improved catalyst employed with a suitable solvent in presence of carbon monoxide.
The improved proeess of the present invention is described herein below with examples, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
EXAMPLE 1
Preparation of 1% Ru/C: 0.0167 g of RuCl3.3H20 was dissolved in 30ml of distilled water and 1 g of activated charcoal was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath and 8 ml of 40% formaldehyde solution was added followed by addition of 2N NaOH solution to make the medium basic (pH=10-12). After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried under vacuum at 60°C.
EXAMPLE 2
Preparation of 1% Ni/C: 0.0167 g of NiCl2.6H2O was dissolved in 30ml of distilled water and 1 g of activated charcoal was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was healed to 80°C in a water bath and 8 ml of 40% formaldehyde solution was added followed by addition of 2N NaOH solution to make the medium basic (pH=10-12). After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried under vacuum at 60°C.
EXAMPLE 3 Preparation of 1% Co/C: 0.0167 g of CoCl2.6H2O was dissolved in 30ml of
distilled water and 1 g of activated charcoal was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath and 8 ml of 40% formaldehyde solution was added followed by addition of 2N NaOH solution to make the medium basic (pH=l()-12). After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried under vacuum at 60°C.
EXAMPLE 4
Preparation of 1% Ru/y-Alumina: 0.0167 g of RuCls. 3 H2O was dissolved in 30ml of distilled water and 1 g of activated -Alumina was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath. After attaining the temperature the pH of the solution was made 4.5 by adding enough quantities of 1 N NaOH solution. There after 10 ml of 1 N solution of sodium formate was added. After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried at 120°C.
EXAMPLE 5
Preparation of 1% Ni/y-Alumina: 0.0167 g of NiCl2. 6.H2O was dissolved in 30ml od distilled water and 1 g of activated y-Alumina was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath. After attaining the temperature the pH of the solution was made 4.5 by adding enough quantities of 1 N NaOH solution. There after 10 ml of 1 N solution of sodium formate
was added. After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried at 120°C.
EXAMPLE 6
Preparation of 1% Co/-Alumina: 0.0167 g of CoCl2. 6 H2O was dissolved in 30ml od distilled water and 1 g of activated -Alumina was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath. After attaining the temperature the pH of the solution was made 4.5 by adding enough quantities of 1 N NaOH solution. There after 10 ml of 1 N solution of sodium formate was added. After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried at 120°C.
EXAMPLE 7
Preparation of Ru/H-ZSM 5: 0.0167 g of RuCl3.3H2O was dissolved in 30ml distilled water and 1 g of H-ZSM 5 was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 8C)°C in a water bath. After attaining the temperature the pH of the solution was made 4.5 by adding enough quantities of 1 N NaOH solution. There after 10 ml of 1 N solution of sodium formate was added. After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried at 120°C.
EXAMPLE 8
Preparation of Ni/H-ZSM 5: 0.0167 g of NiCl2.6H20 was dissolved in 30ml of distilled water and 1 g of H-ZSM 5 was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath. After attaining the temperature the pH of the solution was made 4.5 by adding enough quantities of 1 N NaOH solution. There after 10 ml of 1 N solution of sodium formate was added. After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried at 120°C.
EXAMPLE 9
Preparation of Co/H-ZSM 5: 0.0167 g of CoCl2-6H2O was dissolved 30ml distilled water and 1 g of H-ZSM 5 was added to make a slurry which was kept under vigorous stirring at room temperature. After 6 hours the slurry was heated to 80°C in a water bath. After attaining the temperature the pH of the solution was made 4.5 by adding enough quantities of 1 N NaOH solution. There after 10 ml of 1 N solution of sodium formate was added. After 1 hour stirring at 80°C, the catalyst was filtered, washed thoroughly with warm water several times, and dried at 120°C.
EXAMPLE 10
A 50 ml stirred autoclave was charged with the following reactants
l-(4'-isobutylphenyl) ethanol: 2.5g
l%Ru/C:0.1 g
triphenyl phosphine: 0.08165g
p-tolucne sulphonic acid : 1.065g
LiCl: 0.2365g
H2O: 1.2 mL
Methyl ethyl ketonc: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 470 h"1 and 99% conversion ofp-IBPE with ibuprofen selectivity of 99.2%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 1 1
A 50 ml stirred autoclave was charged with the following rcactants
l-(4'-isobulylphcnyl) cthanol: 2.5g
1% Ru/C (separated from example 10): 0.076 g
triphcnyl phosphine: 0.08165
p-toluene sulphonic acid : 1.065g
LiCl: 0.2365g
H2O: 1.2mL
Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 380 h"1 and 99% conversion of/?-IBPE with ibuprofen selectivity of 99%. The catalyst was filtered out, the solvent evaporated and the reaction mixture re-dissolved in toluene. The solid portion,
which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofcn, which on hydrolysis with acid and extraction with dichloromcthanc, evaporation and vacuum distillation gives the pure product.
EXAMPLE 12
A 50 ml stirred autoclave was charged with the following rcactants l-(4'-isobutylphenyl) ethanol: 2.5g 1% Ru/C (separated from example 11): 0.040 g triphcnyl phosphine: 0.08165g p-tolucnc sulphonic acid : 1.065g LiCl: 0.2365g H2O: 1.2mL Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was
then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 370 h"1 and 99% conversion ofp-IBPE with ibuprolcn selectivity of 99.1%. The catalyst was filtered out, the solvent evaporated and the reaction mixture re-dissolved in toluene. The solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 13 A 50 ml stirred autoclave was charged with the following rcactants
l-(4'-isobutylphenyl) ethanol: 2.5g
l%Ni/C: 0.1 g
triphenyl phosphine: 0.08165g
p-toluenc sulphonic acid : 1.065g
LiCl: 0.2365g
H2O: 1.2 mL
Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon
monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The (JC analysis showed TOP of 300 h"1 and 99% conversion of/;-lBPE with ibuprofen selectivity of 99.2%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 14
A 50 ml stirred autoclave was charged with the following reactants
l-(4'-isobutylphenyl)ethanol : 2.5g
1% Ni/C (separated from example 13): 0.067 g
triphenyl phosphine: 0.08165
p-toluene sulphonic acid : 1.065g
LiCl: 0.2365g
M2O: 1.2Ml
Methyl ethyl kctonc: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 310 h"1 and 98% conversion ofp-IBPE with ibuprofen selectivity of 99.3%. The catalyst was filtered out, the solvent evaporated and the reaction mixture redissolved in toluene. The solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromemane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 15
A 50 ml stirred autoclave was charged with the following reactants l-(4'-isobutylphenyl) ethanol: 2.5g
1% Ni/C (separated from example 14): 0.04 g
triphcnyl phosphine: 0.08165g
p-toluene sulphonic acid : 1.065g
LiCl: 0.2365g
H2O: 1.2 mL
Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofcn, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 308 h~' and 99% conversion of p-IBPE with ibuprofcn selectivity of 99.1%. The catalyst was filtered out, the solvent evaporated and the reaction mixture re-dissolved in toluene. The solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of
ibuprofcn, which on hydrolysis with acid and extraction with dichloromcthane, evaporation and vacuum distillation gives the pure product.
nXAMPLI: 16
A 50 ml stirred autoclave was charged with the following rcactants l-(4'-isobutylphenyl) ethanol: 2.5g l%Co/C:0.1 g
triphenyl phosphine: 0.08165g p-toluene sulphonic acid : 1.065g LiCl: 0.2365g H2O: 1.2mL Methyl ethyl kctonc: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 245 h"1 and 99% conversion of p-lBPE with ibuprofcn selectivity of 99 %. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-tolucnc sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 17 A 50 ml stirred autoclave was charged with the following reactants
l-(4'-isobutylphenyl) ethanol: 2.5g
1% Co/C (separated from example 16): 0.069 g
triphenyl phosphine: 0.08165
p-tolucne sulphonic acid : 1.065g
LiCl:0.2365g
II2O: 1.2 mL
Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was
maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 250 h"1 and 98% conversion ofp-IBPE with ibuprofcn selectivity of 99.3%. The catalyst was filtered out, the solvent evaporated and the reaction mixture re-dissolved in toluene. The solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofcn, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EX AMPLE 18 A 50 ml stirred autoclave was charged with the following reactants
Sec phenethyl alcohol: 2.5g
l%Ni/C:0.1 g
triphcnyl phosphine: 0.08165g
p-toluene sulphonic acid : 1.065g
LiCl: 0.2365g
H2O:1.2mL
Methyl ethyl kctonc: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of 2-phenyl propionic acid, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 170 h"1 and 99% conversion of sec. phenethyl alcohol with 2-phcnyl propionic acid selectivity of 98%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of 2-phenyl propionic acid, which on hydrolysis with acid and extraction with dichloromcthane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 19
A 50 ml stirred autoclave was charged with the following reactants l-(6-mcthoxy-2- naphthyl) ethanol: Ig
l%Ru/C: 0.1 g
triphenyl phosphinc: 0.08165g
p-tolucne sulphonic acid : 1.065g
Lid: 0.2365g
H2O: 1.2 mL
Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of naproxcn, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 130 h"1 and 99% conversion of 6-methoxy naphthyl ethanol with naproxen selectivity of 98.9%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-toluenc sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is

