FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of compound of formula 1.
The present invention particularly relates to an improved process for the preparation of compound of formula I, which is used as an intermediate in the preparation of Ibuprofen, wherein the process is highly cost effective, commercially feasible & industrially advantageous.
BACKGROUND OF THE INVENTION
Ibuprofen is a well known anti-inflammatory drug. Ibuprofen is chemically known as (±)-2-(p-isobutyl phenyl) propionic acid. Ibuprofen is a white powder with a melting point of 74-77° C and is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as cthanol and acetone. Ibuprofen has the following structural formula:
The synthesis of Ibuprofen and its intermediates are disclosed in Journal of the Chemical Society, 1956, p. 4943, Tetrahedron, 65(10), 2015-2021; 2009, EP 0 337 803 Al, US 4,623,736, US 4,981,995, US 5,302,263, Chem. Lett. 2012, 41, 1597-1599, Journal of Organic Chemistry, vol. 52, p. 287, EP 0 400 892 A2 and EP 0 337 803A. '
US 4,623,736 disclose a process for the preparation of Ibuprofen starting from 1-isobutylbenzene which is shown in the scheme given below:

The above process for the preparation of Ibuprofen using compound of formula I is not feasible at industrial level due to the costing of starting materials.
Journal of the Chemical Society, Perkin transissions 1 organic and bioorganic .chemistry (1971-1999) 2575-2581, 1982 also disclose the synthesis of compound of formula I by reacting isobutyl benzene with propionyl chloride to give compound of formula II which is chlorinated using Copper (II) chloride (CuCl2), Lithium chloride (LiCl). The process is shown in the scheme given below:
The process may not be feasible as the reagents used for the chlorination are not£Qst.effective and the vield obtained in the above chlorination is not commercially

effective.
The inventors of the present .invention invented a simple, cost effective chlorination of compound of formula II using simple chlorine gas for chlorination optionally using solvent.
The process of the present invention is highly efficient, industrially feasible and economically viable which substantially eliminate the problems associated with the prior art, and that will be suitable for large-scale preparation such that the process will be safe to handle, simple and easy to carry out with high yield and purity of the product.
OBJECT OF THE INVENTION
The main object of the present invention provides an improved process for the preparation of compound of formula I.
The further object of the invention is to provide a simple, cost effective, improved and robust process for the preparation of compound of formula I which is used as an intermediate in the preparation of Ibuprofen or its salts, wherein the process is simple and cost effective.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved and alternative process for the preparation of compound of Formula I

which comprises a) Reacting compound of Formula III
with compound of Formula IV
wherein X is a halo group, in the presence of a Lewis acid in a solvent to give compound of formula II
b) Chlorinating compound of Formula II with a chlorinating agent optionally in a solvent to give compound of formula I, wherein the chlorinating agent used in step b) is selected from chlorine gas, calcium hypochlorite, sodium hypochlorite, trichloroisocyanuric acid, thionyl chloride, methanesulfonyl chloride, trichloromethanesulforiyl chloride, tert-butyl hypochlorite, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl chloride, cyanuric chloride, N-chlorosuccinimide, N-chlorophthalimide, l,3-dichloro5,5-dimethylhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid, N-chlorosaccharin, chloramine B hydrate and trimethylsilyl chloride.
In a preferred aspect, the present invention provides an improved and alternative process for the preparation of compound of Formula I
CH3 CH3^
F<
T -i r

which comprises chlorinating compound of Formula II
with a chlorine gas optionally in a solvent to give compound of formula I.
In another preferred aspect, the present invention provides an improved and alternative process for the preparation of Ibuprofen or its salts
which comprises
a) Reacting compound of Formula III
with compound of Formula IV
wherein X is halo group, in the presence of a Lewis acid in a solvent to give compound of formula II
b) Chlorinating compound of Formula II with a chlorinating agent optionally in a solvent to give compound of formula I,

wherein the chlorinating agent used in step b) is selected from chlorine gas,
calcium hypochlorite, sodium hypochlorite, trichloroisocyanuric acid, thionyl
chloride, methanesuifonyl chloride, trichloromethanesulfonyl chloride, tert-butyl
hypochlorite,, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl
chloride, cyanuric chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-
dichloro5,5-dimethylhydantoin, sodium dichloroisocyanurate,
trichloroisocyanuric acid, N-chlorosaccharin, chloramine B hydrate and trimethylsilyl chloride, c) Reacting compound of Formula I with compound of formula V
. in the presence of an acid in a solvent to give compound of formula VI,
d) Converting compound of Formula VI to give compound of formula VII
e) Treating compound of Formula VII with base in a solvent to give compound of formula VIII

