Process for the preparation of 2-aryl propionic acids

Details Process for the preparation of 2-aryl propionic acids Process for the preparation of 2-aryl propionic acids

2000-09-14

2003-12-09

Rotman, Alan L. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acids and salts thereof

C562S408000, C562S409000

Reexamination Certificate

active

06660883

ABSTRACT:

This invention relates to an improved process for the preparation of 2-aryl propionic acids. Particularly this invention relates to an improved,process for conversion of aryl alkyl compound such as aryl alkyl alcohols and aryl alkyl halides having the general formula I
or aryl olefins of the general formula II
wherein, R
1
may be aryl, substituted aryl, naphthyl or substituted naphthyl, R
2
, R
3
, R
4
and R
5
may independently be hydrogen, alkyl, aryl, arylalkyl, cycloaliphatic with or without substituents, and X is a halogen atom or an —OH group, to the corresponding 2-aryl propionic acids using a catalyst system based on a heterogeneous metal selected from palladium, platinum, rhodium, iridium, ruthenium, cobalt or nickel.
A majority of the 2-aryl propionic acids 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 materials produced require down stream treatments for disposal. Recently, Hoechst Celanese Corporation has developed 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 patented literature, the catalysts used were mainly Pd(PPh
3
)Cl
2
or PdCl
2
or Pd(OAc)
2
alongwith excess phosphate legends (EP 0,400,892 A3, EP 0,284,310 A1), which gave lower reactions rates (TOF=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, U.S. Pat. No. 5,536,874 and the publication J. Chem. Tech. Biotechnol, 1997, 70, 83-91 describe the carbonylation of p-IBPE in a two phase system wherein one phase is 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 ibuprofen selectivity (59-74%) under mild reaction conditions (90° C., 450 to 900 psig). EP 387502 (1990) and EP 361021 (1990) report the use of homogeneous Nickel catalysts but only in the presence of corrosive iodide promoters and gives low reaction rates and selectivity under even high pressure conditions. GB patent 2199030A (1988), JP 02 164 841 (1990) and JP 63 162 654 (1988) disclose homogeneous Rh complex catalysts for the carbonylation of &agr;-phenyl ethyl alcohol derivatives. However, these give very low reaction rates and use iodide promoters.
Another pathway to 2-aryl propionic acids which is more rewarding is the carbonylation of aryl olefins which can be easily obtained from the catalytic cracking of corresponding saturated hydrocarbons and is more economical. Ali and Alper have reported in a publication J. Mol. Catal. 1992, 77, 7-13, the carbonylation of aryl olefins using Pd(OAc)
2
/dppb/PPh
3
/HCOOH catalyst system. But the reaction rate (TOF=2.2 h
−1
) and 2-aryl propionic acid selectivity (15-20%) were too low, the major product being the 3-aryl propionic acid. More recently, U.S. Pat. No. 5,260,477 disclosed a process for the carbonylation of p-isobutyl styrene to ibuprofen using PdCl
2
(PPh
3
)
2
/10% HCl, under very high CO pressures (300 bar at 120° CO which again have a low reaction rate (TOF=~25 h
−1
) and ibuprofen selectivity (89%). Another U.S. Pat. No. 5,315,026 reported the carbonylation of p-isobutyl styrene to ibuprofen using a PdCl
2
/CuCl
2
/(+)-neomethyl diphenylphosphine/10% HCl catalyst system which gave good ibuprofen selectivity (<98%), but a very low reaction rate (TOF=~25 h
−1
) under 30-200 psig CO pressure at 100° C. the publications New J. Chem. 1997, 21, 529-531 and Catal. Lett., 1997, 47, 43-46 revealed the carbonylation of aryl olefins to 2-aryl propionic acid using a biphasic catalyst system (PdCl
2
/TPPTS) under 50 bar CO pressure at 65-100° C. which also gave low reaction rates (25-50 h
−1
) and low selectivity (60-75%). Other major problem of 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 based on a heterogeneous metal selected from palladium, platinum, rhodium, iridium, ruthenium, cobalt or nickel, a phosphine ligand, a protonic and a halide source provide an improved catalyst system for the carbonylation of compounds of general formula I or II 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 an efficient recycle of the catalyst. Another added advantage is metals such as ruthenium, cobalt or nickel are low cost 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, aryl alkyl halides or olefins.
Accordingly, the present invention provides an improved process for the preparation of 2-aryl propionic acid which comprises subjecting to carbonylation, an aryl compound selected from an aryl alcohol or aryl halide having the general formula I or an aryl olefin having the general formula II, wherein R
1
, may be aryl, substituted aryl, naphthyl or substituted naphthyl, R
2
, R
3
, R
4
and R
5
independently be hydrogen, alkyl, aryl, arylalkyl, cycloaliphatic with or without substituents in the presence of a halide source, a protonic acid, water and a heterogeneous metal selected from palladium, platinum, rhodium, iridium, ruthenium, cobalt or nickel, and a phosphine ligand as a catalyst in an organic solvent such as herein described in carbon monoxide atmosphere, at a temperature between 30 to 130° C., for a period ranging between 0.3. to 24 hrs, at pressures ranging between 50 to 1500 psig, cooling the reaction mixture to ambient temperature, flushing the reaction vessel with inert gas, separating the catalyst, removing the solvent by conventional methods, and isolating 2-aryl propionic acid of formula III wherein, R
1
may be aryl, substituted aryl, naphthyl or substituted naphthyl, R
2
, R
3
, R
4
and R
5
may independently be hydrogen, alkyl, aryl, arylalkyl, cycloaliphatic with or without substituents.
It is preferred, that R
1
is phenyl, naphthyl, or substituted phenyl or substituted naphthyl, for example, 4-isobutylphenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-cyanomethyl, 4-tert-butylphenyl, 4-hydroxyphenyl, or 6-methoxy naphthyl.
It is preferred that R
2
, R
3
, R
4
and R
5
are independently hydrogen, methyl or substituted methyl.
In one of the embodiments of the present invention, the catalyst used may be palladium, platinum, rhodium, iridium, ruthenium, cobalt or nickel as metal powder or as supported metal form.
In another embodiment the supports used may be carbon, or any of the refractory oxides such as &ggr;-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 phosphine, tris(p-chloro phenyl)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.
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 tetrabutyl 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 portonic aci

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