separated, which on hydrolysis and extraction with dichloromethane gives the pure product
RXAMPLF, 20
A 50 nil stirred autoclave was charged witli the following reactants l-(4'-isobutylphenyl) ethanol: 2.5g l%Ni/ZSM5:0.1 g triphenyl phosphine: 0.08165g p-toluene sulphonic acid : 1.065g LiCl: 0.2365g H2O: 1.2 mL Methyl ethyl ketonc: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 210 h"1 and 96% conversion of/>IBPE with ibuprofcn selectivity of 99%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-tolucne sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 21
A 50 ml stirred autoclave was charged with the following rcactants l-(4'-isobutylphenyl) ethanol: 2.5g 1% Ru/y-alumina : 0.1 g triphenyl phosphine: 0.08165g p-toluene sulphonic acid : 1.065g LiCl: 0.2365g H2O: 1.2 mL Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced
immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 280 h"1 and 98% conversion of^-IBPE with ibuprofen selectivity of 98.5%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 22
A 50 ml stirred autoclave was charged with the following reactants l-(4'-isobutylphenyl) ethanol: 2.5g l%Ni/C:0.1 g
triphenyl phosphine: 0.08165g 50%HC1: 1.2ml Methyl ethyl ketone: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times
with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced' immediately. l;or synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 220h-' and 98% conversion of p-IBPE with ibuprofen selectivity of 98.7%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
EXAMPLE 23 A 50 ml stirred autoclave was charged with the following reactants
l-(4'-isobutylphenyl) ethanol: 2.5g
l%Ni/C:0.1g
triphenyl phosphine: 0.08165g
p-tolucne sulphonic acid : 1.065g
LiCl: 0.2365g
1I2O: 1.2mL Toluene: 21.5mL
The contents of the autoclave were flushed with nitrogen and then many times with carbon monoxide. Thereafter, the contents were heated to 115°C. After the temperature is attained, the autoclave was pressurised to 800 psig with carbon monoxide, stirring started and it was observed that gas absorption commenced immediately. For synthesis of ibuprofen, the pressure in the autoclave was maintained constant using carbon monoxide and the progress of the reaction was monitored by observing the pressure drop and by liquid sampling. The reaction was continued until the pressure drop was too low. The reactor was then cooled and the liquid phase analysed by gas chromatography.
The GC analysis showed TOP of 100 h"1 and 97% conversion of p-lEPE with ibuprofen selectivity of 99.2%. The catalyst was filtered out and the solvent evaporated and the reaction mixture re-dissolved in toluene. The precipitated solid portion, which is a mixture of LiCl and lithium salt of p-toluene sulphonic acid was filtered out. The filtrate is treated with saturated solution of sodium bicarbonate two-three times and the aqueous phase is separated to obtain the sodium salt of ibuprofen, which on hydrolysis with acid and extraction with dichloromethane, evaporation and vacuum distillation gives the pure product.
Advantages of the invention
1. Employment of a novel heterogeneous catalyst system under mild reaction
conditions.
2. Provides high reaction rates
3. Provides very high selectivity to 2-aryl propionic acids
4. Provides simple and efficient catalyst separation and recycle.
5. Provides cheaper catalysts under non iodic and non corrosive conditions