f) Converting compound of Formula VIII to Ibuprofen or its salts
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of formula I, which is used as an intermediate in the preparation of Ibuprofen.
The inventors of the present invention have developed an improved process approach for the preparation of Ibuprofen intermediates which are commercially available and cost effective process.
The improved process according to the present invention does not yield any . impurities.including positional impurities more than prescribed levels. Further, the . process involves solvent extractions and work up procedures which gives good yield and quality of the product.
Any of the intermediates used in the preparation of Ibuprofen of the present invention may be isolated or carried out in-situ to Ibuprofen or its salts. Ibuprofen according to the present invention can be in the racemic form or its enantiomeric form.
According to the present invention compound of formula I is prepared by
'reacting, compound of formula III with compound of formula IV using Lewis acid in a
solvent to give compound of formula II which further converted to compound of

formula I by using chlorinating agent. Compound of formula I prepared according to the present invention is preferably used as an intermediate in the preparation of Ibuprofen.
The process of the present invention is schematically represented below:
According to the present invention X is preferably selected from halo groups such as chlorine, bromine, iodine and fluorine. Lewis acid as used in the present invention is selected from Calcium chloride (CaC^), Calcium chloride dihydrate (CaCl2-2H20)5 Ferric chloride (FeCl-0, Aluminium chloride (A1C13), Aluminium bromide (AlBr3), Boron trifluroide (BF3), Boron trichloride (BC13), Tin (IV) chloride (SnCLj), Magnesium chloride (MgCl2).

Chlorinating agent as defined in the present invention is preferably selected from chlorine gas, calcium hypochlorite, sodium hypochlorite, trichloroisocyanuric acid, thionyl chloride, methanesulfonyl chloride, trichloromethanesulfonyl chloride, lert-butyl hypochlorite, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl chloride, cyanuric chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro5,5-dimethylhydantoin, rodium dichloroisocyanurate, trichloroisocyanuric acid, N-chlorosaccharin, chloramine B hydrate and trimethylsilyl chloride. Preferably the present invention involves the use of chlorine gas for the chlorination of compound of formula II.
According to the present invention the conversion of compound of formula VI to compound of formula VII is preferably carried out in the presence of Zinc oxide/zinc chloride in a solvent. Further, the conversion of compound of formula VIII to ibuprofen or its salts is carried out in the presence of an acid.
The term acid as used in the present invention is selected from trifluoroacetic acid (TFA), p-loluenesulfonic acid (PTSA), methane- or trifluoromethanesulfonic acid, HBr in acetic acid, H2SO4, HCI, camphorsulfonic acid and acetic acid.
The term base as used in the present invention is selected from organic base or inorganic base. Inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, Alkoxides and Hydrides. The example of inorganic base includes but not iimited to NaHC03, LiOH, NaOH, KOH, KHC03, LiHC03, Na2C03, K2C03; Li2C03) CaC03, MgC03, sodium hydride, Potassium tert butoxide, Sodium tert butoxide, magnesium hydroxide, MgH2, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof. Organic base is selected from pyridine and its" derivative, piperidine, nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.

The term solvent as used in the present invention is selected from water or acetie acid, methanol, ethanol, n-propanol, isop.rapanol, n-butanol and t.-butanol or benzene* toluene, xylene, heptane, .hexane and eyclohexane or acetone, ethyl methyl ketone, diethyl ketone; methyl tert-butyl ketone, isopropyl ketone or methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or acetonilrjle, propionitrile, butyronitrile and isobutyronitrile or di-tert-butylether, dimethylcther, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol :arid dimethoxyethane. or fcrmamide, DMF, DMSO, DMAC, N-methylr2-pyrrolidone. N-methylforrnamide, N-methyl morpholine, 2-pyrrolidone, 1-ethenyl-2-pyrrolidone and/or mixtures thereof.
Accordingly, the present invention provides an improved and alternative process for the preparation of compound of Formula I
which comprises a) Reacting compound of Formula III
with compound of Formula IVA
in the presence of A1C13 in MDC to give compound of formula II