We Claim
1. An improved process for the preparation of 2- aryl propionic acid
which comprises reacting an alcohol having the general formula 1 of the
drawing accompanying this specification , wherein RI may be aryl, substituted
aryl, napthyl or substituted napthyl, R2, R3, R4 and R5 may independently be
hydrogen , alkyl, aryl, aryl alkyl, cycle aliphatic with or without substituents, a
halide source selected from the group consisting of halide salts or hydrohalic
acid in the range of 5 to 500 moles a protonic acid such as herein described in
the range of 5 to 500moles, water in the concentration range of 1 to 6 %(v/v) ,
hetrogenous ruthenium,cobalt or nickel metal as a catalyst wherein the
concentration of metal is 1 mole of metal for 500 to 50000 moles of alcohol
and a phosphine ligand in the range of 20 to 50 moles in an organic solvent
such as herein described in the carbon monoxide atmosphere in an autoclave at
a temperature ranging between 30 to 130° C, for a period ranging between 50
to 1500 psig, cooling the reaction mixture to ambient temperature, flushing the
autoclave with nitrogen , separating the catalyst, removing the solvent by
conventional methods and isolating the 2- aryl propionic acid of the formula II
of the drawing accompanying the specification wherein R! , R2, RS, R4 and R5
has the same meaning as defined above.
2. An improved process as claimed in claim 1 wherein the catalyst used is
ruthenium, cobalt or nickel as metal powder or as supported metal form.
3. An improved process as claimed in claim 1 and 2 wherein the supports
used may be such as carbon , or any of the refractory oxides such as Y-
alumina, silica, titnia, zirconia or clay or zeolites.