Formula II - b) Chlorinating compound of Formula II with chlorine gas to give compound of formula I, wherein the chlorination is carried out in the absence of a solvent.
T -In:a preferred-embodiment,-the present-invention.provides an improved^nd^ alternative process for the preparation of compound of Formula I
which comprises chlorinating compound of Formula II
with chlorine gas to give compound of formula I, wherein the chlorination is carried out in the absence of a solvent.
.In another preferred embodiment, the present invention provides an improved and alternative process for the preparation of Ibuprofen or its salts
which comprises
a) Reacting compound of Formula III
with compound of Formula IVA

in the presence of a A1C13 in MDC to give compound of formula II
b) Chlorinating compound of Formula II with chlorine gas to give compound of formula I,
wherein the chlorination is carried out in the absence of a solvent, c) Reacting compound of Formula I with compound of formula V
in the presence of p-toluenesulfonic acid (PTSA) in toluene to give compound of formula VI,
d) Treating compound of Formula VI with zinc chloride in toluene to give compound of formula VII

_e)_Treatingjcgmpound_qf Formula VII with sodium hydroxide in toluene to give compound of formula VIII
f) Treating compound of Formula VIII with HC1, in isopropyl alcohol to Ibuprofen or
its salts
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Examplc-1: Preparation of compound of Formula II
140 gm of propionyl chloride (Formula IVA) (1.513 mol) were dissolved in 400mL of methylene chloride and 250 gm of A1C13 to which 200 gm of Isobutyl benzene (Formula III) (1.490 mol) were added temperature between -20 to 30°C under stirred for about 7 hours. 40 mL of cone. HC1 was slowly added to the reaction mixture and stirred for 30 minutes. The organic phase was washed several times with water and separated organic phase of compound of formula II.
Exam'pl.c-2: Preparation of compound: of Formula II

140 gm of propionyl chloride (Formula IVA) ,(1.513 mol) were dissolved in 440mL of heptane and 230 gm. of AICI3? to which 200 gm of Isobutyl benzene (Formula HI.) (1.490 mol) were added temperature between -20 to 110°C under stirred for about 7 hours, 40 mL of cone. HC1 was slowly added to the reaction mixture and stirred for 30 minutes. The organic phase was washed several times with water and separated organic phase was dislilled out and added toluene of compound of formula II which is used as such for the next step.
Example-3: Preparation of compound of Formula I
Organic layer containing compound of Formula II as obtained from example-2 was treated with chlorine gas under stirred at -20 to 40°C for about 6 hours. 200mL water was added after the completion of reaction, separated organic phase and distilled out and to obtain compound of formula I which is used as such for the next step.
ExampIe-4: Preparation of compound of Formula VI.
Organic layer containing compound of Formula I as obtained from example-3 was dissolved in toluene, 180gm of Neopentyl glycol (Formula V) was added, 18gm of p-Toluenesulfonic acid (PTSA) and the reaction mixture was reflux for 5 hours. After completion of the reaction mixture cooled and charges the sodium bicarbonate_ solution, stirred for ISminutes. Separate the organic layer and distilled out minimum quantity of toluene and to obtain compound of formula VI which is used as such for the next step.
Example-5: Preparation of compound of Formula VII.
Organic layer containing compound of Formula VI as obtained from example-4 was added lot wise Zinc chloride and stirred at 130°C for 10 hours to obtain compound of formula VII which is used as such for the next step.

Organic layer containing compound of Formula VII as obtained from example-
5 was. added 59gm of.sodium hydroxide and water, reaction mixture was stirred at 80-
85"C for 4.. hours, and 300 mL of heptane was added and stirred for 30 minutes.
Reaction mixture was cooled and stirred for 3 hours; reaction mixture was filtered and
washed with chilled toluene and dry the material. 1000 mL of water was added to
above material, temperature was raised to 75-80°C, stirred for 1 hour and charged
activated carbon and filter to obtain compound of formula VTII which is used as such
for the'next step.
Example-7: Preparation of compound of Ibuprofen.
Organic layer containing compound of Formula VIII as obtained from example-
6 was added water and pH was adjusted to 1.0 to 2.0 with cone. HC1 and n-hexane
added, stirred at 60-65°C for 30 minutes, reaction mixture was cooled, filtered and
washed with hexanes to afford 200-230gm of Ibuprofen and not less than 99.0%
purity.

We claims:
1. An improved and alternative process for the preparation of compound of Formula I
which comprises
a) Reacting compound of Formula III
with compound of Formula IV
wherein X is halo group, in the presence of a Lewis acid in a solvent to give compound of formula II
b) Chlorinating compound of Formula II with a chlorinating agent optionally in a solvent to give compound of formula I, wherein the chlorinating agent used in step b) is selected from chlorine gas, calcium hypochlorite, sodium hypochlorite, trichloroisocyanuric acid, thionyl chloride, methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl hypochlorite, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl chloride, cyanuric chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro5,5-dimethy lhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid, N-chlorosaccharin, chloramine B hydrate and trimethylsilyl chloride.

2. An improved, and.alternative process as claimed in claim 1, wherein X is halo selected from chlorine, iodine, bromine or fluorine.
3. An improved and alternative process for ths preparation of compound of Formula I
which comprises chlorinating compound of Formula II
with a chlorine gas optionally in a solvent to give compound of formula I. 4. An improved and alternative process for the preparation of Ibuprofen or its salts
which comprises a) Reacting compound of Formula III
with compound of Formula IV
. wherein X is halo group, in the presence of a Lewis acid in a solvent to give compound of formula II

b) Chlorinating compound of Formula II with a chlorinating agent optionally in a solvent to give compound of formula I,
wherein the chlorinating agent used in step b) is selected from chlorine gas,
calcium hypochlorite, sodium hypochlorite, tiichloroisocyanuric acid, thionyl
chloride, methanesulfonyl chloride, trichloromethanesulfonyl chloride, tert-butyl
hypochlorite, dichloromethyl methyl ether, methoxyacetyl chloride, oxalyl
chloride, cyanuric chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-
dichloro5,5-dimethylhydantoin, sodium dichloroisocyanurate,
trichloroisocyanuric acid, N-chlorosaccharin, chloramine B hydrate and trimethylsilyl chloride, c) Reacting compound of Formula I with compound of formula V
in the presence of an acid in a solvent to give compound of formula VI,
d) Converting compound of Formula VI to give compound of formula VII

e) Treating compound" of Formula VII with base in a solvent, to give compound of formula VIII
f) Converting compound of Formula VIII to Ibuprofen or its salts.
5. An improved and alternative process as claimed in claim 4, wherein the lewis acid as used in step a) is selected from Calcium chloride (CaC12), Calcium chloride dihydrate (CaCl2-2H20), Ferric chloride (FeCl3), Aluminium chloride (A1C13), Aluminium bromide (A13r3)., Boron trifluroide (BF3), Boron trichloride (BC13), Tin (IV) chloride (SnCLO, Magnesium chloride (MgCl2).
6. An improved and alternative process as claimed in claim 4, wherein the acid as used in step c) is selected from triftuoroacetic acid (TFA), p-toluenesulfo.nic acid (PTSA), methane- or trifluoromethanesulfonic acid, HBr in acetic acid, H2S04, HC1, camphorsulfonic acid and acetic acid.
7. An improved and alternative process as claimed in claim 4, wherein the base as used in step e) is selected from organic base or inorganic base. Inorganic base is seiected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, Alkoxides and Hydrides. The example of inorganic base includes but not limited toNaHC03, LiOH, NaOFL KOH. KHC03, LiHC03, Na2C03, K2C03> Li2G03, CaC03! MgC03s sodium hydride, Potassium tert butoxide, Sodium tert hutoxide, magnesium hydroxide, MgH;, Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, GaH2. Ca(0^/lc)2 end Ca(OEt)2 and the like or mixtures thereof. -Organic base is selected from pyridine and its derivative, piperidine,

nitrogen containing base. The example of organic base includes but not limited to pyridine, piperidine, dimethyl amino pyridine, picolines, diisopropyl ethyl amine, triethyl amine and the like or mixtures thereof.
8. An improved and alternative process as claimed in claim 4, wherein the solvent as used in any of the above step are selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene, benzene, toluene, xylene, heptane, hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.