4. An improved process as claimed in claims 1 to 3 wherein the phosphinc
ligand used is any of the mono or di phosphines such as triphenyl
phosphine, tris(p-tolyl)phosphinc, tricyclohcxyl phoshinc, tris(p-chloro
phcnyl) phosphine, tris(p-fluoro phenyl)phosphine, tris(p-methoxy phenyl)
phosphine, tributyl phosphine, trisisopropyl phosphine, bisdiphenyl
phosphino ethane, bisdiphenyl phosphino propane and bisdiphenyl
phosphino butane.
5. An improved process as claimed in claims 1 to 4 wherein the halide source
is any of the halide salts such as lithium chloride, sodium chloride,
potassium chloride, lithium iodide, lithium bromide, sodium bromide,
sodium iodide, potassium bromide, potassium iodide, tetrabutyl ammonium
chloride, tetrabutyl ammonium bromide and tetrabutyl ammonium iodide or
hydrohalic acids such as hydrochloric acid, hydrobromic acid and
hydroiodic acid.

6. An improved process as claimed in claims 1 to 5 wherein the protonic acid
used is any of the hydro halic acids such as hydrochloric acid, hydrobromic
acid and hydro iodic acid or other protonic acids such as para toluene
sulphonic acid, methane sulphonic acid, triflouromethane sulphonic acid,
formic acid, oxalic acid, acetic acid and trifluoro acetic acid.
7. An improved process as claimed in claims 1 to 6 wherein the organic
organic solvent used is benzene, toluene, xylenes methyl ethyl ketone, acetone, tetrahydrofuran, dioxan, acetonitrile , N- methyl pyrrolidone .
8. An improved process as claimed in claim 1 to 7 wherein the concentration of
metal is preferably 1 mole for every 800 to 6000 moles and more preferably one
mole for every 1000 to 2000 moles.
9. An improved process as claimed in claims 1 to 8 wherein the amount of halide
source per gram mole of metal is preferably 20 to 300 moles and more preferably
50 to 150 moles.

10. An improved process as claimed in claim 1 to 9 wherein the amount of acid
source per gram mole of metal is preferably 20 to 300 moles and more preferably
50 to 150 moles.
11. An improved process as claimed in claim 1 to 10 wherein the concentration of
water is 3 to 5 %(v/v).
12. An improved process for the preparation of 2- aryl propionic acid as herein
described with reference to examples given.



Documents:

570-del-1999-abstract.pdf

570-del-1999-claims.pdf

570-del-1999-complete specification (granted).pdf

570-del-1999-correspondence-others.pdf

570-del-1999-correspondence-po.pdf

570-del-1999-description (complete).pdf

570-del-1999-drawings.pdf

570-del-1999-form-1.pdf

570-del-1999-form-2.pdf

570-del-1999-form-3.pdf

570-del-1999-form-4.pdf

570-del-1999-form-9.pdf

570-del-1999-petition-138.pdf


Patent Number 192841
Indian Patent Application Number 570/DEL/1999
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 14-Oct-2005
Date of Filing 15-Apr-1999
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 RAGHUNATH VITTHAL CHAUDHARI NATIONAL CHEMICAL LABORATORY, PUNE, 411008, MAHARASHTRA, INDIA.
2 JAYASREE SEAYAD NATIONAL CHEMICAL LABORATORY, PUNE, 411008, MAHARASHTRA, INDIA.
3 SEAYAD ABDUL MAZEED NATIONAL CHEMICAL LABORATORY, PUNE, 411008, MAHARASHTRA, INDIA.
PCT International Classification Number C07C 57/03
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA